reviews - Virology Education

Transcription

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REVIEWS
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Reviews
&
3
2011
Pneumonie.nl
in Antiviral Therapy
INFECTIOUS DISEASES
JOURNAL OF ABSTRACTS AND CONFERENCE REPORTS FROM INTERNATIONAL WORKSHOPS ON INFECTIOUS DISEASES & ANTIVIRAL THERAPY
Meeting report
6th International Workshop on HIV Transmission
Principles of Intervention
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Reviews
&
INFECTIOUS DISEASES
Reviews in Antiviral Therapy & Infectious Diseases is the official journal of abstracts
and conference reports from International Workshops on infectious diseases &
antiviral therapy.
Reviews in Antiviral Therapy & Infectious Diseases publishes peer-reviewed articles relating
to viral diseases including HIV, Hepatitis and emerging viruses. Featured topics include
clinical management, drug resistance, diagnostic applications, pharmacology, transmission
& prevention. Each edition will be dedicated to a specific aspect of viral infection, focusing on
the presentations from the latest international meeting on the topic.
Reviews in Antiviral Therapy & Infectious Diseases aims at translating the latest key scientific
and clinical findings in antiviral therapy into tangible and applicable knowledge to assist
readers in routine clinical management.
Editors-in-chief: Charles A.B. Boucher, MD, PhD,
Erasmus Medical Center Rotterdam,
The Netherlands
Jonathan M. Schapiro, MD,
Sheba Medical Center, Tel Aviv,
Israel
Publisher:
Virology Education, Biltstraat 106, 3572 BJ Utrecht, The Netherlands
Phone: +31-30 2307140 Fax: +31-30 2307148
[email protected]; www.virology-education.com
ISSN:1872-437X
Copyright:
All rights reserved. No part of this publication may be reproduced, stored in a
retrieval system, or transmitted in any form or by any means, electronic, mechanical,
photocopying, recording, or otherwise, without prior permission of the publisher.
© Virology Education.
Reprints:In order to acquire additional reprints of this volume, please contact Virology Education at
[email protected]
Printed on woodfree coated paper
Printed by Labor, Utrecht, The Netherlands (CU-COC-807561)
Disclaimer
The information in this journal is those of the authors and not necessarily reflects the views of the board or the publisher. No responsibility is
assumed by Virology Education for any injury and/or damage to persons or property as result of product liability, negligence or otherwise, or
form any use or operation of any methods, products, instructions, or ideas contained in the material herein. All clinical diagnoses and drug
regimens/dosages must be independently verified. A qualified healthcare professional should be consulted before using any therapeutic
product discussed.
Reviews in Antiviral Therapy & Infectious Diseases - volume 1; 2011 - Supplement
1
open een wereld
van nieuwe
mogelijkheden
ISENTRESS, de eerste
integraseremmer, nu
geregistreerd voor zowel
behandelingsnaïeve als
eerder behandelde volwassenen
met HIV in combinatie met
andere antiretrovirale middelen.
0910RTG09NL416J0909
Dus kies vanaf het eerste begin
ISENTRESS!
ISENTRESS is geïndiceerd in combinatie met andere antiretrovirale geneesmiddelen voor
de behandeling van humaan-immunodeficiëntievirus (HIV-1)-infectie bij volwassen patiënten.
Raadpleeg de volledige productinformatie (SPC) inclusief dosering, contra-indicaties en
waarschuwingen alvorens ISENTRESS voor te schrijven.
Zie elders in dit blad voor de verkorte bijsluiter
ISENTRESS® en univadis zijn geregistreerde handelsmerken van MERCK & Co., Inc., Whitehouse Station, NJ, USA.
Postbus 581, 2003 PC Haarlem, www.msd.nl, www.univadis.nl
Nieuw!
Viramune met Verlengde afgifte
stabiele spiegels met eenmaal daags 1 tablet
• het vertrouwde Viramune nu met verlengde afgifte 1
• eenmaaldaagse dosering van 400 mg 1
• goed bijwerkingenprofiel voor de lange termijn3,4,5,6
1. Samenvatting van de productkenmerken 2. Battegay et al. Clin ther. 2011; 33: 1308-1320 3. elzi et al.
arch intern med. 2010; 170(1): 57-65 4. reliquet et al. HiV lin tirals 2010; 170: 57-65 5. Vallicello et al. aidS
research and human retroviruses. 2011; 27(10) 6. gathe et al. antiviral therapy 2011; 16: 759-69.
Voor productinformatie zie elders in dit blad.
Sterk op de lange termijn
VERKORTE PRODUCTINFORMATIE
ISENTRESS 400 mg filmomhulde tabletten.
Samenstelling
Filmomhulde tablet: 400 mg raltegravir (als kaliumzout).
Indicaties
ISENTRESS is geïndiceerd in combinatie met andere
antiretrovirale geneesmiddelen voor de behandeling
van humaan-immunodeficiëntievirus (hiv-1)-infectie bij
volwassen patiënten.
Deze indicatie is gebaseerd op gegevens over veiligheid en
werkzaamheid uit twee dubbelblinde, placebogecontroleerde
onderzoeken bij eerder behandelde patiënten en een
dubbelblind, met werkzame stof gecontroleerd onderzoek bij
niet eerder behandelde patiënten.
Klinische ervaring
Bewijs voor de effectiviteit van ISENTRESS is gebaseerd
op analyses van 96-weeksdata uit twee lopende,
gerandomiseerde, dubbelblinde, placebogecontroleerde
studies (BENCHMRK 1 en BENCHMRK 2, Protocols 018 en
019) bij eerder met antiretrovirale middelen behandelde, met
hiv-1 geïnfecteerde volwassen patiënten, en analyse van
96-weeksdata uit een lopende, gerandomiseerde, dubbelblinde,
met werkzame stof gecontroleerde studie (STARTMRK,
Protocol 021) bij niet eerder met antiretrovirale middelen
behandelde en met hiv-1 geïnfecteerde volwassen patiënten.
Contra-indicaties
Overgevoeligheid voor het werkzame bestanddeel of voor één
van de hulpstoffen.
Waarschuwingen en voorzorgen
In het algemeen werd in de farmacokinetiek van
raltegravir aanzienlijke inter- en intra-individuele
variabiliteit waargenomen.
Raltegravir heeft een relatief lage genetische barrière
voor resistentie. Daarom moet raltegravir waar mogelijk
gecombineerd worden met twee andere actieve ARTs
om de kans op virologisch falen en het optreden van
resistentie te beperken.
Bij niet eerder behandelde patiënten zijn de klinische
gegevens over gebruik van raltegravir beperkt tot
gebruik in combinatie met twee nucleotide-reversetranscriptaseremmers (NRTIs) (emtricitabine en
tenofovirdisoproxilfumaraat).
De veiligheid en werkzaamheid van ISENTRESS zijn niet
vastgesteld bij patiënten met ernstige onderliggende
leveraandoeningen. Daarom moet ISENTRESS bij patiënten
met een ernstige leverfunctiestoornis met voorzichtigheid
worden toegepast. Patiënten met een al eerder bestaande
leverfunctiestoornis waaronder chronische hepatitis hebben
tijdens antiretrovirale combinatietherapie een verhoogde
frequentie van leverfunctiestoornissen gehad en moeten
volgens de standaardpraktijk worden gecontroleerd.
Er zijn zeer beperkte gegevens over het gebruik van
raltegravir bij patiënten die naast hiv ook geïnfecteerd
zijn met hepatitis B-virus (HBV) of hepatitis C-virus (HCV).
Patiënten met chronische hepatitis B of C die worden
behandeld met antiretrovirale combinatietherapie hebben een
hogere kans op ernstige en mogelijk fatale leverbijwerkingen.
Voorzichtigheid moet worden betracht bij gelijktijdige
toediening van ISENTRESS met sterke inductoren van
uridinedifosfaat-glucuronosyltransferase (UGT) 1A1
(bijvoorbeeld rifampicine). Rifampicine verlaagt de
plasmaconcentraties van raltegravir; de invloed daarvan
op de werkzaamheid van raltegravir is onbekend. Maar als
gelijktijdige toediening met rifampicine onontkoombaar is,
kan verdubbeling van de dosis ISENTRESS worden
overwogen. Myopathie en rabdomyolyse zijn gemeld.
Gebruik met voorzichtigheid bij patiënten die in het verleden
myopathie of rabdomyolyse hebben gehad of anderszins
gepredisponeerd zijn.
Huiduitslag kwam bij eerder behandelde patiënten die een
behandeling met ISENTRESS + darunavir kregen vaker
voor dan bij patiënten die ISENTRESS zonder darunavir of
darunavir zonder ISENTRESS kregen.
ISENTRESS bevat lactose. Patiënten met zeldzame
erfelijke stoornissen als galactose-intolerantie, Lapplactasedeficiëntie of glucose-galactosemalabsorptie mogen
dit geneesmiddel niet gebruiken.
Interacties
Uit in vitro-onderzoek blijkt dat raltegravir geen substraat van
cytochroom P450 (CYP)-enzymen, is, CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, CYP2D6 of CYP3A niet remt geen
inductie van CYP3A4 geeft en het door P-glycoproteïne
gereguleerde transport niet remt. Op basis van deze gegevens
wordt niet verwacht dat ISENTRESS de farmacokinetiek
beïnvloedt van geneesmiddelen die substraten zijn van deze
enzymen of P-glycoproteïne.
Op basis van in vitro- en in-vivo-onderzoeken wordt
raltegravir voornamelijk uitgescheiden door
metabolisme via UGT1A1- geïnduceerde glucuronidatieroute.
Hoewel uit in-vitro-onderzoek gebleken is dat raltegravir
geen remmer is van de UDP-glucuronosyltransferases
(UGTs) 1A1 en 2B7, doet één klinisch onderzoek op grond
van een waargenomen effect op de glucuronidatie
van bilirubine vermoeden dat er in vivo enige remming
van UGT1A1 kan voorkomen. Maar de omvang van het
effect leidt waarschijnlijk niet tot klinisch belangrijke
geneesmiddelinteracties.
Bijwerkingen
Infecties en parasitaire aandoeningen: soms: genitale
herpes†, folliculitis, gastro-enteritis, herpes simplex, infectie
met herpesvirus, herpes zoster, influenza, molluscum
contagiosum, nasofaryngitis, bovensteluchtweginfectie.
Neoplasmata, benigne, maligne en niet-gespecificeerd
(inclusief cysten en poliepen): soms: huidpapilloom.
Bloed- en lymfestelselaandoeningen: soms: anemie†, anemie
wegens ijzergebrek, pijn in lymfeklieren, lymfadenopathie,
neutropenie, trombocytopenie‡‡.
Immuunsysteemaandoeningen: soms:
immuunreconstitutiesyndroom†, geneesmiddelenovergevoeligheid†, overgevoeligheid.
Voedings- en stofwisselingsstoornissen: soms: anorexia,
cachexie, verminderde eetlust, diabetes mellitus,
dyslipidemie, hypercholesterolemie, hyperglykemie,
hyperlipidemie, hyperfagie, meer eetlust, polydipsie.
Psychische stoornissen: vaak: abnormaal dromen,
slapeloosheid, soms: psychische aandoening†,
zelfmoordpoging†, angst, verwarring, neerslachtige
stemming, depressie, ernstige depressie, slapeloosheid in
het midden van de nacht, wisselende stemming, nachtmerrie,
paniekaanval, slaapstoornis, suïcidale gedachten‡‡, suïcidaal
gedrag (vooral bij patiënten met een voorgeschiedenis van
psychische aandoeningen)‡‡.
Zenuwstelselaandoeningen: vaak: duizeligheid, hoofdpijn,
soms: amnesie, carpaaltunnelsyndroom, cognitieve stoornis,
aandachtsstoornis, duizeligheid bij houdingsverandering,
dysgeusie, hypersomnie, hypo-esthesie, lethargie,
geheugenstoornis, migraine, perifere neuropathie,
paresthesie, slaperigheid, spanningshoofdpijn, tremoren.
Oogaandoeningen: soms: visusverslechtering.
Evenwichtsorgaan- en ooraandoeningen: vaak: vertigo,
soms: tinnitus.
Hartaandoeningen: soms: palpitaties, sinusbradycardie,
ventriculaire extrasystoles.
Bloedvataandoeningen: soms: opvliegers, hypertensie.
Ademhalingsstelsel-, borstkas- en mediastinumaandoeningen:
soms: dysfonie, epistaxis, neusverstopping.
Maagdarmstelselaandoeningen: vaak: opgezwollen buik,
buikpijn, diarree, winderigheid, misselijkheid, braken, soms:
gastritis†, last van de buik, pijn in de bovenbuik, gevoeligheid
van de buik, pijn in de anus of het rectum, obstipatie, droge
mond, dyspepsie, pijn in de bovenbuik, erosieve duodenitis,
oprispingen, gastro-oesofageale reflux, gingivitis, glossitis,
odynofagie, acute pancreatitis, maagzweer, rectale bloeding.
Lever- en galaandoeningen: soms: hepatitis†, hepatische
steatose.
Huid- en onderhuidaandoeningen: vaak: huiduitslag‡,
soms: acne, alopecia, dermatitis acneiforme, droge huid,
erytheem, ingevallen gezicht, hyperhidrose, verkregen
lipodystrofie, lipohypertrofie, nachtelijk zweten, prurigo,
pruritus, gegeneraliseerde pruritus, maculaire uitslag,
maculopapulaire uitslag, uitslag bij pruritus, huidlaesie,
urticaria, xeroderma, Stevens Johnson syndroom‡‡.
Skeletspierstelsel- en bindweefselaandoeningen: soms:
artralgie, artritis, rugpijn, pijn in de flank, musculoskeletale
pijn, myalgie, nekpijn, osteopenie, pijn in de extremiteiten,
tendinitis, rabdomyolyse‡‡.
Nier- en urinewegaandoeningen: soms: nierfalen†, nefritis,
nefrolithiase, nycturie, niercyste, nierfunctiestoornis,
tubulo-interstitiële nefritis.
Voortplantingsstelsel- en borstaandoeningen: soms:
erectiestoornis, gynaecomastie, menopauzale verschijnselen.
Algemene aandoeningen en toedieningsplaatsstoornissen:
vaak: asthenie, vermoeidheid, pyrexie, soms: pijn op de
borst, rillingen, oedeem in het gezicht, meer vetweefsel, zich
schrikachtig voelen, malaise, perifeer oedeem, pijn.
Onderzoeken: vaak: verhoogd alanineaminotransferase,
atypische lymfocyten, verhoogd aspartaatamino-transferase,
verhoogde triglyceriden in het bloed, verhoogde lipase, soms:
verlaagde absolute neutrofielentelling, verhoogde alkalische
fosfatase, verlaagd bloedalbumine, verhoogde bloedamylase,
verhoogd bloedbilirubine, verhoogd bloedcholesterol,
verhoogd bloedcreatinine, verhoogd bloedglucose, verhoogd
BUN, verhoogde creatinefosfokinase, nuchter bloedglucose
verhoogd, glucose aanwezig in urine, verhoogd HDL, verlaagd
LDL, verhoogd LDL, minder trombocyten, positief op rode
bloedcellen in urine, grotere tailleomtrek, gewichtstoename,
minder witte bloedcellen.
Letsels, intoxicaties en verrichtingscomplicaties: soms:
onbedoelde overdosis†.
†
met minstens één ernstige bijwerking
‡
In klinisch onderzoek van eerder behandelde patiënten
werd huiduitslag ongeacht causaliteit bij behandelingen
met ISENTRESS + darunavir vaker gezien dan bij die
met ISENTRESS zonder darunavir of darunavir zonder
ISENTRESS. Maar volgens de onderzoeker kwam
geneesmiddelgerelateerde huiduitslag ongeveer even vaak
voor. De voor blootstelling aangepaste frequenties van
huiduitslag (alle oorzaken) waren resp. 10,9, 4,2 en 3,8 per
100 patiëntjaren (PYR) en voor geneesmiddelgerelateerde
huiduitslag resp. 2,4, 1,1 en 2,3 per 100 PYR. Deze huiduitslag
was licht tot matig-ernstig en leidde niet tot stopzetting van
de behandeling.
‡‡
Deze bijwerking is vastgesteld in de periode sinds het
geneesmiddel op de markt is, maar werd in gerandomiseerd
gecontroleerd klinisch fase III-onderzoek (protocols 018,
019 en 021) niet gemeld als zijnde geneesmiddelgerelateerd.
De frequentiecategorie is gedefinieerd als “soms”, in
overeenstemming met de richtlijnen voor de samenvatting
van de productkenmerken (SmPC) (rev. 2 sept. 2009)
op basis van een geschatte bovengrens van het
95 %-betrouwbaarheidsinterval voor 0 voorvallen en het
aantal proefpersonen dat in het klinisch fase III-onderzoek
met ISENTRESS werd behandeld (n=743).
Patiënten die tevens geïnfecteerd zijn met het hepatitis B- en/
of hepatitis C-virus
In fase III-onderzoeken mochten eerder behandelde patiënten
(N = 114/699 ofwel 16 %; HBV=6 %, HCV=9 %, HBV+HCV=1 %)
en niet eerder behandelde patiënten (N = 34/563 of 6 %;
HBV=4 %, HCV=2 %, HBV+HCV=0,2 % met gelijktijdige
chronische (maar geen acute) infectie met hepatitis B en/of
hepatitis C) meedoen op voorwaarde dat de leverfunctietests
bij baseline niet hoger waren dan 5 keer de normale
bovengrens. In het algemeen was het veiligheidsprofiel
van ISENTRESS bij patiënten met een gelijktijdige infectie
met hepatitis B-en/of hepatitis C-virus gelijk aan die van
patiënten zonder hepatitis B-en/of hepatitis C-virus, hoewel
in beide behandelingsgroepen de frequentie van AST- en
ALT-afwijkingen in de subgroep met gelijktijdige infectie met
hepatitis B en/of hepatitis C iets hoger was.
Farmacotherapeutische categorie
Antiviraal middel voor systemisch gebruik, Andere
antiretrovirale middelen, ATC-code: J05AX08
Afleverstatus
UR
Verpakking
ISENTRESS 400 mg is verkrijgbaar in flesjes met 60 tabletten.
Vergoeding en prijzen
ISENTRESS 400 mg wordt volledig vergoed. Voor prijzen:
zie ZI-index.
Raadpleeg de volledige productinformatie (SPC) alvorens
ISENTRESS voor te schrijven.
31 augustus 2010.
Merck Sharp & Dohme BV
Waarderweg 39
2031 BN Haarlem
Tel.: 023 - 5153 153
www.msd.nl
Verkorte 1b-tekst
Viramune® 200 mg tabletten,
Viramune® 400 mg tabletten met verlengde afgifte,
Viramune® 100 mg tabletten met verlengde afgifte en
Viramune® 50 mg/5 ml suspensie voor oraal gebruik
Farmacotherapeutische groep: antivirale middelen voor systemisch gebruik , ATC: J05AGO1. Samenstelling: 1 tablet Viramune 200 mg tabletten bevat 200 mg nevirapine-anhydraat (actieve stof). 1 tablet Viramune 400 mg tabletten met verlengde afgifte bevat 400
mg nevirapine-anhydraat. 1 tabletViramune 100 mg tabletten met verlengde afgiftebevat 100 mg nevirapine-anhydraat. Suspensie voor oraal gebruik bevat 10 mg/ml nevirapine (actieve stof). Indicatie: Viramune is geïndiceerd in combinatie met andere antiretrovirale
geneesmiddelen voor de behandeling van HIV-1 geïnfecteerde volwassenen en kinderen ongeacht de leeftijd. Dosering: Gewenningsdosering gedurende de eerste 2 weken: eenmaaldaags 200 mg nevirapine. Onderhoudsdosering: 400 mg per dag. Bij starten van
Viramune behandeling dient altijd een gewenningsperiode van 2 weken in acht genomen te worden om de kans op huiduitslag te beperken. Deze gewenningsperiode geldt ook indien de behandeling langer dan 1 week onderbroken is. Bij patiënten die tijdens de
14-daagse gewenningsperiode huiduitslag ontwikkelen, mag de dosering niet worden verhoogd voordat de huiduitslag volledig verdwenen is. Alvorens te beginnen met deViramune-therapie, en daarna met regelmatige tussenpozen tijdens de therapie, dient klinisch
laboratoriumonderzoek waaronder leverfunctietesten, te worden uitgevoerd. Voor patiënten van 16 jaar en ouder, of met een gewicht van meer dan 50 kg of met een lichaamsoppervlak groter dan 1,25 m2, is de dosering gedurende de eerste 14 dagen 200 mg per
dag. Na twee weken wordt de dosering verhoogd naar 400 mg per dag. Voor patiënten jonger dan 16 jaar die minder dan 50 kg wegen of minder dan 1,25 m2 lichaamsoppervlak hebben kan suspensie worden gegeven op basis van of het lichaamsgewicht of het
lichaamsoppervlak (zie volledige 1b tekst). De dosering op basis van lichaamsgewicht is voor kinderen tot 8 jaar 4 mg/kg éénmaal daags gedurende twee weken, gevolgd door 7 mg/kg tweemaal daags. De aanbevolen dosering voor patiënten van 8 tot 16 jaar is 4
mg/kg éénmaal daags gedurende twee weken, gevolgd door 4 mg/kg tweemaal daags. De dosering op basis van lichaamsoppervlak (formule van Mosteller) is 150 mg/m2 eenmaal daags gedurende de eerste twee weken gevolgd door 150 mg/m2 tweemaal daags.
Contra-indicaties: Overgevoeligheid voor het werkzame bestanddeel nevirapine of voor één van de hulpstoffen. Kruidenpreparaten die sint-janskruid (Hypericum perforatum) bevatten dienen niet tegelijk met Viramune te worden gebruikt. Gelijktijdig gebruik van
Viramune met rifampicine of ketoconazol wordt niet aanbevolen. Viramune dient niet opnieuw te worden toegediend aan patiënten bij wie de behandeling definitief moest worden gestaakt vanwege ernstige huiduitslag, huiduitslag gepaard gaande met
constitutionele symptomen, overgevoeligheidsreacties, of klinische hepatitis ten gevolge van Viramune gebruik. Viramune dient niet te worden gebruikt bij patiënten met ernstig leverfalen. Indien AST of ALT tijdens de behandeling stijgt tot > 5 keer de bovengrens
van de normaalwaarde dient Viramune direct te worden gestaakt. Wanneer AST en ALT genormaliseerd zijn en wanneer de patiënt geen klinische verschijnselen of symptomen heeft gehad van hepatitis, huiduitslag, constitutioneel eczeem of andere verschijnselen
die wijzen op een gestoorde orgaanfunctie, dan is het mogelijk Viramune te herintroduceren, per geval beoordeeld, met een startdosering van 200 mg per dag gedurende 14 dagen gevolgd door 400 mg per dag. In deze gevallen is een meer frequente levercontrole
vereist. Als de leverfunctie-afwijkingen terugkeren, dient Viramune definitief te worden gestaakt. Waarschuwingen en voorzorgen: De eerste 18 weken van de behandeling met Viramune is een kritische periode, die een nauwkeurige controle van de patiënt vereist
om het mogelijk optreden van ernstige en levensbedreigende huidreacties of ernstige hepatitis of leverfalen uit te sluiten. Het hoogste risico op leveraandoeningen en huidreacties bestaat gedurende de eerste 6 weken van de therapie. Bij patiënten met een
detecteerbare plasma HIV-1 viral load (≥50 kopieën/ml) zijn vrouwelijk geslacht en hogere uitgangswaarden van CD4+ cellen bij het begin van de therapie risicofactoren voor levercomplicaties. Mannen met meer dan 400 CD4+ cellen/mm3 en vrouwen met meer dan
250 CD4+ cellen/mm3 die een detecteerbare viral load hebben bij aanvang van de behandeling, dienen alleen te starten metViramune behandeling als de voordelen opwegen tegen het risico. Huidreacties: Er zijn ernstige, levensbedreigende en zelfs fatale, huidreacties
opgetreden bij patiënten die behandeld werden met Viramune. Hieronder waren gevallen van het Stevens-Johnson syndroom (SJS), toxische epidermale necrolyse (TEN) en overgevoeligheidsreacties gekenmerkt door huiduitslag, constitutionele verschijnselen en verminderd
functioneren van inwendige organen. De behandeling met Viramune moet gestaakt worden bij patiënten die ernstige huiduitslag ontwikkelen, of huiduitslag vergezeld van constitutionele symptomen, zoals koorts, blaarvorming, orale laesies, conjunctivitis, oedeem in het gezicht,
zwellingen, spier- of gewrichtspijn of algehele onbehaaglijkheid. Vrouw en blijken een hoger risico te hebben op het ontwikkelen van huiduitslag dan mannen, ongeacht het gebruik van Viramune. De patiënt dient er nadrukkelijk op te worden gewezen dat huiduitslag de belangrijkste
bijwerking van Viramune is en moet geadviseerd worden huiduitslag onmiddellijk aan de arts te melden. Huiduitslag die samenhangt met het gebruik van Viramune treedt meestal op in de eerste 6 weken na aanvang van de therapie. Daarom dienen patiënten tijdens deze periode
zorgvuldig gecontroleerd te worden op het optreden van huiduitslag. Hepatische reacties: Bij patiënten die worden behandeld met Viramune is ernstige en levensbedreigende hepatotoxiciteit, met inbegrip van fatale hepatische necrose, voorgekomen. Er is melding gemaakt van
afwijkende leverfunctietests tijdens gebruik van Viramune, ook in de eerste weken van de therapie. Omdat er in enkele gevallen, gedurende de eerste weken na aanvang van de therapie met Viramune, melding is gemaakt van klinische hepatitis dient bepaling van ALT en AST de
eerste twee maanden van de behandeling elke twee weken plaats te vinden. In de derde maand dient de controle van de leverfunctie éénmaal, en vervolgens regelmatig plaats te vinden. Overig: Voorzichtigheid is geboden wanneer Viramune wordt voorgeschreven aan zwangere
vrouwen. Viramune kan de plasmaconcentraties van hormonale anticonceptiva doen afnemen. De patiënt dient geadviseerd te worden om naast een hormonaal anticonceptivum ook altijd een ander voorbehoedsmiddel te gebruiken. Nevirapine induceert het leverenzym CYP3A
en mogelijk 2B6. Middelen die door CYP3A en/of CYP2B6 worden gemetaboliseerd kunnen verlaagd zijn als ze samen met Viramune worden gebruikt. Bij gelijktijdig gebruik van Viramune met fluconazol, warfarine, methadon of claritromycine dient de patiënt nauwkeurig te worden
gecontroleerd. Bijwerkingen: De meest frequent gerapporteerde bijwerkingen van Viramune zijn huiduitslag, allergische reacties, hepatitis, afwijkende leverfunctie testen, misselijkheid, braken, diarree, buikpijn, vermoeidheid, koorts, hoofdpijn en spierpijn. De meest voorkomende
bijwerking van Viramune is huiduitslag. De huiduitslag bestaat gewoonlijk uit milde tot matig-ernstige, maculopapuleuze, erythemateuze huiduitslag, met of zonder jeuk, op de romp, het gezicht en de armen en benen. Ernstige en levensbedreigende huidreacties, waaronder het
Stevens-Johnson syndroom (SJS) en toxische epidermale necrolyse (TEN) zijn opgetreden. Bij patiënten die lever en/of huidreacties ondervinden ten gevolge van Viramune gebruik is rhabdomyolyse waargenomen. Distributie: UR. Vergoeding: Viramune wordt volledig vergoed
binnen het GVS. Nadere informatie: de volledige 1b-tekst, productinformatie en publicaties zijn verkrijgbaar bij Boehringer Ingelheim bv, Comeniusstraat 6, 1817 MS Alkmaar, telefoon 0800-2255889. Datum laatste herziening: september 2011.
Report
6th Workshop on HIV Transmission
14-15 July 2011 in Rome, Italy
Report
Report on 6th Workshop on HIV Transmission
J. Albert1, C. Boucher2, M. Cohen3, W. Heneine4, E. Hunter5, P. Kanki6, B. Mathieson7, G. Scarlatti8, R.
Swanstrom9, M. Wainberg10, A. Wensing11
Karolinska Institute, Stockholm, Sweden; 2Erasmus University Rotterdam, The Netherlands; 3University of
North Carolina, Chapel Hill, NC, USA; 4Division of HIV/AIDS Prevention, CDC, Atlanta, GA, USA; 5Emory
University, Atlanta, GA, USA; 6Harvard School of Public Health, Boston, MA, USA; 7Office of AIDS Research at
the National Institutes of Health,Bethesda, MD, USA; 8San Raffaele Scientific Institute in Milan, Italy; 9University
of North Carolina, Chapel Hill, NC, USA; 10McGill University, Montreal, Canada; 11University Medical Center
Utrecht, The Netherlands
1
Written by Wendy Smith on behalf of the Organizng Committee
HIV Transmission – Human Biology
Cell biology of HIV sexual transmission
Dr Hope (Northwestern University, USA) addressed the topic of the cell biology of sexual transmission, especially
the movement of the virus from the lumen of the female genital tract to the target cells, such as T cells and
dendritic cells in the sub basal layer of the epithelium1. The process is very rapid: in macaque models, simian
immunodeficiency virus (SIV) infections can be established within 30-60 minutes of vaginal challenge. Using
virus carrying a photoactivatable GFP fused to Vpr, it has been possible to visualise the virus moving through
the vaginal epithelium of explant cultures. Considerable variation was observed in the rate of movement of
the viruses from the lumen through the epithelium: most of the viral particles only penetrate a short distance
while some are able to penetrate ~50 microns. HIV is able to breach the columnar epithelium of the vagina and
access the underlying target cells. Virus often becomes trapped in the mucus that lines the vaginal epithelium
and protects the endocervix from infection. When neuraminidase was used to cleave sugars from mucus, HIV
was able to penetrate the endocervix more easily. HIV penetrates between the cell junctions of the epithelium
(i.e. interstitial diffusion) rather than directly entering the cells. If EDTA is applied to break down the cell junctions,
HIV is able to penetrate the epithelium more deeply. Dr Hope’s group is now studying interactions between HIV
and tissue obtained from circumcised men in an attempt to understand why circumcision is protective against
HIV infection in men.
Founder viruses
Dr Keane (Murdoch University, Australia) presented a
study of an acute heterosexual transmission of HIV-12.
A 51 year old, East African woman presented to the
clinic five days after non-consensual sexual contact
with a man who was known to be HIV infected. p24
antigen was detected in the woman’s blood but
the EIA and Western Blot results were negative,
indicating early HIV infection prior to seroconversion.
The woman had tested HIV negative in 2003 and
reported no subsequent risky exposures, apart
from the non-consensual sex. The woman started
antiretroviral therapy (ART) one year after infection
and her viral load dropped to ~50 copies/mL within
a few weeks, after having being 70,000 copies/mL
in the absence of therapy. Three founder/transmitted
Disclosure:
Wendy Smith, PhD has disclosed that she does not
serve as a consultant for any commercial companies.
Dr Smith is a professional medical writer who works
for Wordsmiths International Ltd (www.wordsmiths.
eu.com)
6
viruses were identified 15 days post-transmission;
it is possible that more than one founder virus was
transmitted because of the traumatic nature of the
sexual contact. There appeared to be transmission
of an adapted epitope in the shared recipient and
donor HLA C*04:01 restricted epitopes. Phylogenetic
analysis demonstrated that the viral strains from the
donor and recipient were more closely related to
each other than to any strains in the dataset. Limited
HIV viral sequence change was observed in patient/
donor HLA-restricted epitopes. Non-selective CTL
responses were observed and may have contributed
to the rapid rate of disease progression in this case.
Compartmentalisation of HIV
Paired blood and cervicovaginal lavage (CVL)
samples were obtained at Day 0 and Week 16 from
28 women from Malawi and S Africa with chronic
HIV infection3. Viral loads were measured and single
genome amplification and phylogenetic analysis of
env genes were carried out. The Slatkin-Maddison
test for compartmentalisation was applied. The
CVL viral loads were significantly higher in women
who had sexually transmitted infections (STI) than
in those without STIs, even though the plasma
viral loads were similar in both groups. Genetic
characterisation of HIV populations in the 10 paired
blood and genital tract samples demonstrated that
clonal amplification of the virus had occurred in
each compartment. A significant amount of genetic
difference was observed between paired plasma
and CVL viral samples. Compartmentalisation was
observed in 60% of subjects and it was significantly
associated with higher CD4 cell counts, suggesting
that it was associated with the availability of target
cells and not due to reduced immunosurveillance in
a specific compartment. Longitudinal data suggest
that the HIV viral load in the female genital tract is
variable over time. Dr Dukhovlinova (University of
North Carolina at Chapel Hill, USA) suggested that
the presence of a STI could affect the cytokine profile
of the female genital tract and facilitate the influx of
cells from nearby lymphoid tissue. Further studies
are in progress to identify the cytokine profile and
tropism of compartmentalized viral strains.
Cytokine network in semen of HIV positive
men
Semen is a complex fluid that contains spermatozoa
and a number of soluble factors, including cytokines.
The replication of pathogens, such as HIV and
herpesviruses, affects cytokine expression as well
as is affected by cytokines. Blood and seminal
fluid were obtained from 74 HIV-1-infected, ART
naïve men and 33 uninfected men: viral loads and
cytokine profiles were evaluated4. A relationship was
observed between the HIV-1 viral load in the plasma
and the semen. No reactivated herpesviruses were
detected in samples from HIV negative men, with the
exception of low herpesvirus viraemia (CMV, HHV6 and HHV-7) in some semen samples. In HIV-1
infected men, EBV and CMV were detected in the
majority of semen samples and their viral loads were
significantly higher in the semen than the blood. HSV2, HHV-6, HHV-7 and HHV-8 were detected in HIV-1
infected men’s semen but not in their blood. CMV
reactivation was largely compartmentalized in the
HIV-1/CMV co-infected men: in 77% of these men,
CMV was only found in semen compared to 19% who
had detectable CMV levels both in blood and semen.
Concurrent EBV and CMV infection was associated
with significantly higher levels of HIV-1 shedding in
the semen than in HIV-infected men co-infected with
only one of these herpesviruses. In HIV-infected men,
HIV preferentially upregulated cytokines in semen
compared to blood. Based on the results of this study,
the investigators (NIH/NICHD, USA) concluded that
HIV-1 infection is associated with seminal shedding
of CMV and EBV and rearrangement of the cytokine
network in semen. These factors may affect the
sexual transmissibility of HIV-1.
Viral escape – possible mechanism for
immune escape
Several studies have demonstrated the importance
of HIV-1 gp120 variable regions in virus infectivity and
immune escape; the majority of these experiments
have been carried out on subtype B virus but the
most prevalent subtype globally is subtype C5. Virus
isolated from recently infected subjects tends to have
shorter V1-V2 loops and a lower number of putative
N-glycosylation sites (PNGS) than variants isolated
during chronic infection. Dr Cenci (Istituto Superiore
di Sanita, Italy) reported the results of an analysis
of gp120 variable V1-V5 and C3 and C4 constant
regions from clade C viruses isolated from patients at
different disease stages. During chronic infection, the
sequence of amino acids of the V1 and V4 regions and
the number of PNGS increased.New PNGS shifted
appeared in the C-terminus of all the variable regions
with the exception of V3, and in the constant regions
near to the CD4 binding site, possibly protecting the
virus from the immune response. During both recent
and late stage infection, a positive charge correlation
was observed between C3 and V5: this could
support the hypothesis that an open conformation
would be the best fit for binding to cellular receptors.
At the contrary, the presence of a negative correlation
of positive electric charges between the C3 and V4
regions in the Chronic stage could protect the C3-V4
epitope by immune system.
HIV Transmission – Model Systems
A number of model systems, such as ex vivo cervical
tissue cultures, macaques and humanised mice,
have been used to investigate the transmission of
retroviruses and potential methods of protecting
against infection.
Modelling HIV transmission and
dissemination
SIV infection of rhesus macaques can be used to
model HIV transmission and systemic dissemination
of the virus, as well as investigating the effectiveness
of candidate vaccines and other HIV prevention
strategies6. Both single and limited number variant
infections can be simulated, using the rectal, vaginal
or penile route. SIV env and full length clones of
founder viruses have been generated and shown
to be functional in in vitro and in vivo assays, thus
enabling investigators to analyse the particular
characteristics of founder viruses. Transmitted
founder clones recapitulate viral load profiles and
the pathogenetic features of the parental virus in
7
Report
naïve rhesus macaques. Longitudinal analyses of
putatively single variant infections confirmed that
the transmission event involved one viral variant,
regardless of the route of infection.
A model was established to enable Keele and
colleagues (SAIC-Frederick/NIH, USA) to track
SIVmac239 infection following intravaginal challenge
so that the key events in early replication and systemic
dissemination could be dissected6. Synonymous
mutations were introduced into a viral isolate to create
ten clones that were molecular but isogenic tagged
and introduced into female macaques as a nontraumatic vaginal challenge. Real time SGA sequence
analysis was used to identify the tagged clones in
the blood and tissue of euthanized macaques. There
was considerable inter-animal variability in terms of
the number of clones that were transmitted; in the
majority of infections, one major variant and several
minor variants were identified. Infections were multifocal and the virus does not appear to be uniformly
distributed. Virus could be found in draining and then
distal lymphoid tissues before it was distributed to
the plasma, peripheral blood monocyte cells, gastro
intestinal tract or spleen. Not all of the variants
that were identified at mucosal sites were found in
peripheral sites. The initial results were obtained from
unsynchronised animals but current experiments are
using macaques with synchronised menstrual cycles
so that the impact of hormones on SIV transmission
can be identified.
Productive HIV-1 infection of cervical tissue
ex vivo
The human cervix is a major route by which women
acquire HIV from their sexual partners (Figure 1). Dr
Saba (San Raffaele Institute, Italy) has used human
cervical tissue explants to study the process of HIV
infection ex vivo7. The average age of the donor
was 50±1 years old. In this cervical tissue model,
X4 HIV-1 was only able to establish a productive
infection in a few tissues that were enriched with
early differentiated effector memory CD4 T cells
whereas R5 HIV-1 infection was supported efficiently.
During R5 infection, the CD4 T cells appeared to be
HIV-1 gag positive at an earlier stage of infection
than the macrophages. R5 HIV-1 replication in the
cervical explants was modulated by the phase of the
menstrual cycle. There appeared to be a ‘window
of vulnerability’ during the secretory stage of the
cycle (i.e. when progesterone levels were reaching a
peak) when the virus was able to infect the female
genital tract tissues more easily, possibly because
the release of progesterone caused changes in the
mucosa that facilitated infection. Infection was less
likely during the proliferative phase of the menstrual
cycle and during the menopause.
Characterisation of semen leukocytes
Dr Bernard-Stoecklin (Comissariat a l’Energie
Atomique, France) has investigated whether semen
leukocytes act as ‘Trojan horses’ in SIV/HIV mucosal
transmission by analysing the infection process
in macaques8. In humans or animals with primary
infection, the CD4 T cell count in the semen falls
rapidly whereas it tends to increase when ART is
administered during chronic infection. Lymphocytes
in the semen are activated and express higher levels
of CD69 (a proliferation marker) and HLADR (a late
activation marker) than lymphocytes in the blood.
HIV-1 heterosexual transmission in human cervix
DCs
CD4+
T cells
Figure 1. HIV-1 heterosexual transmission in human cervix
Source: Dr Saba, San Raffaele Institute, Italy
8
Macrophages
They express a number of chemokine receptors
and integrins. T cells in the semen are almost all
central memory cells, which are the main targets
for SIV. They are present in the semen at every
stage of the infection process. In summary, seminal
leukocytes express markers that may favour HIV/SIV
transmission.
The impact of semen on HIV infectivity of target
cells has been controversial. The effects of semen
on CD4 T cell phenotype and susceptibility to HIV
infection were investigated by Balandya (Dartmouth
Medical School, USA) et al9. They collected semen
from HIV negative men and incubated centrifuged
seminal plasma from these samples with peripheral
blood monocyte cells and X4 or X5 HIV. Levels of
HIV infection were assessed using TZM-bl cells
and intracellular staining for HIV p24. The results
of these experiments indicate that seminal plasma
protects CD4 T cells from HIV infection and reduces
T cell surface CD4 expression. Seminal plasma also
induces CD4 T cell expression of the CCR5 receptor
and mediates the preferential transmission of R5
HIV. These data show that semen protects cardinal
target cells from HIV infection and contribute to the
previously unexplained preferential transmission of
R5 HIV.
Pre-Exposure Prophylaxis (PrEP) models
Humanized mice (RAG-hu), which lack native B, T
and NK cells, have been utilised as a model system to
investigate the potential of maraviroc and raltegravir to
protect against HIV-1 vaginal transmission10. The mice
were engrafted with human CD34 cells and multilineage human haematopoiesis was subsequently
detected in several organs. HIV-1 was able to infect
RAG-hu mice via the vaginal or rectal mucosal
tissues. Oral administration of maraviroc or raltegravir
for three days prior and post challenge provided
100% protection against HIV-1 infection. CD4 T
cell counts declined rapidly in infected, non-treated
control animals but the cell counts in the treated mice
remained similar to the levels in uninfected control
animals. Additionally, maraviroc was formulated as a
topical microbicidal gel; it was completely protective
against HIV-1 vaginal transmission in RAG-hu mice.
The pharmacokinetic and pharmacodynamic profile
of a single oral dose of maraviroc (44 mg/kg) in
rhesus macaques was studied by Garcia-Lerma and
colleagues (CDC, USA)11. Plasma levels of maraviroc
peaked two hours after administration but levels in
vaginal and rectal secretions peaked at 5 and 24
hours, respectively. Maraviroc was measurable in
vaginal and rectal secretions for up to two and seven
days, respectively, suggesting that this antiretroviral
(ARV) may be useful for PrEP. The pharmacokinetics
of maraviroc in macaques were similar to those in
human beings who had taken 300 mg maraviroc. A
co-receptor occupancy assay was used to analyse
maraviroc binding to CCR5. Levels of maraviroc
that were found in the rectal tissues 2-3 days after
administration were associated with the maximum
levels of CCR5 occupancy and protection against
infection in vitro.
Vaginal absorption of ARVs – the pig tailed
macaque model
The efficacy of ARVs as microbicides probably
depends on how effectively they are absorbed into
the vaginal mucosa. During the menstrual cycle, a
number of physiological changes occur in the vaginal
epithelium that may affect drug absorption (Figure
2)12. Female pig tailed macaques have a bi-phasic
menstrual cycle, similar to humans, and so they
can be used as a model to examine the effects of
menstrual cycle on vaginal drug absorption. During
the follicular phase, the vaginal epithelium is thick
and keratinised; during the luteal phase, it is thin and
more susceptible to HIV infection. A gel containing
5% FTC and 1% tenofovir was applied vaginally
once a week for four weeks and then drug levels
were measured in the plasma at regular intervals.
After a two week washout period, the experiment
was repeated but the gel was applied rectally. In the
vaginal dosing experiments, there were higher levels
of ARV drug absorption during the luteal phase than
the follicular phase. When the gel was applied to
the rectum, drug absorption was unaffected by the
menstrual phase. Maximum levels of drug absorption
were observed within 7-10 days of peak progesterone
levels and were not drug-dependent. It appears that
physiological changes during the menstrual cycle,
such as vaginal epithelial thinning, may explain the
absorption of ARVs formulated as a microbicide.
Prevention of HIV Transmission –
Antiviral and Medical Approaches
Preventing new HIV infections is an essential
component of controlling the global HIV epidemic.
Prevention strategies include antiviral approaches,
e.g. microbicides, and medical interventions, e.g.
use of ARVs to prevent transmission of HIV from
mother to child. PrEP, using single or combined
ARVs, has been studied as a method of preventing
the transmission of HIV from an HIV positive person
to his/her sexual partner(s).
Preventing sexual transmission of HIV-1
CAPRISA 004 assessed the safety and effectiveness
of a 1% tenofovir gel used as a microbicide up to
9
Report
Follicular Phase
Luteal Phase
Estradiol
Progesterone
Day 1
Ovulation
7
Thick, keratinized
vaginal lining
14
21
28
Thin, non-keratinized,
porous vaginal lining
Figure 2. Menstrual cycle phases
Source: Dr Heneine, Centers for Disease Control, USA
12 hours before sex and within 12 hours after sex13.
The effectiveness of the microbicide at 12 months
was 50% and at 30 months it was 39%. The gel
also provided 51% protection against herpes virus 2
(HSV-2) infection which infects 50-60% of S African
sexually active adults. The results of CAPRISA 004
were hailed as the new hope in HIV prevention, even
though the gel did not provide complete protection.
Subsequent studies (Figure 3) have shown the
following successes:
• oral PrEP with tenofovir/FTC prevented HIV infections in men who have sex with men (MSM), with
an effectiveness of 44% at the end of the study
(iPrEx trial);
• ART prevents HIV transmission between sexual
partners, with an effectiveness of 96% (HPTN
052);
• oral PrEP with daily oral tenofovir or tenofovir/FTC
provided 62% and 73% protection in serodiscordant couples, respectively (Partners PrEP);
• daily oral tenofovir/FTC provided 63% protection
in heterosexual men and women (Botswana TDF2
study).
In contrast, the FEM-PrEP study of oral tenofovir/FTC
as PrEP in women was halted for futility. The reasons
for the study’s outcome of no protection against HIV
are being investigated but it is possible that there
was poor adherence or inadequate drug levels were
present at the possible site of infection.
10
Dr Abdool Karim (University of KwaZulu-Natal,
South Africa) provided several additional insights
from the CAPRISA 004 trial13. In macaques,
genital inflammation has been associated with an
increased risk of SIV acquisition. Tenofovir gel use
was not associated with elevated levels of genital
inflammation compared to placebo. However, genital
tract inflammation prior to infection was associated
with an increased susceptibility to HIV infection.
Achieving detectable tenofovir levels in the female
genital tract was associated with a significantly
increased level of protection in women without
elevated cytokine levels (p=0.05). The effectiveness
of the tenofovir gel was not affected by the person’s
HSV-2 status. However, one possible hypothesis
is that men with high semen viral loads were more
likely to transmit HIV than those with low semen viral
loads, possibly suggesting that tenofovir gel is less
effective if the viral load in the semen is high e.g. in
men with acute or early infection. HIV transmission
in the vagina appears to be influenced by the host
(increased genital inflammation may be associated
with increased HIV acquisition); the agent (higher
semen viral load may be associated with increased
risk of infection); and the environment (higher drug
levels in the vagina may reduce the risk of infection).
The results of the CAPRISA 004 study have been
used to model the effects of widespread use of
a 1% tenofovir gel microbicide in S Africa overall
and specifically in KwaZulu Natal province14. The
Study
Treatment for prevention
Effect size (CI)
96% (73; 99)
(Africa, Asia, America’s)
PrEP for discordant couples
73% (49; 85)
(Partners PrEP)
PrEP for heterosexuals
63% (21; 48)
(Botswana TDF2)
Medical male circumcision
54% (38; 66)
(Orange Farm, Rakai, Kisumu)
PrEP for MSMs
44% (15; 63)
(America’s, Thailand, South Africa)
STD treatment
42% (21; 58)
(Mwanza)
Microbicide
39% (6; 60)
(CAPRISA 004 tenofovir gel)
HIV Vaccine
31% (1; 51)
(Thai RV144)
0%
10
20
30
40
50
60
Efficacy
70
80
90 100%
Figure 3. Summary of clinical trial evidence for preventing sexual transmission of HIV in July 2011
Source: Dr. S. Abdool Karim, University of KwaZulu-Natal, Durban, South Africa13.
investigators assumed that the presence of HSV2 infection increases the risk of acquiring HIV by
2-3 fold and, in co-infected people, increases HIV
infectivity by 30-70% per act. HIV infection increases
HSV-2 shedding episodes. In KwaZulu Natal, the
number of prevented infections of HIV or HSV-2 would
be substantially greater in women than men. The
proportion of HSV-2 infections prevented would be
approximately independent of the gel’s effectiveness
against HIV but it would be affected by coverage (i.e.
access to the microbicide). The relationship between
HIV effectiveness and coverage on the proportion of
HIV infections prevented would be non-linear. On a
country-wide scale, the gel would prevent more HIV
infections in provinces where the infection rate is
high i.e. many more infections would be prevented in
KwaZulu Natal than in Northern and Western Cape if
the microbicide coverage was assumed to be 90%
and the effectiveness was assumed to be 54%. Only
113 women-years of microbicide usage would be
required to prevent one HIV infection in women in
KwaZulu Natal, while it would require 445 womenyears of usage in Western Cape. Dr Blower (UCLA,
USA) concluded by stating that, in the light of financial
constraints, a very effective control strategy would be
to target the microbicide roll out to provinces with
high HIV infection rates.
HPTN 052
The results of the HPTN 052 studied were published
in the online version of the New England Journal of
Medicine on 18 July 2011; Dr Cohen (UNC Chapel
Hill, USA) provided an overview of the data to the
Workshop15, 16. The aim of the study was to determine
if providing ART to HIV infected individuals protected
their serodiscordant sexual partners from acquiring
the virus; and to evaluate the optimal time to initiate
ART in order to reduce morbidity and mortality. A total
of 1,763 serodiscordant couples were enrolled. The
HIV+ partner had to have a CD4 cell count of 350-550
cells/mm3 and he/she was randomised to receive
immediate ART or delayed ART (when the CD4 cell
count was <250 cells/mm3). On 28 April 2011, the
Data Safety Monitoring Board recommended that the
results of the trial be announced as soon as possible.
The study was not stopped but modifications to
the study design are in progress: all HIV positive
participants are now being offered ART. During the
trial, 39 infections occurred: 28 were linked and 27 of
these occurred in the delayed therapy arm and one
in the immediate therapy arm (p<0.001). Seventeen
infections occurred in the delayed ART arm when the
index partner’s CD4 cell count was >350 cells/mm3.
A total of seven unlinked infections occurred: four
in the delayed ART arm and three in the immediate
ART arm. Four infections are still being analysed for
evidence of linkage.
The difference between the two arms in terms of
morbidity and mortality did not meet the pre-set
criterion of >20% but it was significant when no preset value was used (p=0.01): 65 events occurred in
the delayed arm and 40 in the immediate arm15. The
difference was driven by cases of extrapulmonary
TB: 17 in delayed ART arm and three in the immediate
11
Report
arm (p=0.0013). There were a similar number of
deaths in each arm: 13 and 10, respectively. The
study will continue for at least one more year to
determine the durability of the prevention benefit;
any differences between the two arms in terms of
prevention benefit; clinical and toxicity events in both
arms; and the level of adherence to ART. Dr Cohen
explained that this was a proof of concept study, not
a public health study: ART was effective in preventing
HIV transmission between monogamous couples in
this study.
Evaluating the effect of ‘Test and Treat’ on
HIV transmission
‘Treatment as Prevention’ is the cornerstone of the
WHO’s Treatment 2.0 initiative and a number of
pilot studies are in progress to evaluate the impact
of expanded access to treatment on HIV incidence
at the population level. Dr Vasarhelyi (BC Centre
for Excellence in HIV/AIDS, Canada) described her
group’s efforts to develop a general performance
indicator for Seek and Treat strategies using
surveillance data17. The indicator was then applied to
surveillance data collected 2003-9 (before the STOP
HIV/AIDS launch) in British Columbia, a Canadian
province, and to simulated data for 2011-17. The
outcome of the model was that the proportion of
diagnosed HIV infections was approximately constant
between 2003 and 2009 in British Columbia. To
demonstrate the performance of the indicator in
detecting changes in the proportion of diagnosed
cases, the model was applied to simulated data for
2011-17. The data were consistent with an annual
increase of 1% in the proportion of diagnosed HIV
infections since the launch of STOP HIV/AIDS. The
development of an indicator for Seek and Test
programmes will enable the performance of such
programmes to be evaluated at the population level.
Activity of griffithsin plus ARVs against
subtype C HIV
Griffithsin is a mannose-specific lectin that is being
investigated as a potential microbicide18. The antiviral
potency of griffithsin in combination with tenofovir,
maraviroc or enfuvirtide against HIV-1 subtypes B
and C, as well as a subtype B X4 virus, was assessed
in a range of assays. All of the combinations were
synergistic and provided superior antiviral potency
against all of the strains studied, compared to
griffithsin alone. Antagonism between the therapeutic
agents was not observed. Griffithsin plus one or
more ARVs has potential as a microbicide; studies
are ongoing in the USA to determine the safety and
efficacy of this approach.
12
Circumcision
The 2009-10 Demographic and Health Survey (DHS)
data from Lesotho have been analysed to determine
the current prevalence of male circumcision and
associated demographic factors for circumcised
males; as well as to determine if male circumcision
has limited the spread of HIV19. Data on the HIV and
circumcision status of 3,074 men was collected: the
HIV prevalence was 18% in men aged 15-59 years;
and ~56% of men were circumcised. Surprisingly, the
HIV prevalence was higher in circumcised men (20%)
than uncircumcised men (15%). Male circumcision
was more common in rural areas (61%) than urban
areas (36%) but HIV prevalence was lower in rural
areas compared to urban areas: 17% vs. 20%.
The majority of men (79%) lived in rural areas. Only
~8% of circumcisions were carried out using clinical
methods, while 92% were carried out with traditional
methods, usually at an initiation school. This method
does not completely remove the foreskin, and so
may be less protective against HIV acquisition than
medical circumcision. Approximately half of the men
were circumcised after becoming sexually active.
The investigators concluded that the use of traditional
methods of circumcision, especially after men have
become sexually active, might limit the protective
effect of male circumcision in Lesotho.
Prevention of Mother to Child
Transmission of HIV (PMTCT)
An HIV infected pregnant woman can transmit HIV
to her baby at any point during pregnancy, labour
and delivery or breastfeeding. Prevention strategies
are therefore needed throughout this long period of
time, Dr Scarlatti (San Raffaele Institute, DIBIT, Italy)
pointed out20. Administering combinations of ARVs
during pregnancy, labour and delivery and avoiding
breastfeeding have reduced MTCT rates to almost
zero in the developed world. The use of single
dose nevirapine changed the perception that it was
impossible to prevent MTCT in developing countries.
Although its use was associated with the emergence
of NNRTI resistance, it not only reduced the number
of paediatric HIV infections but also led to PMTCT
initiatives in resource limited settings (RLS) using
ARV combinations. Since breastfeeding contributes
to paediatric health in RLS, a number of ARV-based
interventions have been developed to protect a baby
from HIV infection during breastfeeding.
Only a few viral variants are detected in newborns,
regardless of the route of transmission (Figure 4). The
transmitted variant is either a major or minor maternal
viral variant. Viruses that are transmitted intra partum
(during labour and delivery) tend to have shorter
variable loops and fewer PNG sites than those that
are transmitted during pregnancy. R5 virus is the
mother
Pregnancy
Placenta
Amniotic
fluid
Labour
Delivery
Breast
feeding
!! a SELECTIVE barrier?
Blood
Secretions
Milk
Blood
Only FEW virus variants
detected in the newborn!
child
Figure 4. Is MTCT a selective or stochastic process?
Source: Dr. G. Scarlatti, San Raffaele Institute, Milan, Italy20
predominant transmitted virus in MTCT: children
who are infected with R5broad phenotype are more
likely to experience early immunological failure than
those who are infected with R5narrow phenotype
virus. R5 viruses preferentially cause dendritic cells
to extend cellular processes through the intestinal
mucosa, thus enabling the R5, but not the X4, viruses
to cross the epithelial layer. Dendritic cells that are
infected with HIV also act as a local viral reservoir
at the mucosal level. Understanding the precise
mechanisms by which MTCT occurs will assist in the
efforts to prevent children being infected with HIV.
The topic of HIV incidence in pregnancy and the
first post partum year was addressed by Dr Lu
(CDC, USA)21. Routine HIV antibody testing during
antenatal care may miss acute infections that are still
in the window period (prior to the development of
antibodies) or infections that occur during pregnancy.
New HIV infections during late pregnancy and
breastfeeding are associated with a very high risk of
MTCT. In 2010, Dr Lu and colleagues undertook a
study of 417 women who had had negative HIV tests
during pregnancy and who were approximately one
year post partum. The one year HIV incidence in
these women was 3.8%. Risk factors for HIV infection
were evaluated with a behavioural survey. Although
20% of the women had had more than one sexual
partner in the previous two years, this finding was not
associated with HIV infection. Women who knew the
HIV status of their partner were significantly less likely
to acquire HIV than those who did not know. Nearly
half (183/417, 43.9%) of the women had been tested
together with their partner. Extrapolating these data
to the total Batswana population, Dr Lu stated that
while the National program found 647 infant infections
through the Early Infant Diagnosis program, as many
as 1329 infant HIV infections may have occurred
in 2010, with 672 (50.6%) due to incident cases of
maternal HIV infection that would not have been
detected in routine antenatal care. Of the 17 infants
born to seroconverting women during the study,
three were found to be HIV positive: one baby died
before ART was initiated; one died after ART was
initiated; and one was alive and taking ART when the
study was completed. Dr Lu commented that these
data have implications for PMTCT programmes since
women continue to be at risk for HIV infection during
pregnancy and while breastfeeding, despite a high
uptake of antenatal HIV testing and counselling.
Women who test HIV negative during pregnancy will
breastfeed their babies, breastfeeding babies are
at high risk for mother-to-child transmission in the
setting of an acute maternal HIV infection. Women
are likely to use condoms for protection. However,
couples testing and counselling tends to be underused. Many women were not aware of their partners’
HIV status, which was the only significant risk factor
found for incident HIV, even in this small cohort.
Based on these data, it has been suggested that
HIV negative women should be retested when they
bring their babies to the clinic for immunization (4
months post partum) or earlier if other risk factors are
present. Educational material needs to be modified
to explain the risks of HIV infection during pregnancy
and breastfeeding. Access to family planning, STI
13
Report
clinics and couples testing and counselling needs to
be improved.
Modes of Transmission and HIV
Prevention Efforts in Vulnerable
Populations
Drug users
Obtaining precise information on the number of
intravenous drug users (IVDU) globally is challenging
but there are believed to be approximately three million
IVDUs living with HIV worldwide22. HIV transmission
occurs by sharing contaminated syringes with other
IVDUs as well as unprotected sex with HIV positive
partners. Other factors associated with HIV acquisition
include unstable housing; and the intensity of use of
intravenous cocaine. In certain settings, age, gender
and use of crack cocaine have been shown to be risk
factors for HIV infection. Preventing HIV transmission
amongst IVDUs is complex, mainly because of its illicit
nature, and has to take into account a wide range of
structural, social and individual factors. Needle and
syringe programmes, as well as opioid substitution
therapy (OST), have been shown to be effective in
reducing HIV transmission amongst IVDUs but
political pressures often make it difficult to ensure
that prevention programmes provide a complete
package of interventions. Data from Australia have
shown that full harm reduction programmes are very
effective, while programmes that only offer a few
harm reduction components are less successful.
OST is only useful for people who are dependent on
opioids; it is ineffective for cocaine users. Effective
OST coverage is poor on a global level, even though
good OST programme retain IVDUs in care for
longer and OST clients are six times less likely to
become HIV positive than IVDUs who do not enter
treatment. Increased access to ART by IVDUs in
Vancouver has been associated with decreases
both in the community plasma viral load and the
HIV incidence density. Despite these successes,
there is a considerable resource gap – several billion
dollars – between the annual amount spent on harm
reduction programmes and the estimated total need.
Dr Bruneau (University of Montreal, Canada) called
for comprehensive healthcare packages for IVDUs.
Decreases in the future HIV prevalence and disease
burden among IVDUs can only be accomplished by
intensifying harm reduction measures among highrisk persons and expanding health care access for
those at the greatest risk of disease and progression,
including access to HIV prevention technologies
such as PrEP.
Although IVDU is a major risk factor for HIV
transmission, Dr Khayatkhoei (Teheran University,
14
Iran) pointed out that non-IV drug users also
participate in high risk behaviour, such as having
unprotected or transactional sex23. Dr Khayatkhoei
therefore compared the prevalence of HIV in IDU
and non-IV drug users in the Imamhossein Hospital
Detoxification Center in Tehran, Iran, in a cross
sectional study between March 2010 and April
2011. The Center is a referral centre that treats
approximately 600 patients per day in the Emergency
Department. In Iran, approximately two million people
are addicted to drugs; 300,000 of them are IVDUs. In
2006, IVDU was the major route of HIV transmission
in Iran. The study population was composed of 200
IVDUs and 200 non-IV DUs. Patients had to have
been opioid drug abusers for at least three years. Of
the IVDUs, 12.5% (25/200) were HIV positive while
this figure was 3.5% (7/200) for non-IV DUs. The risk
of acquiring HIV was 3.9 times higher in IVDUs than
in non-IV DUs. Dr Khayatkhoei stressed that the HIV
prevalence in non-IV DUs is a concern since 82% of
all drug abusers are in the reproductive age range
and therefore would be expected to be sexually
active. She recommended that healthcare workers
are sensitised to this issue and that HIV education
programmes be developed to decrease behavioural
risk factors in both IVDUs and non-IV DUs.
Young girls
HIV disproportionately affects young girls in subSaharan Africa. Dr Kaggwa (PACE, Uganda) explained
that, in Uganda, this part of the epidemic is driven
by cross generational sex (CGS): 10% of Ugandan
girls aged 15-19 years had had sex with a man who
was at least 10 years older in the previous 12 months
(Ministry of Health survey 2006). In partnership
with Johnson and Johnson, the PACE programme
has implemented an anti- CGS project called ‘Go
Getters’ in 50 secondary schools in four regions
in Uganda. A cross sectional survey was carried
out in a representative sample of 2,410 girls aged
15-19 years from 30 secondary schools to assess
sexual behaviour and its determinants. Schools were
classified as low category (LCS) or high category
(HCS), depending on the amount of fees and rates of
university entry as a reflection of the girls’ economic
circumstances. CGS was more common in LCS than
HCS: 9.4% vs. 2.6%. Young girls who had had CGS
were more likely to report early sexual debut; have
multiple older sexual partners; have low confidence
in their ability to reject older men’s advances; and to
perceive CGS as socially acceptable. Half of the girls
had a boyfriend at the time of the survey and 22%
had had sexual intercourse at some point in their life.
In previous year, 22% had had sex and 20% had had
sex with multiple sexual partners. Girls from HCS
were more confident in their ability to reject older
men’s advances; had social support not to engage
in CGS; agreed that women are more at risk of HIV if
they have CGS; and had higher self esteem than girls
from LCS. Based on these results, HIV prevention
programmes should enhance girls’ life skills so that
they are more confident in rejecting older men’s
sexual advances; campaign against CGS; address
the social norms that support CGS; and emphasize
the risks associated with CGS.
Transmitted Drug Resistance (TDR)
Global trends
Dr Wensing (University Medical Centre Utrecht, The
Netherlands) addressed the issue of transmitted
drug resistance (TDR) worldwide24. The SPREAD
network is present in 34 European countries. In order
to collect information on a representative set of newly
diagnosed patients, prospective data are collected
annually in 28 SPREAD countries from patients
with evidence of recent infection (<1 year) and from
patients with an unknown duration of infection. Based
on these data, the prevalence of TDR remained stable
in Europe between 2002 and 2007: ~8-9% for any
class of ARV; ~5-6% for NRTIs; ~3-4% for NNRTIs;
and ~2-3% for PIs. Nationwide data are not available
for the USA but a number of city or state surveys
have demonstrated a similar rate of transmitted drug
resistance in various risk groups (~10%). The WHO
has developed standardised methods to assess
transmitted drug resistance in RLS, especially in
recently infected, ART naïve populations. Between
2002 and 2009, 53 surveys had been completed
in 22 countries: 83% showed low rates of TDR and
17% had moderate rates of TDR. The overall TDR
prevalence was 3.7%. Of the 11 surveys conducted
in 2009, five showed moderate levels of TDR, which
may have implications for treatment and prevention
programmes in these RLS.
The majority of TDR is due to single mutations,
but resistance profiles differ between treated and
untreated individuals24. For example, the M184V and
T215Y mutations are far more common in treated
individuals than untreated individuals. It has been
hypothesised that treated individuals are not the most
important source of drug resistant virus, especially
as ARV resistant viruses tend to be transmitted less
efficiently than susceptible viruses. It is possible that
drug resistant viruses evolve in the new host in the
absence of drug selective pressure. After conducting
a literature survey of cases of TDR, Dr Wensing and
her colleagues identified three different evolutionary
pathways:
1. Reversion – when the transmitted resistant virus
reverted to wild type in the new host.
2. Atypical variants – when the transmitted resistant
virus evolved to become an atypical variant(s).
3. Persistence – when the transmitted resistant virus
persisted in the new host due to a small difference
in the virus’ replicative capacity and/or the emergence of compensatory mutations that became
fixed in the population.
The clinical implications of TDR were studied
retrospectively in the EuroCoord-CHAIN study of
>10,000 patients who started ART after 1997 and
for whom genotypic and clinical follow up data
were available. Although the majority of the patients
(90.5%) were infected with fully susceptible virus,
approximately 10% were infected with TDR virus. Half
of these patients were treated with a regimen that
was fully active and half received a regime that the
virus was resistant to. Although the level of CD4 cell
recovery was similar in all of the patients, individuals
who were treated with sub-optimal regimen had
a higher risk of virological failure. Patients who
received fully active regimens had a similar outcome
to patients infected with susceptible virus if they were
treated with ritonavir boosted PIs (PI/r) but patients
who took NNRTIs were more likely to experience
therapy failure. The reasons for this difference are
not yet clear but it is possible that the higher genetic
barrier to PI/r was a factor. It is also possible that
the presence of NNRTI-resistant minority variants
affected the clinical outcome. Monitoring TDR is
a critical part of ensuring that HIV prevention and
treatment programmes are successful.
European trends in TDR
Prof. Boucher (Erasmus Medical Centre, The
Netherlands) described the results of a study by
the European Society for Antiviral Resistance to
understand the spread of TDR in newly diagnosed
European patients, using a pre-defined strategy that
ensured representative sampling25. Epidemiological,
clinical and virological data were collected
prospectively from 2,800 patients between 2002
and 2005 and 1,630 patients between 2006 and
2007. Approximately half of the patients were MSM
(48%), 35% were heterosexual and 8% were IVDUs.
The majority (79%) were male. Fifty five percent
originated in W Europe; 21% from Eastern Europe
and Central Asia; 11% from Sub Saharan Africa;
and 12% from other continents. The most important
mutations that were detected included T215Y, M41L,
K103N and L90M. The prevalence of drug resistance
was significantly higher in MSM than other groups
in relation to any ARV class, NRTIs and NNRTIs but
not PIs. Trends towards an increase in resistance
to any ARV class and to NRTIs over time were
observed in MSM; this change was significant for
NNRTIs (+4%, p=0.008). By contrast, there was a
trend towards decreased (any ARV class and NRTIs)
15
Report
or stabilised (PIs and NNRTIs) levels of resistance in
heterosexuals. Prof. Boucher concluded that there
are still single TAMs and revertants circulating in HIV
positive Europeans, especially MSM. Resistance to
NNRTIs has increased, mainly in MSM, while the
transmission of mutations associated with resistance
to PIs has decreased in recent years.
TDR in newly diagnosed Japanese patients
Viral samples from 408 newly diagnosed (2007-10)
patients at Nagoya Medical Center, Japan, were
tested for drug resistance using genotypic assays26.
Approximately one third (31%) of the patients had
seroconverted within the 155 days prior to testing while
the remaining patients were classed as ‘long term’
seroconverters. Japanese MSM were diagnosed
at a significantly earlier stage in their infection than
non-Japanese patients (p<0.01) or those who
had acquired HIV via risk factors other than MSM
(p<0.05). TDR was observed in similar proportions in
both recent and long term seroconverters: resistance
to any ARV class was observed in 16% of samples.
Resistance to PIs was observed in 7.1% of samples
from recent seroconverters compared to 9.6% of
long term seroconverters. The figures for NRTIs
and NNRTIs, respectively, were 7.9% and 1.6% in
the recent seroconverters and 5.3% and 2.1% in the
long term seroconverters. There were no statistically
significant differences between the two groups in
terms of TDR. The mutations, T215X and M46I/L
were detected in samples from both recent and
long term seroconverters, suggesting that they have
stabilised within the viral population and become
circulating strains.
TDR and clusters
The early stage of HIV infection is a window of
opportunity for prevention efforts since newly infected
individuals are at high risk of transmitting HIV during
this period (Figure 5)27. Lack of knowledge about their
status means that they are less likely to take protective
measures against transmitting HIV. Clusters of
infections of both wild type and drug resistant virus
have been identified within sexual networks. Over
time, the size and number of clusters in a community
tend to increase. Clustering can lead to the onward
transmission of drug resistant sub-epidemics if these
mutations do not reduce the replication capacity of
the virus. In some cases, a compensatory mutation
arises that reverses the fitness deficits imposed by
a specific mutation e.g. a virus carrying E138K plus
M184I/V has the same replication capacity as wild
type virus. This may have clinical implications for
patients who fail therapy with etravirine or other novel
NNRTIs. It is essential that compensatory mutations,
such as E138K, are monitored in future TDR studies.
Mathematical modelling has been used to identify
HIV variants that are most likely to generate large
transmission clusters and to investigate the effect
of more sensitive resistance detection assays
on increasing observed persistence times28. The
stochastic model of HIV transmission used 10
variants, each with a single point mutation that
conferred resistance to NRTIs or NNRTIs. The
results of the model suggest that there could be a
Viral load &
Infectivity
Early stage infection: The window of opportunity for prevention
1/5 HIV+
Untested
Ag +
AbHAART
0
6 mo
2 yrs
Acute/recent
CLUSTERING
>50%
5 yrs
Chronic Infection
10-20%
Figure 5. Time course of HIV infection
Source: Dr. M. Wainberg, McGill University, Montreal Canada27.
16
10 yrs > 20 yrs
Chronic treated
<<10%
hidden epidemic of HIV strains with intermediate
to low fitness. The use of assays with increasing
sensitivity could substantially increase the detection
of intermediate fitness strains. Small differences in
fitness result in significant differences in persistence
times, cluster sizes and transmission chain lengths.
Strains with high fitness costs (>6%), such as K65R,
are rarely transmitted and are rarely detected in
clusters.
Transmissibility of drug resistant variants
M184V is one of the most common mutations
in patients who fail therapy; it is associated with
resistance to NRTIs. A macaque model of infection
has been used to determine the impact of M184V
on viral transmissibility29. The M184V mutation was
introduced into a R5 tropic SHIV genetic background
and the transmissibility of the virus was evaluated
using a repeat exposure rectal challenge model.
The susceptibility of the variant to FTC was similar
to that of HIV. At standard doses of virus, the
variant was not very transmissible. When the dose
was increased four-fold, the variant had similar
transmission efficiency to that of wild type virus. The
high fitness cost of the M184V mutation resulted in a
reduced peak viraemia compared to wild type virus,
even when higher doses of the mutated virus were
used. Based on the results from this animal model,
the presence of mutations that reduce viral fitness
may reduce the risk of onward transmission of these
mutated viruses.
The M41L mutation is associated with resistance to
NRTIs; it is a thymidine analogue mutation (TAM).
The presence of M41L and at least two other TAMs is
associated with resistance to tenofovir but not to FTC.
Dr Pingen (University Medical Centre Utrecht, The
Netherlands) and colleagues have used genetically
engineered and patient-derived viruses to determine
the impact of M41L on resistance to tenofovir and
FTC30. All viruses that carried M41L as the only
resistance-related mutation were fully susceptible
to both NRTIs. In vitro selection experiments were
carried out in which the viruses were exposed to
increasing concentrations of tenofovir, FTC or both
drugs. After 5-6 passages, the complete RT gene was
sequenced. The results showed that the presence of
M41L did not prevent the selection of K65R or select
for additional TAMs. M41L did not have a major effect
on the development of resistance to tenofovir and/or
FTC, suggesting that therapy with these NRTIs could
be initiated even in the presence of a M41L mutation.
7
19 - 20 JULY 2
012
DC, USA
WASHINGTON
MARK - THE - DATE
19 - 20 July 2012, Washington DC, USA
Abstracts & Presentations of the 6th Workshop on HIV Transmission are available online at
www.virology-education.com
17
Report
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27. Wainberg, M., Transmission within clusters of drugresistant variants of HIV-1. Reviews in Antiviral Therapy
& Infectious Diseases, 2011. 7: p. 17.
28. Wagner, B. HIV drug resistance mutations: identifying
variants most likely to generate large transmission
clusters. in 6th International Workshop on HIV
Transmission. 2011. Rome, Italy.
29. Garcia-Lerma, G. Reduced transmissibility of a drugresistant SHIV162P3 isolate containing the M184V
mutation in macaques. in Reviews in Antiviral Therapy
& Infectious Diseases. 2011. 19.
30. Pingen, M., The frequently transmitted M41L mutation
in RT does not affect the in vitro selection of resistance
against tenofovir and emtricitabine. Reviews in Antiviral
In today’s HIV landscape, we expect to keep them
there, with durable suppression, well-established
tolerability and convenient dosing.1–3 So they can
concentrate on dealing with the challenges of life.
Voor productinformatie zie elders in deze uitgave.
NLRZ-K0003 08/11 687HQ11PM201(3)
Verkorte productinformatie REYATAZ®
Samenstelling: REYATAZ®, harde capsules, bevatten 150, 200 of 300 mg atazanavir per capsule. Indicaties: REYATAZ capsules, gelijktijdig toegediend met lage doseringen ritonavir, zijn bestemd voor de
behandeling van hiv-1 geïnfecteerde volwassenen en pediatrische patiënten in de leeftijd van 6 jaar en ouder in combinatie met andere antiretrovirale middelen. Gebaseerd op de beschikbare virologische en
klinische gegevens van volwassen patiënten, is er geen voordeel te verwachten bij volwassen patiënten met stammen die resistent zijn tegen meerdere proteaseremmers (≥ 4 PI mutaties). Er zijn zeer beperkte
gegevens beschikbaar van kinderen in de leeftijd van 6 jaar tot jonger dan 18 jaar. De keuze voor REYATAZ bij voorbehandelde volwassen en pediatrische patiënten dient gebaseerd te zijn op individuele virale
resistentie tests en de behandelingshistorie van de patiënt. Dosering: volwassen patiënten – De aanbevolen dosering van REYATAZ capsules voor volwassenen is 300 mg eenmaal daags samen met eenmaal
daags 100 mg ritonavir en voedsel. pediatrische patienten vanaf 6 jaar – De dosering van REYATAZ capsules bij pediatrische patiënten is gebaseerd op lichaamsgewicht (15-<20 kg: 150 mg, 20-<40 kg: 200 mg,
≥40 kg: 300 mg; samen met 100 mg ritonavir en voedsel). De beschikbare gegevens ondersteunen niet het gebruik bij pediatrische patiënten die minder dan 15 kg wegen. pediatrische patiënten jonger dan 6 jaar:
REYATAZ wordt niet aanbevolen. Contra-indicaties: Overgevoeligheid voor atazanavir of voor één van de hulpstoffen; leverinsufficiëntie; gelijktijdig gebruik met PDE-remmer sildenafil voor de behandeling van
uitsluitend PAH, rifampicine, St. Jans kruid (Hypericum perforatum) en met substraten van de isovorm CYP3A4 van cytochroom P450 die een smalle therapeutisch breedte hebben (zoals astemizol, terfenadine,
cisapride, pimozide, kinidine, bepridil en ergot alkaloïden; met name ergotamine, dihydroergotamine, ergonovine, methylergonovine). Bijzondere waarschuwingen: Patiënten met chronische hepatitis B of C
die behandeld worden met een antiretrovirale combinatietherapie hebben een verhoogd risico op ernstige en potentieel fatale leverbijwerkingen. Extra voorzorgsmaatregelen kunnen nodig zijn bij gebruik van
REYATAZ bij hemofilie patiënten en bij patiënten met onderliggende leverstoornissen. REYATAZ met ritonavir wordt niet aanbevolen bij patiënten die hemodialyse ondergaan. Speciale voorzichtigheid is nodig bij
patiënten met bestaande cardiale geleidingsproblemen (tweedegraads of hoger atrioventriculair of complexe bundeltakblokkade) of risicofactoren (bradycardie, lang congenitaal QT, electrolyt verstoringen), of bij
gebruik in combinatie met andere geneesmiddelen die mogelijk het PR- en/of QT-interval verlengen en cardiale controle bij kinderen wordt aanbevolen op geleide van de aanwezigheid van klinische bevindingen.
Er zijn meldingen geweest van toegenomen bloeding bij patiënten met type A en B hemofilie. Evaluatie van de fysische kenmerken van de redistributie van vet moet onderdeel uitmaken van klinische beoordeling.
Lipiden-stoornissen dienen klinisch passend te worden behandeld. Het ontstaan van diabetes mellitus, hyperglykemie en exacerbatie van bestaande diabetes mellitus zijn gemeld voor patiënten, die
proteaseremmers kregen in sommige gevallen ook geassocieerd met keto-acidose. Reversibele verhogingen van indirect (niet-geconjugeerd) bilirubine gerelateerd aan remming van UDP-glucuronosyltransferase
(UGT) werden gezien in patiënten die werden behandeld met REYATAZ. Hoewel men aanneemt dat bij de etiologie vele factoren een rol spelen zijn gevallen van osteonecrose vooral gemeld bij patiënten met
voortgeschreden hiv-infectie en/of langdurige blootstelling aan CART. Immuunreactiveringssyndroom kan optreden. Alle symptomen van de ontstekingsreactie moeten worden beoordeeld en zo nodig
worden behandeld. Nefrolithiasie is gemeld en diverse interacties met geneesmiddelen waaronder: statines, NNRTI’s, sterke CYP3A4 inductoren en/of remmers, PDE-5 remmers voor de behandeling van
erectieledisfunctie, antimycotica, gluco- en/of corticosteroïden, salmeterol, maagzuurremmers. Bij gelijktijdig gebruik van een oraal anticonceptivum dient deze tenminste 30 ug ethinylestradiol te bevatten.
REYATAZ capsules bevatten lactose. Bijwerkingen: volwassen patiënten – oedeem, palpitaties, hoofdpijn, perifere neuropathie, syncope, amnesie, duizeligheid, slaperigheid, dysgeusie, oculair icterus, dyspneu,
braken, diarree, buikpijn, misselijkheid, dyspepsie, pancreatitis, gastritis, opgezette buik, orale aften, flatulentie, droge mond, nierstenen, hematurie, proteïnurie, pollakisurie, pijnlijke nier, huiduitslag, urticaria,
alopecia, pruritis, vesiculobulleuze huiduitslag, eczeem, vasodilatatie, spieratrofie, arthralgie, myalgie, myopathie, gewichtsafname, gewichtstoename, anorexie, toegenomen eetlust, hypertensie, lipodystrofie
syndroom, moeheid, pijn op de borst, malaise, koorts, asthenie, verstoorde manier van lopen, allergische reacties, geelzucht, hepatitis, hepatosplenomegalie, gynaecomastie, depressie, verwardheid, angst,
slapeloosheid, slaapstoornissen, abnormale dromen; pediatrische patiënten – veiligheidsprofiel over het geheel genomen vergelijkbaar met dat gezien bij volwassenen, asymptomatische eerste en tweedegraads
atrioventriculaire blokkade. Afleverstatus: UR. Vergoeding en prijzen: volledige vergoeding; voor prijzen zie Z-index. Zie de volledige Samenvatting van Productkenmerken voor aanvullende informatie.
Bristol-Myers Squibb BV, Woerden, tel: 0348-574222. Datering: mei 2011
1. Daar ES et al. Ann Intern Med. 2011;154(7):445-456 2. Molina JM and the CASTLE Study Team. J Acquir Immnune Defic Syndr. 2010;53(3):323-332. 3. REYATAZ®/r, SmPC. Available at www.ema.europa.eu.
Accessed May 2011.
Date of preparation: August 2011 687HQ11PM201(3) NLRZ-A0018
NLRZ_A0018_VPI
(210x148mm)_v1b.indd
1 / 200 mg / 245 mg
VERKORTE PRODUCTINFORMATIE
ATRIPLA 600 mg
filmomhulde tabletten
8/30/11 4:39
Als de patiënten een ernstige uitslag ontwikkelen die gepaard gaat met blaren, desquamatie, mucosaletsels
of PM
koorts, moet de behandeling met Atripla worden stopgezet. Hulpstoffen: Dit geneesmiddel bevat 1 mmol (23,6 mg)
natrium per dosis, waarmee rekening moet worden gehouden bij patiënten met een gecontroleerd natriumdieet.
Zwangerschap: Atripla dient niet tijdens de zwangerschap te worden gebruikt, tenzij strikt noodzakelijk (d.w.z. er
zijn geen andere passende behandelingsopties) Vruchtbare vrouwen: Bij vrouwen die Atripla ontvangen, moet
zwangerschap worden voorkomen. Borstvoeding: Vanwege het gevaar van HIVoverdracht en de mogelijkheid
van ernstige bijwerkingen bij baby’s die borstvoeding krijgen, dienen moeders te worden geïnstrueerd geen
borstvoeding te geven als ze Atripla ontvangen. Bijwerkingen: De meest gerapporteerde, zeer vaak (≥ 1/10)
bijwerkingen zijn: duizeligheid, misselijkheid, huiduitslag,abnormale dromen. Vaak (≥ 1/100, <1/10) werden de volgende
bijwerkingen waargenomen: anorexie, nachtmerrie, depressie, depressieve stemming, angst, slapeloosheid, stemmingsverandering, slaapstoornis, slaperigheid, hoofdpijn, stupor, lethargie, aandachtsstoornis, vertigo, euforie, opvliegers,
diarree, braken, abdominale pijn, flatulentie, opgezette buik, droge mond, nachtelijk zweten, jeuk, hyperpigmentatie
van de huid, dermatitis, verhoogde creatininespiegel in het bloed, verminderde eetlust, vermoeidheid, toegenomen energie, koorts. Soms (> 1/1.000, <1/100): herverdeling van de vet, hypertriglyceridemie, gewichtsverlies, verwarring, desorientatie, verandering in de persoonlijkheid, stemmingswisselingen, verminderde libido, amnesie, ataxie, evenwichtsstoornis, onsamenhangende spraak, wazig zien, veranderde visuele diepte-perceptie, dygeusie, acute pancreatitis,
orale paresthesie, orale hypo-esthesie, urticaria, droge huid, eczeem, acute hepatitis, myalgie, borstvergroting, zich abnormaal voelen, zich zenuwachtig voelen, rillingen, neutropenie, asthenie, zich dronken voelen, paranoia, psychomotrische agitatie,waanvoorstellingen, agressie, nervositeit. Verpakking: HDPE flacon met een kinderveilige sluiting, met
30 filmomhulde tabletten en een silicagel droogmiddel. Doos met 1 of 3 flacons. Afleverstatus: UR. Vergoeding: volledige vergoeding. Prijs: zie Z-index. Registratiehouder: Gilead Sciences International Limited, Cambridge CB21 6GT,
Verenigd Koninkrijk. Datum: 05/2010. Bestudeer de samenvatting van productkenmerken alvorens Atripla voor te schrijven
in het bijzonder vanwege dosering, bijwerkingen, waarschuwingen en voorzorgen bij gebruik, en interacties. Neem voor
meer inlichtingen contact op met de lokale vertegenwoordiger: Gilead Sciences Netherlands B.V., WTC Tower D,
Floor 7, Strawinskylaan 779, 1077 XX Amsterdam.
Samenstelling: Elke filmomhulde tablet bevat 600 mg efavirenz, 200 mg emtricitabine en 245 mg tenofovirdisoproxil (als fumaraat). Farmaceutische vorm: Filmomhulde tablet. Roze, capsulevormige, filmomhulde tablet, met aan de ene kant
“123” gegraveerd en aan de andere kant niets. Farmacotherapeutische groep:
Antivirale geneesmiddelen voor de behandeling van HIVinfecties, combinaties,
ATCcode: J05AR06. Indicaties: Atripla is een vaste dosiscombinatie efavirenz, emtricitabine en tenofovirdisoproxilfumaraat.
Het is geïndiceerd voor de behandeling van infectie met humaan immunodeficiëntievirus1 (HIV1) bij volwassenen met
een virussuppressie tot HIV1RNA-concentratie < 50 kopieën/ml onder hun huidige antiretrovirale combinatietherapie
gedurende meer dan drie maanden. Er mag bij patiënten geen virologisch falen zijn opgetreden bij eerdere antiretrovirale
therapie en het moet bekend zijn dat patiënten voor het begin van hun eerste antiretrovirale behandeling niet geïnfecteerd
waren door virusstammen met mutaties die een significante resistentie veroorzaken tegen een van de drie componenten
van Atripla. Contra-indicaties: Overgevoeligheid voor de werkzame bestanddelen of voor één van de hulpstoffen.
Atripla mag niet worden gebruikt bij patiënten met een ernstige leverfunctiestoornis (CPT graad C). Atripla mag niet
gelijktijdig met terfenadine, astemizol, cisapride, midazolam, triazolam, pimozide, bepridil of ergotalkaloïden (bijvoorbeeld
ergotamine, dihydro-ergotamine, ergonovine en methylergonovine) worden gebruikt, omdat competitie door efavirenz
om cytochroom P450 (CYP) 3A4 kan resulteren in een inhibitie van het metabolisme en potentieel ernstige en/of levensbedreigende bijwerkingen kan uitlokken (bijvoorbeeld hartritmestoornis, langdurige sedatie of respiratoire depressie).
Kruidengeneesmiddelen met St.Janskruid (Hypericum perforatum) mogen niet worden gebruikt als tegelijkertijd ook
Atripla wordt gebruikt, vanwege het risico van een lagere plasmaconcentratie en een geringer klinisch effect van
efavirenz. Efavirenz verlaagt de plasmaconcentratie van voriconazol sterk, terwijl voriconazol de plasmaconcentratie
van efavirenz juist sterk verhoogt. Aangezien Atripla een combinatieproduct met vaste doses is, kan de dosering van
efavirenz niet worden gewijzigd; daarom mogen voriconazol en Atripla niet gelijktijdig worden toegediend. Waarschuwing
en voorzorgen: Als vaste combinatie dient Atripla niet gelijktijdig toegediend te worden met andere geneesmiddelen
die een van dezelfde werkzame componenten bevatten: efavirenz, emtricitabine of tenofovirdisoproxilfumaraat.
Vanwege overeenkomsten met emtricitabine dient Atripla niet gelijktijdig toegediend te worden met andere cytidineanalogen, zoals lamivudine. Atripla dient niet gelijktijdig toegediend te worden met adefovirdipivoxil. Lactaatacidose: Bij
het gebruik van nucleoside-analogen is melding gemaakt van lactaatacidose, gewoonlijk samengaand met hepatische
steatose. De behandeling met nucleoside-analogen moet gestopt worden bij het optreden van symptomatische hyperlactatemie en metabole acidose/lactaatacidose, progressieve hepatomegalie of snel stijgende aminotransferasespiegels.
Om het risico van lactaatacidosise te minimaliseren bij toediening van nucleoside-analogen moeten de patiënten
nauwgezet worden gevolgd. Leverziekte: Atripla is gecontra-indiceerd bij patiënten met een ernstige leverfunctiestoornis. Omdat efavirenz hoofdzakelijk wordt gemetaboliseerd door het cytochroom-P450-systeem (CYP450-systeem),
is bij toediening van Atripla aan patiënten met een lichte tot matig-ernstige leverziekte voorzichtigheid geboden.
De leverziekte moet periodiek door middel van laboratoriumonderzoek worden gecontroleerd. Patiënten met HIV en
gelijktijdige infectie met hepatitisB- of Cvirus (HBV of HCV): Patiënten met chronische hepatitis B of C die een antiretrovirale combinatietherapie ondergaan, lopen een verhoogd risico op ernstige en potentieel fatale leverbijwerkingenStoppen van de behandeling met Atripla bij patiënten met gelijktijdige infectie met HIV en HBV kan gepaard gaan met
ernstige acute exacerbaties van hepatitis. Psychische symptomen: Bij patiënten die met efavirenz zijn behandeld, zijn
psychische bijwerkingen gemeld. Patiënten met een voorgeschiedenis van psychische stoornissen lijken een groter
risico te hebben op deze ernstige psychische bijwerkingen. Convulsies: Bij patiënten die efavirenz gebruikten, zijn
convulsies waargenomen, meestal bij een bekende voorgeschiedenis van toevallen. Bij alle patiënten met toevallen in
de voorgeschiedenis moet voorzichtigheid worden betracht. Nierfunctiestoornis: Het gebruik van Atripla wordt niet
aanbevolen bij patiënten met een matig-ernstige of ernstige nierfunctiestoornis.Het gebruik van Atripla dient te worden
vermeden bij gelijktijdig of recent gebruik van een nefrotoxisch geneesmiddel. Indien gelijktijdig gebruik van Atripla en
nefrotoxische middelen (bv. aminoglycosiden, amfotericine B, foscarnet, ganciclovir, pentamidine, vancomycine,
cidofovir, interleukine2) onvermijdelijk is, moet de nierfunctie wekelijks worden gecontroleerd. Het wordt aangeraden
om bij alle patiënten de creatinineklaring te berekenen voordat wordt begonnen met de behandeling met Atripla.
De nierfunctie (creatinineklaring en serumfosfaat) wordt gedurende het eerste jaar ook elke vier weken gecontroleerd
en daarna elke drie maanden. Aangezien Atripla een combinatieproduct is en het doseringsinterval van de individuele
componenten niet kan worden gewijzigd, moet de behandeling met Atripla worden onderbroken bij patiënten bij wie een
creatinineklaring van < 50 ml/min of een afname van het serumfosfaatgehalte naar < 1,0 mg/dl (0,32 mmol/l) is bevestigd.
Huidreacties: Lichte tot matig-ernstige huiduitslag is gemeld bij gebruik van de individuele componenten van Atripla.
HAART in 1
Referenties: 1. Staszewski S, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine
and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999;341:1865–1873. 2. Robbins GK, et al. Comparison
of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2293–2303. 3. Van Leth F, et al.
Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and
lamivudine: a randomised open-label trial, the 2NN study. Lancet 2004;363:1253–1263. 4. Riddler SA, et al. Class-sparing regimens
for initial treatment of HIV-1 infection. N Engl J Med 2008;358:2095–2106. 5. Lennox J, et al. Raltegravir versus efavirenz regimens
in treatment-naive HIV-1–infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune
Defic Syndr 2010. [Epub ahead of print]. 6. Gotuzzo E, et al. 17th Conference on Retroviruses and Opportunistic Infections. 16–19 February
2010. San Francisco, CA. Abstract K-127. Poster 514. 7. Gallant JE, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine,
lamivudine, and efavirenz for HIV. N Engl J Med 2006;354:251–260. 8. Martinez E, et al. J Acquir Immune Defic Syndr. 2009 Jul
1;51(3):290-7. 9. Sax P, et al. Abacavir–lamivudine versus tenofovir–emtricitabine for initial HIV-1 therapy. N Engl J Med
2009;361:2230–2240. 10. Smith KY, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or
tenofovir/ emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS 2009;23:1547–1556. 11. Martin A, et al. Simplification
of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96-week trial. Clin Infect Dis
2009;49:1591–1601. 12. Post FA, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine
versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviralnaive, HIV-1–infected adults: 48-week results from the
ASSERT study. J Acquir Immune Defic Syndr 2010 sept;55(1):49-57. 13. Arribas JR, et al. Tenofovir disoproxil fumarate, emtriciabine,
and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients. J Acquir Immune Defic Syndr
2008;47:74–78. 14. DeJesus E, et al. Simplification of antiretroviral therapy to a singletablet regimen consisting of efavirenz,
emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected
patients. J Acquir Immune Defic Syndr 2009;51(2):163–174. 15. Hodder SL, et al. Patient-reported outcomes in virologically
suppressed, HIV-1-infected subjects after switching to a simpliofied, single-tablet regimen of efavirenz, emtricitabine, and tenofovir
DF. AIDS Patient Care STDs 2010;24(2);87–96. 16. Airoldi M, et al. One-pill once-a-day HAART: a simplification strategy that improves
adherence and quality of life of HIV-infected subjects. Patient Prefer Adherence 2010;4:1–11.
Report
15 - 16 July 2011 in Rome, Italy
Report
Progress and Controversies in Pediatric HIV Care
Report on the 3rd International Workshop on HIV Pediatrics
J. Ananworanich1, C. Boucher2, D. Burger3, E. Capparelli4, M. Cotton5, C. Giaquinto6, D. Mbori-Ngacha7, L.
Mofenson8
The Thai Red Cross AIDS Research Center, Thailand, 2Erasmus Medical Center Rotterdam, The Netherlands,
University of Nijmegen, The Netherlands, 4University of California San Diego, California, USA, 5Stellenbosch
University J8/Tygerberg Children’s Hospital,South Africa, 6University of Padova, Italy, 7UNICEF East and
Southern Africa Region, South Africa, 8National Institutes of Health, Bethesda, USA
1
3
Written by Mark Mascolini on behalf of the Organizing Committee
Growing up with HIV poses different challenges in resource-rich and poor countries, attendees learned in the
opening session of 3rd International Workshop on HIV Pediatrics. But similar challenges in both regions are not
hard to find, according to keynote speakers Rohan Hazra1 (Eunice Kennedy Shriver National Institute of Child
Health and Human Development, National Institutes of Health, Bethesda, Maryland) and Philippa Musoke2
(Makerere University, Kampala).
Two prospective pediatric cohorts in the United
States recorded dramatic drops in mortality from the
days before combination antiretroviral therapy (cART)
to more recent years,3,4 Hazra noted. The 3553-child
PACTG 219/219C cohort recorded a mortality
plummet from 7.2 per 100 person-years in 1994 to
0.6 per 100 person-years in 2006.3 In the 364-child
PACTS/PACTS-HOPE birth cohort, mortality waned
from 18 per 100 person-years in 1986 to 0.8 per 100
person-years in 2004.4 But for youngsters with HIV,
decades-long survival with HIV means decades of
coping with potential central nervous system disease,
metabolic and insulin dysregulation, and bone, liver,
renal, and cardiovascular disease. Atherosclerosis
does begin in childhood, Hazra stressed.
“The use of [cART] has transformed HIV infection
in children from a fatal illness to a chronic health
condition,” Hazra observed, and, “as with other
chronic conditions, long-term treatment, monitoring,
and management will be critical, and many challenges
will be faced as these children age into adulthood.”
At the same time, he argued, survival of perinatally
infected children into adulthood in rich countries
should encourage “expansion of pediatric treatment
programs in low-resource countries, where most
HIV-infected children live.”
Philippa Musoke spoke for that majority in resource-
Disclosure:
Mark Mascolini has disclosed that he has not
received grants or (research) support from any
commercial entity or served as consultant for such a
company.
22
limited settings, noting that 400,000 infants become
infected with HIV every year, 90% of them in subSaharan Africa.2 While mortality was falling steeply in
HIV-positive US children by 2004,4 an African metaanalysis of perinatal prevention trials in breastfeeding
infants reported from 1999 through 2002 found that
52.5% of children who became infected had died at
2 years of age and 60% by 2.5 years.5
Delayed diagnosis and treatment of HIV in resourcepoor countries explains much of the high mortality,
Musoke said. When women with HIV are not
diagnosed during pregnancy, their HIV-positive
infants also go undiagnosed. Access to HIV DNA
testing of dried blood spots is limited in many lowincome countries, so undiagnosed HIV often persists
in newborns. When children are diagnosed, lack of
appropriate pediatric formulations—and sometimes
perinatal exposure to nevirapine—complicate their
treatment. Malnutrition, tuberculosis, and other
afflictions complicate the course of children who are
diagnosed and begin treatment.
Around the world, UNAIDS estimates that 38% of
children eligible for cART begin treatment, compared
with 43% of adults.6 Across sub-Saharan Africa, only
35% of cART-eligible children get treated, but rates
are higher in South Africa (65%) and Botswana (80%).
As in high-income countries, children typically
respond well to cART in low- and middle-income
countries. Musoke cited a 3936-child study of
children starting cART before the age of 5 years,
90% of them in Africa and the rest in Asia.7 After a
median cART duration of 10.5 months (interquartile
range [IQR] 3.7 to 20.6), 6.3% of children in this
cohort had died and 10.3% were lost to follow-up.
Most deaths, 55%, occurred in the first 6 months of
treatment, and only 3.8% of children experienced
severe antiretroviral toxicity.
rather than waiting until a drop to 250 cells/mm3
lowered the risk of a clinical event 40% (P = 0.01).11
Musoke listed a set of challenges in adolescent HIV
care in resource-poor settings, all of which could be
cited as challenges in high-income countries:
• Knowledge of HIV infection
• Linking to (and retaining in) health care
• Accepting (and adhering to) therapy
• Mental health issues
• Complexities of transition to adult care
• High risk of HIV transmission to sex partners
PREDICT is an open-label trial in Thailand and
Cambodia that randomized antiretroviral-naive
children from 1 to 12 years old to start cART
immediately or to close monitoring every 3 months
and to begin cART when the CD4 percent fell below
15%.8 All children were naive to antiretrovirals,
had a CD4 percent between 15% and 24% upon
enrollment, and had CDC stage A or B disease.
Primary endpoints were AIDS-free survival and
neurodevelopment as measured by the Berry visualmotor integration score at week 144. PREDICT
investigators recruited 300 children (180 Thais and
120 Cambodians) at seven clinical research sites in
Thailand and two in Cambodia. Study retention was
97%. Health workers measured CD4 percent every
3 months. All children started the same regimen—
nevirapine, zidovudine, and lamivudine
Hazra interleaved his data slides with quotes from US
children asked for their thoughts about growing up
with HIV. “At first, I didn’t think that I was going to grow
up with HIV,” one youngster remarked. “I thought I was
going to die from HIV.” Now that HIV-positive children
around the world are learning that death is not a
short-term inevitability, HIV pediatricians everywhere
are learning that cross-cultural exchanges like those
possible at the International HIV Pediatrics Workshop
can afford the deepest insights into a virus that does
not pause at Passport Control.
Pediatric cART: Controversies and
Insights
Immediate cART does not prolong survival
in 1- to 12-year-olds
Contrary to findings in infants under 1 year old and
in adults, a 144-week randomized trial in Thailand
and Cambodia found that immediate cART for
1- to 12-year-olds with moderately advanced HIV
infection did not prolong survival, delay progression
to AIDS, or improve neurodevelopment.8 Children in
the immediate treatment group did grow faster than
those in the delayed treatment group, and they had
lower rates of thrombocytopenia and herpes zoster.
The findings run counter to results of the South
African CHER trial, which found that immediate
cART for children under 1 decreased mortality
by 76% and HIV progression by 75%.9 As a result
of that trial, the World Health Organization (WHO)
recommends immediate cART for children up to 2
years old regardless of CD4 count, CD4 percent,
or WHO clinical stage.10 For 2- to 5-year-olds, WHO
recommends cART for those with a CD4 count at or
below 750 cells/mm3 or a CD4 percent at or below
25%, whichever is lower, regardless of WHO clinical
stage. For children 5 or older, WHO advises starting
cART for all with a CD4 count below 350 cells/mm3,
regardless of WHO clinical stage. In adults, the
international HPTN 052 trial found that starting cART
at a CD4 count between 350 and 550 cells/mm3
Median age was 6.4 years in both treatment arms.
Forty-six children (15%) were 1 to 3 years old, 67
(22%) were 4 to 5, and the rest were older than 5
years of age. In the immediate and deferred arms,
52% and 64% were girls, median CD4 percent stood
at 19% and 20%, and median viral load measured
4.9 and 4.7 log10 copies/mL. Median weight-for-age
Z score and height-for-age Z score were similar in the
two groups (-1.3 in both arms for weight and -1.6 to
-1.7 for height).
After 144 weeks of follow-up, AIDS-free survival was
97.9% in the immediate-cART group and 98.7% in
the deferred group, a nonsignificant difference (P
= 0.49). Incidence of CDC class C events was 7.6
per 1000 person-years in the immediate group and
4.9 per 1000 person-years in the deferred group (3
events versus 2). The Berry visual-motor integration
test score did not differ significantly between the
immediate and deferred arms (84.7 and 86.8, P
= 0.50) at 144 weeks. The PREDICT investigators
called the Berry score a crude measurement of
neurodevelopment, and they are further analyzing
cognitive function and fine motor test results.
Incidence of thrombocytopenia (abnormally low
platelets) was lower in the immediate arm (2.5 versus
24.4 per 1000 person-years, hazard ratio [HR] 9.7, P
= 0.03), as was incidence of herpes zoster (7.5 versus
31.8 per 1000 person-years, HR 4.2, P = 0.03). All
10 cases of thrombocytopenia in the deferred arm
occurred before cART began, and 9 of 13 cases of
herpes zoster occurred before cART began. Weightfor-age Z score improved more in the immediate arm
(0.20 versus 0.08, P = 0.074), as did height-for-age Z
score (0.23 versus 0.00, P = 0.003).
23
Report
40
%CD4 after start ART
30
Immediate
20
C D 4%
Deferred
10
P=0.74
0
12
24
36
48
60
72
84
96
108
120
132
144
Weeks after commencing ART
IMMEDIATE
149
148
147
147
145
143
144
142
142
142
142
142
142
DEFERRED
68
67
60
57
54
51
46
38
27
19
14
8
6
Figure 1. Gains in CD4 percent did not differ between the immediate-cART arm and the delayed arm after
treatment began in the randomized PREDICT trial, which found no mortality difference between the immediate
and deferred arms after 144 weeks.
Source: Thanyawee Puthanakit, HIV-NAT, Bangkok.8
Gains in CD4 percent did not differ significantly
between the two study arms after cART began (P =
0.74) (Figure 1). And proportion of children reaching a
viral load below 50 copies/mL after treatment began
did not differ between the immediate and deferred
arms.
lower in Thailand and Cambodia than in some other
developing countries. Finally, the results should be
considered with special caution in 1- to 3-year-old
children, who represented only 15% of the study
population.
Because PREDICT found that HIV-positive children
who survive beyond infancy with moderate immune
suppression had slow disease progression, the
investigators suggested clinicians have the option
to monitor such children closely and to start cART
when the CD4 percent drops below 15% (although
that approach would fall outside WHO guidelines).
The PREDICT team proposed that this approach
may be useful when children and families are not
ready to embark on lifelong therapy and when cART
programs are scaling up to cover all children in need.
NNRTI or PI first?
Clues from four big studies
But the investigators cautioned that clinical
application of study results should be considered with
the following caveats: First, entry criteria stipulated
that all participants had survived at least the first
year of life without antiretroviral therapy, without an
AIDS disease, and without a CD4 percent decline
below 15%; and two thirds of study participants
had survived the first 5 years of life without AIDS or
cART. Thus by definition these children had slowly
progressive disease. Second, study participants had
their CD4 percent measured every 3 months, an
interval that is more frequent than the usual 6 to 12
months in clinical practice in developing countries.
Third, morbidity and mortality background rates (for
example, form diarrhea and pneumonia) are probably
24
Whether to start cART in infants and children with
a regimen based on a nonnucleoside reverse
transcriptase inhibitor (NNRTI) or a protease inhibitor
(PI) is a pressing question whose answer depends
on an array of variables including exposure to singledose nevirapine (sdNVP) or other antiretrovirals for
prevention of mother-to-child transmission (PMTCT)
and the availability of appropriate, convenient
formulations, which typically means generic products
in low- and middle-income countries.
For children under 3 years old, US Department of
Health and Human Services (DHHS) guidelines
recommend two nucleos(t)ide reverse transcriptase
inhibitors (NRTIs) plus lopinavir/ritonavir, with
nevirapine now listed as an alternative (in children not
exposed to nevirapine perinatally).12 Because children
in both the nevirapine-exposed and unexposed
cohorts of IMPAACT P1060 (summarized below) had a
better CD4 response and better growth than children
in the lopinavir/ritonavir arm, this panel decided that
“liquid nevirapine remains an acceptable alternative
for infants not exposed to single-dose nevirapine
for PMTCT who cannot tolerate lopinavir/ritonavir.”
For children 3 to 6 years old, DHHS recommends
Time to off study treatment or virologic failure
Prop. on TRT with no VF
1.0
0.8
0.6
LPV/r
0.4
NVP
0.2
0.0
Weeks 0
N at risk:
NVP 147
LPV/r 140
Week 24 failure rate
Week 24: NVP - LPV/r: 21.5% (p<0.001)
24
48
72
96
120
144
168
109
125
68
93
47
54
25
33
20
26
12
17
7
9
Figure 2. Among children not perinatally exposed to nevirapine in IMPAACT P1060 cohort 2, those randomized
to treatment with a nevirapine regimen had a 21.5% higher failure/discontinuation rate at 24 weeks than did
children randomized to lopinavir/ritonavir.
Source: Paul Palumbo, Dartmouth-Hitchcock Medical Center.13
two NRTIs plus efavirenz or lopinavir/ritonavir. And
for children 6 years old or older, the panel prefers
two NRTIs plus atazanavir/ritonavir, lopinavir/
ritonavir, or efavirenz. WHO guidelines divide first-line
treatment choices by age (under 12 months, 12 to
24 months, 24 months to 3 years, and 3 or older)
and according to perinatal exposure to nevirapine or
other antiretrovirals, recommending regimens based
on lopinavir/ritonavir, nevirapine, or efavirenz.10
Study participants were 6 months to 3 years old
and eligible for cART by WHO criteria.10 The primary
endpoint in both cohorts was (1) virologic failure
by week 24, or (2) permanent discontinuation of
nevirapine or lopinavir/ritonavir by week 24, or (3)
death. The investigators defined virologic failure as a
confirmed viral load decline less than 1 log10 copies/
mL (10-fold) between weeks 12 and 24 or a viral load
above 400 copies/mL at week 24.
The 3rd International Workshop on HIV Pediatrics
offered insight into this question in reviews of three
randomized trials (IMPAACT P1060, PENPACT 1, and
NEVEREST 2) and one large cohort study (EPPICC).
Presenting IMPAACT P1060 data, Paul Palumbo
(Dartmouth-Hitchcock Medical Center, Lebanon,
New Hampshire) rated nevirapine a very good
pediatric antiretroviral because of its potency, userfriendly formulations, good tolerability, temperature
tolerance, and cost-effectiveness.13 A “parade of
reports” documenting slowly fading resistance to
nevirapine after perinatal exposure began in 2000,
Palumbo noted. As these four studies show, the
choice between nevirapine (or efavirenz) and a
ritonavir-boosted PI is not clear-cut.
• IMPAACT P1060.
Children in cohort 1 (the nevirapine-exposed group)
had (1) an HIV diagnosis by 60 days of age, or (2)
strict formula feeding, or (3) an AIDS-defining event
by 60 days of age. These children came from four
study sites in South Africa and one each in India,
Malawi, Tanzania, Uganda, Zambia, and Zimbabwe.
Almost all children, 95%, were infected with HIV-1
subtype C, and 20% breastfed.13,14
Cohort 1 included 82 children taking nevirapine and
82 taking lopinavir; both groups had a median age
of 0.7 year and a median viral load above 750,000
copies/mL at study entry. Median baseline CD4
percents were 18.9% in the nevirapine group and
19.7% in the lopinavir group. More children taking
nevirapine than lopinavir (62% versus 50%) had at
least WHO stage 3 disease. Median follow-up stood
at 48 weeks (range 0 to 125 weeks).
IMPAACT P1060 focused on two cohorts, one
exposed to sdNVP and one not exposed.13 The
investigators randomized children to nevirapine or
lopinavir/ritonavir, both with zidovudine/lamivudine.
Among nevirapine-exposed children under 12
months old, virologic failure or discontinuation rates
at 24 weeks were 45.3% in the nevirapine group
25
Report
and 23.3% in the lopinavir groups. Virologic failure/
discontinuation rates at 24 weeks in children 12
months or older were 28.9% in the nevirapine group
and 17.5% in the lopinavir group. Among all children
without pretreatment nevirapine resistance on a
standard assay, 24-week failure rates were 35.8%
among those taking nevirapine and 20.3% among
those taking lopinavir (P = 0.06). Among the 18
children with a pretreatment nevirapine resistance
mutation (Y181C in 15 and K103N in 3), failure rates
were 83.3% with nevirapine and 18.2% with lopinavir,
a highly significant difference (P = 0.001).
The 288 children in cohort 2 (not exposed to
nevirapine) came from four sites in South Africa and
one each in India, Malawi, Tanzania, Uganda, Zambia,
and Zimbabwe. These children had a median age
of 1.7 years, and 73% were older than 12 months.
Median pretreatment viral load stood at 535,000
copies/mL and median CD4 percent at 15%. Most
of the children, 81%, were breastfeeding. Median
follow-up was 60 weeks. As in cohort 1, children
were randomized to lopinavir/ritonavir or nevirapine
plus zidovudine/lamivudine.
In cohort 2, virologic failure or off-study rates at week
24 were 40.8% with nevirapine versus 19.3% with
lopinavir (P < 0.001) (Figure 2). Failure or off-study
rates were significantly higher with nevirapine among
children under 12 months old (41.5% versus 19.4%, P
= 0.030) and children 12 months old or older (40.6%
versus 19.2%, P = 0.001). Rates of discontinuation
because of toxicity were higher with nevirapine than
with lopinavir for children under 12 months old (7/41
or 17% versus 1/36 or 3%) and for older children
(22/106 or 21% versus 5/104 or 5%).
Palumbo showed modeling data suggesting that the
once-daily lead-in dose of nevirapine may be too low
given the high starting viral loads in these children
and possible adherence difficulties. Pharmacologist
David Burger (University Medical Center, Nijmegen,
Netherlands) suggested that the ultimate twice-daily
nevirapine dose may also be too low in this population
and deserves further evaluation. Palumbo added that
some children in cohort 2 had nevirapine resistance
mutations at baseline, and IMPAACT investigators are
assessing pretreatment samples with more sensitive
assays. Standard genotyping detected Y181C in 4
children and K103N in 1 before treatment in cohort 2.
• PENPACT 1.
Also designated PENTA 9 and PACTG 390, PENPACT
1 was an open-label trial that randomized children
to begin antiretroviral therapy with a PI or an NNRTI
combination and to switch after virologic failure at a
26
higher versus a lower viral load (above 1000 versus
above 30,000 copies/mL).15,16 Of the 263 analyzed
study participants, half were from Europe, 27% from
the United States, 20% from Brazil or Argentina, and
3% from the Bahamas or Puerto Rico. There were
218 children (83%) in follow-up at the end of the trial
in August 2009, and median follow-up stood at 5
years.
Study participants had a median age of 6.5 years
(range 1 month to 17.8 years), 53% were boys, and
79% were vertically infected. Half were black, one
quarter white, and one quarter Hispanic or another
race or ethnicity. Median pretreatment CD4 percent
stood at 17% (IQR 10% to 25%) and median viral
load at 5.1 log10 copies/mL (about 126,000 copies/
mL). Only 15% of children received antiretrovirals for
PMTCT, and 4% had one or more major resistance
mutations when PENPACT 1 began.
At the end of the trial, 70% of children remained on
their initial regimen, and the proportion switching
antiretroviral classes did not differ between study
arms (P = 0.64). Only 7% of children switched to
a third-line regimen by the end of follow-up, and
proportions did not differ between randomized arms.
Among children who changed regimens, the switch
point was significantly lower in those randomized
to switch at 1000 copies/mL than among those
randomized to switch at 30,000 copies/mL (6720
versus 35,712 copies/mL, P < 0.01). Estimated time
until 10% of children in the 1000-copy-switch group
changed regimens was 54 weeks, compared with
95 weeks until 10% of children in the 30,000-copyswitch arm changed.
Change in viral load from baseline to year 4, the
primary endpoint, did not differ significantly between
the PI group (-3.16 log) and the NNRTI group (-3.31
log) (difference -0.15 log, P = 0.26). Proportions with
a viral load below 400 copies/mL at week 204 did
not differ between the PI group and the NNRTI group
(82% in both) or between the 1000-switch group
and 30,000-switch group (83% versus 80%, P =
0.43). Suppression rates with a 50-copy assay were
similar in the two randomized comparisons. CD4
percent changes also proved similar in these two
comparisons. Adverse event rates did not differ by
trial assignment.
Among children in whom treatment failed, mutations
conferring resistance to PIs were uncommon, and
low-level resistance to lopinavir/ritonavir emerged in
only 1 child. Among children whose NNRTI regimen
failed, NNRTI mutation rates did not differ by viral load
switch point, because NNRTI-resistant HIV is selected
very early during virologic failure. In the NNRTI arm,
NRTI mutations accumulated in approximately 10%
more children in the 30,000-switch group than in
the 1000-switch group. This accumulation rate was
lower than predicted, and NRTI mutations were even
less likely to develop in PI recipients.
Gareth Tudor-Williams (Imperial College, London)
noted that PENPACT 1 is the first randomized trial in
the cART era with follow-up long enough to address
the consequences of early versus later switching
after virologic failure. He suggested the trial raises
the question whether nevirapine-exposed infants
starting lopinavir/ritonavir should delay switching
at virologic failure, because PI resistance rates
were low in children in whom a PI failed and—after
emergence of M184V— further NRTI mutations were
slow to evolve. Tudor-Williams also cautioned that
PENPACT 1 results cannot be compared with those
of IMPAACT P106013 because of the different study
populations and follow-up times.
• NEVEREST 2.
How to apply results of NEVEREST 2 has perplexed
clinicians since these findings were presented at the
1st HIV Pediatrics Workshop and published soon
thereafter.17 The study involved nevirapine-exposed
South African children who began cART with a PIbased regimen (lopinavir/ritonavir or ritonavir). The
195 children who reached and maintained a viral load
below 400 copies/mL for more than 3 months were
randomized to keep taking lopinavir/ritonavir or to
switch to nevirapine. A significantly higher proportion
in the switch arm maintained a viral load below 50
copies/mL to week 52 (56.2% versus 42.4%, P
= 0.01). But a significantly higher proportion in the
lopinavir/ritonavir maintenance group kept their viral
load below 1000 copies/mL (98% versus 80%, P =
0.001).
Ashraf Coovadia (Rahima Moosa Mother and Child
Hospital, Johannesburg), first author of the published
report, updated results through 48 months at the
3rd HIV Pediatrics Workshop.18 Probability of ever
reaching a viral load above 50 copies/mL remained
lower in the nevirapine switch group at 24 months
(51% versus 68%), 36 months (60% versus 69%%),
and 48 months (63% versus 75%). The proportion
of children with a confirmed viral load above 1000
copies/mL remained stable at 24% in the nevirapineswitch arm through 48 months, while the proportion
with a confirmed 1000-copy rebound in the lopinavir/
ritonavir group rose from 5% at 12 months to 11% at
48 months.
In the nevirapine-switch group, 59% of all confirmed
rebounds above 1000 copies/mL occurred by month
6 and the rest occurred by month 12 (Figure 3). In the
lopinavir-maintenance group, only 10% of confirmed
rebounds above 1000 copies/mL occurred by month
Percent of All “Failures” (confirmed >1000cp/mL) occurring
by different time points post randomization
100%
75%
50%
41%
By 48m
By 12m
50%
40%
59%
By 6m
25%
0%
10%
LPV/r Stay
Half of all failures
detected after
12 mos of ART
NVP Switch
All failures detected
within 12 mos of
starting ART
Figure 3. Among nevirapine-exposed South African children who started a lopinavir/ritonavir regimen, reached
and maintained a viral load below 400 copies/mL for more than 3 months, and were randomized to maintain
lopinavir/ritonavir or switch to nevirapine in NEVEREST 2, all virologic failures in the nevirapine group occurred
within 12 months of the switch, while half of failures in the lopinavir/ritonavir group occurred between months
12 and 48.
Source: Ashraf Coovadia, Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa.18
27
Report
6, another 40% occurred by month 12, and the
remaining 50% occurred by month 48.
Among children with a confirmed viral load above
1000 copies/mL after randomization, the failure rate
did not differ between the nevirapine and lopinavir
arms in children with no detectable pretreatment
mutations. But among those with detectable
pretreatment NNRTI mutations, the failure rate was
significantly higher in the nevirapine-switch group
(above 50%) than in the lopinavir-maintenance group
(below 15%) (P = 0.02).
Median CD4 percent at 24 weeks was higher in the
nevirapine group than the lopinavir group (33.2%
versus 30.0%, P < 0.0001), but it is unclear whether
this difference is clinically meaningful. CD4 percent
declined by at least 10% in significantly more children
staying with lopinavir than switching to nevirapine
(16.3% versus 3.2%, P = 0.004). Weight for age
fell by more than 1 Z score in significantly more
children maintaining lopinavir (13.1% versus 4.2%
in the nevirapine-switch group, P = 0.03). Grade
2 alanine aminotransferase (ALT) elevations were
significantly more frequent in the nevirapine group
than the lopinavir group (11.5% versus 2%, P = 0.05),
and there was a trend toward a higher proportion of
grade 3/4 ALT elevations in the nevirapine arm (5.2%
versus 4%, P = 0.08).
NEVEREST 2 investigators concluded that switching
to an NNRTI regimen after perinatal NNRTI exposure
and virologic suppression with lopinavir/ritonavir
“can be accomplished safely if adequate virological
monitoring is in place.” They observed that failure
after a switch to nevirapine occurs within 1 year
of the switch, and that viral load monitoring can
detect these failures and signal the need to return
to lopinavir/ritonavir. The researchers believe more
study is needed to discern the clinical significance of
low-level viremia and the worse CD4 response in the
lopinavir-maintenance group.
• EPPICC.
Four in 5 European infants starting their first cART
regimen after 1996 were still taking their firstline regimen 2 years later, and two thirds had not
switched or interrupted antiretrovirals 5 years later,
according to results of a 9-cohort analysis.19 By
several measures, the best first-line regimen was one
NNRTI plus three NRTIs.
WHO recommends immediate cART for children up
to 2 years old,10 but data on response to early cART
are sparse and, as discussed above, IMPAACT 106013
and PENPACT 115 reached different conclusions
on the optimal first-line regimen (in highly different
28
study populations). To assess first-line responses in
infants, and to determine antiretroviral switch rates
and switch predictors, European researchers pooled
data from nine cohorts in which children younger
than 12 months old started cART between 1996 and
2008.19
European Pregnancy and Paediatric HIV Cohort
Collaboration (EPPICC) investigators defined
virologic response as a viral load below 400 copies/
mL, CD4 response as absolute change in CD4 Z
score from baseline, and switch to second-line
therapy as simultaneously changing either (1) three
or more drugs for any reason or (2) two drugs
because of treatment failure. For purposes of this
analysis, treatment interruption meant stopping all
antiretrovirals for 14 or more days.
The analysis involved 437 infants, 39% in the United
Kingdom and Ireland, 23% in Italy, 19% in France,
and the rest in other European countries. Median age
when cART started was 3.6 months (IQR 2.1 to 5.8),
and 31% of infants had an AIDS diagnosis before
treatment began. Mothers of 34% of these infants
had taken antiretrovirals during pregnancy, and 28%
of infants received neonatal antiretroviral prophylaxis.
One third of infants were breastfed. Most regimens
included either a PI or an NNRTI:
• Unboosted PI plus two NRTIs: 38%
• Ritonavir-boosted PI plus two NRTIs: 15%
• NNRTI plus two NRTIs: 24%
• NNRTI plus three NRTIs: 14%
• PI plus NNRTI plus NRTI or three NRTIs: 8%
The virologic suppression rate rose from 53% in
1996-1999 to 57% in 2000-2003 and to 77% in 20042008. Martina Penazzato (University of Padova, Italy,
and CTU-MRC, London), who presented results for
EPPICC, suggested that improving virologic response
rates reflect better regimen efficacy, more adequate
dosing, and “personalized HIV management leading
to better caregiver adherence.”
Every 10-fold higher pre-cART viral load lowered
chances of virologic suppression at 12 months by
33% (adjusted odds ratio [AOR] 0.67, 95% CI 0.50 to
0.89, P = 0.006). Compared with starting an NNRTI
plus two NRTIs, starting an NNRTI plus three NRTIs
tripled chances of suppression at 12 months (AOR
3.00, 95% CI 1.24 to 7.23, P < 0.001). The study found
no evidence that other first-line regimens improved
or worsened chances of suppression compared with
an NNRTI plus two NRTIs.
Among 203 infants with pretreatment and 12-month
CD4 counts available, median CD4 change was 520
cells/mm3 (IQR 271 to 1340), median CD4 percent
Cumulative probability of switch/planned TI
Cumulatieve incidence (%)
60
switch/TI
50
40
36% (31%-41%)
30
switch
20
planned TI
10
0
0
2
4
6
8
10
Number of years from cART initiation
Figure 4. Analysis of 437 European infants starting their first antiretroviral combination determined that almost
two thirds (64%) were still taking their initial regimen after 5 years of follow-up.
Source: Martina Penazzato, University of Padova, Italy, and Clinical Trials Unit, Medical Research Council,
London, for the European Pregnancy and Paediatric HIV Cohort Collaboration.19
change 6% (IQR -6% to 16%), and median CD4 Z
score change 0.92 (IQR -0.14 to 2.34). Median CD4 Z
score rose by 2.29 in infants starting an NNRTI plus
three NRTIs, compared with 0.65 in those starting an
NNRTI plus two NRTIs and 0.91 in those starting a
ritonavir-boosted PI. Infants whose mothers received
ART during pregnancy had smaller CD4 Z score
gains at 12 months than infants whose mothers did
not receive ART.
During a median follow-up of 5.9 years (IQR 2.3 to
7.6), 77 of 437 infants (18%) switched to a secondline regimen. Among those who switched, 61% had
never reached a viral load below 400 copies/mL on
their first regimen. Switch rates were 3.9 per 100
person-years in children starting an NNRTI plus two
NRTIs, 2.1 per 100 person-years in children starting
an NNRTI plus three NRTIs, and 1.3 per 100 personyears in those starting a boosted PI and two NRTIs;
Penazzato cautioned that these results rest on sparse
data. Ever attaining a viral load below 400 copies/
mL lowered chances of switching 77% (AOR 0.23,
95% CI 0.15 to 0.37, P < 0.001), whereas a confirmed
viral rebound raised chances of switching almost 23
times (AOR 22.8, 95% CI 5.47 to 95.14, P < 0.001).
While 28% of children had one or more treatment
interruptions, 12% had a planned treatment
interruption. Among all children with a treatment
interruption, 38% had a viral load below 400 copies/
mL at the first interruption. Cumulative probability of a
regimen switch or planned treatment interruption was
36% at 5 years (Figure 4). Thus at the 5-year point
64% of children had taken their initially prescribed
regimen consistently.
This study is the first to find that an NNRTI plus three
NRTIs promote better virologic and immunologic
responses than standard three-drug regimens that
include an NNRTI or a boosted PI. Penazzato noted
that further evaluation of first-line cART options and
interruption strategies awaits final analyses of the
randomized CHER9 and ARROW20 trials.
Viral load at 6 weeks of age predicts
mortality up to 1 year
Zimbabwean infants with a viral load above the
group median at 6 weeks of age had a tripled risk of
death during the first 6 months of life, according to
results of a retrospective analysis involving children
in the years before access to antiretroviral therapy or
cotrimoxazole.21,22 Among infants alive at 6 months,
a high 6-week viral load doubled the risk of death
through 1 year of age.
Although viral loads are usually very high in infancy,
US research has linked viral load in infants and
children with disease progression and death.23-26
Because the value of viral load in predicting HIV
disease progression or death in African infants
remains unclear, researchers in Zimbabwe undertook
this study. Andrew Prendergast (ZVITAMBO Project,
Harare) and colleagues analyzed data from the
ZVITAMBO vitamin A trial, which took place in
29
Report
Table 1. Predictors of mortality by 6 and 12 months of age in Zimbabwe
Adjusted hazard
ratio
95% CI
P
Infant viral load above vs below median*
3.07
2.16 to 4.38
<0.001
Maternal CD4 count 200-350 vs >350
2.01
1.34 to 3.01
0.001
Maternal CD4 count <200 vs >350
1.70
1.11 to 2.62
0.015
Infant viral load above vs below median*
2.16
2.03 to 4.38
<0.001
Maternal CD4 count 200-350 vs >350
1.69
1.07 to 2.67
0.025
Maternal CD4 count <200 vs >350
1.94
1.19 to 3.16
0.008
Mortality through 6 months of age
Mortality through 12 months of age
*Median 1.59 million copies/mL.
Source: Andrew Prendergast, ZVITAMBO Project, Harare, Zimbabwe.21
Zimbabwe from 1997 through 2001.22
The analysis involved 453 HIV-positive infants with
a 6-week plasma sample available, including 151
infected in utero and 302 infected intrapartum. Those
two groups did not differ significantly in gender,
weight at birth or 6 weeks, hemoglobin at birth or 6
weeks, or rates of vaginal delivery (87.8% and 90.3%)
or mixed breastfeeding (58.9% and 56.3%). Mothers
of children infected in utero had a significantly higher
CD4 count (median 405 versus 355 cells/mm3, P =
0.004) but also a higher viral load (mean 4.52 versus
4.38 log10 copies/mL, P = 0.055).
Mortality through 6 months was marginally lower in
the intrapartum group than the intrauterine group (P
= 0.07) and in intrapartum girls versus intrauterine
girls (P = 0.07). Median viral load at 6 weeks stood at
1,589,041 copies/mL (IQR 514,809 to 4,965,854) and
did not differ significantly between the intrapartum
group and the intrauterine group or between boys
and girls. Multivariate analysis determined that a
6-week viral load above the median value tripled the
risk of death through 6 months of age and doubled
the risk of death through 12 months of age among
those alive at 6 months (Table 1). Lower maternal CD4
count also independently predicted infant mortality at
6 and 12 months.
The researchers concluded that viral load measured
at a single point—at 6 weeks of age—independently
predicts mortality in infants who have not begun
antiretroviral therapy. They proposed that “rapid
suppression of viremia may be important to reduce
mortality” in infants, a concept supported by results
of the CHER trial.9
30
Viral suppression rates similar with
continuous therapy and treatment
interruption
Two years after a planned treatment interruption (PTI)
trial in children ended, viral suppression rates were
high and similar in children randomized to the PTI
arm and to the continuous therapy arm.27 Nadir CD4
percent above 20% was associated with better CD4
recovery after cART resumed in the PTI arm.
The PENTA 11 trial randomized 109 children to
continuous cART or CD4-guided PTI if they had
(1) a viral load below 50 copies/mL and (2) a CD4
percent at or above 30% for 2- to 6-year-olds or a
CD4 percent at or above 25% and a CD4 count at or
above 500 cells/mm3 if they were 7 to 15 years old.28
After a median follow-up of 130 weeks, no child in
either group had a CDC stage C event, though the
PTI group endured more minor clinical events.
Alexandra Compagnucci (INSERM SC10, Paris)
presented long-term follow-up on 101 of the 109
PENTA 11 participants, 79 from Europe and 22 from
Thailand. Fifty children were in the PTI arm and 51
in the continuous-therapy arm. All 101 children
completed 1 year of follow-up, 95 completed 2
years, and median follow-up stood at 4.6 years. At
the end of PENTA 11, median ages were 11.3 in the
PTI group and 12.1 in the continuous group, median
CD4 percents 32% and 36%, and proportions with a
viral load below 50 copies/mL 60% and 76%.
Up to the end of the main trial, children in the PTI
arm spent 45.2% of the time off cART, compared
with 4.1% in the continuous-therapy arm. During
overall follow-up after the end of the main trial,
PTI participants spent 10.4% of the time off cART,
Table 2. CD4 and viral load outcomes 1 and 2 years after the end of the PENTA 11 treatment interruption trial
Mean or proportion
CD4 percent
CD4 count
HIV RNA <50
copies/mL
Follow-up
year
Continuous cART
PTI
Difference or
risk ratio: PTI vs
continuous
P
+1
35.8
32.7
-3.5
0.014
+2
36.0
34.6
-1.6
0.27
+1
925
808
-126
0.048
+2
864
832
-42
0.44
+1
90%
77%
0.85
0.074
+2
86%
82%
0.95
0.57
PTI: Planned treatment interruption.
Source: Alexandra Compagnucci, INSERM SC10, Paris.27
compared with 1.3% of time in the control arm. In an
analysis excluding follow-up of children on a PTI at
the end of the main trial before they restarted cART,
proportion of time spent off cART was 4.7% in the
PTI group and 1.3% in the continuous-cART group.
At the end of long-term follow-up, no child had died
and no new CDC stage C event developed. One child
had a new CDC stage B event, osteomyelitis, which
developed during the main trial in the PTI group.
Weight- and height-for-age Z scores did not differ
significantly between study arms after 1 and 2 years
of long-term follow-up.
Two children in each study arm switched antiretrovirals
for treatment failure or toxicity after the end of the
main trial. Five children in the PTI group and none in
the control group switched antiretrovirals for regimen
simplification.
One year after the main trial ended, CD4 percent and
CD4 count were significantly lower in the PTI group
than in the continuous-cART group (Table 2). But 2
years after the main trial ended, those differences
diminished and were no longer statistically significant.
One year after the main trial ended, the proportion of
children with a viral load below 50 copies/mL was
marginally lower in the PTI group (P = 0.074), but that
difference was negligible 2 years after the main trial
ended (Table 2, Figure 5).
In an adjusted analysis of CD4 recovery based on
measurements since children resumed cART after
their latest treatment interruption, estimated mean
difference in CD4 percent between those with a nadir
at or above 20% versus below 20% was 3.7% (95%
CI 0.7 to 6.7, P = 0.02). Mean total cholesterol in the
24 months after the end of the main trial did not differ
between the PTI group and the control group.
Proportion HIV-1 RNA <50 copies/ml from end of main trial
Proportion <50 c/ml (%)
100
80
60
CT
PTI
40
20
0
0
6
12
18
Months from end of main trial
24
Figure 5. Two years after the end of the PENTA 11 treatment interruption trial,28 proportions of children with a
viral load below 50 copies/mL were virtually identical in the planned treatment interruption (PTI) group and the
continuous-therapy (CT) group.
Source: Alexandra Compagnucci, INSERM SC10, Paris.27
31
Report
Table 3. Kaplan-Meier 1-year mortality risk according to CD4 percent, CD4 count, and age
Age of child
Under 24 months
24 to 35 months
36 months or older
CD4% <10
21.2%
4.4%
4.6%
CD4% 10 to 14.9
7.4%
2.2%
1.9%
CD4% 15 to 19.9
3.0%
1.3%
0.9%
CD4% >20
2.2%
1.3%
0.5%
CD4 count <100
35.1%
(No events)
8.6%
CD4 count 100 to 199
8.8%
(No events)
2.9%
10.2%
2.7%
1.6%
10.0%
2.3%
0.9%
8.5%
3.6%
0.4%
Source: Mary-Ann Davies, University of Cape Town, South Africa, for IeDEA-SA.29
Although antiretroviral treatment interruptions are
considered unsafe for adults, viability of this strategy
remains an important research topic in children,
who face decades of continuous treatment unless
interruptions prove feasible. PENTA investigators
are pursuing neurocognitive and immunologic
substudies in trial participants.
CD4 predictors of mortality as guides to
switching antiretrovirals
When viral load monitoring is not possible, a CD4
percent below 10% may serve as an antiretroviralswitch signal for children 24 to 35 months old,
according to results of a 17,000-child analysis in the
International Epidemiologic Databases to Evaluate
AIDS in Southern Africa (IeDEA-SA).29 A lower
threshold might be considered for older children,
IeDEA-SA researchers suggested.
Clinicians without access to routine viral load
monitoring must rely on clinical and CD4 changes
to decide when to switch an adult or child from one
regimen to another. But because immunologic failure
has a low positive predictive value for virologic failure,
reliance on CD4 changes may lead to unnecessary
switching in a person without virologic failure.
Mary-Ann Davies (University of Cape Town, South
Africa) and IeDEA-SA colleagues proposed that an
alternative approach for clinics without viral load
monitoring could be based on CD4 percent and
CD4 count thresholds below which mortality begins
32
to increase rapidly in distinct age groups.29 They
planned this study to determine 1-year mortality risk
according to age and current CD4 percent and count
of children taking cART in southern Africa.
The analysis focused on 17,173 children under 16
years old beginning a first-line regimen and having at
least 180 days of follow-up in IeDEA-SA collaborating
cohorts. The investigators considered every time at
which CD4 count or percent was measured after the
first 4.5 months (135 days) on cART as the start of an
observation with time set at 0 and continuing until the
first of (1) 365 days, or (2) date of death, or (3) date of
transfer out, or (4) date of last visit if the child was lost
to follow-up or remained in care at the time of data
transfer. Independent variables in Weibull models
to predict probability of death were age category
(under 24 months, 24 to 35 months, 36 months or
older), CD4 percent and its square at the start of the
observation, and CD4 count and its square at the
start of the observation.
As one would expect, 1-year risk of death was higher
at lower CD4 percents or counts and younger ages
(Table 3). Davies cautioned that these estimates are
based on small numbers of children with low CD4
percents or counts in the two younger age groups.
She added that censoring due to loss of follow-up
may have resulted in an underestimate of mortality
risk.
In children 24 to 35 months old, the Weibull model
determined that mortality risk reached 5% at a CD4
percent of 10%, and started to rise steeply as CD4
percent dropped further. In older children, mortality
risk reached 5% at a CD4 percent of 5% and rose
more steeply below this value. A CD4 percent of
10% is the 2010 WHO threshold for switching cART
in 24- to 59-month-old children.10 WHO guidelines
call for switching 24- to 59-month-old children at a
CD4 count of 200 cells/mm3, which in IeDEA-SA
children this age was associated with a mortality risk
of nearly 10%, rising steeply as CD4 count dropped
further. In children older than 35 months mortality
risk was 5% at a CD4 count of 100 cells/mm3 and
rose steeply as CD4 dropped below this. This is the
WHO guideline threshold for switching to second-line
cART in children 60 months old and older.
The IeDEA-SA investigators reached the following
conclusions for age-related risk of death based on
CD4 percent and count:
• The WHO guideline for switching to second-line
cART at a CD4 percent of 10% is associated with
a 5% risk of dying in the next year for all children
24 months old and older.
• For children 36 months old and older, the risk of
dying reaches 5% only at a CD4% of 5%.
• For children 24 to 35 months old, 1-year mortality risk rapidly approaches 10% at a CD4 count
of 200 cells/mm3 and rises steeply as the CD4
count falls further.
• For children 36 months old and older, a CD4
count of 100 cells/mm3 is associated with less
than a 5% risk of death in the next year.
These findings are relevant to the continuing
controversy over whether viral load monitoring should
be routine for children in resource-poor settings, a
question formally debated at the Pediatrics Workshop
(see next section).
Should viral load monitoring be routine in
resource-poor settings?
No clinician would dream of caring for HIV-positive
children in high-income countries without regular
viral load monitoring. US guidelines, for example,
say “HIV RNA copy number should be assessed as
soon as possible after a child has a positive virologic
test for HIV and every 3 to 4 months thereafter; more
frequent evaluation may be necessary for children
experiencing virologic, immunologic, or clinical
deterioration or to confirm an abnormal value.”12
But in countries where viral load monitoring remains
too high in cost and too hard to access, the question
of routine testing remains unresolved for children
and adults. WHO guidelines for infants and children
state that “viral load determination is desirable,
but not essential, prior to initiating ART” and that
“viral load should be assessed to confirm clinical
or immunological failure where possible, prior to
switching a treatment regimen.”10
Pediatrics Workshop attendees mulled the question
of routine HIV RNA monitoring during a debate by two
leading international pediatric investigators—Louise
Kuhn (Columbia University, New York) arguing that
monitoring should be routine for children in resourcelimited settings,30 and Diana Gibb (Medical Research
Council, UK) maintaining that it should not.31
Kuhn launched her case for routine viral load testing
by citing recent research indicating that annual
monitoring could cut the cART failure rate 75%
in Thai children,32 that routine testing using the
WHO failure threshold of 5000 copies/mL “adds
independent predictive value to immunological and
clinical assessments for identification of children
receiving HAART who are at risk for significant HIVrelated illness,”33 and that regular monitoring may
prevent emergence of NNRTI mutations in children
whose NNRTI regimen is failing.34
The argument favoring routine viral load monitoring,
Kuhn maintained, rests mainly on three pillars:
• Plasma HIV RNA is an excellent marker that directly tracks the underlying mechanism driving
HIV disease.
• Viremia is an early marker allowing for prompt action.
• Cost arguments favor routine monitoring over the
long term.
Viral load assays are accurate and reproducible,
Kuhn noted, and they strongly predict negative
clinical outcomes in children taking cART. In a
study of treated Brazilian children, a viral load above
versus below 5000 copies/mL independently raised
the risk of a WHO stage 3 or 4 event by more than
80% (adjusted hazard ratio [AHR] 1.81, 95% CI 1.05
to 3.11, P = 0.033).33 Every 0.5-log higher viral load
boosted that risk almost 15% (AHR 1.14, 95% CI 1.03
to 1.27, P = 0.016). When an antiretroviral regimen
fails, Kuhn added, rebounding viremia is an “early
warning signal,” spiking well before CD4 counts
wane or HIV-related symptoms emerge.
Although Gareth Tudor-Williams emphasized the
overall slow emergence of NRTI mutations upon
failure of an NNRTI regimen in PENPACT 1 (see
above),15,16 Kuhn cited additional data from this trial
indicating that three or more NRTI mutations arose
significantly more often in children randomized to
switch from an NNRTI regimen at 30,000 copies/
33
Report
Table 4. Accumulation of NRTI mutations with low versus high viral load switch in PENPACT 116
Switch from NNRTI regimen at:
1000 copies/mL
30,000 copies/mL
Number of children
68
64
1 to 2 major NRTI mutations
22%
20%
3 or more major NRTI mutations
—
11%
1 to 2 TAMs
5%
8%
3 or more TAMs
—
7%
P
0.001
0.08
TAMs, thymidine analog mutations.
mL rather than 1000 copies/mL (P = 0.001) (Table
4).16 There was also a trend toward more frequent
emergence of three or more thymidine analog
mutations in the 30,000-copy-switch group (P =
0.08).
Although the high initial cost of viral load testing
weighs against its use in resource-limited settings,
Kuhn argued that long-term costs favor routine
monitoring if it delays use of more expensive secondline regimens. The Thai study cited above estimated
a cost of $359 for preventing 1 year of virologic failure
through optimal viral load monitoring versus $3393
for preventing 1 year of virologic failure and including
antiretroviral costs.32 These investigators proposed
that optimal monitoring timing in similar settings may
be once in the first 6 months of cART then annually.
Kuhn maintained that routine viral load testing
may also have spinoff benefits, such as providing
opportunities for caregiver and child education
and for adherence counseling. The question is not
whether viral load monitoring should be routine, she
concluded, but (1) how frequently testing should be
done, (2) what viral load thresholds should be used,
(3) what response algorithms will work best, (4) how
monitoring systems can be improved, (5) how testing
can be made simpler and less expensive, and (6)
how more and better pediatric treatment options can
be developed.
Framing her rebuttal against routine viral load
monitoring in children seen in resource-constrained
settings, Diana Gibb posed three questions:31
1. What impact does viral load monitoring have on
important outcomes?
2. How affordable and feasible is viral load monitoring in low-income settings?
3. What are the competing priorities?
34
The usual answer to the first question, Gibb
observed, is to guide decisions on when to start
cART and when to switch cART. But a 2003 metaanalysis of 4000 children not receiving cART or
zidovudine monotherapy determined that, although
CD4 measures and viral load both independently
predicted mortality in the short term, CD4
readings were much stronger predictors of disease
progression and death.35
Although viral load is also an independent predictor
of disease progression before and during cART in
adults, Gibb observed, CD4 measures are a much
better predictor of immediate risk of death, and
several studies found that viral load adds little further
prognostic information to CD4 count:
The DART trial in Uganda and Zimbabwe enrolled
3321 symptomatic, antiretroviral-naive adults with
CD4 counts below 200 cells/mm3 and randomized
them to laboratory and clinical monitoring or to
clinically driven monitoring alone.36 Gibb, one of the
DART investigators, noted that CD4 monitoring every
12 weeks had no impact on disease progression
during the first 2 years of cART, and after that it had
only a small impact on progression that appeared
to be driven by a later switch to clinical monitoring.
Although DART did not assess viral load monitoring,
she explained, after 6 years of cART about 80% of
DART patients had a viral load below 50 copies/mL
and about 75% were still taking their first regimen.
The unpublished HBAC trial randomized 1200
Ugandan adults to (1) clinical monitoring, (2) clinical
plus CD4 monitoring, or (3) clinical plus CD4 plus
virologic monitoring. When compared with clinical
monitoring alone, CD4 and viral load monitoring had
a marginally significant benefit in preventing AIDS
or death. But there was no significant difference
between the CD4-and-viral load monitoring group
and the CD4-and-clinical monitoring group.
The PHPT-3 trial randomized 716 Thai adults to a
conventional viral load-driven cART switch strategy
or to a CD4-driven switch.37 Through 60 months of
cART, time to clinical failure (CD4 count below 50
cells/mm3, new AIDS event, or death) was almost
identical in the two study arms, and 38% of events
occurred within the first 6 months of treatment.
In the recently completed PENPACT 1, Gibb reminded
attendees, viral suppression rates in children taking
cART for 4 or more years did not differ between
those who switched when the viral load increased to
1000-copies/mL versus those who waited until the
viral load rose to 30,000-copies/mL (around a year
later on average), regardless of whether they were
taking a PI or an NNRTI.16
Although several groups have described adult African
data showing that those switching treatment based
on clinical symptoms may have an undetectable
viral load (and are thus deemed to have switched
“unnecessarily”), a recent analysis of data from the
DART study showed this was rare if the CD4 was
below 250 cells/mm3.38 Therefore, Gibb argued,
use of a 250-CD4 threshold could prevent many
“unnecessary” switches to second-line treatment.
(Gibb did not mention the 17,000-child IeDEA-SA
cohort study summarized in the preceding section
of this article, which found that a CD4 percent below
10% may be a useful antiretroviral-switch signal for
children 24 to 35 months old.29)
To address the question of cost, Gibb cited four
model-based cost-effectiveness studies of viral
load monitoring, which calculated costs per lifeyear gained ranging from $2526 to $15,25039-42— all
estimates above the 3-fold gross domestic product
cutoff used to determine cost-effectiveness of
interventions in resource-limited countries.43,44
Gibb concluded that “routine viral load monitoring is
not necessary and should not be routine for children
in resource-limited settings” because: (1) its impact
on disease-free survival is very modest, (2) it is not
cost-effective, and (3) “its routine use will be a barrier
to the goal of maximising ART coverage and actually
lead to lives lost.”
Evidence from two studies on second-line
switching
Although HIV Pediatric Workshop attendees weighed
data from four studies on first-line cART options
for children in countries rich and poor,13-19 for a
growing number of children everywhere the question
has become which second-line regimen to chose—if
there is a choice. Two workshop studies addressed
second-line questions: A six-country African study
assessed durability of first-line regimens and reasons
for switching,45 while an Asian study analyzed
efficacy of ritonavir-boosted PI regimens after failure
of a nonnucleoside combination.46
IeDEA-West African investigators reported that only
small proportions of children who met clinical or
immunologic failure criteria in this region switched to
a second-line regimen. These researchers collected
data from nine clinical centers in six countries—
Benin, Burkina Faso, Côte d’Ivoire, Ghana, Mali,
and Senegal.45 They included children under 16
years old starting three or more antiretrovirals from
2000 through 2009 and with at least one available
measurement of CD4 count, CD4 percent, or WHO
clinical stage during the first-line regimen. Routine
viral load monitoring is not available throughout most
of West Africa.
The researchers defined clinical failure as appearance
or reappearance of a WHO clinical stage 3 or 4
event after at least 24 weeks of cART in a treatmentadherent child. They defined immunologic failure as
reaching or returning to a CD4 percent below 10%
for 2- to 5-year-old adherent children or reaching or
returning to a CD4 count below 100 cells/mm3 for
adherent children 5 or over after the first 24 weeks
of therapy. A regimen switch meant (1) changing
from three NRTIs to two NRTIs plus a one PI or one
NNRTI, or (2) changing from two NRTIs plus one PI to
three NRTIs or to two NRTIs plus one NNRTI, or (3)
changing from the PI class or the NNRTI class.
In 2797 children the overall 24-month probability of
switching to a second-line regimen was 23.3% (95%
CI 21.5 to 25.4). In the 2450 children (88%) without
study-defined clinical or immunologic failure, the
24-month probability of switching was 25.3% (95%
CI 23.2 to 27.7). The 227 children (8%) with clinical
failure had a 24-month switching probability of only
2.1% (95% CI 0.8 to 5.5). And the 120 children with
immunologic failure (4%) had a 24-month switching
probability of 26.4% (95% CI 18.8 to 36.4).
Median time to switch in all 456 children (16%) who
changed to a second-line regimen was 7 months
(IQR 3 to 16). A large majority of these children—425
or 93.2%—switched without meeting clinical or
immunologic failure criteria. Withdrawal of nelfinavir in
2007 accounted for most of this nonfailure switching.
Among switchers, 285 children (62.5%) switched
from a first-line nelfinavir regimen.
The low switch rates in children who did meet clinical
or immunologic failure criteria, the investigators
35
Report
suggested, indicates “missed opportunities for
switching to second-line therapy,” perhaps because
key second-line agents such as lopinavir/ritonavir
were not available. The IeDEA-West Africa team
stressed the importance of advocating for access to
monitoring tools and to second-line antiretrovirals for
pediatric HIV programs.
Researchers from the TREAT Asia Pediatric HIV
Observational Database (TApHOD) retrospectively
studied 153 children who switched from a first-line
NNRTI-based regimen (taken for at least 24 weeks)
to a PI-based regimen (taken for at least 24 weeks)
up to 20 March 2010.46 All children were younger
than 18 years old at the switch and had not taken a
PI before the switch.
The study group included 80 girls (52%) and 73 boys
with a median age of 10 years (IQR 7 to 12), a median
CD4 percent of 12.5% (IQR 5.2 to 20.0), a median
CD4 count of 237 cells/mm3 (IQR 90 to 466), and
a median viral load of 4.6 log10 copies/mL (IQR 3.9
to 5.0). Proportions of children with WHO stage 1,
2, 3, and 4 disease were 7%, 25%, 42%, and 26%.
Median first-line duration was 2.6 years (IQR 1.5 to
3.8). Most children (83%) switched to a lopinavir/
ritonavir regimen, while 16% switched to an indinavir/
ritonavir regimen and 1% to atazanavir/ritonavir.
Median weight-for-age Z score did not change
significantly from the switch point (week 0) (-1.9) to
week 48 (-1.9) or week 96 (-1.7). In contrast, median
CD4 percent rose from 13.8% at week 0 to 20.3%
at week 48 and 22.8% at week 96 (P < 0.001).
Proportions of children with viral loads below 400
and 50 copies/mL were 0% and 0% at week 0, 60%
and 49% at week 48, and 65% and 62% at week
96 (P < 0.001 for both comparisons). Median total
cholesterol rose significantly from 167 mg/dL at
week 0 to 187 mg/dL at week 96 (P = 0.002), while
median triglycerides climbed from 120 mg/dL at
week 0 to 160 mg/dL at week 96 (P = 0.006). Median
high-density lipoprotein cholesterol did not change
significantly over the study period.
Multivariate analysis identified four independent
predictors of virologic suppression below 400
copies/mL at 48 weeks:
• Longer duration of first-line NNRTI regimen: OR
1.8 per additional year (95% CI 1.2 to 2.9), P =
0.006
• Younger age: OR 0.8 per additional year (95% CI
0.7 to 0.9), P = 0.007
• Higher weight-for-age Z score: OR 1.7 per
standard deviation (95% CI 1.1 to 2.7)), P = 0.020
• HIV RNA below 10,000 copies/mL at switch: OR
12.6 (95% CI 1.9 to 81.8), P = 0.049
36
Two variables independently predicted immune
recovery, defined as a CD4 percent at or above 25%
in children younger than 5 years or a CD4 count at or
above 500 cells/mm3 in older children:
• Younger age: OR 0.8 per additional year (95%CI
0.7 to 0.9), P < 0.001
• CD4 count at or above 200 cells/mm3 at the
switch: OR 7.7 (95% CI 2.8 to 21.5), P = 0.003
The TApHOD researchers concluded that one third
of children in this Asian cohort do not reach an
undetectable viral load 2 years after switching from
an NNRTI regimen to second-line lopinavir/ritonavirbased cART that includes recycled NRTIs. They
observed that hyperlipidemia was common after
such a switch.
PMTCT: Emerging Issues, Persisting
Controversies
South African PMTCT program cuts early
transmission rate below 4%
Nine years after South Africa launched a program for
prevention of mother-to-child transmission (PMTCT)
of HIV, the transmission rate fell below 4% in the first
4 to 8 weeks of life, according to preliminary results of
a nationwide population-based analysis.47
South Africa began its PMTCT program in 2002 with
single-dose nevirapine and later added zidovudine or
combination antiretrovirals for mothers (depending
on maternal CD4 count) and extended zidovudine or
nevirapine for infants. Estimated national mother-tochild transmission rates in infants up to 2 months old
stood at 8.2% in 2008 and 5.8% in 2009.
Ameena Goga (Medical Research Council, South
Africa) presented results of the new study, which
involved caregiver-infant pairs making the 6-week
infant immunization visit from June through
December 2010. The investigators (Goga, Thu-Ha
Dinh and Debra Jackson) identified HIV-exposed
infants through caregiver report of maternal HIV
positivity or through ELISA analysis of dried blood
spots. They tested samples of HIV-exposed infants
with qualitative HIV DNA PCR to identify infected
infants.
The researchers determined that 3003 infants in 9915
caregiver-infant pairs (30.3%) had been exposed to
HIV, and 2958 of these 3003 infants (98.5%) had PCR
test results. Most mothers of HIV-exposed children
(79.8%) were not married or cohabitating. In the 8
days before the study visit, 20% of women practiced
exclusive breastfeeding, 18% mixed breastfeeding,
and 62% no breastfeeding. Almost two thirds of
Table 5. Factors associated with mother-to-child transmission at 6 weeks in South Africa
Adjusted odds ratio
95% CI
Either maternal ARV or infant ARV prophylaxis
5.2
2.7 to 10.0
<10 weeks of maternal zidovudine plus infant ARV
prophylaxis
2.4
1.2 to 5.1
11 to 30 weeks of maternal zidovudine plus infant ARV
prophylaxis
1.7
0.9 to 3.5
1.6
1.0 to 2.5
Compared with maternal cART
Compared with exclusive breastfeeding or no breast milk
Mixed breastfeeding
ARV, antiretroviral; cART, combination antiretroviral therapy.
Source: Ameena Goga, Medical Research Council, South Africa.47
mothers of HIV-exposed children (62%) said the
pregnancy was unplanned.
Infant HIV prevalence at 4 to 8 weeks (weighted for
sample realization and population live births in 2009)
ranged from 0.6% (95% CI 0.3 to 0.9) in Gauteng
province to 2.1% (95% CI 1.5 to 2.7) in Mpumalanga
province. National infant HIV prevalence stood at
1.1% (95% CI 0.1 to 1.3). Weighted MTCT rate at 4
to 8 weeks ranged from 1.7% (95% CI 0.1 to 4.2) in
Northern Cape province to 6% (95% CI 3.8-8.2) in
Free State province. The national weighted MTCT
rate was 3.5% (95% CI 2.9 to 4.1).
Compared with maternal cART, use of either maternal
or infant antiretroviral prophylaxis raised the risk of
MTCT more than 5 times, and 10 or fewer weeks
of maternal zidovudine plus infant antiretroviral
prophylaxis more than doubled the risk (Table 5).
Compared with maternal cART, there was a borderline
association between 11 to 30 weeks of maternal
zidovudine plus infant antiretrovirals and higher
MTCT risk. Compared with exclusive breastfeeding
or no breastfeeding, mixed breastfeeding increased
the MTCT risk 60%. Variables that did not affect
transmission risk in this analysis were caesarean
section, planned versus unplanned pregnancy, or
physician versus nonphysician birth attendant.
Goga and colleagues cautioned that their analysis
is limited by its reliance on primary or community
health centers, by exclusion of sick infants needing
emergency care and infants older than 8 weeks, by a
sample realization below 75% in three provinces, and
by potential recall bias.
Given those limitations, the investigators concluded
that the national South African MTCT rate 4 to
8 weeks after delivery stands at approximately
3.5%. They suggested that rate may be lowered by
optimizing antiretroviral use during pregnancy and
perinatally and by reducing mixed feeding.
High HIV incidence during pregnancy and
breastfeeding in Botswana
Batswana women who have a negative HIV test during
pregnancy remain at high risk for HIV infection later
in pregnancy and during breastfeeding, according to
results of a 417-woman study.48 Centers for Disease
Control and Prevention (CDC) investigators warned
that undiagnosed incident HIV infection in pregnant
or nursing mothers could result in unanticipated
transmission of the virus to infants.
HIV testing early in pregnancy is “a critical first
step” to reducing HIV transmission, Lydia Lu and
CDC colleagues noted. But an early negative test
is no guarantee that women will remain free of HIV
throughout pregnancy and nursing. In Botswana
more than 95% of pregnant women get tested for HIV
at a median 22 weeks gestation, and HIV prevalence
stood at 32.5% among 43,000 women tested at
antenatal clinics in 2009. Early infant testing indicates
that 4.2% of HIV-exposed infants in Botswana test
positive on their first test.
In 2008 CDC-Botswana investigators retested
400 women in a postlabor ward after they had
tested negative during pregnancy. HIV incidence
in these women was 1.3%. As a result the CDC
recommended routine HIV retesting during the third
trimester or in the maternity ward for women missed
in the third trimester. These researchers planned a
37
Report
follow-up study for 2010 to determine HIV prevalence
in women during the first postpartum year after they
tested negative during pregnancy.
The 2010 study involved 417 women with a
documented negative HIV test during pregnancy who
brought a 9- to 15-month-old child to an immunization
clinic. Women were tested and counseled according
to the standard Botswana algorithm, and they
were interviewed about risk behaviors and feeding
practices.
Eighteen of these 417 women (4.3%) had a positive
HIV test, and the investigators estimated 52-week
incidence at 3.8%. Because 43,000 women become
pregnant in Botswana every year and 32.5% tested
positive in antenatal clinics in 2009, the CDC team
figured that the remaining 67.5%, or 29,025 women,
are assumed to be HIV negative (Figure 6). Based on
the 2008 incidence study findings, the researchers
estimated that 377 of these 29,025 women (1.3%)
become infected during late pregnancy. The 2010
study estimated 1103 (3.8%) become infected during
breastfeeding.
Next the CDC team estimated the impact of maternal
HIV incidence on new infections in infants during
2010. To do so the investigators relied on a 2005
study of Zimbabwean women who became infected
with HIV during pregnancy or while breastfeeding.49
That study found that 73% of infants exposed to
an incident HIV infection in late pregnancy became
infected, and 36% of infants exposed to an incident
HIV infection during breastfeeding became infected.
If 73% of the 377 women infected during pregnancy
in the Botswana study transmitted HIV, 275 infants
would be infected. If 36% of the 1103 women
infected during breastfeeding in the Botswana study
transmitted HIV, 397 infants would be infected.
Early infant testing indicates that the transmission
rate to HIV-exposed infants in Botswana (where
PMTCT is mature and has high uptake) is only 4.2%,
or about 587 infants annually. Thus the estimated
total number of infected infants is 1259, with 672 of
those 1259 (275 + 397, or 53.4%) infected through
an undiagnosed maternal HIV infection acquired later
in pregnancy or while nursing, and in the absence of
PMTCT interventions.
The 18 HIV-exposed infants of mothers with a new
HIV diagnosis in this study had a median age of 10
months when the infants were tested for HIV. All 18
infants had some exposure to breast milk, and 5 were
still breastfeeding at recruitment for the study. Three
of 18 infants (17%) had a positive HIV test; because
the 5 HIV-exposed infants who were breastfeeding
at the time of recruitment did not return for testing,
their final HIV status was not determined. In the entire
study cohort, 259 infants (62%) were breastfeeding
at the time of recruitment. Overall median age at
weaning was 7 months.
Estimated infections in pregnant and post-partum
women, Botswana 2010
43000
pregnant women
Women diagnosed
before during ANC
13975 (32.5%)*
* 2009 ANC
Sentinel
Surveillance
Women assumed
to be HIV-negative
29025 (67.5%)
Women infected
during late pregnancy
377 (1.3%)
Women infected
while breastfeeding
1103 (3.8%)
Figure 6. Based on 2008 and 2010 studies of 417 Batswana women who tested negative for HIV during
pregnancy and were retested at the time of delivery (2008) or in the year after delivery (2010), CDC researchers
estimated that 1.3% of pregnant women became infected with HIV during late pregnancy and 3.8% became
infected while breastfeeding in 2010.
Source: Lydia Lu, Centers for Disease Control and Prevention.48
38
Intrapartum perinatal transmission rate
Predicted IP transmission rate:
With vs. Without sdNVP
0.05
standard treatment
standard treatment + sdNVP
0.04
0.03
0.02
0.01
0
3 to 4 –fold reduction
0
10
20
30
40
50
60
Duration of maternal ZDV treatment (days)
Figure 7. Bayesian modeling determined that adding single-dose nevirapine (sdNVP) to maternal lopinavir/
ritonavir-based cART would lower intrapartum HIV transmission risk 3- to 4-fold.
Source: Marc Lallemant, Chiang Mai University, Chang Mai, Thailand.50
Lu and coworkers concluded that Batswana women
assumed to be HIV-negative during pregnancy and
the first year after delivery will breastfeed, although
some of them may have acquired HIV infection after
their initial negative test. The investigators proposed
that infants may remain at significant risk for HIV
infection in Botswana even when mothers have a
negative HIV test during pregnancy.
Modeling suggests advantage in adding
sdNVP to maternal cART
A Bayesian inference model determined that adding
single-dose nevirapine (sdNVP) to lopinavir/ritonavirbased cART for pregnant women with fewer than
8 weeks of antiretroviral prophylaxis would lower
the risk of perinatal HIV transmission 3- to 4-fold.50
Marc Lallemant (Chiang Mai University, Chang Mai,
Thailand) and colleagues based the model on data
from three PMTCT trials in Thailand.
PHPT-5, a 2008-2010 randomized trial of three
PMTCT strategies (clinicaltrials.gov NCT00409591),51
stopped prematurely when Thailand revised its
PMTCT guidelines to recommend lopinavir-based
cART for all HIV-positive pregnant women as soon as
possible after the first trimester. When trial data were
analyzed, the overall transmission rate was 2.2%, with
no difference between treatment arms. Multivariate
analysis determined that shorter zidovudine
prophylaxis duration almost doubled the risk of HIV
transmission (AOR 1.8 per weekly decrement, 95%
CI 1.3 to 2.4), while each log10 higher viral load more
than doubled the transmission risk (AOR 2.3, 95% CI
1.1 to 4.8).
In planning the Bayesian analysis, Lallemant and
coworkers hypothesized that pregnant women
with fewer than 8 weeks of prophylaxis did not
have enough time to suppress viral replication and
that adding maternal and infant sdNVP to maternal
lopinavir-based cART would significantly reduce the
risk of intrapartum transmission. Using transmission
data from 3876 women enrolled in PHPT-1, 2, and
5, the model assumed (1) that maternal prophylaxis
duration directly affects viral load at delivery, and
(2) that viral load at delivery directly affects risk of
intrapartum transmission. Monte Carlo simulations
predicted transmission rates with and without
sdNVP in relation to duration of maternal and infant
prophylaxis.
The model estimated an HIV transmission rate of
2.6% (95% probability interval [PI] 0.5% to 9.2%) for
the standard of care (lopinavir/ritonavir-based cART
during pregnancy and zidovudine for the newborn).
Adding sdNVP to the standard of care lowered the
estimate to 0.8% (95% PI 0.1% to 2.9%). Maternal
sdNVP would decrease the risk of intrapartum
transmission approximately 60% (AOR 0.39, 95% CI
0.21 to 0.67). Lallemant and colleagues calculated a
3- to 4-fold lower intrapartum transmission risk with
addition of sdNVP (Figure 7).
39
Report
Higher CD4 count during pregnancy (average +
1 standard deviation [SD] versus average) would
lower intrapartum transmission risk more than 35%
(AOR 0.63, 95% CI 0.49 to 0.80). Gestational age
at delivery (average +/- 1 SD versus average) would
increase transmission risk (AOR 1.34, 95% CI 1.07
to 1.64).
Trial simulation determined that an ethical and
scientifically sound single-arm trial with comparison
to historical data and with optimal stopping rules
could be designed with fewer than 400 women to
test the hypothesis that adding maternal and infant
sdNVP to the standard of care lowers the risk of HIV
transmission.
Impact of formula feeding on HIV-exposed
infants in Brazil and South Africa
HIV-exposed but uninfected formula-fed South
African infants had a higher risk of death if born to
mothers with a high viral load or if they had a low birth
weight, according to results of a 1000-infant study
in South Africa and Brazil.52 Karin Nielsen-Saines
(University of California, Los Angeles ) and HPTN
040 colleagues reported that high maternal viral load
and lower maternal education were associated with
infectious significant adverse events in the overall
study group.
The analysis involved formula-fed infants enrolled
in NICHD HPTN 040, a phase 3 trial conducted
between April 2004 and January 2011 at 17 sites
in Brazil, South Africa, Argentina, and the United
States.53 This randomized open-label trial compared
the safety and efficacy of three infant antiretroviral
regimens to prevent vertical HIV transmission. Overall
HIV transmission and intrapartum transmission
were lower in the two- and three-drug arms (singledose zidovudine for 6 weeks plus three doses of
nevirapine, and single-dose zidovudine for 6 weeks
plus nelfinavir and lamivudine for the first 2 weeks)
than in the one-drug arm (single-dose zidovudine for
6 weeks).
Primary aims of the new analysis were to assess the
frequency of and risk factors for severe morbidity
and mortality in a representative subcohort of 1000
HIV-exposed but uninfected formula-fed infants from
Brazilian and South African HPTN 040 sites.52 The
study included live HIV-exposed infants who were
HIV-negative at their 3-month visit and completed 6
months of follow-up. The study pool included HIVexposed infants who died before the 6-month visit
and were not determined to be HIV-positive until the
time of death. The analysis excluded HIV-positive
infants, infants with fewer than 6 months of follow-up,
40
and infants with any evidence of breastfeeding.
Most mothers of the 1000 selected infants were of
black (48.6%) or mixed black/white race (28.6%),
were relatively young (median age 26), had relatively
high CD4 counts (median 466 cells/mm3), and had
detectable virus at delivery (median viral load 13,580
copies/mL). The study group included 766 infants
from Brazil and 234 from South Africa. Their median
birth weight was 3012.5 g (6.6 pounds).
The overall rate of infectious serious (grade 3 to
5) adverse events was 60 per 100 infant-years,
and rates were similar in Brazil (61 per 100 infantyears) and South Africa (59 per 100 infant-years).
Gastrointestinal serious adverse events were more
frequent in South Africa (24.2 versus 4.7 per 100
infant-years), while congenital serious adverse events
(usually congenital syphilis) were more frequent in
Brazil (21.8 versus 3.6 per 100 infant years). Almost
one quarter of infants (23%) had at least one infectious
serious adverse event.
Mean weight-for-age Z score (WAZ) at birth was
lower in South Africa than Brazil (-0.95 versus -0.49),
while mean height-for-age Z score (HAZ) at birth was
similar in South Africa (-0.40) and Brazil (-0.54) (Figure
8). Defining malnutrition as a WAZ at or below -2, the
investigators determined that 11% of South African
infants and 6% of Brazilian infants had malnutrition
at 6 months. WAZ and HAZ declined in both the
South African and Brazilian cohorts from birth to the
month-1 visit, then rebounded to near-normal values
through month 6 (Figure 8).
At 6 months 15 of 234 South African infants (6.4%)
had died, compared with 7 of 766 Brazilian infants
(0.9%). Six-month mortality incidence was 64.1 per
1000 infant-years in South Africa and 9.1 per 1000
infant-years in Brazil. In comparison, 12-month
overall infant mortality incidence stood at 56 per
1000 infant-years in South Africa and 19 per 1000
infant-years in Brazil according to 2006 WHO data.
Multivariate analysis identified four factors that
independently affected the risk of infant mortality
and three that independently affected the risk of
infectious serious adverse events in infants:
Risk of infant mortality:
• South African versus Brazilian birth: AOR 6.22,
95% CI 2.46 to 15.75, P < 0.0001
• Higher maternal viral load at delivery: AOR 1.71,
95% CI 1.01 to 2.91, P = 0.0476
• WAZ at birth < -2 to > -3: AOR 5.16, 95% CI 1.80
to 14.77, P = 0.0022
• WAZ at birth < -3: AOR 6.18, 95% CI 1.80 to
21.31, P = 0.0039
Weight-for-Age and Heigt-for-Age Z-scores
by study visit n=1000 Infants
- 0.05
-0.09
Brazil WAZ
- 0.15
- 0.25
Mean Z- score
- 0.35
- 0.45
- 0.55
-0.34 Brazil HAZ
- 0.40
- 0.49
- 0.54
-0.53 South Africa WAZ
-0.56
- 0.65
-0.67
- 0.75
-0.86
-0.79
- 0.85
- 0.95
-0.95
- 1.05
-0.67 South Africa HAZ
-0.85
-0.95
-1.06
-1.13
- 1.15
- 1.25
Birth
Month 1
Month 3
Month 6
Study Visit
Figure 8. Figure 8. Mean weight-for-age Z score (WAZ) was lower at birth in HIV-exposed but uninfected
South African neonates than in Brazilian neonates in a 1000-infant analysis of HPTN 040. Mean height-for-age
Z score (HAZ) was similar in the two groups at birth. Both scores declined in both cohorts through 1 month of
age, then rebounded. South African WAZ remained substantially lower than Brazilian WAZ at 6 months (-0.53
versus -0.09).
Source: Karin Nielsen-Saines, University of California, Los Angeles.52
Risk of infant infectious serious adverse event:
• Maternal education of 8 years (versus more): AOR
3.47, 95% CI 1.49 to 8.09, P = 0.0040
• Maternal education < 8 years (versus more): AOR
3.65, 95% CI 1.71 to 7.80, P = 0.0009
• Maternal viral load at delivery > 1,000,000 copies/
mL: AOR 9.92, 95% CI 1.56 to 63.08, P = 0.0151
Nielsen-Saines and coworkers concluded that
mortality of HIV-exposed but uninfected formula-fed
infants was lower than the general-population rate in
Brazil but slightly higher than the general-population
rate in South Africa. South African mortality rates for
this group were similar to those of HIV-exposed but
uninfected infants in Zimbabwe.54
Text messaging improves infant follow-up
in Johannesburg
Mobile (cell) phone text messaging to HIV-positive
mothers attending a Johannesburg clinic significantly
improved infant HIV testing follow-up, according to
preliminary results of a randomized study.55 The
finding held true for women diagnosed with HIV only
at delivery and whose infants thus had a higher risk
of HIV infection and mortality.
Rahima Moosa Mother and Child Hospital in
Johannesburg, South Africa performs approximately
10,000 deliveries annually, about 25% to 30%
of them in HIV-positive women. Because testing
women for HIV at delivery can be difficult, the
Hospital has offered routine postpartum testing
since 2008. But follow-up rates are poor, especially
in newly diagnosed women, and loss to follow-up at
this time breaks the cascade of care, prevention, and
monitoring.
In an attempt to improve retention in care, KarlGünter Technau (University of the Witwatersrand,
Johannesburg) and colleagues planned this study
of mobile text messaging to postpartum HIV-positive
women. The study called for 10 weeks of texted
encouragement and reminders for infant PMTCT
medication and appointments. There were three
study groups: women who agreed to text messaging
randomized 1:1 to receive messages (group A1, n =
160) or not to receive messages (group A2, n = 177),
and a third group of women who declined texting
(group B, n = 81)
Proportions of women whose infants kept an HIV
DNA PCR test visit were 90.5% in group A1, 78.2%
in group A2, and 63.0% in group B (group A1 versus
group B, P = 0.003; group A2 versus group B, P =
0.04). When the investigators considered only the
51 women diagnosed with HIV at delivery, PCR test
follow-up rates were 86.7% for group A1, 41.7% for
group A2, and 40.9% for group B.
For the whole study group, return rates to collect
PCR results were 67.3% in group A1, 61.9% in group
41
Report
Table 6. Impact of cART on vertical HIV transmission at 6 months in Africa
Trial: countries
Antiretroviral regimen
CD4 count
Transmission rate
Mma Bana: Botswana57
Abacavir, zidovudine/lamivudine or
>200 cells/mm3
2.1%
Lopinavir/ritonavir, zidovudine/
lamivudine
>200 cells/mm3
0.4%
Kesho Bora: Burkina
Faso, Kenya, South
Africa58
Lopinavir/ritonavir, zidovudine/
lamivudine
200 to 500 cells/
mm3
4.9%
KiBS: Kenya63
Zidovudine/lamivudine plus
nevirapine or nelfinavir
350 to 500 cells/
mm3
3.8%
>500 cells/mm3
3.3%
Source: François Dabis, Université Bordeaux Segalen, France.61
A2, and 23.5% in group B. For newly diagnosed
women, return rates with 67.7% for group A1, 33.3%
for group A2, and 4.5% for group B (P = 0.04 for
group A1 versus group A2).
At the time of the Pediatrics Workshop presentation,
PCR results were available for 309 infants, 18 of
whom (6%) were HIV-positive. Among 26 women
with HIV diagnosed at delivery, 4 (15%) had infants
with a positive PCR test. Among 349 infants with vital
status data, 8 (2.3%) died before 6 weeks of age.
Among 32 women diagnosed with HIV at delivery, 2
(6.3%) had infants who died before 6 weeks.
Technau and colleagues concluded that cell text
messaging improves follow-up for infant HIV DNA
PCR testing and offers additional support for women
newly diagnosed with HIV at delivery. (“Sitting alone
in the room,” one woman told a staff member, “I felt
like I had a friend” when the text message came.)
The investigators noted that texting is an inexpensive
intervention, costing about $1.20 per woman for 10
weeks of messaging. They cautioned that this is not
a “blanket intervention” but requires careful individual
counseling to achieve good results. The researchers
also noted that women may change cell phones or
lose access to them, so a central log-in facility may
be needed for optimal results.
42
recommended cART (from 14 weeks’ gestation to 1
week after breastfeeding stops) as PMTCT option B
for women judged not to need cART for their own
health.59 The alternative PMTCT regimen proposed
by WHO, the so-called option A, is antepartum
maternal zidovudine, single-dose nevirapine at labor,
and in certain cases zidovudine plus lamivudine
during labor and delivery and postpartum, plus
infant antiretroviral prophylaxis, which varies
depending on feeding status. In the United States,
where breastfeeding by HIV-positive mothers is not
recommended, Department of Health and Human
Services guidelines call for at least three antiretrovirals
for pregnant women who do not require treatment for
their own health, regardless of HIV RNA in plasma.60
Pediatrics Workshop organizers invited two PMTCT
experts to debate the proposition that all HIV-positive
pregnant women would take cART, with François
Dabis (Université Bordeaux Segalen, France) making
the case in favor of triple therapy61 and Jeffrey Stringer
(University of Alabama at Birmingham, United States,
and CIDRZ, Zambia) taking the opposite stance.62
Dabis advanced three arguments for cART as
PMTCT:
Should all HIV-positive pregnant women
receive cART?
1. Maternal universal cART prevents almost all pediatric HIV infections.
2. Maternal universal cART saves children’s lives.
3. Maternal universal cART saves mothers’ lives.
Cohort studies47,56 and two randomized trials57,58
found advantages for mothers and neonates
when the mother began combination antiretroviral
therapy (cART) to prevent vertical HIV transmission
(reference47 is reviewed above). Since 2010 WHO has
To support his first point, Dabis cited three studies,
starting with the Mma Bana trial in Botswana, which
found 6-month transmission rates of 0.4% with
lopinavir/ritonavir plus zidovudine/lamivudine and
2.1% with abacavir plus zidovudine/lamivudine taken
by breastfeeding mothers (Table 6).57 The Kesho
Bora trial in Burkina Faso, Kenya, and South Africa
recorded a 4.9% transmission rate at 6 months
in infants of women taking lopinavir/ritonavir plus
zidovudine/lamivudine.58 The single-arm KiBS study
in Kenya recorded 6-month transmission rates of
3.3% among women with a CD4 count above 500
cells/mm3 and 3.8% for those with counts between
350 and 500 cells/mm3 while taking zidovudine/
lamivudine plus nevirapine or nelfinavir.63
The infant life-saving potential of cART became clear
even earlier, Dabis maintained, in a 2004 pooled
analysis of infants born to HIV-positive African
mothers in the absence of any maternal antiretroviral
therapy.5 This 3468 mother-child pair study found
that 35.2% of the 693 HIV-infected children born to
these mothers died before 1 year of age and 52.7%
died by age 2. Maternal death was the strongest
predictor of overall infant death (combining HIVinfected and uninfected children), more than doubling
the risk for a child whose mother died compared with
those whose mothers survived (AOR 2.27, 95% CI
1.62 to 3.19). Maternal CD4 cell count below 200
cells/mm3 almost doubled the risk of overall infant
death compared with infants of mothers with no
immunodeficiency (AOR 1.91, 95% CI 1.39 to 2.62).
Among the 693 HIV-infected children born to these
HIV-positive mothers, maternal death also almost
doubled the risk of infant death (AOR 1.84, 95%
CI 1.21 to 2.82), as did maternal CD4 count below
200 cells/mm3 (AOR 1.86, 95% CI 1.27 to 2.75). In
other words, maternal cART, if available, would have
dramatically changed the mortality pattern of all
children born to HIV-positive mothers.
To make the point that cART promotes survival of
HIV-positive mothers, Dabis cited results of a study
showing that HIV-positive mothers in Zimbabwe had
a 54 times higher risk of death than HIV-negative
women in the 24 months after delivery if their CD4
count lay below 200 cells/mm3.64 In contrast,
compared with the HIV-negative group, HIV-positive
women with 400 to 600 cells/mm3 had a 5.4 times
higher risk of death in the 24 months after delivery,
much lower than the risk in women with a CD4
count below 200 cells/mm3 but still very high. Dabis
also invoked results of the recent HPTN 052 trial to
make the points that cART started at a CD4 count
between 350 and 550 cells/mm3, rather than below
250 cells/mm3, independently lowers the risk of HIV
transmission to cohabitating partners65 and also
reduces the risk of tuberculosis and overall severe
morbidity and mortality (combined) in the treated
person.11
Dabis reported that 15 African countries have picked
WHO option A for PMTCT (maternal zidovudine plus
infant antiretroviral prophylaxis), while 20 prefer option
B (triple therapy from 14 weeks’ gestation to 1 week
after breastfeeding stops). Four countries consider
either option, while Malawi now recommends cART
(efavirenz plus tenofovir/emtricitabine) for life in
pregnant women regardless of CD4 count—option
B+. Dabis maintained that Malawi’s stance is no
longer a theoretical option, because it is simple to
implement, minimizes vertical HIV transmission,
protects the next pregnancy, improves maternal
health and survival, reduces sexual transmission of
HIV, reduces the risk of tuberculosis,11 and treats
hepatitis B coinfection. He noted, though, that this
approach requires careful monitoring of acceptability,
feasibility, outcomes, and safety.
Stringer began his argument by asking if there is
any reason to prefer cART for women who do not
meet WHO criteria for triple therapy and have a CD4
count above 350 cells/mm3. To begin addressing
this question, he cited the BAN trial in Malawi,
which randomized 2369 HIV-positive, breastfeeding
mothers with a CD4 count of 250 cells/mm3 or
higher and their infants to (1) a maternal antiretroviral
regimen, (2) infant nevirapine, or (3) no extended
postnatal antiretroviral regimen (the control group).66
Median maternal CD4 counts stood at 429 cells/
mm3 in the cART arm and 440 cells/mm3 in the
infant-nevirapine arm. At week 28 HIV transmission
rates were significantly lower in the cART arm (2.9%,
P = 0.009 versus control) and the infant-nevirapine
arm (1.7%, P < 0.001 versus control) than in the
control group (7.0%). But the transmission rate did
not differ significantly between the two intervention
arms (P = 0.10).
Does cART for pregnant women offer maternal
advantages over WHO option A? Starting cART at
a CD4 count above 200 cells/mm3 clearly offers a
survival advantage in low-income countries, Stringer
noted, citing a Haitian trial that randomized 816
adults with a CD4 count between 200 and 350 cells/
mm3 to begin cART within 2 weeks of enrollment
or to wait until their count fell below 200 cells/
mm3.67 Through 36 months of follow-up, early cART
significantly improved survival probability by KaplanMeier analysis (P = 0.001).
But starting cART sooner also poses some risks,
Stringer cautioned, as found in a (yet-unpublished)
study of 39,764 women starting cART in Lusaka,
Zambia. Through 6 years of follow-up, rates of four
“bad events” rose gradually but steadily: missing
five pharmacy visits, needing single-antiretroviral
substitution, changing to second-line cART, and
becoming lost to follow-up. The Kaplan-Meier
estimate of at least one “bad event” rose to about
43
Report
Results: HIV prevalence among those tested
0,4
0,35
HIV prevalence
0,3
0,25
0,2
Female
Male
0,15
0,1
0,05
0
12
13
14
15
16
17
18
19
20
21
22
23
24
Age (years)
Figure 9. HIV prevalence in adolescents and young adults tested in a Durban outpatient clinic was higher in
females starting around age 17. Although prevalence rose in both young women and young men in their early
20s, the rate was significantly higher among young women than men from 18 to 24 years of age (P < 0.01). The
arrow indicates the average age of sexual debut in South Africa.
Source: Lynn Ramirez-Avila, Children’s Hospital Boston.68
50% after 2 years of follow-up and to about 80%
after 6 years.
high in the tested group—14% in young men and
22% in young women.
The antepartum testing and postpartum prescribing
of WHO options A and B are similar in complexity,
Stringer argued. Finally, he reminded attendees that
antiretroviral access remains limited in many lowincome countries. He maintained that starting cART
early in pregnant women could deprive others in
greater need of therapy.
South Africa has about 15 million people between 15
and 24 years old, and their HIV prevalence stands at
8.7%. The HIV rate rises steeply during the transition
from adolescence to adulthood: Prevalence is 6.7%
among 15-to-19-year-old girls and 32.7% among
25-to-29-year-old women. Only about one quarter of
girls and young women and 15% of boys and young
men report being tested for HIV.
Stringer offered four conclusions: (1) Women who
need cART for their own health should get it. (2)
There is no randomized evidence of improved infant
or maternal outcomes with universal maternal cART.
(3) cART is not simpler or cheaper than well-planned
short-term antiretroviral prophylaxis. (4) Starting
cART too early in healthcare systems already flush
with patients could prevent those in immediate need
from gaining access.
HIV Testing, Condom Use, Toxicity, and
Resistance
Low HIV testing rate in adolescents at
Durban clinic
In a Durban clinic with a well-established HIV testing
program, only one third of adolescent boys and half
of girls had HIV testing.68 About two thirds of young
adults agreed to testing, and HIV prevalence was
44
Lynn Ramirez-Avila (Children’s Hospital Boston)
and colleagues at Durban’s McCord Hospital
and Massachusetts General Hospital assessed
completion of HIV testing by adolescents and young
adults who came to this outpatient clinic, which has
a routine HIV testing program, and to determine HIV
prevalence in those who got tested. Everyone 12
years old or older who comes to the clinic is offered
routine opt-out HIV testing, which means a health
worker tells them they will be tested unless they
decline testing, as sanctioned by South African law.
Those who agreed had concurrent fingerprick rapid
tests. Testing is included in the clinic fee.
The February 2008 to December 2009 study involved
956 adolescents 12 to 17 years old and 2351 young
adults 18 to 24 years old. Girls and young women
comprised 55% of the adolescent group and 63%
of the young adult group. HIV testing rates were
significantly higher among girls than boys in the
adolescent group (49% versus 33%, P < 0.01), but
rates were similar in young women and men (66%
and 63%). Ramirez-Avila suggested the possibility
that prior HIV testing or known HIV status could
explain why some youngsters declined testing.
Sixty-two of 389 tested adolescents (16%) had a
positive HIV testing, including 42 girls (16%) and
20 boys (16%). Among 1523 tested young adults,
288 (19%) had a positive test, including 213 young
women (22%) and 75 young men (14%), a significant
difference (P < 0.01). HIV prevalence in both boys
and girls was high around 14 years of age, declined
in the later teens, and rose again in the early 20s
(Figure 9). The researchers had no data to explain the
prevalence blip around age 14.
Ramirez-Avila and colleagues cautioned that this
outpatient clinic may not be representative of public
sector clinics because there is a fee for clinic services.
Also, reported prevalence involves only youngsters
who agreed to testing, so overall prevalence in this
age group may be lower.
The investigators concluded that HIV testing rates are
low but positive test rates are high in this population.
They believe these findings point to (1) the need for
further studies evaluating individual and clinic-level
factors that result in HIV testing uptake by youth
and (2) an “urgent need to offer comprehensive and
youth-friendly HIV testing to adolescents and young
adults in epidemic settings.”
Most young people accept opt-out HIV
testing in DC emergency room
Three quarters of 13- to 24-year-olds accepted
rapid opt-out HIV testing in a hospital emergency
department in Washington, DC, the city with the
highest HIV prevalence in the United States and one
with a largely African-American population.69
In 2006 the CDC recommended opt-out HIV
screening for all 13- to 64-year-olds seeking medical
care, regardless of perceived HIV risk, though the
CDC does not suggest the best way to implement
this policy.70 Although numerous studies show that
opt-out HIV testing is generally well accepted in
hospital emergency departments in the United
States, adolescents and young adults made up only
small parts of these study populations.
Washington, DC, the capital of the United States,
has an HIV prevalence around 3%,71 about 6 times
the national rate. Children’s National Medical Center
in Washington launched an opt-out oral-fluid HIV
screening program in March 2009 for adolescents
and young adults 13 years old or older. Natella
Rakhmanina and colleagues planned this study to
evaluate implementation of the screening program
during its first 20 months and to identify barriers
to opt-out screening in a large urban pediatric
emergency department.
Rakhmanina reported that development of the HIV
screening plan involved all relevant staff, including
Screening Algorithm
Patient Triaged
Age ≥ 13?
No
Patient is given
appropratie care
Yes
Patient and guardian (if
present) are informed of
the Opt-Out HIV testing
No
Testing Accepted?
Yes
Patient and Guardian are informed that the test result
will be disclosed to the patient first and then shared
with the guardian, unless the patient refuses.
Terms of disclosure accepted?
Yes
No
Patient given information
about alternate locations
of testing and
information about testing
Patient Tested
Figure 10. An HIV screening algorithm for youngsters visiting a Washington, DC, pediatric emergency
department considered input from all relevant staff sectors, patients, and parents or guardians. This approach
yielded high acceptance rates in the first 20 months of implementation.
Source: Natella Rakhmanina, Children’s National Medical Center, Washington, DC.69
45
Report
hospital administration, emergency personnel,
infectious disease and adolescent health staff, and
laboratory specialists. Evaluating attitudes of patients
and parents or guardians was helpful in developing
the screening algorithm (Figure 10). In the program’s
initial stages, nursing staff offered HIV testing with a
physician order. Later the hospital shifted to a triage
nursing-generated order for HIV testing and added
dedicated testing personnel.
Through the entire study period, 25,737 adolescents
and young adults visited the emergency department,
of whom 4566 (17.7%) got tested for HIV. The
screening rate rose more than 12-fold from May
2009, when 35 patients agreed to testing, to April
2010, when 428 accepted testing. Proportions of
patients approached for HIV screening climbed from
10% in March-August 2009, to 26% in September
2009-February 2010, to 39% in March-August 2010,
and to 45% in September-October 2010.
In those four study periods, acceptance rates were
78%, 64%, 75%, and 70% and proportions actually
tested were 73%, 56%, 70%, and 68%. Age averaged
about 16.5 across the four study periods. African
Americans comprised large majorities of tested
youngsters in every study period, a reflection of the
population the hospital serves.
Rates of reactive tests in the four study periods were
0.35%, 0%, 0.19%, and 0.26%. Numbers of people
who had a confirmed HIV diagnosis and were linked
to care were 1, 0, 3, and 0. Primary reasons for not
offering HIV testing were lack of time (23.9%), deferral
by staff (25.8%), and medical reasons including
unstable condition (16.9%).
The investigators concluded that routine opt-out
rapid oral fluid HIV screening is accepted by most
youth attending a pediatric emergency department.
Transition from physician- to triage nurse-generated
HIV testing orders and addition of dedicated
testing staff significantly increased testing rates.
Rakhmanina and colleagues believe that having the
emergency department staff perform the tests and
developing a billing procedure will be necessary to
integrate this screening program into the hospital’s
standard of care.
Video better than counseling in improving
Bronx teens’ views on condom use
Among sexually active teens and young adults who
came to the emergency department at a Bronx
medical center, a video series did better than
standard counseling in improving scores on intention
to use condoms.72
46
Adolescents and young adults account for
approximately half of all new HIV infections in the
United States every year. Among the 20,000 teens
who become infected annually, 75% are members
of racial or ethnic minorities. Teens are particularly
vulnerable to HIV because (1) half of them begin
sexual intercourse before age 16, when they are
emotionally and biologically immature, (2) many use
alcohol and drugs before having sex, and (3) about
two thirds do not use condoms consistently.
To promote safer sex behaviors among adolescents
attending an urban emergency department, Yvette
Calderon (Jacobi Medical Center, Bronx, NY) and
colleagues planned this randomized trial comparing
the effectiveness of a theory-based HIV educational
video with conventional in-person HIV counseling.
The study began with qualitative research involving
100 Bronx teens to develop the video series, which
provided tailored messaging according to individuals’
initial intentions to use condoms. Those least likely
to use condoms viewed a video that demonstrated
the negative consequences of not using condoms.
Those more likely to use condoms viewed a video
that reinforced condom use as a positive behavior
and showed other teens’ views on using condoms as
a positive behavior. All participants watched a video
that demonstrated proper use of male and female
condoms and dental dams.
Study participants had to be between 15 and 21
years old, sexually active, and clinically stable. All
came to the emergency department on Monday
through Friday between the hours of 8 AM and 4 PM.
(Many sought care for reproductive health problems.)
All participants completed pre- and post-intervention
tests on three variables hypothesized to reduce
unsafe sexual behavior: intention to use condoms,
condom outcome expectancy, and condom selfefficacy (belief in one’s ability to use condoms
effectively). HIV testing was optional in both study
arms.
The investigators randomized 102 participants
(60.8% female) to the video group and 101 (55.4%
female) to the standard-counseling group. Similar
proportions in the video and counseling groups were
Hispanic (59.8% and 57.4%), and similar proportions
were black (34.3% and 42.6%). While 20.6% in the
video group were under 18 years old, 25.7% in the
counseling group were younger than 18. Two thirds
in each group had a prior HIV test.
Nearly all study participants reported vaginal sex in
the past year (97.1% in the video group and 96.0%
in the counseling group). Similar proportions had
oral sex in the past year (72.5% video and 62.4%
Table 7. Pre- to post-test change in sexual risk variables in Bronx teens
Video series
mean change
Counseling
mean change
Mean difference
(video vs counseling)
P
Condom use intention score
+0.98
–0.04
1.02
0.01
Condom self-efficacy
+0.31
+0.05
0.26
0.03
Male condom outcome
expectancy
+0.19
+0.04
0.15
0.30
Female condom outcome
expectancy
+0.16
–0.04
0.20
0.06
Source: François Dabis, Université Bordeaux Segalen, France.61
counseling) and anal sex in the past year (26.5%
and 21.8%). Mean numbers of sex partners were
also similar in the video and counseling groups: 1.41
and 1.42 male partners, and 2.16 and 2.13 female
partners.
Mean change in the three outcome measures
consistently (and often significantly) favored the video
group (Table 7). The video’s impact on condom use
intention score did not differ by gender or ethnicity.
Calderon and colleagues concluded that a youthfriendly video can be a valid way to provide post-test
HIV education and prevention messages in an urban
emergency department serving a high proportion
of minority youth. They noted that longitudinal
studies are needed to determine how long such an
intervention can affect risk-reduction behavior in this
age group.
Lipid and body fat disadvantages with PIs
vs NNRTIs in African children
Compared with South African children who switched
to an NNRTI-based regimen, those who stayed with
a PI combination had unfavorable lipid profiles and
body fat changes, according to results of a 156-child
analysis.73
Numerous studies report body fat abnormalities—
collectively called lipodystrophy—and dyslipidemia
in children taking antiretrovirals in high-income
countries. But little work has addressed these
abnormalities in sub-Saharan Africa. Antiretroviralassociated lipid changes early in life could have
profound long-term consequences for children who
will be taking antiretrovirals for decades.
This analysis by Stephanie Shiau (Columbia University,
New York, NY) and colleagues compared lipid and
body fat changes in South African children enrolled
in the NEVEREST trial, which randomized nevirapineexposed children who reached an undetectable viral
load while taking lopinavir/ritonavir plus stavudine/
lamivudine to continue that regimen or switch to
nevirapine with stavudine/lamivudine.17,18 The analysis
involved 85 children in the lopinavir group and 71 in
the nevirapine group.
At the NEVEREST 2 exit visit, age averaged 5.2 years
in the lopinavir group and 5.0 in the nevirapine group,
and the groups were evenly divided by gender. At
that point cART duration averaged 4.2 years in the PI
group and 4.1 years in the nevirapine group. Weightand height-for-age Z scores and body mass index
Z scores did not differ significantly between the two
groups. High proportions in each group had a viral
load below 50 copies/mL (84.7% in the PI group and
91.6% in the NNRTI group). The nevirapine group had
a higher median CD4 count (1480 versus 1356 cells/
mm3, P = 0.049).
Mean total cholesterol was significantly higher in
the PI group, and a higher proportion of children
taking lopinavir had a total cholesterol level above
200 mg/dL (Table 8). The PI group had lower mean
high-density lipoprotein (HDL) cholesterol, higher
low-density lipoprotein (LDL) cholesterol, and a
higher (worse) total-to-HDL cholesterol ratio. Mean
triglycerides were significantly higher in the PI group,
and a higher proportion of PI-treated children had a
triglyceride level above 150 mg/dL.
A sum of skinfold measures was significantly higher
in the PI group (43 versus 39 mm, P = 0.029), and
percentage of body fat by bioimpedance analysis was
significantly higher in children taking lopinavir (17%
versus 14%, P = 0.042). The groups did not differ in
percentage of upper arm fat, but mean percentage
of upper thigh fat was higher in the PI group (22%
versus 19%, P = 0.021). A ratio of midthigh skinfold
47
Report
Table 8. Lipid changes after 4 years of continued lopinavir versus a switch to nevirapine in South African
children
Lopinavir/ritonavir
(n = 85)
Nevirapine
(n = 71)
P
Total cholesterol (mg/dL)
171 + 39
161 + 31
0.05
Total cholesterol > 200 mg/dL (%)
16
6
0.03
HDL cholesterol (mg/dL)
51 + 14
59 + 16
0.006
LDL cholesterol (mg/dL)
100 + 34
88 + 27
0.018
Total-to-HDL ratio
3.6 + 1.1
2.9 + 0.9
< 0.001
Triglycerides (mg/dL)
94 + 39
72 + 29
< 0.001
Triglycerides > 150 mg/dL (%)
11
2
0.038
Source: Stephanie Shiau, Columbia University, New York, for the NEVEREST trial.73
sum/skinfold sum was significantly higher in children
taking lopinavir (0.24 versus 0.23, P = 0.046). A ratio
of trunk-to-thigh fat was significantly lower in the PI
group (0.55 versus 0.57, P = 0.03).
Shiau and colleagues concluded that, compared with
children who switched to the nevirapine regimen,
those who continued taking lopinavir/ritonavir had
unfavorable cholesterol and triglyceride alterations,
greater overall trunk fat, but less trunk fat in relation to
thigh fat. They proposed that simple anthropometric
measurements, like those used in this study,
“appear to be a valuable method to measure body
fat in young children on ART.” And they cautioned
that unfavorable lipid alterations in children may
increase long-term cardiovascular risk and “should
be considered in antiretroviral treatment strategies.”
High resistance rates in Spanish
youngsters transferred to adult care
Although Spanish youngsters infected with
during childhood had good immunologic
virologic control when transferred to adult care,
thirds had NRTI-related mutations and almost
had PI-related mutations.74
HIV
and
two
half
This study involved young people in the Madrid
Cohort of HIV-1-Infected Children, an eight-hospital
collaboration established in 2000. Of the 534
children enrolled, 198 (37%) are in follow-up, 88
(16%) transferred to adult units, 64 (12%) were lost to
follow-up, and 184 (35%) died. Among the 88 cohort
members transferred to adult units, 52% were young
women, half were infected in 1986-1990, 95.5% were
48
from Europe, 87.5% were white, and age averaged
22.8 years.
Miguel de Mulder (Hospital Ramón y Cajal, Madrid)
and coworkers genotyped plasma samples from 44
youngsters collected closest to the transfer time. At
that point, 64% of the study group had a CD4 percent
between 15% and 24%, and 29% had a higher CD4
percent. Viral loads were below 50 copies/mL in
37%, 51 to 499 copies/mL in 22%, and higher in
42%. Most people in this study group, 82.9%, were
taking antiretrovirals at the time of transfer.
Two thirds of study participants (65%) had at least
one resistance mutation, 65% had an NRTI mutation,
49% had a PI mutation, and 33% had an NNRTI
mutation. While 41% had mutations conferring
resistance to two or more antiretroviral classes, 18%
had resistance to three classes. The most frequent
NRTI mutations were D67N (50%), M41L (45%), and
L210W (32.5%). Only 17.5% had the M184V mutation.
The most common PI mutations were L90M (37.5%),
M46I (37.5%), and V82A (17.5%). The most common
NNRTI mutations were K103N (17.5%) and Y181C
(7.5%).
The investigators cautioned that this relatively high
mutation prevalence “could compromise future longterm ART and clinical management in vertically HIV-1infected patients.” They encouraged multidisciplinary
follow-up and psychosocial support for pediatric
patients transferring to adult units and new strategies
to increase adherence.
New data on TB, other Co-infections,
HIV in CSF
TB therapy raises virologic failure risk in
South African children
Younger age and tuberculosis cotreatment
independently raised the risk of virologic failure of
antiretroviral therapy in a retrospective study of 218
South African children.75
TB coinfection is a major complication of HIV infection
throughout sub-Saharan Africa. Whereas global TB
incidence in 2009 stood at 164 per 100,000 people,
incidence measured 340 in Africa, 500 in South
Africa, 877 in Cape Town, and 1600 in Khayelitsha,
a district outside Cape Town. Elisabetta Walters
(Stellenbosch University, Cape Town) and colleagues
planned this retrospective study to explore virologic
outcomes of cART-treated children also receiving
treatment for TB and children on cART only.
The analysis included children starting cART between
January 2003 and December 2005 and being
treated for TB between April 2002 and December
2008 at Cape Town’s Tygerberg Children’s Hospital.
The cotreatment group included children treated for
TB between April 2002 and December 2008 and
receiving cART and anti-TB therapy together for
at least 2 weeks. Walters and colleagues defined
virologic failure as two consecutive 6-monthly viral
loads above 5000 copies/mL. cART was given
according to 2003-2005 South African guidelines:
KM time to failure curve stratified
by TB co - treatment
two NRTIs plus ritonavir for infants under 6 months
old, two NRTIs plus lopinavir/ritonavir for children
from 6 months to 3 years old or weighing less than
10 kg, and two NRTIs plus efavirenz for children
older than 3 years. Children taking lopinavir/ritonavir
when cotreatment began switched to ritonavir for the
duration of cotreatment.
Of the 218 children studied, 79 (36%) had TB and 139
did not. Median age was 21 months in the TB group
and 36 months in the no-TB group (P = 0.0006),
and weight-for-age Z score was significantly lower in
children with TB -3.27 versus -1.87, P < 0.0001). A
significantly higher proportion in the TB group was
taking a PI regimen (72% versus 42%, P = 0.0001).
Median baseline CD4 percent was marginally lower
in the TB group than in the no-TB group (12% versus
13.5%, P = 0.057), but median baseline viral load
was similar in the two groups (5.77 versus 5.67 log10
copies/mL, P = 0.159).
Independently of TB cotreatment, virologic
suppression 6 and 12 months after cART began was
best in the NNRTI group, followed by the lopinavir/
ritonavir group and the ritonavir group. Kaplan-Meier
analysis determined that time to virologic failure
was significantly faster in children receiving anti-TB
therapy and in children under 1 year old (Figure 11).
Statistical analysis that adjusted for gender, age, antiTB cotreatment, weight-for-age Z score, and baseline
CD4 count and viral load identified younger age and
KM time to failure curve stratified
by age group
Kaplan-Meier survival estimates
1.00
Kaplan-Meier survival estimates stratified by agegroup
0.95
0.90
1.00
No TB
0.85
0.80
3- 5yr
0.90
0.80
0.75
1- 3yr
0.70
0.70
0.65
TB
0.60
P=0.0002
0.60
<1yr
0.50
p=0.0002
Figure 11. Virologic failure of cART by Kaplan-Meier analysis was significantly faster in South African children
also being treated for TB than in those without TB and in children younger than 1 year old than in older children
Source: Elisabetta Walters, Stellenbosch University, Cape Town.75
49
Report
anti-TB cotreatment as independent predictors of
virologic failure. Type of antiretroviral therapy could
not be assessed as a predictor of failure because of
strong colinearity between type of therapy and age
(the youngest children were all taking PIs).
Walters and coworkers questioned whether age
may be a surrogate for other factors contributing
to virologic failure in this analysis. They called for
further work to identify and implement TB preventive
strategies, new antiretroviral strategies for coinfected
children, and alternatives to rifampin for children with
TB.
Most South African infants with TB do not
have household TB contact
Two thirds of HIV-positive or HIV-exposed infants
coinfected with TB did not have an identifiable
household contact for their TB, despite intensive
tracing, according to results of a 45-infant study
in Cape Town, Durban, and Johannesburg, South
Africa.76 Avy Violari (Chris Hani Baragwanath Hospital,
Soweto, South Africa) and coworkers identified only
3 adult nonhousehold contacts for these children.
To determine TB contact status in children, the
researchers assessed participants in the P1041
study, a phase 2/3 double-blind trial that randomized
HIV-positive and exposed children in South Africa
and Botswana to daily isoniazid or matching placebo
for 96 weeks.77 All P1041 participants were 3 to 4
months old at recruitment and had Bacille CalmetteGuérin (BCG) vaccination at birth. The study excluded
infants with a TB exposure history before enrollment
or previous or current treatment for TB. Isoniazid
prophylaxis did not improve TB-disease-free survival
in HIV-positive children or TB-infection-free survival
in HIV-exposed but negative children immunized with
BCG vaccine.
Violari and colleagues studied all children with definite
or probable TB for microbiologically confirmed TB
contacts. The analysis involved 22 HIV-positive
children and 23 HIV-exposed but uninfected children,
with the following numbers and identified contacts
from three study sites:
• Johannesburg: 32 children, 10 household contacts, 2 nonhousehold contacts
• Cape Town: 10 children, 3 household contacts, 1
nonhousehold contact
• Durban: 3 children, no contacts identified
Overall, the investigators identified contacts for
16 of 45 children (35.5%). Among children with
protocol-defined TB, no differences could be found
between those with and without contacts in HIV
50
status, isoniazid versus placebo use, infant age
at TB diagnosis, maternal age at infant diagnosis,
household type (formal versus informal), access to
water, more or fewer than 3 people in the household,
or presence of an adult over 55 years old in the
household. The researchers cautioned, though, that
this analysis rests on a small sample size.
Violari and colleagues proposed that in countries with
a high TB burden, TB exposure of children can occur
outside the home more frequently than in the home.
They recommended that future studies of childhood
TB should undertake aggressive community contact
tracing to learn the origin of incident TB.
Almost 25% of febrile African children
starting cART have bacteremia
Almost one quarter of HIV-positive African children
enrolled in the ARROW trial in whom fever developed
had bacteremia, usually in the first 3 months of
antiretroviral therapy.78 Streptococcus pneumoniae
was the most frequently isolated pathogen.
ARROW is an open-label randomized trial of firstline cART and monitoring strategies at three sites in
Uganda and one in Zimbabwe. The 1206 children
enrolled have a median age of 6 years (IQR 2 to 9),
51% are girls, and 99.4% were vertically infected with
HIV. Median follow-up at the time of this analysis was
156 weeks and maximum follow-up 210 weeks.
Victor Musiime (Joint Clinical Research Centre,
Kampala) and colleagues assessed ARROW
enrollees in whom febrile illness developed,
performing blood cultures and sensitivity analyses
of isolated pathogens. Most children were receiving
cotrimoxazole prophylaxis, most had received
Haemophilus influenzae type B vaccination, but none
had received pneumococcal vaccination.
Culturing 848 samples from 461 children, the
investigators found that 123 samples (14.5%) from
105 children (22.8%) were positive. Among the 105
children with positive isolates, median age was
4 years (range 0.5 to 15), and 54 (51%) were girls.
Culture positivity rates were 18.8% within 3 months
of starting cART, 4.2% between 3 and 11 months,
and 1.6% from month 12 onward.
The most prevalent pathogens were S pneumoniae
(28%), Staphylococcus aureus (9%), other staph
species (9%), other strep species (8%), Klebsiella
pneumoniae (5%), Salmonella species (5%), and
Pseudomonas aeruginosa (5%).
Among S pneumoniae isolates, 8 of 22 (36%) were
Antibiotic susceptibility patterns of other
bacteraemia isolates
Number of susceptible isolates (percentage)
Name of
antibiotic
S. aureus
Salmonella
spp
E.coli
P.aeruginosa
K.pneumoniae
Ceftriaxone
4/5(80%)
5/5(100)
2/2(100)
1/2(50)
0/2(0)
Cefotaxime
3/4(75%)
2/2(100)
2/2(100)
-
0/1 (0)
Meropenem/
Imipenem
-
2/2(100)
3/3(100)
2/2(100)
2/2(100)
Ciprofloxacin
3/3(100%)
3/3(100)
-
2/2(100)
1/1(100 )
Amikacin
-
-
2/2(100)
1/1(100)
1/1(100)
Gentamicin
3/5(60)
3/4(75)
1/2(50)
2/3(67)
0 /2(0)
Erythromycin
5/8(63)
-
-
-
-
Chloramphenicol
1/1(100)
0/1(0)
-
0/1(0)
-
Penicillin
1/4(25)
1/4(25)
0/2(0)
0/1 (0)
0 /3(0)
Cotrimoxazole
0/8(0)
1/3(33)
0/2(0)
0/1 (0)
0/1(0)
Figure 12. Antibiotic susceptibility testing of isolates other than S pneumoniae in 105 of 461 children (22.8%)
with positive blood cultures in the ARROW trial showed high rates of resistance to the most frequently prescribed
antibiotics. S pneumoniae isolates were also often resistant to common antibiotics (see text).
Source: Victor Musiime, Joint Clinical Research Centre, Kampala.78
resistant to oxacillin, 8 of 19 (42%) were resistant
to penicillin G, 21 of 22 (95%) were resistant
to cotrimoxazole, and 5 of 5 were resistant to
gentamicin. All S pneumoniae isolates were
susceptible to ceftriaxone, vancomycin, clindamycin,
cefotaxime, amoxicillin/clavulanic acid, cefuroxime,
and chloramphenicol; 89% were susceptible to
erythromycin, 85% to amoxicillin, and 71% to
ampicillin. Other bacteremia isolates were usually
susceptible to meropenem/imipenem, ciprofloxacin,
amikacin, ceftriaxone, and cefotaxime, while most
were resistant to chloramphenicol, penicillin, and
cotrimoxazole (Figure 12).
Musiime and colleagues believe high rates of
resistance to commonly used antibiotics suggest that
newer agents like ceftriaxone may be more effective
for HIV-positive children with possible bacteremia.
The high prevalence of S pneumoniae in this
pediatric population suggested to the investigators
“a need for effective prophylactic antibiotics and/or
pneumococcal vaccination.”
HBV and HCV rates 5% and 1% in HIVpositive Cambodian children
A study of nearly 1000 HIV-positive children in
Cambodia determined that approximately 5% have
hepatitis B virus (HBV) coinfection and almost 1%
have hepatitis C virus (HCV) coinfection.79 Antibody
response to HBV vaccination was poor in children
not receiving cART, with a low CD4 count, or with a
detectable viral load.
HBV prevalence is assumed to be high in Cambodia,
but rates of HBV and HCV infection in the general
population are not well documented. Little is known
about HBV or HCV coinfection in HIV-positive
children. HBV vaccination, which is essential for
HBV-negative people with HIV, became part of
Cambodia’s National Immunization Program in 2005.
A cross-sectional study involved 974 HIV-positive
children seen between April 2009 and March 2010
at the National Pediatric Hospital, which had 1180
HIV-infected children in care in December 2010. Sam
Sophan (National Pediatric Hospital, Phnom Penh)
and colleagues estimated that 20% of all HIV-positive
children in Cambodia are in follow-up at the National
Pediatric Hospital. The investigators defined HBV
infection as a positive hepatitis B surface antigen
(HBsAg) test and HCV infection as a positive antiHCV antibody test.
A prospective study involved children eligible for
HBV vaccination (negative for HBsAg and hepatitis
B surface antibody), who received Engerix-B
immunization at months 0, 1, and 6. Children with a
severe opportunistic infection or a CD4 percent below
10% were not vaccinated. An anti-HBs antibody
level above 100 mIU/mL 1 month after vaccination
51
Report
The response rate associated with CD4+ status:
%
80
70
70
CD4 ≥350 cells/mL or ≥15%
(N=759)
67,5
CD4 <350 cells/mL or <15%
(N=30)
60
50
40
32,5
30
30
20
10
RR: 2.3
95% CI: 1.3 -3.9
P -value: 0.0001
0
<10 mIU/mL
≥10 mIU/mL
Figure 13. Cambodian children with a CD4 percent at or above 15% or a CD4 count at or above 350 cells/
mm3 had more than a doubled chance of responding to HBV vaccination compared with children with lower
CD4 measures.
Source: Sam Sophan, National Pediatric Hospital, Phnom Penh.79
was considered full protection, a level between 10
and 100 mIU/mL was considered a poor response
requiring a single booster, and a level below 10 mIU/
mL was considered failure to respond.
The study group had a median age of 8.7 years (IQR
5.7 to 11), and 478 (49%) were girls. Most children
(799, 82%) were receiving cART for a median duration
of 31 months (IQR 14 to 47), while 175 (18%) had
never received antiretrovirals. More than half of these
children (61.9%) were born in Phnom Penh. Fortysix children (4.7%) were HBsAg-positive, 122 (12.5%)
were anti-HBs-positive, and 9 (0.9%) were anti-HCVpositive. Median age of HBV-coinfected children
stood at 9.8 years (range 1.3 to 16.3), compared with
a median age of 2.6 years (range 0.4 to 14.5) for HCVcoinfected children.
Among 145 children who received HBV vaccination
as part of the National Immunization Program after
2004, anti-HBs antibodies developed in only 28
(19.3%). Among 236 children whose caregivers
reported that they received three vaccine doses at
private clinics, anti-HBs antibodies developed in only
60 (25.4%). Among 789 HIV-positive children eligible
for HBV vaccination at the National Pediatric Hospital,
median age was 8.6 years (IQR 5.8 to 10.9) and 387
(49%) were girls. In that group, 492 (62.3%) attained
full protection after vaccination, 40 (5.1%) had a poor
response, and 257 (32.6%) had no response.
Children on cART had a median anti-HBs titer of
725 mIU/mL, compared with a titer of 455 mIU/mL
in children not on cART. Children receiving cART had
a 30% higher chance of attaining a response above
10 mIU/mL (RR 1.3, 95% CI 1.1 to 1.5, P = 0.0001).
Children with a CD4 percent at or above 15% or a
CD4 count at or above 350 cells/mm3 had more than
52
a doubled chance of responding to vaccination with
a titer at or above 10 mIU/mL (RR 2.3, 95% CI 1.3 to
3.9, P = 0.0001) (Figure 13). An HIV RNA load below
400 copies/mL raised the chance of an anti-HBs
antibody response 60% (RR 1.6, 95% CI 1.3 to 1.8,
P = 0.0001).
Sophan and colleagues concluded that a high
CD4 count and undetectable viral load are good
predictors of the need for HBV vaccination boosting.
They proposed that routine HBV vaccination for HIVpositive children without knowledge of CD4 levels or
viral load may not yield a good serologic response.
The investigators advised deferring HBV vaccination
for children until after cART controls HIV.
Low CSF HIV load in youth with PML or
measles encephalitis
Romanian adolescents and young adults had lower
HIV RNA in cerebrospinal fluid (CSF) than in plasma if
they had progressive multifocal leukoencephalopathy
(PML) or subacute measles encephalitis.80 But they
had equivalent or higher viral loads in CSF and
plasma if they had HIV encephalopathy.
Higher HIV RNA in CSF correlates with neurocognitive
impairment in adults, but relative viral loads in CSF and
plasma have not been closely studied in youngsters,
in whom neurologic opportunistic infections are
less prevalent than in adults. Many Romanian
infants became infected with HIV-1 subtype F from
1987 through 1990 through unsafe injection and
transfusion practices. They make up the largest part
of a group of young people studied by Luminita Ene
(Dr. Victor Babes Hospital, Bucharest) and colleagues
to compare CSF and plasma loads in youngsters
and in 4 of 8 patients with cryptococcal meningitis,
and (2) significantly lower CSF than plasma
viral load in patients with PML and subacute
measles encephalitis, a difference similar to that in
neurologically asymptomatic patients.
with and without neurologic complications of HIV.
The study also aimed to assess the relevance of
CSF load as a marker for central nervous system
complications in adolescents and young adults.
Of the 132 study participants that had available CSF
and plasma samples, 104 (79%) had neurologic
complications first noted at an average age of 18.7
years. Median time from HIV diagnosis to neurologic
complication was 5.5 years (range 0 to 17 years). Most
study participants (116 or 88%) were parenterally
infected, 6 were vertically infected, and 10 acquired
HIV sexually.
Ene and colleagues speculated that HIV RNA may be
lower in CSF than plasma in young people with PML
or subacute myoclonic measles encephalitis because
of possible interactions between HIV and the viruses
that causes these diseases. Earlier research found
evidence that measles may inhibit HIV replication in
plasma.81-83 The investigators suggested that lower
viral load in CSF than plasma may be an indirect
marker of PML or subacute myoclonic measles
encephalitis.
In the whole study group, median CSF load was
significantly lower than plasma load (2.61 versus
4.23 log10 copies/mL, P < 0.001), though CSF load
correlated positively with plasma load (rho 0.68, P <
0.0001), as well as with albumin level (rho 0.22, P =
0.05) and pleocytosis (rho 0.51, P < 0.001). Thirtynine antiretroviral-naive study participants had a
significantly higher CSF load than 34 participants
on cART but with virologic failure (mean 4.28 versus
2.95 log10 copies/mL, P < 0.001). Among 20 people
previously exposed to cART but not on treatment
at the time of evaluation, CSF load averaged 4.01
log10 copies/mL, which was significantly lower than
in the group with virologic failure but still on cART (P
= 0.002).
cART may limit EBV load in Ugandan
children under 5
Early cART was associated with lower Epstein-Barr
virus (EBV) DNA levels in Ugandan children under 5
years old, according to results of a 187-child study.
Malaria appeared to promote expansion of EBVpositive B cells in these children.
EBV, a herpes virus, infects B lymphocytes and
epithelial cells and can cause serious malignancies
such as Burkitt’s lymphoma, immunoblastic
lymphoma, and nasopharyngeal carcinoma.
People infected with HIV run a high risk of EBVrelated diseases, including non-Hodgkin B-cell
lymphoma. EBV is endemic in Central Africa, with
primary infection occurring during infancy and early
childhood. In Africa EBV is strongly associated with
Burkitt’s lymphoma, which accounts for 75% of
malignancies in children.
Thirty-two study participants had HIV encephalopathy,
22 had PML, 8 had cryptococcal meningitis, 6 had
cerebral toxoplasmosis, 2 had cytomegalovirus
encephalitis, and 2 had TB meningitis. Non-AIDS
neurologic conditions were subacute myoclonic
measles encephalitis in 13, viral encephalitis in 9,
seizures in 4, HIV aseptic meningitis in 2, GuillainBarré syndrome in 1, and facial palsy in 1.
Because there have been no studies of EBV viremia in
HIV-positive African children, Maria Raffaella Petrara
(University of Padova, Padova, Italy) and coworkers
planned this analysis of 187 HIV-positive children
up to 14 years old in a Kampala cohort. Of the 103
The investigators described two distinct patterns
associated with specific neurologic infections
(Table 9): (1) higher CSF than plasma HIV RNA in
half of the 32 patients with HIV encephalopathy
Table 9. HIV RNA in CSF versus plasma in Romanian youth
n
CSF load*
Plasma load*
P
HIV encephalopathy
32
4.62
4.61
NS
PML
21
3.13
4.68
< 0.001
Subacute myoclonic measles encephalitis
13
2.46
3.78
0.006
No neurologic disease
28
2.55
3.23
0.0001
*Mean log10 copies/mL.
Source: Luminita Ene, Dr. Victor Babes Hospital, Bucharest.80
53
Report
children (55%) still naive to antiretrovirals, 83% had
detectable EBV. Among 84 children (45%) receiving
cART, 73% had detectable EBV.
In the entire cohort, 22% had EBV-1, 18% EBV-2, and
38% both types of EBV. Rates of EBV-1 or EBV-2 or
coinfection with both types did not differ substantially
between antiretroviral-naive and experienced
children. EBV levels were significantly higher in
children coinfected with both EBV types than in
those infected only with EBV-1 (P = 0.001) or EBV-2
(P = 0.015). But EBV load did not differ significantly
between children with EBV-1 and those with EBV-2.
Regardless of antiretroviral status, EBV viremia was
nonsignificantly higher in children with clinical malaria
(P = 0.093), a finding leading Petrara and colleagues
to suggest that Plasmodium falciparum malaria may
induce B-cell activation and stimulate EBV-infected
B cells via toll-like receptor 9 (TLR-9) engagement.
Higher EBV viremia in antiretroviral-naive versus
treated children under 5 years old prompted the
investigators to propose that early cART may restrict
EBV replication and expansion of EBV-infected cells
during primary EBV infection.
EBV viremia did not differ significantly between
antiretroviral-treated and naive children. But in
children younger than 5 years, EBV load was
significantly higher in antiretroviral-naive children (P
= 0.017).
4th International Workshop on
HIV Pediatrics
Washington DC, USA
20 - 21 July 2012
MARK - THE - DATE
4th International Workshop on HIV Pediatrics
20 - 21 July 2012, Washington, DC, USA
Abstracts & Presentations of the 3rd International Workshop on HIV Pediatrics are available
online at www.virology-education.com
54
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www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.
htm. Accessed 19 August 2011.
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residents have HIV or AIDS, city study finds; rate up
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72. Calderon Y, Leu CS, Cowan EA, et al. Project Control.
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73. Shiau S, Arpadi S, Strehlau R, et al. Body composition
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74. Navas A, de Mulder M, Gonzalez-Granados I, et al.
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75.Walters E, Reichmuth K, Rabie H, Cotton MF,
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South African children co-treated with highly-active
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15-16 July 2011. Rome, Italy. Abstract O_20.
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58
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