Pharmacoprevention HIV-drugs for prevention

Pharmacoprevention
HIV-drugs for prevention
Marc Vandenbruaene
Instituut Tropische Geneeskunde,
Antwerpen
Youtube filmpje
• Programma: Buiten de zone
– Mama, ik heb aids
A
B
C
Introduction
• Afkortingskunde: What‟s in a name/ abbreviation?
•PEP
•PrEP
•TASP
•PMTCT
Introduction
• PEP: Post-Exposure prophylaxis
– Well known & implemented concept
• HIV-negative person
with needle-stick injury, or sexual risk-contact, or...
takes HIV-drugs to prevent HIV
• Risk situations
– Professional exposure
– Sexual exposure
Introduction
• PrEP: Pre-exposure profylaxis
• HIV-negative person
– Starts taking HIV-drugs
– before sexual risk-contact
• Trials
– Vaginal tablets/rings with HIV-drug
• 1 drug: Tenofovir
– Oral HIV-drugs
• Truvada = Tenofovir + Emtricitabine combination pill
• Viread = Tenofovir
• It works if you take your pills
Introduction
• PrEP
• More questions then answers
– Practically
• Medics & paramedics level
• Patient level
– Ethically
• Low income countries: no antivirals for all HIV-positives
• High income countries: antivirals for HIV-negatives
– Economically
• Cost-effectiviness
• Who will pay?
Introduction
• TASP Treatment as prevention
• Hiv-positive persons
– Treat to prevent hiv-transmission
• What is efficacy of TASP
– In trial setting?
Introduction
• Efficacy of TASP
– trial setting?
96% and more
Biologically
Introduction
• Efficacy of TASP
– trial setting?
96% and less
Behaviourly
Introduction
• PMTCT Prevention Mother-to-child Transmission
– = TASP + PrEP + PEP
Overview presentation
• Lenti-virussen
• PEP: does it work?
–
–
–
–
Mother-child transmission
Health care workers
Monkey experiments & SIV
French army data
• PEP
– Window of opportunity: limited
• HIV-transmission chances
– Extremely low
– Upto extremely high
– What is not a HIV-risk?
Overview presentation
• PEP-Advice before start
– Belgian Aids Reference Centers
• leaflet
– Indication
• What is not a risk situation?
• Risk situations
– Second opinion
– PEP-cocktails
• Follow up after PEP
Literature
• Post-exposure prophylaxis
– New England J Med
• Landovitch and Currier
Websites & webcasts
• Creating an AIDS free generation
– Hillary Clinton at 2012 World AIDS conference
• www.AIDS2012.org
• Hiv-transmission & TASP
– Myron Cohen at 2011 ISSTDR-conference
• International Society for STD Research
– http://www.isstdr.org
• Prevention Belgium PrEP
– BREACH-symposium 2012
TASP
exposure
Clinical Pharmacology & Therapeutics September 2010
Concept drugs for prevention
• Anti-malaria-pills
– When used first time?
• Anticonception pill
– Early 1960‟s
• Anti-gonorhoe-shot, Vietnam War
– Early 1960‟‟
STI bible
STI godfather
USS Enterprise 1939
En route to Pearl Harbor, 8 October 1939.
Photographed from USS Minneapolis
Google et al.
The Kiss. New York City 1945
(Different sailors claimed the copy right of „The Kiss‟).
What sailors in port, tend to do.
Hawai Hula girls
No resistance problem
USS Enterprise 1960
Marines
Pre-exposure prophylaxis for gonorrhoea
• US marines in 1960‟s
– Got IM shot penicilline
– After docking in Hawai
• Before leaving aircraft carrier
– On board again
• Some returned with urethritis
• ‘Gift from their soulmates for 1 night’
King Holmes. Interview Lancet Infectious Diseases, July 2007.
Pre-exposure prophylaxis for gonorrhoea
• US marines in 1960‟s
– Got IM shot penicilline
– After docking in Hawai
• Before leaving aircraft carrier
– Urethritis
• 50% resistant N.gonorrhoea
• 50% non-gonococcal urethritis: Chlamydia
• Chlamydia was not known as urethritis etiology in these days
King Holmes. Interview Lancet Infectious Diseases, July 2007.
Lenti-virusses
• HIV
• SIV
– Simian Immunodeficiency Virus
• Lenti: slow
– In 1970‟
– Time between
• Infection
• First pathology
Lenti-virusses
• Ashley Haase
– In Nature 2010
Lenti-virussen not slow at all!
In first phase of infection!
Vaginal transmission of SIV: fast phase of
lenti-virusses
PEP opportunity
< 72 hours
Nature Vol 464 11 March 2010 217-223
Timing post exposure profylaxis
• As soon as possible after accident
• > 72 hour after exposure
– No sense anymore
– Contact with regional lymfnodes
Pharmaco-prevention: does it work?
• Mother to child transmission, PMTCT
– Trial: Prevention with monotherapy (Retrovir)
• 80% reduction transmission risk
• Health care workers
– Case-control study: monotherapy (Retrovir)
• 80% reduction
• Animal studies
Prevention of SIV in macaques with Tenofovir
24 macaques
6 groups
Intravenous infection SIV
Initiation / duration
24h / 28d
48h / 28d
72h / 28d
24h / 10d
24h / 3d
control group
SIV infected
0/4
2/4
2/4
1/4
4/4
4/4
Tsai et al, J Virol, 1998;72:4265
Prevention of SIV in macaques with Tenofovir
24 macaques
6 groups
Intravenous infection SIV
Conclusion: succes of PEP
Timing start
Duration of therapy
Tsai et al, J Virol, 1998;72:4265
PEP-Cases at ITM
• Last 2 years
– No injuries reported
• Case
– Lab-technician
• Takes tube HIV cultures out of minus 70 refrigirator
– Splash in eye
• Antivirals taken
• Reported to administration
• What can be done to prevent in the future?
Case general hospital Brussels 1998
• Health care provider
– Assistant internal medicine
• Index patient
–
–
–
–
African women intensive care unit
HIV-positif, AIDS-phase (PCP)
Shock, respiratory insufficienty
CD4: 10 per µl
Viral load > 1 million copies/ml
• Urgent need for new central catheder
– Rush
– All personel very busy
• Stick with needle when removing old catheder
Case in general hospital 1998
• PEP taken
– Crixivan/ Retrovir/ Epivir
• Early days of combination ART
– Schedule is not standard!
– 1 month
– Reported to hospital administration
• What can be done to prevent in the future?
Surgeons in training US
% with needle stick injury
High risk patient
HIV or
HBV or
HCV-positif
Surgeons in training
51% did not report
Injury
Cause injury %
Rushed
57
Fatigue
15
Lack skills
12
Lack assistance 9
Not preventable 20
New England J Med, Makary 2007 356;26:2693-2699
U.S. Health-Care Workers
Documented Occupationally Acquired HIV
(Registration until 1999)
OCCUPATION
Nurse
24
Clinical laboratory technician
16
Physician (non-surgeon)
6
Non-clinical laboratory technician
3
Surgical technician
2
Housekeeper / maintenance worker
2
Morgue technician
1
Emergency med technician/paramedic
1
Respiratory therapist
1
Dialysis technician
1
Total
57
Post-exposure prophylaxis
• Expert advice crucial
• Telephone
– Most important instrument
– Medic on call
• Belgian AIDS Reference Centers
– Leaflet
• At ITM
– Also second opinion colleague
PEP
Risk evaluation
• Type of contact: what happened?
– Professional accident
– Sexual exposure
– Injecting drugs
• Profile index
– Patient
– Sex partner
– Needle sharing
• How long ago?
• Hepatitis-B-vaccination status
• HIV-test done before?
PEP after sexual exposture
Risk evaluation
• Type of contact:
– what happened?
• With whom?
• How long ago?
NOT Considered Infectious for HIV
On mucosa
•
•
•
•
Feces
Nasal Secretions
Saliva
Sputum
•
•
•
•
Sweat
Tears
Urine
Vomitus
NOT Considered Infectious for HIV
• Blood on intact skin
Transmission risk per contact if index hiv-positive (estimate)
%
transmission per 10.000 injuries
Professional risk
Needle stick injury
0,3
30
Mucosa contact
0,09
9
Overview article, Raphael Landovitz and Judith Currier, New England J of Med, 2009; 361:1768-75
Risk Factors for HIV Transmission
CDC Case Control Study
Risk Factor
Deep Injury
Visible blood
Terminal illness
In vessel
Retrovir use
Adjusted Odds Ratio (95% CI)
16.2
6
6
4
0.2
Cardo et al., NEJM;1997;337:1485-90 (updated)
Occupational Blood-borne Exposures
Relative Risk of Seroconversion with Percutanous Injury
Seroconversion %
50
50%
40
30
30%
20
10
2%
0.3%
0
HIV
HCV
.
From:
CDC. MMWR 2001;50 (RR11):1-42.
HBsAg+
HBeAg-
HBsAg+
HBeAg+
DHS/Occupational
Exposure/PP
Dosis-effect-relatie:
Virale lading &hiv-overdracht bij discordante koppels
Quinn NEJM 2000;342:921-9
%
25
20
Transmissiekans
per 100
persoonsjaren
15
10
5
0
A
B
C
D
E
Virale lading hiv-positieve index
A: <400
B: 400-3.499
C: 3.500-9.999
D: 10.000- 49.900
E > 50.000
Transmission risk per contact if index hiv-positive (estimate)
%
transmission per 10.000 contacts
Receptive anale sex
’Anus hiv-negative’
1-30
100 – 3000
Receptive vaginal sex
’Vagina hiv-negative’
0,1-10
10
- 1000
Insertive vaginal sex
’Penis hiv-negative’
0,1-1
10
- 100
Insertief anale sex
‘Penis hiv-negativ’
0,1-10
10
- 1000
Overview article, Raphael Landovitz and Judith Currier, New England J of Med, 2009; 361:1768-75
Transmission risk per contact if index hiv-positive (estimate)
%
transmission per 10.000 contacts
Receptive oral sex:
considerably lower, good estimates lacking
Insertive oral sex
considerably lower, good estimates lacking
Overview article, Raphael Landovitz and Judith Currier, New England J of Med, 2009; 361:1768-75
VL Plasma
Tot 100 miljoen
Theoretische curve
Verloop Hiv-virale lading: RNA (VL)
Kopijen per ml
VL Sperma
Indien soa
01234
Weken
1
Jaren
Soa-therapie
5
10
13
PEP after sexual exposture
Risk evaluation
• Type of contact: what happened?
• With whom?
• How long ago?
• Drugs use?
• Previous
– sexually transmitted infections?
– PEP-use
• Hepatitis-vaccination status
• HIV-test done before?
‘Hoogste
hiv-cijfers’
1. Hivpositieven
2. Hoger risico
populatie
3. Brugpopulatie
4. Algemene populatie
Risk groups/ situations/ behaviour
• MSM
– Men who have seks with men
– HIV-prevalence
• Overall Belgium: 2,5 - 4%
• Higher risk settings: 15 (30)%
HIV prevalence : biological
Wim Vanden Berghe, Institute of Tropical Medicine, Antwerp
20
15
14,5
10
N2: clubs
algemene uitgaansetting
4,9
1,8
5
0
N1=152
range : 3,2 - 31,8
N1: bars, sauna's, clubs
Seks ter plaatse mogelijk
N2=205
Sample
N3=221
range : 0,9 - 7,1
N3: plaatsen
Met jonge msm < 25
Risk groups/ situations/ behaviour
• African migrants
– No good data
– 1/3 of HIV-patients in Belgium
– 0,65% of Belgian population
HIV by age and sex in Africa
Lesotho
Cameroon
15
50
Men
Women
Women
HIV prevalence (%)
HIV prevalence (%)
40
10
10
5
Men
40
30
20
10
0
0
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
15-19
20-24
New directions for HIV Prevention Research in Africa
Sten H. Vermund, Vanderbilt University School of Medicine
25-29
30-34
35-39
40-44
45-49
50-54
55-59
2. Hoger risico-populatie:
kleine reeksen
• Prostitueés: vrouwen
– Blanke vrouwen, West-Europese origine
• Gent 2000: 0/400
• Gent 2002: 0/486
• Antwerpen 2002: 1/80 (1%)
– Centraal-Afrikaanse origine
• Gent 2002: 1/96 (1%)
• Antwerpen 2002: 6/74 (8%)
2. Hoger risico-populatie:
kleine reeksen
• Prostitueés: mannen
– Antwerpen 2002:
• 3/11 (27%)
– Brussel 2000:
• 8/21 (38%)
• 20/23 (87%)
2. Hoger risico-populatie:
kleine reeksen
• Drugsgebruikers
– Antwerpen, Free Clinic
– Mannen
• 2001: 9/175 (5,1%)
• 2002: 10/171 (5,8%)
– Vrouwen
• 2001: 6/79 (7,6%)
• 2002: 6/88 (6,8%)
PEP after sexual exposture
Risk evaluation
• Type of contact: what happened?
• With whom?
• How long ago?
Vaginal transmission of SIV: fast phase of
lenti-virusses
PEP opportunity
< 72 hours
Nature Vol 464 11 March 2010 217-223
PEP indications
• www.SBIMC.org
• www.BVIKM.org
HIV drugs available
PEP drugs used
• Tri-therapy= Standard
– 2 Reverse transcriptase inhibitors
– 1 Protease inhibitor
• Bi-therapy
– 2 Reverse transcriptase inhibitors
Often used schedules
• Reverse transcriptase inhibitors
• „2 drugs in one‟
– Combivir
– Truvada
• Protease inhibitors
– Kaletra
– Reyataz
– Darunavir
(booster included)
+booster
+booster
Institute of Tropical Medicine/ UZA
• Standard schedule
– Combivir
– Kaletra
• If index HIV-positive
– & resistance profile known
• Adaptation schedule
Institute of Tropical Medicine/ UZA
• Practically
– Often high rish exposures
• Weekends
• Night
– Starters-kit at emergency ward UZA
• 4 days dose
– Consult ITM as soon as possible
• Counselling
• Follow-up dose
Proposal for prisons
• Organise
– 1. Starters-kit
– 2. Ask advice
• Local AIDS reference center
– Next working day
Do not use
• Viramune
– Hepatotoxicity
– Hypersensitivity
• Stocrin
– In pregnant women
• Ziagen
– hypersensitivity
Beware
• Protease inhibitors
– Anticonception pill not reliable
Communication double message
• HIV
– Often not very infectious
• But if infected
– Early HIV-infection
• Transmission rates extremely high
• Avoid sex
• Use condoms
• Do not get pregnant
VL Plasma
Tot 100 miljoen
Theoretische curve
Verloop Hiv-virale lading: RNA (VL)
Kopijen per ml
VL Sperma
Indien soa
01234
Weken
1
Jaren
Soa-therapie
5
10
13
Lab-tests
• If patient in high risk group
– Is patient already HIV-positive?
• HIV-antibody test: quick test
• If HIV quick test
– Positive: no PEP
Lab-tests
• Baseline
–
–
–
–
–
–
–
Hemato
Transaminases
HIV-antibody test
HIV-antigen test
Syfilis (RPR, TPPA) or (VDRL, TPHA)
Hepatitis A, B, C-serology
Women: pregnancy test
• Hepatitis-B-vaccination
– Rapid schedule if not vaccinated
Lab-tests
• 6 weeks, 3 months
– HIV-antibody test
– Syfilis (RPR, TPPA) or (VDRL, TPHA)
– Hepatitis A, B, C-serology
• If accident in professional setting
– Also testing at 6 months
Can a pill a day prevent HIV
?
Source of slide
Albert Liu
San Francisco Dept of Public Health
Pre-exposure profylaxis: iPrex-trial
• 2499 MSM
– Hiv-negative at start
• Placebo group
• Truvada group
N = 1248
N = 1251
• Characteristics
%
–
–
–
–
South America
US
Thailand
South Africa
– In commercial sexwork
– Hepatitis B not vaccinated
80
9
5
4
40
65
Pre-exposure profylaxis: iPrex-trial
• Hiv-infections N
– Placebo
– Truvada
83
48
• Protection by Truvada use
%
– Overall
44
– >= 50% pill use
– >=90% pill use
50
72
Pre-exposure profylaxis partially works
• HIV-seroconverters
– No resistance observed
– Drugs levels
Pre-exposure profylaxis: Iprex-trial
• Editorial New England Journal of Medicine
– 30 dec 2010
• Free full text
Protection
Protection
If optimal adherence
%
72
80
82
37
FEM-PrEP young women
Lut Van Damme
N Engl J of Med August 2 2012
Young women < 25 year
5,7
5,9
“Do you think you are at risk for HIV-infection?”
70%: “No”
PrEP already in use?
• Survey USA
– Hiv-healthcare workers
• Responding 189/2000
– 45% had questions about PrEP last 6 months
– 19% made a perscription
• IDSA-2011
– Weblink to:
• Poster at Infectious Diseases Society of America Congres
PrEP already in use in Belgium?
• AIDS reference centers via BREACH
– 8 MD‟s from 8 different centres responded
• Formal PrEP request ever?
• Perscription made ever?
„Yes‟: 3/8
„Yes‟: 0/8
– Case report
• Discordant couple: MSM
– Hiv-negative person wants PrEP during holiday
» Intention to buy it in South Africa
» Truvada 50€ (in Belgium: 569,03€)
– Suggestion
• Frequent PEP-users
– Why not PrEP in stead of PEP?
PrEP: Research continues other drugs
• Approved HIV-drugs
– Entree inhibitors
• Maraviroc
– Integrase inhibitors
• Raltegravir
• Investigational drugs
– Long-acting rilpivirine: IM
– GSK 1265744
– Ibalizumab
PrEP: More questions then answers
• Acceptability
– Medics & paramedics level
– Patient level
• Agree to be tested?
• Stigma related to PrEP?
• Adherence: Will people take their drugs?
• Impact
– Does is reduce transmission?
– Can we handle resistance?
PrEP: More questions then answers
• Ethically
– Low income countries: no antivirals for all HIVpositives
– High income countries: antivirals for HIV-negatives
• Economically
– Cost-effectiviness
– Who will pay? Health Insurance?
– Generic drugs in low income countries?
• ….
Pre-exposure profylaxis: meer vragen dan
antwoorden
• Guidelines
– Wie schrijft voor? In welke setting?
– Aan wie toedienen?
• Hoogrisico-situaties
– Seksueel risico
• Gezondheidswerkers?
– Chirurgen?
– Gynaecologen?
• Follow up
– Neveneffecten medicatie?
– Indien hiv-positief
• Hiv-resistentie-testen
TASP Treatment as prevention
HPTN 052-trial
• Discordant couples
–
–
–
–
Sub-Saharan Africa
Brazil
Thailand
Boston
• Index HIV-positive
– CD4 350-550
• Therapy-groups
– Early start
– Late start
Highlights of AIDS 2012
clinicaloptions.com/hiv
HPTN 052: HIV Transmission Reduced by
96% in Serodiscordant Couples
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .0001)
Linked
Transmissions: 28
Delayed
Arm: 27
Immediate
Arm: 1
P < .001
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
Unlinked or TBD
Transmissions: 11
Single transmission in patient
in immediate ART arm believed
to have occurred close to time
therapy began and prior to
HIV-1 RNA suppression
Conclusions
• „Pharmaco-prevention‟
– It works, if you take your pills
• PEP
– Window of opportunity: short
– If PEP-start
• Tri-therapy by preference
– Expert advice
• PrEP
– More questions then answers
– More trials necessary
< 72 hours
Source:
DHHS Guidelines July 2012
NRTI
Compound
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir DF
Zidovudine
Transfer
Yes
Limited
Excellent
Yes
Yes
High
Yes
Evidence
Low
High
High
High
Medium
High
N/A
Sources
Rats
Human
Human
Human
Rats/primates (monkey)
Human
Human
NNRTI
Compound
Efavirenz
Etavirine
Nevirapine
Rilpiverine
Transfer
Yes
Unknown
Yes
Unknown
Evidence
Medium
Sources
Rats/rabbits/primates (human)
High
Human
Protease Inhibitors
Compound
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir/r
Ritonavir
Nelfinavir
Saquinavir
Tipranavir
Transfer
Limited
Limited
Limited
Minimal
Limited
Minimal
Minimal
Minimal
Unknown
Evidence
High
Medium
Low
High
High
High
High
High
Sources
Human
Human
Human
Human
Human
Human
Human
Human
Entry Inhibitors
Compound
Enfuvirtide
Maraviroc
Transfer
Unknown
Unknown
Evidence
Sources
Integrase Inhibitors
Compound
Raltegravir
Transfer
High
Evidence
Medium
Sources
Human/rabbits/rats
Tenofovir vaginal gel applicator
CAPRISA 004- methods
• African HIV-negative women
– South Africa
• N = 1085
• Gel insertion in vagina
– 12 hrs before & within 12 hrs after
• sexual intercourse
CAPRISA 004 – main results
HIV incidence
Tenofovir
Placebo
5.6
9.1
Overall protective effect
39%
Women with >80% adherence
54% protection
CAPRISA 004 - safety
• No safety issues
• Big worry
– Resistance “break-through” infection
• No TDF related resistance detected
– But short follow up
The CAPRISA 004 trial
• Proof of concept trial
– In double-blind, placebo-controlled
Vaginale tabletten (Microbiciden) als hiv-preventie
• Caprisa trial
• Caprisa slide set