Acute HIV infection: Implication for HIV Control and Cure - HIV-NAT

Acute HIV infection:
Implication for HIV Control and Cure
Jintanat Ananworanich, MD, PhD
Deputy Director in Scientific Affairs, HIV-NAT
Chief, SEARCH
The Thai Red Cross AIDS Research Centre
Bangkok, Thailand
[email protected] ;
[email protected]
Outline
• Importance of intervening during acute HIV
infection in HIV control and cure
• Diagnosis of acute HIV infection and clinical
management
• Treatment during acute HIV infection
– SEARCH 010/RV 254 study
– Implication on HIV control
– Implication on HIV cure
• Functional cure
(Viremic control following ART interruption)
• HIV cure in the pediatric population
Acute HIV Infection Research:
Implication for HIV Control and Cure
Identification of subjects during
acute HIV infection (first 4 weeks of infection)
Diagnose HIV at
height
of transmission
potential
Control HIV Spread
Intervene to
preserve
Immunity, limit
viral replication
and reservoir
Understand early
immunologic and
virologic events
Design preventive
vaccine and
treatment strategies
Achieve functional cure
(Undetectable plasma HIV RNA without ART)
Fiebig Laboratory Staging of Acute HIV Infection
Acute
< 4 wk
Early
4 wk- 6 mo
Chronic
> 6 mo
Fiebig I (1-2 wk)
Fiebig II (2-3 wks)
Fiebig III/IV (3-4 wks)
Fiebig EW, AIDS 2003
How do we know someone
has acute HIV infection?
Sensitive HIV EIA (Ag-Ab combo assay)
Positive
HIV-infected
Negative
Not infected
Could this be acute HIV infection?
How do we know someone
has acute HIV infection?
Sensitive HIV EIA (Ag-Ab combo assay)
Positive
HIV-infected
Less sensitive HIV EIA
Positive
Chronic HIV
Negative
Negative
Not infected
Nucleic acid testing
Positive
Acute HIV Infection
Negative
Not infected
Results from the Thai Red Cross Anonymous
Clinic (April 2009 to December 2012)
58,908 sensitive HIV EIA (Ag-Ab combo assay)
4,247 positive
54,661 negative
Less sensitive HIV EIA
4190 positive
Chronic HIV
57 negative
Pooled Nucleic acid testing
47 positive
104 acute HIV
54,614
negative
Not infected
Nucleic acid testing diagnosed HIV earlier than
sensitive EIA by 5 days
SEARCH010/RV254 study
Natural History of Acute HIV Infection in Thais
9
Median Time to VL peak= 14 days (range 7-18 days)
Median VL at peak = 6.7 log (range 5.8-8.5 log)
Median Time to 3rd gen EIA+ = 15 days (range 10-22)
8
Log10 RNA copies/ml
7
6
5
4
3
ARS symptoms
2
1
n=17
0
0
10
20
30
40
50
60
70
80
90
100
days
Day 0 = 1st reactive RNA
RV217 study; PI: Dr. Merlin Robb (MHRP)
Acute Retroviral Syndrome (ARS)
Symptoms
Overall
Fever
Myalgia/headache
Fatigue
Oral ulcer
Skin rash
Sore throat
Diarrhea
Adenopathy
%
87
77
60
57
53
50
50
37
13
Average time from onset of
HIV to ARS symptoms = 11 days
Almost all sought care elsewhere
but none was offered HIV testing
Ananworanich J, Plos One 2012
Should Acutely HIV-infected Patients
be Started on ART?
US guideline
WHO guideline
Consider ART for
acute infection or
seroconversion within
the past 6 months
No specific
recommendation for
acute/primary
infection
CD4 < 500 cells/mm3
CD4 < 350 cells/mm3
SEARCH 010 study
62 of 86 (72%)
35 of 86 (40%)
Antiretroviral Therapy in Acute HIV Infection
•
•
•
•
PRO
Decrease severity of
acute retroviral
syndrome
Preserve immunity
Reduce HIV RNA and
alter viral set point
Reduce risk for
transmission
•
•
•
•
CON
Unknown long-term
clinical benefit
Drug toxicity
Resistance
Quality of life
25-50% of newly infected cases are from
contact with early HIV-infected persons
100% ART coverage is required to eliminate HIV spread
If chronic HIV infection alone is treated
ART coverage for both early and chronic HIV
is required to eliminate HIV spread
Powers KA, Lancet 2011
No intervention
75% chronic
+25% early
+50% early
1990
2000
2010
2040
Powers KA, Lancet 2011
SEARCH 010/RV 254 study:
Acute HIV enrollment/compartment studies/new drugs
Real-time screening of 58,908 samples in Bangkok
by pooled nucleic acid and sequential EIA
Acute HIV infection (AHI) confirmed (n= 104)
86 AHI enrolled
3 days
45% F I/II
2 days
Main protocol
(n=86)
- Clinical
characterization
- Phlebotomy
Optional
procedures
- Sigmoid biopsy (n=63)
- Leukapheresis (n=55)
- Lumbar puncture (n=59)
- MRI/MRS
(n=80)
- Genital secretion (n=82)
ARV protocol
(n=84)
MegaHAART
HAART
Updated from Ananworanich J, PLoS ONE 2012
www.clinicaltrials.gov 00796146
Characteristics
Median age
MSM
Median duration of infection
Fiebig I
Fiebig II
Fiebig III
Median CD4
Median HIV RNA
Bachelor degree or higher
Median monthly income
Illicit drug use at HIV exposure
N of sexual partner in past month
Values
28 years
91%
18 days
34%
11%
47%
383 cells/mm3
5.6 log
62%
30,000 Baht
24%
Mean 3 (max 15)
Reduction in Unprotected Sex after HIV Diagnosis
n/N:
69/83
17/75
SEARCH 010/RV254 Study
Decline of HIV RNA in Semen after ART
SEARCH 010/RV254 Study
Massive CD4 Destruction in the Gut
during Acute HIV Infection
HIV neg
Primary HIV
Brenchley JM, Douek D et al, J Exp Med 2004
Active depletion of CD4+ T cells in the Sigmoid
during acute HIV infection in SEARCH 010 Study
%CD4
1-3 wks
3-4 wks
12 months
Alexandra Schuetz (AFRIMS)
Integrated HIV DNA in Peripheral Blood
Cells is Undetectable in Fiebig I Subjects
No HIV
DNA in
memory
CD4+
subsets
All
undetectable
Fiebig I
(n=19)
Fiebig III
(n=25)
Nicolas Chomont (VGTI-Florida)
Impact of Antiretroviral Therapy Instituted
during Acute HIV Infection
• Gut CD4+ T cells immune reconstitution
(Ananworanich J, PLoS ONE 2012)
• Polyfunctional HIV-specific CD4+ and CD8+ T
cells similar to elite controllers
(Cellerai C, PloS ONE 2011)
• Preservation and restoration of lymph node
structure leading to improved survival of naïve
CD4+ T cells (Zeng M, PLoS PATHOGENS 2012)
• Restoration of B cell function (Moir S, Blood 2010)
• Normalization of immune activation markers
(Markowitz M, 2012 IAS HIV Cure Workshop, Abstract 16551)
SEARCH 010: Rapid HIV RNA Decline after ART
* P < 0.05
* *
HAART: TDF/FTC /EFV
MegaHAART: HAART+RAL+MVC
Shorter Latent Reservoir Half-life when
ART is Initiated during Primary HIV Infection
Primary HIV
Half-life
Chronic HIV
5 months
Time to eradicate 8 years
106 cells
44 months
73 years
Chun TW, JID 2007; Siliciano JD, Nature Med 2003
Will ART Initiated
during Acute HIV Infection
Change the Disease Course?
“Viremic Control following ART Interruption”
Post-Treatment Controllers (PTC)
Trials
French
VL < 50
after no
ART
Time at
ART
ART duration
before
interruption
16%
2-3 mos after
diagnosis
5 years
9%
2-4 mos after
infection
1.5 years
8%
2-3 mos after
seroconversion
1 year
(Hocqueloux L,
2010)
Swiss
(Gianella S, 2011)
Europe
/Australia
(Lodi S, 2012)
PTC was associated with starting ART < 2 months
from HIV exposure
SEARCH 010 study: ART started < 4 weeks from
history of HIV exposure
Early ART may Modify HIV Disease Course
Elite controllers
• 0.5%
• HLA B27, B57
overrepresentation
• High frequencies of HIVspecific CD8+ T cells
Post-ART controllers
• Up to 15.6%
• No HLA B27, B57
overrepresentation
• Low frequencies of HIVspecific CD8+ T cells
Low HIV DNA
Reservoir distribution in short-lived memory CD4+ T cells
Low immune activation
High CD4+ T cell count
Seng R, JAIDS 2008; Hocqueloux L, AIDS 2010; McMichael AJ, Nat Rev Immunol 2010;
Goujard C, Antiviral 2012, Bacchus C, 2012 IAS HIV Cure workshop
SEARCH 010
Total HIV DNA after ART in Early Fiebig AHI
(5 yrs)
Figbig I
Fiebig III
19
25
16
23
12
18
11
18
8
16
7
14
14 post-treatment controllers in ANRS PRIMO/Visconti study
HIV DNA after 20 months on ART was 2.1 log
HIV DNA after 6.5 years off ART was 1.71 log1
1Data
provided by Dr. Christine Rouzioux
Examining interventions during
acute HIV for functional cure
Identify acute HIV
Immediate ART to
minimize reservoir size
preserve immunity
Enrollment across
multi-national sites
ART
New drug classes
Better tissue penetration
Reduce HIV replication
Intervention
vs. no intervention
Reduce latently
Infected cells
Enhance immunity
Make cells
resistant to HIV
ART interruption
Control HIV viremia
HIV may be easier to cure in
children than in adults
• 10 cases reported in the literature of children with
positive PCR or culture with subsequent negative
results
• High immune tolerance/low immune activation in
young infants
• Short half life of replication competent virus from
latently infected cells
• 11 months in early treated children vs. 44 months in
adults treated during chronic infection
• Reports of children treated during infancy having no
detectable HIV DNA, HIV-specific immunity or
replication competent virus
Bryson YJ, NEJM 1995; Roques PA, AIDS 1995; Persaud D, AIDS Hum Retrovirus 2007
HIV may be easier to cure in
children than in adults
• 10 cases reported in the literature of children with
positive PCR or culture with subsequent negative
• Higher immune tolerance/lower immune activation in
young infants
• Shorter half life of replication competent virus from
Could there be no HIV left
latently infected cells
after
10-15
years
treatment?
• 11 months
in early
treatedof
children
vs. 44 months in
adults treated during chronic infection
• Reports of children treated during infancy having no
detectable HIV DNA, no HIV-specific immunity and no
replication competent virus
Bryson YJ, NEJM 1995; Roques PA, AIDS 1995; Persaud D, AIDS Hum Retrovirus 2007
Priority for testing HIV cure in children
• Cohort of teenagers treated with ART from
early infancy and currently have no replication
competent virus and no detectable HIVspecific immunity
– Interrupt ART
– Resume ART if detectable viremia
• Rapid transition from PMTCT prophylaxis to
HAART (days after birth)
– Interrupt ART after 2 years of ART in children who
have no replication competent virus and no
detectable HIV-specific immunity
Conclusions
• Nucleic acid testing allows for identification of early
Fiebig stage acute HIV infection
• Awareness of ARS and having low threshold for HIV
testing in patients with HIV risk and ARS symptoms
will enhance acute HIV detection
• ART during acute HIV infection is associated with
preserved immunity and small reservoir size, and
may alter the HIV disease course
• Post-treatment controllers are more common in
patients treated during acute HIV infection and is
associated with shorter duration from infection
onset to ART initiation
Acknowledgements
SEARCH 010/RV254 study participants and investigators
Funding from the US Military HIV Research Program
Antiretrovirals from the Thai Government Pharmaceutical
Organization, Gilead, Merck and Pfizer
Data and input for this presentation
MHRP/AFRIMS
Alexandra Schuetz
Rapee Trichavaroj
Merlin Robb
Jerome Kim
Nelson Michael
Thai Red Cross AIDS Research Centre
Praphan Phanuphak
Mark deSouza
Frits van Griensven
Tippawan Pankam
Nittaya Phanuphak
James Fletcher
VGTI-Florida
Nitiya Chomchey
Claire Vandergeeten
Duanghathai Suttichom
Nicolas Chomont
Peeraya Mangu
Université Paris Descartes
Somprartthana Rattanamanee
Christine Rouzioux
Suteeraporn Pinyakorn (Statistics)