ART for HIV Prevention:

Transcription

1 ART for HIV Prevention: KENNETH H. MAYER, M.D. Brown University/The Fenway Institute August 22, 2009

2 APPROACHES TO PREVENT HIV TRANSMISSION DECREASE SOURCE OF INFECTION Barrier Protection Treat STI Antiretroviral Therapy Maternal-child transmission partner s HIV load Rx of acute infection Blood screening DECREASE HOST SUSCEPTIBILITY Barrier protection Treat STI PEP PREP Microbicides Vaccines Infection Control Circumcision ALTER RISK-TAKING BEHAVIOR Condom promotion Individual interventions Couples interventions Community-based interventions Structural interventions (e.g., economic)

3 WHY ART FOR PREVENTION? HIV is spreading rapidly, more than 2.5 million new infections expected in the next year! Behavioral interventions have not resulted in long term changes in most settings Vaccines are years away ART is available now! HOWEVER, ART is relatively expensive, needs to be used repetitively, may result in toxicities, and can select for resistance, and may result in behavioral disinhibition.

4 CAN HAART COULD ALTER HIV TRANSMISSION? PLASMA SURVIVAL HIV PLHIV GENITAL TRACT DURATION OF HIV INFECTIOUSNESS TRANSMISSION TRANSMISSION RELEVANT ISSUES: ACCESS, ADHERENCE, PREVENTION, STI RX.

5 PLASMA HIV RNA PREDICTS LIKELIHOOD OF TRANSMISSION All subjects Male-to-Female Transmission Female-to-Male Transmission Transmission rate per 100 Person-Years < > < > < > Viral load (HIV-1 RNA copies/ml) and HIV transmission Source: Quinn N, et al, N Eng J Med 2000

6 HOW HIV INFECTS MUCOSA

7 HIV Transmission Efficiency is Related to Viral Burden and Other STDs Probability of HIV infection in the HIV- partner per contacts HIV plasma RNA in the HIV+ partner (copies/ml) HSV+ HSV- < , ,500-38, >38, Source: Wawer M et al, Lancet 1999

8 T Lymphocytes and Macrophages, but not Motile Spermatozoa, are a Significant Source of HIV in Semen Alison J. Quayle, Chong Xu, Kenneth H. Mayer, Deborah J. Anderson Journal of Infectious Diseases 176: , T lymphocytes and macrophages are principal sources of HIV-1 in semen.

9 Persistent HIV RNA Shedding in Semen Despite Virologic Suppression Longitudinal studies on semen and blood HIV RNA post HAART 1 25 men initiating therapy and undetectable by week 16 12/25 (48%) with isolated HIV shedding 4/25 (16%) with high level viral shedding (>5,000 copies/ml) Semen isolates infectious but no drug resistant mutations 4/13 (31%) men with HIV in semen despite prolonged viral suppression (median 126 mos) 264 pair of semen/blood samples from 145 HIV + men ( ) 2 6% of patient on HAART had detectable HIV RNA in semen 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% % No Plasma and Semen 9 3.4% Yes Plasma and Semen % Yes Plasma, No Semen 7 2.8% No Plasma, Yes Semen 1. Sheth P, et al. 16th CROI; Montreal, Canada; February 8-11, Abst Marcelin A, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 51.

10 APV (20%) LPV (5%) NFV (5%) Male Genital Tract Exposure EFV (3%) SQV (3%) RTV (3%) d4t (2%) ENF (ND) IDV (100%) NVP (70%) ABC (150%) ZDV (200%) TDF (500%) 3TC (600%) 0% 100% 200% 300% 400% 500% SQV (ND) ddi (100%) ABC (150%) IDV (200%) 3TC (400%) FTC (600%) EFV (0.6%) d4t (4%) RTV (20%) ZDV (200%) TDF (400%) Maraviroc DLV (20%) Fusion Inhibitors ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) Nucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Nonnucleoside Reverse Transcriptase Inhibitors Female Genital Tract Exposure (Kashuba et al)

11 Test and Treat? Lancet 2009; 373:48-57

12 Can Chronic HAART Decrease HIV Transmission? HIV in several countries where treatment and prevention have been integrated, e.g. Brazil and Taiwan Counter: Resistant HIV transmission, up to 15-30% of new infections HPTN 052: RCT OF HAART TO ASSESS EFFECT ON TRANSMISSION 1750 HIV discordant couples: India, Brazil, Thailand, Malawi, Zimbabwe, SA Early vs. later ART, CD4 >350 Monthly monitoring, couples counseling

13 Treatment as Prevention? 2,993 couples were followed for a median of 512 days HIV-free Survival of HIV- partners, by ARV status of HIV+ Partner ARV Status CY Observation No. Linked Infections Infection Rate (C-Y) Infection Rate Ratio (95% CI) Not on ARV 5, / On ARV / (0.08, 0.59) Survival Probability Off ARV Censored Logrank P<.0001 On ARV On ARV conservative* / (0.14, 0.73) *Includes 2 partners who seroconverted in the same 3-month interval when the HIVinfected partner initiated ARVs Days Sexual risk behaviors lower in those on ART (19% vs 25%, P<0.05) Both ART and change in behavior independently reduced HIV transmission Sullivan P, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 52bLB.

14 Acute Infections and HIV Prevention Rakai study: 40% of new transmissions were from acutely infected pts (Wawer, JID, 2005) Quebec study: almost ½ new infections were from recently infected pts (Brenner, JID, 2007) Using discordant HIV rapid tests results and RNA pooling, almost 2% of STD clinic pts in Malawi were identified with acute HIV infection (Pilcher, NEJM, 2005) Could the identification of hot spots of newly infected pts present opportunities for early ART and behavioral interventions to slow HIV spread?

15 Basis for PEP recommendations Non-human primates Multiple drugs have been shown to decrease HIV transmission pre or post exposure Single dose NVP to Mother/Infant was protective Not enough time to lower VL in mother So drugs may have been primarily active in infant PEP after needlestick Associated with lower risk in HCW AZT alone associated with 80% decrease Not RCT, retrospective case-control MMWR 2005

16 NPEP IN BRAZILIAN MSM PEP (AZT/3TC) 4 day starter pack 28 day course N=200 high risk men Followed over 24.2 months 68 used PEP 109 times HIV incidence 2.9/100py 10 in those who did not use PEP (N=132) Thought partner was HIV-, Did not appreciate risk of that contact 1 in a PEP user (N=68) Risk Behavior decreased Schechter M et al (2004) JAIDS 35:

17 Declines in Risk Behavior with PEP and Counseling artin et al., AIDS 2004

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19 Sexual Behavior During PREP Trial in West Africa Screening Follow-up Number of partners (30 days) Number of new partners (30 days) Number of sex acts (7 days) Condom use (last act) % 94% Peterson et al, PLOS Medicine, 2007

20 CDC U.S. MSM PrEP Study (Project T; Project PrEPare) 100 TDF 100 Placebo 100 No Pills TDF 100 No Pills Placebo Enrollment 9 months 24 months

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22 Is PrEP being used already? ART is available now, could some be diverted? Two MSM studies, one in SF (Liu, 2007) and one in Boston (Mimiaga, 2009) found that less than 1% have used PrEP. Close to 20% heard of PrEP Context matters: interest in using PrEP was as high as 79% if it was found to be effective, safe, cheap, with minimal side effects.

23 Intermittent PrEP/PEP in Macaques with TDF/FTC Animal model of rectal transmission of HIV % Uninfected macaques 6 groups challenged with physiologic inoculum of R5 virus (10 TCID 50 ) doses of TDF/FTC given before (-) or after (+) challenge TDF/FTC Dosing Number of rectal exposures -22h/+2h HR=16.7, P= days/+2h HR=15.4, P= days/+2h HR=9.4, P=0.003 Daily +2h/+26h (PEP) -2h/+22h Untreated controls (n=32) (9 real time and 23 historical) HR=9.9, P=0.002 HR=4, P=0.03 HR=4.1, P=0.02 Extended window of protection associated with long IC No drug resistance on macaques failing PrEP/PEP Garcia-Lerma C, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 47.

24 WHERE MICROBICIDES MAY WORK

25 Topical PrEP in Macaques with TDF or TDF/FTC Study to assess most effective modality for topical ARV gels 1% TDF or 1% TDF/5% FTC gels in 23 macaques Gel (matrix + preservatives) clear, viscous, odorless, stable at 37 x 6 months 3 ml gel applied 30 mins before vaginal challenge with R5 virus inoculum (10 TCID 50 ) Challenges 2x/week for total 20 challenges 100 % Protected no gel (n=2) placebo gel (n=9) FTC/TDF gel (n=6) TDF gel (n=6) Challenges Dobard C, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 46.

26 Oral vs. Topical PrEP? (HPTN 050) 1000 PMPA ng/ml LLOQ Hours

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