ART FOR HIV PREVENTION: PANACEA OR PANDORA S BOX? KENNETH H. MAYER, M.D.

Transcription

1 ART FOR HIV PREVENTION: PANACEA OR PANDORA S BOX? KENNETH H. MAYER, M.D.

2 HIV TRANSMISSION SIGNIFICANT, LOW PROBABILITY EVENT (<1/100 AVERAGE) MULTIPLE CO-FACTORS ARE INVOLVED PLASMA VIRAL LOAD TRANSMISSION CAN WIDER HAART ACCESS THE SPREAD OF NEW INFECTIONS? SEXUALLY TRANSMITTED INFECTIONS (STI) HIV TRANSMISSION AND ACQUISITION: CAN STI CONTROL HIV SPREAD? BLOOD AND GENITAL HIV MAY CHANGE IN PARALLEL, BUT LOCAL FACTORS, E.G. STI, HAART CONCENTRATIONS MAY ALTER HIV IN DIFFERENT COMPARTMENTS BIOLOGICAL INTERVENTIONS MAY BE INFLUENCED BY BEHAVIORAL ISSUES

3 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 Circumcision 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)

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

5 HOW HIV INFECTS MUCOSA

6 Source: Wawer M et al, Lancet 1999 HSV control: Rationale for HSV-2 control to reduce HIV transmission HIV plasma RNA in the Probability of HIV infection in the HIV- partner per contacts HIV+ partner (copies/ml) HSV+ HSV- < , ,500-38, >38,

7 No. % Syphilis Among Fenway Clients: The new normal Cases Test

8 HIV RNA in Semen (Log 10 copies/ml) Acute HIV and STD episodes (Cohen and Pilcher, JID,

9 WHY ART FOR PREVENTION? HIV is spreading rapidly, more than 5 million new infections in the next year! Behavioral interventions have not resulted in long term changes in most settings Vaccines and Microbicides 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.

10 HOW HAART COULD ALTER HIV TRANSMISSION: NEED TO MONITOR PARTNERS PVL SURVIVAL PLHIV GENITAL TRACT DURATION OF HIV INFECTIOUSNESS TRANSMISSION TRANSMISSION RELEVANT ISSUES: ACCESS, ADHERENCE, PREVENTION, STI RX.

11 Effects of Disease Stage and Zidovudine Therapy on the Detection of Human Immunodeficiency Virus Type 1 in Semen Deborah J. Anderson, Thomas R. O Brien, Joseph A. Politch, Adriana Martinez, George R. Seage III, Nancy Padian, Robert Horsburgh, Kenneth H. Mayer JAMA 267: , Cross-sectional (n=95) and longitudinal (n=35) studies of HIV-1 in semen from HIV+ men. Results: HIV-1 cultured from seminal plasma and semen cells Intermittent shedding HIV with leukocytospermia HIV in advanced disease stage HIV with zidovudine ART

12 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.

13 Patients (%) with detectable HIV in semen Semen HIV in patients with suppressed viral load 100 Potent ART Controls (drug naive) n=55 n=114 p< p= HIV-RNA HIV-DNA Vernazza, Cohen et al., AIDS, 2000

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 Can Chronic HAART Decrease HIV Transmission? HIV INCIDENCE IN BRAZIL AND TAIWAN MULTIPLE REPORTS OF INCREASING TRANSMISSION OF RESISTANT HIV I5-30% OF NEWLY INFECTED PATIENTS HPTN 052: RCT OF HAART TO ASSESS EFFECT ON TRANSMISSION HIV discordant couples:india, Brazil, Thailand, Malawi, Zimbabwe, U.S. Early vs. later ART, CD4 >300 Monthly monitoring, couples counseling

16 Preclinical PEP/PrEP Studies NNRTI or NRTI were protective 70% to 100% Effective/exposure Emtricitabine + Tenofovir The combination was effective Even after repeated rectal exposures (14) The prophylactic activity probably reflects Long intracellular half life Activity in Macrophages High concentration in genital tissues Tsai 95; Van Rompay ; Subbarao 05; Heneine 06

17 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%) ZDV (200%) TDF (400%) d4t (4%) RTV (20%) DLV (20%) ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) Female Genital Tract Exposure Fusion Inhibitors Nucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Nonnucleoside Reverse Transcriptase Inhibitors (Kashuba et al)

18 Example: US DHHS Guidelines for Non- Occupational PEP MMWR 2005

19 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:

20 Patients (%) Tenofovir DF + Emtricitabine or Lamivudine for Non-Occupational PEP Treatment arms TDF/FTC (n=68) TDF/3TC (n=44) AZT/3TC (n=122) AZT/3TC+ 3 rd drug (n=119) Mainly MSM, similar between 20 NPEP arms 0 Mayer KH, et al. JAIDS Regimen Completion Rates % FTC/ TDF 87.5% TDF + 3TC 42.1%* ZDV/ 3TC *P< versus TDF-based regimens 38.8%* ZDV/ 3TC + 3 rd Drug

21 Tenofovir DF + Emtricitabine or Lamivudine for Non-Occupational PEP Tenofovir: diarrhea or abdominal discomfort Zidovudine: nausea and vomiting: AE s more serious FTC/ TDF TDF + 3TC ZDV/ 3TC ZDV/3TC + 3 rd Drug Diarrhea 47.5* Fatigue * Abdominal discomfort Nausea/ vomiting Adverse Events (%) Headache *P<0.05 and P<0.01. Mayer KH, et al. JAIDS. 2007

22 Percent Risk Behavior at Time of Incident Unprotected Anal Sex Alcohol Use Recreational Drug Use Note: TDF/3TC group reported more ua than the AZT/3TC group (30%), and about the same as the AZT/3TC+1 group (52%).

23 RISK BEHAVIOR IS NOT UNIFORM Calendar-based retrospective history on newly infected MSM Susceptible period from 3 months before last negative to first HIV positive test Each row represents a newly infected MSM Each dot represents a report of at least one unprotected anal or oral sex contact with HIV positive or unknown partner S Buchbinder 2005

24 Phase 2, Randomized, Double Blinded, Placebo Controlled Trial Conducted between June 2004 and March 2006 Cameroon; Nigeria; Ghana Objective: Determine the safety and preliminary effectiveness of a daily dose of 300 mg oral TDF vs Placebo for HIV prevention among high risk women also receiving HIV testing, counseling, and condoms Safety Evaluated in N=936 including 428 Person Years

25 HIV Seroconversions 8 on-product seroconversions 2 TDF : 6 placebo Difference is not statistically significant 95% confidence interval = p = 0.24 On TDF seroconversions occurred after 1 and 2 months on product, neither TDF-R Baseline Specimens were not available Peterson, Plos Clinical Trials, 2007

26 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, XVI AIDS Conference, Toronto, 2006

27 PREP and Drug Resistance? TDF/FTC resistance comes with a high fitness cost Monotherapy with TDF No resistance detected after 28d in people (Barditch-Crovo 2001) Resistant minor variants enriched in monkeys (Van Rampay 2007) Non-human primate studies TDF PEP partially effective vs drug resistant SIV (Van Rompay 2000) No TDF resistance after TDF or FTC/TDF failure (Subbarao 2006) FTC resistance intermittently detected (Garcia Lerma 2007) TDF and FTC resistance Makes AZT more active, but diminishes activity of other nrtis Has no effect on other classes of drugs

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29 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

30 PrEP is not already in wide use Outcome Overall (n=851) SF Bay Area (n=403) Circuit Party (n=176) STD Clinic (n=272) Heard of PrEP 18% 20% 19% 15% Knew PrEP user 2% 2% 4% 2% Used PrEP 0.12% 0% 0% 0.39% 1 Would use PrEP if safe/effective 68% (n=563) 69% 66% n/a 1 Had not heard of PrEP and received 30 days of medication from clinician may have been post-exposure prophylaxis (1 month of antiretroviral therapy started shortly after high-risk exposure) Liu, IAS, 2006

31 An orally delivered CCR5 inhibitor Provided partial protection of macaques from SHIV-162P3 vaginal transmission Condition Infected p-value Controls (no inhibitor, including historic controls) 16/18 CMPD 167 for 4 days prior to challenge 3/ CMPD 167 for 10 days post challenge (inc. day 0) 4/ CMPD 167 for 4 days prior + 10 days post challenge 6/ (CMPD 167 +/- 4 days prior + 10 days post challenge 10/ ) Courtesy of John Moore

32 WHERE MICROBICIDES MAY WORK

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

34 NEW ART FOR PREVENTION STUDIES: DRUGS, FREQUENCY, & ROUTE Karim: TDF Vaginal Gel dose just before and just after intercourse MTN: Oral vs. topical chemoprophylaxis; design challenges, double randomization New agents, combinations? Important to have sufficient studies to understand dosing regimens/trade offs using combinations (e.g. cost, AEs, efficacy, adherence)

35 HIV incidence among IDUs has been declining in the U.S.

36 Multivariable analysis of seroconversion risk: Drug use in Explore Drug N at baseline No. of infections Hazard ratio* (95% CI) Heavy alcohol** (1.2, 2.8) Amphetamines (1.4, 2.6) Alcohol/drugs before sex (1.1, 2.3) *REF = no/light/moderate use of alcohol; no speed use; no use before sex ** 4+ drinks every day or 6+ drinks on a typical day

37 CONCLUSIONS Vaccines are years away, antiretrovirals are available now However, because they will need to be used recurrently and are not expected to be 100% protective, further studies of pharmacology, virology and behavioral sciences will be needed to best understand their intended and unintended consequences. They may become part of HAARP: highly active antiretroviral prevention