HIV TRANSMISSION AND PREVENTION KENNETH H. MAYER, M.D. BROWN UNIVERSITY/MIRIAM HOSPITAL FENWAY COMMUNITY HEALTH 5/31/07

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1 HIV TRANSMISSION AND PREVENTION KENNETH H. MAYER, M.D. BROWN UNIVERSITY/MIRIAM HOSPITAL FENWAY COMMUNITY HEALTH 5/31/07

2 Estimates of Per-Contact Risk of HIV Infection

3 HIV TRANSMISSION SIGNIFICANT, LOW PROBABILITY EVENT (<1/100 RISK PER CONTACT ON AVERAGE) MULTIPLE CO-FACTORS ARE INVOLVED PLASMA VIRAL LOAD TRANSMISSION CAN WIDER HAART ACCESS HIV SPREAD? 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, MAY ALTER HIV IN DIFFERENT COMPARTMENTS BIOLOGICAL INTERVENTIONS ARE INFLUENCED BY BEHAVIORAL ISSUES

4 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)

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 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

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

8 HOW HIV INFECTS MUCOSA

9 Semen HIV in patients with suppressed viral load Controls (drug naive) n=55 Patients (%) with detectable HIV in semen p< Potent ART p=0.025 n=114 HIV-RNA HIV-DNA Vernazza, Cohen et al., AIDS, 2000

10 Cervicovaginal HIV and HAART Cu-Uvin et al., AIDS, 2000; 14:415

11 CAN HAART HIV TRANSMISSION? TWO EUROPEAN AND ONE AFRICAN OBSERVATIONAL STUDIES SUGGESTING SERODISCORDANT PARTNERS ON HAART WERE LESS LIKELY TO TRANSMIT HIV (MUSICCO, 1994; CASTILLA, 2005; KAYITENKORE, 2006) HIV INCIDENCE AMONG SF MSM RAISED QUESTIONS ABOUT THE EFFECTIVENESS OF HAART TO DECREASE TRANSMISSION, GIVEN ITS WIDESPREAD USE (KATZ, AJPH, 3/02) WIDER ACCESS TO HAART IN BRAZIL AND TAIWAN ASSOCIATED WITH DECREASED TRANSMISSION. BUT INCREASING TRANSMISSION OF RESISTANT HIV HPTN 052: RCT OF HAART TO ASSESS EFFECT ON TRANSMISSION: 5 COUNTRIES, 1750 C0UPLES

12 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)

13 Acute HIV and STD episodes (Cohen and Pilcher, JID, 2005) STD STD Episode Episode STD STD Episode Episode AIDS AIDS Acute Acute Infection Infection 3 3 wks wks HIV RNA in Semen (Log10 copies/ml)

14 Acute Infections and HIV Prevention Rakai study: 40% of new transmissions were from acutely infected pts (Wawer, JID, 2005) 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 ART and behavioral interventions to slow HIV spread?

15 SEXUALLY TRANSMITTED INFECTIONS AND HIV HIV susceptibility Breakdown of mucosal integrity Recruitment of activated target cells Enhanced cytokine environment HIV shedding Elevated cervicovaginal VL Higher level of seminal HIV RNA Recovery of HIV in genital ulcers

16 SYNDROMIC STI RX. HIV: MWANZA TRIAL Community-based randomization, HIV prevalence relatively low, 1-4% 29% reduction in syphilis 49% reduction in urethritis No changes in condom use or sexual behavior 38% reduction in HIV incidence, in an area with low HIV prevalence Grosskurth et al. Lancet 1995;

17 PERIODIC MASS RX. DID NOT HIV: RAKAI TRIAL Rx. for gonorrhea, chlamydia, trich, BV, chancroid and syphilis q 10 months 20% reduction in syphilis 41% in trichomoniasis No reduction in HIV incidence in an area where HIV prevalence was already >16% HIV prevalence already too high for STI rx to be beneficial, or periodic rx. ineffective?

18 FACTORS TO CONSIDER IN STI CONTROL TO DECREASE HIV TRANSMISSION LOCAL PREVALENCE OF STI AND HIV. HIV INFECTIOUSNESS AND SUSCEPTIBILITY: GUD>INFLAMMATORY. EASE OF DETECTION: GUD EASY. GC, CT, TV: NOW EASY WITH NEW DNA/RNA TESTS, BUT COSTLY CURABILITY RX. RESERVOIR, PARTNERS ROLE OF HSV

19 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, Source: Wawer M et al, Lancet 1999

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

21 POST-EXPOSURE (PEP) ANIMAL DATA: <72 H, 28 D COURSE MOTHER-TO-CHILD TX CDC CASE-CONTROL STUDY OF HCW: AZT ALONE TX. ±80% NON-OCCUPATIONAL NPEP FOR HIV PREVENTION? CONCERNS ABOUT EFFECTS ON PREVENTION MESSAGES

22 NPEP IN BRAZILIAN MSM (SCHECHTER,JAIDS, 4/04) High risk participants educated about PEP use and given AZT/3TC Starter Packs. About 1/3 did not engage in risky behavior 1/3 were risky and used PEP 1/3 were risky and didn t use PEP 10 Acute infections among those who didn t use PEP (SC rate: 4.7%); only one new infection in PEP users (<1%). 89% adherence, highly motivated cohort, >70% side effects; best proof of concept.

23 FENWAY NPEP: LESSONS LEARNED NPEP administration is feasible, but labor intensive, in a community based setting. Trend towards increased utilization. NPEP use does not necessarily lead to behavioral change, but could be an educable moment. NPEP users may be poly-drug users, and may benefit from harm reduction and mental health referrals. Tenofovir + 3TC or FTC well-tolerated (off-label!)

24 EARLY PREP STUDIES 936 women in Cameroon, Nigeria and Ghana Daily dose 300 mg oral tenofovir No safety concerns raised HIV infections: 2 in TDF vs 6 in Placebo (p=0.24), but. No TDF resistance in those who became infected Community engaged, ethical challenges met Conclusion: further efficacy studies warranted (Peterson et al, IAS 2007) Studies underway in Thailand, Botswana, South America, and USA.

25 THE SEARCH FOR THE IDEAL MICROBICIDE Rationale: Unprotected Sex-reproduction, coercion, pleasure Active against a range of sexually transmitted pathogens Not irritating to mucosal surfaces +/- spermicidal formulations Acceptable (odor, color, taste, lubricity, portability, stealth factor )

26 WHERE MICROBICIDES MAY WORK

27 ANTI-HIV VACCINES Failure of VaxGen Many promising CTL approaches in the pipeline, e.g. adenovirus and vaccinia Prime-boost, antibodies and CTLs All many years away

28 Male Circumcision Trials 3 African studies assessed benefit for HIV- men All achieved about 50% in HIV incidence Study in HIV+ men suggested increased transmission if sex resumed too soon. Cultural issues MSM trials? Benefits must be weighed against risks (Bailey; Gray, Lancet, 2007) A relief on the tomb of Ankh-Mahor

29 HIV and STDs Fenway Community Health (Mayer, CDC STD Conference, 2006) # % HIV+ Gonorrhea (n=141) Syphilis (n=51) Chlamydia (n=33) All cases (n=223)

30 What else might explain the increase in sexual risk? Habituation Invisibility Prevention Fatigue Internet Cultural issues Serosorting Party Drugs

31 Counseling Received At That Day s Visit: CAPS HRSA Study Percent of Patients 50% 45% 40% 35% 30% 25% 20% 15% 10% 25% 42% 37% 33% 5% 0% HIV Prevention ART Adherence Emotional Issues Diet & Nutrition

32 What docs can do to prevent HIV: TALK ABOUT SEX Be comfortable with one s own sexuality Recognize that sex is important in people s lives Recognize that sexuality may be fluid, e.g. may change as young people experiment Recognize that sexual orientation and gender identity may be at variance. Sexual history is one part of complete medical exam, so maximal integration is important.

33 The best time to plant a tree was 20 years ago the second best time is today. Social worker comforting AIDS patient, Bangkok