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  • PrEP and interpreting the iPrEx trial results James Wilton Biomedical Science of HIV Prevention Project Coordinator December 6 th , 2010
  • Pre-exposure prophylaxis (PrEP)
  • What is pre-exposure prophylaxis?
    • Breaking it down
    • Pre-exposure = before an exposure
      • Medication used before an exposure occurs
    • Prophylaxis = prevention
      • Medication used for prevention instead of treatment
    • Putting it together
    • Medication used BEFORE an exposure in order to prevent a disease or condition
    • Currently being used
    • Pregnancy (progesterone-based birth control)
    • Malaria (malarone, doxycycline)
    • Tuberculosis (isoniazid)
    • HIV prevention
    •  Antiretrovirals?
  • How would PrEP work?
    • Steps leading to HIV infection
        • An infected body fluid comes into contact with a mucous membrane such as the rectum, vagina, or penis
        • HIV crosses the epithelial barrier and enters underlying tissue
        • Replicates in the mucous membrane tissue (1-3 days)
        • Enters the lymphatic and circulatory system and spreads throughout the body
    • “ Window of opportunity”
      • The time when the amount of virus is small and is replicating at the mucous membrane
      • Antiretrovirals could prevent HIV infection by helping the body clear the virus before it spreads
      • Potential for therapeutic benefit
  • Potential PrEP strategies Route of drug delivery
    • Oral (pill)
    • Topical microbicide(gel)
      • Rectal
      • Vaginal
    • Injection
    • Intravaginal ring
    Dosing schedule
    • Daily
    • Intermittently
    • Coitally (before/sex)
    Number of antiretroviral drugs
    • Single
    • Combination
    Choice of antiretroviral drug
    • Over 25 available
  • What’s being researched?
    • Large-scale studies
    • Oral PrEP
      • Daily pill containing tenofovir (Viread) or tenofovir combined with emtricitabine (Truvada)
    • Topical PrEP
      • 1% tenofovir vaginal gel applied daily or coitally (before/after sex)
    • Smaller Studies
    • Gels used rectally
    • Pills used intermittently or coitally
    • Slow-release intravaginal rings
    • Long-lasting injections
    • Antiretrovirals other than tenofovir and emtricitabine
  • Concerns
    • Partial protection
    • Medical Concerns
      • Safety
      • Drug resistance
    • Behavioral Concerns
      • Adherence
      • Increased risk behavior (risk compensation/disinhibition)
  • CAPRISA 004 Study “ Proof-of-concept” for PrEP
  • CAPRISA Strategy Route of drug delivery
    • Oral (pill)
    • Topical (microbicide)
      • Vaginal Gel
    • Injection
    Dosing schedule
    • Daily
    • Intermittently
    • Coitally
      • Before and after sex
    Number of antiretroviral drugs
    • Single
    • Combination
    Choice of antiretroviral drug
    • Tenofovir
    • Tenofovir + emtricitabine
  • Effectiveness of tenofovir gel
    • Key Points
    • Overall, the HIV incidence was 39% lower among women receiving the tenofovir gel compared to those using a placebo gel
    • Women who used the gel more consistently, both before and after sex, had a greater level of protection against HIV infection
    • The tenofovir gel also reduced the incidence of herpes by 51%
    Effectiveness Overall 39% >80% of sex acts 54% 50-80% of sex acts 38% Less than 50% of sex acts 28%
  • Safety, resistance, and risk behavior
    • No increase in side-effects
      • Mild, self-limiting diarrhea slightly higher in women using the Tenofovir gel
    • No renal toxicity
    • No safety concerns in pregnancy
    • No liver effects in people with Hepatitis B
    • No increase in risk behavior
    • No drug resistance
    • No therapeutic benefit
  • Oral pre-exposure prophylaxis What do we know?
    • Key Points
    • Daily oral tenofovir was generally safe and well tolerated when used by women and men who have sex with men
    • No conclusions could be made on the effectiveness of daily tenofovir
    Study #1 Study #2 Population Heterosexual women (n=~900) Men who have sex with men (n=400) Location(s) Ghana, Nigeria, Cameroon United States Intervention Daily oral tenofovir Daily oral tenofovir Adherence 69% (pill counts) N/A Safety
    • No safety problems
    • No drug resistance
    • No risk compensation
    • Slightly higher frequency of back pain
    • No drug resistance
    • No risk compensation
    # HIV infections 6 (placebo) vs. 2 (daily tenofovir) 3 (placebo) vs. 3 (delayed arm) vs. 0 (daily tenofovir)
  • The Pre-Exposure Prophylaxis Initiative (iPrEx) Study
  • iPrEx Study Basics
    • A Phase III randomized, double-blind, placebo-controlled,
    • safety/efficacy study
    Locations Brazil, Ecuador, Peru, South Africa, Thailand, United States Population Men who have sex with men (n=2499) Study length July 2007 to October 2010 Study groups
    • 1. Daily oral Truvada pill
      • tenofovir (TDF) and emtricitabine (FTC)
    • 2. Daily placebo pill
    Comprehensive package of prevention services
    • HIV testing and risk-reduction counseling
    • Diagnosis and treatment of STIs
    • Condoms
    • Post-exposure prophylaxis
  • iPrEX Strategy Route of drug delivery
    • Oral (pill)
    • Topical (microbicide)
    • Injection
    Dosing schedule
    • Daily
    • Intermittently
    • Coitally
    Number of antiretroviral drugs
    • Single
    • Combination
    Choice of antiretroviral drug
    • Tenofovir
    • Tenofovir + emtricitabine
  • Inclusion/exclusion criteria
    • Inclusion criteria
      • HIV-uninfected men who are 18 years or older
      • High risk for HIV infection (one or more of the following)
        • No condom use during anal intercourse with a male HIV-positive partner or a male partner of unknown HIV status during the last 6 months
        • Anal intercourse with more than 3 male sex partners during the last 6 months
        • Exchange of money, gifts, shelter, or drugs for anal sex with a male partner during the last 6 months
        • Sex with a male partner and STI diagnosis during the last 6 months or at screening
        • Sexual partner of an HIV-infected man with whom condoms are not consistently used in the last 6 months
    • Exclusion criteria
      • Previously diagnosed active or serious infections (ie. Tuberculosis, bone conditions)
      • Active medical problems (ie. heart disease, lung disease, diabetes, cancer)
      • Acute HBV infection or liver cirrhosis
      • Glucose or protein in urine (kidney disorder)
      • History of bone fractures
  • Study participant characteristics
    • Average age was 27 (50% were between 18-24)
    • 1% transgender women
    • Over 70% Hispanic
    • An average of 18 sexual partners in past 12 weeks
    • 40% had transactional sex in past 6 months
    • 60% had unprotected receptive anal intercourse in past 12 weeks
    • 35% infected with HSV-2 (herpes)
  • Study Measures
    • Study visits scheduled every 4 weeks
    • Safety
      • Side-effects
      • Clinical and laboratory adverse events
    • Risk behavior and STIs
    • Adherence
    • HIV status
    • Participants who became HIV-infected
    • CD4 count
    • Viral load
    • Drug resistance
  • Interpreting the results
  • Overall effectiveness of daily Truvada
    • Key Points
    • The HIV incidence in the Truvada group was 44% lower relative to the placebo group
    • The result was statistically significant
    • The overall self-reported adherence was 95%
    • Daily Truvada did not reduce the risk of other STIs
    Truvada Placebo # Study participants 1251 1248 # HIV infections 36 64
  • More effective when taken consistently
    • Key Points
    • Adherence was measured through self-report and pill counts
    • Participants with higher adherence were less likely to become infected
    • Participants had over 90% adherence at 49% of study visits and over 50% adherence at 81% of study visits
    Effectiveness > 90% adherence 73% > 50% adherence 50% < 50% adherence 32%
  • Subanalysis of Truvada group
    • Key Points
    • Many participants did not have drug in their blood despite high self-reported adherence
    • Most participants who became HIV-infected during the trial
    • did not have drug in their blood
    • People with drug in their blood had a 92% lower risk of infection compared to those without drug in their blood
    Participants who remained HIV-negative Participants who became HIV-positive % with drug in their blood 51% 9%
  • Safety of daily Truvada
    • Key Points
    • Daily Truvada was generally safe and well tolerated
    • Elevated serum creatinine levels returned to normal after discontinuing drug
    • Nausea was only higher during the first four weeks
    • Unintentional weight loss may have been due to nausea
    Truvada Placebo Elevated serum creatinine levels 2% 1% Moderate nausea (first 4 weeks) 9% 5% Unintentional weight loss (5% or more) 2.2% 1.1%
  • Risk behavior
    • No evidence of increased risk behavior
      • Total number of sexual partners (in the past 12 weeks) decreased from 12 to 5 partners
      • Use of condoms increased from about 50% to 80%
      • Prevalence of STIs decreased
    • Comprehensive prevention services offered
      • 39,754 visits for HIV counseling and testing
      • 1,019 cases of syphilis were diagnosed and treated
      • 585,000 condoms were distributed
  • Effect of daily Truvada after infection
    • Drug resistance was detected
      • Drug resistance was detected in 2 study participants who started Truvada when they were already HIV-positive
      • No drug resistance was detected in study participants in the Truvada group who became infected during the trial
    • No therapeutic benefit was provided
      • Viral load and CD4 count was similar between those who became infected in the Truvada vs. Placebo group
  • What did the trial tell us?
    • Daily Truvada, in combination with a comprehensive prevention package, reduced HIV incidence among high-risk men who have sex with men.
    • Daily Truvada was more effective when taken consistently
    • The risk of side-effects, toxicity, and drug resistance were low (but this may have been due to poor adherence)
  • What didn’t the trial tell us?
    • Safety/effectiveness of other antiretrovirals
    • The safety and effectiveness of oral Truvada…
      • Over a longer period of time
      • If used only occasionally (intermittently) or coitally
      • In excluded populations (ie. Adolescents and people with underlying health conditions)
      • In preventing against other routes of HIV transmission (ie. intravenous, vaginal/penile)
      • In reducing HIV incidence outside of a clinical trial
    • Risk behavior and adherence under “real life” conditions
    • The “true” risk of drug resistance and side-effects
  • Questions?