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Pre-exposure prophylaxis (PrEP) for HIV prevention. Connie Celum HVTN Full Group Meeting May 2010. Prevention with Antiretrovirals. ARV treatment of HIV+ persons (ART) prevent sexual transmission prevent vertical transmission (pMTCT for mothers) ARV prophylaxis of uninfected persons

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Pre-exposure prophylaxis (PrEP) for HIV prevention

Connie Celum

HVTN Full Group Meeting

May 2010


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Prevention with Antiretrovirals

  • ARV treatment of HIV+ persons (ART)

    • prevent sexual transmission

    • prevent vertical transmission (pMTCT for mothers)

  • ARV prophylaxis of uninfected persons

    • prevent sexual transmission (M  F; M  M)

    • prevent vertical transmission (pMTCT for fetus & breastfeeding infants)

  • Antiretroviral prophylaxis approaches

    • Mucosal (topical) or systemic (oral, SC, IM) or both

    • Pre- or post-exposure

    • Intermittent or continuous dosing


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Can a pill prevent HIV?

Antiretroviral medication, Uganda


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Pre- and post-exposure ART prevents vertical HIV transmission

adjusted HR 0.56, p<0.001

Prolonged nevirapine or nevirapine/zidovudine prophylaxis to breastfeeding infants from Malawi decreased postnatal HIV transmission by half

Kumwenda et al. NEJM 2008


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TDF and FTC/TDF for PrEP transmission

Among the anti-HIV medications currently available, two are generally felt to be the best PrEP candidates:

= TDF (tenofovir)

sold under the trade name Viread

= FTC/TDF (co-formulated emtricitabine + tenofovir)

sold under the trade name Truvada


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TDF and FTC/TDF for PrEP transmission

POTENT:

  • Broad antiviral activity (HIV-1 subtypes, HIV-1&-2)

  • Active against virus types found both in early and late HIV infection (i.e., R5 & X4 viruses)

  • Acts early in the life cycle of HIV (pre-integration) so it can block initial infection

  • Rapidly active (suggesting even intermittent use might be possible)

    SAFE:

  • Favorable safety and tolerability

  • High barrier to resistance, and limited cross-resistance

    EASY:

  • Easy to use (low pill burden, no food restrictions, no drug interactions with contraception/TB meds/antibiotics)


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Preclinical Evaluation of Tenofovir (TDF) and TDF-Emtricitabine (FTC) (N=40)

  • Either FTC or TDF were protective

    • 70% to 100% Effective/exposure

  • Emtricitabine + Tenofovir

    • The combination was 100% effective

    • Even after repeated rectal exposures (14)

  • The prophylactic activity probably reflects

    • Long intracellular half life

    • Activity in macrophages

    • High concentration in genital tissues


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Safety/efficacy trials of tenofovir-based oral/topical PrEP 2010

USA

Thailand

Botswana

Kenya

Malawi

South Africa

Tanzania

Uganda

Zambia

Zimbabwe

>12 studies, up to 13 countries

20,000+ participants

Brazil

Ecuador

Peru




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Timelines 2010

Figure: AVAC


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The iPrEx Study 2010

  • 2499 high risk MSM

  • Randomized 1:1 Daily Oral PREP

  • FTC/TDF vs Placebo

  • Followed on Drug for:

    • HIV seroconversion

    • Adverse Events (especially renal & liver)

    • Metabolic Effects (Bone, Fat, Lipids)

    • HBV Flares among HBsAg+

    • Risk Behavior & STIs

    • Adherence

    • If infected

      • Drug Resistance

      • Viral load

      • Immune responses & CD4 Count

Funded by NIH and BMGF


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HIV discordant couples are key 2010

  • Substantial fraction of new cases of HIV in Africa occur within stable, cohabitating HIV discordant couples (one partner is HIV infected and the other is HIV uninfected).

    • In a couple in which one member is HIV+, there is only a 50:50 chance that the other will be HIV+

  • Even with intensive counseling about strategies to prevent HIV transmission, HIV risk is very high for HIV-uninfected partners in discordant couples.

  • Couples frequently desire to become pregnant.

  • This is challenging when condom use is the

  • main prevention strategy.


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HIV discordant couples 2010

(HIV+ partner does not yet qualify for ART)

Randomize HIV- partners

(normal liver, renal, hematologic function; not pregnant/breastfeeding)

TDF once daily

FTC/TDF once daily

Placebo once daily

Follow couples for 24-36 months

1° endpoint: HIV infection in HIV-negative partner

Co- 1° endpoint: Safety

Partners PrEP Design

Eldoret,

Kisumu,

Nairobi,

Thika,

Kenya

Jinja,

Kabwohe,

Kampala,

Mbale,

Tororo,

Uganda

All receiving HIVprevention services

Sponsored by Bill and Melinda Gates Foundation

& drug donated by Gilead Sciences


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Five study groups & 2 sequential randomizations. 2010

Women will use product for average of 21 months

Funded by NIH and BMGF


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Primary Study Objectives 2010

Estimate the effectiveness of

1) daily tenofovir 1% gel compared to a vaginal placebo gel, and

2) oral TDF & oral FTC/TDF compared to oral placebo

in preventing HIV infection among women at risk for sexually transmitted HIV infection

Evaluate the extended safety of daily tenofovir 1% gel, oral TDF, and oral FTC/TDF in women at risk for HIV infection


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Secondary Study Objectives 2010

Adherence/Behavioral:

Evaluate adherence to daily regimens of vaginal gel vs. oral tablets used to prevent HIV infection

Evaluate behavior change (sexual activity, condom use, intravaginal practices) in women who use either daily vaginal gel or daily oral tablets

HIV-1 Drug Resistance:

Assess frequency of HIV-1 drugresistance in women who acquire HIV-1 while using study product

Standard genotype analysis & more sensitive methods to detect low frequency drug-resistant variants


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Characteristics of ongoing PrEP efficacy trials 2010

  • HIV seroconversion is 1° endpoint = event-driven trials

    • Studies continue until a pre-defined number of endpoints achieved (=timeline uncertain)

  • Safety is co-1° endpoint

    • Given sample sizes, will provide large amount of safety data

  • Distinct trials

    • Population/route of exposure: IDUs, heterosexual women & men, MSM

    • Agent: TDF, FTC/TDF, vaginal TDF gel

    • Location: Africa, Americas, Asia

    • Follow-up: 1-3 years per person

  • Trial designed to detect ~50-70% efficacy

    • Larger trials also designed so that lower limit of 95% confidence bound will exclude low efficacy (25-30%)

  • Seroconverters followed for ≥1 year

    • CD4, HIV-1 RNA, resistance testing


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Challenges to current PrEP trials 2010

  • Complex trials

    • Monthly visits for HIV testing, study drug & counseling

    • Quarterly lab testing (kidney, liver, hematology)

    • Regulatory review & approvals

  • High adherence

    • Motivation to take a pill a day for 1-3 yrs to reduce HIV risk

    • Need robust measures of adherence to interpret efficacy results

  • Sufficient HIV incidence to measure efficacy

    • Declining incidence (behavior change, ART scale up)

    • Intensive prevention services

  • High expectations & anxieties about PrEP


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Anticipating results from multiple PrEP trials 2010

  • UNAIDS / CDC / GCM stakeholders meeting – Kampala, March 2009

    • Consensus for need for multiple trials of PrEP, to ensure confidence in efficacy estimates and efficacy across populations

    • Strong consensus that positive efficacy results in one trial, or two, should not halt other trials

      • Particularly necessary to understand safety and efficacy in women & in Africa


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What we will know from current PrEP trials 2010

  • If positive results (from ≥ 2 studies) have proof of concept

    • TDF and/or FTC/TDF prevents HIV, in the populations studied

    • Possibility of differential efficacy (or lack of) of different agents / populations

  • Demonstration of safety & tolerability

    • In healthy individuals

    • Inform frequency and intensity of safety monitoring required

  • Some understanding of the relationship between adherence and efficacy

    • Modestly accurate objective measures of adherence (e.g., pill counts)

    • Potentially biomarkers of adherence (plasma, PBMC, hair tenofovir levels)

    • Suggestion of whether less-than-daily use may have efficacy

  • Preliminary understanding of resistance

    • Relatively few infections (total <250) expected in PrEP-exposed subjects

    • In context of monthly HIV testing and immediately discontinuation of drug

  • Behavior

    • In context of clinical trial counseling and knowledge that may be on placebo


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What we will 2010not know from current PrEP trials

  • Full spectrum of safety (&efficacy) in other populations

    • Pregnant and breastfeeding women

    • Adolescents (especially young African women)

    • Chronic active hepatitis B infection

    • Use beyond 1-3 years

  • Adherence

    • Long-term adherence and direct measure of intermittent use efficacy

  • Other agents for systemic/topical PrEP

    • e.g., TMC 278 LA, dalpivirine

  • Resistance

    • Risk of resistance with longer time between HIV tests

    • Persistence and spread of resistant virus, if occurs

    • Effect of community resistance on efficacy

  • Behavior

    • How much will behavior change if PrEP has protection against HIV?

    • How much will behavior change reduce efficacy?


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Implementation: what’s next? 2010

  • Conduct and completion of the trials

  • Cost-effectiveness analysis

  • Safety studies in

    • Women desiring pregnancy

    • Lactating women

    • High-risk youth

    • Pregnant women?

  • Pilot studies

    • Target populations? High-risk MSM, sex workers, discordant couples

      • On what scale could PrEP be successfully implemented?

      • Need for viral RNA or Ag testing before implementation?

    • Degree of safety monitoring & HIV testing

    • Adherence & risk behavior if PrEP is known to be safe & effective

  • Non-inferiority studies:

    • Intermittent / periodic dosing

    • Other alternative agents – TMC 278, new agents (maraviroc?)


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Ethical & Implementation Conundrums of Standard of Care in HIV Vaccine & Prevention Trials

  • What constitutes standard to provide to research participants?

  • Provide if proven efficacy but not implemented widely?


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Panel Discussion: HIV Vaccine & Prevention Trials Implications for HIV vaccine Trials

  • What level of evidence is needed to provide PrEP to vaccine trial participants?

    • 1 trial regardless of study population?

    • 2 trials in populations being recruited into ph IIb/III vaccine trials that show efficacy (eg MSM and heterosexuals)?

  • What obligations do we have to provide PrEP to vaccine trial participants?

    • Await normative body guidance (ie CDC and WHO guidelines)?

    • Obligation to provide PrEP if not available through public funding?

    • Is provision of PrEP based on specific behavioral criteria, as would be used for targeting PrEP for public health (e.g. through CDC/WHO guidelines)?

  • Potential impact of PrEP on sample size of phase III trials & recruitment to HIV vaccine trials?


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