CDC Safety and Efficacy Trials of Tenofovir for HIV Prophylaxis

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CDC Safety and Efficacy Trials of Tenofovir for
HIV Prophylaxis

• PACHA Briefing
• February 7, 2005
• Lynn Paxton
• Division of HIV/AIDS Prevention
• National Center for HIV, STD, and TB Prevention

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Overview of Presentation

• Rationale for HIV prophylaxis
• Tenofovir Disoproxil Fumarate (TDF)
• CDC tenofovir prophylaxis studies
• Extended safety trial in MSM in the US
• Safety and efficacy trials in IDUs in Thailand
  and in heterosexuals in Botswana
• CDC/NIH consultation in December 2004

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Rationale for HIV Prophylaxis (1)

• Need for biomedical interventions to complement
  existing HIV prevention strategies 14,000 new
  HIV infections each day globally, and 40,000 new
  HIV infections annually in U.S.
• Absence to date of effective HIV vaccines or
  microbicides
• Systemic HIV infection does not occur
  immediately, so HIV prophylaxis could prevent or
  modify viral replication and spread
• Thus, HIV prophylaxis could function as an
  oral vaccine or microbicide

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Rationale for HIV Prophylaxis (2)

• Treatment medications used as prophylaxis for
  bacteria, fungi, and the malaria parasite why
  not for HIV?
• HIV prophylaxis effective to reduce perinatal
  transmission 50 risk reduction from single
  dose nevirapine to mother and infant
• HIV post-exposure prophylaxis
• recommended by HHS for occupational exposures
  81 risk reduction from AZT
• HHS recommendations for sexual and parenteral
  exposures are in press at MMWR

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Previous Studies Demonstrating Efficacy of
Tenofovir Prophylaxis in Monkeys

• 4 weeks of daily TDF starting 48 hrs pre- and 4
  or 24 hrs post- IV SIV challenge protected 25/25
  rhesus macaques - Tsai, Science 1995
• 2 doses of TDF 4 hours pre- and 20 hours post-
  oral SIV challenge protected 4/4 newborn macaques
  - Van Rompay AIDS 1998
• 2 weeks of TDF immediately following oral SIV and
  IV SHIV challenge protected 3 of 4 newborn
  macaques - Van Rompay, ARHR 1998

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Tenofovir Disoproxil Fumarate (TDF)

• Highly potent antiretroviral produced by Gilead
  and approved by FDA in 2001 for use in
  HIV-infected persons
• More than 12,000 patients on TDF in clinical
  trials over 150,000 patients on TDF in clinical
  setting
• Low incidence of side effects
• Once a day dosing with long serum half-life
• Low levels of induced resistance

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Primary Concerns with TDF Prophylaxis

• Behavioral disinhibition some evidence that
  HAART availability has led to increases in risk
  behavior - although previous vaccine trials
  showed decreases in risky behaviors in MSM and
  IDUs
• Toxicities in HIV-infected persons
• less likely in uninfected persons who are on
  fewer medications and are generally healthier
• Kidney decreased renal function
• bone decreased bone mineral density
• gastrointestinal nausea, diarrhea
• Selection for resistant viruses in persons who do
  become HIV-infected
• Will closely monitor behaviors, toxicities, and
  resistance during trials

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Overview of Planned TDF Studies

• Gates-funded FHI efficacy trial in female sex
  workers in progress in Cameroon, Nigeria and
  Ghana study in high-risk men in Malawi planned
• NIH-funded UCSF/Gates-funded Australia efficacy
  trial in female sex workers in Cambodia on hold
  at present
• CDC non-human primate study in progress
• CDC extended safety study in US MSM
• CDC safety and efficacy studies in IDUs in
  Thailand and heterosexuals in Botswana

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CDC U.S. Extended Safety Trial

• Two sites
• AIDS Research Consortium of Atlanta (ARCA)
• San Francisco Department of Health (SFDPH)

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Study Objectives and Design

• Objective to assess clinical, laboratory and
  behavioral safety and adherence and
  acceptability
• Design randomized double-blind placebo
  controlled phase II extended safety study with
  11 TDF/placebo
• Duration 24 months with safety committee review
  of data at 6, 12, and 18 months
• Community consultation held in January 2004

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Study Design

• 400 HIV-N MSM (200 per site) 25 men of color
• 9 month delay in enrollment of 200 men to assess
  behavioral changes once TDF prophylaxis started
• Close monitoring of seroconverters for resistance
  and clinical outcomes
• Adverse events, and access to HIV care if
  infected, managed through physician referral
• Protocol at IRB, start date in Feb 2005

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TDF Studies in Thailand and Botswana
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BMA Drug Treatment Clinics
CDC Lab
BMA Lab
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CDC Clinic Sites in Botswana
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TDF Studies in Thailand and BotswanaCommonalities

• Phase II/III randomized, double-blind,
  placebo-controlled safety and efficacy trials
  with 11 TDF/placebo
• Phase II safety trials 200 person-years
  followed by DSMB review (single DSMB for both
  studies) if safety criteria met, will roll into
  Phase III efficacy trials
• Screening, enrollment, monthly and quarterly
  visits
• Interviews, physical exams, labs, HIV testing,
  risk reduction counseling, adherence assessments,
  side effect monitoring

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TDF Studies in Thailand and BotswanaCommonalities

• Endpoints HIV seroconversion, adverse events,
  risk behaviors, adherence, altered viral load set
  point in seroconverters
• Seroconverters viral loads, CD4 counts,
  antiretroviral resistance
• Received IRB clearance, planned start date Feb
  2005

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TDF Studies in Thailand and BotswanaStudy Design
Differences

• Thailand
• n1600
• HIV-N IDUs past 6 mos
• 20-60 years
• 90 men, 10 women
• 80 power to detect a 50 reduction in HIV
  assuming an HIV incidence of 3-4
• 12 mo enrollment, 12 mo follow-up, 6 mo close-out

• Botswana
• n1200
• HIV-N heteros past 3 mos
• 18-29 years
• 50 men, 50 women
• 80 power to detect a 50 reduction in HIV
  assuming an HIV incidence of 5
• 15 mo enrollment, 12 mo follow-up, 6 mo close-out

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TDF Studies in Thailand and BotswanaCritical
Components

• Thailand
• Recruitment - extension study and peer referral
• Community relations club with IDUs, external
  advisory board
• If infected, ARVs through BMA/MOPH
• Coverage for adverse events through BMA with
  reimbursement by CDC

• Botswana
• Recruitment - VCT, STD / family planning clinics,
  radio print, TV ads
• Community and participant advisory boards
• If infected, ARVs through MOH
• Coverage for adverse events through MOH

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Coordination of Tenofovir Trials with CDC Global
AIDS Program Activities in Thailand

• The Thailand Ministry of Public Health U.S. CDC
  collaboration (TUC) supports and coordinates
  programmatic and research activities for IDUs in
  Bangkok
• Program services for IDUs provided through GAP
  include VCT, treatment and care for HIV,
  screening and preventive therapy for
  tuberculosis, hepatitis B immunization, and
  community outreach services for IDUs

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Coordination of Tenofovir Trials with PEPFAR/GAP
Activities in Botswana

• The BOTUSA project supports and coordinates
  programmatic and research activities in Botswana
• PEPFAR/GAP-funded projects will assist with
  community mobilization and recruitment for the
  trial Tebelopele VCT centers, Makabaneng radio
  drama, and Total Community Mobilization
• PEPFAR/GAP contributes to the national ARV
  program through the support of training for
  clinicians and of laboratory infrastructure

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CDC/NIH TDF Consultation Atlanta, Dec 9-10, 2004

• Impact of demonstrated efficacy in one trial on
  other trials
• HHS recommendations for TDF use in the US
  acceptable efficacy level, differing transmission
  routes, unstudied populations
• Monitoring for usage, increased risk behavior,
  HIV incidence, adverse events
• Impact on existing HIV prevention programs
  domestically and internationally
• Impact on future vaccine and microbicide trials
• Future HIV prophylaxis research with other ARVs,
  less frequent dosing schedules, other delivery
  systems

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Communications Strategy

• Development of fact sheets and QAs, and
  distribution through outreach and posting on CDC
  website
• Identification and preparation of CDC,
  site-specific, and third-party spokespersons to
  respond to media inquiries
• Targeted outreach to key media and opinion
  leaders on importance of tenofovir trials, high
  quality of prevention services, and safeguards
  for trial participants
• Ongoing monitoring of and response to media
  coverage

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Conclusions

• Assessment of TDF as HIV prophylaxis is a
  rational next step in HIV prevention research
• CDC will be conducting complementary studies in
  the prevention of homosexual, parenteral, and
  heterosexual transmission
• HIV prophylaxis represents our best hope for an
  effective biomedical HIV prevention tool in the
  near future