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Microbicides : A new hope for HIV prevention

Microbicides : A new hope for HIV prevention. HIV Center , Columbia University, New York - 24 March 2011. Salim S. Abdool Karim, MBChB , PhD Professor of Clinical Epidemiology, Columbia University Adjunct Professor of Medicine, Cornell University

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Microbicides : A new hope for HIV prevention

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  1. Microbicides:A new hope for HIV prevention • HIV Center, Columbia University, New York - 24 March 2011 Salim S. Abdool Karim, MBChB, PhD Professor of Clinical Epidemiology, Columbia University Adjunct Professor of Medicine, Cornell University Pro Vice-Chancellor (Research), University of KwaZulu-Natal

  2. Outline • Brief review of the main CAPRISA 004 trial results • A new hope… • Three key lessons from CAPRISA 004 • Adherence • Breakthrough infection clues • HSV-2 impact • Conclusions

  3. HIV prevalence in pregnant women in rural Vulindlela, South Africa (2005-2008)

  4. The urgent need for new prevention:Age & gender profile of HIV infection: South Africa 10 Male Female 8 6 Prevalence (%) 4 2 0 <9 10-14 15-19 20-24 25-29 30-39 40-49 >49 Source: AbdoolKarim Q, AbdoolKarim SS, Singh B, Short R, Ngxongo S. AIDS 1992; 6: 1535-9

  5. Abdool Karim Q, et al. Clinical Infectious Diseases 2010; 50(S3):S122–S129

  6. Preventing sexual spread of HIV: • Existing accepted proven HIV prevention strategies - ABCCC: • Abstinence • Behaviour (Be faithful) • Condoms (Male & Female) • Counselling and Testing • Circumcision (Medical Male) Which of these are prevention tools for young women in Africa?

  7. Africa needs new HIV prevention technologies • In South Africa the epidemic continues to grow despite increased prevention efforts • Male condom distributed in 2002/3: 358 million • Female condom distribution doubled from 1,3 million in 2003 to 2,6 million in 2004 • Combating the HIV epidemic is not only about scaling proven prevention – we also need new prevention technologies • New HIV prevention technologies are urgently needed in Africa, especially those that empower women

  8. Past and current microbicide trials 1st class: Surfactants eg. N9, SAVVY 2nd class: Polymers eg. PRO2000, Carraguard, Cellulose Sulfate (CS) 3rd class: ARVs eg. Tenofovir gel CAPRISA 004 Tenofovir gel trial Kenya N-9 sponge trial CONRAD CS trial FHI CS Trial MTN003 –VOICE Tenofovir gel & tablet trial FHI N-9 film trial PopCouncil Carraguard trial FACTS 001 Tenofovir gel trial Zena Stein publishes seminal article “HIV prevention: the need for methods women can use” UNAIDS COL-1492 trial HPTN PRO2000 & BufferGel trial CAPRISA 008 Tenofovir gel implementation trial FHI SAVVY trial MDP 0.5% PRO2000 trial IPM dapivarine ring 2% PRO2000 ‘90 ‘92 ’98 ’00 ‘03 ‘04 ‘04 ’05 ’05 ’07 ’09 ‘11 Safe but not effective Increased HIV infection Stopped for futility Effective Planned

  9. CAPRISA 004 assessed the safety and effectiveness of 1% tenofovir gel • BAT 24 coitally-related gel use • Insert 1 gel up to 12 hours Before sex, • insert 1 gel as soon as possible within 12 hours After sex, • no more than Two doses in 24 hours asap 72 hrs asap CAPRISA 004 tenofovir gel regimen HIVNET 012 nevirapine regimen 12 hrs Onset of labour Delivery

  10. Methods • Proof of concept double-blinded, randomized, placebo-controlled trial • Enrolled high risk HIV uninfected women reporting two coital acts in past 30 days – known high risk populations from pre-trial feasibility studies • Endpoint driven trial (92 HIV endpoints) • HIV infection is primary safety & effectiveness endpoint: • HIV negative: 2 negative rapid HIV tests • HIV endpoint: PCR+ in 2 separate blood specimens Positive Western blot • Intent-to-treat analysis except for adherence analysis Intent-to-treat analysis

  11. CAPRISA Vulindlela Clinic KwaZulu-Natal Midlands CAPRISA eThekwini Clinic Durban City Centre CAPRISA 004: Urban and Rural sites

  12. Screening and Enrollment • 1075 excluded: • 536 HIV positive • 142 did not return • 132 not sexually active • 51 pregnant or planning a pregnancy • 37 participating in other research • 33 refused participation • 26 not keen to use contraceptives • 24 allergic to latex • 23 planning to relocate • 23 medical condition • 19 unable to attend study visits • 14 unable to provide informed consent • 15 other reasons Screened: 2160 Enrolled & randomized: 1085 • 196 excluded: • 135 co-enrolled • 50 in other study <1 year ago • 1 <18 years (ineligible age) • 8 pre-existing HIV (PCR +) • 2 no follow up HIV test Enrolled eligible: 889 Vulindlela: 611 eThekwini: 278

  13. Study Overview: Enrollment & Retention Enrolled Eligible: 889 Tenofovir: 445 Placebo: 444 • 10 lost to follow up • 12 terminated early • 1 died • 15 lost to follow up • 8 terminated early Retention: 94.8% Completed study: 421 Completed study: 422

  14. Effectiveness of tenofovir gel in preventing HIV infection 39% lower HIV incidence with tenofovir gel 95% Confidence Interval: 6-60, p=0.017

  15. HIV infection rates in the Tenofovir and placebo gel groups: Kaplan-Meier survival probability Tenofovir Placebo p=0.017 After 12 months of gel use: HIV endpoints: 65 Effectiveness: 50% P-value: 0.007 (0.017)

  16. HIV infection rates in the tenofovir and placebo gel groups:24 month Kaplan-Meier survival probability (0.017)

  17. Impact of adherence on effectiveness of tenofovir gel

  18. Outline • Brief review of the main CAPRISA 004 trial results • A new hope… • Three key lessons from CAPRISA 004 Adherence Breakthrough infection clues HSV-2 impact • Conclusions

  19. 2010: Proof of Concept for microbicides 1st class: Surfactants eg. N9, SAVVY 2nd class: Polymers eg. PRO2000, Carraguard, Cellulose Sulfate (CS) 3rd class: ARVs eg. Tenofovir gel CAPRISA 004 Tenofovir gel trial Kenya N-9 sponge trial CONRAD CS trial FHI CS Trial MTN003 –VOICE Tenofovir gel & tablet trial FHI N-9 film trial PopCouncil Carraguard trial FACTS 001 Tenofovir gel trial Zena Stein publishes seminal article “HIV prevention: the need for methods women can use” UNAIDS COL-1492 trial HPTN PRO2000 & BufferGel trial CAPRISA 008 Tenofovir gel implementation trial FHI SAVVY trial MDP 0.5% PRO2000 trial IPM dapivarine ring 2% PRO2000 ‘90 ‘92 ’98 ’00 ‘03 ‘04 ‘04 ’05 ’05 ’07 ’09 ‘11 Safe but not effective Increased HIV infection Stopped for futility Effective Planned

  20. The CAPRISA 004 trial is in Science’s Top 10 Scientific Breakthroughs in 2010

  21. 25 The CAPRISA 004 trial is in Nature’s round-up of the top science news stories of the past 12 months

  22. Two randomised trials led the field. Mark Loeb and colleagues’ study of the effect of influenza vaccination in children on community infection rates won with 38% of the vote. A close second, with 35% of the vote, was a study (CAPRISA 004) of the effectiveness of tenofovir gel to prevent HIV infection in women.

  23. O Magazine, November 2010, pp80-82

  24. Global distribution of print & online media coverage of CAPRISA 004

  25. Readership of CAPRISA 004 online stories: Top 20

  26. 30 CAPRISA 004 gets its own Wikipedia page!

  27. Outline • Brief review of the main CAPRISA 004 trial results • A new hope… • Three key lessons from CAPRISA 004 • Adherence • Breakthrough infection clues • HSV-2 impact • Conclusions

  28. Lesson 1: Adherence can be improved

  29. Motivational interviewing: A strategy for enhancing adherence • Q1 in 2008, median self-reported adherence ̴100% We raised our concern with the Fishers who then developed an intervention based on their IMB model – implemented in Oct 2008 (midway in trial) • Participant-centered & interviewer-driven technique • Rationale – Participants more likely to act upon a self-motivating statement • For example, instead of telling the participant when to use the gel in relation to sex, they are asked to develop their own solutions to improve gel use

  30. Product effectiveness before and afterthe MI based adherence intervention

  31. Adherence before and after motivational interviewing

  32. Lesson 2: Breakthrough infections provide valuable clues

  33. MIP-3a MIP-3a MIP-1a MIP-1a MIP-1b MIP-1b IFN-a IFN-a Vaginal cytokines and tenofovir gel: Potential role in breakthrough HIV infection Li and Haase (2009) showed that genital tract inflammation was a necessary step in the initiation of a productive HIV infection across the female genital mucosa 1 3 Recruitment of DCs & DC production of inflammatory cytokines Inflammatory cytokine recruitment of activated CD4 T cells Infection of activated T cells by HIV CD4 CCR5 CD4 2

  34. Looking for the pro-inflammatory cytokines… 20 cytokines measured in CVL by Luminex Pro-inflammatory Anti-inflammatory Regulatory Stimulate and regulate B and T cells that have immunological memory Recruit immune cells to infection sites Regulate immune cells and suppress inflammatory responses IL-1α IL-1β IL-6 IL-12p40 IL-12p70 TNF-α Eotaxin IL-8 IP-10 MCP-1 MIP-1α MIP-1β RANTES GM-CSF IFN-γ IL-2 IL-7 IL-15 IL-10 IL-1β IL-6 IL-8 Important pro-inflammatory cytokines... Doncel, Chandra & Fichorova (2004)

  35. Tenofovir gel does not increase cytokines: Evidence from high gel users who remained uninfected Placebo (n=16) versus Tenofovir (n=24) Pro-inflammatory Anti-inflammatory Adaptive * * * Y: n=16 X: n=24

  36. Pre-infection genital inflammation predicts HIV acquisition in both trial arms Pro-inflammatory Anti-inflammatory Adaptive * * * Fold difference in cytokines: women (pre-infection) who acquired HIV versus women who remained negative

  37. Correlations between CVL viral load and CVL cytokine levels Cytokine concentration (pg/ml) As found in our previous studies, there was a strong relationship between HIV shedding and CVL cytokine concentrations. HIV-1 RNA concentration (copies/ml)

  38. Increased cytokines (which predict HIV risk) are not raised by HIV – they are present before HIV infection Pro-inflammatory Anti-inflammatory Adaptive Fold change in cytokine concentrations in matched CVLs from women following HIV infection and pre-infection 35 women matched pre- and post-infection

  39. Elevated systemic inflammatory cytokine levels associated with increased susceptibility to HIV • Question: Is • immune • activation also present systemically, in • woman who • acquire HIV? • Significantly higher • levels of: • TNF-α • IL-2 • IL-7 • IL12-p70 • All also ↑ in CVL

  40. Activation of NK cells predicts HIV acquisition Exposed Pre-infection (n=44) Exposed Uninfected (n=36) Reduced CD38+ NK cellsHIV acquisition

  41. …the differences are not confined to NK cells CD8+ T-cell function

  42. Tenofovircervico-vaginal fluid concentrations correlate with HIV infection BLD BLQ 84 75 Percent infected 57 50 50 33 20 0 CVF Concentration (ng/mL)

  43. Lesson 3: A second effect on HIV protection – Indirectly through HSV-2 prevention

  44. Impact of tenofovir gel on genital herpes • High prevalence of HSV-2 infection • ~ 20% in sexually active adults globally • ~ 50 - 60% in South African sexually active adults • Commonest cause of genital ulcer disease – mostly asymptomatic • There is no cure or effective prevention (other than condoms) 51% protection against HSV-2 by tenofovir gel 95% Confidence Interval: 22%-70%, p=0.003

  45. Tenofovircervico-vaginal fluid concentrations correlate with HSV-2 infection 2 p = 0.03 6% 24% in vitro EC50 ~240uM, 104 ng/mL BLD BLQ 28 23 22 13 0 0 0

  46. Effectiveness in HIV prevention in HSV-2 positive and negative women

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