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Microbicides: A new hope for HIV prevention 1 Salim S. Abdool Karim, MBChB, PhD Professor of Clinical Epidemiology, Columbia University Adjunct Professor.

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Presentation on theme: "Microbicides: A new hope for HIV prevention 1 Salim S. Abdool Karim, MBChB, PhD Professor of Clinical Epidemiology, Columbia University Adjunct Professor."— Presentation transcript:

1 Microbicides: A new hope for HIV prevention 1 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 HIV Center, Columbia University, New York - 24 March 2011

2 Outline Brief review of the main CAPRISA 004 trial results A new hope… Three key lessons from CAPRISA 004 1.Adherence 2.Breakthrough infection clues 3.HSV-2 impact Conclusions

3 Age Group (Years) HIV Prevalence (N=1237) ≤1610.6% 17-1821.3% 19-2033.0% 21-2244.3% 23-2451.1% HIV prevalence in pregnant women in rural Vulindlela, South Africa (2005-2008)

4 Source: Abdool Karim Q, Abdool Karim SS, Singh B, Short R, Ngxongo S. AIDS 1992; 6: 1535-9 The urgent need for new prevention: Age & gender profile of HIV infection: South Africa 0 <910-14 Prevalence (%) 15-1920-2425-2930-3940-49 2 4 6 8 10 Female Male >49

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

6 Preventing sexual spread of HIV: Existing accepted proven HIV prevention strategies - ABCCC:  A bstinence  B ehaviour (Be faithful)  C ondoms (Male & Female)  C ounselling and Testing  C ircumcision (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

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

10 10 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 HIVNET 012 nevirapine regimen CAPRISA 004 tenofovir gel regimen asap 72 hrs 12 hrs Onset of labour Delivery CAPRISA 004 assessed the safety and effectiveness of 1% tenofovir gel

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12 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

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

14 Screening and Enrollment 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 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 Vulindlela: 611 eThekwini: 278 14 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 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 Enrolled eligible: 889

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

16 Effectiveness of tenofovir gel in preventing HIV infection 16 Tenofovir gel N = 445 Placebo gel N = 444 # HIV infections3860 HIV incidence (per 100 women-years) 5.69.1 39% lower HIV incidence with tenofovir gel 95% Confidence Interval: 6-60, p=0.017

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

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

19 Impact of adherence on effectiveness of tenofovir gel 19 # HIVN HIV incidence Effect p-value TFVPlacebo High adherers (>80% gel adherence) 363364.29.3 54% 0.03 Intermediate adherers (50-80% adherence) 201816.310.0 38% 0.29 Low adherers (<50% gel adherence) 413676.28.6 28% 0.30

20 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

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

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24 The CAPRISA 004 trial is in Science’s Top 10 Scientific Breakthroughs in 2010 24

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

26 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.

27 27 O Magazine, November 2010, pp80-82

28 Global distribution of print & online media coverage of CAPRISA 004 28

29 Readership of CAPRISA 004 online stories: Top 20 Articles With Known Readership Total Page Views WEB.de1 3 260 326 962 Comcast.net2 2 740 821 662 BBC Brasil1 1 736 381 796 GMX1 972 286 780 T-Online.de1 875 070 383 High Speed Online2 569 435 800 Yahoo! News7 559 341 339 Yahoo! Finance US3 462 694 805 L'Internaute1 453 888 102 Voila1 441 322 544 Arcor1 429 389 400 FOX News.com1 410 871 459 Charter2 376 073 702 Spiegel Online1 372 391 043 Tiscali1 348 917 118 About.com1 348 289 603 AOL1 320 557 258 G11 318 090 469 Abril.com1 316 060 461 29

30 CAPRISA 004 gets its own Wikipedia page! 30

31 Outline Brief review of the main CAPRISA 004 trial results A new hope… Three key lessons from CAPRISA 004 1.Adherence 2.Breakthrough infection clues 3.HSV-2 impact Conclusions

32 32 Lesson 1: Adherence can be improved

33 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

34 Product effectiveness before and after the MI based adherence intervention Before MI (<01 Oct 08) After MI (>01 Oct 08) Tenofovir (N=387) Placebo (N=387) Tenofovir (N=418) Placebo (N=410) # HIV infections18242135 HIV incidence (per 100 women yrs) 7.59.94.88.4 IRR 0.750.57 Effectiveness25%43% CI (p-value)-45;61 (p=0.37)-1, 68 (p=0.04)

35 After MI training % (N) Level of adherence High (>80%) Moderate (50-80%) Low (<50%) Total Before MI training % (N) High (>80%) 91.5 (183)3.5 (7)5.0 (10) 30.2 (200) Moderate (50-80%) 39.3 (55)41.4 (58)19.3 (27) 21.2 (140) Low (<50%) 13.7 (44)20.5 (66)65.8 (212) 48.6 (322) Total 42.6 (282)19.8 (131)37.6 (249) 100 (662) Adherence before and after motivational interviewing

36 Lesson 2: Breakthrough infections provide valuable clues 36

37 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 MIP-1b MIP-1a IFN-a MIP-3a MIP-1b MIP-1a IFN-a MIP-3a CD4 CCR5 1 2 3 1.Recruitment of DCs & DC production of inflammatory cytokines 2.Inflammatory cytokine recruitment of activated CD4 T cells 3.Infection of activated T cells by HIV Vaginal cytokines and tenofovir gel: Potential role in breakthrough HIV infection

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

39 Tenofovir gel does not increase cytokines: Evidence from high gel users who remained uninfected Pro-inflammatoryAnti-inflammatoryAdaptive Y: n=16 X: n=24 * * * Placebo (n=16) versus Tenofovir (n=24)

40 Pro-inflammatoryAnti-inflammatoryAdaptive Pre-infection genital inflammation predicts HIV acquisition in both trial arms * * * Fold difference in cytokines: women (pre-infection) who acquired HIV versus women who remained negative

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

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

43 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 Elevated systemic inflammatory cytokine levels associated with increased susceptibility to HIV

44 *Adjusted OR for infection (*for arm, age, HSV-2 status) p95%CI NK: CD380.5960.0021(0.43-0.83) NK: CD696.1720.8(0-1000) NK: HLA-DR2.3680.12(0.79-7.094) Activation of NK cells predicts HIV acquisition Reduced CD38+ NK cells   HIV acquisition Exposed Pre-infection (n=44) Exposed Uninfected (n=36)

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

46 BLDBLQ Tenofovir cervico-vaginal fluid concentrations correlate with HIV infection CVF Concentration (ng/mL) Total # women198672561 Number infected166341120 Percent infected 84 75 50 57 50 20 33 0

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

48 Tenofovir gel N = 202 Placebo gel N = 224 # HSV-2 infections2958 HSV-2 incidence per 100wy 9.920.2 Impact of tenofovir gel on genital herpes 51% protection against HSV-2 by tenofovir gel 95% Confidence Interval: 22%-70%, p=0.003 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)

49 in vitro EC50 ~240uM, 10 4 ng/mL Total # women2722 14 4 10 155 Number infected65 4 0 0 20 BLDBLQ 22 23 0 0 0 28 13 24% 6%  2 p = 0.03 Tenofovir cervico-vaginal fluid concentrations correlate with HSV-2 infection

50 50 # HIV infections N HIV incidence Incidence Rate Ratio Effect 95% Confidence Interval p- value Tenofovir gel (CI) Placebo gel (CI) Overall effectiveness of tenofovir gel HIV endpoints98889 5.6 (4.0, 7.7) 9.1 (6.9, 11.7) 0.6139%6, 600.017 Effectiveness of tenofovir gel by study exit HSV-2 status HSV-2 positive75541 7.3 (4.9, 10.5) 11.2 (8.2, 14.9) 0.6535%-6, 610.070 HSV-2 negative23339 3.3 ( 1.5, 6.3) 5.6 (3.1, 9.5) 0.5842%-45, 780.209 Effectiveness in HIV prevention in HSV-2 positive and negative women

51 Three key lessons from CAPRISA 004: Implications for future PrEP trials 1.Each breakthrough infection provides valuable clues – eg. role of genital & systemic inflammation 2.ARVs → HSV-2 prevention and shedding → HIV  HSV-2 in sample (↑HSV-2 → ↑HIV but may ↓effectiveness) 3.Adherence, adherence, adherence!!!  Select populations & sites for high adherence  Follow-up after 12-18 months: ↓adherence →↓effect size  Monitor adherence during trial (inspect vs expect)  Adherence can be improved with interventions

52 Study Effect size (CI) STD treatment (Mwanza trial) 42% (21; 58) Circumcision (Orange Farm, Rakai, Kisumu trials) 54% (38; 66): M-A HIV Vaccine (Thai RV144 trial) 31% (1; 51) Efficacy 0% 10 20 30 40 50 60 70 80 90 100% Clinical trial evidence for preventing sexual HIV transmission – March 2010

53 Study Effect size (CI) STD treatment (Mwanza trial) 42% (21; 58) Circumcision (Orange Farm, Rakai, Kisumu trials) 54% (38; 66): M-A HIV Vaccine (Thai RV144 trial) 31% (1; 51) Efficacy 0% 10 20 30 40 50 60 70 80 90 100% 39% (6; 60) Microbicide (CAPRISA 004 tenofovir gel trial) PrEP for MSM (iPrEx Truvada trial) 42% (18; 60) Clinical trial evidence for preventing sexual HIV transmission – March 2011

54 Next steps in microbicide trials Licensure steps: Truvada: proceeding to licensure – FDA does not require a confirmatory trial Tenofovir gel: not proceeding to licensure – FDA requires a confirmatory trial (VOICE trial may suffice, if it shows protection) EMA: has questions on 39% protection – has initiated a consultation on the minimum level for licensure

55 Towards implementation Level of effect for public health policy? Effectiveness at 1 year Circumcision: 50% (CI: 28% - 66%) Tenofovir gel: 50% (CI: 15% - 72%) Source: Siegfried N et al. Male circumcision preventing heterosexual acquisition of HIV in men. Int J Epidemiol 2010; 39: 968-972 Abdool Karim Q et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for prevention of HIV infection in women. Science 2010; 329: 1168-1174

56 Efficacy Study PMTCT - HIVNET 012 41 Tenofovir gel – high adherence 54 Tenofovir gel – low adherence 28 Tenofovir gel - CAP 004 39 0% 10 20 30 40 50 60 70 80 90 100% CAPRISA 004 tenofovir gel HIVNET 012 - nevirapine asap 72 hrs 12 hrs asap Tenofovir gel – medium adherence 38 Towards implementation Level of effect for public health policy? Evidence from HIVNET 012 & CAPRISA 004

57 Acknowledgements Financial support: Jointly funded by US & SA governments  United States Government – USAID  South African Government – Department of Science & Technology Trial Oversight Committee:  CAPRISA: Q Abdool Karim, SS Abdool Karim  FHI: W Cates, L Dorflinger, and D Taylor  USAID: L Claypool, J Manning, J Spieler  CONRAD: H Gabelnick  LIFElab (TIA): B Okole, C Montague  Gilead Sciences: J Rooney, Howard Jaffe Tenofovir & placebo gel: Provided by CONRAD & Gilead Sciences FHI Statistical & regulatory support: S Cameron, D Sokal & D Taylor Research infrastructure & training: US NIH’s CIPRA Program & the Columbia University - Southern African Fogarty Training Program

58 The CAPRISA 004 Trial Group Principal Investigators:Q Abdool Karim & SS Abdool Karim Site Directors: JA Frohlich, ABM Kharsany, KP Mlisana Project coordinators: C Baxter, LE Mansoor Site co-ordinators: NA Arulappan, S Maarschalk Assistant site co-ordinators:H Humphries, G Parker, J Richards, J Upton Study Gynaecologist: S Sibeko Clinicians: B Mdluli, N Miya, L Mtongana, N Naicker, Z Omar, D Sokal (FHI) Nurses: DD Chetty, F Dlamini, SD Gumede, Z Gumede, NE Khambule, N Langa, BT Madlala, N Madlala, N Mkhize, ZL Mkhize, M Mlotshwa, C Ndimande, N Ngcobo, C Ntshingila, B Phungula, TE Vumase Counsellors: NB Biyela, N Dladla, T Dlamini, CT Khwela, N Mayisela, MR Mlaba, J Mchunu, Z Msimango, D Nkosi, T Shange Pharmacists:L Chelini, TN Gengiah, A Gray, B Maharaj, GI Masinga, A Naidoo, M Upfold Pharmacist’s assistants:B Moodley, Y Naidoo, C Ngcobo, T Nzimande, L Zondi Statisticians:AC Grobler, D Taylor (FHI), L Werner, N Yende Data management:R Lallbahadur, M Mdladla, K Naidoo, T Nala, C Pillay, P Sikakane, T Zondo Quality assurance:T Govender, N Mvandaba, F van Loggerenberg, I van Middelkoop Laboratory:J Naicker,V Naranbhai, N Ndlovu, N Samsunder, S Sidhoo, P Tshabalala J Ledwaba (NICD) & L Morris (NICD), Behavioural Science: J Fisher (UConn), K MacQueen (FHI) Cohort co ordinators:LR Luthuli, F Ntombela Cohort administrators:PF Chonco, DP Magagula, PC Majola, T Ndlovu, L Ngobese, N Ngubane, NM Zwane Community outreach:N Bhengu, P Buthelezi, PD Lembethe, BF Mazibuko, SF Mdluli, WN Mkhize, SP Ndlovu, S Ngubane, RM Ogle, RB Xulu Administrative staff:N Amla, SA Barnabas, T Malembe, M Matthews, YT Miya, A Mqadi, S Panday, S Sibisi, B Zulu, M Swart,

59 CAPRISA 004 eThekwini team CAPRISA 004 Vulindlela team The CAPRISA 004 Protocol Team gratefully acknowledges the dedication and commitment of the study participants without whom this study would not be possible


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