Preventing HIV infection in young women in Africa University of Johannesburg, 17 August 2016 Quarraisha Abdool Karim, PhD Associate Scientific Director: CAPRISA Professor in Clinical Epidemiology, Columbia University Adjunct Professor in Public Health, University of KwaZulu-Natal

Bridging Disparities What science can do and what society can become Science - locally responsive but globally relevant Why we need women in science Why science needs women Importance of high quality, robust and rigorous science in partnership with potential beneficiaries Status of women key for societal transformation

CAPRISA’s goal & affiliations Goal: To undertake globally relevant & locally responsive research that contributes to understanding HIV pathogenesis, prevention & epidemiology as well as TB-HIV treatment CAPRISA hosts a DST-NRF Centre of Excellence in HIV Prevention CAPRISA hosts a MRC HIV-TB Pathogenesis and Treatment Research Unit UNAIDS Collaborating Centre for HIV Research and Policy

TB & HIV mortality in SA - 2013 CAPRISA research focuses on the 2 biggest problems in HIV High HIV incidence in young women High death rates from HIV-TB co-infection Age and sex prevalence of HIV (1990) TB & HIV mortality in SA - 2013 South Africa

Young women at high HIV risk: Who? Why? What works? Who - source of infection? Why so vulnerable? What works for prevention? Why? Who? What works? Young women at high HIV risk

About 6,000 new HIV infections each day The world has made impressive progress in the HIV response, but the spread of HIV has yet to be controlled! In 2015, worldwide there were: 1.2 million HIV deaths 37 million living with HIV 2.1 million new infections About 6,000 new HIV infections each day Source: UNAIDS Global Report 2016

Global HIV epidemic at a glance About 6,000 new HIV infections each day 2 out of 3 new HIV infections are in sub-Saharan Africa 1 out of 3 new HIV infections are in youth (15-24yr) Source: UNAIDS Global Report 2015

About 6,000 new HIV infections each day The world has made impressive progress in the HIV response, but the spread of HIV has yet to be controlled! In 2015, worldwide there were: 1.2 million HIV deaths 37 million living with HIV 2.1 million new infections About 6,000 new HIV infections each day Source: UNAIDS Global Report 2016

Adolescents dying from HIV, 2015 N=41,000 Global Epidemiology of HIV in Adolescents: # dying of HIV Adolescents dying from HIV, 2015 N=41,000 West/Central Europe North America N<250* East Europe & Central Asia N<300* Middle East and North Africa N<500 Asia-Pacific N=4,000 West and Central Africa N=12,000 Latin America and the Caribbean N=1,000 Eastern & southern Africa N=24,000 UNAIDS 2015 estimates. *2014 data

With <1% of the world’s population, South Africa has 18% of the HIV infections Rank Country % of people with HIV in the world 1 South Africa 18% 2 Nigeria 9% 3 India 6% 4 Kenya 5% 5 Mozambique 4% 6 Uganda 7 Tanzania 8 Zimbabwe 9 USA 10 Malawi 3% Remaining countries 39% 33% Top 10 countries: People living with HIV 61% 35 countries account for 90% of new HIV infections globally Source: UNAIDS Global Report 2014

Young Women at High Risk

The South African HIV Epidemic: A diversity of epidemics at a district level

HIV in South Africa: Disproportionate burden of HIV in young women AIDS 1992, 6:1535-1539 Southern & eastern Africa have 70% of the world’s HIV burden South Africa 1990 HIV in 15–24 year men and women (2008–2011) Young women have up to 8 times more HIV than men

In KwaZulu-Natal, HIV prevalence declining too slowly in young women Overall HIV prevalence in rural Vulindlela (2001-2013) Moving average HIV prevalence in pregnant women in Vulindlela Age Group (Years) HIV Prevalence (N=4818) ≤16 11.5% 17-18 21.3% 19-20 30.4% 21-22 39.4% 23-24 49.5% >25 51.9% Year HIV prevalence (%) National HIV prevalence (%) 01 02 03 04 05 06 07 08 09 10 11 12 13 32 35 41 43 37 38 34 40 44 25 27 28 30 29 Source: Kharsany ABM et al , JAIDS 2015

High rates of HIV in adolescent girls and young women in South Africa Age Group (years) HIV Prevalence (2010) % (95% Confidence Interval) Male (n=1252) Female (n= 1423) 15 1.0 (0.0 - 2.2) 2.6 (1.2 - 4.0) 16-17 1.1 (0.2 - 2.0) 6.1 (2.6 - 9.6) 18-19 1.5 (0 - 3.7) 13.6 (9.0 - 18.1) ≥20 1.8 (0 - 3.9) 24.7 (6.3 - 43.1)

Risk factors for HIV acquisition in female high school students Adjusted OR p-value Age <18 years 2.67 (1.67-4.27) <0.001 HSV-2 seropositive 4.35 (2.61-7.24) Experience of pregnancy 1.66 (1.10-2.51) 0.016 Experience of >1 adult deaths in household 1.97 (1.13-3.44) SOCIAL as well as BIOLOGICAL vulnerability to infection Abdool Karim Q, Kharsany ABM, Leask K, Ntombela F, Humphries H, Frohlich JA, Samsunder N, Grobler A, Dellar R, Abdool Karim SS. Sexually Transmitted Infections 2014;

HSV-2 infection increases HIV risk in CAPRISA 004 women HSV-2 incident infections HSV-2 positive n=58 HSV-2 Negative n=164 # HIV infections 11 13 HIV incidence / 100 person-yrs 12.3 5.3 HR for HIV risk in incident HSV-2: 2.4 (CI: 1.1-5.4), p = 0.03 Prevalent HPV infection increases HIV risk Prevalent HPV Women-years (n/N) HIV Incidence rate (95% CI) HPV- 330.5 (8/204) 2.4 (1.1 - 4.8) HPV+ 880.3 (59/575) 6.7 (5.1 - 8.6) HR for prevalent HPV: 2.8 (CI: 1.3 – 5.9), p=0.007 *Multivariate model fitted to HIV incidence adjusting for Study arm, Self-reported condom use, Age, Baseline HSV-2 status, Self-reported sex acts in the last month, and Age at sexual debut.

Preventing the sexual spread of HIV: Existing accepted proven HIV prevention strategies - ABCC: Abstinence Behaviour (Be faithful) Condoms (Male & Female) Circumcision (Medical Male) Which of these are prevention tools for young women in Africa?

A long road: Several disappointing microbicide trial results over 18 years

CAPRISA 004 tenofovir gel trial results Tenofovir gel prevents HIV in women 39% protection against HIV overall 54% effective in women with high adherence 74% protection with high tenofovir levels Tenofovir gel prevents HSV-2 infection in women (NEJM 2015) 51% reduction in HSV-2 incidence First results to show that antiretroviral drugs can prevent sexual transmission of HIV & HSV-2

Tenofovir gel results at the 2010 International AIDS Conference & published online by Science at the same time

Abdool Karim Q, et al. Science 2010 > 1400 Citations (Scopus) CAPRISA 004 findings ranked in Top 10 Scientific Breakthroughs of 2010 by Science Abdool Karim Q, et al. Science 2010 > 1400 Citations (Scopus)

New WHO PrEP guidelines New WHO policy on ARVs to prevent the spread of HIV by sex (Pre-exposure prophylaxis - PrEP): Daily Truvada PrEP recommended as global standard for all at high risk New WHO PrEP guidelines “..the use of daily oral pre-exposure prophylaxis is recommended as an additional prevention choice for people at substantial risk of HIV infection as part of combination prevention approaches..”

Varying effectiveness of oral and topical PrEP in women Study Effect size (CI) TDF2 – daily Truvada (Heterosexual women - Botswana) 75%* (24; 94) Partners PrEP – daily oral Tenofovir (Discordant couples – Kenya, Uganda) 71%* (37; 87) Partners PrEP – daily Truvada (Discordant couples – Kenya, Uganda) 66%* (28; 84) Oral PrEP FEMPrEP – daily Truvada (Women – Kenya, South Africa, Tanzania) 6% (-52; 41) MTN003/VOICE – daily Truvada (Women – South Africa, Uganda, Zimbabwe) -4% (-49; 27) MTN003/VOICE – daily Viread (Women - South Africa, Uganda, Zimbabwe) -49% (-129; 3) CAPRISA 004 – coital Tenofovir gel (Women – South Africa) 39% (6; 60) Topical PrEP MTN003/VOICE – daily Tenofovir gel (Women – South Africa, Uganda, Zimbabwe) 15% (-21; 40) FACTS 001– coital Tenofovir gel (Women – South Africa) 0% (-40, 30) -130 -60 -40 -20 20 40 60 80 100 *point estimate for women only Effectiveness (%)

Adherence is essential & partnerships with the community enhances adherence # HIV N HIV incidence Effect p-value TFV Placebo High adherers (>80% gel adherence) 36 336 4.2 9.3 54% 0.03 Intermediate adherers (50-80% adherence) 20 181 6.3 10.0 38% 0.29 Low adherers (<50% gel adherence) 41 367 6.2 8.6 28% 0.30 CAPRISA 004 was developed… …”after extensive consultation with international scientific experts and review of monkey challenge data.” “Just as importantly, it followed detailed consultation with the communities involved.” Source: Abdool Karim S, Abdool Karim Q, Nature, 446; 2007 Source of data in table: Abdool Karim Q, Abdool Karim SS, Frolich J, et al. Science 2010

High vaginal tenofovir concentrations needed at exposure Probability of HIV infection Placebo gel Tenofovir gel TFV ≤1000ng/ml TFV >1000ng/ml p=0.01* 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0.18 Years on study 0.0 0.5 1.0 1.5 2.0 2.5 *comparing women with tenofovir concentration >1000ng/ml vs placebo. Adjusted p=0.03 CHERYL – please

Why? Pre-existing genital inflammation increases HIV acquisition risk in women Genital inflammation and the risk of HIV acquisition in women Lindi Masson1,2#, Jo-Ann S. Passmore1,2,3*#, Lenine J. Liebenberg1#, Lise Werner1, Cheryl Baxter1, Kelly B. Arnold4, Carolyn Williamson1,2, Francesca Little5, Leila E. Mansoor1, Vivek Naranbhai1, Douglas A. Lauffenburger4, Katharina Ronacher6, Gerhard Walzl6, Nigel J. Garrett1, Brent L. Williams7, Mara Couto-Rodriguez7, Mady Hornig7, W. Ian Lipkin7, Anneke Grobler1, Quarraisha Abdool Karim1,8 and Salim S. Abdool Karim1,8 IL-8 IL-1α TNF-α IL-1β IL-10 MIP-1β MIP-1α MCP-1 IP-10 IL-6 IL-7 GM-CSF Max Later became HIV-infected (n=58) Remained HIV-uninfected (n=58) Genital tract chemokines (MIP-1α, MIP-1β, IP-10, IL-8) were associated with HIV acquisition Min Women who later became HIV-infected had pre-infection genital inflammation OR: 3.2

Prevotella bivia is strongly associated with inflammation and enhanced HIV acquisition P. bivia+ OR* P value HC 19.2 (95% CI: 4.0-92.4) p<0.001 HIV+ 12.7 (95% CI: 2.1-77.8) p=0.006 *adjusted odds ratio 22 women were HIV positive & had inflammation – 9/22 (41%) had P. bivia Women with P. bivia were 19 times more likely to have genital inflammation and 13 times more likely to acquire HIV Williams B, et al. IAS 2016

Tenofovir highly protective with Lactobacillus dominance (LD) 60.0% of LD women compared to 61.4% of non-LD women had >50% gel adherence. (monthly empty applicator returns) >50% Gel Adherence All participants Lactobacillus dominant non- Lactobacillus dominant Tenofovir Placebo # HIV-1 infections 13 26 4 15 9 11 HIV-1 incidence per 100 person-years 3.7 8.6 1.9 8.5 6.4 HIV-1 protection effectiveness 95% CI, P-value 56% (12, 79) P=0.013 78% (29, 95) P=0.003 26% (-98, 73) P=0.558 Gel adherence, as assessed by monthly empty applicator returns, was similar in both groups. 60% of lacto-dominant and 61% of non-Lacto dominant women had >50% gel adherence. In all participants, those with high adherence had an overall protective effect of 56% offered by tenofovir gel. In the lacto-dominant group, protective effect of tenofovir was 78% in high adherers. In contrast, even with high adherence, protective effect of tenofovir was only 26% in the non-lacto group, that was not statistically significant. This corresponded to a 3-fold lower protection in the non-Lacto group. Burgener A, Klatt N et al. IAS 2016

Cycle of HIV transmission Schematic of sexual networks from clusters with heterosexual transmission Men 25-40 years (N=79) Knew HIV status: 21.5% VL > 50,000 : 37.1% Community HIV prevalence: 40.3% Most young women <25 years acquire HIV from older men (Mean age difference = 8.7 years) Most men & women 25-40 years acquire HIV from similarly aged partners (Mean age difference = 1.1 years) 39% of the men linked to a woman < 25 are simultaneously also linked to a woman 25-40 years Young women <25 years (N=43) Knew HIV status: 23.3% 62% of male partners are 25-40 years Women 25-40 years (N=56) Knew HIV status: 42.6% 63% of male partners are 25-40 years Community HIV prevalence: 22.3% Community HIV prevalence: 59.8% When young women reach >25 years they continue the cycle De Oliviera T, Kharsany A, et al. IAS 2016

Breaking Cycles of HIV transmission Schematic of sexual networks from clusters with heterosexual transmission VMMC for HIV negative men <25 years Antiretroviral therapy for HIV+ men >25 years PrEP for women <25 years with SRH services – pH, antibiotics, probiotics Women 25-40 years Anti-retroviral treatment

Developing a potent V1-V2 Ab from SA patient - CAPRISA 256 Next: New prevention for women by 4 injections a year - passive immunisation Developing a potent V1-V2 Ab from SA patient - CAPRISA 256 Y CAP256-VRC26.25 IgG Days Following Challenge Log RNA Copies/ml 2 mg/kg 0.4 mg/kg 0.08 mg/kg Sham Effective in monkeys Effective in monkeys Highly potent antibody Kills 72% of subtype C HIV GMP manufacture for human studies in 2017

Acknowledgements CAPRISA is funded by: DAIDS, NIAID, National Institutes of Health US Agency for International Development (USAID) President’s Emergency fund for AIDS Relief (PEPFAR) US Centers for Disease Control and Prevention (CDC) South African Department of Science and Technology (DST) National Research Foundation (NRF) MACAIDS Fund (via Tides Foundation) Medical Research Council (MRC) The Victor Daitz Foundation CAPRISA is the UNAIDS Collaborating Centre for HIV Research and Policy CAPRISA hosts a DST-NRF Centre of Excellence in HIV Prevention CAPRISA hosts a MRC HIV-TB Pathogenesis and Treatment Research Unit CAPRISA Partner Institutions:

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