1. 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

2. 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

3. 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

4. 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
South Africa

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Young Women at High Risk

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

13. HIV in South Africa: Disproportionate burden of HIV in young women
AIDS 1992, 6:
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

14. In KwaZulu-Natal, HIV prevalence declining too slowly in young women
Overall HIV prevalence in rural Vulindlela
( )
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

15. 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 ( )
2.6 ( )
16-17
1.1 ( )
6.1 ( )
18-19
1.5 ( )
13.6 ( )
≥20
1.8 ( )
24.7 ( )

16. Risk factors for HIV acquisition in female high school students
Adjusted OR
p-value
Age <18 years
2.67
( )
<0.001
HSV-2 seropositive
4.35
( )
Experience of pregnancy
1.66
( )
0.016
Experience of >1 adult deaths in household
1.97
( )
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;

17. 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: ), 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 ( )
HPV+
880.3 (59/575)
6.7 ( )
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.

18. 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?

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

20. 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

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

22. 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)

23. 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..”

24. 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 (%)

25. 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

26. 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

28. 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

29. Prevotella bivia is strongly associated with inflammation and enhanced HIV acquisition
P. bivia+ OR*
P value HC
19.2
(95% CI: )
p<0.001
HIV+
12.7
(95% CI: )
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

30. 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

31. Cycle of HIV transmission
Schematic of sexual networks from clusters with heterosexual transmission
Men 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 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 years
Young women <25 years (N=43)
Knew HIV status: 23.3%
62% of male partners are years
Women years (N=56)
Knew HIV status: 42.6%
63% of male partners are 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

32. 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 years
Anti-retroviral treatment

33. 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

34. 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:

36. FOR WOMEN IN SCIENCE PROGRAM
The L’Oréal-UNESCO For Women in Science program was founded in 1998 with a simple aim; to ensure that women are fairly represented at all levels in science. Since its creation, the L’Oréal-UNESCO For Women in Science Program has awarded 92 Laureates in 112 countries for their scientific excellence and granted fellowships to 2,438 talented young women to pursue promising research projects. These brilliant women researchers have, each in their own way, truly made the world a better place.
Over the last 18 years,
2,530 Women scientists recognized in 112 countries
92 Awards Laureates honoured for excellence in science, including two who went on to win the Nobel Prize
2,438 Talented young women granted Fellowships to pursue promising research projects
250 Fellowships given worldwide this year over 6,531 applications
Each year, five outstanding researchers are awarded, one from each of the five world’s regions :
Africa and the Arab States, Asia-Pacific, Europe, Latin America and North America,
in Life or Physical Sciences in alternating years.

37. The ‘For Women in Science’ manifesto
Join the movement and sign the Manifesto on :