1. “No conflicts of interest to declare”
Conflict of Interest
“No conflicts of interest to declare”

2. Lessons Learned from Tenofovir Vaginal Gel Studies
Topical agents for PrEP: As Good as Systemic PrEP?
IAS symposium, 24 July 2017
Salim S. Abdool Karim
Director: CAPRISA
CAPRISA Professor of Global Health, Columbia University
Pro Vice-Chancellor (Research): University of KwaZulu-Natal
Adjunct Professor of Medicine, Cornell University
CAPRISA is the UNAIDS
Collaborating Centre for
HIV Research and Policy
CAPRISA hosts a DST-NRF Centre of Excellence in HIV Prevention

3. Overview Current clinical trial evidence for tenofovir gel
4 lessons from tenofovir gel trials:
Adherence is a challenge
Vaginal microbiome impacts topical PrEP efficacy
Genital inflammation undermines gel protection
Potential multi-purpose technology (HIV & HSV-2)
The world needs many options…
Conclusion

4. Current clinical trial evidence for tenofovir gel
Effect size
(95% CI)
Study
CAPRISA 004 – coital Tenofovir gel
(South Africa)
39% (6; 60)
MTN003/VOICE – daily Tenofovir gel
(South Africa, Uganda, Zimbabwe)
15% (-21; 40)
FACTS 001– coital TFV gel
(South Africa)
0% (-40, 30)
-40
-20 20 40 60 80
100
Effectiveness (%)

5. Lesson 1: Adherence is essential
Association between drug detection and HIV incidence in tenofovir gel studies
Source: a - Marrazzo et al. NEJM 2015; b - Kashuba et al. JAIDS 2015; c - Rees et al. CROI 2015

6. High adherence is essential
# 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, Frohlich J, et al. Science 2010

7. Women with Lactobacillus dominance Women with <50% Lactobacilli
Lesson 2:
Women with Lactobacillus dominance
Women with <50% Lactobacilli
Effectiveness: 61%
(95%CI: 11; 84%), p=0.013
Effectiveness: 18%
(95%CI: -77; 63%), p=0.644

8. Vaginal microbiome impacts tenofovir & tenofovir-DP concentrations
Abiotic
L. Iners
L. Crispatus
G. vaginalis
TFV alone
TFV + cells
TFV + cells + G. vaginalis
TFV + cells + L. Iners
TFV + cells + L. Crispatus

9. Lesson 3: Genital inflammation reduces tenofovir gel efficacy in women
Adherence < 50%
Adherence > 50%
Probability of HIV infection
Placebo gel
Tenofovir gel
Inflammation
Inflammation
No inflammation
No inflammation
*Genital inflammation defined as >5/9 cytokines elevated
Source: McKinnon et al. submitted manuscript

10. Low cytokines
High cytokines

11. Lesson 4: Topical tenofovir prevents HSV-2
Aaaa
Aaa
aaa
Probability of HSV-2 infection
0.5
0.4
0.3
0.2
0.1
0.0
p=0.003
Tenofovir gel
Placebo gel
Months of follow-up 6 18 30
Effectiveness: 51% (95%CI: 23-70%), p=0.003

12. HIV prevalence in pregnant SA rural women (2001-2013)
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%
The need for prevention tools for young women in Africa remains urgent
Source: Abdool Karim Q, 2014

13. A range of options is needed…
Truvada
ARV rings
eg. Dapivirine
Broadly
neutralising antibodies
Injectable
ARVs: Cabotegravir & Rilpivirine
CAP256-VRC26.25 IgG
Potential future prevention technologies
Topical ARV gels
New oral ARVs
eg. F/TAF
Altering the
vaginal
microbiome -
Treat BV & Lactin-V
ARV
implants eg. TAF
Multi-purpose
technologies

14. Conclusion Tenofovir gel prevents HIV and HSV-2 in women
Trial outcomes varied - zero to modest efficacy
Adherence is a challenge
Future PrEP trials need to factor in the effects of genital inflammation and the vaginal microbiome
Women want a range of HIV prevention options
While tenofovir gel could contribute to HIV prevention, the higher priority is a long-acting formulation that reduces the burden of adherence on women, especially young women…

15. Acknowledgements RESEARCH SUPPORT WAS PROVIDED BY:
Key investigators involved in these studies:
Quarraisha Abdool Karim, CAPRISA & Columbia University
Adam Burgenor, Public Health Agency of Canada
Nichole Klatt, University of Washington-Seattle
Jo-Ann Passmore, CAPRISA & University of Cape Town
Carolyn Williamson, CAPRISA & University of Cape Town
Lyle McKinnon, CAPRISA & University of Manitoba
Research teams involving >180 scientists & students
RESEARCH SUPPORT WAS PROVIDED BY: