AIDS 2010: Proof-of-concept that an antiretroviral can prevent HIV infection

CAPRISA 008 Tenofovir Gel Implementation Trial Good Adherence in Trial of Topical Pre-Exposure Prophylaxis Integrated into Family Planning Services Dr Leila E Mansoor (PhD) * Co-Principal Investigator * on behalf of the CAPRISA 008 team AIDS 2016 – Durban, South Africa – 22 July 2016

Introduction WHO recommended the roll-out of pre-exposure prophylaxis (PrEP) to reduce HIV transmission in populations at substantial risk. In Africa, a key target for PrEP implementation is young women, the group at highest risk. However, PrEP efficacy is highly variable in this group:  VOICE Trial: -49% (95% CI: -129 to 3) for daily oral TDF  Botswana TDF2 trial: 75% (95% CI: 24 to 94) for daily oral TDF/FTC. Product effectiveness in “real-world” settings can also differ markedly from product efficacy observed in clinical trials. Limited data exist, beyond clinical trials, to guide the introduction of PrEP in health care services. Many young women utilize existing family planning (FP) services – presents an opportunity for introducing PrEP as part of their established sexual and reproductive health (SRH) services.

Purpose:To assess adherence and effectiveness of topical PrEP (tenofovir gel) integration into FP services – while simultaneously providing post-trial tenofovir gel access to CAPRISA 004 women Design:Open-label, 2-arm, randomized controlled, non- inferiority trial (conducted between 2012 – 2015) Population:HIV-uninfected women who previously participated in the CAPRISA 004 trial Measurements:Demographics – Sex acts – Applicator counts – Adherence – Clinic retention – HIV incidence – Service preference Study summary

Intervention and control groups Control arm:CAPRISA trial clinics with monthly provision & monitoring of tenofovir gel – similar to the CAPRISA 004 clinical trial Intervention arm:Public sector FP services with 2-3 monthly provision & monitoring of tenofovir gel The use of Quality Improvement (QI) methodology to promote reliable service delivery. Two-step approach: QI used to strengthen FP services to be better prepared for expansion QI framework used to assist FP services to add tenofovir gel provision to current SRH service

268 (37.4%) were excluded 52 not interested in participation 51 had relocated 48 were working / studying 47 were HIV positive 38 did not return for screening visit 12 were not traceable 11 were pregnant or planning a pregnancy 4 had died 5 other reason Screened: 448 (56.9%) Eligible for CAPRISA 008: (9.3%) could not be contacted 66 (14.7%) were excluded 37 did not return timeously 20 were HIV positive 6 were not sexually active 2 were pregnant 1 was co-enrolled in another trial Enrolled: 382 (48.6%) Pre-screened: 716 * (91.1%) * This includes 3 participants who were screened for CAPRISA 008 in error ; 1 was screened out and 2 were enrolled Study consort Vulindlela: 266 eThekwini: 116

FP service: 193 Trial clinic: 189 Analysed: 189Analysed: were excluded 2 were HIV positive 2 co-enrolled in another trial 6 were excluded 4 were HIV positive 1 no post-randomization follow-up 1 pregnant at enrolment Enrolled: 382 Completed study: 174 (92.1%) Completed study:167 (91.3%) 15 did not complete the study 10 refused further participation 4 were lost to follow-up 1 withdrawn from study 16 did not complete the study 9 refused further participations 3 were lost to follow-up 1 withdrawn from study 2 died 1 relocated Study consort …cont. Retention: 92.1%Retention: 92.3%

Selected baseline characteristics --- similar between FP service and trial clinics --- Variable FP service (N=189) Trial clinic (N=183) p-value Socio-demographic characteristic Age (mean;±SD; range) Parity (mean;±SD; range) Education level (n,%): Didn’t complete high school High school completed Tertiary education initiated Hormonal contraception (n,%) * 29.5; ±5.8; ; ±1.1; (41.3) 98 (51.9) 13 (6.9) 182 (96.2) 29.3; ±5.3; ; ±1.0; (42.6) 92 (50.3) 13 (7.1) 172 (93.9) Sexual behavioural characteristics Total lifetime sex partners (mean;±SD; range) Sex acts: past 30 days (mean;±SD; range) Anal sex: past 30 days (n/N,%) Living with regular partner (n/N,%) Male condom use (n,%): Always Sometimes Never 3; ±2.5; ; ±6.7; /188 (0.5) 35/187 (18.7) 65 (34.4) 95 (50.3) 29 (15.3) 3; ±2.7; ; ±5.9; /183 (1.1) 38/183 (20.8) 78 (42.6) 86 (47.0) 19 (10.4) * Hormonal contraception includes depo-provera [222 (59.7%)], oral [75 (20.1%)], nur-isterate [56 (16.6%)], and implants [1 (0.25%)]

Quarterly retention rates Target: 90% per annum --- similar between FP service and trial clinics ---

Adherence, drug levels & HIV incidence --- similar between FP service and trial clinics --- FP service (N=189) (95% CI) Trial clinic (N=183) (95% CI) Adherence Mean returned used applicators per month Mean number of sex acts per month Mean adherence [gel/(sex x2)] 5.2 ( ) 3.6 (3.2 – 4.1) 79.9% (76.7 – 83.2) 6.0 ( ) 4.5 (4.0 – 5.0) 73.9% (70.7 – 77.1) Mean difference5.92% (1.5 to 10.6) Drug levels (N=313) % with detectable drug levels at 12 months39.5% ( )43.6% (36.1 – 51.4) Risk ratio0.91 (0.70 to 1.18) % with detectable drug levels when sex is reported within 7 days % with detectable drug levels when no recent sex is reported 81/139 (58.3%) 49/174 (28.2%) HIV incidence HIV incidence per 100 women years3.5 (1.8 – 6.0)3.6 (1.9 – 6.3) Incidence rate ratio0.96 (0.40 to 2.35) Higher adherence (mean difference = 5.92% [CI: ]) in FP service clinics met the pre-defined non-inferiority criteria.

HIV incidence in an age-comparable historical CAPRISA 004 placebo control group Incidence rate (95% CI) in CAPRISA 008 Incidence rate (95% CI) in women of comparable age from CAPRISA 004 Difference: IRR ratio (95% CI) 3.5 ( )6.2 (CI ) Difference: -2.7 IRR: 0.56 Overall HIV incidence rate was 44% lower than that observed in an age-comparable historical placebo-control group from the CAPRISA 004 Tenofovir Gel trial

Preference for receiving HIV prevention Total (N=372) N (%) FP service (N=189) N (%) Trial clinic (N=183) N (%) Private general practitioner Public PHC/FP clinic Mobile clinic Doesn’t want to use study product Missing Other * 27 (7.3) 280 (75.3) 6 (1.6) 1 (0.3) 12 (3.2) 46 (12.4) 11 (6.0) 147 (80.3) 5 (2.7) 0 (0.0) 6 (3.2) 20 (10.9) 16 (9.0) 133 (75.1) 1 (0.6) 6 (3.3) 26 (14.7) * Other = CAPRISA Clinic (44), pharmacy (1), a place that opens on weekends (1)

In summary At baseline women assigned to FP service and trial clinics were similar. During the study four critical markers were similar between the FP service and trial clinics:  Retention rates (92.1% vs 92.3%)  Adherence – estimated as the proportion of reported sex acts covered by two gel doses ( 79.9% vs 73.9%)  Genital tenofovir levels at month 12 (39.5% vs 43.6%) Genital tenofovir was detected in 58.3% of 139 women reporting sex within 7 days but only in 28.2% of 174 women reporting no recent sex.  HIV incidence rates (3.5 per 100 wy vs 3.6 per 100 wy) HIV incidence rate was 44% lower than HIV incidence in an age- comparable historical CAPRISA 004 placebo control group (3.5 vs 6.2 per 100 wy). Most women (75.3%) expressed a preference for receiving HIV prevention from FP service clinics.

Conclusion Integration of PrEP into FP services is feasible, acceptable and can achieve good adherence, similar to those achieved in clinical trial settings. While some of the behaviors related to PrEP may be formulation dependent, this study provides broadly applicable information on –  the motivation of women to initiate PrEP,  maintain follow-up, and  adhere to tenofovir-containing HIV prevention in FP clinic services. This clinical trial evidence may be helpful to policy makers and health care providers planning on implementing oral PrEP scale-up.

Acknowledgements Financial support:  USAID (USA & SA) through CONRAD  The South African Government’s Department of Science & Technology (DST) through the Technology Innovations Agency (TIA)  M-A-C AIDS fund through the Tides Foundation Trial oversight committee:  CAPRISA: Q Abdool Karim, SS Abdool Karim, LE Mansoor  USAID (US): D Stanton, L Claypool, M Barnhart  USAID (Pretoria): A Thambinayagam, V Francis  CONRAD: J Schwartz, G Doncel  DST/TIA: S Gumbi, G Loots, M Selematsela, J Coates  M-A-C AIDS/Tides: N Mahon, A Flynn, R Burman  Gilead Sciences: J Rooney Tenofovir & placebo gel: Provided by CONRAD & Gilead Sciences FHI 360: K Torjesen, M Chen IHI: K Mate, P Barker, M Tshabalala, N Mobisson-Etuk CONRAD regulatory support: A Spagnoli