Background

1. Lack of Effectiveness of ART as an HIV Prevention Tool for Sero-discordant Couples in a Rural ART Program in Uganda J Birungi, H Wang, M Ngolobe, K Muldoon, S Khanakwa, R King, P Kaleebu, K Shannon, L Lourenco, J Min, J Montaner, E Mills, Y Chen, DM Moore

2. Background • ART coverage has expanded to > 8 million people worldwide. • Expansion of ART has been associated with reductions in new HIV diagnoses in industrialized countries. • HPTN 052 found 96% efficacy of early ART in preventing HIV transmission in sero-discordant couples.

3. HAARP study site HAARP study conducted at a rural TASO HIV clinic HAARP study “The Highly Active Anti-retroviral therapy as Prevention” Study funded by CHIR and CANFAR TASO stands for The AIDS Support Organization TASO is an NGO with 11 HIV Clinic across Uganda 0ver 80,000 HIV positive Registered clients with 50,000 receiving HAART funded by PEPFAR

4. Study Objective • To examine the effectiveness of ART as prevention among sero-discordant couples in a programmatic setting in rural Uganda, without routine access to VL testing. • Compare couples where the HIV +ve partner was on HAART with those whose partner was not yet on HAART. Primary end point: • HIV incidence among co-habiting/married, stable, sexual partners of HIV-positive TASO clients.

5. Study Design

6. Methods • Enrolled two groups of HIV sero-discordant couples: • ART group : HIV -positive partner was receiving ART (CD4≤250 or WHO stage IV illness) • Non-ART group: HIV positive partner not yet eligible for ART • Both groups received HIV risk-reduction counseling and condoms every 3 months. • HIV negative partner tested for HIV every 3 months.

7. Methods (continued) • Plasma and serum collected every 6 months • VL testing at the end of study or on last sample prior to sero-conversion. • HSV-2 testing conducted on enrollment samples (and repeated on last sample for those tested negative). • Genotypic sequencing for new infections where VL ≥ 1000 copies/ mL.

8. Analytic Methods • Compared ART and non-ART couples using Wilcoxon Rank Sum and Chi-squared tests. • Calculated incidence rate ratios - ART Group Requirement: Received ART for >3 months • Cox proportional hazards modeling with ART as a time-dependent variable.

9. Results • Enrolled 586 couples. • 348 (59%) of the positive participants received ART during the study • 249 on ART at enrollment • 99 began ART after enrollment • Median ART-use at enrollment (for participants on ART) was 2.5 years.

10. Baseline characteristics

11. Results - Baseline Characteristics • ART couples were more likely to report • Condom-use at last sex (67% vs. 58%; p = 0.003) • Longer relationships (12 vs. 10 years; p=0.018) • ART couples were older • Median 43 vs. 40 years for men; • 36 vs. 33 years for women; p =0.002, for both • ART couples had • Lower rates of circumcision (p= 0.053) • No differences between the two groups in: • Polygamy; Pregnancy intentions; Injectable contraception-use

12. Results - HIV Incidence • Median follow-up was 1.3 years • 17 infections diagnosed in follow-up • 9 (ART group) • 8 (non-ART group) • Incidence • 2.09 per 100 pyrs for ART group • 2.30 per 100 pyrs for non-ART group • Incidence Rate Ratio of 0.91 among ART participants (p=0.84) • Only 7% of all ART pts had VL >1000 copies/ mL • 3/7 (43%) of ART sero-converters • 7/7 (100%) of non-ART sero-converters • Only 3 virus pairs currently sequenced of non-ART couples • 2 of 3 were linked transmissions

13. Determinants of Seroconversion

14. Cox PH Modelling • Univariate – All participants • ART-use HR = 1.07 (0.41-2.80) • Stratified analyses • HR for ART use: • 1.01 (0.34-3.03) in couples with uncircumcised men • 1.02 (0.13-7.85) in couples with circumcised men • 1.05 (0.35-3.18)in HIV negative participants who were HSV2 + at enrollment • 1.03 (0.34-3.12) in couples where the HIV negative participant was female • Insufficient power for adjusted model

15. Conclusions • ART-use was not associated with reduced risk of HIV transmission in this study • Reasons are unclear: • ART use was associated with reduction in viral load • High VL was associated with increased transmission • Possible explanations: • Single VL measurement is not reflective of true viremia • Underreporting of outside sexual partners • Co-factors facilitating transmission at low level viremia • Confounding factors not accounted for in our stratified analyses • It is difficult to extrapolate the results of RCTs in ideal situations to real life setting in low-income countries

16. So, What does this mean for treatment as prevention? • It is important to collect data on the real-world effectiveness of ART in terms of preventing HIV transmission among representative populations especially in Africa • Our results do not question that ART works as a prevention tool, only that the effect can be undermined by other biological, social and cultural factors which also affect HIV transmission risk.

17. Acknowledgments • TASO Uganda Senior Management • Robert Ochai E.D. • TASO Jinja Staff • Medical Research Council • Study participants • Dr. Christine Nabiryo • Dr. Alex Coutinho • Dr. Heiner Grosskurth • Canadian Institutes for Health Research • Canadian Foundation for AIDS Research • PEPFAR & American people HAARP study team • David Moore PI • Pontiano Kaleebu Co-PI • Julio Montaner Co-PI • Moses Ngolobe • Maureen Nyonyintono • Sarah Khanakwa • Rachel King • Katie Muldoon, Lillian Lourenco • Hong Wang, Wendy Zhang, Yalin Chen , Jeong Min • Kate Shannon, Ed Mills • CAPT network

18. Thank You