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

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.

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

HAARP study site

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.

Study Design

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.

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.

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.

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.

Baseline characteristics

Not ever on ART (n = 238)

Began ART during the study(n =99 )

On ART at enrollment

(n = 249)

P- value

CD4 cell count at enrollmentMedian (IQR) 515 (389 - 684) 248 (156 - 366) 392 (240 - 539) <0.001

HIV positive participant is male (%) 121 (51%) 60 (61%) 150 (60%) 0.074

Age of male partner Median (IQR) 40 (34 - 47) 41 (36 - 50) 43 (37 - 50) 0.002Age of female partnerMedian (IQR) 33 (29 - 40) 36 (30 - 40) 36 (30 - 40) 0.002 Always use condoms (male response) 138 (58%) 61 (62%) 167 (67%) 0.003Duration (years) of relationship Median (IQR) 10 (5 - 18) 12 (6 - 22) 12 (6 - 21) 0.018

Circumcision Status of male partner 102 (43%) 44 (45%) 83 (34%) 0.053

HSV2 sero-positive (HIV negative participant) 183 (77%) 84 (87%) 203 (83%) 0.067

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

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

Determinants of Seroconversion Seroconverters

(n=17)No seroconversion

(n=527)P- value

ART use (at least 3 months) 9 (53%) 317 (60%) 0.550

HIV positive participant male (%) 13 (76%) 293 (56%) 0.088

>1 sexual partner reported by female 0 8 (2%) 0.999

Age of sexual debut (female) Median (IQR) 15 (14 -16) 16 (15 -18) 0.018

Male sexual decision making (male response)

10 (59%) 184 (35%) 0.044

Duration of relationship with primary partner (in years)

8 (5-12) 12 (6-20) 0.167

Polygamous partnership 8 (47%) 126 (24%) 0.042

Male partner circumcised 4 (24%) 210 (40%) 0.163

HSV2 positive (HIV negative partner) 13 (93%) 425 (81%) 0.592

VL >1000 copies/ mL 9 (64%) 168 (35%) 0.027

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

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

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.

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

Thank You