Delay of Antiretroviral Therapy Initiation is Common in East African HIV-Infected

Individuals in Serodiscordant Partnerships

Andrew Mujugira, Connie Celum, Katherine K. Thomas, Carey Farquhar, Nelly Mugo, Elly Katabira, Elizabeth A. Bukusi, Elioda

Tumwesigye, and Jared M. Baeten for the Partners PrEP Study Team

7th IAS Conference on HIV Pathogenesis, Treatment and PreventionKuala Lumpur, Malaysia, 2013

Preface

• Antiretroviral therapy (ART) has both treatment and prevention benefits.

• Recent WHO guidance recommends ART initiation for all persons with a known HIV-uninfected partner, as a strategy to prevent HIV transmission.

• However, in sub-Saharan Africa, <50% of HIV-infected persons eligible for ART initiation are on treatment.

WHO 2003, 2011

Rationale

• Evaluate why some HIV-1 infected individuals decline or delay ART despite active counseling of ART benefits and access to ART services.

• Personal and provider barriers to ART initiation include stigma, denial of need for ART, lack of symptoms, fear of ART side effects, lengthy pre-treatment processing, and lack of access to CD4 testing.

• Understanding factors associated with ART-eligible individuals delaying or declining treatment may help design strategies to motivate treatment initiation at higher CD4 thresholds.

Micek 2009, Geng 2010, Losina 2010, McGrath 2010

Study Population

• 4747 heterosexual HIV-serodiscordant couples enrolled in the Partners PrEP Study, a RCT of daily oral antiretroviral pre-exposure prophylaxis (PrEP) to decrease HIV acquisition within HIV serodiscordant couples.

• HIV-uninfected partners were randomized to receive daily oral PrEP or placebo and followed for up to 36 months.

• HIV-infected partners were followed in prospective observational fashion, with quarterly study visits and 6-monthly CD4 counts.

Mujugira PLoS One 2011, Baeten NEJM 2012

Study Procedures• Eligibility criteria for HIV-infected partners:

– CD4 cell count ≥250 cells/μL– no history of clinical AIDS-defining diagnoses– not otherwise meeting national guidelines for ART initiation

• ART-eligible participants were actively counseled to initiate ART, provided with a referral letter detailing CD4 count & HIV clinical status & linked to a care facility of their choice.

• Data on referral outcomes, and barriers to ART initiation were recorded at the next scheduled study visits.

Data Analysis

• Primary outcome: initiation of combination ART.

• Participants who started ART >6 months after referral were considered to have delayed ART initiation.

• Cumulative probability of ART initiation estimated using Kaplan-Meier methods. Cox proportional hazards regression model used to identify independent predictors of ART non-initiation.

Study Profile

Baseline Characteristics Characteristics HIV-infected persons who became

ART-eligible (N=1998)Age in years, median (IQR) 34 (28, 40) 18-24 258 (13) 25-34 804 (40) 35-44 660 (33) ≥ 45 276 (14)Sex: Women Men

1163 (58)835 (42)

At enrollmentN (%)

At ART-eligibilityN (%)

CD4 count (cells/μL), median (IQR) <200 200-250 251-350 >350

393 (322, 495) 0 (0)0 (0)

697 (35)1301 (65)

273 (221, 328) 299 (15)583 (30)874 (43)242 (12

WHO clinical stage : 1 2 3 4

1132 (57)637 (32)229 (12)

0 (0)

796 (40)776 (39)388 (19)

38 (02)

Cotrimoxazole prophylaxis: Yes No

1476 (74)522 (26)

1920 (96)78 (04)

ART Initiation

Initiated ART at 6 months at 12 months at 24 months

1422 (71%)60.8%78.8%91.5%

ART Initiation, by CD4 count

• ART initiation differed according to CD4 cell count as measured at the time of referral

CD4 count at referral (cells/μL) Overall ART initiation At six months

<200 200-250 251-350 >350

87%83%63%55%

66%69%55%32%

Correlates of ART non-initiation Characteristic Adjusted Model

HR (95%) p-valueCD4 count at referral <200 201-250 251-350 >350

Referent1.41 (0.92, 2.18)

3.41 (2.30, 5.306)6.23 (3.53, 10.99)

0.12<0.001<0.001

WHO clinical stage 3 or 4 1 or 2

Referent1.52 (1.02, 2.26) 0.04

Alcohol consumption NoneAny

Referent1.54 (1.20, 1.98) 0.001

Age and sex were not significant in the adjusted model

Self-reported barriers to ART initiation

① Lengthy pre-treatment processing– Pre-ART visits to assess willingness and ability to start ART– Typically 3 weekly or monthly visits for adherence counseling– Associated with longer time to ART start (49 vs 14 days, p<0.01). No

effect on adherence >90% in first 3 months of ART (p=0.26), or HIV viral load >400 copies/ml at 3 months (p=0.97)

② Repeat CD4 counts above the ART eligibility threshold– Provider policy to do own CD4 testing instead of using referral CD4– Discrepancies probably due to physiologic intra-subject variability or

assay performance at different laboratories– May misclassify persons as ART ineligible

Siedner PLoS One 2012

Hanna, CID 2013

Partners PrEP Cohort North American AIDS Cohort

Mujugira, unpublished

ART initiation comparable to N. America

Months since ART referral

Conclusions• In the context of a clinical trial with close CD4 monitoring, regular

counseling of ART benefits, and active linkage to HIV care, approximately 40% of HIV-infected participants had not initiated ART 6 months after referral.

• Higher CD4 counts, asymptomatic HIV disease, and alcohol consumption predicted ART non-initiation.

• Provider barriers, e.g. lengthy pre-treatment processing & repeat CD4 counts were commonly reported impediments to delays in starting ART. <5% reported stigma-related personal barriers.

• Strategies to motivate ART initiation, particularly for asymptomatic persons with higher CD4 counts, are needed.

Partners PrEP Study Team• Sites:

– Eldoret, Kenya (Moi U, Indiana U): Edwin Were (PI), Ken Fife (PI), Cosmas Apaka– Jinja, Uganda (Makarere U, UW); Patrick Ndase (PI), Elly Katabira (PI), Fridah Gabona– Kabwohe, Uganda (KCRC): Elioda Tumwesigye (PI), Rogers Twesigye – Kampala, Uganda (Makarere U): Elly Katabira (PI), Allan Ronald (PI), Edith Nakku-Joloba– Kisumu, Kenya (KEMRI, UCSF): Elizabeth Bukusi (PI), Craig Cohen (PI), Josephine Odoyo– Mbale, Uganda (TASO, CDC): Jonathan Wangisi (PI), Akasiima Mucunguzi– Nairobi, Kenya (KNH/U Nairobi, UW): James Kiarie (PI), Carey Farquhar (PI), Grace John-Stewart

(PI), Harrison Tamooh– Thika, Kenya (KNH/U Nairobi, UW): Nelly Mugo (PI), Kenneth Ngure– Tororo, Uganda (CDC, TASO): Jim Campbell (PI), Jordan Tappero (PI), Aloysious Kakia

• University of Washington Coordinating Center:Connie Celum (PI and Co-Chair), Jared Baeten (Co-Chair and Medical Director), Deborah Donnell (Statistician), Justin Brantley, Tami Cloutier, Robert Coombs, Amy Dao, Shauna Durbin, Mira Emmanuel-Ogier, Lisa Frenkel, Carlos Flores, Harald Haugen, Renee Heffron, Ting Hong, Jim Hughes, Erin Kahle, Johanna Karas, Becky Karschney, Lara Kidoguchi, Meighan Krows, Matt Leidholm, Jai Lingappa, Toni Maddox, Angela McKay, Julie McElrath, Allison Mobley, Susan Morrison, Nelly Mugo, Andrew Mujugira, Vikram Nayani, Patrick Ndase, Apollo Odika, Hilda O’Hara, Dana Panteleeff, Jennifer Revall, Marothodi Semenya, John Sparkman, Kathy Thomas, Ellen Wilcox

• Adherence Ancillary Study: David Bangsberg, Jessica Haberer, Norma Ware, Monique Wyatt, Steve Safren, Christina Psaros, Craig Hendrix, Namandjé Bumpus

• DF/Net (data center): Lisa Ondrejcek, Darryl Pahl, Jae Chong• CLS (laboratory oversight): Wendy Stevens, Charlotte Ingram, Ute Jentsch, Mukthar Kader, Nombulelo

Gqomane, Feroza Bulbulia, Jan van den Heuvel• ClinPhone/Perceptive Informatics (randomization)

• Gilead (study drug donation): Jim Rooney• Bill & Melinda Gates Foundation (study funder): Stephen Becker• HIV serodiscordant couples who tested, screened, & participated