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 Prevention
Kuala 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 HIVuninfected 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 preexposure 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 6monthly 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 noninitiation.
Study Profile
4747 HIV-infected participants
2563 not eligible for ART during study
period
2184 became eligible for ART
6 died before referral
2178 referred for ART initiation
168 had no subsequent visit
12 lost to follow-up
1998 completed at least 1 follow-up
visit to assess ART status
1422 initiated ART
Baseline Characteristics
Characteristics
Age in years, median (IQR)
18-24
25-34
35-44
≥ 45
Sex: Women
Men
HIV-infected persons who became
ART-eligible (N=1998)
34 (28, 40)
258 (13)
804 (40)
660 (33)
276 (14)
1163 (58)
835 (42)
At enrollment
N (%)
At ART-eligibility
N (%)
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)
CD4 count (cells/μL), median (IQR)
<200
200-250
251-350
>350
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)
<200
200-250
251-350
>350
Overall ART initiation
At six months
87%
83%
63%
55%
66%
69%
55%
32%
Correlates of ART non-initiation
Characteristic
CD4 count at referral
<200
201-250
251-350
>350
Adjusted Model
HR (95%)
p-value
Referent
1.41 (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
Referent
1.52 (1.02, 2.26)
0.04
Alcohol consumption
None
Any
Referent
1.54 (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
ART initiation comparable to N. America
Partners PrEP Cohort
North American AIDS Cohort
Months since ART referral
Mujugira, unpublished
Hanna, CID 2013
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
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Sites:
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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
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Adherence Ancillary Study: David Bangsberg, Jessica Haberer, Norma Ware, Monique Wyatt,
Steve Safren, Christina Psaros, Craig Hendrix, Namandjé Bumpus
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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
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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