Initiation and Noninitiation of ART
At the time of ART eligibility, the median CD4 count was 273 cells per microliter (IQR, 221–330): 292 (15%) had CD4 counts <200 cells per microliter, 1410 (72%) had CD4 counts between 200 and 350 cells per microliter, and 256 (13%) had CD4 counts >350 cells per microliter with concurrent WHO stage 3 or 4 HIV disease. Most (96%) were on trimethoprim-sulfamethoxazole chemoprophylaxis. The median time from study enrollment to ART eligibility was 1.4 years (IQR, 0.7–1.8). After becoming ART eligible, participants were followed for a median of 1.4 years (IQR, 0.5–1.9), contributing a total of 1236 person-years of follow-up for the assessment of ART initiation.
Of the 1958 HIV-infected participants with follow-up, 1431 (73.1%) initiated ART. The cumulative probabilities of initiating ART at 6, 12, and 24 months were 49.9%, 70.0%, and 87.6%, respectively. For those initiating ART, the median time from eligibility to starting ART was 5.5 months (IQR, 2.8–8.3). The likelihood of ART initiation differed according to CD4 cell count at the time of eligibility (Fig. 2), with higher cumulative probabilities of ART initiation at 6 and 12 months for those with lower CD4 counts: among those with CD4 counts <200 cells per microliter, 63% and 83%, compared with 59% and 80% for those with CD4 counts of 200–250 cells per microliter, 43% and 63% for those with CD4 counts between 251 and 350 cells per microliter, and 33% and 48% for those with CD4 counts >350 cells per microliter (log rank P < 0.001).
In multivariate analysis, age <25 years [adjusted hazard ratio (AHR), 1.39; P = 0.001], higher education (AHR, 1.25; P < 0.001), lack of income (AHR, 1.15; P = 0.02), and higher CD4 count (AHR, 1.43; P < 0.001 for 251–350 cells per microliter and AHR, 1.95; P < 0.001 for >350 cells per microliter) predicted ART noninitiation (Table 2). Gender, alcohol consumption, and unprotected sex with the HIV-uninfected partner were not related to delay in ART initiation.
In sensitivity analyses restricted to HIV-infected participants for whom referral dates were available (N = 1642), the median time from ART eligibility to referral was 2.7 months (IQR, 0.5–2.8), and the median time from referral to ART initiation was 3.2 months (IQR, 2.4–7.2). The cumulative probabilities of ART initiation at 6, 12, and 24 months from the time of referral were 56.8%, 75.5%, and 89.4%, respectively. Similar to the primary analysis using time from ART eligibility, younger age, higher education, lack of income, and higher CD4 count were significantly associated in multivariate analysis with delay in ART initiation when time from ART referral was used (data not shown).
Of the 1642 participants for whom the precise timing of referral for ART could be abstracted, chart notes were further reviewed to assess spontaneously reported barriers to ART initiation for 1568 (96%) (Table 3). Sixty-eight percent of ART initiators and 39% of noninitiators did not report specific impediments to starting treatment. For ART initiators, provider barriers included pretreatment processing (10%) and repeat CD4 counts at the referral clinic, which were greater than the ART eligibility threshold (6%); 41% of ART noninitiators reported provider barriers [including pretreatment counseling about ART (18%), and high repeat CD4 counts (18%)] to ART initiation. Few (<5%) participants openly described stigma-related personal barriers as impediments to ART access.
In this prospective study of East African, ART-eligible, HIV-infected persons with known HIV-uninfected partners, all received regular clinical and immunological monitoring, ART counseling, and active linkage to HIV care at partnering HIV clinics, and half of the treatment-eligible participants delayed ART initiation for more than 6 months after becoming eligible for ART. Younger age, higher education, lack of income, and higher CD4 counts were predictors of ART noninitiation. Provider barriers including several required pretreatment eligibility assessment and counseling sessions, and repeat CD4 counts above the ART eligibility threshold, were commonly reported impediments to ART initiation.
The cumulative proportion of HIV-infected participants that initiated ART in our study is somewhat higher than in several studies from sub-Saharan Africa: in those studies, the overall proportion was 62.9%.13 Notably, the approximate 50% 6-month cumulative probability of ART initiation in our cohort is comparable to that reported in North America over the past decade.14 Regular counseling, clinical monitoring, and active linkage to HIV care in the context of a clinical trial likely motivated start of ART in our population. Our finding that lower CD4 counts predicted sooner ART initiation is consistent with previous studies,15 perhaps because HIV-infected persons with known lower CD4 counts may be more motivated to start treatment, are given priority by ART providers, or more strongly encouraged to start ART by providers.16 Nevertheless, there was still considerable delay in our population of HIV-infected individuals in serodiscordant couples initiating ART for their own health.
We found that younger age and higher CD4 counts were associated with noninitiation of ART.17 Asymptomatic younger persons may be less motivated to commence life-long treatment, choosing instead to “live positively.”18 In a South African study, 37% of clients who declined ART cited feeling healthy as the reason not to commence treatment.19 Treatment providers may have been less likely to initiate ART in persons with higher CD4 counts, particularly during the period when revised ART initiation guidelines (increasing the threshold from 200–250 to 350 cells/µL) were being implemented in Kenya and Uganda. Anecdotally, phone calls to referral centers were sometimes employed to remind referral clinicians of updated national guidelines. In view of recent WHO guidance to initiate ART in HIV-infected members of serodiscordant couples regardless of CD4 count, counseling of ART-eligible persons and training programs for providers should emphasize the clinical and prevention benefits of earlier ART initiation and address negative perceptions of treatment. Studies from other settings have found that lack of income, particularly as it relates to transport costs, is an economic barrier to ART initiation.20 Although we provided transport re-imbursements for study visits, participants may have had difficulty accessing ART from other providers. We found that higher education was associated with ART noninitiation; the reasons for delayed ART initiation related to education are unknown but may relate to a more nuanced understanding of CD4 thresholds for starting treatment and thus requests for repeat CD4 counts before accepting referrals, employment demands, or other factors.
Pre-ART patient visits to assess willingness, readiness, and ability to start ART were a common cause of delayed treatment initiation in our cohort. A recent study from Uganda found no benefit of additional visits before ART initiation on adherence or HIV RNA concentrations.21 In that study, participants who completed the 3 sessions for pre-ART counseling had significant delays from ART eligibility to initiation, compared with those who received counseling at the time of ART initiation. We also found that clinics repeated CD4 counts, which when above the ART eligibility threshold, were a provider barrier to ART initiation; the variability in CD4 test results could be due to physiologic intrasubject variability of CD4 counts22 or assay performance between laboratories, and counseling about the difference in CD4 counts and the need for a subsequent CD4 test to verify ART eligibility could confuse patients, and lead to a substantial delay in ART initiation. ART providers should recognize the intraperson and intra-laboratory variability in CD4 counts, and utilize trends of CD4 count decline and counts provided from referring providers, to avoid misclassifying persons as ART ineligible.23 Stigma, fear of disclosure, and denial of the need to start treatment are important barriers to ART access24 but may be underrepresented among mutually disclosed clinical trial participants. Among Kenyan HIV serodiscordant couples, fear of ART side effects and stigma were common reasons for reluctance to initiate early ART.25,26 Importantly, lack of ART availability at referral centers was not a significant barrier to ART initiation in our cohort. For known HIV serodiscordant couples, HIV prevention services, including offering PrEP as a bridge until the HIV-infected partner initiates ART, may be particularly important in HIV serodiscordant couples in which the HIV-infected partner declines or delays ART initiation despite knowledge of the dual treatment and prevention benefits of ART and active linkage to HIV care.
The strengths of our study include the prospective design that permitted longitudinal follow-up of a large cohort of HIV-infected individuals, who received HIV primary care at quarterly visits and ascertainment of immunological and ART status. Our study has limitations. HIV-infected participants enrolled in a clinical trial with regular counseling, clinical, and laboratory monitoring may have been more intensive than what is generally implemented in many African settings. To understand barriers to ART initiation, we abstracted data from clinical charts, which relied on participants' self-reports. These qualitative data may have underestimated the range of barriers encountered, but still provide valuable insight.
In summary, among East African HIV-infected individuals who were eligible for ART, had a known HIV-uninfected partner, and were thus motivated to prevent HIV transmission, half did not initiate ART for at least 6 months indicating the importance of individual and structural barriers to ART. Future studies should evaluate strategies to address structural barriers to ART, such as repeat CD4 counts and multiple pre-ART eligibility visits, and to motivate ART initiation, particularly for young asymptomatic persons with higher CD4 counts, including HIV-infected members of serodiscordant couples.
The authors are grateful to the study participants for their participation and dedication. The authors thank clinicians Nyawira Gitahi-Kamau, Scovia Khakhasa, Rita Makabayi Mugabe, Betty Meli, Agnes Nakyanzi, Emmanuel Ocamaare, Edna Tindimwebwa, Imeldah Wakhungu, and Helen Wanja from the study sites for their contributions to data collection. The authors thank Justin Brantley for programming assistance.
University of Washington Coordinating Center and Central Laboratories, Seattle, WA: Connie Celum (principal investigator, protocol co-chair), Jared M. Baeten (medical director, protocol co-chair), Deborah Donnell (protocol statistician), Robert W. Coombs, Lisa Frenkel, Craig W. Hendrix, Jairam R. Lingappa, and M. Juliana McElrath.
APPENDIX 2 Partners PrEP Study Team Study Sites and Site Principal Investigators
Eldoret, Kenya (Moi University, Indiana University): Kenneth H. Fife, Edwin Were; Kabwohe, Uganda (Kabwohe Clinical Research Center): Elioda Tumwesigye; Jinja, Uganda (Makerere University, University of Washington): Patrick Ndase, Elly Katabira; Kampala, Uganda (Makerere University): Elly Katabira, Allan Ronald; Kisumu, Kenya (Kenya Medical Research Institute, University of California San Francisco): Elizabeth Bukusi, Craig R. Cohen; Mbale, Uganda (The AIDS Support Organization, CDC-Uganda): Jonathan Wangisi, James D. Campbell, Jordan W. Tappero; Nairobi, Kenya (University of Nairobi, University of Washington): James Kiarie, Carey Farquhar, Grace John-Stewart; Thika, Kenya (University of Nairobi, University of Washington): Nelly R. Mugo; Tororo, Uganda (CDC-Uganda, The AIDS Support Organization): James D. Campbell, Jordan W. Tappero, Jonathan Wangisi.
Data management was provided by DF/Net Research, Inc. (Seattle, WA) and site laboratory oversight was provided by Contract Laboratory Services (CLS) of the Wits Health Consortium (University of the Witwatersrand, Johannesburg, South Africa).
Study medication was donated by Gilead Sciences.
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Keywords:© 2014 by Lippincott Williams & Wilkins
HIV; CD4; linkage to care; antiretroviral therapy; Africa