The study was halted for futility upon the recommendation of the DSMB at its third annual review when interim analysis showed no significant differences in viral load suppression at any time point in the two treatment arms. At the time the study was halted, 114 participants (83%) the DOT-ART arm had reached the 12 month follow-up point compared with 108 participants (79%) in the Self-ART arm. However, primary endpoint data were available on 110 participants in the DOT-ART arm and for 103 participants in the Self-ART arm. The proportion of patients with plasma HIV-1 viral load less than 400 copies/ml in the intention-to-treat analysis, where missing equals failure, at 12 and 24 months was 72.8% and 60.6% in the DOT-ART arm vs. 68.4 and 59.6 in the Self-ART arm (Table 2). Somewhat lower but similar proportions of patients in both treatment arms had viral load less than 50 copies/ml at both time points, as well. In as-treated analyses, 90% of patients in both arms had viral load less than 400 at 12 months (P = 0.94) and 85 vs. 92% had viral load less than 400 at 24 months (P = 0.16). Of patients who achieved virologic suppression, there was no difference in the time to virological rebound (viral load more than 400 copies/ml) following initial suppression of viral load to less than 400 copies/ml by study arm (log-rank test P = 0.468).
Patients in the DOT-ART arm had significantly higher median CD4 cell count changes between baseline and 6 months than patients in Self-ART [148 cells/μl (IQR 84–222) vs. 111 cells/μl (IQR 44–196) P = 0.02], but changes were similarly distributed at all other time-points beyond 6 months (Table 3). The median adherence assessed by pill counts was more than 95% at all time-points in both arms during follow-up. Baseline predictors of virologic suppression (viral load less than 400 copies/ml) at 12 months in a multivariate logistic regression analysis were cumulative pill count adherence more than 90% [odds ratio (OR) 12.4, 95% confidence interval (CI) 2.7–56.4; P = 0.001], female sex (OR 3.8, 95% CI 1.2–12.6 P = 0.028) and baseline CD4 cell count more than 200 cells/μl (OR 4.76, 95% CI 1.0–25 P = 0.05).
There were 29 deaths during the study, nine in the DOT-ART arm (6.6%) and 20 (14.6%) in the Self-ART arm (Log-rank test from Kaplan–Meier analysis: P = 0.02, Fig. 2). Deaths occurred uniformly during follow-up time and were not clustered in the first several months of treatment, as shown in Fig. 2. There was no difference in the time to new or recurrent AIDS-defining illness for the two study arms. In a Cox proportional hazards analysis controlling for covariates of age, sex and baseline CD4 cell counts, study arm was an independent predictor of death (DOT vs. Self-ART: HR 0.38, 95% CI 0.17–0.86 p-value: 0.02). Reported causes of death in the Self-ART arm were tuberculosis (n = 6); chronic diarrhea (n = 3); cryptococcal meningitis (n = 3); Pneumocystis jirovecii pneumonia (n = 2); encephalopathy (n = 1); pulmonary embolism (n = 1); and unknown (n = 4). Reported causes of death in the DOT-ART arm were: isosporiasis (n = 2); stroke (n = 1); HIV-associated nephropathy (n = 1); lactic acidosis (n = 1); COPD or respiratory collapse (n = 2); convulsions (n = 1); and tuberculosis (n = 1).
In this study, partial DOT-ART by patient-nominated treatment supporters had no effect on the primary endpoint, namely the proportion of patients with undetectable HIV viral load (viral load less than 400 copies/ml) at 12 or 24 months. Participants in both arms had high adherence to treatment and virologic suppression was similar in both intent-to-treat and as-treated analyses. Patients in the DOT-ART arm had better early CD4 cell count increases, but the difference was not statistically significant beyond 6 months. Nonetheless, we documented a significant survival benefit in the DOT-ART arm after controlling for other factors associated with death.
Adherence, assessed by pill counts, was high and not significantly different between the two study arms at 6, 12, 18 and 24 months. The intriguing finding that mortality was lower in the DOT-ART arm despite the absence of virologic benefit might be explained by better virologic suppression before 6 months, but virologic data were not recorded for this time period. The better early CD4 cell count responses in the DOT-ART arm suggest that this might be the case. In addition, trained treatment supporters and the resources they provided to patients in the DOT-ART arm may have facilitated patients' better use of medical services for treatment or preventive care, which could reduce morbidity and mortality, but we have no data to support this hypothesis. Finally, the finding that mortality was lower in the DOT-ART arm might be due to chance.
Several other community-based randomized trials testing DOT-ART interventions have been conducted. Wohl et al.  in the United States studied a mixed ART-naive and ART-experienced population without selection for risk factors for nonadherence in whom community workers administered DOT-ART for 6 months, whereas the ACTG A5073 study by Gross et al.  evaluated DOT-ART strategies delivered by a health professional (pharmacist, nurse, etc.) in unselected ART-naive patients in the United States, Caribbean and one site in South Africa. Both of these studies found that DOT did not confer a significant advantage for either virologic suppression or adherence. Macalino et al. compared a community-based once-daily DOT delivered by outreach workers vs. self-administered therapy in a randomized trial of 87 active substance users followed for only 3 months in the United States. These authors found a benefit to DOT-ART, although secondary analyses showed that the entire benefit was limited to ART-experienced patients who had failed prior antiretroviral regimens.
Our study did not include ART-experienced patients. Failure to show a benefit suggests that implementing DOT-ART with patient-nominated community treatment supporters in an unselected treatment-naive population may be unnecessary in settings where average ART adherence has been shown to be high. However, HIV-infected individuals at greater risk for poorer adherence may benefit from such interventions. For example, Altice et al.  conducted a 6-month community-based trial of DOT-ART in injection drug users and found an advantage with respect to both virologic suppression and CD4 cell count increases; however, a 6-month post-intervention analysis failed to show the persistence of the intervention effect at improving virological outcomes . Our study population had no injection drug users, as is usual for African cohorts.
Our study has a number of possible implications. First, the lack of benefit of the DOT intervention on the primary endpoint of virologic suppression should limit enthusiasm for wide implementation in unselected HIV-infected populations starting ART. At the very least, a general requirement for DOT-ART cannot be supported by the results of this trial. However, as shown by Amico et al.  in a meta-analysis of randomized controlled trials, studies targeting groups with poor ART adherence had stronger effects than those targeting groups with mixed adherence levels preintervention. Second, social capital provided by a trusted patient-nominated treatment supporter may contribute to survival through a mechanism unrelated to viral load and should be assessed in future studies. Indeed, qualitative data by our group  and others  support this hypothesis. In the latter study seeking to explain high adherence rates found in sub-Saharan Africa, Ware et al.  argue that, in the face of extreme poverty, individuals rely heavily on social capital, ‘the use of relationships to obtain benefits and achieve desired ends’, to obtain basic resources, such as food or transportation. Their social capital and patients' interests in preserving their support ties and minimizing inordinate dependency on them enhanced and motivated their adherence to ART.
Therefore, even without extensive additional interventions, HIV-infected patients in resource-limited settings such as South Africa may rely heavily on social capital to obtain needed resources to adhere to their ART, and that the availability of treatment supporters is likely based on patients' existing social capital. A model of potential pathways linking social support and health proposed by Uchino  illustrates how randomization to DOT-ART may have contributed to improved survival. According to this model, social support can influence either or both behavioral processes (health-promoting behaviors, such as care-seeking, in addition to medication adherence) and psychological processes (e.g., decreased depression, heightened sense of control and self-efficacy), which, in turn, contribute to biological processes that may ultimately lead to decreased morbidity and mortality. Our data are intriguing in this regard, but we have no evidence of a direct antiviral effect as a mechanism for the survival benefit.
Our study has several strengths. First, this is believed to be the first randomized controlled trial evaluating patient-nominated, community-based treatment supporters for DOT-ART with a report of robust biological and clinical endpoints in a resource-limited setting. Second, this is among the few reports documenting relatively long-term (up to 24-month) high level of ART adherence in sub-Saharan Africa regardless of intervention.
This study also has limitations. The DOT-ART intervention was stopped at 12 months and the transition phase did not ensure that participants developed a set of adherence strategies to replace DOT-ART, although patients and their treatment supporters might have continued DOT-ART on their own after 12 months. Therefore, the results of a longer intervention are not known, which is relevant considering that ART adherence does tend to decrease with time. In addition, the relatively low incidence of AIDS-defining illness and death limit our ability to make final conclusions about clinical benefits of DOT-ART with nominated treatment supporters.
In summary, in this randomized, controlled trial of partial DOT compared with standard of care, DOT by treatment supporters did not improve virologic outcomes, but was associated with significantly better 6-month CD4 cell count increases and survival which was not explained by improved virologic or immunologic outcomes. The overall proportions of patients who had undetectable viral loads at 24 months in the intent-to-treat analysis were disappointingly low at only 60%. This finding underscores the importance of identifying additional interventions to improve the outcomes of ART for patients in resource-limited settings. Additional community-based programs to support treatment adherence and improve clinical outcomes are needed, and studies of such interventions should be sufficiently large to detect clinical endpoints and focus on populations with poorer adherence. Finally, more research attention is needed to examine characteristics of treatment supporters nominated by patients in each condition and ways in which they may or may not have affected patients' adherence or survival.
The authors wish to thank the study participants, treatment supporters, students, interns and the clinical staff at GF Jooste Hospital, Manenberg, Cape Town, South Africa, for their contributions to this study; and Joanna Downer, PhD, for critical reading and editing of this manuscript.
Study design (J.B.N., A.E., R.E.C., A.R.K., G.M.), drafting and writing of the manuscript (J.B.N., G.M., R.E.C.); data management (C.M., M.R.); data analysis (M.A.C., J.B.N.); data interpretation (J.B.N., R.E.C., M.A.C., H.S., G.M., A.R.K.); implementation, monitoring and patient follow-up (A.E., R.G., J.B.N., G.M.); editing and final approval of the manuscript (all); administrative and logistic support (A.E., R.G., G.M., R.E.C.).
Trial Registration: Clinicaltrials.gov registration number: NCT00076804.
Consultant, J.B.N. (Pfizer), R.E.C. (Bristol-Myers Squibb). Honoraria, J.B.N. (GlaxoSmithKline, Merck-Sharp-Dohme for continuing medical education lectures) and G.M. (Merck-Sharp-Dohme and Abbott). Other, J.B.N. (Aspen Pharmaceuticals, GlaxoSmithKline for conferences and travel grants).
This work was supported by the U.S. National Institute of Allergy and Infectious Diseases grants AI 5535901, AI 016137 (REC) and AI 068582-01(JBN); J.B.N. also was supported by a European Developing Countries Clinical Trial Partnership Senior Fellowship Award TA-08-40200-021.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
adherence; antiretroviral therapy; directly observed therapy; HIV-1; randomized controlled trial; treatment supporter