Thirteen studies in the systematic review assessed CD4 cell count according to our definition of immunologic response: the mean change in CD4 cell count from baseline to the time of DOT-HAART completion.53,55,58-61,66,69,81,86,87,100,101 We obtained necessary data for computation of mean difference and its standard error from 9 studies and/or authors. For the remaining 4 studies,53,59,87,101 we inferred the mean change and standard deviations from other data available (see Supplemental Digital Content 1, http://links.lww.com/QAI/A43). Four studies showed significantly greater increase in the DOT-HAART group.53,58,60,66 As summarized in Figure 4, DOT-HAART was associated with greater increase in CD4 cell count (RE WMD 43 cells/μL, 95% CI: 12, 74 cells/μL) compared with standard of care. As with virologic suppression, the effects varied widely, as indicated by the significant Q test and a Higgin I2 value greater than 50% (P < 0.001, I2 = 82.6%, 95% CI: 71.5% to 89.4%). Meta-analysis of DOT-HAART durability on change in CD4 included 5 studies for which postintervention data were available55,65,85-87 and did not show a significant effect (RE WMD: 40 cells/μL, 95% CI: −13 to 93 cells/μL).
Six of the studies included in the systematic review assessed adherence as taking at least 95% of prescribed doses at time of DOT-HAART completion.61,65,69,84,87,100 Of data available, we found that 88% (359 of 408) of those receiving the intervention compared with 75% (302 of 402) of patients in control groups achieved ≥95% adherence. As shown in Figure 5, the studies analyzed showed a positive intervention effect on adherence (RE RR: 1.17, 95% CI: 1.03 to 1.32). Again, the results varied from study to study (P = 0.01, I2 = 62.7%, 95% CI: 9.3% to 84.6%), with between-study variability explaining 63% of the total variance in the effect.
To explore sources of heterogeneity in the effects of DOT-HAART on undetectable viral load, we stratified the studies and conducted meta-regressions by 8 variables, as shown in Table 2. Although meta-regression analyses were not statistically significant, several trends in treatment effects by stratified meta-analyses were notable. Treatment effect was greater among studies delivering DOT at patients' residences compared with those delivering clinic-based DOT; in HAART-experienced individuals compared with HAART-naive individuals; in nonresource-poor settings compared with resource-poor settings; in substance-using populations compared with nonsubstance-using populations; and in those receiving enhanced DOT compared with those given nonenhanced DOT. Effect estimates were greater among nonrandomized observational studies compared with RCTs, although this meta-regression did not show evidence for a significant difference (P = 0.52). Associations with virologic suppression in RCTs did not meet statistical significance (RR = 1.18, 95%CI: 0.99, 1.42, P = 0.068). There were no differences in the effect of DOT-HAART by presence of baseline virologic or immunologic differences (P = 0.66) or by differential attrition (P = 0.96).
In this systematic review of controlled DOT-HAART studies, we observed an overall beneficial effect of DOT-HAART on virologic, immunologic, and adherence outcomes. DOT-HAART was found to improve HAART adherence, supporting the presumed mechanism of DOT-HAART effectiveness on clinical outcomes through improved antiretroviral adherence.4,9,102,103 Qualitative data suggest that other mechanisms may also mediate DOT-HAART effectiveness, including positive effects on patients' trust and communication with providers; increased patient motivation to engage in daily activities and become involved in the community; improved adherence to other aspects of medical care; and greater the utilization of other forms of social and adherence support.30,44,65,104-106
We encountered large variation in methodologic quality, intervention design, and population characteristics and explored their influence on the observed virologic effects through stratification and meta-regression. When stratified by study design, the positive effect of DOT-HAART on virologic and immunologic outcomes among RCTs was attenuated and not statistically significant, whereas the association remained significant in nonrandomized studies. The meta-analysis by Ford et al107 also found a lack of effect among RCTs (RR = 1.04 (95% CI: 0.91 to 1.20, P = 0.55), but this summary estimate was smaller than our findings. The potential reason for the difference may be that Ford et al107 included effect estimates from the postintervention period, during which the efficacy of DOT-HAART may have waned, as indicated by our findings. Experts often rely on RCTs for causal inference as randomization prevents the imbalance of confounding factors between intervention and control groups. Recognizing that those who were selected for DOT may have differed from those who received standard of care in characteristics that would affect outcomes, we investigated the impacts of baseline virologic or immunologic differences and of differential attrition on effect heterogeneity. Meta-regressions and stratifications did not detect any significant difference in effect based on these study characteristics. Thus, we cannot attribute the difference in effect between RCTs and nonrandomized studies to these factors. Instead, these findings may reflect true differences in effect by population characteristics or intervention design that varied between RCTs and nonrandomized studies. Nonrandomized DOT-HAART experiences may have allowed greater flexibility in intervention design and modification and may have enrolled vulnerable populations in whom the intervention effect could be greatest.
Beyond methodological quality, there were considerable variations in DOT-HAART interventions and populations targeted. Meta-regression analyses failed to identify a clear source of heterogeneity. Nonetheless, some of the trends in intervention effect upon stratification merit further discussion. Greater effect on virologic outcome was observed among substance-using and HAART-experienced cohorts. These findings support the intuitive hypothesis that individuals at greatest risk of treatment nonadherence (including HAART-experienced individuals108,109 and substance users53,60,61,74,110) benefit most from this intervention. Residence and methadone-based DOT-HAART interventions demonstrated greater treatment effect compared with clinic-based interventions, although the effect among methadone-based interventions was not statistically significant. Choosing a convenient site-such as a methadone clinic or the patient's residence-could enhance the effect of the intervention. Interventions delivered in patient homes, community-based vans, prisons, and methadone clinics may impose minimal additional burden on patients' routines. On the other hand, the time and expenses of daily travel to a site (eg, HIV clinic, hospital) that is not part of a patient's daily routine may pose important barriers to DOT-HAART adherence, in particular in resource-poor settings where the relative cost of traveling to health facilities may be even greater.
Not all DOT is the same. Enhanced DOT-HAART, defined as an intervention that provides additional material or behavioral adherence support not offered to the control group, seemed to enhance treatment effect. Consensus guidelines for treatment of tuberculosis endorsing DOT have pointed out that studies of DOT with enablers have shown the highest treatment completion rates.91 Our findings suggest that the same observation may be true for DOT-HAART and that the use of additional motivations for adherence may improve outcomes,70,87,111 particularly among substance users.53,74,112-114 Ongoing RCTs such as that of Bangsberg et al84 and MOTIV8 are examples of enhanced DOT-HAART interventions intended to maximize the potential impact of DOT by administering other forms of adherence support, such as case management or adherence counseling based on motivational interviewing and cognitive behavioral techniques.51,84,104 Final data from such studies will provide important information on enhanced forms of DOT-HAART.
Although there were few studies that assessed postintervention effect, we found that initial intervention effect may wane after completion of DOT support. Although these findings are consistent with a meta-analysis of a wide spectrum of HIV treatment adherence interventions,34 exploring this time-limited effect may be even more important for DOT-HAART, if the mechanism of action is through improved adherence via direct supervision. If DOT-HAART is to have a sustained effect on postintervention outcomes, interventions must be designed to engender psychosocial and behavioral changes in patients through DOT encounters, such as those described by several groups studying DOT-HAART.53,57,65,87,100,104,115 For this reason, although we did not identify a significant difference in intervention effect of enhanced vs. nonenhanced DOT on immediate outcomes, we speculate that enhanced DOT-HAART could lead to more lasting durability of intervention effect. Efforts to sustain the benefits of DOT postintervention may also require closer attention to the transition from DOT to self-administration and to individualizing DOT through varied frequency, intensity, and duration of support.116 If DOT-HAART effect is not durable, another option would be long-term or even life-long DOT-HAART for certain individuals or populations.41 Creating and implementing durable HAART adherence interventions remains an enormous challenge.34,85,87
Our review has several limitations. It was not feasible to blind abstractors to authors, institutions, or journals of the data reviewed; however, use of a standard extraction form, resolution of discordant abstractions, and involvement of third party minimized bias from lack of blinding. We could not overcome some of the heterogeneity across studies and differences in adherence measures, and we were unable to investigate the moderating effect of other potential variables, including unmeasured differences in DOT vs. control groups. As previously mentioned, the small number of studies limited the inferences that could be drawn from meta-regressions. To better understand findings across studies and to assemble data for the purposes of meta-analysis with greater ease in the future, we recommend that all forthcoming controlled studies on DOT-HAART report the 3 outcome measures as defined in this analysis.
Despite these limitations, our review of peer-reviewed controlled studies shows that DOT-HAART seems to be effective among selected patient populations, such as those with a history of prior HAART experience and/or substance use. Features of DOT-HAART which may increase treatment effect include nonclinic-based DOT and the provision of additional forms of adherence support. Because the impact of DOT-HAART on virologic response did not reach statistical significance when restricted to RCTs, the efficacy of DOT-HAART still remains in question. Areas for future research include assessment of long-term treatment effects and the refinement of DOT-HAART interventions to optimize the intensity, duration, and frequency according to patient need. Similar to the body of knowledge that has guided decisions on DOT for tuberculosis, efficacy trials should be complemented by outcomes data from large-scale DOT-HAART programs and cost-effectiveness analyses to inform public health decisions regarding whether and under what circumstances DOT-HAART should be employed.
For their correspondence, input, and kind support, we would like to thank Sidney Atwood, Sergio Babudieri, David Bangsberg, Ronald Bosch, Kimberly Cullen, Allison DeLong, Molly Franke, Wendy Garland, José Girón González, Ana Horta, John Idoko, Massimiliano Lanzafame, Gregory Lucas, Grace Macalino, Donna Mildvan, Jennifer Mitty, Jean Nachega, Cynthia Pearson, Kathleen Ragland, Michael Rich, Avina Sarna, and Amy Wohl.
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