To our knowledge, this is the first prospective, randomized, controlled trial of DAART among HIV-infected drug users—a group that, in prior studies, demonstrated poor adherence, compared with other populations of HIV-infected patients. Both acceptance (84% of those randomized to the intervention initiated DAART) and retention (69% of those who initiated DAART completed 6 months of therapy) were high. The intention-to-treat results from this trial demonstrate improved virologic and immunologic benefit in patients who receive DAART, compared with those who self-administer their HIV therapy, as prescribed by their clinician. Namely, at the end of treatment, 71% of patients receiving DAART versus 55% of patients receiving SAT achieved virologic success, and the mean reduction in viral load was ~1 log10 copies/mL greater among the patients receiving DAART. Patients who received DAART had an increase in CD4+ T lymphocyte count that was 180 cells/µL greater than that achieved by the patients who received SAT. This is particularly impressive because of the relatively high median CD4+ T lymphocyte count at baseline in a group of antiretroviral-experienced patients who had potentially achieved significant immunologic recovery prior to entry into this study. These results appear to be robust to inferences made through several different analytic approaches.
Because surrogate markers of virologic suppression and immunologic function are predictive of clinical outcomes [32
], it is likely that improvements in these markers should provide clinical benefit to an HIV-infected population that has typically not fully benefited from antiretroviral therapy. In addition, reductions in HIV-1 RNA levels of the magnitude demonstrated among the patients receiving DAART (1.2 log10
copies/mL) have been significantly associated with reduced heterosexual transmission of HIV infection [39
Despite these promising results, several questions about DAART remain if it is to be used more widely. This study, for example, does not describe the primary determinants of success of a DAART program. It is clear, both from this trial and from other observational studies [40
], that an effective DAART program involves far more than simply directly observing treatment. Perhaps even more important to patient outcomes is the intensive social and medical support that DAART programs may provide. Indeed, in previously published reports involving the DAART arm of this study, training of the DAART workers [31
] and provision of enhanced medical and social services were important determinants of outcome [41
]. It is possible that these forms of support can be provided without the direct supervision component; DAART may simply be one logistically and programmatically effective way to do so. It is also unclear what role, if any, beepers played as a reminder for patients. Another study that used a “reminder” actually resulted in a reduction in adherence and no benefit from the device [42
]. Additional prospective randomized, controlled trials and observational cohort studies of standard DAART, compared with “enhanced” DAART, in which additional services are provided, will be required to answer these important questions.
An additional component of the services provided as part of the DAART intervention is vigilance with respect to anti-retroviral treatment regimens. Patients receiving DAART were significantly more likely to be changed to an alternative regimen during the course of this study—in these instances, simplified regimens that involved a once-daily protease inhibitor combined with other antiretroviral medications. Although we were unable to assess this phenomenon because of the small number of patients, it may have been a result of the DAART outreach workers’ and DAART clinicians’ responsiveness to the adverse effects experienced by the patients, as well as the patients’ desires to simplify their regimens. These potential confounders will need to be addressed in future studies.
Other crucial issues include which patients are most likely to benefit from DAART, when DAART should be initiated, and for how long DAART should be continued. This study was designed to assess as broad a patient base as possible, including patients having, essentially, the entire range of HIV-1 RNA levels and CD4+
T lymphocyte counts. This was done to provide a rigorous, clear assessment of efficacy for DAART in a general, “real-world” population of drug users who are likely to be encountered by clinicians and public health practitioners. More research will be required to adequately describe patients who will benefit most from DAART interventions, because such interventions may not be cost-effective, unless patients with poor adherence to treatment are targeted [43
The DAART intervention also provided a rather inflexible (and potentially undesirable or unrealistic) transition from DAART to SAT at 6 months, rather than at a point determined by a decision between the patient and provider or by some other predictor of long-term success. To determine the optimal duration of DAART, the durability of the intervention needs to be assessed. This will be partially informed by the 12-month outcomes of this study—a planned analysis that is forthcoming.
Of note, this trial does not provide evidence for the use of DAART as anything other than a voluntary program. All patients in this study had the option of refusing DAART without any repercussions in their HIV care, and 14 patients (16%) originally randomized to receive DAART withdrew participation without receiving a single directly administered dose, because they did not want to participate. It is unlikely that any use of DAART as a coercive strategy will ever be desirable on ethical, legal, public health, or clinical grounds [44
In summary, this randomized, controlled trial of DAART among HIV-infected drug users achieved its primary outcome and several secondary outcomes, showing virologic and immunologic benefits at the end of the 6-month intervention. Among this difficult-to-engage population of drug users, we also exhibited high rates of both acceptance and retention of DAART. This trial provides, to our knowledge, the first support for DAART as an effective strategy to improve clinical outcomes among HIV-infected drug users, using a randomized, controlled design. Further investigation is warranted to delineate which patients should receive DAART, when DAART should be initiated, the optimal duration of DAART, and how services should be organized to reap the most benefit from DAART.