Among antiretroviral-experienced adults taking methadone for opioid dependence, 24-weeks of DOT was more efficacious for improving adherence and lowering VL than self-administered antiretroviral medications. Using an intent-to-treat approach, adherence in the DOT group was significantly higher at all assessment points than adherence in the TAU group. During the 24-week trial, participants in the DOT group maintained high adherence, while adherence among participants in the TAU group dropped. Further, while there was no change in VL in the TAU group, VL decreased by 0.5 log10
copies/ml in the entire DOT group, and by 1.07 log10
copies/ml among DOT participants with detectable baseline VL. Despite similar proportions of participants in both groups with undetectable VL at baseline (51% DOT, 42% TAU), at week 24 this proportion increased to 71% in the DOT group and did not change in the TAU group. In fact, among TAU participants with undetectable baseline VL, 21% experienced viral rebound. While several DOT studies have reported decreases in VL (Altice et al., 2007
; Conway et al., 2004
; Lucas et al., 2006
; Macalino et al., 2007
) and modest improvements in self-reported adherence (Altice et al., 2007
; MA et al., 2008
; Pearson et al., 2007
), ours is one of the few DOT trials to report improvements in objectively measured adherence at multiple time points.
Unlike most DOT programs, we enrolled participants with both detectable and undetectable baseline VL (Goggin et al., 2007
). To examine the effect of DOT among those with undetectable baseline VL, who are often not considered DOT candidates, we stratified analyses by baseline VL (detectable versus undetectable). We found that the DOT intervention significantly improved adherence even among participants with undetectable baseline VL.
The decrease of 0.52 log10
copies/ml we found among the entire DOT group is less than that found in other DOT studies. In addition to our trial participants having a lower baseline log VL (2.81 copies/ml) than those in other DOT studies (Lucas et al., 2006
; Macalino et al., 2007
; Wohl et al., 2006
), another explanation for this modest VL decrease is the inclusion of participants with undetectable baseline VL. While the proportion of DOT participants with viral suppression increased from 51% to 71% during the trial, almost half (47%) the DOT participants with detectable baseline VL achieved viral suppression. Our finding of a three-fold increase in the odds of viral suppression at trial end among DOT participants compared to TAU participants is consistent with the work of both Altice et al and Lucas et al, who reported similar results among samples of drug users (Altice et al., 2007
; Lucas et al., 2004
). Taken together, these data strongly suggest that DOT is an effective intervention for achieving viral suppression, the ultimate goal of HIV treatment, among drug using populations.
Enrolling patients with undetectable baseline VL into DOT trials is relatively uncommon, and our ability to examine the effect of the intervention in this group is unique. Though VL did not change significantly in the TAU group, 21% of TAU participants with undetectable baseline VL experienced viral rebound. The effect of DOT on viral suppression among participants with undetectable baseline VL has been examined by Altice et al who also found that among those with undetectable baseline VL, more DOT than standard care participants maintained viral suppression (Altice et al., 2007
). These results suggest that DOT is efficacious in preventing virologic failure among participants who are already meeting clinical goals.
Though evidence in support of antiretroviral DOT programs is mounting, important questions still remain. In particular, the minimally efficacious dose of DOT is unclear. Because of differences in antiretroviral dosing and methadone pick-up schedules the proportion of observed antiretroviral doses in our trial varied from 86% among participants on once-daily regimens with a 6 day/week methadone pick-up schedule to 36% among participants on twice-daily regimens with a 5 day pick-up schedule. Among drug users in a community-based DOT program, Altice et al found that adherence was significantly higher with observed than unobserved medication doses, suggesting that a greater number of observed doses may improve outcomes (Altice et al., 2004
). In contrast, Lucas et al found that in a methadone clinic based DOT program, the percent of observed doses was not associated with virologic failure, suggesting that even minimal participation in a DOT program may improve outcomes (Lucas et al., 2007
). The effect of DOT programs on adherence with unobserved, or “take-home”, doses merits further research.
Despite ongoing research, little is known about the optimal target population for antiretroviral DOT programs, and this has important cost implications. Our intervention was efficacious among participants who had been HIV-infected for a median of 13 years and were all antiretroviral experienced. Despite long-term opioid replacement therapy with high-doses of methadone, over half was using cocaine at baseline, and approximately one third was using non-methadone opioids. These findings support the recommendation that DOT should be offered to all methadone maintained patients, regardless of active drug use. To better understand the potential benefit of DOT to drug users, future research should examine the effect of DOT on active versus former drug users, and the efficacy of DOT for reducing substance use.
Our study has several important strengths. First, HIV providers made all clinical decisions and we did not restrict antiretroviral dosing regimens. Second, frequency and duration of research visits were the same in each group, minimizing the risk of attention bias. Lastly, the DOT intervention utilized existing methadone resources. The main difference between our trial and a program without additional funding was the specially prepared pill trays for observed and take-home antiretroviral doses. Ad hoc DOT occurs in our clinics for non-HIV medications (e.g., benzodiazepines), and in these cases nurses dispense daily doses directly from patients' medication bottles, which are stored in the clinic. Nonetheless, the cost effectiveness of DOT programs remains an open question (Goldie et al., 2003
Limitations to generalizability should be noted. First, because our trial was conducted in a network of methadone clinics with fully integrated onsite HIV care, the feasibility and efficacy of DOT in methadone clinics with off-site medical care is unknown. In addition, we only enrolled patients who attended the methadone clinic at least 5 days per week limiting our ability to extend our results to patients who attend clinic less frequently.
These findings have important policy implications. HIV care and substance abuse treatment must be further integrated before DOT can be widely implemented in methadone clinics. Though this model would be most effective if methadone treatment programs had on-site HIV care, antiretroviral DOT could be achieved through close partnerships between HIV clinics and substance abuse treatment programs. For example, with coordination among off-site HIV specialists, community pharmacies, and methadone clinic staff, antiretroviral mediations could be delivered directly to methadone clinics and then dispensed by methadone clinic nurses as observed doses. Lastly, to increase the feasibility of methadone based DOT programs, efforts to provide on-site HIV care in methadone clinics should be aggressively pursued. Allowing higher reimbursement rates for treatment of HIV is one step towards this goal, and could increase the number of existing methadone clinics capable of providing DOT.
In conclusion, this study adds to the literature on antiretroviral DOT programs by demonstrating efficacy of DOT in a randomized trial of antiretroviral experienced, methadone maintained patients, many with ongoing drug use. Future DOT trials should determine the optimal dose and duration of antiretroviral DOT for drug users. In addition, to inform allocation of resources, research efforts should focus on identifying the most appropriate target population from both a clinical and cost-effectiveness perspective. Our finding that DOT was efficacious in a sample that was heterogeneous regarding both baseline VL and drug use suggests that antiretroviral DOT programs have the potential to provide substantial clinical benefit to drug users on methadone for opioid dependence.