Directly administered antiretroviral therapy benefits drug users with adherence problems

In both resource-limited and wealthy countries, IDUs make up a significant and growing proportion of the HIV-infected population. Some studies have suggested that individuals with a history of injecting drug use are disproportionately non-adherent to anti-HIV therapy compared with non-IDUs. Consequently, interventions such as DAART - based on the model of DOT for tuberculosis (TB) - have been explored, with previously published studies from Canada and Ireland showing promising results.

Investigators from Johns Hopkins University in Baltimore, Maryland, initiated a prospective study of DAART at a university-affiliated methadone clinic in 2001, and extended the project in 2003 to two further community-based urban methadone clinics. Eighty-two IDUs who were initiating or reinitiating antiretroviral therapy received supervised doses of their anti-HIV drugs at the clinic on the mornings on which they received methadone. The drugs were given in a private room away from the methadone-dispensing window, and evening doses were given to participants for self-administration. An additional emergency supply of three days' anti-HIV drugs was also provided in case of unplanned absence from the clinic.

Viral load and CD4 cell counts in the DAART group were compared with three concurrent comparison groups drawn from the Johns Hopkins HIV Cohort, all of whom were self-administering their own antiretroviral therapy: 75 IDUs receiving methadone; 244 IDUs not receiving methadone; and 490 non-IDUs. Compared with the other groups, participants receiving DAART were more likely to be antiretroviral naive, more likely to take a once-daily regimen and less likely to use a non-nucleoside reverse transcriptase inhibitor (NNRTI).

After twelve months of antiretroviral therapy, 56% of DAART participants achieved a viral load below 400 copies/ml, compared with 32% in the self-administered IDU methadone group (p=0.009), 33% of IDUs not receiving methadone and self-administering antiretrovirals (p=0.001), and 44% in the self-administered non-IDU group (p=0.077).

A median CD4 cell count increase of 74 cells/mm³ was seen in the DAART group after twelve months. This increase was significant compared with the self-administered IDUs receiving methadone (21 cells/mm³; p=0.04) and of borderline statistical significance compared with the IDUs not receiving methadone and self-administering antiretrovirals (33 cells/mm³; p=0.09).

The investigators note that the participants receiving DAART had an improved retention to medical treatment (83% at three months in the DAART group, compared with 61% of the IDUs receiving methadone, 73% in the IDUs not receiving methadone and 80% in the non-IDU group), although 48% had discontinued DAART after twelve months. This still contrasts with a 2005 US study which was reported on aidsmap last year, in which the majority of DAART participants had dropped out after six months.

The investigators add that, "DAART participants experienced higher rates of viral suppression than did participants in the IDU comparison groups, even when missing values were excluded." They point out, however, than an important limitation to their study was that the comparison groups were not randomised, and adherence was not measured in the comparison groups.

Nevertheless, according to the accompanying editorial by Timothy Flanigan and Jennifer Mitty of Brown Medical School, this study suggests, "that for patients who are active IDUs, among whom the barriers to adherence and retention in medical care are significantly higher [than non-IDUs], a structured program would be highly beneficial."

The editorial goes on to argue that "the attitude that active IDUs are untreatable because of the challenges of poor adherence is antiquated," and that active substance abusers with low CD4 counts should not have their anti-HIV treatment delayed, because it is "life-saving, even if adherence is suboptimal."

Providing directly administered antiretroviral therapy (DAART, also known as directly observed therapy, or DOT) alongside opioid substitution therapy for injecting drug users (IDUs) may provide substantial clinical benefit to IDUs with previously adherence difficulties, according to the results of a study from the United States, published in the April 28^th electronic edition of Clinical Infectious Diseases. An accompanying editorial calls the provision of DAART at methadone clinics a "highly promising" adherence intervention.

In addition, a randomised adherence intervention study published in the same edition of the journal, comparing community-delivered DAART, clinic-based weekly adherence counselling, and the current standard of care at three public health clinics serving low-income patients, found that neither community-based DAART nor intensive adherence counselling provided any additional benefit over and above the standard of care.

A second study published in the same issue reported results from the first randomised, controlled trial to evaluate the impact of community-delivered DAART and weekly adherence case management on CD4 cell counts and viral loads.

Here, 250 treatment-naive and treatment-experienced (with only one previous antiretroviral regimen failure) individuals attending one of three public HIV clinics serving people of low income in Los Angeles County were enrolled a six month study, and randomised to three groups. The majority (75%) of participants were male; 64% earned less than $10,000 a year; 56% spoke Spanish only; 64% were Latino and 24% African American.

For five days a week, 82 participants had one dose of their anti-HIV drug combination delivered to their home by a community worker who observed them taking the pills. Evening, weekend and holiday doses were left for self-administration, and adherence was measured by empty package collection. Another 84 participants met with a case manager at their HIV clinic every week, and were given counselling to help overcome any barriers they had encountered to antiretroviral adherence. A control group received the standard of care, which included ad hoc one-on-one counselling at two of the three study clinics, as well as quarterly adherence counselling with a case manager.

After six months, using an intent-to-treat analysis, no statistical differences were found between the three groups in either achieving a viral load below 400 copies/ml (54% in the DAART group, 60% in the intensive counselling group and 54% in the standard of care group; p>0.05) or in median CD4 count rises (63, 78 and 69 cells/mm³, respectively; p>0.05).

The authors conclude that among patients with limited prior antiretroviral experience and adherence barriers that had not been assessed before randomisation, "no improvements in virologic, immunologic, or adherence-based benefits were observed in the DAART and [intensive counselling] intervention groups, compared with the [standard of care] group, largely because the response amongst patients with the [standard of care] was so strong. These data, combined with the findings of previous research, suggest that these adherence-support interventions may be most beneficial to HIV-infected persons with documented adherence problems."

In their editorial, Flanigan and Mitty praise the study for its methodology and robustness, and conclude that "standard clinic-based adherence counselling...may be adequate for most patients." However, they add, community-based DAART "may be most amenable to a short-term intervention (e.g. for three months)" due to the added inconvenience for the patient, but that community-based DAART may be a way to address adherence in active IDUs who are not currently receiving opioid substitution therapy.

"Innovative interventions, such as methadone clinic-based or community-based DAART programmes," they conclude, "can achieve laudable success stories."