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Sustained Benefit from a Long-Term Antiretroviral Adherence Intervention: Results of a Large Randomized Clinical Trial
Global Health Sciences Literature Digest
Published January 30, 2007
Journal Article

Mannheimer SB, Morse E, Matts JP, Andrews L, Child C, Schmetter B, Friedland GH; Terry Beirn Community Programs for Clinical Research on AIDS. Sustained Benefit from a Long-Term Antiretroviral Adherence Intervention: Results of a Large Randomized Clinical Trial. J Acquir Immune Defic Syndr. 2006 Dec 1;43 Suppl 1:S41-7.


To assess the efficacy of two adherence interventions (medication managers and medication alarms) among HIV patients in the US initiating antiretroviral therapy (ART).

Study Design

This was a 2x2 clinical trial, in which a site or group was assigned to either medication managers (MM), medication alarms (ALR), MM + ALR, or usual care (control group).


This study took place through a community-based HIV clinical trial network from November 1999 through January 2002. The network has 17 units and 160 collaborating HIV primary-care sites throughout the United States.


Study participants who were enrolled in the Flexible Initial Retrovirus Suppressive Therapies (FIRST) study of the Community Programs for Clinical Research on AIDS (CPCRA) were eligible to co-enroll in this adherence study. A total of 928 study participants were cluster-randomized: 10 clusters (256 patients) in the MM arm, 10 clusters (254 patients) in the ALR arm, nine clusters (196 patients) in the MM + ALR arm, and nine clusters (222 patients) in the control arm. The mean age of participants was 38 years; 22% were female, 55% African-American, 25% White, 17% Latino, and 3% Other.


The medication manager (MM) intervention involved using trained staff to individually provide study participants with adherence support over time, using standardized guidelines. Individually tailored adherence support plans were developed, based on responses to a questionnaire evaluating knowledge, motivation, and adherence skills. Staff made weekly telephone contact for the first three weeks, followed by monthly calls thereafter. Face-to-face follow-up occurred at one and four months post-randomization, and every four months thereafter.

The electronic medication reminder system (ALR) used a small portable alarm programmed to sound and flash at the time that ART doses were to be taken. The ALR addressed forgetfulness, the most commonly reported reason for missed ART doses. CPCRA staff were trained and held responsible for the distribution, programming, and monitoring of the devices. A standardized instrument was used to monitor participants' ALR use at one and four months after randomization and every four months thereafter. Both interventions were long term (offered for a median of 30 months), started before or at the time of ART initiation, and continued throughout follow-up.

Primary Outcomes

The primary outcome was virologic failure, defined as the first plasma HIV RNA level >2000 copies/µL occurring on or after the four-month follow-up visit, regardless of whether undetectable HIV RNA levels were achieved earlier. Secondary outcomes included plasma HIV RNA level, CD4 cell count, adherence, ART regimen changes, ART resistance, grade 4 adverse events, and quality of life indicators.


Primary data analysis compared participants in MM versus no MM groups, and those randomized to ALR versus those with no ALR. Intention-to-treat (ITT) analysis was performed, meaning that all FIRST study clusters that were randomized were analyzed, regardless of whether patients consented to participate in the adherence study. Patients receiving the MM intervention had a 13% lower rate of first virologic failure using ITT analysis (p=0.13); this was similar when evaluating only those who consented to participate (relative risk [RR]=0.84; p=0.10). Neither set of results was statistically significant. However, sub-group analysis of MM participants, randomized to protease inhibitor-based ART and those on 2-Class ART (both compared to no MM), had statistically significant reductions in virologic failure (28.6 vs 41.2 per 100 person-years, RR=0.72, p=0.01). There was also a trend favoring MM among those randomized to non-nucleoside reverse transcriptase inhibitor-based ART. Significant long-term benefits associated with MM included a sustained higher mean increase in CD4 cell count from baseline (difference=22.5 cells/mm3; p=0.01) and a sustained higher rate of reporting 100% adherence (odds ratio [OR] =1.42; p<0.001). For those who received ALR, the rate of first virologic failure was 25% higher (37.8 vs. 29.2 per 100 person-years; p=0.02) using ITT analysis. Evaluating only participants who consented to participate also revealed 25% higher rates of virologic failure among those in ALR arms (p=0.03). Among those who achieved an HIV RNA level <2000 copies/µL in the first eight months, the rate of first virologic failure was 11% higher in ALR groups (p=0.34). In other sub-group analyses, a significantly worse outcome was only seen in the 3-class sub-group (40.1 vs. 22.8 per 100 person-years; p<0.01). No significant differences were seen for any other long-term secondary endpoints.


The authors conclude that an interpersonal, multifaceted, long-term adherence support intervention is effective in promoting HIV medication adherence, resulting in improved HIV virologic and immunologic outcomes among persons initiating ART.

Quality Rating

Using the Jadad criteria, this study received a high quality rating. The randomization scheme has been described elsewhere, an intention-to-treat analysis was performed, and loss to follow-up was briefly described. Double-blinding was impossible due to the nature of the intervention. Because of the complexity of the study analysis, it was difficult to determine the specific components of the intervention strategies that were most effective.

In Context

Improved responses to therapy associated with adherence in this study are similar to those achieved with other successful behavioral interventions.(1,2) The impact of the MM intervention is consistent with the adherence literature showing that multifaceted, comprehensive, and repetitive adherence support is the most effective intervention, probably because it provides human contact and support. The significant reductions in virologic failure seen among MM participants on 2-class ART are more relevant for current HIV therapy, because 3-class ART is not recommended as standard of care.(3) The cause of the negative effect noted in association with the ALR intervention is unclear, but research staff noticed problems associated with the ALR device, including malfunctioning, as well as patient concerns around confidentiality. Other studies have shown that reminders may benefit those with impaired cognitive function.(4)

Programmatic Implications

This study reinforces the importance of person-to-person contact and support in assisting patients to adhere to ART regimens. Even though patients may indicate that they "forget" to take medications as the primary reason for poor adherence, it is likely that the issue is more complex, since the automatic reminder system did not seem to be useful. Although this study was performed in the US, support from and contact with healthcare staff is also important to persons on ART in resource-poor regions. See the Mukherjee, et al review for a description of additional logistical/economic barriers to adherence and follow-up among poor in Haiti.(5) In general, there may not be a "one-size-fits-all" adherence intervention for everyone on ART.


  1. Roter DL, Hall JA, Merisca R, et al. Effectiveness of interventions to improve patient compliance: a meta-analysis. Med Care 1998;36:1138–1161.
  2. Haynes RB, McKibbon KA, Kanani R. Systematic review of randomized trials of interventions to assist patients to follow prescriptions for medications. Lancet 1996;348:383–386.
  3. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents - A Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. May 4, 2006.
  4. Andrade AS, McGruder HF, Wu AW, et al. A programmable prompting device improves adherence to highly active antiretroviral therapy in HIV-infected subjects with memory impairment. Clin Infect Dis 2005;41: 875–882.
  5. Mukherjee JS, Ivers L, Leandre F, et al. Antiretroviral therapy in resource-poor settings: decreasing barriers to access and promoting adherence. J Acquir Immune Defic Syndr 2006 Dec 1;43 Suppl 1:S123-S126.