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The introduction of highly active antiretroviral therapy (HAART) has produced a dramatic reduction in mortality among HIV-infected individuals [1–4]. Whereas the level of adherence to HAART is closely associated with suppression of the HIV viral load in plasma [5–14], a relationship between adherence and disease progression has not been established. Here we examine the relationship between pill-count adherence  and progression to AIDS, in a representative cohort of homeless and marginally housed individuals.Three hundred and thirty HIV-positive individuals were recruited into the Research in Access to Care in the Homeless (REACH) cohort between July 1996 and April 2000. We performed adherence assessments in 76 of the 81 (94%) individuals without AIDS who were taking HAART on or after January 1998. Pill counts are conducted every 3–6 weeks at the subject's usual place of residence (single room occupancy hotel, shelter, or other) on an unannounced day as previously described . The HIV-1 viral load was determined monthly and the CD4 cell count was determined quarterly. Record match, through the San Francisco Department of Public Health AIDS Surveillance Registry, was used to identify opportunistic infections not otherwise detected by study protocol. No patients were lost to follow-up during the study.Progression was defined as a decline in the CD4 cell count to below 200 cells/μl or the development of an opportunistic infection during follow-up. Adherence to antiretroviral medication was based on unannounced pill counts, and was measured as the mean percentage of pills taken over the observation period (0–100%), and categorized as 50% or less, 51–90%, or over 90%. The relationship between adherence and progression-free survival was assessed using the Kaplan–Meier method with the three adherence groups compared by log-rank test. A Cox proportional hazards model was used to calculate relative risk (RR) with 95% confidence intervals (CI), and to adjust the relationship of adherence with progression-free survival for CD4 cell count, viral load, and months of HAART therapy at baseline. Baseline characteristics with a P value of less than 0.10 were considered candidates for adjustment. We tested each potential confounder in a two-predictor Cox proportional hazards model that included the potential confounder and adherence.The sample was composed mostly of non-white (59%) men (86%) who had a high prevalence of recent injection drug use (29%), lifetime psychiatric hospitalization (32%), and homelessness (93%).At entry, 47 individuals (62%) were on a protease inhibitor-containing regimen; 23 (30%) were on a non-nucleoside-based regimen; five (7%) were taking a regimen containing both a protease inhibitor and a non-nucleoside reverse transcriptase inhibitor; and one (1%) was taking three nucleoside analog reverse transcriptase inhibitor. A total of 47 (61%) individuals were antiretroviral naive before their current HAART regimen. At baseline, subjects had already received a median of 14 months of HAART.Median pill-count adherence in the 76 individuals was 65%. One-third (31%) had low adherence (≤ 50%); half (49%) had moderate adherence (51–90%); and 20% had high adherence (> 90%).None of the high-adherence group developed an AIDS event during observation (mean observation time 16 months), compared with 8% with moderate adherence (13 months) and 41% with low adherence (11 months) (P = 0.0012, log-rank test).In a bivariate analysis, each 10% difference in mean adherence was associated with a 28% reduction in risk of progression to AIDS (RR 0.72; 95% CI 0.59–0.87). In addition to adherence, baseline CD4 cell count, baseline viral load, and the proportion of months with viral suppression all predicted progression to AIDS (P < 0.05). Failure to complete high school (P = 0.