The results of the FIRST study have already been reported; the three strategy arms were well balanced in terms of demographic and other baseline characteristics [10
]. Of the 1397 participants randomlyassigned in FIRST, 1379 (99%) with at least one adherence assessment during follow-up were included in this analysis. Overall, 85% of the expected adherence self-report forms were completed; there were no differences in completion rates among the three strategies.
During a median follow-up period of 60 months, differential adherence was reported at least once by 403 participants (29%; ). It was more commonly reported by participants randomly assigned to the three-class strategy (35%) than the NNRTI (28%) or PI (25%) strategies (P = 0.005; ). Not all participants were on their originally randomly assigned treatment strategy at the time that differential adherence was first reported. In the three-class, NNRTI and PI strategies, 61, 78 and 76% of participants were on their initial strategy at the time differential adherence was first reported.
Percentage of participants reporting differential adherence at any time during follow-up: overall and by randomized strategy
Summary statistics for differential adherence, overall and by randomized strategy
Overall, 134 individuals reported differential adherence on more than one occasion ( and ). This represented 10% of the overall population, and 33% of those individuals reporting differential adherence at any point during the study. By randomized strategy, reporting differential adherence on more than one occasion was more common in participants randomly assigned to the NNRTI (12%) and three-class (11%) strategies than the PI strategy (6%; P = 0.007). The maximum number of times that differential adherence was reported was 13 times (72% of follow-up visits for that individual) by a participant randomly assigned to the NNRTI strategy.
Characteristics at baseline for participants who reported differential adherence at least once during follow-up and for those who never reported differential adherence are presented in . The median age of the overall population was 38 years; 17% were Latino; 54% were black; 21% were women; 61% were men reporting a history of sex with other men; 15% reported a history of injection drug use; and 38% reported an AIDS diagnosis before study enrollment. The median baseline CD4 lymphocyte count was 163 cells/μl and the median baseline HIV-RNA level was 5.1 log10 copies/ml. In multivariate logistic regression models, no baseline demographic or disease-specific factors were significant predictors of differential adherence during follow-up (data not shown).
Demographic and baseline factors among participants with and without differential adherence.
Of the 403 individuals with differential adherence, 146 (36%) reported it before initial virological failure and 71 (18%) had antiretroviral resistance detected at the time of initial virological failure. A summary of the multivariate Cox proportional hazards regression analyses is presented in . For the overall cohort, differential adherence before initial virological failure was associated with an increased risk of initial virological failure compared with those with no differential adherence (HR 1.33, 95% CI 1.10–1.60). Similarly, participants reporting differential adherence before initial virological failure had an increased risk of initial virological failure with antiretroviral resistance (HR 1.34, 95% CI 1.03–1.75) compared with those without differential adherence. By randomized strategy, differential adherence significantly increased the risk of initial virological failure (HR 1.63, 95% CI 1.22–2.19) and initial virological failure with antiretroviral resistance (HR 1.75, 95% CI 1.16–2.64) in the three-class strategy but not in the PI or NNRTI strategies.
Table 3 Hazard ratios (95% CI) from multivariate cox regression analyses of time to initial virological failurea and time to initial virological failurea with antiretroviral resistance: overall and by randomized treatment strategy in the Community Programs for (more ...)
Other factors significantly associated with time to initial virological failure in the multivariate model for the overall cohort included mean cumulative adherence (HR 1.24 per 10% decrease), age (HR 0.82, per 10-year increase), black race (HR 1.79 compared with white or other individuals), baseline CD4 lymphocyte count (HR 0.95 per 100 cell increase), baseline log10 HIV-RNA (HR 1.37 per log10 increase), and not being on antiretroviral medications (HR 3.56 compared with those on antiretroviral medications; ). These same factors, except for not being on antiretroviral medications, were significantly associated with time to initial virological failure with antiretroviral resistance ().
The overall cohort was used to explore a potential ‘dose effect’ for differential adherence using Cox regression models adjusted for the same baseline and time-updated covariates as in . Compared with participants not reporting any differential adherence, those reporting differential adherence only once before initial virological failure had a significantly increased risk of initial virological failure (HR 1.28, 95% CI 1.04–1.57), whereas those reporting differential adherence more than once had an even greater risk (HR 1.54, 95% CI 1.08–2.20; ). Similarly, compared with participants without differential adherence, those who reported differential adherence only once had an increased risk of initial virological failure with antiretroviral resistance (HR 1.22, 95% CI 0.91–1.64), although this finding was not statistically significant. Participants who reported differential adherence more than once had twice the risk of initial virological failure with resistance compared with those without differential adherence (HR 1.93, 95% CI 1.19–3.15).
Fig. 2 Evaluation of the ‘dose-effect’ of differential adherence: adjusted hazard ratios for participants with differential adherence (once or more than once) compared with participants with no differential adherence in the Community Programs (more ...)
In adjusted Cox regression models, differential adherence was not associated with the composite endpoint of progression of HIV disease to AIDS or death (HR 1.17, 95% CI 0.86–1.58). Similarly, differential adherence was not associated with the time to first CD4 lymphocyte count of less than 200 cells/μl among the 618 participants with baseline CD4 lymphocyte counts of 200 cells/μl or greater (HR 0.98, 95% CI 0.60–1.60).