Our results demonstrate that adherence of individuals decreased during chronic HIV therapy. Furthermore, we showed that the degree of incomplete adherence to modern HAART was strongly associated with increased mortality. Of note, the adherence association with mortality was modified by HAART regimen, and patients on efavirenz-based NNRTI therapies were particularly at a higher risk of mortality if nonadherent. Our results highlight the need to develop further strategies to help sustain sufficiently high levels of adherence to sustain long-term viral suppression and therefore avoid disease progression and death.
This was the first study that we know of to evaluate the longitudinal and the gradated impact of adherence and type of HAART regimen on the mortality risk in a cohort of patients exclusively on HAART and with a long follow-up. Several studies report evidence on the association between adherence and mortality among HIV-infected individuals.1,24,41–44
However, most of these studies are cross-sectional, and therefore, they can misclassify the level of adherence because patients’ adherence behavior changes over time. Few longitudinal studies have examined the role of adherence on mortality.44–49
These longitudinal studies, as ours, confirm the importance of high levels of adherence to avert mortality, and they have shown that patients change their level of adherence over time, with longer periods on treatment being associated with lower adherence levels.20,28,31–33
Different HAART regimens have also been suggested to have a different impact on the risk of mortality with boosted PI–based regimens having a superior survivorship over NNRTI-based regimens.50,51
Unfortunately, the prior studies failed to address the complex interaction of adherence and HAART therapy on mortality. We found no such difference among the highly adherent subgroup but a benefit of being on a boosted PI in those with suboptimal adherence.
Several features of this study are noteworthy. Our study represents the first attempt to assess risk of mortality by class of HAART regimen, restricted to currently recommended regimens. Of note, we did so after adjusting for time-dependent adherence, which accounts for changes in an individual’s adherence pattern over time, and several other fixed and time-dependent factors. This study was based on a large population-based sample including patients within a province-wide treatment program, in which all individuals had free access to medical attention, antiretroviral therapy, and laboratory monitoring. We are confident, therefore, that our results are not biased by access to therapy issues, a factor that has often compromised the interpretation of other population-based and cohort-based studies. Overall, in this population, the median CD4 for therapy initiation was as low as 170 cells per cubic millimeter (IQR: 80–250 cells/mm3), even though HAART and care for HIV disease in the province of British Columbia is free of charge to eligible individuals. One reason for this could have been the reluctance of some patients, particularly if asymptomatic, to embrace a lifelong commitment to take antiretroviral therapy because of reservations regarding toxicity/tolerability or just because of the complicated lifestyle of some patients. Also, this study provides a substantially longer follow-up time than most previous studies (median: 33 months; IQR: 22–48 months). Finally, delayed reporting of deaths was not likely a factor in this study because most deaths were reported within 3 months of death through active follow-up with physicians and hospitals and regular linkages to the province’s Vital Statistics Agency.
An important limitation in this study relates to the fact that, at this time, accurate information on methadone or current IDU among our population is not available. It is possible that the lack of this information may have influenced the results of our analysis for this population group. In the future, it would be worthwhile to explore whether there is a difference in duration of first regimen between active drug users receiving boosted PIs and NNRTIs to properly assess if the nondifferential mortality risk found in this study still holds.
In conclusion, our results demonstrate that individual adherence to HAART decreased significantly during the 5 years of study. Furthermore, incomplete adherence to modern HAART was strongly associated with increased mortality. Of note, the latter association was modified by HAART regimen, within the modern HAART regimens included in the study. Our findings suggest that in nonadherent individuals, boosted PIs may be preferred over NNRTIs. Of course, a contemporaneous strategy would be to develop interventions to help sustain sufficiently high levels of adherence over time. Further research is needed to elucidate whether these trends apply to other modern HAART regimens not included in our study population.