 history of injection drug use was associated with HAART modifications, Kaplan-Meier methods and Cox proportional hazards models [23] were fit to determine the cumulative incidence and relative hazards of modifying the first HAART regimen. Analyses were conducted with two different outcomes and risk sets: (1) we used data from individuals with study visits after HAART initiation to evaluate the time from first reported use of HAART to the first time of HAART discontinuation or downshifting, and (2) we used data from individuals reporting consistent HAART use to evaluate the time from first reported use of HAART to the first time of switch of HAART regimen. For each model, the primary exposure variable of interest was history of injection drug use. Additional factors included in multivariate models were measured up to the time of HAART initiation: age at HAART initiation, race/ethnicity (black, Hispanic, or other), sex, nadir pre-HAART CD4+ lymphocyte count, peak pre-HAART HIV viral load, prior AIDS diagnosis, pre-HAART (baseline) antiretroviral experience, alcohol and tobacco use, employment, and income. In each of these models, we adjusted for overall secular trends using calendar time as a time-varying covariate. However, because the observed differences in HAART modification patterns appeared to change over the course of follow-up, we also report the results of a model limited to data contributed in 1999 or later (after abacavir had been approved and began to be reported in the cohorts). This included data from individuals who initiated HAART in 1999 as well as from individuals who initiated earlier – the latter contributions are considered left-truncated and contribute to the analysis using standard staggered (late) entry techniques.
Lastly, we also examined the association of time-varying report of injection drug use with separate analyses. First, we included a time-varying indicator of current IDU in the model that also controlled for history of injection drug use. Second, we refined the analysis to compare individuals reporting current and former injection drug use with those never reporting a history of injection drug use.
Results
Participant characteristics
Participants' characteristics at first HAART visit
Patterns and trends of HAART use
The proportion of HAART users taking a regimen containing 1) a PI but no NNRTI (dark gray), 2) a NNRTI but no PI (light gray), 3) both a PI and NNRTI (white), 4) neither a PI nor NNRTI (black), plotted over time for each study. The proportion is plotted at the midpoint of each visit window.
The prevalence of switching (black), downshifting (white), and discontinuation (gray) is plotted over time for each study at the midpoint of each visit window.
Predictors of first HAART modification
Kaplan-Meier estimates of the cumulative incidence proportion of individuals with HAART discontinuation.
Relative hazard of HAART discontinuation (including downshifting) and HAART switching among participants initiating HAART prior to 10/1/04
In separate analyses, we examined the impact of current and former injection drug use (the latter including those individuals with a baseline history of injection drug use but no current active use). The results from these analyses were similar to those described above: for the entire dataset, there was an elevated risk of discontinuation among those reporting current injection drug use (adjusted RH = 1.65, 95% CI: 1.23–2.22) but not former users (adjusted RH = 1.16, 95% CIL 0.96–1.41) as compared with those never reporting use. These effects were attenuated when the data were restricted to 1999 and later (current users adjusted RH = 1.32, 95% CI: 0.90–1.94; former users adjusted RH = 1.00, 95% CI: 0.77–1.31).
For evaluating time to HAART regimen switch, 1,211 individuals contributed 1,931 person-years of continuous HAART use with 675 switch events. No differences in IDU were apparent in the median time to HAART switch among consistent HAART users (1.5 years for both). This was supported by the results of the Cox regression analysis (Table 2), where both univariate and multivariate analysis indicated a null association with history of injection drug use. Time-updated analysis of current injection drug use showed similar patterns: in comparison to those never reporting injection drug use, there were no significant increased risk of HAART switch among current users (adjusted RH = 1.03, 95% CI: 0.84, 1.28) or former users (adjusted RH = 1.12, 95% CI: 0.74–1.69).
Discussion
The importance of maintaining patients on consistent, long-term HAART has been established as an effective means of suppressing HIV RNA replication and restoring immune function [1]. The initial HAART regimen is especially critical in maintaining a positive prognosis by delaying onset of clinical AIDS and allowing for future regimen options [1, 24]. When HIV develops resistance to a drug, it often develops cross-resistance with several drugs in the same class, severely limiting future treatment alternatives [25]. However, despite these concerns, many patients may need to modify therapy in order to find a regimen that is more suitable for them, whether to avoid side effects or increase convenience, or due to virologic failure [12].
Such treatment issues are of particular concern among HIV-infected injection drug users [26]. Findings from an earlier study by Chen et al [14] found that a history of injection drug use was independently associated with the probability of switching or discontinuing a HAART regimen. In this study, we observed that time from HAART initiation to first regimen modification was significantly shorter among injection drug users. However, after adjusting for potential confounders and examining data in the era of more advanced HAART regimens, we observed that the hazard of HAART modification was attenuated and not significantly different between those with and without a history of injection drug use.
These results suggest that other factors may be leading to the increased risk of HAART modifications in the ALIVE study and among IDU populations in general. We recognize that a history of IDU in itself may be both confounded and a consequence of a variety of factors (e.g. incarceration, history of physical abuse, etc). Income level, employment, smoking and alcohol use were shown to confound the relationship (e.g. the effect of IDU was attenuated in Model 2 as compared to Model 1) but adjusting for them did not completely eliminate the association between IDU history and HAART modification. We did identify several factors that proved to be predictive of HAART modification, the strongest and most consistent were measures of HIV disease progression (a higher pre-HAART peak HIV RNA level, pre-HAART antiretroviral experience) but also and minority race/ethnicity status. These findings are consistent with most prior studies that have investigated HAART regimen modifications [11, 12, 16, 17], and suggests that these modifications may occur due to failure of the previous regimen, and may also be linked to access to care. Previous work by Silverberg et al [27] working with the US military cohort (which has racial/ethnic diversity but universal access to health care) has not demonstrated any differences in HAART effectiveness by race, thus suggesting that socio-behavioral factors (e.g. access or quality of care, clinical depression, therapy adherence) may be more likely determinants of HAART success. Unfortunately, these were not uniformly measured in the three cohorts and therefore could not be assessed as potential confounders in our analyses.
The main limitation of this study is that all data on antiretroviral use and HAART modification were based on self-report. Therefore, it is possible that participants may have misreported or underreported what medications they were using. However, data on antiretroviral use were obtained using photo-medication study aids to facilitate recall of drug usage and both the common and brand names were used in the interview. Additionally, in an unpublished analysis performed on a convenience sample subset of the MACS participants, in which the medical records were available and abstracted to compare with the self-reported medication data, it was found that 95% of the drug records were in concordance with the self-reported data (L. Jacobson, personal communication). However, this sub-study was performed only in the MACS and it is possible that some of the differences seen between the MACS and ALIVE are due to a higher level of misreport or lack of recall in the ALIVE study. If true, this would be an indication of the necessity of increased patient education among IDUs regarding the medications they are using with emphasis on the importance of adherence.
The lack of data on viral drug resistance profiles and co-morbidities among the participants in each cohort is an additional limitation of this study. Drug resistance and co-morbidities are an important potential reason for HAART therapy modification that we were not able to investigate in this study. A strength of the current study, however, is its prospective design, allowing for determination of exposure variables prior to the outcome (e.g. HAART modifications) using standardized protocols implemented as part of three long-running interval cohort studies [28]. Additionally, the common design of all three parent studies and data collection instruments facilitated comparisons between the cohorts using compatible covariates and a common algorithm for the determination of HAART modifications.
In conclusion, we have demonstrated that in more recent years there is no impact of reported use of injection drugs on HAART modification. These data imply efforts to simplify and increase potency of antiretroviral regimens have been successful at improving HAART maintenance among a group at high risk for failure. However, the persistent association of race/ethnicity and low income with HAART discontinuation provides important direction and motivation for improving methods for HAART utilization among these high-risk groups.
Declarations
