Because being on ART was strongly correlated with viral suppression and the proportion of subjects on ART at baseline was high, a subanalysis was conducted to assess the impact of BUP/NX treatment among the 119 subjects who were not on ART at baseline; 109 of these subject had complete data for analysis (see Fig 3). This is a group of subjects who would be likely to gain the most clinical benefit from initiating and remaining on ART because doing so at nearly all CD4 strata is associated with improved morbidity and mortality.35-37 Among subjects not initially on BUP/NX, subjects who were prescribed BUP/NX for three or four quarters (N = 64 [58.7%]) were not only significantly more likely to receive ART, but were also more likely to suppress HIV-1 RNA levels to below the limits of detection compared with those prescribed BUP/NX for shorter time periods. This finding held true at each quarter of observation and throughout the study.
Although not depicted in tables or figures, the proportion subjects on ART at baseline that remained on it by the fourth quarter decreased to 87.7%. The proportion of this subgroup who achieved viral suppression by the end of the fourth quarter, however, had increased from 67.0% to 76.9%, but this did not quite reach statistical significance (P = 0.09). Prescription of BUP/NX for three or four quarters among those on ART at baseline was not associated with significant improvements in viral suppression (β = 1.13; 95% confidence interval [CI], 0.95-1.35) or changes in CD4 counts (β = 9.30; 95% CI, -10.2 to 28.7), but did confirm sustained clinical benefit without evidence of clinical deterioration.
This is the largest multisite, observational study of HIV-infected patients prescribed BUP/NX. Over time, the overall sample of subjects who initiated BUP/NX, irrespective of whether they were on ART or not at baseline, were more likely to be prescribed ART and have increases in CD4 counts. For this group, however, increasing retention on BUP/NX was not associated with these outcomes. The finding that the majority of the sample was already on ART at baseline likely explains the lack of association of increased retention on BUP/NX with improving HIV treatment outcomes because most were already optimally engaged in care. To test whether retention on BUP/NX is likely to result in improved HIV treatment outcomes, the stratified analysis of those off of ART at baseline provides considerable insight. Among the group who was at highest risk for an adverse clinical outcome-those not on ART at baseline-longer retention on BUP/NX was significantly associated with higher rates of ART initiation and viral suppression that approached parity with those already on ART at baseline. Achievement of parity in viral suppression over time in this group suggests the potential for a ceiling effect for this outcome. Although not associated with improved HIV treatment outcomes among those who were already on ART at baseline, retention on BUP/NX appears to sustain already maximized positive benefits and does not worsen HIV treatment outcomes among those already experiencing this benefit.
Being on ART is strongly associated with increases in CD4 count; an increase in CD4 count in clinical trials and observational studies is strongly associated with decreased morbidity and mortality.38,39 Although being prescribed BUP/NX did not demonstrate an independent effect on viral suppression over time for the entire sample, this likely reflects the large number of subjects already receiving ART and high levels of viral suppression at baseline and sustained throughout the study. Nevertheless, prescription of BUP/NX, irrespective of duration on treatment, was highly correlated with receiving ART and improved CD4 counts that increased over time. As such, just initiating BUP/NX treatment in an HIV clinical care setting is associated with more individuals receiving ART, although the greatest contribution to this outcome is among those who were not on ART at baseline and especially those who were retained on BUP/NX. The increased association of receiving ART may reflect the notion that initiating treatment for their opioid dependence was sufficient to get patients to take ART, clinicians to prescribe it because they felt the patients were motivated and engaged, or both. Moreover, ART use itself was the single most important individual contributor to viral suppression. These findings differ slightly from recent data from Roux et al from France that found that retention on opioid agonist treatment was associated with long-term virologic HIV suppression with slightly better outcomes for those on methadone compared to those on buprenorphine. This French study, however, had only 113 subjects of which only 53 were on buprenorphine (without naloxone).40 Subjects in the French study were followed for 5 years, considerably longer than the 1 year of follow-up in our study. Our data suggest that there is relatively high retention on ART among those who were already on it but that the greatest benefits are for those who were not on ART. This is particularly true for subjects who are retained on BUP/NX for longer (three or four quarters) time periods.
In a US study of 93 HIV-infected opioid-dependent patients randomized to BUP/NX treatment provided on-site at an HIV clinic versus referral to offsite substance abuse treatment, on-site BUP/NX-treated patients were more likely to remain engaged in HIV care. Different from our study, however, their subjects did not have an increased likelihood of being prescribed ART or increase their CD4 lymphocyte counts over time. Similar to our study was the finding that there was no significant improvement in their viral suppression rates.27 Unlike our study, however, only 46 subjects received BUP/NX, over half were on ART at baseline, and there was no assessment among those who were not on ART at baseline. In summary, our longitudinal cohort assessment confirms several positive HIV treatment benefits from being prescribed BUP/NX, especially if retained in treatment among those not on ART at baseline.
Importantly, there were several covariates that positively and negatively contributed to HIV treatment outcomes. Being homeless was associated with a 40% reduced likelihood of being on ART among all subjects. Multiple studies confirm this association,41 including the influence of homelessness on poor access to and delayed entry into HIV care,42,43 the decreased likelihood of receiving ART primarily because of physician concerns,43,44 and the decreased adherence to ART once inititated.43 Other studies, however, suggest that once prescribed ART, homeless persons are willing and able to successfully adhere to ART.45,46 The lack of association of homelessness with HIV-1 RNA and CD4 counts among those prescribed ART in our study confirms this latter finding, suggesting that homelessness itself should not preclude ART prescription.
This study also confirms that active use of alcohol and higher addiction severity contributes negatively to HIV treatment outcomes among patients prescribed BUP/NX treatment. First, alcohol use severity negatively impacted receipt of ART. This finding is consistent with findings from other studies that demonstrate the negative impact of alcohol use on receipt of ART.47,48 Alcohol use severity did not, however, negatively impact virologic or immunologic outcomes, but this may be attributed to its strong independent negative effect on receiving ART and therefore the sample size was insufficient to demonstrate a benefit for a group whose alcohol use disorders were not being treated. Stimulant use, primarily of cocaine, did not influence receipt of ART, viral suppression, or changes in CD4 lymphocyte count. Although cocaine use has been associated with poor antiretroviral adherence49 and increased HIV disease progression in some studies,50 it did not negatively impact surrogates of HIV treatment successes in this observational study.
Active alcohol and drug use have both been negatively correlated with HIV treatment outcomes.51 The current study appears to be the first to demonstrate that increasing levels of drug addiction severity, rather than just drug or alcohol use itself, are associated with poor HIV treatment outcomes. In this case, only alcohol use severity was associated with not receiving ART, whereas drug use severity was independently associated with poor viral suppression outcomes. There is insufficient information from this study, however, to speculate whether it was continuous alcohol drinking or binge drinking that contributed most to these findings. Nonetheless, there is much to suggest that even reductions in severity of alcohol or drug use, especially among these opioid-dependent patients with significant drug and alcohol comorbidity, is critical to improve HIV treatment outcomes.47 Both behavioral and pharmacologic treatment options for alcohol52 and drug dependence53 should be considered for those with the highest levels of addiction severity among HIV-infected persons.1
Improved mental health and general health quality of life were associated with being on ART. It is unclear from these data, however, whether it was receipt of ART that resulted in improved quality-of-life or whether being in a better mental and physical state was associated with access to and receipt of ART. These data do, however, support other studies that show an association of ART with improving quality of life54,55 that have been demonstrated in prospective observational studies.33,56 One potential explanation is that ART use is associated with decreased depressive symptoms33 and reductions in cognitive impairment,57 and as a result, subjects derived improved quality-of-life. Further insights into these associations are explored further within this supplement.58
It is not surprising that being on ART was the strongest correlate for virologic suppression. Similarly, being on ART was strongly correlated with increases in CD4 counts. It is unclear, however, why being Hispanic was associated with improved virologic outcomes. This observation was not replicated, however, when only subjects on ART were examined (data not shown). One explanation may be specialized Spanish-speaking and adherence education services were available at a few representative sites. The number of sites was too large to make inferences between sites given the existing sample size.
Improved general health quality of life was significantly associated not only with being on ART, but also with viral suppression. In contrast to previous studies, this study had the availability of contemporary regimens, including simplified, better-tolerated combinations and boosted protease inhibitors, which appear to reduce the likelihood of resistance and allow lower adherence levels to achieve robust virologic control.59-61 It is possible that contemporary ART regimens, which are tolerated better and more amenable to perturbations in adherence, resulted in improved quality-of-life measures and overrode the effects of cocaine use and mental illness that have been associated with poor adherence outcomes in other studies.
CD4 lymphocyte counts are the best predictor of HIV-related morbidity and mortality.62,63 It is therefore imperative to restore and retain immune function. Compared with baseline, BUP/NX- treated subjects steadily and significantly increased their CD4 counts over time (Fig. 2); therefore, efforts that retain individuals in HIV care, such as initiating BPN/NX when indicated, are likely to have the most optimal treatment outcomes and reduce HIV progression.64 Studies of BUP/NX treatment for longer durations, however, are needed because HIV is a chronic condition requiring a lifetime of treatment. Also contributing to improvements in CD4 count was the receipt of psychiatric medications. Untreated mental illness has been associated with decreased access to ART65-67 and decreased ART adherence once prescribed.68,69 In this study, over half of subjects met criteria for “triple diagnosis”-mental illness, substance use disorder, and HIV. Our study, similar to findings from Mellins et al,69 confirms that those individuals with triple diagnosis who receive treatment for all three conditions (psychiatric medications, BUP/NX, and ART) can achieve improved HIV treatment outcomes, particularly ones that are associated with reductions in HIV progression. Minimally, it now allows for a single HIV clinician to effectively treat the triply diagnosed client without requiring multiple referrals and provision of fragmented care.25,70
Although this study has important implications for HIV-infected persons who are dependent on opioids, it does have limitations. First, the study represents a naturalistic observation of HIV-infected patients who are initiated on BUP/NX. As a consequence of a naturalistic observational study rather than a longitudinal cohort with systematically consistent measures, there was considerable variation in the rigor with which CD4 counts, viral load measurements, and recording of retention on BUP/NX and ART were obtained, resulting in missing values. Although GEE is one of the most robust ways of overcoming concerns about missing values, there remains some possibility that those with missing values, despite the values being missing at random, did not contribute equally to positive health outcomes solely as a matter of retention. Retention in HIV care is a well-known obstacle for this population. Second, there is no reliable comparison group. Assumptions for the entire group are based solely on the initiation of a single prescription (in some cases a single dose) of BUP/NX. As such, we cannot assert that initiating BUP/NX is better than other available treatment modalities for opioid dependence for this population, such as prescription of methadone or extended release naltrexone. We do know, however, that those who were retained on BUP/NX at least three or four quarters did have improved HIV treatment outcomes compared with those who were not retained. This finding may in part be the result of the lack of specificity of our variable measuring retention on BUP/NX (receiving a single dose during any quarter) and the naturalistic setting of the study, which may contribute to missing data. Third, the models of treatment delivery varied considerably across sites71 and it is possible that the treatment delivery strategy resulted in differing outcomes. This is the largest, multisite evaluation of BUP/NX treatment on HIV treatment outcomes and despite these limitations, it appears that BUP/NX prescription for the entire sample was associated with several improved HIV treatment outcomes, especially time-dependent improvement in prescription of ART and increased CD4 counts. Retention on BUP/NX does have its greatest impact on those not already receiving ART, but it also appears to sustain the benefit already conferred by ART among those on it at baseline.
Buprenorphine/naloxone's availability has the potential to markedly increase access to opioid agonist treatment for HIV-infected patients.23 Although considerable challenges in the implementation of BUP/NX treatment in HIV clinical care settings remain, this multisite study confirms several of the positive HIV treatment outcomes associated with integration of BUP/NX treatment into HIV specialty care settings.72 As a result, if BUP/NX becomes routinely available in this setting, it has the potential to improve access to ART and reduce morbidity and mortality among HIV-infected opioid-dependent patients who have traditionally been less likely to access and adhere to ART. Further investigations remain, however, to assess the long-term benefits of BUP/NX treatment and to improve its assimilation into standard HIV medical care practices.
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APPENDIX 1: BHIVES COLLABORATIVE
The CORE Center (Chicago, IL), El Rio Santa Cruz Neighborhood Health Center (Tucson, AZ), Johns Hopkins University (Baltimore, MD), Miriam Hospital (Providence, RI), Montefiore Medical Center (Bronx, NY), OASIS, (Oakland, CA), Oregon Health Sciences University (Portland, OR), University of California San Francisco Positive Health Program at San Francisco General Hospital (San Francisco, CA), University of Miami Medical School (Miami, FL), Yale University School of Medicine (New Haven, CT), and The New York Academy of Medicine (New York, NY).