Cocaine use is prevalent among patients infected with HIV and those entering treatment for opioid dependence.1,2 It has been reported in 40% to 46% of patients entering methadone and buprenorphine/naloxone treatment3-5 and is associated with increased rates of psychiatric disorders, HIV risk behaviors, criminal activity and negative social interactions6-10 and can predict shorter treatment retention and poorer treatment outcomes.10-12 A recent pharmacokinetic study examining the impact of cocaine use on methadone treatment in opioid-dependent patients found that methadone-maintained patients who were regularly using cocaine had evidence of lower methadone levels and more rapid methadone clearance.13 A similar pharmacokinetic study evaluating buprenorphine levels in cocaine using and cocaine nonusing cohorts found that cocaine users had lower buprenorphine plasma concentrations.14 A study of patients receiving buprenorphine treatment through a drug treatment program revealed that patients with ongoing cocaine use had more drug use and legal and psychiatric problems.15 In a recent analysis, we found that patients who were using cocaine before initiating primary care office-based buprenorphine/naloxone treatment and those who used cocaine while engaged in treatment were less likely to be retained in treatment and had fewer weeks of continuous opioid-negative urine toxicology tests.16 Notably in this study, over 30% of patients who had no evidence of cocaine use in the 30 days before treatment and had no evidence of cocaine use during the first 2 weeks of treatment initiated cocaine use during treatment.
Although ongoing cocaine use clearly has adverse implications for addiction treatment outcomes in HIV-infected patients, it also adversely affects HIV outcomes. HIV-infected patients who use cocaine have poor access to and use of HIV healthcare services,17-22 are less likely to receive antiretroviral therapy compared with those who use other drugs,19,22,23 have poor adherence to HIV antiretroviral therapy,24-29 and appear to have accelerated progression of their HIV disease.30-33 Given the growing evidence of the efficacy of buprenorphine/naloxone in treating opioid dependence,34 in office-based settings,4,35 including HIV clinical settings,36 it is critical to evaluate the association between cocaine use and treatment outcomes in opioid-dependent HIV-infected patients. Therefore, the purpose of the current study is to evaluate the associations between baseline and in-treatment cocaine use and both substance use and HIV outcomes in a cohort of HIV-infected patients receiving office-based buprenorphine/naloxone treatment.
We performed an analysis of patients enrolled in the Buprenorphine and Integrated HIV Care Model Demonstration Project (BHIVES)37 including data contributed by nine sites participating in this national multisite study. Eligible subjects underwent uniform assessments at each site at baseline and every 3 months (quarterly) for 1 year.
Subjects met the following eligibility criteria: age 18 years or older, HIV-infected, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for opioid dependence, aspartate transferase or alanine transferase less than five times normal, not dependent on benzodiazepines or alcohol, not pregnant, not acutely suicidal or psychiatrically impaired, able to understand English or Spanish, and willing to participate in the study for 1 year. The study was approved by the Institutional Review Boards at each site and written informed consent was obtained for all subjects.
All patients received daily treatment with buprenorphine/naloxone. Based on the resources available at each site, patients received varying levels of psychosocial counseling as part of their opioid dependence treatment.37
We collected demographic and clinical data at baseline and at each subsequent quarter. Clinical data included CD4 lymphocyte count, log10 HIV RNA, and HIV drug and sex risk behaviors. HIV medication adherence was measured using the Center for Adherence Support Evaluation Adherence Index, a simple composite measure of self-reported antiretroviral therapy adherence with a range of scores from 3 to 20. A Center for Adherence Support Evaluation score greater than 10 is associated with 95% HIV antiretroviral medication adherence.38 Substance use characteristics as well as self-reported illicit opioid and cocaine use were also collected using the Addiction Severity Index-Lite.39 Because urine toxicology data were collected for clinical care and not for research purposes in some sites, the study sites were not consistent in their timing or use of urine toxicology analysis. Therefore, urine toxicology data are not included in this analysis. We defined baseline cocaine use as any self-reported cocaine use within 30 days of the baseline assessment. In-treatment cocaine use was defined as any self-reported cocaine use within 30 days before the quarterly interview.
Because cocaine use before entry into treatment (baseline) may be associated with worse outcomes and because patients who are abstinent from cocaine at baseline may initiate cocaine use during treatment (in treatment), we assessed outcomes among two not mutually exclusive groups. The first analysis was conducted in those patients who provided a response at baseline regarding their cocaine use (N = 299). The second analysis was conducted only in those patients (N = 266, 89% of baseline sample) who remained in treatment for at least one quarter. Primary outcome measures assessed in both groups included retention in buprenorphine/naloxone treatment and proportion of patients with self-reported cocaine and illicit opioid use across quarters. Retention in buprenorphine/naloxone treatment was defined as the receipt of at least one dose of buprenorphine/naloxone in a given study quarter. Other outcome measures included adherence to HIV antiretroviral medications, changes in CD4 counts and log10 HIV RNA, and needle-sharing and condom use risk behaviors. All data were analyzed using SPSS 15.0 for Windows (SPSS Inc, Chicago, IL). Using chi-square and t tests, we first conducted preliminary analyses of the comparability of baseline measures for subjects with and without cocaine use and the possible need for including baseline variables as covariates in the analyses of treatment outcome data. The effects of cocaine use on buprenorphine retention were analyzed using the Kaplan-Meier product limit method and the generalized Wilcoxon test. Generalized estimating equations were used to assess changes in dichotomous outcomes over time. Mixed model analysis was applied when the outcome variable was expressed continuously.
The demographic and clinical characteristics of the 299 patients who received at least one dose of buprenorphine/naloxone and provided data on baseline cocaine use are listed in Table 1.
Of the 299 patients, the mean age was 45 years, 68% were male, 51% were black, and 57% had greater than or equal to a high school education. Their mean years of opioid dependence was 17, the majority of patients reported current injection drug use (60%), they had a mean years of HIV diagnosis of 12 years, and 60% were receiving antiretroviral medication. Sixty-six percent (N = 197) of patients reported baseline cocaine use. Baseline cocaine users were more likely to be black (P = 0.045), primarily use heroin, as opposed to other opioids (P = 0.01), were less likely to be receiving antiretroviral medications (P = 0.04), had higher log10 HIV RNA levels (P = 0.02), and were more likely to be engaging in needle-sharing (P = 0.02).
Substance Use Outcomes
Baseline Cocaine Use
Patients who reported cocaine use at baseline (N = 197) as compared with those who reported no cocaine use at baseline (N = 102) had similar rates of treatment retention in all follow-up periods (Table 2; Fig 1).
In-Treatment Cocaine Use
Patients reporting in-treatment cocaine use (N = 173) had lower rates of treatment retention only during the first quarter (P = 0.03) but higher rates of treatment retention at all subsequent follow-up time points as compared with those who reported no in-treatment cocaine use (N = 93) (Table 3).
Illicit Cocaine and Opioid Use
Baseline Cocaine Use
The odds of using cocaine during treatment for those with baseline cocaine use was 14 times higher than those without baseline cocaine use (odds ratio [OR], 14.76; confidence interval [CI], 9.0-24.2; P < 0.05) (Table 2). A greater proportion of those with baseline cocaine use had illicit opioid use during the first quarter (P = 0.02). Over time, those with baseline cocaine use were 1.4 times more likely to use illicit opioids during treatment than those without baseline cocaine use (OR, 1.43; CI, 1.02-2.00; P = 0.04) (Table 2).
In-Treatment Cocaine Use
A greater proportion of patients reporting in-treatment cocaine use as compared with those without in-treatment cocaine use reported illicit opioid use during the first quarter (P = 0.02). Patients with in-treatment cocaine use were 1.4 times more likely to use illicit opioids over time than those patients without in-treatment cocaine use (OR, 1.42; CI, 1.01-2.00; P = 0.04) (Table 3).
HIV Antiretroviral Medication Adherence
Baseline Cocaine Use
Patients reporting baseline cocaine use had poorer adherence to their HIV antiretroviral medications than those without baseline cocaine use during all four quarters (all P values < 0.05). There were no differences in HIV antiretroviral adherence over time between those with and those without baseline cocaine (β = -0.07; CI, -1.4 to 0.01; P ≤ 0.07) (Table 2).
In-Treatment Cocaine Use
There were no differences in HIV antiretroviral medication adherence in all four quarters (all P values > 0.05) or over time (β = -0.06; CI, -1.35 to 0.10; P ≤ 0.10) between patients with in-treatment cocaine use as compared with those without in-treatment cocaine use (Table 3).
CD4 Lymphocyte Counts
Baseline Cocaine Use
Although there was a trend toward lower CD4 lymphocyte counts in those patients with baseline cocaine use (except for during the third quarter), there were no differences in CD4 lymphocyte counts in the four quarters (all P values > 0.05) and over time (baseline use: β = -19.8; CI, -80.1 to 40.5; P > 0.05) (Table 2).
In-Treatment Cocaine Use
In contrast, those patients with in-treatment cocaine use had lower CD4 counts in all four quarters and this difference reached statistical significance in the fourth quarter (P = 0.02) (Table 3). Over time there were no differences in CD4 counts (β = 15.1; CI, -43.0 to 73.3; all P > 0.05) (Table 3).
Log10 HIV RNA Levels
Baseline Cocaine Use
Those with baseline cocaine use compared with those who reported no baseline cocaine use had higher log10 HIV RNA levels, except for during the third quarter, but this difference was not significant (Table 2). However, baseline cocaine users had a higher log10 HIV RNA level, on average 0.26 points higher than nonusers, over time (β = 0.26; CI, 0.05 to 0.48; P ≤ 0.02).
In-Treatment Cocaine Use
Those with in-treatment cocaine use generally had higher log10 HIV RNA levels than those without in-treatment cocaine use, except for during the third quarter, and this difference reached statistical significance in the fourth quarter (P = 0.03) (Table 3). Over time there were no differences in the log10 HIV RNA levels (β = 0.15; CI, -0.07 to 0.36; P > 0.05).
HIV Risk Behaviors
Baseline Cocaine Use
There was a higher proportion of baseline cocaine users compared with noncocaine users who reported needle-sharing during the first quarter (P = 0.01). This difference did not persist in the other quarters or over time (Table 2). There were no differences in condom use in each quarter (all P-values > 0.05) or over time based on baseline cocaine use (OR, 0.95; CI, 0.58 to 1.54; P > 0.05).
In-Treatment Cocaine Use
There was no difference in needle sharing in each quarter (all P values > 0.05) or over time (OR, 1.30; CI, 0.65 to 2.60; P > 0.05) based on in-treatment cocaine use. There was no difference in noncondom use in each quarter (all P values > 0.05) or over time (OR, 1.44; CI, 0.85 to 2.46; P > 0.05) based on in-treatment cocaine use (Table 3).
We found that baseline and in-treatment cocaine use in HIV-infected patients who are receiving buprenorphine/naloxone for the treatment of opioid dependence has considerable implications in terms of its association with ongoing illicit drug use during treatment. Patients with baseline cocaine use were significantly more likely to use cocaine during treatment than those without baseline cocaine use. Even more critical and relevant to the current study examining the treatment of opioid dependence is that there was a very substantial association between both baseline and in-treatment cocaine use and the likelihood of ongoing opioid use during buprenorphine/naloxone treatment. Regarding HIV outcomes, those with baseline cocaine use had poorer medication adherence than those without baseline cocaine use and although this association was statistically significant, it has uncertain clinical significance. We found no association between in-treatment cocaine use and antiretroviral medication adherence. In addition, although cocaine use, either at baseline or during treatment, was associated with lower CD4 counts, cocaine use did not impact CD4 counts over time. Finally, those with baseline cocaine use had higher log10 HIV RNA levels at baseline and over time.
Our results are similar to and contrast with prior research. Similar to a recent study16 in which we found that patients who were using cocaine at the time of initiating buprenorphine/naloxone treatment and those who with in-treatment cocaine use had fewer weeks of continuous opioid abstinence, the current study found baseline and in-treatment cocaine use associated with an approximately 1.5 times increased risk of self-reported opioid use at follow-up time points. In contrast, although the earlier study revealed a significant impact on treatment retention, the current study did not find this association. This likely reflects the greater medication dispensing requirements (three times to once per week) and stricter definition of treatment dropout (off of medication for greater than 7 days) used in the earlier randomized, controlled clinical trial.35 The rate of observed cocaine use in the current study, 60% of patients at baseline cocaine and 65% of patient during treatment, is similar to rates described in other studies.1,2 Similarly, our results demonstrating trends toward poorer medication adherence, lower CD4 counts, and higher HIV RNA levels are consistent with previous findings. Studies have demonstrated that active cocaine use is associated with poor adherence to antiretroviral therapy24-29 and HIV disease progression.30-33
Our study has limitations. First our results are based on self-reported drug use not confirmed by urine toxicology analyses. This could lead to underreporting of drug use. Second, because studies were conducted across a number of sites, the study samples and treatment interventions may have differed in ways that we did not evaluate. Third, it is possible that patients using cocaine were differentially retained and the results represent reporting bias. Fourth, because the eligibility criteria for this multisite study excluded individuals with dependence on sedatives, benzodiazepines, or alcohol and severe or co-occurring untreated psychiatric conditions, our findings may not generalize to HIV-infected patients receiving buprenorphine/naloxone with these comorbidities. Fifth, given that retention in buprenorphine/naloxone treatment was defined as the receipt of at least one dose of medication in a given study quarter, some subjects could be minimally involved in the study for most of each quarter, which is a considerably different level of involvement than a full participant. Sixth, our analysis of cocaine use was not time-varying, reflecting our desire to categorize patients as baseline and/or in-treatment cocaine users. Finally, the analyses were not corrected for multiple comparisons.
There is evidence of the association between ongoing drug use and adverse health outcomes in HIV-infected patients. There is also growing evidence of the effectiveness of buprenorphine/naloxone treatment to treat opioid dependence in HIV-infected patients.36,40 There are, however, substantial levels of cocaine use in this population and our results provide novel findings that indicate that cocaine use before initiation of and during buprenorphine/naloxone treatment is associated with worse substance use and HIV treatment outcomes. These findings also highlight that although buprenorphine/naloxone does not appear to mitigate the impact of cocaine use on outcomes, it does not appear to make these outcomes worse.
There are a number of potential explanations as to how cocaine use could be associated with ongoing illicit opioid use. Patients who continue to use cocaine may be more likely to have access to and use illicit opioids. There may be physiological explanations for the higher rate of opioid use in cocaine users who are receiving buprenorphine/naloxone treatment. A recent pharmacokinetic study that revealed that patients with concomitant cocaine use had lower buprenorphine plasma concentrations proposed that one mechanism might be that cocaine-induced vasoconstriction might reduce buprenorphine/naloxone sublingual absorption or increase buprenorphine metabolism.41 These latter mechanisms could reduce buprenorphine and norbuprenorphine levels and result in illicit opioid use to counteract opioid craving and/or withdrawal. Based on the high rates of cocaine use and the detrimental effects of cocaine use in HIV-infected opioid-dependent patients, further research that explores pharmacologic and psychosocial treatments for cocaine, that are feasible and efficacious in office-based settings, will likely help improve substance use and HIV treatment outcomes seen with buprenorphine/naloxone treatment.
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APPENDIX I: 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).