- Split View
-
Views
-
Cite
Cite
Brian Conway, Jennie Prasad, Robert Reynolds, John Farley, Michelle Jones, Salima Jutha, Nadine Smith, Annabel Mead, Stanley DeVlaming, Directly Observed Therapy for the Management of HIV-Infected Patients in a Methadone Program, Clinical Infectious Diseases, Volume 38, Issue Supplement_5, June 2004, Pages S402–S408, https://doi.org/10.1086/421404
- Share Icon Share
Abstract
The objective of this prospective, observational clinical study was to evaluate the safety and efficacy of once-daily and twice-daily directly observed therapy (DOT) in human immunodeficiency virus (HIV)—infected patients undergoing methadone treatment. Methadone and highly active antiretroviral therapy (HAART) were dispensed daily as DOT, with patients in the twice-daily HAART group self-administering the second dose. Clinical and laboratory end points were monitored, along with the impact of ongoing cocaine use. We studied 54 patients coinfected with HIV and hepatitis C virus. At baseline, the median virus load was 111,000 copies/mL, and the median CD4+ cell count was 165 cells/mm3. After a median of 24 months, 17 of 29 patients in the once-daily HAART group and 18 of 25 in the twice-daily HAART group had virus loads of <400 copies/mL, regardless of ongoing cocaine use. Thirty-two patients required methadone dose adjustment, which was managed without modification of HAART. Treatment-limiting hepatic toxicity was rare. A DOT program of coadministered methadone and HAART can be implemented with good results, even for patients who continue to use cocaine.
The treatment of HIV-infected injection drug users (IDUs) presents multiple challenges, including problems of adherence to therapy and access to care. Adherence is predictive of successful virological suppression by HAART [1] and may be more difficult to achieve in IDUs [2]. In fact, in a methadone maintenance program enrolling HIV-positive persons, adherence to antiretroviral therapy was estimated to be a problem for ∼50% of patients [3]. On the basis of such data, HAART may be less likely to be prescribed to IDUs, even when this would be medically indicated [4–6]. In a study of 404 HIV-positive IDUs, 49% received no therapy, and 14% actually received substandard monotherapy [5]. In another study of 177 subjects, only 40% received antiretroviral therapy, which generally was given as dual therapy despite the availability of triple therapy during the study period [4]. More recently, increasing numbers of IDUs appear to be receiving treatment, at least in circumstances in which there are few (if any) financial barriers to access to HAART [7]. There is, however, a suggestion that the rate of virological suppression is lower, a fact that may or may not be fully explained by differences in adherence [8].
These problems with adherence and access to care are further compounded by the increased potential for HAART-related adverse events. Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) occurs frequently in HIV-positive IDUs because of the common modes of transmission of these 2 viruses. All classes of antiretroviral drugs have the potential to induce or exacerbate liver function abnormalities [9], a risk that is increased in patients with preexisting viral hepatitis [10, 11]. In addition, most antiretroviral drugs appear to interact with methadone, frequently requiring adjustment of either the methadone or the HAART regimen for patients undergoing concurrent therapy for addiction and HIV infection [12, 13].
Directly observed therapy (DOT) has been proposed as a strategy for increasing adherence to antiretroviral treatment, for monitoring the multiple health issues associated with IDUs, and for increasing access to HAART [2, 14–18]. Compared with self-administered therapy, DOT resulted in a better virological response in a trial carried out among prisoners [19]. This strategy has been used successfully for the treatment of pulmonary tuberculosis for many years [20]. In addition, DOT has demonstrated efficacy in increasing adherence to HAART among patients enrolled in a methadone program [2] and in improving virological suppression in nonadherent patients [14, 18]. Simple regimens, including once-daily dosing, have been shown to be effective in the general population [21–23] and among IDUs [24], and the convenience of this dosing schedule may further improve the feasibility of DOT programs.
We describe the results of once-daily and twice-daily HAART as DOT among HIV-infected IDUs participating in a methadone treatment program within an established North American inner city multidisciplinary health care clinic.
Materials and Methods
Drug treatment and monitoring. All patients were HIV-infected IDUs enrolled in a methadone treatment program coordinated through a multidisciplinary health care clinic on the downtown east side of Vancouver (the Pender Community Health Centre). In addition to drug treatment, other available services included primary care, nursing, addiction counseling, and on-site consultation with an infectious diseases specialist. Appropriate informed consent was obtained, and clinical research was conducted in accordance with guidelines for human experimentation as specified by the US Department of Health and Human Services.
At baseline, all patients underwent a complete medical history and physical examination by one of the clinic physicians. In addition, appropriate blood tests were performed, including a complete blood cell count, assessment of hepatic function, and serological studies for other pathogens, including HCV. CD4+ cell counts and plasma virus load measurements were recorded before the initiation of or change in HAART within this observational study. Because patients receiving methadone treatment are normally expected to ingest each daily dose under a pharmacist's supervision, investigators elected to couple antiretroviral delivery with this existing system. Participants requiring twice-daily HAART were given the second dose in a small packet to take at home and were questioned about its administration the following morning.
Patients were counseled at the initiation of antiretroviral therapy to watch for signs of methadone withdrawal and were reassured that staff would respond quickly with dose adjustments. Clinical manifestations of toxicity (including methadone withdrawal) were monitored daily and reported to the physician as appropriate. Laboratory monitoring was completed at week 2 (when liver function tests were performed) and then quarterly (when complete blood cell count, liver function tests, CD4+ cell count, and plasma virus load determinations were performed). Tests were performed more frequently if clinically indicated (i.e., for clinical manifestations of toxicity and/or nonadherence to therapy). Urinalysis was done every 2 weeks to detect ongoing use of recreational drugs (a usual component of methadone treatment). Illicit drug use was scored on the basis of results of urinalyses, as follows: a score of 0 indicated that 0% of urinalysis results were positive for cocaine, 1 indicated 0%–24% were positive, 2 indicated 25%–49% were positive, 3 indicated 50%–74% were positive, 4 indicated 75%–99% were positive, and 5 indicated 100% were positive. Ongoing heroin use was monitored in a similar fashion. Methadone dose adjustments were individualized on the basis of patient and physician collaboration.
Analysis of viral and immunologic outcomes. Plasma HIV load was measured with the Amplicor HIV-1 Monitor assay (Roche Diagnostics). Plasma virus load was defined as being below the limit of quantitation if it was <400 or <50 HIV RNA copies/mL. Immunologic response was monitored by means of CD4+ cell count, as measured by flow cytometry at the local reference laboratory. We report virus suppression and immunologic response for patients receiving once-daily HAART and those receiving twice-daily HAART. In additional analyses, we report these parameters for antiretroviral-naive and antiretroviral-experienced patients and for patients receiving a backbone of 2 nucleoside analogues with either nevirapine or 1 or 2 protease inhibitors (PIs) and for whom a minimum of 6 months of follow-up had been completed. The effect of concomitant recreational drug use on virus suppression and immunologic recovery was examined. Adjustment of methadone dosing was evaluated, as was hepatic toxicity. Student's t test was used for all statistical comparisons, which were completed on an intention-to-treat basis.
Results
Baseline characteristics. The study included 54 HIV-infected IDUs (of whom 26 were male and 28 were female) receiving concurrent HAART and methadone regimens. All patients were coinfected with HCV. At the initiation of therapy, the median virus load for the total group was 111,000 copies/mL (range, 2900–840,000 copies/mL). The median baseline CD4+ cell count was 170 cells/mm3 (range, 9–1100 cells/mm3). The median follow-up for all subjects was 24 months (range, 5–58 months).
Distribution of antiretroviral therapy regimens. Twenty-nine patients (54%) were treated with once-daily regimens: 20 received a nonnucleoside reverse-transcriptase inhibitor (NNRTI) plus nucleoside reverse-transcriptase inhibitors (NRTIs), 7 received PIs plus NRTIs, and 2 received triple-class regimens (table 1). Currently, the once-daily HAART regimen of didanosine, 3TC, and nevirapine is the treatment of choice for the initial HAART, in our program. The median baseline plasma virus load for the once-daily HAART group was 85,800 copies/mL (range, 2900–840,000 copies/mL), and the median baseline CD4+ cell count was 190 cells/mm3 (range, 9–1100 cells/mm3).
The remaining 25 patients (46%) received twice-daily HAART regimens: 14 received NNRTIs plus NRTIs, 5 received PIs plus NRTIs, and 6 received triple-class regimens (table 2). The median baseline plasma virus load for the twice-daily HAART arm was 138,000 copies/mL (range, 8900–750,001 copies/mL), and the median baseline CD4+ cell count was 140 cells/mm3 (range, 9–570 cells/mm3). There was no significant difference at baseline between the once-daily and the twice-daily HAART groups with respect to virological or immunologic measurements.
Evaluation of once-daily and of twice-daily regimens. Both the once-daily group and the twice-daily group achieved statistically similar rates of virological suppression (figure 1A). After a median follow-up of 25 months (range, 13–50 months), 17 (59%) of 29 patients in the once-daily group had virus loads of <400 copies/mL, and 12 (41%) had loads suppressed to <50 copies/mL. Median follow-up for the twice-daily group was 22 months (range, 5–58 months); 18 (72%) of these patients had virus loads of <400 copies/mL, and 16 (64%) had loads of <50 copies/mL. Changes in CD4+ cell counts in the 2 patient groups were similar (figure 1B). Median cell counts for the once-daily and twice-daily groups were restored to 290 cells/mm3 and 290 cells/mm3, respectively. Although no significant differences were observed between the 2 groups, both exhibited a significant increase in CD4+ cell count from baseline (P = .01 for the once-daily group and P < .005 for the twice-daily group).
Evaluation of antiretroviral-naive and antiretroviral-experienced patients. A subanalysis of patients' treatment experience before enrollment in our DOT program indicated that 42 (78%) of 54 had previous exposure to various combinations of antiretroviral monotherapy and multidrug therapy. Differences in the distribution of treatment experience were not seen between patients in the once-daily group and the twice-daily group or between patients who received NNRTI-based and those who received PI-based regimens, and inclusion of this parameter in the analysis did not alter the rate of response to therapy (data not shown).
Effect of concomitant cocaine use. Urinalyses revealed that 48 patients (89%) used concomitant cocaine or heroin (injected or otherwise); 34 of these (63%) were identified as frequent users ( >50% of test results positive between study initiation and follow-up) (tables table 1 and table 2). However, illicit drug use did not affect virological response to HAART: 31 (65%) of the ongoing users (of any degree) achieved virus suppression to <400 copies/mL, compared with 21 (62%) of the 34 frequent users and 35 (65%) of the overall study population. If we consider a threshold of virological suppression of 50 copies/mL, these figures become 24 (50%) of ongoing users, 17 (50%) of frequent users, and 28 (52%) of the overall study population.
Methadone dose adjustment. Thirty-two patients (59%) required adjustment of their methadone dose (tables table 1 and table 2). Twenty-one of these patients (66%) achieved virus suppression to <400 copies/mL (12 of 19 subjects in the once-daily group and 9 of 13 in the twice-daily group). This rate of virological suppression was not different from that observed in the overall study group. There was a trend among patients receiving nevirapine or efavirenz (n = 33) to require a greater median increase in their methadone doses than did patients not receiving either of these agents (n = 21) (increase of 10 mg vs. 0 mg/day; P = .24). No other statistically significant baseline covariates for the change in methadone dose were observed (including age, sex, pre-HAART methadone dose, or baseline alanine aminotransferase level) . These methadone dose adjustments did not necessitate any modification of antiretroviral therapy, nor was there any association between methadone dose and virological suppression.
Hepatic safety. Liver function test results are available for all patients at the latest follow-up, and 21 were recorded as abnormal at that time, the majority of which (17 of 21) were grade 1. The association of such abnormalities with plasma HCV load was not examined. The mean baseline alanine transaminase level for all subjects was 51 IU/L, and the mean value at the latest follow-up was only 62 IU/L. Over the entire study, 2 cases of grade 3 liver function test result abnormalities were observed (in patients 3 and 27; table 1) and were successfully managed without long-term sequelae.
Patients receiving treatment with nevirapine-containing regimens were evaluated separately. The mean alanine aminotransferase level for this group was 54 IU/L at the initiation of therapy and 63 IU/L at the latest follow-up.
Discussion
These data indicate that DOT may be an appropriate method of combining anti-HIV therapy with addiction treatment, especially when ongoing participation in a methadone program can provide a preexisting infrastructure for the easy implementation of such a program. The majority (65%) of patients in the present cohort achieved virus suppression at latest follow-up (median, 2 years). Other studies examining DOT have also shown success with this strategy. For example, Stenzel et al. [14] showed that, among previously nonadherent patients, about one-half of whom were active substance abusers, 56% achieved virus suppression to <400 copies/mL by 12 months after initiation of therapy. In a study of DOT for HIV-infected prisoners, Fischl et al. [19] found that, after 80 weeks, virus load was suppressed to <400 copies/mL in 95% of patients, compared with only 75% of patients in a self-administered therapy group. Our response rates are somewhat lower. This likely relates to the fact that a number of subjects were lost to follow-up (because of accidental death from drug overdoses or because of incarceration), which would be counted as treatment failures in our analysis. Furthermore, a number of patients were episodically nonadherent to both HAART and methadone as a result of a relapse in drug addiction, and still others, despite being adherent, were previously treated with pre-HAART regimens. All of these persons were included in this initial observational study. As we move forward, we will be able to design strategies to intervene to limit the impact of a number of these factors and improve the rate of virological suppression we are able to achieve in this population.
Both once-daily HAART and twice-daily HAART resulted in similar immunologic and virological responses to therapy. Once-daily dosing is more convenient and makes the institution of a DOT program logistically simpler, because ingestion of all doses can be observed with a minimal expenditure of resources, if such observation is already required for methadone administration or for some other reason. Once-daily dosing of an NNRTI-based regimen with 2 NRTIs has been shown to be effective in observational studies, whether the NNRTI is nevirapine [24] or efavirenz [25]. With recent pharmacokinetic and clinical data [21–23, 26–29] suggesting that most NRTIs and some PIs can be administered once or twice daily, the options that may be available for DOT will increase dramatically, both for first-line therapy and for more advanced therapy.
It is worth noting that we found no association between ongoing frequent cocaine use (defined as >50% of urine-screening results positive for recreational drugs) and virological suppression. Because of the small number of patients who abstained from cocaine use for the entire period of observation, it was not possible for us to evaluate response to HAART in such a comparison group. Nonetheless, the results emphasize one of the strengths of our approach; namely, that the medical intervention, linked to methadone administration, will remain effective as long as it occurs, independently of other activities that happen throughout the rest of the day. For patients who are responding to HAART (the majority of our cohort), this may afford us a unique opportunity to intensify addiction-related interventions while reducing the likelihood that HIV disease progression will interfere with these efforts.
The overall rate of virological suppression in the cohort must be placed in context. In another study conducted in Vancouver, Palepu et al. [8] found that current IDUs were less likely to achieve virus suppression than were non-IDUs. Of importance, the authors were unable to determine if their patients actually took their medications. In another study, Arnsten et al. [17] reported that the strongest predictor of poor adherence and, in turn, failure to maintain virus suppression was active cocaine use in patients taking non-DOT therapies. The approach of combining DOT with methadone maintenance successfully addressed this challenge among cocaine users in our cohort.
In our experience, DOT is available 7 days a week. Indeed, an earlier study examining DOT and adherence in patients receiving methadone treatment revealed that adherence to antiretroviral therapy declined on the weekend when DOT was not being done [2]. The immunologic and virological results in this cohort receiving DOT are noteworthy, because most of the patients had previously received antiretroviral therapy. With the availability of more effective drugs and more once-daily dosing options, and the expansion of addiction services to prevent relapses of drug use, even better results should be obtained as our cohort expands. This report, therefore, represents a “proof-of-concept” on which to build ongoing efforts.
Adjustment in methadone doses was necessary for most patients, who had been receiving stable methadone doses for ⩾6 months, in most cases. Although this represented a significant departure from the usual pattern of practice (in which such significant and rapid changes in the dose of methadone are not frequently required), this was managed quite successfully within our integrated clinic, and no patient required a change in antiretroviral therapy because of this intervention. We observed a trend toward a greater increase in methadone dose for patients receiving nevirapine or efavirenz-based HAART compared with patients receiving other regimens. This is likely related to decreased serum methadone levels attributed to the induction of the cytochrome P-450 enzyme system in patients receiving nevirapine or efavirenz [30, 31]. The lack of statistical significance is probably due to the small sample size. Despite HCV coinfection in all subjects, only 2 cases of grade 3 liver function test abnormalities were observed. Recent studies have emphasized the potential for all antiretrovirals to cause hepatotoxicity, even suggesting that coinfection with HBV or HCV and HIV confers further risk for this adverse event [10, 11]. There has been concern that nevirapine-containing regimens in particular are associated with increased risk for drug-induced liver injury [32, 33]. Of note, the regular contact between health care workers and patients afforded by a DOT program adds to the benefit of more frequent monitoring of liver function test abnormalities, as well as monitoring of other drug-associated adverse events. Early detection allows for more timely intervention to prevent adverse clinical outcomes.
Taken together, our results are promising. They indicate that DOT can be successful, even for difficult-to-treat HIV-infected patients with ongoing problems of addiction and HCV coinfection. The more convenient once-daily dosing schedule appears to be effective and may therefore be the strategy of choice in this patient population. Our program highlights the need to bring addiction treatment and HIV-infection care closer together; in North America, the two historically have all too frequently been segregated. Although the approach of our treatment center is based on a multidisciplinary philosophy of integrating addiction treatment with comprehensive medical care, we believe that our results could be reproduced by similar initiatives in cases in which physical integration is not possible, as long as there is a common plan of treatment that involves all caregivers.
References
Financial support: National Institutes of Health (grant AI-43271; to B.C.); unrestricted educational grant from Boehringer Ingelheim Pharmaceuticals to the University of British Columbia.
Conflict of interest: B.C. has received or is receiving research grants from Abbott Laboratories, Agouron Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Chiron, GlaxoSmithKline, Merck Sharp Dome, Pfizer Pharmaceuticals, Pharmacia & Upjohn, and Schering Canada; he also is currently a member of the HIV Scientific Advisory Boards of Agouron Canada and Bristol-Myers Squibb Canada. S.D. is currently a member of the HIV Scientific Advisory Boards of Agouron Canada and Bristol-Myers Squibb Canada.
Comments