Stanley DeVlaming

Directly observed therapy for the treatment of hepatitis C virus infection in current and former injection drug users.

Background and Aim:  There are few studies investigating the treatment of hepatitis C virus (HCV) infection in current and former drug users. With this in mind, we sought to evaluate the antiviral efficacy of interferon alpha‐2b (IFN α‐2b) or pegylated‐interferon alpha‐2b (PEG‐IFN α‐2b) and ribavirin (RBV) in injection drug users (IDU) enrolled in a directly observed therapy (DOT) program, as measured by sustained virologic response (SVR).

Current Approaches to HCV Infection in Current and Former Injection Drug Users

Abstract Injection drug use (IDU) accounts for 75% of incident cases of hepatitis C virus (HCV) infection in the developed world. Of those infected with HCV, up to 80% will go on to develop chronic disease. Intervention with effective treatment in eligible subjects will limit the impact of the long-term consequences of infection. The use of combination therapy with pegylated interferon and ribavirin may lead to a cure in up to 80% of treated individuals who carry genotype 2 or 3 isolates. Such individuals account for up to 45% of certain cohorts, such as in the inner city of Vancouver. Historically, many IDUs have not received treatment for HCV infection even if it were medically indicated. Recent data (including our own) suggest that, in the right context, response rates similar to those reported in clinical trials of HCV therapy can be achieved in IDUs, even with ongoing drug use. This is all the more important given that prior infection may protect against re-infection even in the presence of ongoing risk behaviors for HCV transmission. The keys to a successful program appear to be appropriate patient selection as well as the delivery of care within an appropriate setting, preferably with a multidisciplinary team in a way that addresses the issue of addiction and other conditions simultaneously. The development of such programs may be quite complex, but the ultimate benefit (for the treated population and for society as a whole) is certainly worth the effort.

And now for something completely simple

‵...some would say that the era of once-daily HAART is upon us. Others would advocate for randomized controlled trials including more established twice-daily combinations before such a statement can be made. Although these studies may be interesting, there are a number of individual patients who will not wait.′

Methadone dosing strategies in HIV-infected injection drug users enrolled in a directly observed therapy program.

Objectives:We have measured methadone dose adjustments and treatment responses after nevirapine (NVP)-, efavirenz (EFV)-, ritonavir-boosted lopinavir (LPV/r), or atazanavir (ATV; with or without ritonavir)-based highly active antiretroviral therapy (HAART) was initiated in injection drug users (IDUs). Methods:We identified 120 IDUs receiving HAART and methadone within a directly observed therapy (DOT) program. Follow-up was according to clinical standards, with changes in methadone dose being made as required to achieve clinical stabilization within the first 3 months of HAART. Results:The observed median methadone dose changes from baseline were 20 mg/d (P < 0.001) in patients on NVP, with 32 (86%) of 37 patients requiring daily dose increases, and 7.5 mg/d (P = 0.004) in patients on EFV, with 11 (61%) of 18 patients requiring daily dose increases. Conversely, median changes were 0 mg/d for patients on LPV/r (P = 0.56) or ATV (P = 0.95). Virologic suppression (HIV RNA <400 copies/mL) was achieved in 26 (70%) of 37, 12 (67%) of 18, 25 (76%) of 33, and 24 (75%) of 32 patients receiving NVP-, EFV-, LPV/r-, and ATV-based regimens, respectively (P = 0.89). Conclusions:Although methadone-based DOT can be a successful tool for the coadministration of HAART, careful monitoring is required to ensure that methadone withdrawal does not adversely affect the goals of treatment, particularly when nonnucleoside reverse transcriptase inhibitors are used.

Primary drug resistance in antiretroviral-naïve injection drug users

OBJECTIVES We evaluated the prevalence of primary HIV drug resistance in a population of 128 injection drug users (48 female) prior to initiating antiretroviral therapy. METHODS Genotypic and phenotypic profiles were obtained retrospectively for the period June 1996 to February 2007. Genotypic drug resistance was defined as the presence of a major mutation (IAS-USA table, 2007 revision), adding revertants at reverse transcriptase (RT) codon 215. Phenotypic drug resistance was defined as the fold change associated with >or=80% loss of the wild type virologic response due to viral resistance based on virtual phenotype analysis. RESULTS Genotypic drug resistance was uncommon, and was only identified in six (4.7%) cases, all in the RT gene (L100I, K103N, Y181C, M184V, Y188L, and T215D). There were no cases of multi-class or protease inhibitor (PI) resistance. However, polymorphisms in the protease and RT genes were extremely common. Phenotypic drug resistance was also identified in six (4.7%) patients, four in the RT gene (in patients with mutations K103N, Y181C, M184V and Y188L) and two the protease gene (in two patients with minor PI mutations). In addition, 25 (19.5%) of the patients had reduced susceptibility to PIs, defined as resistance>20% but <80% of the wild type virologic response, with no primary PI mutations detected in all these patients. CONCLUSION The prevalence of primary HIV drug resistance was low in this population of injection drug users.

Clinical Implications of Mutations at Reverse Transcriptase Codon 135 on Response to NNRTI-Based Therapy

To evaluate the impact of mutations at reverse transcriptase codon 135 on treatment outcomes in patients receiving NNRTI-based antiretroviral therapy, a total of 68 patients (30 with and 38 without baseline mutations at codon 135) were evaluated. Median increases in CD4 counts were 135 and 90 cells/mm3 (p=0.32), virologic suppression (HIV RNA < 400 copies/mL) was achieved in 16 (53%) and 16 (42%) patients (p=0.50), while NNRTI resistance was detected in 10/14 (71%) and 16/22 (73%) in patients with and without mutations at codon 135, respectively. Patients who experienced a virologic breakthrough and had a baseline mutation at codon 135 were more likely to evolve a single NNRTI resistance mutation (8/14 vs 4/22, p=0.029) but less likely to evolve multiple NNRTI resistance mutations (2/14 vs 12/22, p = 0.033). Mutations at codon 135 do not affect response rates, but affect the pattern of development of NNRTI resistance mutations. This has important implications for the subsequent use of newer NNRTIs such as etravirine in salvage therapy.

Hepatitis C virus (HCV) infection and re-infection among HCV- and HIV/HCV-infected injection drug users

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Directly Observed Therapy with Azithromycin for Skin and Soft Tissue Infections in Injection Drug Users

To the Editor: The prevalence of skin and soft tissue infections (SSTIs) among injection drug users (IDUs) is estimated to be between 21% and 32% (1,2). Several studies (3) indicate that SSTIs are a leading cause of morbidity and hospitalization among IDUs. In the field of HIV infection, the directly observed therapy (DOT) program is one strategy that has been proposed to address issues of adherence and to increase access to treatment (4). Several studies (5) have demonstrated the feasibility and efficacy of the DOT programs in community-based clinics. In the present study, we sought to evaluate the efficacy of a three-day course of oral azithromycin within a methadone-based DOT program for the outpatient treatment of SSTIs in IDUs. The study was a prospective, observational study in a clinical setting conducted at the Pender Community Health Centre in Vancouver, British Columbia, between 2001 and 2003. IDUs who were enrolled in a methadone treatment program were eligible to participate if a SSTI diagnosis was made, and for whom outpatient treatment with azithromycin was appropriate according to the treating physician. Azithromycin (Zithromax, Pfizer Canada Inc) was prescribed at 500 mg/day for three days, to be given by a pharmacist within a DOT program, beginning on the day the diagnosis was made. The antibiotic was coadministered with methadone, and adherence was reported as a function of the number of witnessed doses. In addition, appropriate drainage of subcutaneous abscesses was undertaken. As a usual component of methadone treatment, urinalyses were performed every two weeks to detect the ongoing use of recreational drugs, including cocaine and opiates. The evaluation of clinical efficacy was the main end point of the study. Clinical cure was defined as the resolution of all signs and symptoms of infection or sufficient improvement such that additional or alternative therapy was not required. Clinical failure was defined as a lack of clinical response, the use of additional antibiotics or a recurrence of the same condition within eight weeks. All statistical evaluations were performed using an intent-to-treat methodology, using the χ2 or Fishers exact test, as appropriate. All statistical tests were two-sided, with statistical significance established at α =0.05. There were 62 subjects (42 male and 20 female) enrolled in the study: 26 (42%) with cellulitis, 16 (26%) with cellulitis and abscesses, and 20 (32%) with other SSTIs (nine with skin lesions and ulcerations, four with impetigo, four with furuncles, and three with wounds and burns). All were receiving methadone as part of the long-term management of their addiction, while 58 (94%) were also infected with hepatitis C virus. At eight weeks, a clinical response to azithromycin was achieved in 54 of 62 (87%) cases. Considering only the HIV-positive subjects, a clinical response was observed in 38 of 45 (84%) cases, while in HIV-negative subjects, a clinical response was observed in 16 of 17 (94%) cases (P=0.43). In the overall group, 16 of 22 (73%) subjects nonadherent to methadone during the three days of antibiotic treatment were cured, compared with 38 of 40 (95%) subjects who were adherent to methadone (P=0.019). Moreover, 32 of 40 (80%) subjects known to be active IDUs during the study period were treated successfully with azithromycin compared with 22 of 22 (100%) subjects who were not active IDUs (P=0.042). The results of the present study demonstrate that a three-day, once daily oral course of azithromycin within a DOT setting leads to clinical response rates in 87% IDUs with SSTIs for whom outpatient treatment is appropriate. These results are consistent with those of clinical trials of azithromycin in adult populations at far less a risk of nonadherence to medications, in whom cure rates of 76% to 99% have been reported (6). The main limitation of the study is that it was not a randomized controlled trial in which patients were required to have microbiological confirmation of the diagnosis. It should be remembered that, as in the cases included in the present study, the diagnosis of SSTIs is often a clinical one. Without the benefit of microbiological data, it is difficult to assess the role of macrolide resistance on any clinical failures observed in our cohort. This is certainly an issue that has to be monitored prospectively if we are to implement a strategy for the management of SSTIs in IDUs using short-course macrolide therapy. In conclusion, a three-day course of azithromycin within a DOT program can be clinically effective in treating acute SSTIs in IDUs with a degree of therapeutic success that equals or exceeds that which is associated with the use of this agent in the general population. Our data suggest that DOT may be an appropriate method of combining acute medical therapy with addiction treatment and mirrors the success of DOT for chronic medical conditions such as HIV. However, surveillance programs to monitor the evolution of azithromycin resistance will have to be maintained to ensure that the intervention remains effective over time, particularly in the era of methicillin-resistant Staphylococcus aureus.