Jesse D. Raffa

Low uptake of treatment for hepatitis C virus infection in a large community‐based study of inner city residents

Summary.  Despite the availability of effective therapy for hepatitis C virus (HCV) infection, there are little data on the uptake of treatment. We evaluated factors associated with HCV infection and the uptake of HCV treatment in a large community‐based inner city cohort in Vancouver, Canada. The Community Health and Safety Evaluation is a cohort study of inner city residents recruited from January 2003 to June 2004. HIV and HCV status and information on prescriptions for HCV treatment were determined through linkage with provincial databases. HCV prevalence was calculated and factors associated with HCV infection were identified. HCV treatment uptake and incidence of HCV infection from January 2000 to December 2004 were expressed in terms of person‐years of observation. Among 2913 individuals, HCV antibody testing was performed in 2118 and the HCV seroprevalence was 64.2% (1360 of 2118). In total, 1.1% of HCV antibody‐positive individuals (15 of 1360) initiated treatment for HCV infection from January 2000 to December 2004 [0.28 cases per 100 person‐years (95% CI, 0.15–0.46)]. Three of 15 (20.0%) treated individuals achieved a sustained virological response. During the same period, the incidence of HCV infection was 7.26 cases (95% CI, 5.72–8.80) per 100 person‐years. Overall, the rate of new HCV seroconversions in this cohort in the study period was about 25 times the rate of HCV treatment uptake. There are extremely low rates of HCV treatment initiation and very limited effectiveness, despite a high prevalence of HCV infection in this large community‐based cohort of inner city residents with access to universal healthcare.

Hepatitis C virus reinfection in injection drug users

Spontaneous clearance of hepatitis C (HCV) may provide protection against reinfection. In a large community‐based cohort study of 3,553 inner‐city residents (mainly injection drug users), we identified HCV‐infected individuals in whom virological clearance had occurred and compared the rate of reinfection in this group with that observed in previously uninfected members of the same cohort. We identified 926 HCV‐uninfected and 658 HCV‐infected viremic subjects at baseline, with 152 of 658 (23.1%) spontaneously clearing viremia over a median follow‐up of 5.2 years (IQR, 2.8‐7.4). At baseline, individuals with HCV clearance were more likely to be HIV coinfected (P < .001) and to be engaged in frequent illicit drug use (P = .004) and injection drug use (P < .001). The occurrence of HCV infection was lower in individuals with previous infection (14/152, 9.2%) compared with that in those without previous infection (172/926, 18.6%), with incidence rates of 1.8 (95% CI, 0.9‐3.0 cases/100 person‐years) and 8.1 (95% CI, 6.9‐9.4 cases/100 person‐years) cases/100 person‐years, respectively, after accounting for follow‐up. In a logistic regression analysis, with previous HCV infection assessed as a covariate with other potential confounding variables (age, sex, ethnicity, HIV infection, housing status, and illicit and injection drug use), individuals with previous HCV infection and viral clearance were 4 times less likely to develop infection than those infected for the first time (adjusted odds ratio, 0.23; 95% CI, 0.10‐0.51, P < .001). In conclusion, individuals with clearance of HCV infection may have a lower risk of acquiring HCV than individuals who have never been infected, despite ongoing exposure to HCV. (HEPATOLOGY 2006;44:1139–1145.)

Factors associated with spontaneous clearance of hepatitis C virus among illicit drug users.

BACKGROUND Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 25% of individuals. METHODS To better understand the characteristics associated with clearance, the present study evaluated HCV clearance in a community-based cohort study. The Community Health and Safety Evaluation project recruited 3553 individuals via community organizations and door-to-door canvassing of a random sample of single occupancy hotels in the community to monitor uptake of health services and to estimate the incidence of communicable infections. Cohort data were linked with longitudinal laboratory databases, including HCV antibody and polymerase chain reaction assay results. RESULTS Overall, 762 individuals had HCV antibody and RNA testing performed between 1999 and 2005. Spontaneous HCV clearance was observed in 179 individuals (23.5%), while HCV persistence was observed in 583 individuals (76.5%). The ability to develop protective immunity against HCV, as demonstrated by viral clearance, occurred more often in individuals of Aboriginal ethnicity (adjusted OR [AOR] 2.9, 95% CI 2.0 to 4.3; P<0.001) and female individuals (AOR 1.6, 95% CI 1.1 to 2.4; P=0.01). The rate of spontaneous HCV clearance was reduced in individuals using any type of illicit drugs (AOR 0.54, 95% CI 0.29 to 1.00; P=0.05) and those with HIV coinfection (AOR 0.58, 95% CI 0.38 to 0.88; P=0.01). Of 218 HIV-infected subjects, 48 of 51 (94%) in whom the order of HCV and HIV infection was established were infected with HCV a median of 2.4 years (range 0.2 to 10 years) before becoming infected with HIV. CONCLUSIONS Aboriginal ethnicity and female sex were associated with increased rates of HCV clearance, while HIV coinfection and illicit drug use were associated with increased HCV persistence.

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).

Continued low uptake of treatment for hepatitis C virus infection in a large community-based cohort of inner city residents

Despite advances in HCV treatment, recent data on treatment uptake is sparse. HCV treatment uptake and associated factors were evaluated in a community‐based cohort in Vancouver, Canada.

Reinfection with hepatitis C virus following sustained virological response in injection drug users.

Background and Aim:  Despite that 60–90% of injection drug users (IDUs) are infected with hepatitis C virus (HCV) infection, IDUs are often denied therapy based on concerns of reinfection following treatment. However, there are little data in this regard. We evaluated HCV re‐infection following sustained virologic response (SVR) among HCV‐infected IDUs having received HCV treatment in a multidisciplinary program.

Impact of hepatitis C virus infection on all-cause and liver-related mortality in a large community-based cohort of inner city residents

Summary.  The aim of this study was to measure the impact of hepatitis C virus (HCV) infection on mortality in a cohort of inner city residents. The Community Health and Safety Evaluation is a community‐based study of inner city residents followed retrospectively and prospectively through linkages with provincial virology and mortality databases. We identified participants having received HCV antibody testing, evaluated cause‐specific mortality rates and factors associated with all‐cause and liver‐related mortality using Cox Proportional Hazards models. Overall, 2332 participants received HCV antibody testing (recent non‐injection drug use – 81%). The prevalence of HCV and HIV was 64% (1495 of 2332) and 21% (485 of 2332), respectively. Between January 2003 and December 2007, there were 180 deaths (192 per 10 000 person‐years; 95% CI: 165, 222), with 21% HIV‐related, 20% drug‐related and 7% liver‐related. Mortality was associated with age >50 [adjusted hazard ratio (AHR) 2.80 vs <40 years (referent group); 95% CI 1.93, 4.07, P < 0.001] and HIV infection (AHR 3.81; 95% CI 2.72, 5.34, P < 0.001), but not positive HCV antibody status (AHR 1.19; 95% CI 0.83, 1.72, P = 0.35). Liver‐related mortality was associated with age >50 [AHR 18.49 vs <40 years (referent group); 95% CI 2.27, 150.41, P < 0.001] and positive HCV antibody status (AHR 7.69; 95% CI 0.99, 59.98, P = 0.052). This study demonstrates a high rate of mortality in this population, particularly those with HIV. HCV‐infected inner city residents >50 years of age were at significant risk of liver‐related mortality. Continued surveillance of this population infected with HCV in the 1970s and 1980s is important.

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.

Multivariate longitudinal data analysis with mixed effects hidden Markov models.

Multiple longitudinal responses are often collected as a means to capture relevant features of the true outcome of interest, which is often hidden and not directly measurable. We outline an approach which models these multivariate longitudinal responses as generated from a hidden disease process. We propose a class of models which uses a hidden Markov model with separate but correlated random effects between multiple longitudinal responses. This approach was motivated by a smoking cessation clinical trial, where a bivariate longitudinal response involving both a continuous and a binomial response was collected for each participant to monitor smoking behavior. A Bayesian method using Markov chain Monte Carlo is used. Comparison of separate univariate response models to the bivariate response models was undertaken. Our methods are demonstrated on the smoking cessation clinical trial dataset, and properties of our approach are examined through extensive simulation studies.