Predictors of 007 triphosphate concentrations in dried blood spots in persons with hepatitis C and active drug or alcohol use.

BACKGROUND: Sofosbuvir is converted to its active form, 007 triphosphate (007-TP), within cells. To date, the association between treatment adherence and 007-TP in dried blood spots (DBS) and factors that influence this relationship remain unknown. OBJECTIVES: To examine relationships between adherence and 007-TP concentrations in DBS and identify factors that influence 007-TP in DBS. METHODS: Persons with HCV or HIV/HCV coinfection and self-reported drug and/or alcohol use were randomized to one of two technology-based approaches for monitoring 12 week adherence to once-daily ledipasvir/sofosbuvir. Convenience blood samples were collected every 2 weeks during treatment. 007-TP in DBS was quantified using LC/MS and analysed using mixed-effects models. RESULTS: A total of 337 observations were available from 58 participants (78% male; 21% black; 22% Hispanic/Latino; 26% cirrhotic; 78% HIV-coinfected). The mean half-life of 007-TP in DBS was 142 h (95% CI 127-156) and concentrations increased by 7.3% (95% CI 2.2-12.6) for every 10% increase in between-visit adherence. Geometric mean (95% CI) 007-TP concentrations in DBS were 301 (247-368), 544 (462-639) and 647 (571-723) fmol/punch by adherence categories of ≤50%, >50 to ≤80%, and >80%. Adherence, time on therapy, increasing age and decreased estimated glomerular filtration rate were associated with higher 007-TP, whereas increased time since last dose, male sex, black race and higher BMI were associated with lower 007-TP. CONCLUSIONS: 007-TP has an extended half-life in DBS and concentrations increased with adherence. Further research is needed to examine additional factors that affect 007-TP and the clinical utility of this measure.

Adherence to Direct-Acting Antiviral Therapy in People Actively Using Drugs and Alcohol: The INCLUD Study.

BACKGROUND: Hepatitis C virus treatment in persons who use drugs (PWUD) is often withheld due to adherence and reinfection concerns. In this study, we report treatment outcomes, technology-based adherence data, and adherence predictors in PWUD and/or alcohol. METHODS: INCLUD was a prospective, open-label study of ledipasvir/sofosbuvir for 12 weeks in PWUD aged 18-70 years. Participants were randomized to wireless (wirelessly observed therapy) or video-based directly observed therapy (vDOT). Drug use was assessed every 2 weeks. Sustained virologic response (SVR) was examined by intention-to-treat and as-treated. Factors associated with missing ≥1 dose(s) between visits were examined using generalized linear models. RESULTS: Sixty participants received ≥1 ledipasvir/sofosbuvir dose (47 human immunodeficiency virus [HIV]/hepatitis C virus [HCV], 13 HCV only; 78% male; 22% black; 25% cirrhotic). Substance use occurred at 94% of person-visits: 60% marijuana, 56% alcohol, 37% methamphetamine, 22% opioids, 17% cocaine, and 20% injection drug use. The SVR by intention-to-treat was 86.7% (52 of 60) and as-treated was 94.5% (52 of 55). Confirmed failures included 1 relapse, 1 reinfection, and 1 unknown (suspected reinfection). Median total adherence was 96% (interquartile range [IQR], 85%-100%; range, 30%-101%), and between-visit adherence was 100% (IQR, 86%-100%; range, 0%-107%). The odds of missing ≥1 dose between visits increased with HIV coinfection (2.94; 95% confidence interval [CI], 1.37-6.32; P = .006), black race (4.09; 95% CI, 1.42-11.74; P = .009), methamphetamine use (2.51; 95% CI, 1.44-4.37; P = .0.001), and cocaine use (2.12; 95% CI, 1.08-4.18; P = .03) and decreased with marijuana use (0.34; 95% CI, 0.17-0.70; P = .003) and vDOT (0.43; 95% CI, 0.21-0.87; P = .02). CONCLUSIONS: Persons who use drugs achieved high SVR rates with high, but variable, ledipasvir/sofosbuvir adherence using technology-based methods. These findings support efforts to expand HCV treatment in PWUD.