Patterns of Drug and Alcohol Use and Injection Equipment Sharing Among People With Recent Injecting Drug Use or Receiving Opioid Agonist Treatment During and Following Hepatitis C Virus Treatment With Direct-acting Antiviral Therapies: An International Study.

BACKGROUND: In many settings, recent or prior injection drug use remains a barrier to accessing direct-acting antiviral treatment (DAA) for hepatitis C virus (HCV) infection. We examined patterns of drug and alcohol use and injection equipment sharing among people with recent injecting drug use or receiving opioid agonist treatment (OAT) during and following DAA-based treatment. METHODS: SIMPLIFY and D3FEAT are phase 4 trials evaluating the efficacy of DAA among people with past 6-month injecting drug use or receiving OAT through a network of 25 international sites. Enrolled in 2016-2017, participants received sofosbuvir/velpatasvir (SIMPLIFY) or paritaprevir/ritonavir/dasabuvir/ombitasvir ± ribavirin (D3FEAT) for 12 weeks and completed behavioral questionnaires before, during, and up to 2 years posttreatment. The impact of time in HCV treatment and follow-up on longitudinally measured longitudinally measured behaviors was estimated using generalized estimating equations. RESULTS: At screening, of 190 participants (mean age, 47 years; 74% male), 62% reported any past-month injecting 16% past-month injection equipment sharing, and 61% current OAT. Median alcohol use was 2 (Alcohol Use Disorders Identification Test-Consumption; range, 1-12). During follow-up, opioid injecting (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.92-0.99) and sharing (OR, 0.87; 95% CI, 0.80-0.94) decreased, whereas no significant changes were observed for stimulant injecting (OR, 0.98; 95% CI, 0.94-1.02) or alcohol use (OR, 0.99; 95% CI, 0.95-1.04). CONCLUSIONS: Injecting drug use and risk behaviors remained stable or decreased following DAA-based HCV treatment. Findings further support expanding HCV treatment to all, irrespective of injection drug use. CLINICAL TRIALS REGISTRATION: SIMPLIFY, NCT02336139; D3FEAT, NCT02498015.

Adherence to sofosbuvir and velpatasvir among people with chronic HCV infection and recent injection drug use: The SIMPLIFY study.

BACKGROUND: This study investigated treatment adherence among people with recent injecting drug use in a study of sofosbuvir/velpatasvir therapy for HCV infection. METHODS: SIMPLIFY is an international open-label, single-arm multicentre study that recruited participants with recent injecting drug use (previous six months) and chronic HCV genotype (G) 1-6 infection between March and October 2016 in seven countries (19 sites). Participants received sofosbuvir/velpatasvir once-daily for 12 weeks administered in a one-week electronic blister pack (records the time and date of each dose) for 12 weeks. We evaluated non-adherence (<90% adherent) as measured by electronic blister-pack assessed using logistic regression and generalised estimating equations (continuous) with detailed analyses of dosing dynamics. RESULTS: Among 103 participants, 97% (n = 100) completed treatment. Median adherence to therapy was 94%. Overall, 32% (n = 33) were considered non-adherent (<90% adherence). Adherence significantly decreased over the course of therapy. Recent stimulant injecting (cocaine and/or amphetamines) at treatment initiation and during treatment was independently associated with non-adherence. Inconsistent dose timing (standard deviation of daily dose timing of ≥240 min) was also independently associated with non-adherence to therapy. Factors associated with inconsistent dose timing included lower levels of education and recent stimulant injecting. SVR was similar among adherent and non-adherent populations (94% vs. 94%, P = 0.944). CONCLUSION: This study demonstrated high adherence to once-daily sofosbuvir/velpatasvir therapy among a population of people with recent injecting drug use. Recent stimulant injecting prior to and during DAA therapy and inconsistent dose-timing during treatment was associated with non-adherence. However, there was no impact of non-adherence on response to therapy, suggesting that adherence is not a significant barrier to successful DAA therapy in people with recent injecting drug use.

Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial.

BACKGROUND: Despite revised guidelines that no longer exclude people who inject drugs (PWID) from treatment for hepatitis C virus (HCV) infection, many clinicians are reluctant to treat recent PWID. This study aimed to evaluate the efficacy of sofosbuvir and velpatasvir therapy in people with chronic HCV infection and recent injection drug use. METHODS: In this open-label, single-arm phase 4 trial (SIMPLIFY), we recruited participants with recent injection drug use (past 6 months) and chronic HCV genotype 1-6 infection from seven countries (19 sites). Participants received oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. Therapy was given in 1-week electronic blister packs to record the time and date of each dose. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after completion of treatment (SVR12; defined as HCV RNA <12 IU/mL), analysed in all patients who received at least one dose. This study is registered with ClinicalTrials.gov, number NCT02336139, and follow-up is ongoing to evaluate the secondary endpoint of HCV reinfection. FINDINGS: Between March 29, and Oct 31, 2016, we enrolled 103 participants; 29 (28%) of whom were female, nine (9%) had cirrhosis, 36 (35%) had HCV genotype 1, five (5%) had genotype 2, 60 (58%) had genotype 3, and two (2%) had genotype 4. 61 (59%) participants were receiving opioid substitution therapy during the study, 76 (74%) injected in the past month, and 27 (26%) injected at least daily in the past month. 100 (97%) of 103 participants completed treatment; two people were lost to follow-up and one person died from an overdose. There were no virological failures. 97 (94%, 95% CI 88-98) of 103 people achieved SVR12. Three participants with an end-of-treatment response did not have a SVR; two were lost to follow-up and one had reinfection. Drug use before and during treatment did not affect SVR12. Treatment-related adverse events were seen in 48 (47%) patients (one grade 3, no grade 4). Seven (7%) patients had at least one serious adverse event; only one such event (rhabdomyolysis, resolved) was possibly related to the therapy. One case of HCV reinfection was observed. INTERPRETATION: HCV treatment should be offered to PWID, irrespective of ongoing drug use. Recent injection drug use should not be used as a reason to withhold reimbursement of HCV therapy. FUNDING: Gilead Sciences.

Changes in risk behaviours during and following treatment for hepatitis C virus infection among people who inject drugs: The ACTIVATE study.

BACKGROUND: The risk of hepatitis C virus (HCV) reinfection due to continued injecting risk behaviours might remain a barrier to HCV treatment among people who inject drugs. We aimed to evaluate changes in risk behaviours during and following HCV treatment among people with ongoing injecting drug use or receiving opioid substitution treatment (OST). METHODS: ACTIVATE was an international multicentre clinical trial conducted between 2012 and 2014. Participants with HCV genotypes 2/3 infection were treated with peg-interferon/ribavirin for 12 or 24 weeks and completed a self-administered behavioural questionnaire at each study visit. The impact of time in treatment and follow-up on longitudinally measured recent (past month) behavioural outcomes was evaluated using generalized estimating equations. RESULTS: Among 93 enrolled participants (83% male, median age 41 years), 55 (59%) had injected in the past month. Any injecting drug use decreased during HCV treatment and follow-up (OR 0.89 per incremental study visit; 95% CI 0.83-0.95). No significant changes were found in ≥daily injecting (OR 0.98; 95% CI 0.89-1.07), use of non-sterile needles (OR 0.94; 95% CI 0.79-1.12), sharing of injecting paraphernalia (OR 0.87; 95% CI 0.70-1.07) or non-injecting drug use (OR 1.01; 95% CI 0.92-1.10). Hazardous alcohol use decreased throughout (OR 0.56; 95% CI 0.40-0.77) and OST increased between enrolment and end of treatment (OR 1.48; 95% CI 1.07-2.04). CONCLUSIONS: Recent injecting drug use and hazardous alcohol use decreased, while OST increased during and following HCV treatment among participants with ongoing injecting drug use. These findings support further expansion of HCV care among PWID.

Efficacy of response-guided directly observed pegylated interferon and self-administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study.

BACKGROUND: There are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. METHODS: ACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). RESULTS: Among 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. CONCLUSION: This study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response.

Adherence to response-guided pegylated interferon and ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: the ACTIVATE study.

BACKGROUND: The aims of this analysis were to investigate treatment completion and adherence among people with ongoing injecting drug use or receiving opioid substitution therapy (OST) in a study of response-guided therapy for chronic HCV genotypes 2/3 infection. METHODS: ACTIVATE was a multicenter clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b (PEG-IFN) and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Outcomes included treatment completion, PEG-IFN adherence, ribavirin adherence, and sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). RESULTS: Among 93 people treated, 59% had recently injected drugs (past month), 77% were receiving OST and 56% injected drugs during therapy. Overall, 76% completed treatment. Mean on-treatment adherence to PEG-IFN and ribavirin were 98.2% and 94.6%. Overall, 6% of participants missed >1 dose of PEG-IFN and 31% took <95% of their prescribed ribavirin., Higher treatment completion was observed among those receiving 12 vs. 24 weeks of treatment (97% vs. 46%, P < 0.001) while the proportion of participants with 95% on-treatment ribavirin adherence was similar between groups (67% vs. 72%, P = 0.664). Receiving 12 weeks of therapy was independently associated with treatment completion. No factors were associated with 95% RBV adherence. Neither recent injecting drug use at baseline nor during therapy was associated with treatment completion or adherence to ribavirin. In adjusted analysis, treatment completion was associated with SVR (aOR 23.9, 95% CI 2.9-193.8). CONCLUSIONS: This study demonstrated a high adherence to directly observed PEG-IFN and self-administered ribavirin among people with ongoing injecting drug use or receiving OST. These data also suggest that shortening therapy from 24 to 12 weeks can lead to improved treatment completion. Treatment completion was associated with improved response to therapy. ACTIVATE trial registration number: NCT01364090 - May 31, 2011.