Efficacy and Safety of Sofosbuvir/Velpatasvir in Patients With Chronic Hepatitis C Virus Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ASTRAL Trials

Abstract

In this analysis of the ASTRAL trials (non-opioid substitution therapy [OST], n = 984; OST, n = 51) evaluating the once-daily, pan-genotypic regimen of sofosbuvir/velpatasvir for hepatitis C virus infection, OST did not impact completion, adherence, sustained virologic response (SVR12), or safety. SVR12 was 96% (95% confidence interval, 87%, >99%) in those receiving OST.

People who inject drugs (PWID) are disproportionately affected by hepatitis C virus (HCV) infection [1]. People with a history of injection drug use include those who have stopped injecting, those with recent injecting, and those receiving opioid substitution therapy (OST; eg, methadone or buprenorphine), some of whom may also have recently injected drugs. Data are lacking on HCV treatment outcomes with interferon-free direct-acting antiviral agents (DAAs) among people receiving OST, particularly people with genotypes (G) other than HCV G1.

The phase 3 ASTRAL 1–3 trials evaluated the efficacy and safety of sofosbuvir/velpatasvir in patients with chronic HCV genotypes 1–6 [2, 3]. People receiving stable OST were eligible for inclusion, but people with clinically relevant illicit drug use within 12 months or a positive urine drug test at screening were excluded. No drug screens were performed during or following treatment. These clinical trial populations are highly selected, included people on stable OST, excluded people with recent drug use, and may not be representative of recent PWID populations. However, there are little data on interferon-free DAA therapy among people receiving OST.

The aim of this post hoc analysis was to evaluate treatment completion, adherence, sustained virologic response (SVR), and safety of sofosbuvir/velpatasvir in people receiving OST without drug use at screening.

METHODS

Study Participants and Design

From 18 July 2014 to 19 December 2014 participants were enrolled in 3 international, multicenter, randomized open-label trials, including ASTRAL 1–3 (ClinicalTrials.gov: NCT02201940, NCT02220998, and NCT02201953) [2, 3]. A fixed-dose combination tablet of sofosbuvir/velpatasvir 400 mg/100 mg was administered for 12 weeks in patients with chronic HCV genotypes 1–6. These studies have been described previously [2, 3].

Participants receiving OST were eligible for inclusion in the ASTRAL studies. Patients were excluded if they had clinically significant drug use within 12 months of screening (as assessed by the investigator) or a noncannabinoid detected by a positive urine drug test during the screening phase not explained by a prescription medication. No drug screens were performed during or following treatment.

Study Endpoints

In this analysis, endpoints included treatment completion, adherence (≥90% of doses), SVR12, safety (adverse events [AEs] and serious AEs), and reinfection. The analysis population included all randomized patients who received at least 1 dose of sofosbuvir/velpatasvir. Adherence was calculated by dividing the number of total doses received during therapy (determined by pill counts at all study visits) by the total expected number of doses. SVR12 was defined as the absence of quantifiable HCV RNA in serum (<25 IU/mL) measured by COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test, v2.0 (Roche Molecular Systems) at 12 weeks after the end of study treatment. All participants were monitored for viral recurrence at 4, 12 (SVR12), and 24 weeks (SVR24) following the completion of treatment. As previously described [2, 3], deep sequencing of HCV NS5A/NS5B was performed for all patients at baseline and at virologic failure to distinguish viral relapse from reinfection.

Statistical Analysis

The proportion of participants with treatment completion, ≥90% adherence, SVR12, and safety were compared among people receiving and not receiving OST. Comparisons were made using 2-sided Fisher exact test. All P values are 2-sided; a level of 0.05 was considered statistically significant. Statistical analysis was performed using SAS 9.2 software (SAS Institute Inc., Cary, North Carolina).

RESULTS

Participant Characteristics

Of the 1035 patients enrolled and treated with sofosbuvir/velpatasvir (ASTRAL-1, n = 624; ASTRAL-2, n = 134; ASTRAL-3, n = 277), 51 (5%) were receiving OST at enrollment (67% methadone, 33% buprenorphine). Among people receiving OST (n = 51), the mean age was 49 years (standard deviation [SD] 10), 76% (n = 39) were male, 25% (n = 13) had cirrhosis, 22% (n = 11) had previous HCV treatment experience, and mean HCV RNA was 6.3 log IU/mL (SD 0.70; Supplementary Table 1). Among people not receiving OST (n = 984), the mean age was 53 years (SD 11), 60% (n = 591) were male, 21% (n = 207) had cirrhosis, 28% (n = 280) had previous HCV treatment experience, and mean HCV RNA was 6.3 log IU/mL (SD 0.70).

Among people receiving OST (n = 51), the HCV genotype prevalence was 24% G1a (n = 12), 2% G1b (n = 1), 16% G2 (n = 8), 47% G3 (n = 24), and 12% G4 (n = 6); there were no G5 or G6. Among people receiving OST and HCV G1 (n = 13) and G3 (n = 24), 31% (n = 4) and 38% (n = 9) had cirrhosis. Among people not receiving OST (n = 984), the HCV genotype prevalence was 20% G1a (n = 198), 12% G1b (n = 117), 23% G2 (n = 230), 26% G3 (n = 253), 11% G4 (n = 110), 4% G5 (n = 35), and 4% G6 (n = 41). Among people not receiving OST and HCV G1 (n = 315) and G3 (n = 253), 22% (n = 69) and 28% (n = 71) had cirrhosis, respectively.

Study Outcomes

The proportion of participants completing HCV therapy was 96% (95% confidence interval [CI], 87%, >99%; 49/51) among participants receiving OST compared with 99.7% (95% CI, 99%, >99%; 981/984) among those not receiving OST (P = .02; Supplementary Table 2). The reasons for treatment discontinuation among people receiving OST (n = 2) included 1 participant lost to follow-up and 1 participant with adverse events (anxiety, headache, and disturbance in attention; discontinued after 1 dose). The reasons for treatment discontinuation among people not receiving OST (n = 3) included 1 participant lost to follow-up, 1 participant with lack of efficacy, and 1 participant with an adverse event (anxiety attack; discontinued after 13 doses).

The proportion of participants with ≥90% adherence to therapy was 90% (95% CI, 79%, 97%; 46/51) among participants receiving OST compared with 96% (95% CI, 95%, 97%; 946/984) among those not receiving OST (P = .06). Among the 5 participants with adherence <90% among those receiving OST, 3 did not return study drug bottles and adherence could not be determined (missing bottles were counted as missed doses), 1 discontinued due to adverse events, and 1 was lost to follow-up.

The proportion of participants with SVR12 among those receiving OST (96%; 95% CI, 87%, >99%; 49/51) was similar to those not receiving OST (98%; 95% CI, 97%, 99%; 966/984; P = .26). SVR12 stratified by HCV genotype is shown in Figure 1 and Supplementary Table 3. Of the 2 participants on OST who did not achieve SVR12, 1 with G2 HCV infection discontinued treatment after 1 dose of the study drug due to AEs and 1 with G3 infection was lost to follow-up after completing 5 days of treatment. In those receiving OST, SVR was lower in those with <90% adherence compared with those with ≥90% adherence (60% vs 100%; P = .01). In those with HCV G3 and cirrhosis (n = 9), SVR12 was 100% (95% CI, 66%–100%).

Figure 1.

Sustained virologic response (SVR) in patients with chronic hepatitis C virus genotypes 1–4 receiving and not receiving opioid substitution therapy (OST) and sofosbuvir/velpatasvir in the ASTRAL 1–3 studies.

The proportion with AEs (86% vs 79%; P = .29) was similar among participants receiving and not receiving OST. The proportion with serious AEs (6% vs 2%; P = .10) was higher in those receiving OST but was not statistically significant. AEs were mostly mild or moderate in severity. Serious AEs in those receiving OST included abdominal pain (n = 1), bronchitis (n = 1), and palpitations (n = 1).

There were no cases of HCV reinfection in the 24 weeks following the end of treatment among participants receiving OST. However, there was 1 patient not receiving OST who was determined to have HCV reinfection by deep sequencing at time of virologic failure (pretreatment G3; reinfection G1a).

DISCUSSION

This post hoc analysis of data from the ASTRAL clinical trials demonstrates that there is no significant difference in SVR12 between people receiving and not receiving OST without recent drug use who received treatment with sofosbuvir/velpatasvir. These findings provide support for current international clinical recommendations that advocate for HCV therapy for people receiving OST [4–6].

The comparable SVR12 outcomes in this post hoc analysis are consistent with previous data of interferon-based HCV therapy [7–9] and interferon-free DAA therapy for chronic HCV G1 among people receiving OST [10–12]. However, this study adds considerably to the literature, given that almost all studies of DAA therapy among people receiving OST are restricted to people with HCV G1, G4, or G6. In this study, the SVR12 was 96% among people receiving OST with chronic HCV G3. This is encouraging, given that a sizable proportion of people receiving OST are infected with this genotype globally [5].

This study has several limitations. People who were active drug users at baseline were excluded from participation and represented a selected population engaged in care. This study did not collect data on injection drug use or perform urine drug testing during or following therapy. These findings may not be generalizable to other PWID populations (particularly those with recent drug use). The sample size and follow-up duration in this study were limited. Further studies are needed, particularly to characterize reinfection. Lastly, this was a post hoc analysis that was not specified a priori. However, given the paucity of data on DAA treatment outcomes among people receiving OST, these data may provide important information on HCV management in this population.

In conclusion, these data demonstrate that sofosbuvir/velpatasvir is well tolerated and effective among people receiving OST. This study highlights the importance for further clinical trials with larger sample sizes to evaluate DAA therapy among people with ongoing drug use. Currently, clinical trials are evaluating interferon-free therapy among PWID with recent drug use (SIMPLIFY, NCT02336139; HERO, NCT02824640).

Supplementary Data

Supplementary materials are available at http://cid.oxfordjournals.org. Consisting of data provided by the author to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the author, so questions or comments should be addressed to the author.