Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid Substitution Therapy: An Analysis of Phase 3 Studies

Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid... Open Forum Infectious Diseases MAJOR ARTICLE Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid Substitution Therapy: An Analysis of Phase 3 Studies 1 2 3 4 5 5 5 5 5 Jason Grebely, Jordan J. Feld, David Wyles, Mark Sulkowski, Liyun Ni, Joe Llewellyn, Heshaam M. Mir, Nika Sajed, Luisa M. Stamm, 5 5 5 6 7 8 9 10 Robert H. Hyland, John McNally, Diana M. Brainard, Ira Jacobson, Stefan Zeuzem, Marc Bourlière, Graham Foster, Nezam Afdhal, and Gregory J. Dore 1 2 3 The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia; Toronto Centre for Liver Disease, Toronto, Ontario, Canada; Division of Infectious Diseases, Denver Health and Hospital 4 5 6 7 Authority, Denver, Colorado; Johns Hopkins University, Baltimore, Maryland; Gilead Sciences, Inc., Foster City, California; Mount Sinai Beth Israel, New York, New York; Johann Wolfgang 8 9 10 Goethe University Medical Center, Frankfurt am Main, Germany; Hospital Saint Joseph, Marseille, France; Queen Mary University London, London, United Kingdom; Beth Israel Deaconess Medical Center, Boston, Massachusetts Background. Hepatitis C virus (HCV) direct-acting antiviral therapy is effective among people receiving opioid substitution therapy (OST), but studies are limited by small numbers of nongenotype 1 (GT1) patients. The aim of this study was to evaluate the treatment completion, adherence, SVR12, and safety of sofosbuvir-based therapies in HCV patients receiving and not receiving OST. Methods. Ten phase 3 studies of sofosbuvir-based regimens included ION (ledipasvir/sofosbuvir ± ribavirin for 8, 12, or 24 weeks in GT1), ASTRAL (sofosbuvir/velpatasvir for 12 weeks in GT1-6), and POLARIS (sofosbuvir/velpatasvir and sofosbuvir/ velpatasvir/voxilaprevir in GT1-6). Patients with clinically significant drug use (last 12  months) or noncannabinoids detected at screening were ineligible. Results. Among 4743 patients, 4% (n = 194) were receiving OST (methadone; n = 113; buprenorphine, n = 75; other, n = 6). Compared with those not receiving OST (n = 4549), those receiving OST (n = 194) were younger (mean age, 48 vs 54), more oen ft male (73% vs 61%), GT3 (38% vs 17%), treatment-naïve (78% vs 65%), and cirrhotic (36% vs 23%). Among those receiving and not receiving OST, there was no significant difference in treatment completion (97% vs 99%, P = .06), SVR12 (94% vs 97%, P  =  .06), relapse (0.5% vs 2.1%, P = .19), adverse events (78% vs 77%, P = .79), or serious adverse events (3.6% vs 2.4%, P = .24). There was no difference in SVR12 in patients with cirrhosis (99% vs 95%, P = .25) or those with G3 (95% vs 95%, P = .77) in those receiving OST. Among patients receiving OST, SVR12 was high among those receiving methadone (95%) and buprenorphine (96%). Conclusion. Sofosbuvir-based therapies are effective and safe in patients receiving OST. Keywords. DAA; drug use; hepatitis C virus; interferon-free; ledipasvir; PWID; sofosbuvir; velpatasvir; voxilaprevir. People who inject drugs (PWID) are disproportionately ae ff cted populations of PWID receiving DAA therapy, including those by hepatitis C virus (HCV) infection [1, 2]. Despite increas- receiving OST, are needed to change HCV health policy and ing liver-related morbidity and mortality among PWID [2, 3], clinical practice. some clinicians are reluctant to prescribe direct-acting antiviral People with a history of injecting drug use include former (DAA) therapy for PWID or people receiving opioid substitu- injectors who have ceased injecting and recent PWID [9]. Some tion therapy (OST) based on concerns of poor adherence, lower people with a history of injecting drug use may also be receiv- response to therapy, and high rates of reinfection [4]. This is ing OST (eg, methadone, buprenorphine) for the management inconsistent with international guidelines recommending that of opioid dependence. Interferon-based therapy is effective in all people should receive HCV treatment and that PWID should people with a history of injecting drug use, including those be prioritized, given the potential to reduce transmission to with recent injecting drug use and those receiving OST, with others [5–8]. Further data on treatment outcomes among responses similar to that observed in large clinical studies [10–12]. Although data are emerging on outcomes to DAA- based HCV therapy among PWID receiving OST [13–23], most studies are limited by small numbers of HCV nongeno- Received 1 September 2017; editorial decision 21 December 2017; accepted 17 January 2018. Correspondence: J.  Grebely, PhD, The Kirby Institute, UNSW Sydney, Wallace Wurth type 1 patients. There are also no published studies on the effi- Building, UNSW NSW 2052 Australia (jgrebely@kirby.unsw.edu.au). cacy and safety of sofosbuvir/velpatasvir/voxilaprevir in people Open Forum Infectious Diseases receiving OST. © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Phase 3 studies of sofosbuvir-based therapy (the ION, Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits ASTRAL, and POLARIS studies) included the evaluation of unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.DOI: 10.1093/ofid/ofy001 ledipasvir/sofosbuvir with or without ribavirin, sofosbuvir/ HCV Treatment for People Receiving OST • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Study End Points velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir in patients In this analysis, the end points included treatment comple- with chronic HCV genotype 1–6 [24–30]. People receiving tion, adherence (≥90% of doses), SVR12, safety (adverse events stable OST were eligible for inclusion, but people with clin- [AEs], serious AEs, and hemoglobin level <10 g/dL), and rein- ically relevant illicit drug use within 12  months of screening fection. The analyzed population included all randomized or illicit drugs (excluding cannabinoids) detected by a urine patients who received ≥1 dose of study medication. Adherence drug test at screening were excluded from study participation. was measured by counting the number of unused tablets in the These clinical trial populations are highly selected and may returned bottles to derive the number of administrated tablets. not be representative of recent PWID populations. However, In situations where a bottle was not returned, the number of studies in these populations contribute to the growing body tablets administered from that bottle will be assumed to be of evidence on interferon-free DAA therapy among people 0.  Adherence was calculated by dividing the number of total receiving OST, particularly people with HCV nongenotype 1 doses administered during therapy (determined by pill counts infection. at week 4, 8, 12, 16, and 24 [where applicable] study visits) by e Th aim of this post hoc analysis of the phase 3 studies of the total expected number of prescribed doses. SVR12 was sofosbuvir-based therapy was to evaluate the treatment comple- defined as the absence of quantifiable HCV RNA in serum (<25 tion, adherence, SVR12, and safety of sofosbuvir-based therapy IU/mL or <15 IU/mL), measured by COBAS TaqMan HCV in patients receiving OST and not receiving OST. Test, v2.0 (Roche Molecular Systems), at 12 weeks after the end METHODS of study treatment. Participants were monitored for recurrence (viral relapse or reinfection) at 4 weeks, 12 weeks (SVR12), and Study Participants and Design 24 weeks (SVR24) following the completion of treatment. Deep From October 2012 to May 2016, participants were enrolled in sequencing of the HCV NS5A and NS5B genes was performed 10 multicenter, randomized clinical studies, including ION-1–3 for all patients at baseline and again for all patients with viro- (ClinicalTrials.gov identifier: NCT01701401, NCT01768286, logic failure in samples obtained at the first time point of failure and NCT01851330, respectively [24–26]), ASTRAL-1–3 with an HCV RNA >1000 IU/mL [24–30]. Phylogenetic analy- (ClinicalTrials.gov: NCT02201940, NCT02220998, and ses were used to distinguish viral relapse from reinfection. NCT02201953, respectively [27, 28]), and POLARIS-1–4 (ClinicalTrials.gov: NCT02607735, NCT02607800, Statistical Analysis NCT02639338, and NCT02639247 [29, 30]). Descriptive statistics, including means, frequencies, and per- In the ION-1–3 studies, a fixed-dose combination tablet of centages (with 95% confidence intervals [CIs] for SVR12) were ledipasvir/sofosbuvir 90 mg/400 mg was administered for 8, 12, used to summarize the data. The proportion of participants or 24 weeks with or without ribavirin in patients with chronic with treatment completion, ≥90% adherence, SVR12, and AEs HCV genotype 1 infection [24–26]. Twice-daily ribavirin dose was compared among people receiving and not receiving OST. was given according to body weight (1000 mg daily < 75 kg or Comparisons were made using a 2-sided Fisher exact test. All 1200 mg daily ≥ 75 kg). In the ASTRAL-1–3 studies, a fixed-dose P values are 2-sided; a level of .05 was considered statistically combination tablet of sofosbuvir/velpatasvir 400 mg/100 mg was significant. Statistical analysis was performed using SAS 9.4 administered for 12 weeks in patients with chronic HCV geno- software (SAS Institute Inc., Cary, NC). types 1–6 [27, 28]. In the POLARIS studies, a fixed-dose com- RESULTS bination tablet of sofosbuvir/velpatasvir 400  mg/100  mg was administered for 12 weeks or a fixed-dose combination tablet of Participant Characteristics sofosbuvir/velpatasvir/voxilaprevir 400 mg/100 mg/100 mg was Overall, 4743 patients were enrolled and treated in the ION administered for 8 or 12 weeks in patients with chronic HCV (n = 1952; ION-1, n = 865; ION-2, n = 440; ION-3, n = 647), genotypes 1–6 [29, 30]. ASTRAL (n = 1035; ASTRAL-1, n = 624; ASTRAL-2, n = 134; Participants receiving OST (eg, methadone or buprenor- ASTRAL-3, n  =  277), and POLARIS studies (n  =  1756; phine with and without naloxone) were eligible for inclusion POLARIS-1, n  =  263; POLARIS-2, n  =  941; POLARIS-3, (OST determined based on reported concomitant medica- n = 333; POLARIS-4, n = 219). Among individuals in all these tions). Patients were excluded from enrollment in these stud- studies, 4% (n = 194) were receiving OST at enrollment. ies if they had clinically significant drug use within 12 months e c Th linical characteristics of the study participants are of screening (as assessed by the investigator based on partic- shown in Table 1. Among patients receiving OST (n = 194), 27% ipant self-report or medical chart review) or illicit drug use (n = 53) received ledipasvir/sofosbuvir with or without ribavi- (excluding cannabinoids) detected by a urine drug test during rin (for 8, 12, or 24 weeks), 47% (n = 92) received sofosbuvir/ the screening phase that was not explained by a prescription velpatasvir for 12 weeks, and 25% (n = 49) received sofosbuvir/ medication. The designs and results of these studies have been velpatasvir/voxilaprevir (for 8 or 12 weeks). Among patients not described previously [24–30]. receiving OST (n = 4549), 42% (n = 1899) received ledipasvir/ 2 • OFID • Grebely et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Baseline Demographic and Clinical Characteristics of Patients HCV Treatment Completion and Adherence With Chronic HCV Infection Receiving Sofosbuvir-Based Therapies in the The proportion of participants completing HCV therapy ION, ASTRAL, and POLARIS Phase 3 Clinical Trials, by Receipt of Opioid was 97.4% (189/194; 95% CI, 94.1%–99.2%) among partic- Substitution Therapy ipants receiving OST, compared with 98.9% (4501/4549; 95% CI, 98.6%–99.2%) among those not receiving OST (P  =  .064) No OST at OST at Enrollment (Table  2). The reasons for treatment discontinuation among Enrollment (n = 4549), patients receiving OST (n  =  5) included AEs (n  =  1), loss to Characteristic (n = 194), n (%) n (%) follow-up (n = 1), consent withdrawal (n = 1), lack of efficacy Mean (SD) age, y 48 (10.7) 54 (10.4) (n = 1), and noncompliance (n = 1). The reasons for treatment Male sex, n (%) 141 (73) 2770 (61) HCV genotype, n (%) discontinuation among patients not receiving OST (n  =  48) 1a 84 (43) 2109 (46) included AEs (n  =  19), loss to follow-up (n  =  10), consent 1b 12 (6) 816 (18) withdrawal (n = 6), protocol violation (n = 6), lack of efficacy 2 14 (7) 409 (9) (n = 4), noncompliance (n = 1), and pregnancy (n = 2). Among 3 74 (38) 787 (17) patients receiving OST, the proportion of participants complet- 4 10 (5) 269 (6) ing therapy with ledipasvir/sofosbuvir with or without ribavirin 5 0 54 (1) 6 0 86 (2) was 96.2% (51/53), sofosbuvir/velpatasvir was 96.7% (89/92), HCV RNA log IU/mL, mean (SD) 6.3 (0.7) 6.3 (0.7) and sofosbuvir/velpatasvir/voxilaprevir was 100% (49/49). HCV RNA ≥ 800 000 IU/mL, n (%) 142 (73) 3456 (76) e p Th roportion of participants with ≥90% adherence to ther - Fibrosis stage apy was 90.2% (175/194; 95% CI, 85.1%–94.0%) among partic- F0 42 (22) 826 (18) ipants receiving OST, compared with 94.3% (4291/4549; 95% F1 23 (12) 410 (9) F2 45 (24) 1141 (25) CI, 93.6%–95.0%) among those not receiving OST (P  =  .027) F3 30 (16) 721 (16) (Table 2). Of the 19 patients receiving OST who had ˂90% cal- F4 51 (27) 1410 (31) culated adherence, 12 patients achieved SVR12 and 7 patients Treatment-experienced, n (%) 42 (22) 1568 (34) failed to achieve SVR12 (3 were lost to follow-up, 1 withdrew Therapy consent on day 29, 1 had virologic breakthrough and drug lev- Ledipasvir/sofosbuvir ± ribavirin 8 (4) 423 (9) (8 wk) els consistent with nonadherence, 1 discontinued on day 1 due Ledipasvir/sofosbuvir ± ribavirin 32 (16) 835 (18) to AE, 1 was discontinued by the investigator on day 5 due to (12 wk) nonadherence). Among patients receiving OST, the proportion Ledipasvir/sofosbuvir ± ribavirin 13 (7) 641 (14) of participants with ≥90% adherence with ledipasvir/sofosbuvir (24 wk) Sofosbuvir/velpatasvir (12 wk) 92 (47) 1643 (36) with or without ribavirin was 88.7% (47/53), sofosbuvir/vel- Sofosbuvir/velpatasvir/voxilaprevir 41 (21) 570 (13) patasvir was 89.1% (82/92), and sofosbuvir/velpatasvir/voxila- (8 wk) previr was 93.9% (46/49). Sofosbuvir/velpatasvir/voxilaprevir 8 (4) 437 (10) (12 wk) HCV Treatment Outcomes OST, n (%) The proportion with SVR12 among those receiving OST was Methadone 113 (58) - 94.3% (183/194; 95% CI, 90.1%–97.1%) compared with 96.8% Buprenorphine 35 (18) - Buprenorphine/naloxone 40 (21) - for those not receiving OST (4405/4549; 95% CI, 96.3%–97.3%; Other 6 (3) - P  =  .062) (Table  2). SVR12 by treatment type and duration Abbreviations: HCV, hepatitis C virus; OST, opioid substitution therapy. for participants receiving and not receiving OST is shown in Nineteen patients were classified as other, unknown, or missing, and all were not receiv - Table 2. ing OST at enrollment. Among patients receiving OST, the proportion of partic- ipants with SVR12 with ledipasvir/sofosbuvir with or with- sofosbuvir with or without ribavirin (for 8, 12, or 24 weeks), out ribavirin was 92.5% (49/53), sofosbuvir/velpatasvir was 36% (n  =  1643) received sofosbuvir/velpatasvir for 12 weeks, 94.6% (87/92), and sofosbuvir/velpatasvir/voxilaprevir was and 22% (n  =  1007) received sofosbuvir/velpatasvir/voxila- 95.9% (47/49). Further, among patients with HCV genotype 3, previr (for 8 or 12 weeks). the response to therapy among patients receiving sofosbuvir/ Among patients receiving OST (n = 194), 36% (n = 70) had velpatasvir was 95.8% (46/48) and receiving sofosbuvir/vel- cirrhosis, 22% (n  =  42) were treatment-experienced, and 38% patasvir/voxilaprevir was 92.3% (24/26). (n = 74) were infected with HCV genotype 3. Among patients Among patients receiving OST, the proportion of partici- not receiving OST (n  =  4549), 23% (n  =  1041) had cirrhosis, pants with SVR12 among people with F0 was 88.1% (37/42), 34% (n = 1568) were treatment-experienced, and 17% (n = 787) with F1 was 91.3% (21/23), with F2 was 97.8% (44/45), with F3 were infected with HCV genotype 3. was 93.3% (28/30), and with F4 was 98.0% (50/51). HCV Treatment for People Receiving OST • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Treatment and Safety Outcomes Among Patients With Chronic HCV Infection Receiving Sofosbuvir-Based Therapies in the ION, ASTRAL, and POLARIS Phase 3 Clinical Trials, by Receipt of Opioid Substitution Therapy  Characteristic OST at Enrollment No OST at Enrollment P Overall, n/N (%) Treatment completion 189/194 (97.4) 4501/4549 (98.9) .064 ≥90% adherence 175/194 (90.2) 4291/4549 (94.3) .027 SVR12 183/194 (94.3) 4405/4549 (96.8) .062 Adverse events 152/194 (78.4) 3517/4549 (77.3) .79 Severe adverse events 7/194 (3.6) 108/4549 (2.4) .24 Ledipasvir/sofosbuvir ± ribavirin Treatment completion 51/53 (96.2) 1863/1899 (98.1) .28 ≥90% adherence 47/53 (88.7) 1791/1899 (94.3) .12 SVR12 49/53 (92.5) 1839/1899 (96.8) .093 Adverse events 47/53 (88.7) 1513/1899 (79.7) .12 Severe adverse events 2/53 (3.8) 50/1899 (2.6) .65 Sofosbuvir/velpatasvir Treatment completion 89/92 (96.7) 1634/1643 (99.5) .022 ≥90% adherence 82/92 (89.1) 1559/1643 (94.9) .029 SVR12 87/92 (94.6) 1601/1643 (97.4) .099 Adverse events 68/92 (73.9) 1251/1643 (76.1) .62 Severe adverse events 4/92 (4.3) 33/1643 (2.0) .13 Sofosbuvir/velpatasvir/voxilaprevir Treatment completion, n (%) 49/49 (100.0) 1004/1007 (99.7) 1.00 ≥90% adherence 46/49 (93.9) 941/1007 (93.4) 1.00 SVR12 47/49 (95.9) 965/1007 (95.8) 1.00 Adverse events 37/49 (75.5) 753/1007 (74.8) 1.00 Severe adverse events 1/49 (2.0) 25/1007 (2.5) 1.00 Abbreviations: HCV, hepatitis C virus; OST, opioid substitution therapy. Among patients receiving OST across treatment regimens, DISCUSSION there was no difference in SVR12 in those receiving methadone This post hoc analysis of sofosbuvir-based therapies from and buprenorphine (94.7% vs 96.0%, P = 1.0), patients with and the ION, ASTRAL, and POLARIS studies demonstrated high without cirrhosis (98.6% vs 91.9%, P = .089), and patients with SVR12 rates among patients receiving OST, including those genotype 3 as compared with genotype 1a (94.6% vs 95.2%, with HCV genotype 3 receiving sofosbuvir/velpatasvir and P = .850). sofosbuvir/velpatasvir/voxilaprevir. Similar treatment comple- Safety tion, SVR12, and AE rates were observed among patients with The proportions with AEs (78.4%; 95% CI, 71.9%–83.9%; chronic HCV genotypes 1–6 receiving and not receiving OST, vs 77.3%; 95% CI, 76.1%–78.5%; P  =  .790) (Tables 2 and 3) although patients not receiving OST had a significantly higher and serious AEs (3.6%; 95% CI, 1.5%–7.3%; vs 2.4%; 95% CI, proportion with ≥90% adherence. Collectively, these data add 2.0%–2.9%; P = .200) (Table 2) were similar among participants to the body of evidence supporting the efficacy and safety of receiving and not receiving OST. AEs were mostly mild or mod- DAA treatment for HCV among people receiving stable OST, erate in severity. consistent with international recommendations [5–8]. HCV Reinfection Overall, the SVR was 94% among patients receiving OST Two patients were found to have reinfection with a different and sofosbuvir-based therapy, with no observed difference in genotype than at baseline. Neither subject was receiving OST response compared with those not receiving OST, which is con- at baseline. One patient enrolled in ASTRAL-3 had genotype sistent with previous post hoc analyses of the ION and ASTRAL 3a at baseline and received SOF/VEL for 12 weeks. The patient studies [21, 22] and other studies in this population [23]. These achieved SVR4 and was found to have genotype 1a 12 weeks results are also comparable with a large phase 3 study of peo- after the completion of therapy. Another patient enrolled in ple receiving stable OST (recent injecting drug use at screen- POLARIS-2 had genotype 1a and received SOF/VEL for 12 ing was permitted) and HCV genotype 1, 4, and 6 infection weeks. The patient achieved SVR12 but was found to have gen- receiving elbasvir/grazoprevir for 12 weeks, where an SVR of otype 3a 24 weeks after therapy. 91% was observed [20]. This study adds to the literature by 4 • OFID • Grebely et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Adverse Events Among Patients With Chronic HCV Infection Receiving Sofosbuvir-Based Therapies in the ION, ASTRAL, and POLARIS Phase 3 Clinical Studies, by Receipt of Opioid Substitution Therapy OST at Enrollment No OST at Enrollment Ledipasvir/ Ledipasvir/ Adverse Sofosbuvir ± Sofosbuvir/Velpatasvir/ Sofosbuvir ± Sofosbuvir/Velpatasvir/ Event, Ribavirin Sofosbuvir/Velpatasvir Voxilaprevir Ribavirin Sofosbuvir/Velpatasvir Voxilaprevir n (%) (n = 53) (n = 92) (n = 49) (n = 1899) (n = 1643) (n = 1007) Adverse events in >10% Headache 12 (22.6) 20 (21.7) 8 (16.3) 443 (23.3) 450 (27.4) 269 (26.7) Fatigue 19 (35.8) 18 (19.6) 11 (22.4) 556 (29.3) 364 (22.2) 222 (22.0) Nausea 12 (22.6) 14 (15.2) 12 (24.5) 253 (13.3) 184 (11.2) 150 (14.9) Diarrhea 4 (7.5) 7 (7.6) 5 (10.2) 151 (8.0) 110 (6.7) 183 (18.2) Insomnia 5 (9.4) 5 (5.4) 3 (6.1) 232 (12.2) 112 (6.8) 59 (5.9) Vomiting 4 (7.5) 6 (6.5) 6 (12.2) 60 (3.2) 42 (2.6) 24 (2.4) Abbreviations: HCV, hepatitis C virus; OST, opioid substitution therapy. providing further data among patients with cirrhosis and geno- included population is likely at lower risk of reinfection, given type 3 infection in people receiving OST, enabling a more pre- that they were not using illicit drugs at the time of treatment cise estimate of outcomes in this population. Also, this is the initiation. Further long-term studies of HCV reinfection among first study to report outcomes with the combination of sofos- people receiving OST and recent PWID are required to more buvir/velpatasvir/voxilaprevir in patients stable on OST. These fully characterize the risk of HCV reinfection and associated data are consistent with previous data demonstrating that inter- risk factors. feron-based HCV therapy is safe and effective among people This study has a number of limitations. People with active receiving OST [10–12, 31–33]. Collectively, these data support drug use at baseline were excluded from participating in the DAA therapy for patients stable on OST. ION, ASTRAL, and POLARIS studies, and as such, enrolled Treatment completion was high among people receiving OST participants represented a selected population likely to be (97%), with no difference between those not receiving OST, con- engaged in care. er Th efore, these findings may not be generaliz- sistent with other studies of interferon-free [21, 22] and inter- able to other PWID populations (particularly those not receiv- feron-based therapy [10–12, 31, 32]. Adherence to therapy was ing stable OST or recent PWID). Further, this was also a post significantly lower in people receiving OST as compared with hoc analysis, which was not defined prior to the initiation of those not receiving OST (90% vs 94%), although it is uncertain these studies. Also, the data with respect to adherence must be whether this would be clinically significant. In a meta-analy- interpreted with caution. Adherence in these studies was meas- sis of interferon-based studies among PWID, engagement in ured by counting the number of pills in returned pill bottles. In addiction treatment was associated with higher treatment com- instances where participants did not return their pill bottles, a pletion [12]. Previous studies have demonstrated that the colo- conservative measure of adherence was used and adherence for cation of HCV services and drug treatment can be successfully that period was assumed to be 0%. Given limited data on inter- integrated [34], with the colocation of HCV care in OST clinics feron-free treatment outcomes among people receiving OST welcomed by the large majority of participants and providers (particularly people with cirrhosis and HCV genotype 3), these [35]. Further efforts are needed to expand the integration of data still provide important guidance for HCV management in HCV DAA therapy in drug and alcohol clinics and community these populations. health clinics that also provide OST. Also, improved education In conclusion, these data demonstrate that sofosbuvir-based and training of practitioners working in drug treatment clinics therapy is effective and well tolerated among patients receiv- about HCV testing, liver disease assessment, and HCV treat- ing OST. Although this study provides important data to add ment are required to further develop competency and expand to the literature on HCV therapy in people receiving OST, fur- HCV treatment access for people receiving OST. ther data are still needed on DAA therapy among people with It is notable that there were no cases of HCV reinfection recent or ongoing injecting drug use. Ongoing clinical trials following DAA therapy among people receiving OST in the evaluating interferon-free therapy among PWID with recent ION, ASTRAL, and POLARIS studies. Previous studies have drug use (SIMPLIFY, NCT02336139; HERO, NCT02824640) demonstrated reinfection rates ranging from 1% to 5% per 100 and PWID with recent drug use and/or those receiving OST person-years following successful interferon-based [10, 36–38] (D3FEAT, NCT02498015) will hopefully provide further data and DAA therapy [20] among people with a history of inject- in this regard. Global HCV elimination efforts will require the ing drug use or those receiving OST. However, the sample size inclusion of PWID as a key priority population, and strategies and duration of follow-up in this study are limited, and the are needed to enhance HCV care in this important group. HCV Treatment for People Receiving OST • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Acknowledgments 16. Schìtz A, Moser S, Marchart K, et al. Direct observed therapy of chronic hepatitis C with interferon-free all-oral regimens at a low-threshold drug treatment facili- Disclaimers. e Th Kirby Institute is funded by the Australian ty-a new concept for treatment of patients with borderline compliance receiving Government Department of Health and Ageing. The views expressed in opioid substitution therapy. Am J Gastroenterol 2016; 111:903–5. this publication do not necessarily represent the position of the Australian 17. Scherz N, Brunner N, Bruggmann P. Direct-acting antivirals for hepatitis C in Government. Jason Grebely is supported by a National Health and Medical patient in opioid substitution treatment and heroin assisted treatment: real-life Research Council Career Development Fellowship. Gregory Dore is sup- data. J Hepatol 2017; 66:S726. ported through National Health and Medical Research Council of Australia 18. Dillon J, Mauss S, Nalpas C, et  al. Efficacyand safety of Simeprevir-containing Practitioner Fellowship. hepatitis C therapy in patients on opiate substitution therapy. J Hepatol 2017; 66:S520. Financial support. This work was supported by Gilead Sciences. 19. Boyle A, Marra F, Fox R, et al. Partial directly observed therapy with ombitasvir/ Potential conifl cts of interest. Jason Grebely is a consultant/advisor paritaprevir based regimens allows for successful treatment of patients on daily and has received research grants from AbbVie, Bristol-Myers Squibb, supervised methadone. J Hepatol 2017; 66(1):S282. Cepheid, Gilead Sciences, Merck, and Merck Sharp & Dohme. Stefan 20. Dore GJ, Altice F, Litwin AH, et al; C-EDGE CO-STAR Study Group. Elbasvir- Zeuzem is a consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences, grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist Intercept, Janssen, Merck, and Merck Sharp & Dohme. Gregory Dore therapy: a randomized trial. Ann Intern Med 2016; 165:625–34. is a consultant/advisor to and has received research grants from Abbvie, 21. Grebely J, Mauss S, Brown A, et  al. Efficacy and safety of ledipasvir/sofosbuvir Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck, with and without ribavirin in patients with chronic HCV genotype 1 infection Roche, GlaxoSmithKline, and Abbott Diagnostics. Liyun Ni, Joe Llewellyn, receiving opioid substitution therapy: analysis of phase 3 ION trials. Clin Infect Dis 2016; 63:1405–11. Heshaam M.  Mir, Nika Sajed, Luisa M.  Stamm, Robert H.  Hyland, John 22. Grebely J, Dore GJ, Zeuzem S, et al. Efficacy and safety of sofosbuvir/velpatasvir McNally, and Diana M.  Brainard are employees of Gilead Sciences. All in patients with chronic hepatitis C virus infection receiving opioid substitution authors have submitted the ICMJE Form for Disclosure of Potential therapy: analysis of phase 3 ASTRAL trials. Clin Infect Dis 2016; 63:1479–81. Conflicts of Interest. Conflicts that the editors consider relevant to the con- 23. Lalezari J, Sullivan JG, Varunok P, et al. Ombitasvir/paritaprevir/r and dasabuvir tent of the manuscript have been disclosed. plus ribavirin in HCV genotype 1-infected patients on methadone or buprenor- phine. J Hepatol 2015; 63:364–9. References 24. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir 1. Degenhardt L, Peacock A, Colledge S, et al. Global prevalence of injecting drug for untreated HCV genotype 1 infection. N Engl J Med 2014; 370:1889–98. use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV 25. Afdhal N, Reddy KR, Nelson DR, et  al; ION-2 Investigators. Ledipasvir and in people who inject drugs: a multistage systematic review. Lancet Glob Health sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 2017; 5:e1192–207. 370:1483–93. 2. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV 26. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and infection. Nat Rev Gastroenterol Hepatol 2013; 10:553–62. sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 3. Grebely J, Dore GJ. What is killing people with hepatitis C virus infection? Semin 2014; 370:1879–88. Liver Dis 2011; 31:331–9. 27. Feld JJ, Jacobson IM, Hézode C, et  al; ASTRAL-1 Investigators. Sofosbuvir and 4. Asher AK, Portillo CJ, Cooper BA, et  al. Clinicians’ views of hepatitis C virus velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; treatment candidacy with direct-acting antiviral regimens for people who inject 373:2599–607. drugs. Subst Use Misuse 2016; 51:1218–23. 28. Foster GR, Afdhal N, Roberts SK, et  al; ASTRAL-2 Investigators; ASTRAL-3 5. EASL. EASL recommendations on treatment of hepatitis C 2016. J Hepatol 2017; Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N 66:153–94. Engl J Med 2015; 373:2608–17. 6. AASLD/IDSA. HCV Guidance: Recommendations for Testing, Managing, and 29. Jacobson IM, Lawitz E, Gane EJ, et  al. Efficacy of 8 weeks of sofosbuvir, vel- Treating Hepatitis C. Available at: https://www.hcvguidelines.org/. Accessed 18 patasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 ran- March 2017. domized trials. Gastroenterology 2017; 153:113–22. 7. Grebely J, Robaeys G, Bruggmann P, et  al; International Network for Hepatitis 30. Bourlière M, Gordon SC, Flamm SL, et  al; POLARIS-1 and POLARIS-4 in Substance Users. Recommendations for the management of hepatitis C virus Investigators. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection among people who inject drugs. Int J Drug Policy 2015; 26:1028–38. infection. N Engl J Med 2017; 376:2134–46. 8. WHO. Guidelines for the Screening Care and Treatment of Persons With Chronic 31. Grebely J, Matthews GV, Hellard M, et  al; ATAHC Study Group. Adherence to Hepatitis C Infection. 2016.WHO. http://www.who.int/hepatitis/publications/ treatment for recently acquired hepatitis C virus (HCV) infection among inject- hepatitis-c-guidelines-2016/en/. Accessed 13 January 2018. ing drug users. J Hepatol 2011; 55:76–85. 9. Larney S, Grebely J, Hickman M, et al. Defining populations and injecting param- 32. Grebely J, Dalgard O, Cunningham EB, et al. Efficacy of response-guided directly eters among people who inject drugs: implications for the assessment of hepatitis observed pegylated interferon and self-administered ribavirin for people who C treatment programs. Int J Drug Policy 2015; 26:950–7. inject drugs with hepatitis C virus genotype 2/3 infection: the ACTIVATE study. 10. Aspinall EJ, Corson S, Doyle JS, et  al. Treatment of hepatitis C virus infec- Int J Drug Policy. 2017; 47:177–186. tion among people who are actively injecting drugs: a systematic review and 33. Grebely J, Alavi M, Micallef M, et al; ETHOS Study Group. Treatment for hepatitis C meta-analysis. Clin Infect Dis 2013; 57(Suppl 2):S80–9. virus infection among people who inject drugs attending opioid substitution treat- 11. Hellard M, Sacks-Davis R, Gold J. Hepatitis C treatment for injection drug users: ment and community health clinics: the ETHOS study. Addiction 2016; 111:311–9. a review of the available evidence. Clin Infect Dis 2009; 49:561–73. 34. Alavi M, Grebely J, Micallef M, et  al; Enhancing Treatment for Hepatitis C in 12. Dimova RB, Zeremski M, Jacobson IM, et al. Determinants of hepatitis C virus Opioid Substitution Settings (ETHOS) Study Group. Assessment and treatment treatment completion and efficacy in drug users assessed by meta-analysis. Clin of hepatitis C virus infection among people who inject drugs in the opioid substi- Infect Dis 2013; 56:806–16. tution setting: ETHOS study. Clin Infect Dis 2013; 57(Suppl 2):S62–9. 13. Grebely J, Puoti M, Wedemeyer H, et al. Safety and efficacy of ombitasvir, pari- 35. Treloar C, Rance J, Grebely J, Dore GJ. Client and staff experiences of a co-located taprevir/ritonavir and dasabuvir with or without ribavirin in chronic hepatitis C service for hepatitis C care in opioid substitution treatment settings in New South patients receiving opioid substitution therapy: a pooled analysis across 12 clinical Wales, Australia. Drug Alcohol Depend 2013; 133:529–34. trials. J Hepatol 2017; 66:S514. 36. Simmons B, Saleem J, Hill A, et al. Risk of late relapse or reinfection with hepatitis 14. Grebely J, Jacobson IM, Kayali Z, et al. SOF/VEL/VOX for 8 or 12 weeks is well C virus after achieving a sustained virological response: a systematic review and tolerated and results in high SVR12 rates in patients receiving opioid substitution meta-analysis. Clin Infect Dis 2016; 62:683–94. therapy. J Hepatol 2017; 66:S513. 37. Cunningham EB, Applegate TL, Lloyd AR, et al. Mixed HCV infection and rein- 15. Christensen S, Schober A, Mauss S, et  al. DAA-treatment of HCV-infected fection in people who inject drugs–impact on therapy. Nat Rev Gastroenterol patients on opioid substitution therapy (OST): does the clinical setting mat- Hepatol 2015; 12:218–30. ter? Data from the German Hepatitis C-Registry (DHC-R). Hepatology 2016; 38. Midgard H, Bjøro B, Mæland A, et al. Hepatitis C reinfection after sustained viro- 64(S1):982A–3A. logical response. J Hepatol 2016; 64:1020–6. 6 • OFID • Grebely et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid Substitution Therapy: An Analysis of Phase 3 Studies

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Open Forum Infectious Diseases MAJOR ARTICLE Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid Substitution Therapy: An Analysis of Phase 3 Studies 1 2 3 4 5 5 5 5 5 Jason Grebely, Jordan J. Feld, David Wyles, Mark Sulkowski, Liyun Ni, Joe Llewellyn, Heshaam M. Mir, Nika Sajed, Luisa M. Stamm, 5 5 5 6 7 8 9 10 Robert H. Hyland, John McNally, Diana M. Brainard, Ira Jacobson, Stefan Zeuzem, Marc Bourlière, Graham Foster, Nezam Afdhal, and Gregory J. Dore 1 2 3 The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia; Toronto Centre for Liver Disease, Toronto, Ontario, Canada; Division of Infectious Diseases, Denver Health and Hospital 4 5 6 7 Authority, Denver, Colorado; Johns Hopkins University, Baltimore, Maryland; Gilead Sciences, Inc., Foster City, California; Mount Sinai Beth Israel, New York, New York; Johann Wolfgang 8 9 10 Goethe University Medical Center, Frankfurt am Main, Germany; Hospital Saint Joseph, Marseille, France; Queen Mary University London, London, United Kingdom; Beth Israel Deaconess Medical Center, Boston, Massachusetts Background. Hepatitis C virus (HCV) direct-acting antiviral therapy is effective among people receiving opioid substitution therapy (OST), but studies are limited by small numbers of nongenotype 1 (GT1) patients. The aim of this study was to evaluate the treatment completion, adherence, SVR12, and safety of sofosbuvir-based therapies in HCV patients receiving and not receiving OST. Methods. Ten phase 3 studies of sofosbuvir-based regimens included ION (ledipasvir/sofosbuvir ± ribavirin for 8, 12, or 24 weeks in GT1), ASTRAL (sofosbuvir/velpatasvir for 12 weeks in GT1-6), and POLARIS (sofosbuvir/velpatasvir and sofosbuvir/ velpatasvir/voxilaprevir in GT1-6). Patients with clinically significant drug use (last 12  months) or noncannabinoids detected at screening were ineligible. Results. Among 4743 patients, 4% (n = 194) were receiving OST (methadone; n = 113; buprenorphine, n = 75; other, n = 6). Compared with those not receiving OST (n = 4549), those receiving OST (n = 194) were younger (mean age, 48 vs 54), more oen ft male (73% vs 61%), GT3 (38% vs 17%), treatment-naïve (78% vs 65%), and cirrhotic (36% vs 23%). Among those receiving and not receiving OST, there was no significant difference in treatment completion (97% vs 99%, P = .06), SVR12 (94% vs 97%, P  =  .06), relapse (0.5% vs 2.1%, P = .19), adverse events (78% vs 77%, P = .79), or serious adverse events (3.6% vs 2.4%, P = .24). There was no difference in SVR12 in patients with cirrhosis (99% vs 95%, P = .25) or those with G3 (95% vs 95%, P = .77) in those receiving OST. Among patients receiving OST, SVR12 was high among those receiving methadone (95%) and buprenorphine (96%). Conclusion. Sofosbuvir-based therapies are effective and safe in patients receiving OST. Keywords. DAA; drug use; hepatitis C virus; interferon-free; ledipasvir; PWID; sofosbuvir; velpatasvir; voxilaprevir. People who inject drugs (PWID) are disproportionately ae ff cted populations of PWID receiving DAA therapy, including those by hepatitis C virus (HCV) infection [1, 2]. Despite increas- receiving OST, are needed to change HCV health policy and ing liver-related morbidity and mortality among PWID [2, 3], clinical practice. some clinicians are reluctant to prescribe direct-acting antiviral People with a history of injecting drug use include former (DAA) therapy for PWID or people receiving opioid substitu- injectors who have ceased injecting and recent PWID [9]. Some tion therapy (OST) based on concerns of poor adherence, lower people with a history of injecting drug use may also be receiv- response to therapy, and high rates of reinfection [4]. This is ing OST (eg, methadone, buprenorphine) for the management inconsistent with international guidelines recommending that of opioid dependence. Interferon-based therapy is effective in all people should receive HCV treatment and that PWID should people with a history of injecting drug use, including those be prioritized, given the potential to reduce transmission to with recent injecting drug use and those receiving OST, with others [5–8]. Further data on treatment outcomes among responses similar to that observed in large clinical studies [10–12]. Although data are emerging on outcomes to DAA- based HCV therapy among PWID receiving OST [13–23], most studies are limited by small numbers of HCV nongeno- Received 1 September 2017; editorial decision 21 December 2017; accepted 17 January 2018. Correspondence: J.  Grebely, PhD, The Kirby Institute, UNSW Sydney, Wallace Wurth type 1 patients. There are also no published studies on the effi- Building, UNSW NSW 2052 Australia (jgrebely@kirby.unsw.edu.au). cacy and safety of sofosbuvir/velpatasvir/voxilaprevir in people Open Forum Infectious Diseases receiving OST. © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Phase 3 studies of sofosbuvir-based therapy (the ION, Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits ASTRAL, and POLARIS studies) included the evaluation of unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.DOI: 10.1093/ofid/ofy001 ledipasvir/sofosbuvir with or without ribavirin, sofosbuvir/ HCV Treatment for People Receiving OST • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Study End Points velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir in patients In this analysis, the end points included treatment comple- with chronic HCV genotype 1–6 [24–30]. People receiving tion, adherence (≥90% of doses), SVR12, safety (adverse events stable OST were eligible for inclusion, but people with clin- [AEs], serious AEs, and hemoglobin level <10 g/dL), and rein- ically relevant illicit drug use within 12  months of screening fection. The analyzed population included all randomized or illicit drugs (excluding cannabinoids) detected by a urine patients who received ≥1 dose of study medication. Adherence drug test at screening were excluded from study participation. was measured by counting the number of unused tablets in the These clinical trial populations are highly selected and may returned bottles to derive the number of administrated tablets. not be representative of recent PWID populations. However, In situations where a bottle was not returned, the number of studies in these populations contribute to the growing body tablets administered from that bottle will be assumed to be of evidence on interferon-free DAA therapy among people 0.  Adherence was calculated by dividing the number of total receiving OST, particularly people with HCV nongenotype 1 doses administered during therapy (determined by pill counts infection. at week 4, 8, 12, 16, and 24 [where applicable] study visits) by e Th aim of this post hoc analysis of the phase 3 studies of the total expected number of prescribed doses. SVR12 was sofosbuvir-based therapy was to evaluate the treatment comple- defined as the absence of quantifiable HCV RNA in serum (<25 tion, adherence, SVR12, and safety of sofosbuvir-based therapy IU/mL or <15 IU/mL), measured by COBAS TaqMan HCV in patients receiving OST and not receiving OST. Test, v2.0 (Roche Molecular Systems), at 12 weeks after the end METHODS of study treatment. Participants were monitored for recurrence (viral relapse or reinfection) at 4 weeks, 12 weeks (SVR12), and Study Participants and Design 24 weeks (SVR24) following the completion of treatment. Deep From October 2012 to May 2016, participants were enrolled in sequencing of the HCV NS5A and NS5B genes was performed 10 multicenter, randomized clinical studies, including ION-1–3 for all patients at baseline and again for all patients with viro- (ClinicalTrials.gov identifier: NCT01701401, NCT01768286, logic failure in samples obtained at the first time point of failure and NCT01851330, respectively [24–26]), ASTRAL-1–3 with an HCV RNA >1000 IU/mL [24–30]. Phylogenetic analy- (ClinicalTrials.gov: NCT02201940, NCT02220998, and ses were used to distinguish viral relapse from reinfection. NCT02201953, respectively [27, 28]), and POLARIS-1–4 (ClinicalTrials.gov: NCT02607735, NCT02607800, Statistical Analysis NCT02639338, and NCT02639247 [29, 30]). Descriptive statistics, including means, frequencies, and per- In the ION-1–3 studies, a fixed-dose combination tablet of centages (with 95% confidence intervals [CIs] for SVR12) were ledipasvir/sofosbuvir 90 mg/400 mg was administered for 8, 12, used to summarize the data. The proportion of participants or 24 weeks with or without ribavirin in patients with chronic with treatment completion, ≥90% adherence, SVR12, and AEs HCV genotype 1 infection [24–26]. Twice-daily ribavirin dose was compared among people receiving and not receiving OST. was given according to body weight (1000 mg daily < 75 kg or Comparisons were made using a 2-sided Fisher exact test. All 1200 mg daily ≥ 75 kg). In the ASTRAL-1–3 studies, a fixed-dose P values are 2-sided; a level of .05 was considered statistically combination tablet of sofosbuvir/velpatasvir 400 mg/100 mg was significant. Statistical analysis was performed using SAS 9.4 administered for 12 weeks in patients with chronic HCV geno- software (SAS Institute Inc., Cary, NC). types 1–6 [27, 28]. In the POLARIS studies, a fixed-dose com- RESULTS bination tablet of sofosbuvir/velpatasvir 400  mg/100  mg was administered for 12 weeks or a fixed-dose combination tablet of Participant Characteristics sofosbuvir/velpatasvir/voxilaprevir 400 mg/100 mg/100 mg was Overall, 4743 patients were enrolled and treated in the ION administered for 8 or 12 weeks in patients with chronic HCV (n = 1952; ION-1, n = 865; ION-2, n = 440; ION-3, n = 647), genotypes 1–6 [29, 30]. ASTRAL (n = 1035; ASTRAL-1, n = 624; ASTRAL-2, n = 134; Participants receiving OST (eg, methadone or buprenor- ASTRAL-3, n  =  277), and POLARIS studies (n  =  1756; phine with and without naloxone) were eligible for inclusion POLARIS-1, n  =  263; POLARIS-2, n  =  941; POLARIS-3, (OST determined based on reported concomitant medica- n = 333; POLARIS-4, n = 219). Among individuals in all these tions). Patients were excluded from enrollment in these stud- studies, 4% (n = 194) were receiving OST at enrollment. ies if they had clinically significant drug use within 12 months e c Th linical characteristics of the study participants are of screening (as assessed by the investigator based on partic- shown in Table 1. Among patients receiving OST (n = 194), 27% ipant self-report or medical chart review) or illicit drug use (n = 53) received ledipasvir/sofosbuvir with or without ribavi- (excluding cannabinoids) detected by a urine drug test during rin (for 8, 12, or 24 weeks), 47% (n = 92) received sofosbuvir/ the screening phase that was not explained by a prescription velpatasvir for 12 weeks, and 25% (n = 49) received sofosbuvir/ medication. The designs and results of these studies have been velpatasvir/voxilaprevir (for 8 or 12 weeks). Among patients not described previously [24–30]. receiving OST (n = 4549), 42% (n = 1899) received ledipasvir/ 2 • OFID • Grebely et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Baseline Demographic and Clinical Characteristics of Patients HCV Treatment Completion and Adherence With Chronic HCV Infection Receiving Sofosbuvir-Based Therapies in the The proportion of participants completing HCV therapy ION, ASTRAL, and POLARIS Phase 3 Clinical Trials, by Receipt of Opioid was 97.4% (189/194; 95% CI, 94.1%–99.2%) among partic- Substitution Therapy ipants receiving OST, compared with 98.9% (4501/4549; 95% CI, 98.6%–99.2%) among those not receiving OST (P  =  .064) No OST at OST at Enrollment (Table  2). The reasons for treatment discontinuation among Enrollment (n = 4549), patients receiving OST (n  =  5) included AEs (n  =  1), loss to Characteristic (n = 194), n (%) n (%) follow-up (n = 1), consent withdrawal (n = 1), lack of efficacy Mean (SD) age, y 48 (10.7) 54 (10.4) (n = 1), and noncompliance (n = 1). The reasons for treatment Male sex, n (%) 141 (73) 2770 (61) HCV genotype, n (%) discontinuation among patients not receiving OST (n  =  48) 1a 84 (43) 2109 (46) included AEs (n  =  19), loss to follow-up (n  =  10), consent 1b 12 (6) 816 (18) withdrawal (n = 6), protocol violation (n = 6), lack of efficacy 2 14 (7) 409 (9) (n = 4), noncompliance (n = 1), and pregnancy (n = 2). Among 3 74 (38) 787 (17) patients receiving OST, the proportion of participants complet- 4 10 (5) 269 (6) ing therapy with ledipasvir/sofosbuvir with or without ribavirin 5 0 54 (1) 6 0 86 (2) was 96.2% (51/53), sofosbuvir/velpatasvir was 96.7% (89/92), HCV RNA log IU/mL, mean (SD) 6.3 (0.7) 6.3 (0.7) and sofosbuvir/velpatasvir/voxilaprevir was 100% (49/49). HCV RNA ≥ 800 000 IU/mL, n (%) 142 (73) 3456 (76) e p Th roportion of participants with ≥90% adherence to ther - Fibrosis stage apy was 90.2% (175/194; 95% CI, 85.1%–94.0%) among partic- F0 42 (22) 826 (18) ipants receiving OST, compared with 94.3% (4291/4549; 95% F1 23 (12) 410 (9) F2 45 (24) 1141 (25) CI, 93.6%–95.0%) among those not receiving OST (P  =  .027) F3 30 (16) 721 (16) (Table 2). Of the 19 patients receiving OST who had ˂90% cal- F4 51 (27) 1410 (31) culated adherence, 12 patients achieved SVR12 and 7 patients Treatment-experienced, n (%) 42 (22) 1568 (34) failed to achieve SVR12 (3 were lost to follow-up, 1 withdrew Therapy consent on day 29, 1 had virologic breakthrough and drug lev- Ledipasvir/sofosbuvir ± ribavirin 8 (4) 423 (9) (8 wk) els consistent with nonadherence, 1 discontinued on day 1 due Ledipasvir/sofosbuvir ± ribavirin 32 (16) 835 (18) to AE, 1 was discontinued by the investigator on day 5 due to (12 wk) nonadherence). Among patients receiving OST, the proportion Ledipasvir/sofosbuvir ± ribavirin 13 (7) 641 (14) of participants with ≥90% adherence with ledipasvir/sofosbuvir (24 wk) Sofosbuvir/velpatasvir (12 wk) 92 (47) 1643 (36) with or without ribavirin was 88.7% (47/53), sofosbuvir/vel- Sofosbuvir/velpatasvir/voxilaprevir 41 (21) 570 (13) patasvir was 89.1% (82/92), and sofosbuvir/velpatasvir/voxila- (8 wk) previr was 93.9% (46/49). Sofosbuvir/velpatasvir/voxilaprevir 8 (4) 437 (10) (12 wk) HCV Treatment Outcomes OST, n (%) The proportion with SVR12 among those receiving OST was Methadone 113 (58) - 94.3% (183/194; 95% CI, 90.1%–97.1%) compared with 96.8% Buprenorphine 35 (18) - Buprenorphine/naloxone 40 (21) - for those not receiving OST (4405/4549; 95% CI, 96.3%–97.3%; Other 6 (3) - P  =  .062) (Table  2). SVR12 by treatment type and duration Abbreviations: HCV, hepatitis C virus; OST, opioid substitution therapy. for participants receiving and not receiving OST is shown in Nineteen patients were classified as other, unknown, or missing, and all were not receiv - Table 2. ing OST at enrollment. Among patients receiving OST, the proportion of partic- ipants with SVR12 with ledipasvir/sofosbuvir with or with- sofosbuvir with or without ribavirin (for 8, 12, or 24 weeks), out ribavirin was 92.5% (49/53), sofosbuvir/velpatasvir was 36% (n  =  1643) received sofosbuvir/velpatasvir for 12 weeks, 94.6% (87/92), and sofosbuvir/velpatasvir/voxilaprevir was and 22% (n  =  1007) received sofosbuvir/velpatasvir/voxila- 95.9% (47/49). Further, among patients with HCV genotype 3, previr (for 8 or 12 weeks). the response to therapy among patients receiving sofosbuvir/ Among patients receiving OST (n = 194), 36% (n = 70) had velpatasvir was 95.8% (46/48) and receiving sofosbuvir/vel- cirrhosis, 22% (n  =  42) were treatment-experienced, and 38% patasvir/voxilaprevir was 92.3% (24/26). (n = 74) were infected with HCV genotype 3. Among patients Among patients receiving OST, the proportion of partici- not receiving OST (n  =  4549), 23% (n  =  1041) had cirrhosis, pants with SVR12 among people with F0 was 88.1% (37/42), 34% (n = 1568) were treatment-experienced, and 17% (n = 787) with F1 was 91.3% (21/23), with F2 was 97.8% (44/45), with F3 were infected with HCV genotype 3. was 93.3% (28/30), and with F4 was 98.0% (50/51). HCV Treatment for People Receiving OST • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Treatment and Safety Outcomes Among Patients With Chronic HCV Infection Receiving Sofosbuvir-Based Therapies in the ION, ASTRAL, and POLARIS Phase 3 Clinical Trials, by Receipt of Opioid Substitution Therapy  Characteristic OST at Enrollment No OST at Enrollment P Overall, n/N (%) Treatment completion 189/194 (97.4) 4501/4549 (98.9) .064 ≥90% adherence 175/194 (90.2) 4291/4549 (94.3) .027 SVR12 183/194 (94.3) 4405/4549 (96.8) .062 Adverse events 152/194 (78.4) 3517/4549 (77.3) .79 Severe adverse events 7/194 (3.6) 108/4549 (2.4) .24 Ledipasvir/sofosbuvir ± ribavirin Treatment completion 51/53 (96.2) 1863/1899 (98.1) .28 ≥90% adherence 47/53 (88.7) 1791/1899 (94.3) .12 SVR12 49/53 (92.5) 1839/1899 (96.8) .093 Adverse events 47/53 (88.7) 1513/1899 (79.7) .12 Severe adverse events 2/53 (3.8) 50/1899 (2.6) .65 Sofosbuvir/velpatasvir Treatment completion 89/92 (96.7) 1634/1643 (99.5) .022 ≥90% adherence 82/92 (89.1) 1559/1643 (94.9) .029 SVR12 87/92 (94.6) 1601/1643 (97.4) .099 Adverse events 68/92 (73.9) 1251/1643 (76.1) .62 Severe adverse events 4/92 (4.3) 33/1643 (2.0) .13 Sofosbuvir/velpatasvir/voxilaprevir Treatment completion, n (%) 49/49 (100.0) 1004/1007 (99.7) 1.00 ≥90% adherence 46/49 (93.9) 941/1007 (93.4) 1.00 SVR12 47/49 (95.9) 965/1007 (95.8) 1.00 Adverse events 37/49 (75.5) 753/1007 (74.8) 1.00 Severe adverse events 1/49 (2.0) 25/1007 (2.5) 1.00 Abbreviations: HCV, hepatitis C virus; OST, opioid substitution therapy. Among patients receiving OST across treatment regimens, DISCUSSION there was no difference in SVR12 in those receiving methadone This post hoc analysis of sofosbuvir-based therapies from and buprenorphine (94.7% vs 96.0%, P = 1.0), patients with and the ION, ASTRAL, and POLARIS studies demonstrated high without cirrhosis (98.6% vs 91.9%, P = .089), and patients with SVR12 rates among patients receiving OST, including those genotype 3 as compared with genotype 1a (94.6% vs 95.2%, with HCV genotype 3 receiving sofosbuvir/velpatasvir and P = .850). sofosbuvir/velpatasvir/voxilaprevir. Similar treatment comple- Safety tion, SVR12, and AE rates were observed among patients with The proportions with AEs (78.4%; 95% CI, 71.9%–83.9%; chronic HCV genotypes 1–6 receiving and not receiving OST, vs 77.3%; 95% CI, 76.1%–78.5%; P  =  .790) (Tables 2 and 3) although patients not receiving OST had a significantly higher and serious AEs (3.6%; 95% CI, 1.5%–7.3%; vs 2.4%; 95% CI, proportion with ≥90% adherence. Collectively, these data add 2.0%–2.9%; P = .200) (Table 2) were similar among participants to the body of evidence supporting the efficacy and safety of receiving and not receiving OST. AEs were mostly mild or mod- DAA treatment for HCV among people receiving stable OST, erate in severity. consistent with international recommendations [5–8]. HCV Reinfection Overall, the SVR was 94% among patients receiving OST Two patients were found to have reinfection with a different and sofosbuvir-based therapy, with no observed difference in genotype than at baseline. Neither subject was receiving OST response compared with those not receiving OST, which is con- at baseline. One patient enrolled in ASTRAL-3 had genotype sistent with previous post hoc analyses of the ION and ASTRAL 3a at baseline and received SOF/VEL for 12 weeks. The patient studies [21, 22] and other studies in this population [23]. These achieved SVR4 and was found to have genotype 1a 12 weeks results are also comparable with a large phase 3 study of peo- after the completion of therapy. Another patient enrolled in ple receiving stable OST (recent injecting drug use at screen- POLARIS-2 had genotype 1a and received SOF/VEL for 12 ing was permitted) and HCV genotype 1, 4, and 6 infection weeks. The patient achieved SVR12 but was found to have gen- receiving elbasvir/grazoprevir for 12 weeks, where an SVR of otype 3a 24 weeks after therapy. 91% was observed [20]. This study adds to the literature by 4 • OFID • Grebely et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Adverse Events Among Patients With Chronic HCV Infection Receiving Sofosbuvir-Based Therapies in the ION, ASTRAL, and POLARIS Phase 3 Clinical Studies, by Receipt of Opioid Substitution Therapy OST at Enrollment No OST at Enrollment Ledipasvir/ Ledipasvir/ Adverse Sofosbuvir ± Sofosbuvir/Velpatasvir/ Sofosbuvir ± Sofosbuvir/Velpatasvir/ Event, Ribavirin Sofosbuvir/Velpatasvir Voxilaprevir Ribavirin Sofosbuvir/Velpatasvir Voxilaprevir n (%) (n = 53) (n = 92) (n = 49) (n = 1899) (n = 1643) (n = 1007) Adverse events in >10% Headache 12 (22.6) 20 (21.7) 8 (16.3) 443 (23.3) 450 (27.4) 269 (26.7) Fatigue 19 (35.8) 18 (19.6) 11 (22.4) 556 (29.3) 364 (22.2) 222 (22.0) Nausea 12 (22.6) 14 (15.2) 12 (24.5) 253 (13.3) 184 (11.2) 150 (14.9) Diarrhea 4 (7.5) 7 (7.6) 5 (10.2) 151 (8.0) 110 (6.7) 183 (18.2) Insomnia 5 (9.4) 5 (5.4) 3 (6.1) 232 (12.2) 112 (6.8) 59 (5.9) Vomiting 4 (7.5) 6 (6.5) 6 (12.2) 60 (3.2) 42 (2.6) 24 (2.4) Abbreviations: HCV, hepatitis C virus; OST, opioid substitution therapy. providing further data among patients with cirrhosis and geno- included population is likely at lower risk of reinfection, given type 3 infection in people receiving OST, enabling a more pre- that they were not using illicit drugs at the time of treatment cise estimate of outcomes in this population. Also, this is the initiation. Further long-term studies of HCV reinfection among first study to report outcomes with the combination of sofos- people receiving OST and recent PWID are required to more buvir/velpatasvir/voxilaprevir in patients stable on OST. These fully characterize the risk of HCV reinfection and associated data are consistent with previous data demonstrating that inter- risk factors. feron-based HCV therapy is safe and effective among people This study has a number of limitations. People with active receiving OST [10–12, 31–33]. Collectively, these data support drug use at baseline were excluded from participating in the DAA therapy for patients stable on OST. ION, ASTRAL, and POLARIS studies, and as such, enrolled Treatment completion was high among people receiving OST participants represented a selected population likely to be (97%), with no difference between those not receiving OST, con- engaged in care. er Th efore, these findings may not be generaliz- sistent with other studies of interferon-free [21, 22] and inter- able to other PWID populations (particularly those not receiv- feron-based therapy [10–12, 31, 32]. Adherence to therapy was ing stable OST or recent PWID). Further, this was also a post significantly lower in people receiving OST as compared with hoc analysis, which was not defined prior to the initiation of those not receiving OST (90% vs 94%), although it is uncertain these studies. Also, the data with respect to adherence must be whether this would be clinically significant. In a meta-analy- interpreted with caution. Adherence in these studies was meas- sis of interferon-based studies among PWID, engagement in ured by counting the number of pills in returned pill bottles. In addiction treatment was associated with higher treatment com- instances where participants did not return their pill bottles, a pletion [12]. Previous studies have demonstrated that the colo- conservative measure of adherence was used and adherence for cation of HCV services and drug treatment can be successfully that period was assumed to be 0%. Given limited data on inter- integrated [34], with the colocation of HCV care in OST clinics feron-free treatment outcomes among people receiving OST welcomed by the large majority of participants and providers (particularly people with cirrhosis and HCV genotype 3), these [35]. Further efforts are needed to expand the integration of data still provide important guidance for HCV management in HCV DAA therapy in drug and alcohol clinics and community these populations. health clinics that also provide OST. Also, improved education In conclusion, these data demonstrate that sofosbuvir-based and training of practitioners working in drug treatment clinics therapy is effective and well tolerated among patients receiv- about HCV testing, liver disease assessment, and HCV treat- ing OST. Although this study provides important data to add ment are required to further develop competency and expand to the literature on HCV therapy in people receiving OST, fur- HCV treatment access for people receiving OST. ther data are still needed on DAA therapy among people with It is notable that there were no cases of HCV reinfection recent or ongoing injecting drug use. Ongoing clinical trials following DAA therapy among people receiving OST in the evaluating interferon-free therapy among PWID with recent ION, ASTRAL, and POLARIS studies. Previous studies have drug use (SIMPLIFY, NCT02336139; HERO, NCT02824640) demonstrated reinfection rates ranging from 1% to 5% per 100 and PWID with recent drug use and/or those receiving OST person-years following successful interferon-based [10, 36–38] (D3FEAT, NCT02498015) will hopefully provide further data and DAA therapy [20] among people with a history of inject- in this regard. Global HCV elimination efforts will require the ing drug use or those receiving OST. However, the sample size inclusion of PWID as a key priority population, and strategies and duration of follow-up in this study are limited, and the are needed to enhance HCV care in this important group. HCV Treatment for People Receiving OST • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Acknowledgments 16. Schìtz A, Moser S, Marchart K, et al. Direct observed therapy of chronic hepatitis C with interferon-free all-oral regimens at a low-threshold drug treatment facili- Disclaimers. e Th Kirby Institute is funded by the Australian ty-a new concept for treatment of patients with borderline compliance receiving Government Department of Health and Ageing. The views expressed in opioid substitution therapy. Am J Gastroenterol 2016; 111:903–5. this publication do not necessarily represent the position of the Australian 17. Scherz N, Brunner N, Bruggmann P. Direct-acting antivirals for hepatitis C in Government. Jason Grebely is supported by a National Health and Medical patient in opioid substitution treatment and heroin assisted treatment: real-life Research Council Career Development Fellowship. Gregory Dore is sup- data. J Hepatol 2017; 66:S726. ported through National Health and Medical Research Council of Australia 18. Dillon J, Mauss S, Nalpas C, et  al. Efficacyand safety of Simeprevir-containing Practitioner Fellowship. hepatitis C therapy in patients on opiate substitution therapy. J Hepatol 2017; 66:S520. Financial support. This work was supported by Gilead Sciences. 19. Boyle A, Marra F, Fox R, et al. Partial directly observed therapy with ombitasvir/ Potential conifl cts of interest. Jason Grebely is a consultant/advisor paritaprevir based regimens allows for successful treatment of patients on daily and has received research grants from AbbVie, Bristol-Myers Squibb, supervised methadone. J Hepatol 2017; 66(1):S282. Cepheid, Gilead Sciences, Merck, and Merck Sharp & Dohme. 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J Hepatol 2016; 64:1020–6. 6 • OFID • Grebely et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy001/4850695 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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