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Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial
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"In conclusion, these findings document that elbasvir-grazoprevir is effective and well tolerated for treating HCV infection in PWID who are receiving OAT."
"Eligible patients were receiving OAT [Opioid Agonist Therapy] with methadone, buprenorphine, or buprenorphine-naloxone for at least 3 months before enrollment and were at least 80% adherent to OAT appointments.....More than 50% of patients in each group had positive results on UDS [urine drug screen] for at least 1 potential drug of abuse, excluding methadone and buprenorphine, at each visit. .....In the active-phase DTG, adherence greater than 95% was reported in 95.8% of patients (91 of 95)......Despite reservations concerning HCV treatment in patients who use drugs, this study demonstrated excellent treatment adherence in a population receiving stable OAT despite ongoing drug use among most participants.....5 had signs consistent with probable reinfection......The SVR12 was 91.5% (95% CI, 86.8 to 95.0) in the ITG and 89.5% (95% CI, 81.5 to 94.8) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8 to 96.9) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event.""
August 9 2016 Annals
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"Globally, an estimated 130 million to 170 million persons have hepatitis C virus (HCV) infection (1). Morbidity and mortality from chronic HCV infection continue to increase, particularly among persons who inject drugs (PWID) (2). In most high-income countries, PWID are the major population affected by HCV, although injection drug use-related HCV epidemics are emerging in many other locales, with an estimated HCV prevalence of 60% to 80% (1, 3). Yet, most trials of direct-acting antiviral (DAA) therapies for HCV have excluded persons with recent injection drug use, although small studies suggest favorable outcomes among those receiving opioid-agonist therapy (OAT) (4).......The SVR12 was 91.5% (95% CI, 86.8 to 95.0) in the ITG and 89.5% (95% CI, 81.5 to 94.8) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8 to 96.9) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event."
More than 50% of patients in each group had positive results on UDS [urine drug screen] for at least 1 potential drug of abuse, excluding methadone and buprenorphine, at each visit. There were no meaningful differences in drug use between the study groups: day 1 UDS results were positive in 62% of patients in the ITG and 53% in the DTG. .....During the initial treatment period, adherence greater than 95% (>79 doses) was reported by 96.5% of patients
"In conclusion, these findings document that elbasvir-grazoprevir is effective and well tolerated for treating HCV infection in PWID who are receiving OAT. The risk for reinfection warrants further study......These outcomes support the previously reported evidence from interferon-containing regimen studies that people who use drugs can achieve HCV treatment outcomes similar to those of the general HCV population (19). In the United States, most states restrict Medicaid-based access to sofosbuvir-based therapy to patients without evidence of ongoing illicit drug use (20). The results of this study suggest that access to interferon-free DAA therapy should be expanded to patients receiving OAT, including the removal of drug use-based restrictions, providing further support for international guidelines (21-23)."
Of considerable clinical and public health interest is the potential effect of HCV reinfection after successful treatment of high-risk populations, including PWID (24, 25). High levels of HCV reinfection might compromise benefit from both the individual patient and public health perspectives. Preliminary data from this study indicate that HCV reinfection in the early posttreatment period (to 24 weeks) may occur, with 6 cases of probable HCV reinfection detected, 3 of which were identified at 1 clinical site. The observation that 4 of 6 patients with reinfections had positive results on opioid testing during posttreatment follow-up suggests that injection drug use was the probable source of reinfection. An ongoing extension of this study will evaluate drug use behaviors and the incidence and outcome of HCV reinfection over a 3-year period after treatment. Of interest, 3 of the 6 patients categorized as having HCV reinfection subsequently had undetectable HCV RNA levels without additional HCV treatment, indicating that not all reinfection cases develop viral persistence and drawing attention to the possible role of an augmented HCV-specific immune response after DAA therapy (26, 27). Ultradeep sequencing confirmed that the patients with probable reinfection did not have baseline mixed HCV infection, with potential nonclearance of the nondominant strain.
From 2 September 2014 through 9 December 2014, investigators screened 371 treatment-naive patients aged 18 years or older with chronic HCV GT1, GT4, or GT6 infection and a baseline HCV RNA level of 10 000 IU/mL or greater in 13 countries, and 301 patients were enrolled (see footnote to Figure 1). Eligible patients were receiving OAT [Opioid Agonist Therapy] with methadone, buprenorphine, or buprenorphine-naloxone for at least 3 months before enrollment and were at least 80% adherent to OAT appointments. Patients actively using drugs of potential abuse while receiving OAT were not excluded. Patients with HIV-1 infection either were naive to antiretroviral therapy or were receiving stable antiretroviral therapy with tenofovir or abacavir; emtricitabine or lamivudine; and dolutegravir, raltegravir, or rilpivirine before enrollment. Planned enrollment included up to 20% of patients with cirrhosis as demonstrated by aspartate aminotransferase (AST)-platelet ratio index combined with FibroTest (BioPredictive), hepatic elastography, or biopsy (Supplement 1).
Despite reservations concerning HCV treatment in patients who use drugs, this study demonstrated excellent treatment adherence in a population receiving stable OAT despite ongoing drug use among most participants. Treatment adherence in this study was similar to that in other interferon-free DAA trials in the general HCV population, which excluded patients with illicit drug use. Drug use also did not seem to affect elbasvir-grazoprevir efficacy.
On the basis of GT assessment, sequencing, and phylogenetic analysis, 7 of the 12 patients with viral recurrence had findings consistent with relapse, and 5 had signs consistent with probable reinfection.
During the initial treatment period, adherence greater than 95% (>79 doses) was reported by 96.5% of patients (192 of 199) in the ITG and 100% of those in the placebo-phase DTG (97 of 97). In the active-phase DTG, adherence greater than 95% was reported in 95.8% of patients (91 of 95).
More than 50% of patients in each group had positive results on UDS [urine drug screen] for at least 1 potential drug of abuse, excluding methadone and buprenorphine, at each visit. There were no meaningful differences in drug use between the study groups: day 1 UDS results were positive in 62% of patients in the ITG and 53% in the DTG. Based on UDS results, drug use remained relatively stable throughout treatment (Figure 2).
Seventy-eight percent of patients (59 of 76) in the ITG and DTG groups with a positive benzodiazepine UDS result at baseline also had a benzodiazepine listed as a concomitant medication, indicating that most probably were using prescription benzodiazepines. Positive UDS results at baseline or during treatment (2 or more positive UDS results) did not affect adherence or efficacy, regardless of which drug class was positive on UDS (Tables 3 and 4 of Supplement 1).
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9 August 2016
Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial
Gregory J. Dore, MD; Frederick Altice, MD; Alain H. Litwin, MD; Olav Dalgard, MD; Edward J. Gane, MD; Oren Shibolet, MD; Anne Luetkemeyer, MD; Ronald Nahass, MD; Cheng-Yuan Peng, MD; Brian Conway, MD; Jason Grebely, PhD; Anita Y.M. Howe, PhD; Isaias N. Gendrano, MPH; Erluo Chen, MPH; Hsueh-Cheng Huang, PhD; Frank J. Dutko, PhD; David C. Nickle, PhD; Bach-Yen Nguyen, MD; Janice Wahl, MD; Eliav Barr, MD; Michael N. Robertson, MD; Heather L. Platt, MD, on behalf of the C-EDGE CO-STAR Study Group*
Ann Intern Med. Published online 9 August 2016
Abstract
Background: Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID).
Objective: To evaluate elbasvir-grazoprevir in treating HCV infection in PWID.
Design: Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688)
Setting: Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States.
Patients: 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid-agonist therapy (OAT).
Intervention: The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks.
Measurements: The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events.
Results: The SVR12 was 91.5% (95% CI, 86.8 to 95.0) in the ITG and 89.5% (95% CI, 81.5 to 94.8) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8 to 96.9) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event.
Limitation: These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID.
Conclusion: Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT.
Globally, an estimated 130 million to 170 million persons have hepatitis C virus (HCV) infection (1). Morbidity and mortality from chronic HCV infection continue to increase, particularly among persons who inject drugs (PWID) (2). In most high-income countries, PWID are the major population affected by HCV, although injection drug use-related HCV epidemics are emerging in many other locales, with an estimated HCV prevalence of 60% to 80% (1, 3). Yet, most trials of direct-acting antiviral (DAA) therapies for HCV have excluded persons with recent injection drug use, although small studies suggest favorable outcomes among those receiving opioid-agonist therapy (OAT) (4). The once-daily dosing, low side-effect profile, and shortened treatment duration of interferon-free DAA regimens are particularly suited to HCV treatment in PWID.
Elbasvir-grazoprevir is a fixed-dose combination recently approved in the United States for treating HCV genotypes (GTs) 1 and 4 (5). Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) have demonstrated potent in vitro activity against most HCV GTs, including first-generation protease inhibitor resistance-associated variants (RAVs), as well as RAVs related to daclatasvir and ledipasvir treatment failures (6-8). Phase 1 studies found no clinically significant drug interactions between methadone or buprenorphine and elbasvir or grazoprevir (9-11). A once-daily, oral, 12-week regimen of elbasvir-grazoprevir demonstrated favorable safety and high efficacy in a phase 3 clinical development program among treatment-naive and -experienced patients with HCV monoinfection or HIV-HCV co-infection (12-15).
The objective of this study of the CO-STAR (Hepatitis C Patients on Opioid Substitution Therapy Antiviral Response) trial was to evaluate the efficacy and safety of a 12-week regimen of elbasvir-grazoprevir for PWID with HCV infection receiving OAT.
Methods
Patients
From 2 September 2014 through 9 December 2014, investigators screened 371 treatment-naive patients aged 18 years or older with chronic HCV GT1, GT4, or GT6 infection and a baseline HCV RNA level of 10 000 IU/mL or greater in 13 countries, and 301 patients were enrolled (see footnote to Figure 1). Eligible patients were receiving OAT with methadone, buprenorphine, or buprenorphine-naloxone for at least 3 months before enrollment and were at least 80% adherent to OAT appointments. Patients actively using drugs of potential abuse while receiving OAT were not excluded. Patients with HIV-1 infection either were naive to antiretroviral therapy or were receiving stable antiretroviral therapy with tenofovir or abacavir; emtricitabine or lamivudine; and dolutegravir, raltegravir, or rilpivirine before enrollment. Planned enrollment included up to 20% of patients with cirrhosis as demonstrated by aspartate aminotransferase (AST)-platelet ratio index combined with FibroTest (BioPredictive), hepatic elastography, or biopsy (Supplement 1).
Study Design and Interventions
C-EDGE CO-STAR (protocol 5172-062) was a randomized, placebo-controlled, multisite, double-blind trial of the once-daily, fixed-dose combination of elbasvir (50 mg) and grazoprevir (100 mg) (Figure 1 and Figure 1 of Supplement 1). Randomization was done centrally through an interactive voice and integrated Web response system, and was stratified according to GT and presence or absence of cirrhosis. Patients were randomly assigned 2:1 to the immediate-treatment group (ITG) (blinded elbasvir-grazoprevir for 12 weeks) or the deferred-treatment group (DTG) (placebo for 12 weeks, followed by 4 weeks of follow-up, then 12 weeks of open-label treatment with elbasvir-grazoprevir). Patients remained blinded until the 16-week visit to allow all safety data through week 12 to be reviewed before unblinding. Patients were followed for 24 weeks after they completed active treatment. In addition, they were eligible to enroll in a 3-year observational study to assess the durability of the sustained virologic response (SVR), incidence of HCV reinfection, and drug use behaviors. Three-year follow-up data were unavailable at the time of this report.
Study Assessments
Hepatitis C virus GT was assessed at enrollment with the Versant HCV Genotype 2.0 Assay (Line Probe Assay; Siemens Healthcare). Hepatitis C virus RNA was assessed at baseline; at day 7; every 2 weeks during treatment; and at follow-up weeks 4, 8, 12, and 24 for the ITG and DTG, during both the placebo and active treatment phases, by using COBAS AmpliPrep and COBAS TaqMan HCV 2.0 (Roche) (lower limit of quantitation, 15 IU/mL).
Safety was assessed by monitoring clinical adverse events (AEs) and laboratory values. At screening, assessments included physical examination, electrocardiography, and evaluation of hepatitis B and HIV status. At screening and each study visit, spontaneously reported AEs and laboratory measurements, including complete blood count and chemistry and coagulation panels, were evaluated. Urinalysis was done at baseline and treatment weeks 4, 8, and 12. Nonspecific hepatic laboratory "events of clinical interest" were defined to create a sensitive screen for the presence of potential liver abnormalities. These events were categorized as tier 1 AEs and included the following laboratory abnormalities, which were assessed from the start of study therapy through 14 days after treatment and were not associated with virologic failure: alanine aminotransferase (ALT) or AST levels greater than 500 IU/L, ALT or AST levels greater than 3 times the baseline value and greater than 100 IU/L, or alkaline phosphatase levels greater than 3 times the upper limit of normal. Urine drug screening (UDS) was conducted at each study visit for the following substances: amphetamines, barbiturates, benzodiazepines, buprenorphine, cannabinoids, cocaine, methadone, other opioids, phencyclidine, and propoxyphene.
Study End Points
The primary efficacy end point was the proportion of patients in the ITG achieving an SVR, defined as an HCV RNA level less than the lower limit of quantitation (<15 IU/mL) at 12 weeks after the end of treatment (SVR12). A secondary end point was SVR24 (HCV RNA <15 IU/mL 24 weeks after the end of active treatment). The incidence of clinical and laboratory AEs in ITG patients treated with elbasvir-grazoprevir was compared with that in DTG patients during the placebo phase. Hepatic events of clinical interest were designated as tier 1 AEs and included the first instance of an ALT or AST level greater than 3 times the upper limit of normal and greater than 100 IU/mL, or the first instance of an alkaline phosphatase level greater than 3 times the upper limit of normal. Tier 2 AEs included the proportion of patients with at least 1 AE, a drug-related AE, a serious AE, a serious and drug-related AE, and an AE leading to discontinuation.
Analysis of Viral Resistance and Recurrence
Hepatitis C virus genotyping of the patients who had a virologic recurrence was conducted to determine whether there was a change in GT from baseline. Viral resistance was assessed at baseline, at time of failure, and at all subsequent follow-up time points in patients who met the criteria for virologic failure (HCV RNA >15 IU/mL, measured from 2 separate blood draws within 2 weeks). Hepatitis C virus population sequencing (NS3 and NS5A genes; sensitivity about 25%) was done to assess resistance and to distinguish viral relapse from probable reinfection in patients with viral recurrence (see Supplement 2, for the HCV sequencing analysis method). To assess the possibility of a mixed infection at baseline, ultradeep sequencing was done on the baseline sample with GT-dependent primers of the GT found at recurrence.
Adherence
Study medication was dispensed every 2 weeks. An electronic study medication diary was provided to patients to assess adherence. Patients were asked to enter the time and dose taken daily; they also could program medication reminders.
Statistical Analysis
All patients were analyzed based on their randomized treatment assignment, and all randomly assigned patients were included in the main safety and efficacy analyses, except for 5 patients in the DTG who discontinued treatment during the placebo phase and could not be included in the efficacy evaluation of the DTG while receiving active treatment. Patients who stopped treatment and had not had a relapse before the time of discontinuation were considered as treatment failures. These analyses follow intention-to-treat principles. The protocol (Supplement 2) specified the primary efficacy end point as SVR12 in the ITG, defined as HCV RNA less than 15 IU/mL at 12 weeks after treatment in an analysis that considered patients with reinfection as responders. The more conservative analysis presented here assumed that reinfections were treatment failures, and we provide the other results (reinfections = responders) as ancillary. We calculated 95% CIs for SVR and differences in AE incidence by using the Clopper-Pearson and Miettinen-Nurminen methods, respectively (16, 17).
The study planned to randomly assign 300 patients in a 2:1 ratio to the ITG or DTG. Assuming a response rate of at least 85% in the ITG, the study had greater than 99% power to demonstrate the superiority of SVR12 to the reference rate of 67%, with a 1-sided α level of 2.5% (18). The reference SVR12 rate of 67% was derived at the time this protocol was initiated from the phase 2 trial of sofosbuvir plus peginterferon plus ribavirin in GT1-infected patients with HIV co-infection after adjustments for the expected higher proportion of patients with cirrhosis and improved safety profile in this trial.
Study Oversight
The trial was approved by the institutional review board or independent ethics committee at each participating site and conducted in adherence with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements.
Role of the Funding Source
The sponsor (Merck) funded the study, collected the data, monitored study conduct, and performed the statistical analyses.
RESULTS
Baseline Characteristics
Of 371 patients screened for enrollment, 301 were randomly assigned: 201 to the ITG and 100 to the DTG. Baseline characteristics were similar between the 2 groups (Table 1).
Efficacy
The SVR12 rate was 91.5% (184 of 201 [95% CI, 86.8% to 95.0%]) in the ITG and 89.5% (CI, 81.5% to 94.8%) in the active-phase DTG (Table 2). Although SVR12 was similar in GT1a-, GT1b-, and GT4-infected patients, it was lower in the few patients with GT6 infection (Table 2). In the ITG overall, the SVR12 of 91.5% and the lower bound of the 95% CI both were greater than the historical reference rate of 67%. Of the 17 patients who did not achieve SVR12, 12 had viral recurrence and 5 had nonvirologic reasons for failure (discontinuation due to an AE [n = 1], an administrative reason [n = 1], or loss to follow-up [n = 3]). On the basis of GT assessment, sequencing, and phylogenetic analysis, 7 of the 12 patients with viral recurrence had findings consistent with relapse, and 5 had signs consistent with probable reinfection (Figure 3 of Supplement 1). When patients with probable reinfection were assumed to have a response, SVR12 was 94.0% (189 of 201 [CI, 89.8% to 96.9%]). At 24 weeks, 2 additional relapses were identified and 12 more patients were lost to follow-up (Table 2). Table 1 of Supplement 1 shows the percentage of patients with an HCV RNA level less than 15 IU/mL in the ITG and in both the placebo and active phases of the DTG.
In the DTG, 100 patients received placebo for the first 12 weeks, and as expected, all patients had detectable HCV RNA at treatment week 16, or day 1 of active treatment. After the 4-week unblinding period, 95 patients started open-label study medication. Of these, 85 (89.5% [CI, 81.5% to 94.8%]) achieved SVR12 in the analysis that considered reinfections to be treatment failures (Table 2). This SVR12 is similar to that in the ITG, and the lower bound of the 95% CI is greater than the 67% reference rate. Of the 10 patients categorized as having failures, 3 had viral recurrence (breakthrough [n = 2] and relapse [n = 1]) and 7 were lost to follow-up. Through week 24, 1 additional patient had viral recurrence, with data consistent with probable reinfection, and another 3 patients were lost to follow-up (Table 2).
Subgroup analyses showed consistently high virologic response rates in several subgroups, including the important subgroups of patients with cirrhosis and those with positive UDS results (Figure 2 of Supplement 1). In the few patients of Asian or other race/ethnicity, as well as those with GT6 infection (all of whom were Asian), SVR12 was lower, with wide CIs.
The proportion of patients with HCV RNA less than 15 IU/mL (intention-to-treat population) at various time points during and after treatment is shown in Table 1 of Supplement 1. A per protocol analysis of SVR12 by GT is defined and provided in Table 2 of Supplement 1.
Adherence
During the initial treatment period, adherence greater than 95% (>79 doses) was reported by 96.5% of patients (192 of 199) in the ITG and 100% of those in the placebo-phase DTG (97 of 97). In the active-phase DTG, adherence greater than 95% was reported in 95.8% of patients (91 of 95).
UDS
More than 50% of patients in each group had positive results on UDS for at least 1 potential drug of abuse, excluding methadone and buprenorphine, at each visit. There were no meaningful differences in drug use between the study groups: day 1 UDS results were positive in 62% of patients in the ITG and 53% in the DTG. Based on UDS results, drug use remained relatively stable throughout treatment (Figure 2). Seventy-eight percent of patients (59 of 76) in the ITG and DTG groups with a positive benzodiazepine UDS result at baseline also had a benzodiazepine listed as a concomitant medication, indicating that most probably were using prescription benzodiazepines. Positive UDS results at baseline or during treatment (2 or more positive UDS results) did not affect adherence or efficacy, regardless of which drug class was positive on UDS (Tables 3 and 4 of Supplement 1).
Reinfections
Eighteen patients had recurrent viremia after active treatment through week 24: 14 in the ITG and 4 in the active-phase DTG. Recurrent viremia was determined to be probable reinfection in 5 of the 14 patients in the ITG (all with recurrent viremia at follow-up week 8) and 1 patient in the DTG (recurrent viremia at follow-up week 24). Probable reinfection was supported by population sequencing and phylogenetic analysis (Figure 3 of Supplement 1). From the end of treatment through follow-up week 24 for all patients, the incidence of reinfection was 4.6 reinfections (CI, 1.7 to 10.0 reinfections) per 100 person-years (130.6 person-years of follow-up). In 4 of 6 cases of probable reinfection, the HCV GT at failure was determined to differ from that at baseline (Table 4 of Supplement 1). In all 6 cases, phylogenetic analysis determined that the virus at baseline and the one present at recurrence were from distinct lineages (Figure 3 of Supplement 1). Ultradeep sequencing of the baseline samples with the GT-dependent primers based on the viral recurrence sample failed to amplify, indicating that these patients acquired a new virus and did not have a mixed infection at baseline. Of note, in 3 of the 6 cases, recurrent viremia was transient, with subsequent HCV RNA after recurrence undetectable. In 4 of 6 probable cases of reinfection, the patients tested positive for opioids other than OAT (Table 5 of Supplement 1).
Viral Resistance
Baseline NS3 RAVs were detected via population sequencing in 43.0% of patients with GT1a infection (64 of 149) and 10.3% with GT1b infection (3 of 29). Of the NS3 RAVs known to confer a greater than 5-fold decrease in grazoprevir potency, D168A was detected in only 1 GT1a-infected patient, who subsequently achieved SVR12; none was detected in any GT1b-infected patient. Baseline NS5A RAVs were detected in only 2% of GT1a-infected patients (3 of 150) and in 10.3% of GT1b-infected patients (3 of 29). All 3 patients with GT1a infection harbored M28V (2 achieved SVR12), and all 3 with GT1b infection harbored Y93H (all achieved SVR12). Among patients with GT1 infection, SVR12 was achieved by 98.2% (109 of 111) of those without and 95.5% (64 of 67) of those with detectable NS3 RAVs. Regarding GT1-infected patients without and those with detectable baseline NS5A RAVs, SVR12 was achieved by 97.7% (169 of 173) and 83.3% (5 of 6), respectively. No GT4-infected patients had detectable NS3 RAVs at baseline, and 100% of GT4-infected patients with baseline NS5A RAVs (3 of 3) achieved SVR12. All 5 patients with GT6 infection had baseline NS3 RAVs, and 60% of them (3 of 5) achieved SVR12; 75% of those with baseline NS5A RAVs (3 of 4) achieved SVR12, and the 1 patient without a baseline RAV did not achieve SVR12. For specific NS3 and NS5A RAVs detected, see Supplement 1.
Safety
The safety profile of elbasvir-grazoprevir in the ITG was generally similar to that of placebo in the DTG (Table 3), with low frequencies of serious AEs (3.5% in the ITG and 4% in the DTG) and discontinuations due to AEs (<1% in the ITG and 1% in the DTG). Of the 201 ITG patients, 1 discontinued treatment because of a drug-related AE: moderate-intensity abdominal pain at day 13. Of the 100 DTG patients, 1 discontinued treatment during the placebo phase after being hospitalized with pneumonia and developing acute respiratory distress syndrome; the patient subsequently died. No ITG patient met criteria for any hepatic event of clinical interest, whereas 2 DTG patients receiving placebo met criteria for ALT or AST levels greater than 3 times the baseline value and greater than 100 IU/mL. Eleven patients had serious AEs during the treatment period and the first 14 days of follow-up: 7 in the ITG (7 of 201 [3.5%]) and 4 in the DTG (4 of 100 [4.0%]). One serious AE in each treatment group was considered drug related. The most common AEs reported were fatigue, headache, nausea, and diarrhea (Table 3).
Discussion
This study demonstrated high efficacy and safety of 12 weeks of elbasvir-grazoprevir in PWID with HCV infection who were receiving OAT. To our knowledge, this is the first trial of DAA agents for HCV treatment that did not specifically exclude patients who were actively using drugs with high abuse potential. Previously, interferon-free HCV therapy trials excluded patients with illicit drug use because of concerns regarding visit and medication adherence and interactions with nonprescription drugs. The SVR12 rates observed in this trial are similar to the results of the C-EDGE Treatment-Naive and C-EDGE Co-Infection trials, which excluded patients currently using drugs (14, 15).
Subgroup analysis showed comparable response rates among patients with GT1a, GT1b, and GT4 infections. In the few patients with GT6 infection, the SVR12 rate was much lower than in those with any other GT. The GT6 strain is found primarily in southern China, Hong Kong, Taiwan, and Southeast Asia. Of the 9 GT6-infected patients enrolled, 5 in the ITG and 3 in the DTG were from Taiwan, and 1 patient in the DTG was from Australia. Two of the 5 GT6-infected patients with viral recurrence had findings consistent with probable reinfection.
Despite reservations concerning HCV treatment in patients who use drugs, this study demonstrated excellent treatment adherence in a population receiving stable OAT despite ongoing drug use among most participants. Treatment adherence in this study was similar to that in other interferon-free DAA trials in the general HCV population, which excluded patients with illicit drug use. Drug use also did not seem to affect elbasvir-grazoprevir efficacy. These outcomes support the previously reported evidence from interferon-containing regimen studies that people who use drugs can achieve HCV treatment outcomes similar to those of the general HCV population (19). In the United States, most states restrict Medicaid-based access to sofosbuvir-based therapy to patients without evidence of ongoing illicit drug use (20). The results of this study suggest that access to interferon-free DAA therapy should be expanded to patients receiving OAT, including the removal of drug use-based restrictions, providing further support for international guidelines (21-23).
Of considerable clinical and public health interest is the potential effect of HCV reinfection after successful treatment of high-risk populations, including PWID (24, 25). High levels of HCV reinfection might compromise benefit from both the individual patient and public health perspectives. Preliminary data from this study indicate that HCV reinfection in the early posttreatment period (to 24 weeks) may occur, with 6 cases of probable HCV reinfection detected, 3 of which were identified at 1 clinical site. The observation that 4 of 6 patients with reinfections had positive results on opioid testing during posttreatment follow-up suggests that injection drug use was the probable source of reinfection. An ongoing extension of this study will evaluate drug use behaviors and the incidence and outcome of HCV reinfection over a 3-year period after treatment. Of interest, 3 of the 6 patients categorized as having HCV reinfection subsequently had undetectable HCV RNA levels without additional HCV treatment, indicating that not all reinfection cases develop viral persistence and drawing attention to the possible role of an augmented HCV-specific immune response after DAA therapy (26, 27). Ultradeep sequencing confirmed that the patients with probable reinfection did not have baseline mixed HCV infection, with potential nonclearance of the nondominant strain.
Resistance-associated variants did not seem to affect efficacy in GT1- or GT4-infected patients, because high SVR rates were achieved in patients with and without NS3 or NS5A RAVS. In consideration of the U.S. Food and Drug Administration's prescribing information, few GT1a-infected patients with baseline NS5A RAVs (n = 3) would meet the treatment guideline for 16 weeks of elbasvir-grazoprevir plus ribavirin.
This study has limitations. First, although illicit drug use was monitored by UDS before and during treatment, we do not have data on injection drug use behaviors. A key focus of the posttreatment observational study is the collection of such data. Second, the adherence monitoring tool may have promoted adherence. Further studies are required to evaluate potential interventions to support adherence in patients who use drugs. Third, these results may not be generalizable to the broader population of people who use drugs, most of whom are not in addiction treatment programs. The generalizability also is limited regarding GTs other than GT1 and GT4; only a few patients with GT6 infection were enrolled, and persons with GT2, GT3 (shown to be highly prevalent in PWID), and GT5 infections were not studied in this trial. Additional evaluation of interferon-free DAA therapy is required in these populations.
In conclusion, these findings document that elbasvir-grazoprevir is effective and well tolerated for treating HCV infection in PWID who are receiving OAT. The risk for reinfection warrants further study.
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