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Randomized trials of ombitasvir/paritaprevir/r+dasabuvir ±
ribavirin
vs telaprevir+pegIFN/ribavirin in adults with genotype 1 HCV - published
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EASL: Abbvie at EASL 2015 - Healthcare Economics, Clinical Trials - (05/11/15)......
EASL: Malachite-I Phase 3b Trial of Ombitasvir/Paritaprevir/r and Dasabuvir ± Ribavirin or Telaprevir + Peginterferon/Ribavirin in Treatment-Naïve Adults With Hc v Genotype 1 - (04/27/15).......
EASL: Malachite-II : Phase 3b Trial of Ombitasvir/Paritaprevir/r and Dasabuvir + Ribavirin or Telaprevir + Peginterferon/Ribavirin in Peginterferon/Ribavirin Treatment-Experienced Adults With Hcv Genotype 1- (04/24/15)
"Significant advances have occurred rapidly in chronic HCV treatment with approval of new DAAs. Studies of DAA regimens in HCV GT1-infected patients have demonstrated higher SVR rates and better tolerability profiles than previously reported for first generation protease inhibitors co-administered with pegIFN/RBV[[2], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]].
However, evidence-based policy centers have highlighted the lack of direct comparative trials demonstrating the efficacy and safety benefits of IFN-free regimens versus pegIFN-containing regimens[19]. This is the first report of head-to-head studies of an all-oral, DAA(OBV/PTV/r+DSV+/-RBV) and a pegIFN-containing(TPV+pegIFN/RBV) regimen that quantitatively compares efficacy and safety benefits in treatment-naïve and treatment-experienced HCV GT1-infected patients.
In HCV GT1-infected patients without cirrhosis, all-oral 12-week combination regimens of OBV/PTV/r+DSV+/-RBV demonstrate SVR12 rates of 97-99%, while 12 weeks of TPV with 24-48 weeks of pegIFN/RBV achieves SVR12 rates of 66-82%. OBV/PTV/r+DSV+/-RBV is associated with generally better mental and physical health and tolerability, with lower rates of severe and serious adverse events and treatment discontinuation due to toxicity, compared to TPV+pegIFN/RBV. OBV/PTV/r+DSV+/-RBV represents a significant advancement over pegIFN-based regimens with first generation protease inhibitors. Taken together, data from the MALACHITE-I and -II studies support the preferential use of IFN-free regimens, where available, for the treatment of HCV infection in this patient population.
As expected based upon results of previous trials, SVR12 rate was numerically higher with OBV/PTV/r+DSV+/-RBV than TPV+pegIFN/RBV regardless of subgenotype or prior treatment status[[2], [9], [10], [11], [12], [13], [17]]. The efficacy difference between the regimens persisted despite numerically higher SVR rates for TPV+pegIFN/RBV than previously reported[[2], [13]]. The higher SVR rates of TPV+pegIFN/RBV may be related to exclusion of cirrhotic patients and absence of black patients, who are less likely to respond to TPV+pegIFN/RBV, and improved management of adverse events associated with TPV-containing regimens by experienced healthcare providers[[2], [17], [20], [21]].
improvement in PCS scores over baseline was observed as early as treatment week 8 in patients on OBV/PTV/r+DSV+/-RBV. Similarly, mean changes in WPAI-HCV scores indicate that patients receiving OBV/PTV/r+DSV+/-RBV were better able to perform work during treatment than patients receiving TPV+pegIFN/RBV. These findings indicating improved health-related quality of life in patients receiving an IFN-free versus an IFN-containing regimen are consistent with previous reports examining regimens separately[[2], [23], [24], [25], [26]].Ó
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Article in Press
Randomized trials of ombitasvir/paritaprevir/r+dasabuvir±ribavirin vs telaprevir+pegIFN/ribavirin in adults with genotype 1 HCV
Journal of Hepatology
Gregory J. Dore, Brian Conway, Yan Luo, Ewa Janczewska, Brygida Knysz, Yan Liu, Adrian Streinu-Cercel, Florin Alexandru Caruntu, Manuela Curescu, Richard Skoien, Wayne Ghesquiere, Wodzimierz Mazur, Alejandro Soza, Francisco Fuster, Susan Greenbloom, Adriana Motoc, Victoria Arama, David Shaw, Istvan Tornai, Joseph Sasadeusz, Olav Dalgard, Danielle Sullivan, Xuan Liu, Mudra Kapoor, Andrew Campbell, Thomas Podsadecki
Abstract
Background & Aims
Telaprevir plus peginterferon/ribavirin(TPV+pegIFN/RBV) remains a therapeutic option for chronic HCV genotype(GT) 1 infection in many regions. We conducted two open-label, phase 3b trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir+/-ribavirin(OBV/PTV/r+DSV+/-RBV) and TPV+pegIFN/RBV.
Methods
Treatment-naïve(MALACHITE-I) or pegIFN/RBV-experienced(MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV +weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12 weeks of TPV+pegIFN+weight-based RBV and 12-36 additional weeks of pegIFN/RBV. Primary endpoint was sustained virologic response 12 weeks post-treatment(SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.
Results
311 treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97%(67/69) and 82%(28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+pegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99%(83/84), 98%(81/83), and 78%(32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+pegIFN/RBV-treated GT1b-infected patients.
Among treatment-experienced patients, SVR12 rates were 99%(100/101) and 66%(31/47) with OBV/PTV/r+DSV+RBV and TPV+pegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV+/-RBV than TPV+pegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, P<0.05) and rates of hemoglobin decline to<10g/dL(0-4% and 34-47%, respectively, P<0.05) were lower for OBV/PTV/r+DSV+/-RBV than TPV+pegIFN/RBV.
Conclusions
Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12-week, multi-targeted OBV/PTV/r+DSV+/-RBV regimens and 66-82% with 24-48 total weeks of TPV+pegIFN/RBV. OBV/PTV/r+DSV+/-RBV was associated with generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.
Introduction
HCV genotype(GT) 1 is the most prevalent HCV GT worldwide[1]. In treatment-naïve GT1-infected patients, triple therapy with the first generation HCV NS3/4A protease inhibitor telaprevir and peginterferon/ribavirin(TPV+pegIFN/RBV) results in sustained virologic response(SVR) rates of approximately 75%[2].
Among patients who previously failed to achieve SVR with pegIFN/RBV therapy, retreatment with TPV+pegIFN/RBV results in SVR rates of 31-84% depending on type of previous response[3]. TPV+pegIFN/RBV therapy requires up to 48 weeks of treatment and results in significant adverse events such as influenza-like symptoms, depression, rash, nausea, and pancytopenia, leading to a high discontinuation rate[[2], [4], [5], [6]]. Many patients are pegIFN-intolerant or have contraindications to pegIFN/RBV therapy that preclude the treatment. New direct-acting antiviral(DAA) therapies that provide a significant advancement in chronic HCV treatment are approved and have replaced TPV/+pegIFN/RBV in many areas. However, TPV+pegIFN/RBV is still widely available and remains the choice treatment in regions including Latin America and Asia. There is a lack of direct comparison between the IFN-free DAA regimens and previous standard of care such as TPV+pegIFN/RBV.
The 3-DAA combination regimen of ombitasvir(OBV), paritaprevir coadministered with ritonavir(PTV/r), and dasabuvir(DSV)+/-RBV is approved for treatment of HCV GT1-infected patients with or without cirrhosis in areas including the United States, Canada, and European Union[7]. OBV is an NS5A inhibitor, PTV is an HCV NS3/4A protease inhibitor, and DSV is a nonnucleoside NS5B polymerase inhibitor[8]. In phase 3 trials, these 3-DAA regimens resulted in SVR12 rates of 95-100% in GT1a- and GT1b-infected treatment-naïve and pegIFN/RBV-experienced, non-cirrhotic and cirrhotic patients; discontinuation due to adverse events occurred in 0-2% of patients[[7], [9], [10], [11], [12], [13]]. Here, we report results of the first trials performing head-to-head comparisons of the safety and efficacy of a pegIFN-free regimen(OBV/PTV/r+DSV+/-RBV) and previous standard of care(TPV+pegIFN/RBV) in treatment-naïve(MALACHITE-I) and treatment-experienced(MALACHITE-II) HCV GT1-infected patients without cirrhosis.
Patients and methods
Study design and participants
MALACHITE-I and MALACHITE-II(Clinicaltrials.gov, NCT01854697 and NCT01854528) are phase 3b, randomized, open-label studies. MALACHITE-I enrolled patients in Australia, Canada, Europe, and South America. MALACHITE-II enrolled patients in Australia, Europe, and South America. Patients were 18-65 years of age with chronic HCV GT1 infection and HCV RNA >10,000 IU/mL. Exclusion criteria included positive hepatitis B surface antigen or anti-HIV antibody screen, and current or past evidence of cirrhosis. In MALACHITE-I, patients with previous use of anti-HCV therapy were excluded. Patients in MALACHITE-II had documentation of adherence with prior pegIFN/RBV therapy with a prior relapse (undetectable HCV RNA at the end of therapy with HCV RNA detectable within 52 weeks of treatment follow-up), partial response(≥2 log10IU/mL reduction in HCV RNA at week 12 of therapy, but HCV RNA detectable at the end of treatment), or null response(<2 log10IU/mL reduction in HCV RNA at week 12 of treatment or<1 log10IU/mL reduction in HCV RNA at week 4 of therapy). Details are in the Supplement.
Ethics committee approval was obtained. Each patient provided written informed consent. The study was conducted in accordance with International Conference on Harmonization guidelines and Declaration of Helsinki ethical principles.
Randomization
In MALACHITE-I, HCV GT1a-infected patients were randomized 2:1 to OBV/PTV/r+DSV+RBV(arm A) or TPV+pegIFN/RBV(arm B). HCV GT1b-infected patients were randomized 2:2:1 to OBV/PTV/r+DSV+RBV(arm C), OBV/PTV/r+DSV(arm D), or TPV+pegIFN/RBV(arm E). Randomization was stratified by IL28B genotype(CC, non-CC). In MALACHITE-II, patients were randomized 2:1 to OBV/PTV/r+DSV+RBV or TPV+pegIFN/RBV. Randomization was stratified by HCV subgenotype(1a, non-1a) and previous response to pegIFN/RBV treatment(relapsers, partial responders, null responders). Random allocation sequences were computer-generated by the sponsor and interactive response technology was utilized for randomization of patients to treatment. Treatment allocation was open-label.
Procedures
Patients received 12 weeks of co-formulated OBV/PTV/r(25mg/150mg/100mg once daily) and DSV(250mg twice daily) with or without weight-based RBV or 12 weeks of TPV(750mg every 8 hours) co-administered with pegIFN(pegIFN alpha-2a, 180μg subcutaneously weekly) and weight-based RBV with an additional 12 or 36 weeks of pegIFN/RBV, depending on virologic response at treatment week 4-12. Total daily dose of RBV was 1000mg for body weight<75kg or 1200mg for body weight≥75kg, administered in 2 daily doses. All patients are being followed for 48 weeks post-treatment. Adherence was assessed by pill and syringe counts and Medication Event Monitoring System(MEMS) caps, which record daily dosing history.
HCV RNA was measured at screening, baseline, and at visits throughout the treatment and post-treatment periods. RNA extraction and determination of plasma HCV RNA levels were performed by a central laboratory. The Roche High Pure System Viral Nucleic Acid Kit was used for RNA extraction. Plasma HCV RNA level determination was by the Roche COBAS TaqMan® real-time reverse transcriptase-PCR assay v2.0(lower limit of detection[LLOD] and lower limit of quantitation[LLOQ] are 15 IU/mL and 25 IU/mL, respectively). On-treatment virologic failure was defined as confirmed HCV RNA≥lower limit of quantitation(LLOQ) after HCV RNA< LLOQ during treatment, a confirmed increase in HCV RNA from nadir >1 log10IU/mL during treatment, or failure to achieve HCV RNA< LLOQ by week 6(OBV/PTV/r+DSV+/-RBV arms) or week 16(TPV+pegIFN/RBV arms). Post-treatment relapse was defined as confirmed HCV RNA≥LLOQ after the end of treatment in a patient who completed treatment with HCV RNA< LLOQ at final treatment visit. Resistance-associated variant(RAV) testing was by population sequencing at baseline and population and/or clonal sequencing at post-baseline.
Patients completed the Short Form-36 version 2 Health Survey(SF-36v2), a self-administered patient-reported outcome(PRO) questionnaire assessing functional health and well-being. Scores are aggregated into a Mental Component Summary(MCS) and a Physical Component Summary(PCS), with higher scores indicating better health. The SF-36v2 was completed at baseline and every 4-12 weeks. Patients also completed a Work Productivity and Activity Impairment questionnaire specific for HCV(WPAI-HCV, details in supplement).
Treatment-emergent adverse events were defined as those occurring between treatment day 1 and 30 days post-treatment. Clinical laboratory testing was performed at screening, baseline, and at visits throughout the treatment and post-treatment periods.
Outcomes
In both studies, the primary endpoint was percentage of patients with SVR12(HCV RNA< LLOQ 12 weeks after the last dose of study drug). Secondary endpoints included mean change from baseline to final treatment visit in the SF-36v2 MCS and PCS and percentages of patients with on-treatment virologic failure and post-treatment relapse.
Statistical analysis
In MALACHITE-I, the primary efficacy analysis tested non-inferiority of SVR12 rates for OBV/PTV/r+DSV+RBV to TPV+pegIFN/RBV in GT1a-infected patients(arm A versus B) and OBV/PTV/r+DSV to TPV+pegIFN/RBV in GT1b-infected patients(arm D versus E). Because a previous trial demonstrated non-inferiority of OBV/PTV/r+DSV to OBV/PTV/r+DSV+RBV in GT1b-infected patients, arm D rather than arm C was compared with arm E in the primary efficacy analysis in GT1b-infected patients per protocol[11]. The percentage of patients achieving SVR12 in each arm and a 2-sided 95% confidence interval(CI) for the difference in SVR12rates(arm A-B, arm D-E) were calculated. If the lower bound of the CI for the difference was above the non-inferiority margin(-10.5%), OBV/PTV/r+DSV+/-RBV was considered non-inferior to TPV+pegIFN/RBV in that subgenotype. In secondary endpoint analyses, mean changes in SF36-v2 MCS and PCS scores from baseline to final treatment visit were compared in arm A versus B and arm D versus E using an ANCOVA model with treatment arm as a factor and baseline SF-36v2 MCS or PCS score, respectively, and region as covariates. SVR12 rates in arm A versus B and arm D versus E were compared using a logistic regression model with treatment arm, baseline log10 HCV RNA level, and IL28B genotype(CC, non-CC) as predictors at the #945=0.05 significance level. If the logistic regression failed to converge, a stratum-adjusted Mantel Haenszel approach was used. Mean changes from baseline to final treatment visit in SF-36v2 MCS and PCS scores were compared between regimens in all treatment-naïve patients (1a- and 1b-infected) in post-hoc analyses.
In MALACHITE-II, the primary efficacy analysis compared the percentage of patients achieving SVR12 between treatment arms using a logistic regression model with treatment arm, baseline log10 HCV RNA level, HCV subgenotype(1a, non-1a), and previous pegIFN/RBV treatment response(relapser, partial responder, null responder) as predictors at the #945=0.05 significance level. In secondary efficacy analyses, mean changes in SF-36v2 MCS and PCS scores from baseline to final treatment visit were compared between treatment arms using an ANCOVA model with treatment arm as a factor and baseline SF36-v2 MCS or PCS score, respectively, and region as covariates.
Each study used a fixed-sequence testing procedure for primary and secondary efficacy analyses to control the type I error rate. In MALACHITE-I, the testing procedure was conducted in GT1a- and 1b-infected patients separately; the order of analyses within each subgenotype was: SVR12 non-inferiority, SF-36v2 MCS, SF-36v2 PCS, and SVR12 superiority. In MALACHITE-II, the order of analyses was SVR12 analysis, SF-36v2 MCS analysis, and SF-36v2 PCS analysis. Details of efficacy endpoint analyses and sample size determination for each study are in the Supplement.
Demographic, efficacy, and safety analyses were on the modified intention-to-treat population, defined as all patients who were randomized and received ≥1 dose of study drug. SAS®(SAS Institute, Inc., Cary, NC) for the UNIX operating system was used for all analyses. All statistical tests and CIs were 2-sided with an #945 level of 0.05. CIs were calculated using normal approximation to the binomial distribution unless the point estimate was 0% or 100%, in which case Wilson score method was used. Frequencies of treatment-emergent adverse events and post-baseline laboratory abnormalities were compared between treatment groups by FisherŐs exact test.
Roles of the funding source
The sponsor contributed to trial design, data analysis and interpretation, and the decision to submit this report for publication. The first draft of this report was written by a sponsor-employed medical writer and revised critically by all authors. All authors had full access to the data. The corresponding author had final responsibility for the decision to submit the manuscript for publication.
Results
In the treatment-naïve study, 404 patients were screened; 311 were randomized and received study drug(Fig. 1, Supplemental Fig. 1). In the treatment-experienced study, 222 patients were screened, 154 were randomized, and 148 received study drug (Fig. 1, Supplemental Fig. 2). Reasons for exclusion are in Supplemental Tables 1&2. Patient characteristics are in Table 1. In each study the majority of patients(≥95% receiving OBV/PTV/r+DSV+/-RBV and ≥86% receiving TPV+pegIFN/RBV) were adherent with planned dosing of each study drug. Among 75 treatment-naïve patients receiving TPV+pegIFN/RBV, 59 received 24 weeks of pegIFN/RBV while 16 received 48 weeks. Among 47 treatment-experienced patients receiving TPV+pegIFN/RBV, 10 received a 24-week regimen(all prior relapsers) and 37 received a 48-week regimen(2 relapsers, 12 partial responders, 23 null responders).
Fig. 2
SVR12 rates. OBV, ombitasvir; PTV, paritaprevir; DSV, dasabuvir; RBV, ribavirin; TPV, telaprevir; pegIFN, peginterferon, GT, genotype. Bars indicate 95% confidence intervals. P value shown for arm C versus E is based on logistic regression. P value shown for arm D vs E is based on a stratum-adjusted Mantel Haenszel approach. SVR12 rate was not compared between arms A and B by logistic regression analysis as the fixed-sequence testing procedure concluded with the failure of the SF-36v2 MCS analysis in GT1a-infected patients. In treatment-experienced patients P value is based on a logistic regression.
Efficacy
Treatment-naïve patients(MALACHITE-I)
Among HCV GT1a-infected patients, 97%(67/69)(95% CI 93-100) receiving OBV/PTV/r+DSV+RBV and 82%(28/34)(95% CI 69-96) receiving TPV+pegIFN/RBV achieved SVR12(Fig. 2). The SVR12 rate difference of 15%(95% CI 1-28) demonstrated protocol-defined non-inferiority of OBV/PTV/r+DSV+RBV to TPV+pegIFN/RBV in GT1a-infected patients. Among HCV GT1b-infected patients, 98%(81/83)(95% CI 94-100) receiving OBV/PTV/r+DSV and 78%(32/41)(95% CI 66-91) receiving TPV+pegIFN/RBV achieved SVR12. The difference of 20%(95% CI 6-33) demonstrated protocol-defined non-inferiority of OBV/PTV/r+DSV to TPV+pegIFN/RBV in GT1b-infected patients. The SVR12 rate for OBV/PTV/r+DSV was also superior to TPV+pegIFN/RBV(P=0.005). The SVR12 rate of 99%(83/84)(95% CI 97-100) in OBV/PTV/r+DSV+RBV-treated, GT1b-infected patients was non-inferior(difference=21%, 95% CI 8-34%) and superior(P=0.002) to that for TPV+pegIFN/RBV.
Four of 236 patients(2%) receiving OBV/PTV/r+DSV+/-RBV versus 9 of 75 patients(12%) receiving TPV+pegIFN/RBV met protocol-specified criteria for on-treatment virologic failure or post-treatment relapse(Table 2). Available data showed the 3 patients receiving OBV/PTV/r+DSV+/-RBV with on-treatment virologic failure were adherent to study drugs. At the time of failure, these patients had variants at resistance-associated positions in the amino acid sequences for NS3, NS5A, and/or NS5B that were not present at baseline. One GT1b-infected patient receiving OBV/PTV/r+DSV+RBV met the criteria for post-treatment relapse but had GT2a infection, consistent with reinfection. Most patients in the TPV+pegIFN/RBV arm who experienced virologic failure had RAVs present in NS3 at the time of failure.
Treatment-experienced patients(MALACHITE-II)
A total of 100 of 101 patients receiving OBV/PTV/r+DSV+RBV achieved SVR12(99%, 95% CI 97-100%)(Fig. 2). Thirty-one of 47 patients receiving TPV+pegIFN/RBV achieved SVR12(66%, 95% CI 53-79%). SVR12 rate was significantly different between treatment arms(odds ratio=54, 95% CI 7-430; P<0.001). SVR12 rates were numerically higher with OBV/PTV/r+DSV+RBV than TPV+pegIFN/RBV in subgroups of patients based on genotype or prior treatment experience(Supplemental Table 4). SVR12 rates were 100%(49/49) and 57%(13/23) in prior null responders receiving OBV/PTV/r+DSV+RBV and TPV+pegIFN/RBV, respectively.
There were no on-treatment failures or post-treatment relapses with OBV/PTV/r+DSV+RBV; the 1 patient not achieving SVR12 had missing data, but had HCV RNA< LLOQ at the end of treatment(Table 2). Among patients receiving TPV+pegIFN/RBV, 23% met protocol-specified criteria for virologic failure. Most patients receiving TPV+pegIFN/RBV who experienced virologic failure had RAVs present in NS3 at the time of failure.
Patient-Reported Outcomes(PROs)
Mean changes from baseline to final treatment and post-treatment week 12 visit in SF-36v2 MCS and PCS in treatment-naïve and treatment-experienced patients are in Fig. 3. When GT1a- and GT1b-infected treatment-naïve patients were analyzed separately, mean changes at the final treatment visit in MCS and PCS with OBV/PTV/r+DSV+/-RBV versus TPV+pegIFN/RBV were significantly different in GT1b-infected patients(P<0.05). Mean change in MCS was not significantly different for OBV/PTV/r+DSV+RBV versus TPV+pegIFN/RBV in GT1a-infected patients, preventing statistical testing of subsequent secondary endpoints in GT1a-infected patients per protocol. In a post-hoc analysis, mean changes at the final treatment visit in SF-36v2 MCS and PCS were significantly different between patients receiving OBV/PTV/r+DSV+/-RBV and TPV+pegIFN/RBV in the overall population of treatment-naïve patients(P<0.05). Similarly, mean changes in SF-36v2 MCS and PCS were significantly different between patients receiving OBV/PTV/r+DSV+/-RBV and TPV+pegIFN/RBV in the overall population of treatment-experienced patients(P<0.05). Overall, mean changes at post-treatment week 12 in MCS and PCS were not significantly different between OBV/PTV/r+DSV+/-RBV and TPV+pegIFN/RBV in treatment-naïve or -experienced patients. Across the two studies, 46% and 58% of patients receiving OBV/PTV/r+DSV+/-RBV showed numerical improvement over baseline at final treatment visit in MCS and PCS, respectively; 27% and 22% of patients receiving TPV+pegIFN/RBV showed numerical improvement in MCS and PCS, respectively.
Overall, the difference between the two regimens in the changes from baseline in MCS and PCS throughout the treatment and post-treatment periods in both treatment-naïve and treatment-experienced patients favored the OBV/PTV/r+DSV+/-RBV regimen(Fig. 4). Comparable differences in WPAI-HCV between regimens were observed(Supplemental Fig. 3).
Fig. 3
Mean changes in SF-36v2 mental and physical component summary scores from baseline to end of treatment and to post-treatment week 12. OBV, ombitasvir; PTV, paritaprevir; DSV, dasabuvir; RBV, ribavirin; TPV, telaprevir; pegIFN, peginterferon; BL, baseline; EOT, end of treatment (final treatment visit); PTW12, post-treatment week 12. Bars show mean scores at baseline (determined for patients with end of treatment data), end of treatment, and post-treatment week 12. Numbers over bars are mean changes (standard deviation). Mean changes and standard deviations for post-treatment week 12 are based on the baseline for patients who had post-treatment week 12 data. Thus, in some cases, this baseline differs from the baseline presented (for patients with end of treatment data), but does not impact the interpretation. Analyses in all treatment-naïve patients were not pre-specified. Mean change in PCS was not compared between arms A and B by logistic regression analysis as the fixed-sequence testing procedure concluded with the failure of the SF-36v2 MCS analysis in GT1a-infected patients. indicates P<0.05, P<0.01 and P<0.001, respectively, for comparison to TPV+pegIFN/RBV arm.
Fig. 4
Mean changes from baseline during the treatment and post-treatment periods in SF-36v2 mental and physical component summary scores. OBV, ombitasvir; PTV, paritaprevir; DSV, dasabuvir; RBV, ribavirin; TPV, telaprevir; pegIFN, peginterferon; BL, baseline; W, treatment week; PTW, post-treatment week.
Adverse events
Safety data were combined according to treatment regimen within each study. Adverse event frequency was lower with OBV/PTV/r+DSV+/-RBV versus TPV+pegIFN/RBV(P<0.05)(Table 3). The majority of treatment-emergent adverse events observed were mild with OBV/PTV/r+DSV+/-RBV and moderate with TPV+pegIFN/RBV. Notably, rash occurred less frequently with OBV/PTV/r+DSV+/-RBV versus TPV+pegIFN/RBV(P<0.05). One treatment-naïve patient receiving TPV+pegIFN/RBV but none receiving OBV/PTV/r+DSV+/-RBV experienced toxic skin eruption. The rates of adverse events commonly associated with RBV, such as anemia, pruritus, rash, nausea, and asthenia, were lower with OBV/PTV/r+DSV+RBV versus TPV+pegIFN/RBV(P<0.05). Depression was also less frequent with OBV/PTV/r+DSV+/-RBV than TPV+pegIFN/RBV(0-2% versus 6-9%, P<0.05). In treatment-naïve GT1b-infected patients, the frequencies of these adverse events were numerically lower with OBV/PTV/r+DSV than OBV/PTV/r+DSV+RBV, consistent with their known association with RBV.
In both studies the rates of serious adverse events and treatment discontinuation due to adverse events were lower with OBV/PTV/r+DSV+/-RBV versus TPV+pegIFN/RBV(P<0.05). Serious adverse events occurred in 2 patients receiving OBV/PTV/r+DSV+RBV(one treatment-naïve[1%] and one treatment-experienced[1%]), no patient receiving OBV/PTV/r+DSV, and 14 patients receiving TPV+pegIFN/RBV(9 treatment-naïve[12%], 5 treatment-experienced[11%]). One treatment-naïve patient(1%) receiving OBV/PTV/r+DSV+RBV and no patient receiving OBV/PTV/r+DSV discontinued treatment due to adverse events, versus 6 treatment-naïve patients(8%) and 5 treatment-experienced patients(11%) receiving TPV+pegIFN/RBV. Details are in Supplemental Tables 5&6.
Decreased hemoglobin levels
Among treatment-naïve patients, 3 receiving OBV/PTV/r+DSV+RBV(2%), none receiving OBV/PTV/r+DSV, and 35 receivingTPV+pegIFN/RBV(47%) had hemoglobin declines to<10g/dL(P<0.05, versus TPV+pegIFN/RBV)(Table 3). Among treatment-experienced patients, 4 receiving OBV/PTV/r+DSV+RBV(4%) versus 16 receiving TPV+pegIFN/RBV(34%) had hemoglobin declines to<10g/dL(P<0.05). Five treatment-naïve patients(3%) and 2 treatment-experienced patients(2%) receiving OBV/PTV/r+DSV+RBV modified RBV dose due to anemia; all achieved SVR12. Thirty-two treatment-naïve patients(43%) and 15 treatment-experienced patients(32%) receiving TPV+pegIFN/RBV modified RBV dose due to anemia; SVR12 rates were 84% and 93% in treatment-naïve and treatment-experienced patients, respectively. Twelve patients receiving TPV+pegIFN/RBV(6 treatment-naïve, 6 treatment-experienced) had a blood transfusion, and one treatment-experienced patient received erythropoietin.
Other laboratory abnormalities
No patient discontinued OBV/PTV/r+DSV+/-RBV due to laboratory abnormalities. Six treatment-naïve patients(4%) and one treatment-experienced patient(1%) receiving OBV/PTV/r+DSV+RBV had total bilirubin elevations>3X the upper limit of normal(ULN)(Table 3). These elevations were comprised mainly of indirect bilirubin, peaked at week 1 of treatment, and normalized or stabilized thereafter. Total bilirubin elevations>3X ULN occurred in 2 treatment-naive patients(3%) and 1 treatment-experienced patient(2%) receiving TPV+pegIFN/RBV.
One treatment-naïve patient(1%) receiving OBV/PTV/r+DSV+RBV had isolated elevations of aminotransferases>5X ULN within the first month of treatment that led to study drug interruption for 14 days. Aminotransferase levels normalized by post-treatment week 4. The patient had no other liver function test abnormalities, and achieved SVR12. One(1.0%) treatment-experienced patient receiving OBV/PTV/r+DSV+RBV and 3(6.4%) receiving TPV+pegIFN/RBV had at least one alanine aminotransferase measurement>5X ULN. In the patient receiving OBV/PTV/r+DSV+RBV this elevation was concurrent with an elevation in aspartate aminotransferase>5X ULN. These values declined without treatment interruption or discontinuation and normalized at post-treatment week 4; this patient had no clinically significant bilirubin elevation.
Discussion
Significant advances have occurred rapidly in chronic HCV treatment with approval of new DAAs. Studies of DAA regimens in HCV GT1-infected patients have demonstrated higher SVR rates and better tolerability profiles than previously reported for first generation protease inhibitors co-administered with pegIFN/RBV[[2], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]]. However, evidence-based policy centers have highlighted the lack of direct comparative trials demonstrating the efficacy and safety benefits of IFN-free regimens versus pegIFN-containing regimens[19]. This is the first report of head-to-head studies of an all-oral, DAA(OBV/PTV/r+DSV+/-RBV) and a pegIFN-containing(TPV+pegIFN/RBV) regimen that quantitatively compares efficacy and safety benefits in treatment-naïve and treatment-experienced HCV GT1-infected patients.
As expected based upon results of previous trials, SVR12 rate was numerically higher with OBV/PTV/r+DSV+/-RBV than TPV+pegIFN/RBV regardless of subgenotype or prior treatment status[[2], [9], [10], [11], [12], [13], [17]]. The efficacy difference between the regimens persisted despite numerically higher SVR rates for TPV+pegIFN/RBV than previously reported[[2], [13]]. The higher SVR rates of TPV+pegIFN/RBV may be related to exclusion of cirrhotic patients and absence of black patients, who are less likely to respond to TPV+pegIFN/RBV, and improved management of adverse events associated with TPV-containing regimens by experienced healthcare providers[[2], [17], [20], [21]].
PRO assessments provide patientsŐ perspective on the impact of treatment on daily life and work. PROs were evaluated using the SF-36v2 and WPAI-HCV instruments, which are standard PRO tools for general diseased and HCV-infected populations, respectively. In general, mean changes in SF-36v2 MCS and PCS scores from baseline were numerically or significantly different between OBV/PTV/r+DSV+/-RBV and TPV+pegIFN/RBV throughout the treatment period, with the difference indicating better mental and physical health in patients receiving OBV/PTV/r+DSV+/-RBV. Decreases in health-related quality of life through treatment week 12 and return to baseline after treatment have previously been reported for patients receiving TPV+pegIFN/RBV[22]. The largest differences in mental and physical health between the two regimens were observed at treatment week 12. SF-36v2 MCS in patients on all regimens and PCS scores in patients on TPV+pegIFN/RBV were near baseline levels by post-treatment week 12; improvement in PCS scores over baseline was observed as early as treatment week 8 in patients on OBV/PTV/r+DSV+/-RBV. Similarly, mean changes in WPAI-HCV scores indicate that patients receiving OBV/PTV/r+DSV+/-RBV were better able to perform work during treatment than patients receiving TPV+pegIFN/RBV. These findings indicating improved health-related quality of life in patients receiving an IFN-free versus an IFN-containing regimen are consistent with previous reports examining regimens separately[[2], [23], [24], [25], [26]].
While PROs were evaluated using standard PRO tools for this population, these analyses had limitations. The impact of knowledge of treatment efficacy on PRO measures is not known, as there were no specific instructions to investigators on informing patients of their virologic response before PRO questionnaire completion. Furthermore, the studies were not specifically designed to assess the potential impact of physiological differences(e.g. anemia associated with IFN or RBV use) on changes in PRO measures.
Safety data support better tolerability of OBV/PTV/r+DSV+/-RBV than TPV+pegIFN/RBV regardless of subgenotype or prior treatment status. Across groups of patients receiving OBV/PTV/r+DSV+/-RBV there were up to 4 adverse events with a frequency of>10% while across groups of patients receiving TPV+pegIFN/RBV there were up to 24 adverse events with a frequency of>10%, demonstrating the contrast in breadth of symptoms experienced by patients on the regimens. While the frequency of common adverse events was numerically higher with OBV/PTV/r+DSV+RBV than the RBV-free regimen in treatment-naïve GT1b-infected patients, OBV/PTV/r+DSV+RBV was well-tolerated and discontinuation due to adverse events was infrequent, consistent with previous reports[11].
The adverse event profile of RBV is being redefined in the era of pegIFN-free therapies. The numerically higher frequencies of adverse events such as anemia, nausea, pruritus, rash, insomnia, and asthenia in treatment-naïve patients receiving OBV/PTV/r+DSV+RBV versus the RBV-free regimen suggest that these are more likely associated with RBV use. Rates and severity of these adverse events were significantly lower with OBV/PTV/r+DSV+RBV versus TPV+pegIFN/RBV. Hemoglobin declines were less frequent and severe with OBV/PTV/r+DSV+RBV than TPV+pegIFN/RBV. The greater frequency and severity of anemia with the pegIFN-containing regimen may reflect bone marrow suppressant effects of IFN that prevent compensatory reticulocytosis[[27], [28]]. Hemoglobin declines in patients receiving OBV/PTV/r+DSV+RBV were managed by RBV dose modification alone while some patients receiving TPV+pegIFN required blood transfusion or erythropoietin. The high SVR12 rates among patients who reduced RBV are consistent with previous reports indicating RBV reduction does not impact efficacy of either regimen[[9], [10], [11], [13], [29]].
The most common laboratory abnormality with OBV/PTV/r+DSV+/-RBV was a transient elevation in bilirubin(predominantly indirect bilirubin), consistent with the known roles of PTV as an inhibitor of the OATP1B1 and OATP1B3 transporters and RBV-induced hemolysis[[18], [30]]. Alanine aminotransferase and bilirubin elevations observed with OBV/PTV/r+DSV+/-RBV were infrequent and generally isolated abnormalities that recovered without drug discontinuation, consistent with previous studies[[10], [11], [12]].
The trials were designed as open-label because the well-known adverse event profile of TPV+pegIFN/RBV prevented effective blinding of investigators and patients. While the open-label design may have influenced reporting of adverse events, it would not affect objective endpoints such as SVR12 and laboratory abnormalities. Adverse event profiles were consistent with those reported in blinded trials[[2], [10], [11], [13], [17]]. Because patients in the United States had significant access to all-oral DAA therapies through clinical trials at the time of enrollment, United States sites were not included. The trials were limited by the exclusion of cirrhotic patients. The safety and efficacy of OBV/PTV/r+DSV+RBV was previously characterized in a phase 3 trial dedicated to patients with compensated cirrhosis(N=380); 12-24 weeks of treatment achieved SVR rates of 92-97%[12]. In cirrhotic patients, TPV+pegIFN/RBV therapy generally has a total duration of 48 weeks with reduced efficacy compared to non-cirrhotic patients[[2], [3], [17]]. Therefore, exclusion of cirrhotic patients should not change the general conclusions.
The treatment-experienced study was limited by the low number of GT1a-infected patients enrolled. This resulted from the dominance of GT1b infection in Europe, one of the major study locations. However, 96%(166/173) of GT1a-infected patients receiving 12 weeks of OBV/PTV/r+DSV+RBV achieved SVR12 in a phase 3 trial in non-cirrhotic, treatment-experienced patients in Australia, North America, and Europe[13]. Because phase 2 data were available for treatment-naïve but not treatment-experienced GT1b-infected patients receiving OBV/PTV/r+DSV without RBV at the time of study design, the treatment-experienced study did not include an arm with GT1b-infected patients receiving the RBV-free regimen[31]. More recently available phase 3 data demonstrated SVR12 rates of 100%(91/91) in treatment-experienced, GT1b-infected patients receiving a RBV-free OBV/PTV/r+DSV regimen[9].
In HCV GT1-infected patients without cirrhosis, all-oral 12-week combination regimens of OBV/PTV/r+DSV+/-RBV demonstrate SVR12 rates of 97-99%, while 12 weeks of TPV with 24-48 weeks of pegIFN/RBV achieves SVR12 rates of 66-82%. OBV/PTV/r+DSV+/-RBV is associated with generally better mental and physical health and tolerability, with lower rates of severe and serious adverse events and treatment discontinuation due to toxicity, compared to TPV+pegIFN/RBV. OBV/PTV/r+DSV+/-RBV represents a significant advancement over pegIFN-based regimens with first generation protease inhibitors. Taken together, data from the MALACHITE-I and -II studies support the preferential use of IFN-free regimens, where available, for the treatment of HCV infection in this patient population.
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