Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1.

BACKGROUND: An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin. METHODS: In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks. RESULTS: Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events. CONCLUSIONS: In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.).

Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.

BACKGROUND: The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B. RESULTS: A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P<0.05 for all comparisons). Reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients in group A, whereas grade 1 reductions occurred in 2.5% of the patients in group B. CONCLUSIONS: In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.).

ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.

BACKGROUND: Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis. METHODS: We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [CI], 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%. RESULTS: A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events. CONCLUSIONS: In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.).

Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.

BACKGROUND: In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin. METHODS: We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin. RESULTS: A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively. CONCLUSIONS: Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415.).

ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV.

BACKGROUND: The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS: The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

Efficacy of Direct-Acting Antiviral Combination for Patients With Hepatitis C Virus Genotype 1 Infection and Severe Renal Impairment or End-Stage Renal Disease.

BACKGROUND & AIMS: Although hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct-acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD). METHODS: We performed a single-arm, multicenter study of treatment-naïve adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15-30 mL/min/1.73 m(2)) or stage 5 (estimated glomerular filtration rate, <15 mL/min/1.73 m(2) or requiring hemodialysis). Twenty patients were given ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir for 12 weeks. Patients with HCV genotype 1a infections also received ribavirin (n = 13), whereas those with genotype 1b infection did not (n = 7). The primary end point was sustained virologic response (serum HCV RNA <25 IU/mL) 12 weeks after treatment ended (SVR12). We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. RESULTS: All 20 patients completed 12 weeks of treatment. Eighteen of the 20 patients achieved SVR12 (90%; 95% confidence interval: 69.9-97.2). One patient death after the end of the treatment (unrelated to the treatment) and 1 relapse accounted for the 2 non-SVRs. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an AE. Four patients experienced serious AEs; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients due to anemia; 4 received erythropoietin. No blood transfusions were performed. CONCLUSIONS: In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088.

Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials.

AIM: The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. METHODS: Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations. RESULTS: The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin (n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. CONCLUSION: The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen.

Evaluation of Drug-Drug Interactions Between Hepatitis C Antiviral Agents Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and HIV-1 Protease Inhibitors.

BACKGROUND: Guidelines for the treatment of human immunodeficiency virus (HIV) infection consistently recommend initiation of antiretroviral therapy in patients with hepatitis C virus (HCV)/HIV-1 coinfection. Therefore, potential drug interactions between antiretroviral drugs and HCV direct-acting antiviral agents (DAAs) must be carefully considered. The objective of this investigation was to evaluate the compatibility of a novel combination of DAAs (the 3D regimen) with commonly prescribed HIV-1 protease inhibitors (PIs). METHODS: Five phase 1, multiple-dose, open-label pharmacokinetic studies were performed in 144 healthy volunteers. Participants in each study were randomly assigned 1:1 into cohorts assessing the effects of the steady-state 3D regimen on steady-state HIV-1 PIs or vice versa. The 3D regimen comprised ombitasvir (25 mg once daily), paritaprevir/ritonavir (150/100 mg once daily), and dasabuvir (250 or 400 mg twice daily). The HIV-1 PIs assessed included atazanavir, darunavir, and lopinavir (administered with ritonavir). Safety, tolerability, and pharmacokinetic parameters were assessed to evaluate the compatibility of the drug regimens. RESULTS: Coadministration of the 3D regimen with the evaluated HIV-1 PIs was generally well tolerated in healthy volunteers. Morning administration of atazanavir (300 mg once daily) and darunavir regimens exhibited no clinically meaningful drug interactions with the 3D regimen. However, owing to higher paritaprevir and/or ritonavir exposures, evening administration of atazanavir (300 mg) plus ritonavir (100 mg) or lopinavir/ritonavir (800/200 mg) with the 3D regimen is not recommended. CONCLUSIONS: The 3D regimen can be coadministered with morning atazanavir and darunavir regimens. However, evening atazanavir plus ritonavir and lopinavir/ritonavir regimens are not recommended in combination with the 3D regimen.

Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: The MALACHITE-I/II trials.

BACKGROUND & AIMS: Telaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb 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 12weeks of TPV+PegIFN+weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies. RESULTS: Three hundred eleven 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 12week, 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 a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.

Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.

The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.