Daclatasvir/asunaprevir/beclabuvir, all-oral, fixed-dose combination for patients with chronic hepatitis C virus genotype 1.

BACKGROUND AND AIM: This multinational (Taiwan, South Korea, Russia) phase 3 study evaluated the all-oral, ribavirin-free, fixed-dose combination (DCV-TRIO) of daclatasvir (NS5A inhibitor) 30 mg, asunaprevir (NS3 inhibitor) 200 mg, and beclabuvir (NS5B inhibitor) 75 mg, in patients with chronic hepatitis C virus genotype-1 infection, with or without compensated cirrhosis. METHODS: UNITY-4 (NCT02170727) was an open-label, two-cohort study in which 169 patients, treatment-naive (n = 138) or treatment-experienced (n = 31), received twice-daily DCV-TRIO for 12 weeks with 24 weeks of post-treatment follow-up. The primary efficacy end point was sustained virologic response at post-treatment week 12 (SVR12) in treatment-naive patients. RESULTS: Eighty-eight (52%) patients were men, 81 (48%) Taiwanese, 78 (46%) Korean, and 10 (6%) Russian; 23 (14%) had compensated cirrhosis, and 52 (31%) were IL28B (rs1297860) non-CC genotype. Baseline resistance-associated NS5A polymorphisms (L31 and/or Y93) were detected in 25/165 (15%) patients with available genotype-1 sequencing data. SVR12 was achieved by 98.6% (136/138; 95% confidence interval: 94.9-99.8%) of treatment-naive and 100% (31/31; 95% confidence interval: 88.8-100%) of treatment-experienced patients. Both virologic failures were found to be infected with hepatitis C virus genotype-6g; 100% SVR12 was observed for genotype-1a (n = 8) and genotype-1b (n = 157). Two patients experienced serious adverse events. Eight (5%) patients experienced reversible grade 3/4 alanine aminotransferase or aspartate aminotransferase elevations, leading to discontinuation in four (2%); all achieved SVR12. There were no grade 3/4 total bilirubin increases and no deaths. CONCLUSIONS: Twelve weeks of DCV-TRIO was well tolerated and provided 100% SVR12 in treatment-naive and treatment-experienced patients with genotype-1 infection, with or without cirrhosis, including those with baseline NS5A-L31 or NS5A-Y93 resistance-associated substitutions.

Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study).

BACKGROUND & AIMS: The phase 2, FOURward study (NCT02175966) investigated short-duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1. METHODS: Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice-daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks. RESULTS: Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 106  IU/mL). Most patients had undetectable HCV-RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV-RNA (<2 million IU/mL, 71% [n=5/7]; ≥2 million IU/mL, 33% [n=7/21]). None of the 16 non-SVR12 patients had NS3 or NS5B resistance-associated substitutions (RAS) detected at failure. All 15 patients retreated with DCV-TRIO + RBV for 12 weeks achieved SVR12. All regimens were well tolerated. CONCLUSIONS: Short-duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype-1 infection and high baseline viraemia. Non-SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV-TRIO + RBV for 12 weeks led to SVR in all patients.

Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection.

BACKGROUND: DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies. METHODS: In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b). RESULTS: SVR12 rates ≥95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged ≥65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4 weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred. CONCLUSION: SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles.

Daclatasvir and Peginterferon/Ribavirin for Black/African-American and Latino Patients with HCV infection.

 Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection. MATERIAL AND METHODS: In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate. RESULTS: Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log10) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (AEs) occurred in 9 black/AA and 6 Latino patients. CONCLUSION: SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% CIs were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1.

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients. METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.

A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin.

BACKGROUND AND AIM: Daclatasvir plus asunaprevir has demonstrated efficacy and safety in patients with chronic hepatitis C virus genotype 1b infection. This study focused on evaluating daclatasvir plus asunaprevir in interferon (±ribavirin)-ineligible or -intolerant Asian patients with genotype 1b infection from mainland China, Korea, and Taiwan. METHODS: Interferon (±ribavirin)-ineligible and -intolerant patients with genotype 1b infection received daclatasvir 60 mg tablets once daily plus asunaprevir 100 mg soft capsules twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment week 24 (SVR24). RESULTS: Of the 159 patients treated, 89.3% were Chinese, 65.4% were female, and 73.6% were interferon-intolerant. Cirrhosis was present in 32.7% of patients, and 40.3% had IL28B non-CC genotypes. SVR24 was achieved by 145/159 (91.2%) patients (100% concordance with SVR12) and was similarly high in cirrhotic patients (47/52, 90.4%). SVR24 was higher in patients without baseline NS5A (L31M or Y93H) resistance-associated variants (RAVs) (137/139, 98.6%), including those with cirrhosis (43/44, 97.7%). Prevalence of baseline NS5A RAVs was low (19/159, 11.9%), particularly in mainland China (10/127, 7.9%). One death (0.6%), five serious adverse events (3.1%), and three grade 4 laboratory abnormalities (1.9%) occurred on treatment; none were considered related to study drugs. Two patients (1.3%) discontinued because of adverse events. Treatment was generally well tolerated regardless of cirrhosis status. CONCLUSIONS: Daclatasvir plus asunaprevir achieved a SVR24 rate of 91.2%, rising to 98.6% in patients without baseline NS5A RAVs, and was generally well tolerated in interferon (±ribavirin)-ineligible or -intolerant patients with genotype 1b infection from mainland China, Korea, and Taiwan.

NS5A Sequence Heterogeneity and Mechanisms of Daclatasvir Resistance in Hepatitis C Virus Genotype 4 Infection.

BACKGROUND: Daclatasvir is an NS5A inhibitor approved for treatment of infection due to hepatitis C virus (HCV) genotypes (GTs) 1-4. To support daclatasvir use in HCV genotype 4 infection, we examined a diverse genotype 4-infected population for HCV genotype 4 subtype prevalence, NS5A polymorphisms at residues associated with daclatasvir resistance (positions 28, 30, 31, or 93), and their effects on daclatasvir activity in vitro and clinically. METHODS: We performed phylogenetic analysis of genotype 4 NS5A sequences from 186 clinical trial patients and 43 sequences from the European HCV database, and susceptibility analyses of NS5A polymorphisms and patient-derived NS5A sequences by using genotype 4 NS5A hybrid genotype 2a replicons. RESULTS: The clinical trial patients represented 14 genotype 4 subtypes; most prevalent were genotype 4a (55%) and genotype 4d (27%). Daclatasvir 50% effective concentrations for 10 patient-derived NS5A sequences representing diverse phylogenetic clusters were ≤0.080 nM. Most baseline sequences had ≥1 NS5A polymorphism at residues associated with daclatasvir resistance; however, only 3 patients (1.6%) had polymorphisms conferring ≥1000-fold daclatasvir resistance in vitro. Among 46 patients enrolled in daclatasvir trials, all 20 with baseline resistance polymorphisms achieved a sustained virologic response. CONCLUSIONS: Circulating genotype 4 subtypes are genetically diverse. Polymorphisms conferring high-level daclatasvir resistance in vitro are uncommon before therapy, and clinical data suggest that genotype 4 subtype and baseline polymorphisms have minimal impact on responses to daclatasvir-containing regimens.

Randomized controlled trial of the NS5A inhibitor daclatasvir plus pegylated interferon and ribavirin for HCV genotype-4 (COMMAND-4).

BACKGROUND: Treatment options for HCV genotype-4 (GT4) are limited. This Phase III study (COMMAND-4; AI444-042) evaluated the efficacy and safety of daclatasvir (DCV), a pan-genotypic HCV NS5A inhibitor, with pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in treatment-naive patients with HCV GT4 infection. METHODS: Patients were randomly assigned (2:1; blinded) to treatment with DCV 60 mg (n=82) or placebo (n=42) once daily plus PEG-IFN 180 µg weekly and RBV 1,000-1,200 mg/day (weight-based) twice daily. DCV-treated patients with undetectable HCV RNA at weeks 4 and 12 (eRVR) received 24 weeks of DCV plus PEG-IFN/RBV; those without eRVR received an additional 24 weeks of PEG-IFN/RBV. All placebo-treated patients received 48 weeks of PEG-IFN/RBV. The primary end point was sustained virological response (SVR) at post-treatment week 12 (SVR12). RESULTS: Patients were 75% IL28B non-CC and 11% had cirrhosis. SVR rates (HCV RNA < lower limit of quantitation [LLOQ]) at post-treatment week 12 or later (imputed to include patients missing SVR12 assessments but had SVR after post-treatment week 12) were 82% (67/82) with DCV plus PEG-IFN/RBV versus 43% (18/42) with PEG-IFN/RBV (P<0.0001). In DCV recipients, SVR12 rates were comparable across subgroups. The safety and tolerability profile of DCV plus PEG-IFN/RBV was comparable to that of PEG-IFN/RBV. Discontinuations due to adverse events occurred in 4.9% of patients receiving DCV plus PEG-IFN/RBV and 7.1% of patients receiving PEG-IFN/RBV. CONCLUSIONS: In treatment-naive patients with HCV GT4 infection, DCV plus PEG-IFN/RBV achieved higher SVR12 rates than PEG-IFN/RBV alone. These data support DCV-based regimens for treatment of HCV GT4 infection, including all-oral combinations with other direct-acting antivirals (AI444-042; ClinicalTrials.gov NCT01448044).

Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1.

BACKGROUND: The combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1). METHODS: This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks. RESULTS: Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised. CONCLUSIONS: Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).

Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection.

IMPORTANCE: The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE: To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS: Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES: The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULTS: Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea. CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01979939.

Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis.

IMPORTANCE: Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. OBJECTIVE: All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. INTERVENTIONS: All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Sustained virologic response at posttreatment week 12 (SVR12). RESULTS: One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5% CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.4%-100.0%) for patients in the treatment-naive group and 87% (97.5% CI, 75.3%-98.0%) for those in the treatment-experienced group. Three serious adverse events were considered to be treatment related and there were 4 adverse event-related discontinuations. Treatment-emergent grade 3 or 4 alanine aminotransferase elevations were observed in 4 patients, of which 1 had concomitant total bilirubin elevation. CONCLUSIONS AND RELEVANCE: In this open-label uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR12.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA

Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C.

UNLABELLED: Treatment for chronic hepatitis C virus (HCV) infection is evolving from interferon (IFN)-based therapy to direct-acting antiviral (DAA) agents, yet some safety concerns have arisen involving cardiac toxicity. In this study, we sought to better understand the potential off-target toxicities of new DAAs. We retrospectively evaluated the clinical and pathological findings of the sentinel case in a phase II study that led to clinical development discontinuation for BMS-986094, an HCV nucleotide polymerase (nonstructural 5B) inhibitor. We also report on outcomes from other patients in the same study, including electrocardiogram changes, cardiovascular biomarkers, and transthoracic echocardiograms. Thirty-four patients received IFN-free BMS-986094 regimens. Six patients had left ventricular ejection fractions (LVEFs) <30%, 8 had LVEFs 30%-50%, and 11 required hospitalization for suspected cardiotoxicity. Of the patients with LVEF <50%, 6 had normalization of systolic function after a median of 20 days. T-wave inversions were the most sensitive predictor of LVEF dysfunction. B-type natriuretic peptide levels increased over time and correlated with the degree of LVEF dysfunction. Pathological analysis of cardiac tissue revealed severe myocyte damage with elongated myofibrils without gross necrosis. These findings were consistent with some results of recent primate studies that were conducted to further investigate the potential mechanisms of BMS-986094 toxicity. CONCLUSION: A novel nucleotide analog polymerase inhibitor developed for HCV treatment may cause a toxic cardiomyopathy. Ongoing surveillance of DAAs for cardiotoxicities may be beneficial, especially among patients at higher risk for cardiovascular disease.

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial.

BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 µg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING: Bristol-Myers Squibb.

Involvement of the second extracellular loop and transmembrane residues of CCR5 in inhibitor binding and HIV-1 fusion: insights into the mechanism of allosteric inhibition.

C-C chemokine receptor 5 (CCR5), a member of G-protein-coupled receptors, serves as a coreceptor for human immunodeficiency virus type 1 (HIV-1). In the present study, we examined the interactions between CCR5 and novel CCR5 inhibitors containing the spirodiketopiperazine scaffolds AK530 and AK317, both of which were lodged in the hydrophobic cavity located between the upper transmembrane domain and the second extracellular loop (ECL2) of CCR5. Although substantial differences existed between the two inhibitors--AK530 had 10-fold-greater CCR5-binding affinity (K(d)=1.4 nM) than AK317 (16.7 nM)-their antiviral potencies were virtually identical (IC(50)=2.1 nM and 1.5 nM, respectively). Molecular dynamics simulations for unbound CCR5 showed hydrogen bond interactions among transmembrane residues Y108, E283, and Y251, which were crucial for HIV-1-gp120/sCD4 complex binding and HIV-1 fusion. Indeed, AK530 and AK317, when bound to CCR5, disrupted these interhelix hydrogen bond interactions, a salient molecular mechanism enabling allosteric inhibition. Mutagenesis and structural analysis showed that ECL2 consists of a part of the hydrophobic cavity for both inhibitors, although AK317 is more tightly engaged with ECL2 than AK530, explaining their similar anti-HIV-1 potencies despite the difference in K(d) values. We also found that amino acid residues in the beta-hairpin structural motif of ECL2 are critical for HIV-1-elicited fusion and binding of the spirodiketopiperazine-based inhibitors to CCR5. The direct ECL2-engaging property of the inhibitors likely produces an ECL2 conformation, which HIV-1 gp120 cannot bind to, but also prohibits HIV-1 from utilizing the "inhibitor-bound" CCR5 for cellular entry--a mechanism of HIV-1's resistance to CCR5 inhibitors. The data should not only help delineate the dynamics of CCR5 following inhibitor binding but also aid in designing CCR5 inhibitors that are more potent against HIV-1 and prevent or delay the emergence of resistant HIV-1 variants.

Progressive outer retinal necrosis in the era of highly active antiretroviral therapy: successful management with intravitreal injections and monitoring with quantitative PCR.

BACKGROUND: Progressive outer retinal necrosis (PORN) is an ocular disease in individuals with AIDS and is associated with substantial morbidity. The optimal management of PORN and its clinical course in the HAART era is unclear. OBJECTIVE: We report a case of successfully managed PORN that provides insight into the monitoring and treatment of this disease. STUDY DESIGN: Intravitreal injections and intravenous therapy targeted towards varicella zoster virus (VZV) were used to treat PORN. HAART was initiated for HIV-1 therapy. Serial PCR for VZV was performed on aqueous humor to monitor the clinical course. RESULTS: The presence of VZV DNA from aqueous humor correlated with clinical exacerbations of disease. Initiation of twice weekly intravitreal injections with dual antiviral drugs appeared to be an important therapeutic intervention that resulted in remission of PORN. Secondary prophylaxis against VZV was successfully withdrawn after HAART induced partial immune recovery. CONCLUSION: In addition to aggressive therapy with intravitreal injections, HAART and quantitative measurements of VZV DNA from aqueous humor have important roles in the management of PORN. A multidisciplinary approach involving specialists in infectious diseases, ophthalmology, and clinical microbiology will improve the chances for successful long-term outcomes.