Immunogenicity and safety of BPZE1, an intranasal live attenuated pertussis vaccine, versus tetanus-diphtheria-acellular pertussis vaccine: a randomised, double-blind, phase 2b trial.

BACKGROUND: Bordetella pertussis epidemics persist as transmission remains unabated despite high acellular pertussis vaccination rates. BPZE1, a live attenuated intranasal pertussis vaccine, was designed to prevent B pertussis infection and disease. We aimed to assess the immunogenicity and safety of BPZE1 compared with the tetanus-diphtheria-acellular pertussis vaccine (Tdap). METHODS: In this double-blind, phase 2b trial at three research centres in the USA, healthy adults aged 18-50 years were randomly assigned (2:2:1:1) via a permuted block randomisation schedule to receive BPZE1 vaccination followed by BPZE1 attenuated challenge, BPZE1 vaccination followed by placebo challenge, Tdap followed by BPZE1 attenuated challenge, or Tdap followed by placebo challenge. On day 1, lyophilised BPZE1 was reconstituted with sterile water and given intranasally (0·4 mL delivered to each nostril), whereas Tdap was given intramuscularly. To maintain masking, participants in the BPZE1 groups received an intramuscular saline injection, and those in the Tdap groups received intranasal lyophilised placebo buffer. The attenuated challenge took place on day 85. The primary immunogenicity endpoint was the proportion of participants achieving nasal secretory IgA seroconversion against at least one B pertussis antigen on day 29 or day 113. Reactogenicity was assessed up to 7 days after vaccination and challenge, and adverse events were recorded for 28 days after vaccination and challenge. Serious adverse events were monitored throughout the study. This trial is registered with ClinicalTrials.gov, NCT03942406. FINDINGS: Between June 17 and Oct 3, 2019, 458 participants were screened and 280 were randomly assigned to the main cohort: 92 to the BPZE1-BPZE1 group, 92 to the BPZE1-placebo group, 46 to the Tdap-BPZE1 group, and 50 to the Tdap-placebo group. Seroconversion of at least one B pertussis-specific nasal secretory IgA was recorded in 79 (94% [95% CI 87-98]) of 84 participants in the BPZE1-BPZE1 group, 89 (95% [88-98]) of 94 in the BPZE1-placebo group, 38 (90% [77-97]) of 42 in the Tdap-BPZE1 group, and 42 (93% [82-99]) of 45 in the Tdap-placebo group. BPZE1 induced broad and consistent B pertussis-specific mucosal secretory IgA responses, whereas Tdap did not induce consistent mucosal secretory IgA responses. Both vaccines were well tolerated, with mild reactogenicity and no serious adverse events related to study vaccination. INTERPRETATION: BPZE1 induced nasal mucosal immunity and produced functional serum responses. BPZE1 has the potential to avert B pertussis infections, which ultimately could lead to reduced transmission and diminished epidemic cycles. These results should be confirmed in large phase 3 trials. FUNDING: ILiAD Biotechnologies.

Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial.

Importance: Effective treatments for patients with severe COVID-19 are needed. Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1ß antibody, in patients hospitalized with severe COVID-19. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227). Main Outcomes and Measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. Conclusions and Relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT04362813.

Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: Pegbelfermin (BMS-986036), a PEGylated human fibroblast growth factor 21 (FGF21) analogue, has previously been shown to improve markers of metabolism and liver fibrosis in obese patients with type 2 diabetes. In this phase 2a study, we aimed to evaluate the safety and efficacy of pegbelfermin in patients with non-alcoholic steatohepatitis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2a study, we recruited adults (aged 21-75 years) with a body-mass index of at least 25 kg/m2, biopsy-confirmed non-alcoholic steatohepatitis (fibrosis stage 1-3), and a hepatic fat fraction of at least 10% when assessed by magnetic resonance imaging-proton density fat fraction. These patients were enrolled at 17 medical centres in the USA. Eligible patients were stratified by type 2 diabetes status and they were randomly assigned (1:1:1) by a computer-based system to receive subcutaneous injections of placebo once a day, 10 mg pegbelfermin once a day, or 20 mg pegbelfermin once a week, all for 16 weeks. Participants, the study team administering treatment, and investigators analysing outcomes (who were independent of the study team and had no further involvement) were masked to treatment groups. The primary outcomes were safety and the absolute change in hepatic fat fraction after 16 weeks of treatment. All patients who were randomly assigned to groups and received the study drug or placebo were included in the primary analyses. This trial was registered with ClinicalTrials.gov, number NCT02413372. FINDINGS: Between May 12, 2015, and Aug 4, 2016, 184 overweight or obese patients with non-alcoholic steatohepatitis were screened for study inclusion. Of these, 95 (52%) patients were excluded because they no longer met study criteria and 80 (43%) patients entered the placebo lead-in phase. After further exclusions, 75 (94%) patients were randomly assigned to groups, received at least one dose of treatment (25 patients to receive 10 mg pegbelfermin once a day; 24 patients to receive 20 mg pegbelfermin once a week, and 26 patients to receive placebo), and were included in the primary analysis. A prespecified interim analysis at week 8 showed a greater than expected change in the primary outcome and supported early closing of patient enrolment, since this analysis indicated that the full planned sample size was not needed. We observed a significant decrease in absolute hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (-6·8% vs -1·3%; p=0·0004) and in the group receiving 20 mg pegbelfermin weekly (-5·2% vs -1·3%; p=0·008) compared with the placebo group. Most adverse events were mild; the most common events were diarrhoea in eight (16%) of 49 patients treated with pegbelfermin and two (8%) of 26 patients treated with placebo and nausea in seven (14%) patients treated with pegbelfermin and two (8%) patients treated with placebo. There were no deaths, discontinuations due to adverse events, or treatment-related serious adverse events. INTERPRETATION: Treatment with subcutaneously administered pegbelfermin for 16 weeks was generally well tolerated and significantly reduced hepatic fat fraction in patients with non-alcoholic steatohepatitis. Further study of pegbelfermin is warranted in patients with non-alcoholic steatohepatitis. Additional studies that use liver biopsies would allow for the assessment of pegbelfermin's effects on liver histology. Moreover, further studies should allow assessments of the safety and effectiveness of pegbelfermin in a larger number of patients. FUNDING: Bristol-Myers Squibb.

In Vitro Activity of Iclaprim against Isolates in Two Phase 3 Clinical Trials (REVIVE-1 and -2) for Acute Bacterial Skin and Skin Structure Infections.

Iclaprim, a selective bacterial dihydrofolate reductase inhibitor, and other antibiotics were tested against Gram-positive isolates from two phase 3 studies of acute bacterial skin and skin structure infections (ABSSSIs) (REVIVE-1 and -2). Seven hundred ninety baseline isolates, including Staphylococcus aureus, ß-hemolytic streptococci, and Streptococcus anginosus group, underwent antibacterial susceptibility testing. Iclaprim had an MIC90 of 0.12 µg/ml for S. aureus (0.12 µg/ml for methicillin susceptible, 0.25 µg/ml for methicillin resistant), 0.25 µg/ml for ß-hemolytic streptococci, and 0.008 µg/ml for S. anginosus group. Iclaprim demonstrated potent activity against these Gram-positive ABSSSI isolates.

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.).

Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens.

BACKGROUND & AIMS: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies. METHODS: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression. RESULTS: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. CONCLUSIONS: SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders.

Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence.

UNLABELLED: Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post-liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV genotypes. The open-label ALLY-1 study assessed the safety and efficacy of a 60-mg once-daily dosage of daclatasvir (pan-genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24-week follow-up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on-treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child-Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval [CI], 67.9%-92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child-Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%-99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment-related serious adverse events. CONCLUSION: The pan-genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post-liver transplantation recurrence or advanced cirrhosis.

Long-Term Follow-Up of Children Treated With Peginterferon and Ribavirin for Hepatitis C Virus Infection.

OBJECTIVES: The aim of the study was to describe the 5-year follow-up of children who received peginterferon and ribavirin in a global, open-label study. METHODS: A 5-year follow-up study of 107 children and adolescents ages 3 to 17 years with chronic hepatitis C virus infection who received peginterferon and ribavirin for 24 or 48 weeks. No drugs were administered during follow-up. RESULTS: Ninety-four patients were enrolled in the long-term follow-up portion of the study; the median duration of follow-up was 287 weeks (range, 73-339). Of 63 patients with sustained virologic response who were enrolled, 54 completed 5 years of follow-up; none had relapse in the 5-year follow-up period. Significant decreases in height z scores were observed during treatment. The effect of treatment on height z score was larger in patients treated for 48 weeks compared with those treated for 24 weeks (mean change from baseline to the end of treatment was -0.13 [P < 0.001] and -0.44 [P < 0.001] in the 24- and 48-week treatment groups, respectively). Among patients treated for 24 weeks, full recovery of height z scores to baseline was observed by 1 year of follow-up, whereas only partial recovery was observed during 5 years of follow-up in patients treated for 48 weeks (mean change from baseline to the final follow-up visit was -0.16 (P = NS) and -0.32 (P < 0.05) in the 24- and 48-week treatment groups, respectively). Similar patterns were observed for weight and body mass index z scores. CONCLUSIONS: Impairment of growth should be considered when assessing the risk-benefit profile of peginterferon/ribavirin therapy in children with hepatitis C virus infection. In deciding to treat children with chronic hepatitis C virus, considerations should include both deferring treatment in patients during optimal growth periods, and the possibility that interferon-free regimens may be available to children in the next 5 to 10 years.

12 Weeks of Daclatasvir in Combination With Sofosbuvir for HIV-HCV Coinfection (ALLY-2 Study): Efficacy and Safety by HIV Combination Antiretroviral Regimens.

BACKGROUND: Highly effective hepatitis C virus (HCV) direct-acting antiviral therapies that do not require modification of human immunodeficiency virus (HIV) antiretroviral regimens are needed. We evaluated the efficacy and safety of daclatasvir + sofosbuvir (DCV + SOF) for 12 weeks by antiretroviral (ARV) regimen in HIV-HCV-coinfected patients. METHODS: In the randomized, open-label ALLY-2 study, HIV-HCV-coinfected patients received 8 or 12 weeks of once-daily DCV 60 mg (dose-adjusted as-necessary for concomitant ARVs) + SOF 400 mg. Results were stratified by ARV class for the 151 patients who received 12 weeks of DCV + SOF. RESULTS: Fifty-one patients were HCV treatment experienced, 100 were treatment naive, 89% male and 33% black. HCV genotypes were: genotype 1a (GT1a; 69%), GT1b (15%), GT2 (8%), GT3 (6%), and GT4 (2%). Sustained virologic response 12 weeks post-treatment (SVR12) was 97% and was similar across ARV regimens (P = .774): protease inhibitor-based, 97% (95% confidence interval [CI], 90%-99.7%); nonnucleoside reverse transcriptase inhibitor-based, 100% (95% CI, 91%-100%); and integrase inhibitor based, 95% (95% CI, 83%-99.4%). SVR12 among patients receiving either tenofovir disoproxil fumarate or abacavir as part of their antiretroviral therapy regimen was 98% (95% CI, 93%-99.5%) and 100% (95% CI, 85%-100%), respectively. Age, gender, race, cirrhosis, HCV treatment history, GT , and baseline HCV RNA did not affect SVR12. No discontinuations were attributed to treatment-related adverse events. CONCLUSIONS: DCV + SOF x12 weeks is a highly efficacious, all-oral, pan-GT HCV treatment for HIV-HCV coinfected patients across a broad range of ARV regimens. CLINICAL TRIALS REGISTRATION: NCT02032888.

Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection.

BACKGROUND & AIMS: We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients. METHODS: This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12). RESULTS: For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation. CONCLUSIONS: Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.

Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection.

BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS: Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

All-oral daclatasvir plus asunaprevir for chronic hepatitis C virus (HCV) genotype 1b infection: a sub-analysis in Asian patients from the HALLMARK DUAL study.

BACKGROUND & AIMS: Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b (GT-1b) infection in the HALLMARK DUAL trial. This post hoc analysis was conducted to determine the efficacy and safety of this treatment in Asian patients. METHODS: Treatment-naive patients were randomly assigned (2:1; double-blinded) to receive DCV (60 mg once daily) plus ASV (100 mg twice daily) or placebo for 12 weeks. Subsequently, placebo patients entered another study, and the remaining patients continued treatment for an additional 12 weeks. Non-responders to peginterferon/ribavirin and ineligible/intolerant patients received dual therapy for 24 weeks. Sustained virological response at post-treatment Week 12 [sustained virological response (SVR)12] and safety outcomes were evaluated. RESULTS: This post hoc analysis included 186 Asian patients (Korean, 78; Taiwanese, 85; others, 23), of whom 32.3% were cirrhotic. SVR12 was observed in 92.3, 78.6 and 80.0% of treatment-naive, ineligible/intolerant and non-responder patients, respectively, and was comparable with non-Asian patients. SVR12 by baseline factors including age, viral load, interleukin-28B genotype and cirrhosis status was similar between the Asian sub-cohorts. Among 18 Asian patients with NS5A-Y93H or NS5A-L31M/V resistance-associated variants (RAVs), seven patients achieved SVR12. Multivariate regression analysis showed a significant influence of NS5A RAVs in both Asian and non-Asian cohorts. The incidence of serious adverse events in Asian patients was low (7.2%). Two Taiwanese patients had elevated alanine aminotransferase (≥5.1 × ULN); both achieved SVR12. CONCLUSIONS: All-oral dual therapy with DCV + ASV resulted in high SVR rates and was well tolerated in Asian patients with HCV GT-1b infection.

On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir.

BACKGROUND AND AIMS: Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS: In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS: Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS: On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis.

BACKGROUND & AIMS: We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV). METHODS: Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes. RESULTS: In the Japanese phase 3 study, SVR12 was achieved by 91% of patients with cirrhosis (n = 22) and 84% of patients without cirrhosis (n = 200); in the global phase 3 study, SVR12 was achieved by 84% of patients with cirrhosis (n = 206) and by 85% of patients without cirrhosis (n = 437). The frequency of serious adverse events, adverse events leading to treatment discontinuation and treatment-emergent grade 3/4 laboratory abnormalities was low (<10%) and similar among patients with (n = 229) or without (n = 689) compensated cirrhosis receiving DCV+ASV. Grade 3/4 reductions in platelets and neutrophils were more common among patients with cirrhosis (1.3 and 2.2%, respectively) compared with those without cirrhosis (both 0.6%). Grade 3/4 liver function test abnormalities were less common among patients with cirrhosis (1.8%) compared with those without cirrhosis (3.5-4.7%). Alanine aminotransferase elevations were not associated with hepatic decompensation. CONCLUSIONS: The safety and efficacy of DCV+ASV were similar in patients with or without compensated cirrhosis. This all-oral, interferon- and ribavirin-free combination is an effective and well-tolerated treatment option for patients with HCV GT1b infection and cirrhosis. Trial registrations numbers: Clinicaltrials.gov identifiers: NCT01012895; NCT01051414; NCT01581203; NCT01497834.

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

Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders.

BACKGROUND & AIMS: Improved therapies for peginterferon/ribavirin null or partial responders are needed. This study evaluated daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) plus peginterferon alfa-2a and ribavirin in this patient population. METHODS: This open-label, phase 3 study (HALLMARK-QUAD; NCT01573351) treated patients with chronic hepatitis C virus (HCV) genotype 1 (n=354) or 4 (n=44) infection who had a prior null or partial response to peginterferon/ribavirin. Patients received daclatasvir 60 mg once-daily plus asunaprevir 100mg twice-daily, with weekly peginterferon alfa-2a and weight-based ribavirin for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) among genotype 1-infected patients. RESULTS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated SVR12 rates of 93% (95% CI 90-96) in prior non-responders infected with HCV genotype 1. SVR12 rates among genotype 4-infected patients were 98% (95% CI 93-100); one patient had a missing post-treatment week-12 HCV-RNA measurement, but achieved an SVR at post-treatment week 24, yielding a 100% SVR rate in genotype 4 patients. Prior peginterferon/ribavirin response, sex, age, IL28B genotype, or cirrhosis status did not influence SVR12 rates. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%), and ALT/AST elevations (3% each). CONCLUSIONS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated high rates of SVR12 in genotype 1- or 4-infected prior null or partial responders. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens.

All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study.

BACKGROUND: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FINDINGS: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). INTERPRETATION: Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. FUNDING: Bristol-Myers Squibb.

Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study.

BACKGROUND: Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. METHODS: A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. RESULTS: A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. CONCLUSIONS: Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).

Predictors of consent to pharmacogenomics testing in the IDEAL study.

INTRODUCTION: Pharmacogenomic testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL (Individualized Dosing to Assess Optimal Pegylated Interferon Therapy) clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia. OBJECTIVE: To characterize the groups of patients who accepted or declined pharmacogenomic testing in the IDEAL study. METHODS: Clinical and demographic factors and treatment outcomes were compared at all sites that had approved pharmacogenomic testing. Differences between patients who consented to and declined pharmacogenomic testing were analyzed using Student's t-test and χ²-test. RESULTS: In total, 109 of 118 sites participated in the pharmacogenomic substudy, and 1674 of 2949 (57%) patients enrolled at these sites consented to pharmacogenomic testing. More patients treated in academic medical centers than in community centers (60 vs. 52%, P<0.001) provided consent. More men than women (58 vs. 54%, P=0.04) consented to pharmacogenomic testing. There was no significant difference in pharmacogenomic participation between patients from different racial groups, including whites and African Americans (58 vs. 54%, P=0.07). Treatment outcomes were also similar according to pharmacogenomic participation. CONCLUSION: In the IDEAL study, patient consent to pharmacogenomic testing did not introduce selection bias. Treatment at an academic center and male sex were associated with higher rates of pharmacogenomic testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined pharmacogenomic testing.