Karen Sims

Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection

BACKGROUND & AIMS The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. METHODS We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). RESULTS In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. CONCLUSIONS In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.

A randomized trial of daclatasvir in combination with asunaprevir and beclabuvir in patients with chronic hepatitis C virus genotype 4 infection

Please cite this article as: Hassanein, T., Sims, K.D., Bennett, M., Gitlin, N., Lawitz, E., Nguyen, T., Webster, L., Younossi, Z., Schwartz, H., Thuluvath, P.J., Zhou, H., Rege, B., McPhee, F., Zhou, N., Wind-Rotolo, M., Chung, E., Griffies, A., Grasela, D.M., Gardiner, D.F., A Randomized Trial of Daclatasvir in Combination With Asunaprevir and Beclabuvir in Patients With Chronic Hepatitis C Virus Genotype 4 Infection, Journal of Hepatology (2015), doi: http://dx.doi.org/10.1016/j.jhep.2014.12.025

Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case–control study

The epidemiology of nontuberculous mycobacteria (NTM) disease in solid organ transplant recipients is poorly defined.

1423 INTERIM ANALYSIS OF AN INTERFERON (IFN)- AND RIBAVIRIN (RBV)-FREE REGIMEN OF DACLATASVIR (DCV), ASUNAPREVIR (ASV), AND BMS-791325 IN TREATMENT-NAIVE, HEPATITIS C VIRUS GENOTYPE 1-INFECTED PATIENTS

13.6±1.8 g/dL [8.8–17.5], respectively. After 12W, a complete early virological response was obtained in 34 (83%) boceprevir patients and in 35 (61%) telaprevir patients (p = 0.026). Among 17 boceprevir and 16 telaprevir patients, 14 (82%) and 7 (43%) achieved an end of treatment response (EOT) with an undetetectable viral load, respectively (p = 0.032). Among 9 boceprevir and 5 telaprevir patients, 6 and 1 achieved SVR12, respectively. Among 6 patients in the boceprevir group, 3 achieved SVR24. In the telaprevir group, 29 patients discontinued therapy (serious adverse events, n = 13; virological breakthrough, n = 6; non-response, n = 9). In the boceprevir group, 14 patients discontinued therapy (serious adverse events, n = 5; virological breakthrough, n = 2; non-response, n = 4; retransplantation, n = 1). Four patients died in a context of infectious disorders: boceprevir, n = 2 (W20/W24); telaprevir, n = 2 (W2/W9). The most common side effect was anemia in 85% of patients: 95% and 96% in boceprevir and telaprevir groups received erythropoietin alone or combined with ribavirin dose reduction. Conclusion: In liver transplanted patients, EOT rate was 82% and 38% with boceprevir and telaprevir, respectively. Among the overall population, 44% of patients discontinued therapy because of treatment failure or occurrence of serious adverse events.

Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection

ABSTRACT BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.)

Common Infections in the Lung Transplant Recipient

Infections are a major cause of morbidity and mortality after lung transplantation. Pretransplant assessments for infection risk and immunization updates may help reduce posttransplant infections. In addition careful choice of posttransplant prophylaxis for cytomegalovirus and fungal infections is critical. Because of the potential association of infections such as respiratory viral infections and gram-negative bacterial infections with bronchiolitis obliterans syndrome, prompt attention to these pathogens is critical. Choice of antimicrobials for prophylaxis and treatment should take into consideration both adverse effects and drug interactions associated with antimicrobial choice.

Daclatasvir + asunaprevir + beclabuvir ± ribavirin for chronic HCV genotype 1-infected treatment-naive patients

This phase‐2b study examined the safety and efficacy of an all‐oral, interferon‐free combination of the NS5A replication complex inhibitor daclatasvir (DCV), the NS3 protease inhibitor asunaprevir (ASV), and the nonnucleoside NS5B polymerase inhibitor beclabuvir (BCV) with or without ribavirin in patients with HCV genotype (GT) 1 infection.

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.

Organic Anion Transporting Polypeptide-Mediated Transport of, and Inhibition by, Asunaprevir, an Inhibitor of Hepatitis C Virus NS3 Protease

Asunaprevir (ASV), an investigational, highly protein‐bound inhibitor of hepatitis C virus NS3 protease, shows considerable hepatic compartmentalization in animal models. Preclinical data showed ASV inhibition of human OATP1B1 (IC50 = 0.3 μM), OATP2B1 (0.27 μM), and, to a lesser extent OATP1B3 (3.0 μM), confirmed by modest (<2‐fold) clinical elevations in rosuvastatin exposure with concomitant ASV. Although no significant OATP transport of ASV was observed in vitro at standard micromolar assay concentrations, clinical coadministration of ASV with a single dose of the OATP inhibitor rifampin gave large, variable increases in ASV plasma Cmax (21‐fold mean) and AUCinf (15‐fold mean), consistent with reduced hepatic uptake. In vitro reevaluation at therapeutically relevant low‐nanomolar concentrations of unbound ASV showed active, saturable human hepatocyte uptake (Km = 0.685 μM) and rifampin‐reversible transport by OATP1B1 and OATP2B1, but not OATP1B3. At therapeutically relevant concentrations, ASV is therefore a sensitive substrate for, and weak inhibitor of, human OATP1B1, 1B3 and 2B1.

A randomized trial in healthy subjects to assess the bioequivalence of an atazanavir/cobicistat fixed-dose combination tablet versus administration as separate agents.

BACKGROUND Cobicistat (COBI) is an alternative pharmacoenhancer to ritonavir. A fixed-dose combination (FDC) tablet containing atazanavir (ATV) and COBI has been developed for the treatment of HIV-1-infected patients. METHODS This open-label, single-centre, single-dose, crossover study, randomized 64 healthy subjects to one of eight treatment sequences. Under light meal conditions, maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) to infinity (AUCINF) and AUC to the last measurable concentration (AUC0-T) for ATV and COBI administered as an FDC of ATV/COBI (300/150 mg) were compared to those following administration as separate agents given together; bioequivalence was concluded if the 90% CIs of the geometric mean ratios fell within the predetermined range of 0.80, 1.25. ATV and COBI pharmacokinetic parameters following administration as the FDC or as separate agents were also compared under fasted conditions. The effect of food (light and high-fat meals) on the pharmacokinetics of ATV and COBI for the FDC was also assessed. RESULTS ATV and COBI administered in an FDC tablet were bioequivalent to the individual agents when given with a light meal. Under fasted conditions, pharmacokinetic parameters for ATV and COBI were similar for the individual components and the FDC. For the FDC, systemic exposure to ATV increased with a light meal compared to fasted conditions, and ATV concentration 24 h post-dose was similar with a light meal compared with a high-fat meal. CONCLUSIONS ATV/COBI (300/150 mg) FDC tablet was bioequivalent to coadministration as separate agents with a light meal in healthy subjects. Clinicaltrials.gov identifier NCT01837719.