All-oral Regimens Research Articles

HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment

This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53–61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis.Trial Registration: ClinicalTrials.gov NCT01830127.

Assessing the Budget Impact and Economic Outcomes of the Introduction of Daclatasvir + Asunaprevir and Sofosbuvir/Ledipasvir for the Treatment of Chronic Hepatitis C Virus Infection in Japan

BackgroundThe advent of highly efficacious, well-tolerated, all-oral direct-acting antiviral regimens has revolutionized the standard of care for patients chronically infected with hepatitis C virus. As efficacy and safety rates converge, prescribers and payers need to consider value for money. ObjectivesTo evaluate the health economic value of daclatasvir + asunaprevir versus sofosbuvir/ledipasvir via a cost-effectiveness analysis, and determine the optimal treatment considering both costs and health outcomes in Japan. MethodsA previously published Markov model was used to estimate the cost-effectiveness of daclatasvir + asunaprevir compared with sofosbuvir/ledipasvir on the basis of a matching-adjusted indirect comparison of pivotal trials and modeling inputs specific to the Japanese setting. A de novo budget impact model was developed and used to predict the cost implications of differing treatment sequences. ResultsCost-effectiveness results demonstrated minimal difference in terms of benefit (0.037 fewer QALYs and 0.014 fewer life-years with daclatasvir + asunaprevir); nevertheless, a significant difference in cost was predicted (estimated ¥2,299,700 [US $21,695] reduction with daclatasvir + asunaprevir). The budget impact analysis estimated that treatment with daclatasvir + asunaprevir is expected to be less expensive than treatment with sofosbuvir/ledipasvir (as the proportion of patients initially treated with sofosbuvir/ledipasvir increased from 0% to 100%, total costs increased from ¥206 to ¥403 billion [US $1.94 billion to US $3.80 billion]). ConclusionsOn the basis of results from an established cost-effectiveness model and a conventional budget impact analysis, treatment with daclatasvir + asunaprevir is expected to be cost-saving compared with treatment with sofosbuvir/ledipasvir in Japan with similar health outcomes, regardless of treatment sequence.

Assessing the Effect of Injectable or Oral Routes of Treatment Administration on Patient-Reported Outcomes and out-of-Pocket Costs Among Patients with Multiple Myeloma

Introduction: Healthcare resource use and patient preference play a major role in treatment decisions for multiple myeloma (MM); therefore, it is important to understand the impact of cancer treatment on patient-reported outcomes in a real-world setting. This study aimed to characterize the impact of MM treatments by oral or injectable routes of administration on work productivity, healthcare resource use, and out-of-pocket costs, from the patient perspective.Methods: This was a cross-sectional survey of 137 US MM patients identified from the Lightspeed GMI global panel and its partners, aged ≥18 years who were currently on a treatment regimen comprised of either oral therapy only (oral users) or on injectable therapy with or without oral medication (injectable users). Patients completed a web based self-administered survey and the study assessed patient’s experiences using the Work Productivity and Activity Impairment (WPAI) questionnaire and patient-centric questions related to MM. Patient characteristics, treatment history, healthcare resource use and patient-reported outcomes were summarized and compared between oral and injectable users. Multivariable analyses estimated the association between oral vs. injectable route of administration and outcomes of the WPAI, the number of oncologist/hematologist visits in the past three months, hours spent at appointments related to MM treatment in the past month, feeling upset or frustrated while at the doctor’s office (not at all/rarely vs. somewhat often/often/very often; 5 point Likert scale), out-of-pocket costs for oncologist/hematologist visits in the past three months, and financial burden regarding all MM related out-of-pocket expenses (no burden/some burden vs. moderate/high/extremely high burden; 5 point Likert scale). Analyses were adjusted for patient characteristics that differed significantly between oral and injectable users (sex, line of therapy, number of treatments, length of time of current regimen, number of days since last treatment dose, prior radiation treatment, education, BMI, and performance status).Results: A total of 137 respondents participated in the study, of which 43.1% reported currently being on an oral only regimen and 56.9% on an injectable regimen. Patient characteristics were generally similar between treatment cohorts with an average age of 55.7 years (SD=13.7), mean time since diagnosis of 4.3 years (SD=4.3), currently employed (44.5%), having health insurance coverage (97.1%) and mean number of comorbidities (mean=0.3 (SD=0.9), adjusted Charlson comorbidity index). Oral users were less likely to report prior radiation treatment (1.7% vs. 12.8%), and more likely to be on 1st line therapy (64.4% vs. 42.3%, p=0.024) than injectable users. On average oral users reported being on less MM prescriptions in their current regimen than injectable users (1.2 vs. 1.7, p<0.001). In univariate analysis of the WPAI, among the employed sample, oral users reported significantly lower overall work impairment than injectable users (52.4% vs. 68.3%, p=0.049). This was primarily driven by decreased impairment while at work (presenteeism: 46.8% vs. 62.3%, p=0.044) while no difference in absenteeism from work due to impairment (17.9% vs. 21.8%, p=0.446) was found. In multivariable analysis, these differences were no longer significant.After adjusting for patient characteristics, oral users reported fewer oncologist/hematologist visits in the past three months (3.0 vs. 4.7, p=0.027) and lower out-of-pocket costs for all these visits ($130.47 vs $329.49, p=0.025). Oral users were numerically more likely to report no burden/some financial burden regarding all MM related out-of-pocket expenses (45.7% vs. 30.9%, p=0.221), and spend less time spent at appointments related to MM treatments in the past month (5.4 vs. 7.2 hours, p=0.145). Oral users were more likely to report not at all/rarely experiencing frustration while at the doctor's office (80.6% vs. 57.1%, p=0.042).Conclusions: Findings suggest that an all-oral treatment regimen was associated with less healthcare resource use and financial burden than an injectable treatment regimen, and potentially less work productivity loss. However, the latter should be interpreted with caution given the small sample size of employed respondents. These findings should be taken into consideration while making treatment decisions with MM patients. DisclosuresGupta:Celgene Corporation: Consultancy, Research Funding; Kantar Health: Employment. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Liebert:Kantar Health: Employment; Celgene Corporation: Consultancy, Research Funding. Parikh:Celgene Corporation: Employment, Equity Ownership, Research Funding.

(Re)moving the needle: prospects for all-oral treatment for multidrug-resistant tuberculosis.

Currently recommended regimens for multidrug-resistant tuberculosis (MDR-TB) contain painful daily injections and are unsuccessful in approximately half of patients. Removal of the injectable agent to fashion all-oral regimens could transform MDR-TB treatment and access to care. To explore evidence for all-oral treatment regimens. We review evidence on drugs that could be included in injection-free MDR-TB regimens. The oral drugs considered have an indication for or are recommended for off-label use for TB or MDR-TB, and have demonstrated bactericidal activity. Drugs with weak bactericidal activity should have limited prior population exposure and evidence of effectiveness in MDR-TB regimens. Bedaquiline, delamanid, and linezolid all display strong bactericidal activity, while clofazimine has weak bactericidal activity. They all have limited prior population exposure and demonstrated effectiveness in MDR-TB regimens. Despite widespread exposure to pyrazinamide and late-generation fluoroquinolones in the population, all are bactericidal and have shown great value when included in treatment regimens for MDR-TB. The evidence supports the use of all-oral regimens comprising new and existing drugs for MDR-TB treatment. Existing evidence of bactericidal activity and efficacy for these drugs provides a convincing argument for transitioning MDR-TB treatment towards all-oral regimens. These new regimens could mitigate the delivery, cost, and adherence challenges inherent to the current standard.

Secondary prophylaxis of hepatocellular carcinoma: the comparison of direct-acting antivirals with pegylated interferon and untreated cohort.

During the past two decades, several studies showed reduced rates of hepatocellular carcinoma recurrence in patients with HCV-related cirrhosis after interferon-based antiviral therapies respect to untreated controls, even without reaching viral clearance. The recent development of new all-oral regimens with direct-acting antivirals has radically improved the therapeutic management of hepatitis C. Nevertheless, paradoxical, or at least unexpected, high rates of both occurrence and recurrence of hepatocellular carcinoma after a treatment with direct-acting antivirals, have been reported in the recent literature. These findings generated a strong rebound in the hepatology community and are at present still controversial. We sought to compare the hepatocellular carcinoma recurrence-free survival of a historical cohort treated with pegylated interferon/ribavirin and an untreated cohort with a cohort treated with direct-acting antivirals.

Delamanid in the treatment of multidrug-resistant tuberculosis.

Otsuka has been engaged in anti-tuberculosis drug development efforts for over 30 years, and is the leading private sector funder of tuberculosis (TB) research and development. Delamanid (DLM), discovered by Otsuka's scientists, has been shown to provide benefit with respect to short-term surrogate markers and long-term treatment outcomes, and it has received regulatory approval for treatment of adult pulmonary multidrug-resistant TB (MDR-TB) as one of only two new anti-tuberculosis drugs in the last 40 years. Lack of drug-drug interactions with major antiretrovirals and efficacy against MDR-TB allow DLM's applicability in a wide range of MDR-TB patients. Current and future efforts are focused on replacing less safe and less efficacious second-line drugs with DLM, its contribution to all-oral and/or shortened treatment regimens, and, ultimately, inclusion in a pan-TB regimen. This manuscript provides a brief review of DLM.

The value of cure associated with treating treatment-naïve chronic hepatitis C genotype 1: Are the new all-oral regimens good value to society?

All-oral regimens are associated with high cure rates in hepatitis C virus-genotype 1 (HCV-GT1) patients. Our aim was to assess the value of cure to the society for treating HCV infection. Markov model for HCV-GT1 projected long-term health outcomes, life years, and quality-adjusted life years (QALYs) gained. The model compared second-generation triple (sofosbuvir+pegylated interferon+ribavirin [PR] and simeprevir+PR) and all-oral (ledipasvir/sofosbuvir and ombitasvir+paritaprevir/ritonavir+dasabuvir±ribavirin) therapies with no treatment. Sustained virological response rates were based on Phase III RCTs. We assumed that 80% and 95% of HCV-GT1 patients were eligible for second-generation triple and all-oral regimens. Transition probabilities, utility and mortality were based on literature review. The value of cure was calculated by the difference in the savings from the economic gains associated with additional QALYs. Model estimated 1.52 million treatment-naïve HCV-GT1 patients in the US. Treating all eligible HCV-GT1 patients with second-generation triple and all-oral therapies resulted in 3.2 million and 4.8 million additional QALYs gained compared to no treatment respectively. Using $50,000 as value of QALY, these regimens lead to savings of $185 billion and $299 billion; costs of these regimens were $109 billion and $128 billion. The value of cure with second-generation triple and all-oral regimens was $55 billion and $111 billion, when we conservatively assumed only drug costs. Cost savings were greater for HCV-GT1 patient cured with cirrhosis compared to patients without cirrhosis. The recent evolution of regimens for HCV GT1 has increased efficacy and value of cure.

Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.

Hepatitis C Virus and Antiviral Drug Resistance.

Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens.

The impact of hepatitis C virus outside the liver: Evidence from Asia.

Between 80 and 115 million people worldwide are chronically infected with hepatitis C virus, with 60%-90% of these being undiagnosed. Untreated chronic hepatitis C (CHC) is associated with progressive liver disease, cirrhosis, hepatocellular carcinoma and liver-related mortality. A number of extrahepatic manifestations are also reported in CHC patients, further adding to the burden of the disease. CHC also impacts patients in terms of lower health-related quality of life, higher levels of fatigue and reduced productivity. Furthermore, the later stages of disease are costly for both healthcare systems and society. Pegylated-interferon (PEG-IFN)+ribavirin (RBV), for many years the mainstay of treatment, leads to sustained virological response (SVR) in 40%-70% of patients. However, a substantial number of patients are ineligible for treatment, and many patients fail to achieve SVR with this regimen. Furthermore, PEG-IFN+RBV leads to impairment of patient-reported outcomes during treatment, and most patients suffer from adverse events, associated with poor adherence, treatment discontinuation and treatment failure. The approval of second-generation direct-acting antivirals (DAAs) has revolutionized the treatment of CHC patients. All-oral, PEG-IFN and RBV-free regimens have higher efficacy rates, shorter treatment durations, fewer adverse events, higher adherence rates and improvement in PROs from as early as Week 4, compared to PEG-IFN+RBV regimens. The aim of this article is to review the evidence for HCV infection as a systemic disease, summarizing the impact of hepatitis C and its treatments on clinical, patient and economic outcomes, with a focus on data from Asia and Japan specifically.

All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.

Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. To assess efficacy of all-oral HCV therapy in advanced liver disease. Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.

New Direct Acting Antiviral Agents for the Treatment of Hepatitis C: 2016 and Beyond.

Hepatitis C is one of the commonest public health problems with 130 million people infected worldwide and the burden is increasing. Previously, Interferon along with Ribavirin was the mainstay of treatment but it was associated with toxic side effects. An all-oral regimen with higher rates of sustained viral response (SVR), minimal side effects and no restriction for liver fibrosis staging, was long awaited. Several all-oral interferon-free direct acting antiviral agents (DAAs) have now been approved by FDAfor different genotypes of HCV. These include Sofosbuvir, Ledipasvir, Daclatasvir, Simeprevir, Dasabuvir, Ombitasvir, Paritaprevir and Ritonavir. These agents are also available in different combinations commercially under various trade names. Anumber of studies have proved their efficacy and the AASLD and EASLguidelines recommend several options for each genotype in different categories including treatment naïve, relapsers, failure, compensated and decompensated cirrhosis. The purpose of this article is to review the persistently changing treatment regimens for hepatitis C and to simplify the dynamicity of the subject and selection of appropriate regimen for these patients.

Daclatasvir: A Review in Chronic Hepatitis C.

The hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (Daklinza(®)) is indicated for use in combination with sofosbuvir, with or without ribavirin, in a pangenotypic all-oral regimen. In patients with chronic HCV genotype 1 or 3 infection without cirrhosis, a 12-week regimen of daclatasvir plus sofosbuvir achieved high sustained virological response rates 12weeks' post-treatment (SVR12), regardless of prior treatment experience, according to the results of the AI444040 and ALLY-3 trials. In the ALLY-3+ trial, high SVR12 rates were achieved with a 12- or 16-week regimen of daclatasvir plus sofosbuvir and ribavirin in patients with chronic HCV genotype 3 infection and advanced fibrosis or compensated cirrhosis. A daclatasvir plus sofosbuvir-based regimen demonstrated efficacy in patients with chronic HCV genotype 1, 3 or 4 infection and advanced cirrhosis or post-transplant recurrence in the ALLY-1 trial, and in patients co-infected with HCV genotype 1, 3 or 4 and HIV-1 in the ALLY-2 trial. Results of clinical trials were supported by real-world data from early-access programmes that included high numbers of patients who would have been excluded from phase 3 trials because of advanced disease and/or concomitant medical conditions. Daclatasvir plus sofosbuvir with or without ribavirin was generally well tolerated. In conclusion, an all-oral regimen comprising daclatasvir plus sofosbuvir with or without ribavirin is an important option for use in treatment-naive or treatment-experienced patients with chronic HCV genotype 1, 3 or 4 infection, including in patients with advanced liver disease, post-transplant recurrence and HIV-1 co-infection.

Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients.

Predictors of sustained virological response (SVR) to all-oral HCV regimens can inform nuanced treatment decisions. We evaluated effectiveness and identified predictors of SVR for ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ±RBV) and ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) ±RBV in patients treated in routine practice. Observational, intent-to-treat cohort of 21,142 genotype-1 patients initiating 8 or 12 weeks of LDV/SOF ±RBV or 12 weeks of OPrD ±RBV at any Veterans Affairs facility. Multivariate logistic regression models were constructed to model SVR and identify predictors. SVR was 91.2% (9,781/10,720) for LDV/SOF, 89.6% (3,266/3,646) for LDV/SOF+RBV, 91.7% (1,197/1,306) for OPrD and 87.8% (3,365/3,832) for OPrD+RBV. For LDV/SOF ±RBV, reduced odds of SVR occurred in African-Americans (0.80, 95% CI 0.70, 0.92, P<0.001), body mass index (BMI)<25 (0.77, 95% CI 0.66, 0.90, P<0.001), BMI≥30 (0.77, 95% CI 0.67, 0.89, P<0.001), proton pump inhibitors (PPIs; 0.81, 95% CI 0.71, 0.92, P<0.001), decompensated liver disease (0.58, 95% CI 0.45, 0.74, P<0.001) and FIB4>3.25 (0.60, 95% CI 0.53, 0.69, P<0.001). For OPrD ±RBV, FIB-4>3.25 negatively predicted SVR (0.72, 95% CI 0.59, 0.88, P<0.001). Detectable 4-week on-treatment HCV RNA≥15 IU/ml reduced SVR odds for both regimens (LDV/SOF ±RBV OR 0.49, 95% CI 0.41, 0.58, P<0.001; OPrD ±RBV OR 0.38, 95% CI 0.29, 0.50, P<0.001). Receipt of OPrD+RBV compared to LDV/SOF reduced odds of SVR (OR 0.70, 95% CI 0.62, 0.80, P<0.001). Mental health diagnosis did not impact likelihood of SVR. The diversity and size of this cohort allowed for extensive examination of regimen-specific predictors of SVR. FIB-4>3.25 and detectable 4-week on-treatment HCV RNA had the greatest negative impact. African-American race, low or high BMI, and PPIs negatively impacted odds of SVR for LDV/SOF ±RBV. Mental health diagnoses did not.

Direct-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy.

Clinical trials of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection reported high response rates in HCV/HIV coinfection, similar to those obtained in HCV monoinfection. We evaluated the safety and efficacy of these regimens in a clinical practice setting. In this prospective observational study, all the HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting from December 2014 to December 2015 were included in the analysis. Sustained virological response 12 weeks after the end of therapy (SVR12) and reported adverse events (AEs) were evaluated. Resistance-associated variants (RAVs) were analysed in a subgroup of patients at baseline and at the time of viral rebound in those with virological failure. One-hundred and nine patients (51 HCV-infected and 58 HCV/HIV-coinfected) were enrolled in the study. Sixty per cent had cirrhosis and 52% were pegylated interferon and ribavirin (pegIFN/RBV)-experienced. Thirty-six per cent received ombitasvir + paritaprevir/ritonavir + dasabuvir, 25% sofosbuvir + daclatasvir, 16% sofosbuvir + simeprevir, 17% sofosbuvir + ribavirin and 6% sofosbuvir + ledipasvir; ribavirin was used in 57% of subjects. The SVR12 rate was 91% and 96% in HIV-infected and uninfected patients, respectively (P = 0.44). The 4-week HCV viral decline was similar in the two groups. RAVs were found at baseline in 23 of 49 patients and did not affect SVR12. No predictors of SVR12 were identified in our cohort. Treatment with all-oral DAA combinations of patients infected with HCV and with HCV/HIV under real-life conditions led to high and similar rates of SVR12. Moreover, the historical factors associated with a sustained virological response to pegIFN/RBV were not predictive of the response to all-oral DAAs.

Discovery of ravidasvir (PPI-668) as a potent pan-genotypic HCV NS5A inhibitor

This Letter describes the synthesis, representative structure activity relationship (SAR), activity and PK profiles of a series of functionalized benzimidazole–naphthylene–imidazole derivatives as HCV NS5A inhibitors. This effort successfully led to the discovery of ravidasvir (PPI-668), which has been well tolerated and shown high sustained viral response rates as a key component in all-oral combination regimens in multiple human clinical trials.

Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection.

Genotype 4 hepatitis C virus (HCV) was considered difficult to treat in the era of pegylated interferon-alpha (Peg-IFN-α) and ribavirin regimens. We evaluated the efficacy and safety of therapy with the nonstructural (NS) 5A inhibitor, ledipasvir, combined with the NS5B polymerase inhibitor, sofosbuvir, in patients with HCV genotype 4. In this phase 2, open-label study, 44 patients (22 treatment naïve and 22 treatment experienced) received a fixed-dose combination tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir orally once-daily for 12 weeks. The primary endpoint was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (SVR12). Among study participants, HCV genotype 4 subtypes were well represented (4a, n = 25; 4d, n = 10; other subtypes, n = 9). Ten patients (23%) had compensated cirrhosis. Of the 22 treatment-experienced patients, 21 (95%) had a non-CC IL-28B genotype. All 44 patients completed the full 12 weeks of dosing. The SVR12 rate was 93% (41 of 44; 95% confidence interval, 81-99). SVR12 rates were similar between treatment-naïve (95%; 21 of 22) and treatment-experienced (91%; 20 of 22) patients. All 3 patients who did not achieve SVR12 had virological relapse within 4 weeks of the end of treatment; all 3 had baseline HCV RNA ≥800,000 IU/mL, a non-CC IL-28B genotype, and pretreatment NS5A resistance-associated variants. None of the patients who relapsed had cirrhosis. The most common adverse events were asthenia, headache, and fatigue. No patients experienced a serious adverse event. The all-oral regimen of ledipasvir and sofosbuvir is an effective and safe treatment for a wide range of HCV 4 subtypes in both treatment-naïve and -experienced patients, including those with compensated cirrhosis. (EudraCT number: 2013-003978-27; Clinicaltrials.gov NCT02081079) (Hepatology 2016;64:1049-1056).

Desirable Characteristics of Hepatitis C Treatment Regimens: A Review of What We Have and What We Need.

There have been dramatic advancements in the treatment of chronic hepatitis C (HCV) infection. This is largely due to the approval of several direct-acting antiviral agents (DAAs) from a variety of medication classes with novel mechanisms of action. These therapies are a welcomed advancement given their improved efficacy and tolerability compared to pegylated interferon and ribavirin (RBV)-based regimens. These convenient, all-oral regimens treat a variety of genotypes and often offer high cure rates in a variety of HCV-infected populations. While there are several benefits associated with these therapies, there are also notable shortcomings. Shortcomings include diminished response or need for adjunctive RBV in difficult-to-treat populations (decompensated cirrhosis, active substance abuse patients, advanced kidney disease, etc.), activity against select genotypes, substantial drug–drug interaction potential, and high cost. Therefore, while current DAA-based therapies have several favorable attributes, each also has its limitations. The purpose of this review is to (1) identify the characteristics of an ideal HCV treatment regimen, (2) describe desirable features of existing regimens, (3) summarize limitations of existing regimens, and (4) introduce promising emerging therapies. This manuscript will serve as a guide for evaluating the caliber of future HCV treatment regimens.

Does Hepatitis C Treatment Adherence Affect Risk of Liver Transplantation? A Historical Cohort Study.

Chronic hepatitis C virus (HCV) is the primary cause of liver failure leading to transplantation, and medication adherence is essential to the therapeutic efficacy of HCV treatments. While there is evidence linking poor adherence with increased utilization and cost, published literature lacks examination of the association between medication adherence and risk of liver transplant. In addition, the impact of HCV treatment on total costs of liver transplantation is not well documented. To compare (a) the relative risk of liver transplant by adherence in patients treated for HCV and (b) the total health care costs in treated and untreated patients who require liver transplant. This observational, historical cohort study was conducted using administrative data from the Humana Research Database. To be included, patients were required to have a documented HCV diagnosis or treatment between January 1, 2008, and June 30, 2013. Patients were excluded if they had a hepatitis B diagnosis, were not fully insured by a commercial or Medicare Advantage Prescription Drug plan, or were outside the age range of 19-89 years. No minimum pre- or post-index enrollment period was required, and patients were followed for their entire post-index enrollment through December 31, 2013. The study population was divided into treated and untreated groups and then subdivided by presence or absence of a liver transplant. Date of liver transplant was defined as the index date for untreated liver transplant patients; otherwise, the index date was defined as either the date of first observed HCV treatment or diagnosis date (if no treatment or liver transplant). Cox proportional hazards models were used to estimate the relative risk of liver transplant by level of treatment adherence (> 80%, 50%-79%, and < 50%) based on proportion of days covered. General linearized models with log link and gamma distribution were used to compare median total health care costs from index date until end of study period (or death/disenrollment, whichever came first) between treated and untreated liver transplant patients. All costs were converted to 2013 U.S. dollars and reported as total costs per patient and per patient per month (PPPM) to account for varying follow-up periods. Of the 53,423 patients identified with HCV, 10,377 met exclusion criteria, leaving 43,046 patients (primarily Caucasian, males, mean age of 58 years) in the initial cohort. Only 6.29% (n = 2,708) of the total HCV cohort received HCV treatment, and less than 1% (n = 366, 0.8%) received a liver transplant. Although there were no significant differences in the risk of liver transplant by adherence level, there was an upwards trend in the rate of liver transplant as adherence worsened (> 80%: 1.25%; 50%-79%: 1.30%; and < 50%: 1.99%), and the average days to liver transplant was longer with higher adherence (> 80%: 683; 50%-79%: 623; < 50%: 454). Only 48 (13.11%) patients who received a liver transplant were treated for HCV. Adjusted median total and PPPM health care costs measured from index date until end of the study period were significantly higher for patients who received HCV treatment compared with those who did not (total=$231,139 vs. $86,167, adjusted P < 0.001; PPPM=$20,583 vs. $5,778, adjusted P = 0.008), driven by HCV-related medical costs and total pharmacy costs. Adherence with HCV regimens did not affect risk of liver transplant, underscoring the need for further evidence linking treatment adherence to future liver transplant risk. HCV-treated patients who required liver transplant incurred significantly higher health care costs than those without HCV treatment before liver transplant. Introduction of newer all-oral direct-acting antiviral regimens, with higher acquisition costs, will require further research to more accurately assess medication adherence and its relationship with transplantation, as well as with total health care costs. No outside funding supported this research. Ems, Worley, Racsa, Gregory, Anderson, and Holt are employees of Humana. Brill has participated in a physician advisory board at Humana. The authors have no other financial disclosures to report. Study concept and design were contributed by Ems, Racsa, Worley, and Anderson, along with Gregory, Brill, and Holt. Racsa took the lead in data collection, along with Ems and Worley. All authors participated in data interpretation. Anderson, along with the other authors, wrote the manuscript, which was revised by Brill and Holt, with assistance from the other authors.

Management of Hepatitis C/HIV Coinfection in the Era of Highly Effective Hepatitis C Virus Direct-Acting Antiviral Therapy.

The increased life expectancy of persons infected with human immunodeficiency virus (HIV) treated with antiretroviral therapy (ART) has resulted in renewed attention to non-HIV-related diseases exacerbated by HIV infection. Coinfection with hepatitis C virus (HCV) is a particular area of concern, as the global prevalence has been estimated at 2.5-5 million people. In this article, we discuss the epidemiology of HCV infection and reinfection, HCV-related liver disease progression in the era of effective ART, and the efficacy of emerging HCV treatment strategies in persons with HIV/HCV coinfection. New data regarding treatment of persons with HIV/HCV coinfection suggest that HCV treatment should be a priority in those with HIV. Results from recent studies using all-oral HCV regimens have shown high rates of sustained virologic response in both clinical trials and real-world settings. A multidisciplinary approach to HCV treatment in those with HIV is recommended for optimal patient management. Following HCV cure, practitioners also need to be mindful of the risks for HCV reinfection and educate patients on protective measures.