Nancy Reau

Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection

BACKGROUND In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. METHODS We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. CONCLUSIONS Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).

Effectiveness of Simeprevir Plus Sofosbuvir, with or Without Ribavirin, in Real-World Patients with HCV Genotype 1 Infection

BACKGROUND & AIMS The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.

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.

Early Predictors of Anemia in Patients With Hepatitis C Genotype 1 Treated With Peginterferon Alfa-2a (40KD) Plus Ribavirin

OBJECTIVE:Adherence to ribavirin is one factor that is critically important in the treatment of hepatitis C virus infection. However, ribavirin can be associated with clinically significant hemolytic anemia resulting in dose modifications in up to one-quarter of patients. Currently, baseline predictors of considerable anemia are not sufficiently discriminating for routine therapeutic intervention. The objective of this analysis was to elucidate baseline and on-treatment factors predictive of a considerable hemoglobin drop at week 4.METHODS:Multivariate logistic regression analysis was used to explore possible predictors for considerable hemoglobin decline (≥2.5 g/dL) at week 4 among patients receiving peginterferon alfa-2a (40KD) and ribavirin (1,000/1,200 mg/day).RESULTS:A total of 555 patients were included in this analysis. At week 4, 236 patients exhibited a ≥2.5 g/dL decrease in hemoglobin. By regression analysis the most important independent variables associated with a decrease in hemoglobin of ≥2.5 g/dL were baseline creatinine clearance (P= 0.0003) and a rapid decline in hemoglobin of ≥1.5 g/dL at week 2 (P < 0.0001). Considerable hemoglobin decreases at week 4 were also significantly associated with early ribavirin dose reductions and a lower cumulative daily dose of ribavirin.CONCLUSION:Patients with impaired renal function may be at an increased risk of ribavirin-related anemia and should be monitored accordingly. Furthermore, a hemoglobin drop of ≥1.5 g/dL by week 2 was an excellent early predictor for subsequent considerable hemoglobin decreases and might be used to identify candidates for early intervention against anemia in order to help maintain ribavirin dosing and avoid suboptimal exposure.

Vanishing bile duct syndrome.

Perhaps no condition associated with chronic cholestasis is less understood than vanishing bile duct syndrome, a term that refers loosely to the group of acquired disorders associated with progressive destruction and disappearance of the intrahepatic bile ducts and, ultimately, cholestasis. Although the array of insults resulting in poor bile flow is vast, most adult patients who have chronic cholestasis have either primary biliary cirrhosis (or primary sclerosing cholangitis; in some cases, however, a cause cannot be identified. This article reviews the multiple causes, postulated pathophysiology, clinical features, and treatment options for this syndrome.

Sticker shock and the price of new therapies for hepatitis C: Is it worth it?

T he new era of antiviral therapy for hepatitis C holds great promise to finally rein in a public health nightmare, but at what expense? It has been estimated that a 12-week course of therapy could cost in excess of

Long-term outcomes after treatment with interferon and ribavirin in HCV patients.

84,000. Much has been written in the lay press regarding the price of these newer therapies, which has led to concerns about the ability of our healthcare system to effectively implement and deliver these treatments to those in greatest need. Can we justify these costs? To better understand this, it is necessary to frame the discussion in the context of the economic burden of chronic liver disease against the retail cost of therapy. Product price also reflects drug development and productions expense; however, this is very difficult to access. What is success and what is it worth? According to the Oxford Dictionary, success is the accomplishment of an aim or purpose. In medicine, success can be hard to define. However, when it comes to hepatitis C therapy, sustained viral response (SVR) is a wellestablished surrogate for treatment success, and has been equated with a cure. Not only is SVR durable, with a less than 1% chance for late relapse, SVR has been associated with lower rates of liver cancer, cirrhosis, transplant, and all-cause mortality. It leads to improved quality of life, lower risk of metabolic complications such as insulin resistance, improves glycemic control in those who are diabetic, and recovers neurocognitive function. It is difficult to argue this is not success—both for the patient as well as society. How much is this worth? What is the price of prevention? Hepatitis C virus (HCV) is generally asymptomatic (and thus not a significant economic burden) until advanced liver disease occurs. This was confirmed by a recent study that compared the economic burden for U.S. patients with chronic hepatitis C, stratified by severity of liver disease, in a large private health insurance claims database from 2003 to 2010. The database included claims for all prescription medications and all medical services submitted for payment. Researchers examined claims from 53,796 patients with chronic hepatitis C: 41,858 (78%) without cirrhosis, 3,718 (7%) with compensated cirrhosis, and 8,220 (15%) with endstage liver disease. Overall, the annual healthcare costs were estimated to be

Ribavirin-Free Regimen With Sofosbuvir and Velpatasvir Is Associated With High Efficacy and Improvement of Patient-Reported Outcomes in Patients With Genotypes 2 and 3 Chronic Hepatitis C: Results From Astral-2 and -3 Clinical Trials

24,176 for patients with chronic hepatitis C infection. However, when examined by disease stage, advanced disease consumed a substantially larger proportion of the total. Average annual costs were

Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin

17,277 for patients with no cirrhosis,

ACG Clinical Guideline: Liver Disease and Pregnancy

22,752 among patients with well-compensated cirrhosis, and