Marcelo Silva

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme Corp.

Peginterferon alfa-2b and Ribavirin: Effective in Patients With Hepatitis C Who Failed Interferon alfa/Ribavirin Therapy

BACKGROUND & AIMS Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. METHODS This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 microg/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigators request. RESULTS Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (< or =600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. CONCLUSIONS Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus

BACKGROUND & AIMS Interferon therapy has been associated with a number of severe side effects when administered to patients with decompensated cirrhosis caused by chronic hepatitis B. The safety and potential efficacy of a low-dose, titratable regimen of interferon alfa-2b in patients with decompensated liver disease caused by chronic hepatitis B virus infection were studied. METHODS Twenty-six patients were treated at five medical centers. Five patients had Childs class A status, 15 had Childs B status, and 6 had Childs C status. Treatment was continued for 24 weeks whenever possible. Dose adjustments were made according to predefined safety criteria. RESULTS All patients with Childs A status responded with a sustained loss of serum hepatitis B virus DNA, reduction in aminotransferase activity, and clinical stabilization. Only 5 patients with Childs B (33%) and no patients with Childs C status reached similar end points. The probability of survival was greater in responders than in nonresponders (P = 0.017). Three patients each developed serious infections or greater than twofold increases in serum aminotransferase levels during therapy. CONCLUSIONS Low-dose, titratable interferon therapy is safer than previously reported regimens. Nonetheless, serious infections were observed relatively frequently, and this therapy should be reserved for individuals with mild to moderate hepatic decompensation, preferably patients with Childs A status.

Entecavir therapy for lamivudine‐refractory chronic hepatitis B: Improved virologic, biochemical, and serology outcomes through 96 weeks

In hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients who were refractory to current lamivudine therapy, switching to entecavir was superior to continued lamivudine at week 48 for histologic improvement, viral load reduction by polymerase chain reaction and alanine aminotransferase normalization. We assessed the efficacy, safety, and resistance profile of entecavir through 96 weeks of treatment. A total of 286 patients were randomized and treated with entecavir 1 mg (n = 141) or continued lamivudine 100 mg (n = 145). At week 52, 77 entecavir‐treated patients who had a protocol‐defined virologic response (HBV branched DNA [bDNA] < 0.7 MEq/mL but HBeAg‐positive) continued blinded therapy for up to 96 weeks. Patients were assessed for efficacy, safety, and emerging resistance. Cumulative proportions of all treated patients who achieved confirmed efficacy endpoints were also analyzed. Between week 48 and the end of dosing, the proportions of patients with HBV DNA <300 copies/mL by polymerase chain reaction increased from 21% to 40%, and alanine aminotransferase normalization (≤1× upper limit of normal) increased from 65% to 81%. In the second year, HBeAg seroconversion was achieved by 10% of patients. Of the 77 patients in the second year treatment cohort, entecavir resistance emerged in six patients, and seven experienced virologic breakthrough (five with genotypic resistance acquired before year 2). The safety profile of entecavir in the second year of therapy was consistent with that reported during year 1. Conclusion: Through 96 weeks of treatment, 1 mg entecavir resulted in continued clinical benefit in lamivudine‐refractory HBeAg‐positive chronic hepatitis B patients with a safety profile comparable to lamivudine. (HEPATOLOGY 2008.)

Fulminant or subfulminant non-A, non-B viral hepatitis: The role of hepatitis C and E viruses

BACKGROUND Although non-A, non-B (NANB) viral hepatitis has been implicated as an etiology of fulminant hepatitis, hepatitis C virus (HCV) has not been shown to result in acute hepatic failure and hepatitis E virus (HEV) has predominantly been associated with fulminant hepatitis among pregnant women. METHODS Using polymerase chain reaction to detect HCV and HEV genomes, four-antigen radioimmunoblot assay (4-RIBA) to measure anti-HCV antibodies, and enzyme-linked immunosorbent assay (ELISA) to detect anti-HEV immunoglobulin M (IgM) antibodies, 17 patients with sporadic fulminant or subfulminant hepatitis of presumed NANB viral etiology were studied. RESULTS The diagnosis of acute NANB viral hepatitis was made based on clinical information, serological tests, biochemical profiles, and pathological features. All 17 patients were negative for anti-HEV IgM antibodies and HEV RNA in either serum and/or liver. HCV RNAs were detected in 2 patients although anti-HCV antibodies were negative in all of them. CONCLUSIONS It is shown that HCV is infrequently associated with and HEV is not an identifiable cause of presumed NANB fulminant or subfulminant hepatitis in this patient population. Although further studies will be required for identification of the causative agent, it is possible that another agent is responsible for the occurrence of sporadic NANB fulminant or subfulminant hepatitis.

Trends and projections of hepatitis C virus epidemiology in Latin America

Background and aim: The purpose of the present investigation is to provide an analysis of previous works on the epidemiology of the hepatitis C virus (HCV) infection from six countries throughout Latin America, to forecast the future HCV prevalence trends in Argentina, Brazil, Mexico and Puerto Rico, and to outline deficiencies in available data, highlighting the need for further research.

Hepatic dysfunction accompanying acute cocaine intoxication

We identified 39 patients with acute cocaine intoxication and rhabdomyolysis over an 8-year period. Twenty-three of the patients (59%) demonstrated biochemical evidence for hepatic dysfunction. Sixteen of these patients had severe liver injury as defined by an alanine aminotransferase (ALT) of greater than 400 U/l (group A). Seven had an ALT between 36-399 U/l (group B) and 16 showed no evidence of liver injury (group C). In contrast to those with normal ALT, the clinical course of the group A patients was more often accompanied by profound hypotension (44 vs. 0%, p less than 0.025), disseminated intravascular coagulation (50 vs. 0%, p less than 0.005), hyperpyrexia (75 vs. 25%, p less than 0.025) and acute renal failure (81 vs. 0%, p less than 0.001). Seven of the group A patients expired (44%). Histologic examination of liver tissue obtained from post-mortem samples demonstrated extensive centrilobular and midzonal necrosis in three cases and panlobular necrosis in two others. A mild lymphocytic infiltrate with bile duct proliferation was present in each specimen. We conclude that cocaine intoxication can be accompanied by liver dysfunction which is most likely multifactorial; the presence of severe dysfunction identifies a patient with potentially significant morbidity and mortality.

Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: A multicenter prospective study

BACKGROUND & AIM Retrospective studies show an association between proton pump inhibitor (PPI) therapy and spontaneous bacterial peritonitis (SBP). We investigate the relationship between PPI and SBP in decompensated cirrhotic patients in a large nationwide prospective study. METHODS Seven hundred seventy patients with a diagnosis of decompensated cirrhosis were admitted consecutively in 23 hospitals in Argentina from March 2011 to April 2012; the patients were carefully investigated for PPI consumption in the previous 3 months. In total, 251 patients were excluded because of active gastrointestinal hemorrhage, antibiotic use during the preceding weeks, HIV-positive status and immunosuppressive therapy. RESULTS Two hundred twenty-six out of 519 patients (43.5%) had received PPI therapy within the last 3 months. In 135 patients, PPIs were administered for longer than 2 weeks. A bacterial infection was shown in 255 patients (49.1%). SBP was diagnosed in 95 patients out of 394 patients with ascites (24.7%). There was no significant difference in the rate of PPI consumption between the infected and the non-infected patients (44.3% vs. 42.8%) or between the SBP patients and the patients with ascites without SBP (46% vs. 42%). In the SBP patients, the duration of PPI administration did not influence the rate of SBP occurrence. The type of bacteria and the origin of SBP infection were similar in the patients with and without PPI. CONCLUSION In the current large, multicenter, prospective study, PPI therapy, specifically evaluated at admission of consecutive cirrhotic patients, was not associated with a higher risk of SBP.

Antiviral activity of boceprevir monotherapy in treatment-naive subjects with chronic hepatitis C genotype 2/3

BACKGROUND & AIMS To examine the antiviral activity of boceprevir, a hepatitis C virus (HCV) protease inhibitor, in HCV genotype (G) 2/3-infected patients. METHODS We assessed boceprevir and telaprevir activity against an HCV G2 and G3 isolates enzyme panel, in replicon, and in phenotypic cell-based assays. Additionally, a phase I study evaluated the antiviral activity of boceprevir monotherapy (200mg BID, 400mg BID, or 400mg TID) vs. placebo for 14 days in HCV G2/3 treatment-naive patients. RESULTS Boceprevir and telaprevir similarly inhibited G1 and G2 NS3/4A enzymes and replication in G1 and G2 replicon and cell-based assays. However, telaprevir demonstrated lower potency than boceprevir against HCV G3a enzyme (Ki=75 nM vs. 17 nM), in the G3a replicon assay (EC₅₀=953 nM vs. 159 nM), and against HCV G3a NS3 isolates (IC₅₀=3312 nM vs. 803 nM) in the cell-based assay. In HCV G2/3-infected patients, boceprevir (400 mg TID) resulted in a maximum mean decrease in HCV RNA of -1.60 log vs. -0.21 log with placebo. CONCLUSIONS In vitro, boceprevir is more active than telaprevir against the HCV G3 NS3/4A enzyme in cell-based and biochemical assays and against G3 isolates in replicon assays. In HCV G2/3-infected treatment-naive patients, decreases in HCV RNA levels with boceprevir (400 mg TID) were comparable to those observed with the same dose in HCV treatment-experienced G1-infected patients.

Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4–5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy. METHODS In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment-emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350. FINDINGS Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99·1%; 95% CI 95·3-100·0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98·0%; 92·9-99·7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84·6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations. INTERPRETATION These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme.