Prevention of allograft HCV recurrence with peri-transplant human monoclonal antibody MBL-HCV1 combined with a single oral direct-acting antiviral: A proof-of-concept study.

Patients with active hepatitis C virus (HCV) infection at transplantation experience rapid allograft infection, increased risk of graft failure and accelerated fibrosis. MBL-HCV1, a neutralizing human monoclonal antibody (mAb) targeting the HCV envelope, was combined with a licensed oral direct-acting antiviral (DAA) to prevent HCV recurrence post-transplant in an open-label exploratory efficacy trial. Eight subjects received MBL-HCV1 beginning on the day of transplant with telaprevir initiated between days 3 and 7 post-transplantation. Following FDA approval of sofosbuvir, two subjects received MBL-HCV1 starting on the day of transplant with sofosbuvir initiated on day 3. Combination treatment was administered for 8-12 weeks or until the stopping rule for viral rebound was met. The primary endpoint was undetectable HCV RNA at day 56 with exploratory endpoints of sustained virologic response (SVR) at 12 and 24 weeks post-treatment. Both subjects receiving mAb and sofosbuvir achieved SVR24. Four of eight subjects in the mAb and telaprevir group met the primary endpoint; one subject achieved SVR24 and three subjects relapsed 2-12 weeks post-treatment. The other four subjects experienced viral breakthrough. There were no serious adverse events related to study treatment. This proof-of-concept study demonstrates that peri-transplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.

Open-label study of faldaprevir plus peginterferon and ribavirin in hepatitis C virus genotype 1-infected patients who failed placebo plus peginterferon and ribavirin.

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥ 800,000 IU/mL (80% vs 58%) and a non-CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥ 2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir.

Grazoprevir plus peginterferon and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection: a randomized trial.

UNLABELLED: Grazoprevir (MK-5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25-100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty-seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100-mg arm and 22 days in the 25- and 50-mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25-, 50- and 100-mg arms, respectively (per-protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25- and 100-mg arms). CONCLUSION: These data support further study of the grazoprevir 100-mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).

Efficacy and tolerability of rifaximin in combination with lactulose in end-stage liver disease patients with MELD greater than 20: a single center experience.

BACKGROUND: Rifaximin is a non-absorbable antibiotic which is approved for the treatment of hepatic encephalopathy (HE) in the United States. Our goal was to retrospectively assess this in patients with very advanced liver disease with our center data. METHODS: Between 2003 and 2010, we examined a total of 286 consecutive patients from our center who were on a combination of rifaximin and lactulose, who had been evaluated or listed as eligible for a liver transplant. Patients who received less than 3 months of rifaximin and lactulose were excluded. Patients who had incomplete data; specifically, a lack of MELD score upon hospital admission were excluded from this analysis. The retrospective chart review was approved by the institutional review board. RESULTS: We observed a total of 723 hospitalizations among the patients. Of the 723 hospitalizations, 218 were due to portosystemic encephalopathy (PSE), whereas 505 were due to other causes. We observed that patients with a MELD < 20 had an average of 2.5 hospitalizations per 6 month period, and that those with a MELD > 20 had an average of 1.6 hospitalizations per 6 month period for HE. At the same time, patients who had a MELD score < 20 had 3.29 hospitalizations for HE unrelated causes and those whose MELD was >20 had 3.73 hospitalizations for causes not related to HE. In this cohort 65% of all hospitalizations from HE were in patients whose MELD was < 20, and 35% of all hospitalizations were for patients with a MELD > 20. CONCLUSION: In our experience, HE related hospitalizations were lower in patients whose MELD > 20 who were on a combination of rifaximin and lactulose compared to patients with MELD < 20. In contrast, patients whose MELD > 20 had greater hospitalizations for non HE events which may be an expected result owing to the overall increased severity of their liver disease. The limitation of this study is its retrospective nature and single center experience. In conclusion, administration of rifaximin appears to significantly reduce hospitalizations from HE in patients with MELD > 20 and therefore is advocated in maintenance of remission of HE in patients with very advanced liver disease.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.

BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Rifaximin for the treatment of hepatic encephalopathy.

BACKGROUND: Previous studies suggest that rifaximin is efficacious in the treatment of hepatic encephalopathy. OBJECTIVE: To evaluate the efficacy and safety of rifaximin in addition to lactulose in improving hospitalization outcomes in patients with hepatic encephalopathy. METHODS: Hospital records of patients evaluated for liver transplantation at a single center between January 2006 and May 2008 were reviewed. Hospitalizations for hepatic encephalopathy and other conditions and the incidence of spontaneous bacterial peritonitis and adverse events were analyzed. RESULTS: Charts of 65 patients who were treated with rifaximin and lactulose were analyzed. Patients received lactulose (20-120 g/d; lactulose phase) before treatment with rifaximin (400- 1200 mg/d; rifaximin phase). During the rifaximin phase, the risk, number, and duration of hospitalizations for hepatic encephalopathy were reduced compared with the lactulose phase. Treatment, age, and Model for End-Stage Liver Disease score were independent predictors of hospitalizations for hepatic encephalopathy (P < .05). The rifaximin phase had fewer hospitalizations than the lactulose phase (36 vs 47, respectively) and a smaller percentage of patients with repeated hospitalizations than the lactulose phase (5% vs 14%, respectively; P = .006) for conditions other than hepatic encephalopathy. A smaller percentage of patients had evidence of spontaneous bacterial peritonitis during the rifaximin phase than the lactulose phase (2% vs 12%, respectively; P = .02). Rifaximin was better tolerated than lactulose. CONCLUSIONS: Addition of rifaximin to lactulose therapy significantly reduced the risk and duration of hospitalizations for hepatic encephalopathy.

Herpes simplex hepatitis.

We report a 76-year-old man who presented with hepatitis. IgM antibodies to herpes simplex virus were positive and scraping from skin lesions showed presence of herpetic inclusion bodies. The patient died 4 days after the onset of illness.