Navigating Diagnostic Challenges: A Case of Acquired Hepatocerebral Degeneration Presenting as Worsening Hepatic Encephalopathy in Chronic Liver Disease.

This case report details the complex diagnostic odyssey of a 60-year-old female grappling with chronic liver disease, initially diagnosed with hepatic encephalopathy (HE). Despite initial treatment with lactulose and rifaximin, her neurological symptoms worsened, leading to the identification of concurrent acquired hepatocerebral degeneration (AHD). This condition is characterised by cognitive decline, movement disorders and distinctive imaging abnormalities. The discussion highlights the challenges in distinguishing AHD from HE, underscoring the sophisticated diagnostic and management strategies required for such intricate cases in the realm of chronic liver disease. LEARNING POINTS: Recognizing coexisting conditions: emphasize the importance of identifying acquired hepatocerebral degeneration (AHD) alongside hepatic encephalopathy (HE) in patients with chronic liver disease. This recognition is crucial for comprehensive assessments and understanding the progression of neurological symptoms.Addressing management challenges: highlight the complexities of managing AHD due to limited therapeutic options and potentially irreversible outcomes. Discuss the challenges in decision-making, such as considering liver transplantation for patients with advanced neurological symptoms, and the need for exploring alternative therapeutic strategies.Conducting comprehensive evaluations: stress the significance of thorough evaluations in patients with chronic liver disease presenting with neurological symptoms. This comprehensive approach can help uncover underlying conditions like AHD, which may require different management strategies than those initially considered.

Liver Transplantation Using Hepatitis C Virus-Viremic Donors Into Hepatitis C Virus-Aviremic Recipients as Standard of Care.

Liver transplantation (LT) using allografts from hepatitis C virus (HCV)-viremic/nucleic acid testing-positive donors' (DNAT+) organs into HCV-aviremic recipients (rHCV-) has been limited owing to nearly universal HCV transmission and concerns regarding availability, safety, and efficacy post-LT with direct-acting antiviral (DAA) therapy. We report our experience of LT using DNAT+ organs into rHCV- as a routine standard of care. Following verification of DAA access, absence of critical drug-drug interactions (DDIs) with DAAs, and informed consent, allocated DNAT+ organs were offered to patients on the waiting list for LT irrespective of recipient HCV status. Between June 2018 and December 2019, 292/339 rHCV- received an LT. Forty-seven patients were excluded from analysis because of recipient HCV viremia, refusal to receive DNAT+ organs, or inability to receive DAA therapy post-LT. Of these 292 patients, 61 rHCV- received DNAT+ livers (study group), and 231 rHCV- received DNAT- (aviremic donors [nuclear acid test-negative donors]) livers (control group). Recipient and donor characteristics as well as 1-year post-LT patient and graft survival were similar between groups. In the study group, 4 patients died, and 1 patient required retransplantation within the first year post-LT (all unrelated to HCV); 56 patients received DAA therapy, with a median time from LT to the start of DAA treatment of 66.9 days (interquartile range [IQR], 36-68.5), and 51 patients completed DAA treatment, all achieving sustained virologic response for 12 or more weeks (SVR-12) (1 patient required retreatment owing to relapse following initial DAA therapy). No patients had evidence of fibrosing cholestatic hepatitis or extrahepatic manifestations of HCV. This report indicates that transplantation of DNAT+ livers into rHCV- and subsequent DAA therapy is associated with clinical outcomes comparable to those achieved with DNAT- allografts.

Maternal knowledge of the risk of vertical transmission and offspring acquisition of hepatitis B.

INTRODUCTION AND OBJECTIVES: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. MATERIALS AND METHODS: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. RESULTS: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p=0.02) or diagnosis of HBV (p=0.02). CONCLUSIONS: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5-15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.

Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials.

BACKGROUND & AIMS: Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. METHODS: We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. RESULTS: Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. CONCLUSIONS: Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. LAY SUMMARY: Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients. TRIAL REGISTRATION DETAILS: Clinicaltrials.gov numbers NCT03053050 and NCT03053063.

Noninvasive Tests Accurately Identify Advanced Fibrosis due to NASH: Baseline Data From the STELLAR Trials.

Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration-controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5-fold cross-validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0-F2 fibrosis and 2,262 with F3-F4 fibrosis. Significant differences between median values of NITs for patients with F0-F2 versus F3-F4 fibrosis were observed: -0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB-4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P < 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB-4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB-4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real-world population.

Total Alanine Aminotransferase (ALT) Flares in Pregnant North American Women With Chronic Hepatitis B Infection: Results From a Prospective Observational Study.

INTRODUCTION: Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV. METHODS: Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy. RESULTS: Among the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation. DISCUSSION: Spontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.

Nonalcoholic steatohepatitis: the new frontier for liver transplantation.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease globally and nonalcoholic steatohepatitis is projected to become the most common indication for liver transplantation. The purpose of this review is to highlight key issues surrounding NAFLD as an indication for liver transplantation, including its increasing prevalence, outcomes related to liver transplantation, development of post liver transplant NAFLD and NAFLD in the liver donor pool. RECENT FINDINGS: With the advent of direct-acting antiviral therapies, the proportion of patients on the liver transplant list or undergoing liver transplant for chronic hepatitis C infection is steadily decreasing. In contrast, the number transplants performed for NAFLD is increasing. By 2030, it is estimated that the incidence of decompensated cirrhosis and hepatocellular carcinoma will increase by 168 and 137%, respectively, and the number of deaths will increase by 178%. SUMMARY: Liver transplantation cures cirrhosis but does not treat the underlying metabolic disease associated with NAFLD. Thus, strategies to control comorbidities in patients with NAFLD prior to transplant are needed to decrease waitlist mortality and the recurrence of NAFLD after liver transplant. NAFLD in the donor pool is also a growing concern. Strategies to minimize steatosis and expand the number of donors are critical to meet the growing demand for liver transplantation.

Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.

BACKGROUND & AIMS: T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS: We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS: Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS: HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis.

BACKGROUND: As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS: We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS: Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

Sustained virologic response rates with telaprevir-based therapy in treatment-naive patients evaluated by race or ethnicity.

BACKGROUND: The phase 3 studies of telaprevir (T) in combination with peginterferon α-2a and ribavirin (PR) in treatment-naive genotype 1 chronic hepatitis C virus-infected patients (ADVANCE/ILLUMINATE) were not designed a priori to assess the effect of race and ethnicity on treatment response. However, these factors are important given the lower sustained virologic response (SVR) rates observed in black and Hispanic/Latino patients treated with PR. GOALS: This retrospective pooled analysis evaluated the effect of race or ethnicity on treatment-naive patient response to telaprevir-based therapy and assessed resistant variant profiles. MATERIALS AND METHODS: This analysis comprised patients enrolled in ADVANCE (N=363) and ILLUMINATE (N=540) who received 12 weeks of telaprevir in combination with PR followed by 12 or 36 weeks of PR alone and patients in ADVANCE (N=361) who received 48 weeks of PR alone. Race and ethnicity were self-reported and not mutually exclusive. RESULTS: Higher SVR rates were observed with telaprevir-based therapy compared with PR in blacks [n=99 (62%) vs. n=28 (29%), respectively] and in Hispanics/Latinos [n=89 (72%) vs. n=38 (39%)]. The SVR was lower in telaprevir-treated blacks [n=99 (62%)] compared with nonblacks [n=791 (78%)] and in Hispanic/Latinos compared with non-Hispanics/Latinos [n=89 (72%) vs. n=801 (76%)]. Low discontinuation rates due to adverse events, including rash and anemia, were observed across subgroups. Resistance profiles were similar among the subgroups. CONCLUSIONS: Treatment-naive black and Hispanic/Latino patients with genotype 1 chronic hepatitis C virus infection may benefit from telaprevir-based therapy, an important finding given the lower SVR rates observed in these patients when they are treated with PR alone.

Liver transplantation at the ochsner clinic: quality and outcomes improvement.

BACKGROUND: In 2005, the results published by the Scientific Registry of Transplant Recipients showed that Ochsner Clinic Foundation's patient and graft survival rates were statistically lower than expected, and the United Network for Organ Sharing Membership and Professional Standards Committee placed our center under peer review. METHODS: In response, patient outcomes prior to August 2005 were carefully reviewed in a transparent fashion and protocols were written to standardize treatments. We renewed the focus on patient-related outcomes and regulatory adherence and empowered frontline staff to express their views, allowing for real teamwork to develop. Multiple changes were implemented in the everyday running of the program. A quality assurance and performance improvement plan (QAPI) was initiated to improve outcomes. RESULTS: In 2012, the Ochsner liver transplant program became the largest liver transplant program in the United States by volume and in 2013 was awarded the prestigious CareChex award, acknowledging it as the number one program in terms of quality of care and outcomes for liver transplantation. CONCLUSION: The methodical application of this QAPI program achieved a remarkable transformation of the Ochsner liver transplant program and exemplifies what is possible with strong teamwork from dedicated and talented staff.

Acute liver failure caused by herpes simplex virus in a pregnant patient: is there a potential role for therapeutic plasma exchange?

A young woman presented with a febrile illness in the third trimester of pregnancy. Laboratory investigation revealed severe acute hepatitis with thrombocytopenia and coagulopathy. Liver injury progressed despite emergent caesarian section and delivery of a healthy infant. Therefore, therapeutic plasma exchange (TPE) was performed on three consecutive days post-partum for a presumed diagnosis of acute liver failure (ALF) associated with pregnancy due to hemolysis, elevated liver enzymes, and low platelets (HELLP) or acute fatty liver of pregnancy (AFLP). Treatment with TPE was followed by biochemical and clinical improvement but during her recovery herpes simplex virus type 2 (HSV-2) infection was diagnosed serologically and confirmed histologically. Changes in the immune system during pregnancy make pregnant patients more susceptible to acute HSV hepatitis, HSV-related ALF, and death. The disease is characterized by massive hepatic inflammation with hepatocyte necrosis, mediated by both direct viral cytotoxicity and the innate humoral immune response. TPE may have a therapeutic role in acute inflammatory disorders such as HSV hepatitis by reducing viral load and attenuating systemic inflammation and liver cell injury. Further investigation is needed to clarify this potential effect. The roles of vigilance, clinical suspicion, and currently accepted therapies are emphasized.

Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation.

Long-term prophylaxis with hepatitis B immunoglobulin (HBIG) for the prevention of hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) in patients with chronic HBV infection is inconvenient and costly. This randomized, prospective phase 2 study compared emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) after HBIG withdrawal to FTC/TDF plus HBIG for the prevention of HBV recurrence after OLT. Forty patients with a median time since liver transplantation of 3.4 years (interquartile range = 1.9-5.6 years) received 24 weeks of open-label FTC/TDF plus HBIG before randomization. Patients who maintained confirmed viral suppression were randomized to continue FTC/TDF plus HBIG (n = 19) or receive FTC/TDF alone (n = 18) for an additional 72 weeks. No patient experienced HBV recurrence through 72 weeks of the study while he or she was receiving the randomized treatment. Both treatment arms were safe and well tolerated; no serious or severe drug-related adverse events were observed. Renal function was consistent with that observed in a posttransplant population. The withdrawal of HBIG after 6 months' treatment with FTC/TDF should be considered in liver transplant recipients to prevent chronic HBV recurrence.

Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.

BACKGROUND: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. METHODS: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 µg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. FINDINGS: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. INTERPRETATION: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. FUNDING: Gilead Sciences.

PROPEL: a randomized trial of mericitabine plus peginterferon alpha-2a/ribavirin therapy in treatment-naïve HCV genotype 1/4 patients.

UNLABELLED: Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment-naïve HCV genotype 1 or 4 patients were randomized to double-blind treatment with oral mericitabine at a dosage of 500 mg twice-daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha-2a (Peg-IFNα-2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A-C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A-E) continued Peg-IFNα-2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow-up; SVR-24). VR rates were higher in arms A-D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non-CC IL28B genotypes. However, the overall SVR-24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response-guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine-resistance mutations (S282T) were observed during mericitabine therapy. CONCLUSION: Treatment with mericitabine plus Peg-IFNα-2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN-free and IFN-containing trials of mericitabine of longer treatment duration are ongoing.