Marianne Maynard

A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis

BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. METHODS We conducted a 12-month, randomized, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of HD-UDCA (28-35 mg/kg per day) in 126 patients with biopsy-proven NASH and elevated alanine aminotransferase (ALT) levels. The primary study end point was reduction in ALT levels from baseline in patients treated with HD-UDCA compared with placebo. Secondary study end points were the proportion of patients with ALT normalization, relative reduction in the scores of serum markers of fibrosis and hepatic inflammation, and safety and tolerability. RESULTS HD-UDCA significantly reduced mean ALT levels -28.3% from baseline after 12 months compared with -1.6% with placebo (p<0.001). At the end of the trial, ALT levels normalized (≤35 IU/L) in 24.5% of patients treated with HD-UDCA and in 4.8% of patients who received placebo (p=0.003). Both results were not accounted for by changes in weight during the trial. HD-UDCA significantly reduced the FibroTest® serum fibrosis marker (p<0.001) compared with placebo. HD-UDCA also significantly improved markers of glycemic control and insulin resistance. There were no safety issues in this population. CONCLUSIONS Treatment with HD-UDCA was safe, improved aminotransferase levels, serum fibrosis markers, and selected metabolic parameters. Studies with histologic end points are warranted.

Evolution of hepatitis B viral load and viral genome sequence during adefovir dipivoxil therapy

Summary.  Phase II and III clinical trials of adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B have shown that this hepadnavirus polymerase inhibitor is well tolerated and effectively suppresses hepatitis B virus (HBV) replication. We therefore analysed the evolution of viral load and the emergence of HBV polymerase mutants in a 22‐patient subgroup from a phase III clinical trial of ADV for the treatment of HBeAg‐positive chronic hepatitis B. HBV DNA serum titres were quantified using a real‐time polymerase chain reaction (PCR) assay with molecular hybridization probes. Emergence of polymerase mutants was assessed by direct sequencing of the viral reverse transcriptase domain after PCR amplification of HBV DNA isolated from serum. Our results indicated that ADV therapy effectively suppressed HBV replication in these patients (median serum HBV decrease at week 48 of treatment = 4.3 log10 copies/mL). The initial drop of HBV DNA titres in serum at week 12 of ADV therapy seemed to be predictive of subsequent HBe seroconversion (P = 0.059). Neither viral breakthrough nor the selection of drug resistant mutants were observed during the study period. Our results showed that ADV administration for 48–72 weeks effectively suppresses HBV replication without the emergence of resistant viral mutants.

Clinical relevance of total HCV Core antigen testing for hepatitis C monitoring and for predicting patients’ response to therapy

Summary. To study the correlation between total Hepatitis C virus (HCV) Core antigen (Ag) and HCV‐RNA, and to assess the proficiency of HCV Core Ag testing in monitoring and predicting virologic response during and after pegylated interferon (PEG‐IFN) and ribavirin combination therapy.

Boceprevir and telaprevir-based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and model for end-stage liver disease score.

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)‐NS3/NS4A protease inhibitors (PI)] in association with PEG‐IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow‐up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty‐one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non‐response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non‐responders to 59.1% in partial non‐responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end‐stage liver disease (MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI‐based triple therapy leads to high rates of virological response even in previously non‐responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.

Association of anti‐E1E2 antibodies with spontaneous recovery or sustained viral response to therapy in patients infected with hepatitis C virus

The monoclonal antibody (mAb) D32.10 recognizes a discontinuous epitope encompassing three regions E1 (amino acids 297‐306), E2A (amino acids 480‐494), and E2B (amino acids 613‐621) juxtaposed on the surface of serum‐derived hepatitis C virus (HCV) particles (HCVsp). The mAb D32.10 inhibits efficiently and specifically the binding of HCVsp to human hepatocytes. Therefore, we investigated the clinical relevance of anti‐E1E2A,B response in the serum of patients infected with HCV. To this end, an enzyme‐linked immunosorbent assay (ELISA) using synthetic E1‐, E2A‐, and E2B‐derived peptides was used. The ELISA was validated in terms of sensitivity, specificity, and test efficiency. The detection of the anti‐E1E2 D32.10 epitope‐binding antibodies during natural HCV infection in more than 300 HCV‐positive sera demonstrated significantly (P < 0.001) higher prevalence of these antibodies: (1) in patients who spontaneously cured HCV infection (46 of 52, 88.5%) showing high titers (70% ≥ 1/1000) compared to never‐treated patients with chronic hepatitis C (7 of 50, 14%) who actively replicated the virus, and (2) in complete responders (20 of 52, 38.5%) who cleared virus following treatment and achieved a sustained viral response compared to nonresponders (4 of 40, 10%). Serum anti‐E1E2 antibodies were monitored before, during, and after the current standard‐of‐care therapy (pegylated interferon plus ribavirin) in responder and nonresponder patients. Optimal cutoff values were assessed by receiver operating characteristic curve analysis. One month prior to therapy initiation, the threshold of 1131 (optical density × 1000) gave 100% and 86% positive and negative predictive values, respectively, for achieving or not achieving a sustained viral response. Conclusion: The anti‐E1E2 D32.10 epitope‐binding antibodies are associated with control of HCV infection and may represent a new relevant prognostic marker in serum. This unique D32.10 mAb may also have immunotherapeutic potential. (HEPATOLOGY 2010)

Pharmacological exposure to ribavirin: A key player in the complex network of factors implicated in virological response and anaemia in hepatitis C treatment

Ribavirin remains today a pivotal drug in the treatment of hepatitis C; in standard double therapy, as well as in triple combination with direct antiviral agents, ribavirin reduces relapse and can double the sustained virological response obtained with peginterferon alone or in association with direct antiviral agents. In the complex network of interacting factors determining sustained virological response independently of known predictive factors related to host and virus, two modern tools are emerging: polymorphisms in the IL28B gene and very early exposure to ribavirin. The use of a pharmacokinetic-pharmacodynamic model of early ribavirin exposure to adjust the dose individually would help promote a safer ribavirin use and improve sustained virological response. The variability of the influence of ribavirin exposure on anaemia is probably genetically determined; however, the low prevalence of the implicated protective alleles of the inosine triphosphate pyrophosphatase gene could explain their lack of influence on sustained virological response.

Perspectives on therapy of hepatitis B

Despite a high rate of viral clearance by immunocompetent adults, and the availability of efficient vaccines a large proportion of the world’s population (400 million) is chronically infected with hepatitis B virus (HBV). This is due to the fact that vertical transmission of HBV in neonates leads to a chronic infection in 90% of cases. The pathology is immune-mediated. The coexistence of repeated cycles of HBV replication and immune lysis of infected hepatocytes is associated with fibrosis, cirrhosis, and hepatocellular carcinoma. There are still 250 000 deaths each year resulting from hepatitis B. Current strategies for treating hepatitis B have focused on clearance of active HBV infection through suppression of viral replication. The efficacies of these treatments have been determined by monitoring the levels of HBV DNA in serum, serum alanine aminotransferase (ALT) levels, loss of viral antigens (HBeAg and HBsAg), seroconversion (antiHBe and anti-HBs), and ultimately by improvements in liver histology. Interferon-a (IFN-a) and the nucleoside analogs (lamivudine and adefovir) have proven their effectiveness by these clinical markers and are currently approved for treatment of chronic hepatitis B. Sustained virological response rate, however, ranges between 15 and 40% [1]. The actual rate of sustained response in non selected patients is supposed to be lower. Following the introduction of IFN acting mainly through immune potentiation, the development of new antivirals that inhibit the viral polymerase has provided new hope in the therapy of chronic hepatitis B. However, due to the slow kinetics of viral clearance, longterm treatment is mandatory and unfortunately, the spontaneous genetic heterogeneity of the virus prompted drug resistant mutants selected by the treatment. It is, therefore, similar to human immunodeficiency virus (HIV), critical to develop new antiviral strategies to better combat wild-type and mutant HBV infections.

Pretreatment predictive factors for hepatitis C therapy outcome: relevance of anti-E1E2 antibodies compared to IP-10 and IL28B genotypes.

BACKGROUND Unique serum anti-E1E2 antibodies were shown to be associated with spontaneous recovery or predictive of sustained virological response (SVR) in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (PEG-IFN/RBV) therapy. The objectives were to establish the relationship between pretreatment anti-E1E2 titres and HCV RNA kinetics during PEG-IFN/RBV therapy, and to examine whether the combined determination of interleukin (IL)28B rs12979860 and rs8099917, pretreatment inducible protein (IP)-10 levels and/or anti-E1E2 improved the prediction of SVR. METHODS Sera from 26 treatment-naive consecutive HCV patients treated with PEG-IFN/RBV for 48 weeks were analysed. Serum anti-E1E2 titres and pretreatment IP-10 levels were measured by enzyme-linked immunosorbent assays. The IL28B variants were determined using genotyping real-time polymerase chain reaction method. Viral decline was measured at weeks (W) 4 and 12 and SVR assessed 6 months after the end of therapy. RESULTS Baseline anti-E1E2 titres were correlated with HCV RNA decline at W4 and W12 and were highly predictive of SVR with 100% of patients negative for anti-E1E2 failing to achieve SVR. Receiver operating characteristic curve analyses indicate that the best prediction of SVR (AUC 0.990) was obtained with the combination of anti-E1E2 and IP-10 levels. Predictive values were better than those obtained with IP-10 alone or in combination with IL28B variants. CONCLUSIONS Pretreatment serum anti-E1E2 response predicts HCV RNA clearance kinetics and treatment outcome. The combination of anti-E1E2 and IP-10 significantly improved the prediction of treatment response. This warrants further investigation and validation on larger cohorts of patients in the context of new therapeutic strategies.

Care of hepatitis C virus infection in France: modifications in three consecutive surveys between 1995 and 2010

To determine the characteristics of hepatitis C (HCV)‐infected patients in 2010 and compare this survey with those reported in 1995 and 2001.

Increased Ribavirin Bioavailability Associated With Telaprevir Use in Hepatitis C Patients Treated With PEGylated -Interferon/Ribavirin/Telaprevir Triple Therapy

Background: Anemia is more frequent in patients receiving telaprevir with PEGylated interferon/ribavirin (PEG-IFN/RBV) than in those receiving PEG-IFN/RBV alone. Objectives: The objective was to measure the impact of telaprevir on RBV bioavailability and to assess the concomitant renal function. Materials and Methods: Thirty-seven hepatitis C virus (HCV) patients non-responders to a previous course of PEG-IFN/RBV therapy and re-treated with triple therapy combining PEG-IFN/RBV and telaprevir were analyzed. RBV bioavailability was measured before the triple therapy initiation, during telaprevir treatment at week (W) 4 and W8, and after telaprevir cessation (post W16). The renal function was assessed by estimating the glomerular filtration rate (eGFR). Results: At W4, RBV bioavailability, expressed as mg/L/daily dose/kg body weight, was significantly increased (median increase = 0.06 mg/L/dose/kg; P < 0.001). In parallel, the renal function was impaired with a mean eGFR decrease of -6.8 mL/minutes/1.73 m² (P = 0.109). Between W4 and W8, RBV bioavailability continued to increase (P < 0.001) but subsequently decreased slightly after telaprevir discontinuation with a concomitant restoration of the renal function (eGFR increase of 6.34 mL/minutes/1.73 m²). Conclusions: Our results indicated a reversible increase in RBV bioavailability after telaprevir exposure, which might be linked to the impairment of the GFR. This also suggests a RBV-telaprevir pharmacological interaction, a possible source of severe anemia observed under triple therapy. These results suggest that RBV pharmacological monitoring may be clinically relevant, especially in the context of first-generation HCV protease inhibitor-based therapy.