Hepatitis C (HCV) therapy for HCV mono-infected and HIV-HCV co-infected individuals living in Nepal.

BACKGROUND: Despite direct-acting antivirals (DAA), aims to "eradicate" viral hepatitis by 2030 remain unlikely. In Nepal, an expert consortium was established to treat HCV through Nepal earthquakes aftermath offering a model for HCV treatment expansion in a resource-poor setting. METHODOLOGY/PRINCIPAL FINDINGS: In 2015, we established a network of hepatologists, laboratory experts, and community-based leaders at 6 Opioid Substitution Treatment (OST) sites from 4 cities in Nepal screening 838 patients for a treatment cohort of 600 individuals with HCV infection and past or current drug use. During phase 1, patients were treated with interferon-based regimens (n = 46). During phase 2, 135 patients with optimal predictors (HIV controlled, without cirrhosis, low baseline HCV viral load) were treated with DAA-based regimens. During phase 3, IFN-free DAA treatment was expanded, regardless of HCV disease severity, HIV viremia or drug use. Sustained virologic response (SVR) was assessed at 12 weeks. Median age was 37 years and 95.5% were males. HCV genotype was 3 (53.2%) or 1a (40.7%) and 32% had cirrhosis; 42.5% were HIV-HCV coinfected. The intention-to-treat (ITT) SVR rates in phase 2 and 3 were 97% and 81%, respectively. The overall per-protocol and ITT SVR rates were 97% and 85%, respectively. By multivariable analysis, treatment at the Kathmandu site was protective and substance use, treatment during phase 3 were associated with failure to achieve SVR. CONCLUSIONS/SIGNIFICANCE: Very high SVR rates may be achieved in a difficult-to-treat, low-income population whatever the patient's profile and disease severity. The excellent treatment outcomes observed in this real-life community study should prompt further HCV treatment initiatives in Nepal.

Perinatal hepatitis B virus transmission in Lao PDR: A prospective cohort study.

BACKGROUND: Mother-to-child transmission of hepatitis B virus (HBV) is the main cause of new infections worldwide. We aimed at assessing the percentage of infants successfully immunized in two major hospitals in Vientiane, Lao PDR where HB immune globulin (HBIg) is not available. METHODS: We studied a prospective cohort of chronically HBV infected pregnant women and their infants until 6 months post-partum from January 2015 to March 2017. All infants received HB vaccine at birth and 6, 10 and 14 weeks thereafter, and HBV status was assessed at 6 months of age. HBV surface gene sequencing was performed in infected mother-infant pairs. RESULTS: Of 153 mothers with HB surface antigen (HBsAg), 60 (39%) had detectable serum HBe antigen (HBeAg). HBeAg positive pregnant women were younger than those negative (median age 26 versus 28 years; p = 0.02) and had a significantly higher HBV viral load at delivery (median 8.0 versus 4.0 log10 IU/mL, p <0.001). Among the 120 infants assessed at 6 months of age, 5 (4%) were positive for HBsAg and had detectable HBV viral load by polymerase chain reaction. All were born to mothers with HBeAg and viral load >8.5 log10 IU/mL. However, only four (3.3%, 95% CI 0.5% to 7.0%) had a virus strain closely related to their mother's strain. HBV surface gene mutations were detected in 4 of the 5 infected infants. Anti-HBs antibody levels were below 10 IU/L in 10 (9%) uninfected infants at 6 months of age. CONCLUSIONS: Mother-to-child transmission occurred less frequently than expected without the use of HBIg. Adding HBIg and/or maternal antiviral prophylaxis may have prevented some of these infections. The observation of unsatisfactory levels of anti-HBs antibodies in 9% of the uninfected infants at 6 months highlights the need for improvement of the universal immunization procedures.

Non-F HBV/HDV-3 coinfection is associated with severe liver disease in Western Brazilian Amazon.

The clinical outcome of hepatitis B virus (HBV) infection may be related to host and viral genetic factors, as well as to the type of infection (monoinfection and coinfection). To analyze the distribution/combination of HBV/hepatitis D virus (HDV) genotypes and the associated clinical characteristics, 409 serum samples from patients with chronic HBV (94 of them coinfected by HDV) followed at the Viral Hepatitis Referral Center of Rio Branco, Brazil were enrolled. HBV DNA and HDV RNA were amplified, respectively, by polymerase chain reaction (PCR) and nested PCR using specific primers in the PreC/C region and the S gene, and by reverse-transcription PCR and seminested PCR using specific primers in the delta antigen region and sequenced. The proportion of women (56.1%) was significantly higher than males in this cohort ( P < 0.01). Women were significantly younger (39.8 years; 8-77 years) than males (44.7 years; 12-79 years; P < 0.01). Sixty-eight (18%) patients were infected with HBV-F genotype and 264 (69.8%) with HBV/non-F genotypes. Coinfection by HDV was detected in 23.9% (94 of 409) of this population and was more frequent in male (54.2%, 51 of 94) than in female patients (44.7%, 42 of 94; P = 0.015). HDV-3 was the most prevalent (88.9%) genotype. Almost 70% of HDV-3 coinfected patients were infected with HBV/non-F genotypes. Severe liver disease was diagnosed in 41 patients, 60.9% (25 of 41) of them coinfected with HDV. HBV/HDV coinfection was associated with male sex, age above 30 years, severe liver disease, and increased alanine aminotransferase levels. HBV/HDV-3 coinfection is associated with severe liver disease, in Rio Branco, Brazil.

Hepatitis C in Laos: A 7-Year Retrospective Study on 1765 Patients.

Hepatitis C virus (HCV) is a global health concern, notably in Southeast Asia, and in Laos the presentation of the HCV-induced liver disease is poorly known. Our objective was thus to describe a comprehensive HCV infection pattern in order to guide national health policies. A study on a group of 1765 patients formerly diagnosed by rapid test in health centres was conducted at the Centre of Infectiology Lao Christophe Merieux in Vientiane. The demographic information of patients, their infection status (viral load: VL), liver function (aminotransferases) and treatments were analysed. Results showed that gender distribution of infected people was balanced; with median ages of 53.8 for men and 51.6 years for women (13-86 years). The majority of patients (72%) were confirmed positive (VL > 50 IU/mL) and 28% of them had high VL (> 6log10). About 23% of patients had level of aminotransferases indicative of liver damage (> 40 IU/mL); but less than 20% of patients received treatment. Patients rarely received a second sampling or medical imaging. The survey also showed that cycloferon, pegylated interferon and ribavirin were the drugs prescribed preferentially by the medical staff, without following any international recommendations schemes. In conclusion, we recommend that a population screening policy and better management of patients should be urgently implemented in the country, respecting official guidelines. However, the cost of biological analysis and treatment are significant barriers that must be removed. Public health resolutions should be immediately enforced in the perspective of meeting the WHO HCV elimination deadline by 2030.

Contrasting Timing of Virological Relapse After Discontinuation of Tenofovir or Entecavir in Hepatitis B e Antigen-Negative Patients.

Stopping long-term nucleos(t)ide analogue therapy increases hepatitis B virus (HBV) surface antigen (HBsAg) loss rates in HBV e antigen (HBeAg)-negative patients. Viral rebound may induce immune responses facilitating functional cure. We analyzed which factors are associated with timing of virological relapse in 220 Asian HBeAg-negative patients from the prospective ABX203 vaccine study. Unexpectedly, only the type of antiviral therapy was significantly associated with early virological relapse, defined as an HBV DNA load of >2000 IU/mL until week 12, and relapse occurred earlier in patients treated with tenofovir versus those treated with entecavir (median time, 6 vs 24 weeks; P < .0001). This should be considered for future trials and monitoring of patients after treatment discontinuation.

Hepatitis B and hepatitis D virus infections in the Central African Republic, twenty-five years after a fulminant hepatitis outbreak, indicate continuing spread in asymptomatic young adults.

Hepatitis delta virus (HDV) increases morbidity in Hepatitis B virus (HBV)-infected patients. In the mid-eighties, an outbreak of HDV fulminant hepatitis (FH) in the Central African Republic (CAR) killed 88% of patients hospitalized in Bangui. We evaluated infections with HBV and HDV among students and pregnant women, 25 years after the fulminant hepatitis (FH) outbreak to determine (i) the prevalence of HBV and HDV infection in this population, (ii) the clinical risk factors for HBV and/or HDV infections, and (iii) to characterize and compare the strains from the FH outbreak in the 1980s to the 2010 HBV-HDV strains. We performed a cross sectional study with historical comparison on FH-stored samples (n = 179) from 159 patients and dried blood-spots from volunteer students and pregnant women groups (n = 2172). We analyzed risk factors potentially associated with HBV and HDV. Previous HBV infection (presence of anti-HBc) occurred in 345/1290 students (26.7%) and 186/870 pregnant women (21.4%)(p = 0.005), including 110 students (8.8%) and 71 pregnant women (8.2%), who were also HBsAg-positive (p = 0.824). HDV infection occurred more frequently in pregnant women (n = 13; 18.8%) than students (n = 6; 5.4%) (p = 0.010). Infection in childhood was probably the main HBV risk factor. The risk factors for HDV infection were age (p = 0.040), transfusion (p = 0.039), and a tendency for tattooing (p = 0.055) and absence of condom use (p = 0.049). HBV-E and HDV-1 were highly prevalent during both the FH outbreak and the 2010 screening project. For historical samples, due to storage conditions and despite several attempts, we could only obtain partial HDV amplification representing 25% of the full-length genome. The HDV-1 mid-eighties FH-strains did not form a specific clade and were affiliated to two different HDV-1 African subgenotypes, one of which also includes the 2010 HDV-1 strains. In the Central African Republic, these findings indicate a high prevalence of previous and current HBV-E and HDV-1 infections both in the mid-eighties fulminant hepatitis outbreak and among asymptomatic young adults in 2010, and reinforce the need for universal HBV vaccination and the prevention of HDV transmission among HBsAg-positive patients through blood or sexual routes.

Anti-E1E2 antibodies status prior therapy favors direct-acting antiviral treatment efficacy.

INTRODUCTION: Presence of anti-E1E2 antibodies was previously associated with spontaneous cure of hepatitis C virus (HCV) and predictive before treatment of a sustained virological response (SVR) to bi- or tri-therapy in naïve or experienced patients, regardless of HCV genotype. We investigated the impact of anti-E1E2 seroprevalence at baseline on treatment response in patients receiving direct-acting antiviral (DAA) therapy. MATERIAL AND METHODS: We screened anti-E1E2 antibodies by ELISA in serum samples collected at treatment initiation for two groups of patients: 59 with SVR at the end of DAA treatment and 44 relapsers after DAA treatment. Nineteen patients received a combination of ribavirin (RBV) or PEG-interferon/ribavirin with sofosbuvir or daclatasvir and others received interferon-free treatment with DAA±RBV. HCV viral load was measured at different time points during treatment in a subgroup of patients. RESULTS: A significant association was observed between presence of anti-E1E2 and HCV viral load<6log10 prior treatment. Among patients with anti-E1E2 at baseline, 70% achieved SVR whereas among patients without anti-E1E2, only 45% achieved SVR. Conversely, 66% of patients experiencing DAA-failure were anti-E1E2 negative at baseline. In the multivariate analysis, presence of anti-E1E2 was significantly associated with SVR after adjustment on potential cofounders such as age, sex, fibrosis stage, prior HCV treatment and alanine aminotransferase (ALT) level. CONCLUSIONS: The presence of anti-E1E2 at treatment initiation is a predictive factor of SVR among patients treated with DAA and more likely among patients with low initial HCV viral load (<6log10). Absence of anti-E1E2 at baseline could predict DAA-treatment failure.

Efficiency and Safety of an Early Dose Adjustment of Ribavirin in Patients Infected With Hepatitis C Underexposed to the Drug and Treated With Peginterferon Ribavirin.

BACKGROUND: Ribavirin exposure after the first dose (D0AUC0-4h) >1755 mcg·h·L is predictive of sustained virological response (SVR) in patients with hepatitis C treated with peginterferon and ribavirin. The aim of this study was to test the benefit of ribavirin early dose adjustment based on this target in naïve patients infected with genotype 1. METHODS: A multicenter randomized controlled trial with two parallel groups; fixed-dose (FD) group: standard of care in 2010-2011, ie, peginterferon-α2a 180 mcg·wk and weight-based ribavirin 1000-1200 mg/d during 48 weeks; adapted-dose (AD) group: increase of ribavirin dose if D0AUC0-4h <1755 mcg·h·L. RESULTS: A total of 221 patients were included, 110 in the AD group and 111 in the FD group with similar baseline characteristics. In the perprotocol analysis, SVR was higher in the AD group (55.1% versus 40.4%; P = 0.042), especially in patients with D0AUC0-4h <1755 mcg·h·L (54.3% versus 31.9%; P = 0.029). In the intention-to-treat analysis, the difference was not significant (50% versus 41%; P = 0.197). Ribavirin trough concentrations (C0s) at week 4 of treatment (intention-to-treat analysis) were higher in patients achieving SVR (2.06 versus 1.72 mg/L, P = 0.003). In the subgroup of patients with AUC0-4h <1755 mcg·h·L, 46% of patients with AD achieved a C0 >2.0 mg/L versus 22% of patients with FD (P = 0.013). Grade 1 anemia (but not other grades) was more frequent in the AD group (70% versus 48%, P = 0.001). The number of dose reductions or discontinuation of ribavirin was similar in both groups. CONCLUSIONS: Early ribavirin dose adjustment increases SVR in patients underexposed to ribavirin without increasing grade II-IV anemia. Such a strategy could be useful in patients with no access to new antiviral drugs.

Hepatitis: After HCV cure, HBV cure?

Current treatments efficiently control chronic HBV infection but they do not lead to its elimination. Now, Ebert and colleagues have shown that cellular inhibitor of apoptosis proteins (cIAPs) prevent TNF-mediated killing of infected hepatocytes and that cIAP antagonists might lead to HBV cure by promoting death of infected cells.

Anti-E1E2 antibodies do predict response to triple therapy in treatment-experienced Hepatitis C Virus-cirrhosis cases.

BACKGROUND AND AIMS: We previously showed that pre-treatment serum anti-E1E2 predicted hepatitis C virus (HCV) RNA viral kinetics (VKs) and treatment outcome in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (Peg-IFN/RBV) double therapy. Here, we determined whether baseline anti-E1E2 was correlated with the on-treatment VK and could predict virological outcome in treatment-experienced HCV-infected cirrhotic patients receiving protease inhibitor-based triple therapy. METHODS: Sera from 19 patients with HCV genotype 1 infection and compensated cirrhosis who failed to respond to a prior course of Peg-IFN/RBV were selected at time 0 before starting triple therapy with boceprevir or telaprevir. We assessed patients with sustained viral response 12 weeks after the end of triple therapy (SVR12) by analyzing VKs at weeks 4, 12, 24, 36, 48 (end of treatment) and 60. RESULTS: Patients baseline characteristics were similar to the well-defined CUPIC cohort (age, HCV subtype, baseline viremia, and treatment history). Among the 19 patients, 11 achieved an SVR12. Fifteen patients were positive for pre-treatment anti-E1E2 and all of them achieved SVR12. Moreover, anti-E1E2 and SVR12 correlated with prior response to IFN/RBV therapy (relapse, partial or null response). CONCLUSIONS: Baseline anti-E1E2 could be considered as a new biomarker to predict SVR12 after triple therapy in this most difficult-to-treat population. These results warrant further validation on larger cohorts including patients receiving highly effective direct-acting antivirals to explore whether this test could help in better defining treatment duration for these very costly molecules.

Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure.

HBV infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Although HBV infection can be efficiently prevented by vaccination, and treatments are available, to date there is no reliable cure for the >240 million individuals that are chronically infected worldwide. Current treatments can only achieve viral suppression, and lifelong therapy is needed in the majority of infected persons. In the framework of the French National Agency for Research on AIDS and Viral Hepatitis 'HBV Cure' programme, a scientific workshop was held in Paris in June 2014 to define the state-of-the-art and unanswered questions regarding HBV pathobiology, and to develop a concerted strategy towards an HBV cure. This review summarises our current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to ultimately address unmet medical needs in the treatment of chronic HBV infection.

Hepatitis B virus infection.

Hepatitis B virus infection is a major public health problem worldwide; roughly 30% of the world's population show serological evidence of current or past infection. Hepatitis B virus is a partly double-stranded DNA virus with several serological markers: HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG. It is transmitted through contact with infected blood and semen. A safe and effective vaccine has been available since 1981, and, although variable, the implementation of universal vaccination in infants has resulted in a sharp decline in prevalence. Hepatitis B virus is not cytopathic; both liver damage and viral control--and therefore clinical outcome--depend on the complex interplay between virus replication and host immune response. Overall, as much as 40% of men and 15% of women with perinatally acquired hepatitis B virus infection will die of liver cirrhosis or hepatocellular carcinoma. In addition to decreasing hepatic inflammation, long-term antiviral treatment can reverse cirrhosis and reduce hepatocellular carcinoma. Development of new therapies that can improve HBsAg clearance and virological cure is warranted.

Occult HBV infection in Morocco: from chronic hepatitis to hepatocellular carcinoma.

BACKGROUND & AIMS: Morocco is one of low to intermediate endemic areas for hepatitis B virus (HBV) infection, but no reports have been published on Occult HBV infection (OBI). To determine the prevalence of OBI and its clinical impact among patients with cryptogenic and HCV-related chronic liver disease in Morocco. METHODS: A total of 152 HBsAg-negative patients (60 patients with cryptogenic hepatitis and 92 HCV carriers) were enrolled in this study. Sera collected from all patients were tested for anti-HBc and anti-HBs antibodies. OBI was assessed in serum and liver tissue samples using highly sensitive PCR assays targeting Surface, X and core regions of the HBV genome and confirmed by Southern blot hybridization. RESULTS: A high rate of anti-HBc positivity was found among patients with HCV infection (57/92, 61.95%) compared to those with cryptogenic hepatitis (24/60, 40%) (P = 0.034). A high prevalence of OBI was found among patients with HCV infection (42/92, 45.65%) compared to those with cryptogenic hepatitis (17/60, 28.3%) (P = 0.013). In both groups, the prevalence of OBI increased in parallel with advancing stage of liver disease (χ2 = 6.73; P = 0.0095). The highest proportion of OBI was reached among HCV-related HCC cases (62.5%). Multivariate Cox regression analysis revealed that older age (≥56 years), positivity for anti-HBc and presence of OBI were independent risk factors for the development of HCC in HCV-infected patients. CONCLUSION: This study helps to understand the current status of OBI and its impact on the severity of liver disease in Moroccan patients.

Diversity of hepatocellular carcinoma clones bearing hematopoietic malignancies-related chromosomal translocation.

Interpatient heterogeneity of hepatocellular carcinoma has been in-depth addressed. Intrapatient heterogeneity is less known. Four clones were freshly isolated from an Edmondson grade I HCV-associated hepatocellular carcinoma. Biochemical approaches, functional assays and cytogenetics were used. Albumin inducibility was uncoupled from canonical cytokeratin profiles, suggesting pathological combinations of hepatospecific and biliary markers. Poor differentiation and TGFß's proproliferative effect on all clones were observed. TGFß, Interferon α and doxorubicin sensitivity levels were found highly heterogeneous. Progenitor and stem cells markers OV6 and EpCAM were mutually exclusively expressed. All clones were CD44+, while none expressed CD90, CD133, or CD117. Three clones displayed a liver progenitor OV6+ phenotype, and were susceptible to hepatocytic differentiation, among which one fibroblastoid clone displayed intrahepatic parenchymal engraftment capability. A fourth clone, the less motile, displayed a cancer stem cell EpCAM+ phenotype, was essentially ß-catenin negative, and was as expected devoid of hepatocytic differentiation capability, yet the most sensitive to doxorubicin treatment. Cytogenetics evidenced in all clones a t(12;22)(p11;q11) translocation found in several myelodysplastic syndromes. All clones, that probably derive from EpCAM+ tumor cells, display aberrant E-cadherin cytosolic localization. Because of their diverse pathophysiolocal features, these freshly isolated, low population doubling-defined, HCC clones may provide novel opportunities to tackle HCC heterogeneity in a single patient background for therapy improvement purposes, especially regarding recently developed targeted strategies.

A brief history of hepatitis milestones.

Hepatitis has been a major plague of mankind. The history of the discovery of causative viruses is one of the most fascinating scientific adventures of this half century. Individualization of several types of hepatitis only emerged after world war two. Their identification has been associated with milestones which revolutionized medicine and public health. The discovery of HBV brought the first ever vaccine not prepared by tissue culture but initially directly from plasma and soon the first vaccine produced by genetic engineering. HBV vaccine proved to be the first "anti-cancer" vaccine by preventing hepatocellular carcinoma and practically eradicating it from childhood in Taiwan. Successful vaccines became also available for HAV and more recently HEV. The discovery of HCV in 1989 opened a new era since it was the first virus was identified by a direct molecular approach. Two billion people are infected with HBV and 350 million are chronic carriers of the virus. The extraordinary effectiveness of HBV vaccination was best illustrated in Taiwan and Singapore where in less than 2 decades HBs Ag carriers dropped from 9,1% to 2,7% and HCC from 27% to 17%. Successful development of nucleos(t)ides analogs make it now possible to fully control disease progression with a daily pill long term therapy. The progress in HCV therapy has been even more spectacular and successful treatment jumped from 6 % with interferon alone in 1986 to more than 80% in 2013 with triple combination therapies. Remarkably chronic hepatitis C is the only chronic disease which is curable. It will be soon possible to eradicate HCV infection with, an all oral, daily single pill (containing several molecules) for 3 to 6 months which will cure over 90% of patients. This unprecedented therapeutic victory benefiting hundred millions of people matches the triumphs over small pox, polio and tuberculosis. The next 10 years should undoubtedly witness cure or full control over all forms of acute and chronic hepatitis.

Predictors of the therapeutic response in hepatitis C. A 2013 update.

Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma. Current therapy based on pegylated-interferon-α (PEG-IFN) and ribavirin (RBV) combination has limited efficacy and is poorly tolerated. Disease progression is highly variable and pre-therapeutic prediction of response to treatment remains difficult. Although viral kinetics proved most useful to monitor duration of therapy, other predictors would be helpful to identify patients with the best chance of subsequent treatment response prior initiation of antiviral therapy (double or triple therapy). The predictive power of IL28B polymorphism is well-recognized and has become the reference biomarker for clinicians in patients treated with double therapy. The combination of serum IP-10 and IL28B SNPs increases predictive value of treatment response. Recently, anti-E1E2 antibodies appear to closely correlate with therapeutic outcome and predict the complete elimination of HCV. They may represent a new relevant prognostic biomarker of double therapy response. Since the introduction of triple therapy including protease inhibitors (telaprevir/boceprevir), the major priority is to help patients who failed on double therapy, and there is now an urgent need for robust pre-therapeutic predictors of response to better select the patients to treat. Indeed, the relevance of IL28B polymorphism and IP-10 serum concentration are limited in triple therapy. Many new drugs are currently under investigation and there is hope that effective and well-tolerated IFN-free regimens may become a part of future therapy. In this context, this will help to identify the most powerful predictive marker and/or to assess the benefit of anti-E1E2 in decision to treat.

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.

Improved rolling circle amplification (RCA) of hepatitis B virus (HBV) relaxed-circular serum DNA (RC-DNA).

For functional analysis of HBV isolates, epidemiological studies and correct identification of recombinant genomes, the amplification of complete genomes is necessary. A method for completely in vitro amplification of full-length HBV genomes starting from serum RC-DNA is described. This uses in vitro completion/ligation of plus-strand HBV RC-DNA and amplification using Rolling-Circle Amplification, eventually followed by a genomic PCR. The method can amplify complete HBV genomes from sera with viral loads ranging from >1.0E+8 IU/ml down to 1.0E+3 IU/ml. The method can be applied to archived sera that have undergone long-term storage or to archived DNA serum extracts. The genomes can easily be cloned. HBV genotypes A-G can all be amplified with no apparent problems. A recombinant subgenotype A3/genotype E genome was identified and fully sequenced.

Antiviral effect, safety, and pharmacokinetics of five-day oral administration of Deleobuvir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C.

Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.