Hepatitis C subtype distribution in chronically infected patients with mild liver fibrosis in France: the GEMHEP study.

Treatment options for Hepatitis C infection have greatly improved with direct-acting antiviral (DAA) combinations achieving high cure rates. Nevertheless, the cost of this treatment is still high and access to treatment in many countries has been preferentially reserved for patients with more severe fibrosis (F3 and F4). In this French nationwide study, we investigated the epidemiological characteristics and genotype distribution of hepatitis C virus (HCV) in treatment-naive patients with METAVIR fibrosis stages between F0 and F2 in order to identify patient profiles that became eligible for unrestricted treatment in a second period. Between 2015 and 2016 we collected data from nine French university hospitals on a total of 584 HCV positive patients with absent, mild or moderate liver fibrosis. The most represented genotypes were genotype 1b (159/584; 27.2%), followed by genotype 1a (150/584; 25.7%); genotype 3 (87/584: 14.9%); genotype 4 (80/584; 13.7%). Among genotype 4: 4a was predominantly encountered with 22 patients (27.5% of genotype 4). Genotypes 1b and 1a are currently the most frequent virus types present in treatment-naive patients with mild fibrosis in France. They can be readily cured using the available DAA. Nevertheless, non-a/non-d genotype 4 is also frequent in this population and clinical data on the efficacy of DAA on these subtypes is missing. The GEMHEP is the French group for study and evaluation of viral hepatitis on a national scale. Data collection on epidemiological and molecular aspects of viral hepatitis is performed on a regular basis in all main French teaching hospitals and serves as a basis for surveillance of these infections. Analysis and trends are regularly published on behalf of the GEMHEP group. Data collection was performed retrospectively over the 2015-2016 period, covering nine main university hospitals in France. A total of 584 hepatitis C positive patients were included in this study. Genotyping of the circulating viruses showed a high prevalence of genotypes 1b and 1a in our population. The epidemiology of hepatitis C is slowly changing in France, particularly as a consequence of the rise of 'non-a non-d' genotype 4 viruses mainly originating from African populations. More data concerning treatment efficacy of these genotypes is needed in order to guide clinical care.

No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment.

A major hurdle in the long-term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF-treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1-2 to <4% over years 3-8. Forty-one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty-nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance-associated mutations. No accumulation of conserved site changes was detected. The long-term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.

Baseline HBsAg and HBcrAg titres allow peginterferon-based 'precision medicine' in HBeAg-negative chronic hepatitis B patients.

Quantitative hepatitis B core-related antigen (qHBcrAg) has been proposed as an additional marker to quantitative HBsAg (qHBsAg), for management of chronic hepatitis B. Evaluate baseline combination of qHBsAg and qHBcrAg for identification of patients that could benefit from pegylated interferon-alpha-2a (PegIFN)-based therapy. Sixty-two HBeAg-negative patients treated with PegIFN or PegIFN plus tenofovir disoproxil fumarate (PegIFN+TDF). HBsAg and HBcrAg titres were evaluated at baseline. Thirty patients received PegIFN and 32 PegIFN+TDF. SR was 10 of 30 and 17 of 32 in PegIFN and PegIFN+TDF patients, respectively. Cut-offs determined by maximized Youden's index for identifying patients likely to respond to therapy were as follows: 3.141 log10 IU/mL and 3.450 log10 U/mL for HBsAg and HBcrAg, respectively. At the end of 3 years post-treatment follow-up, HBsAg loss was observed in 7 of 30 and 6 of 32 in PegIFN and PegIFN+TDF patients, respectively. The AUC was estimated to be 0.716 (95% CI [0.578, 0.855]) for HBsAg and 0.668 (95% CI [0.524, 0.811]) for HBcrAg (P=.5541). PPVs for AUCs(95%CI) were 0.762(0.590-0.947), 0.714(0.533-1.000) and 0.800(0.611-1.000), and NPVs for AUCs(95%CI) were 0.756(0.660-0.899), 0.718(0.630-0.857) and 0.765(0.675-0.889) for qHBsAg, qHBcrAg and the combination of both markers, respectively. Baseline qHBsAg 3.141 log10 IU/mL and qHBcrAg 3.450 log10 U/mL thresholds used separately or in combination allow prediction of response, prior to PegIFN-based therapy, with a PPV of 80.3% and NPV of 76.5%. Baseline qHBsAg is predictive of HBsAg loss. Both markers could be used, separately or in combination, for PegIFN-based 'precision therapy'. Our results emphasize that the combination of PegIFN alpha-2a plus TDF with 53% of SR might be an alternative to finite therapy.

IFNL3 (IL28B) polymorphism does not predict long-term response to interferon therapy in HBeAg-positive chronic hepatitis B patients.

UNLABELLED: The impact of IFNL3 (IL28B) polymorphism on response to interferon (IFN) treatment in patients infected with hepatitis B virus (HBV) is controversial. We aimed to investigate whether IFNL3 polymorphism (rs12979860) influences the long-term response of chronic hepatitis B (CHB) treatment to conventional IFN. DESIGN: Ninety-seven HBeAg-positive patients treated with IFN were evaluated in this study. Associations were investigated between IFNL3 genotypes and (i) HBeAg seroconversion at the end of treatment (EOT), (ii) sustained virological response (SVR) and (iii) HBsAg seroconversion through long-term follow-up (LTFU). Patients were followed for a median of 14 years. The majority of patients were infected with HBV genotype A (69.6%) and were Caucasian (77.9%). Ninety-five patients were genotyped at rs12979860. Similar IFNL3 distribution was observed among the different ethnicities (P = 0.62) or across HBV genotypes A through G (P = 0.70). Thirty-six patients experienced HBeAg seroconversion at EOT; HBeAg seroconversion rates were 37.0 and 35.5% in patients with CC and CT/TT genotypes, respectively (P = 0.82). Among the 44 patients (45%) who achieved a SVR, SVR rates were 48.9 and 39.6% in patients with CC and CT/TT IL28B genotypes, respectively (P = 0.80). HBsAg seroconversion occurred through LTFU in 28 patients. HBsAg seroconversion rates were 25.5 and 31.2% in patients with CC and CT/TT genotypes, respectively (P = 0.51). No significant relationship between IFNL3 rs12979860 and fibrosis stage was observed (P = 0.85). IFNL3 genotype was neither associated with SVR, nor with HBeAg seroconversion and long-term HBsAg seroconversion in HBeAg-positive CHB patients responding to IFN therapy.

Predictors associated with treatment initiation and switch in a real-world chronic hepatitis B population from five European countries.

In Europe, healthcare systems differ between countries and different factors may influence Chronic hepatitis B (CHB) treatment choices in different counties. This analysis from a prospective, longitudinal, non-interventional study in five EU countries aimed to explore determinants associated with treatment initiation or switch in patients with CHB. A total of 1267 adult patients with compensated CHB in Germany, France, Poland, Romania and Turkey were prospectively followed for up to 2 years (March 2008-December 2010). Determinants of treatment initiation or switch were analysed using multivariate Cox proportional hazards regression. Median time since CHB diagnosis was 2.6 (0-37.7) years. Among 646 treatment-naïve patients, the probability of treatment initiation during follow-up was higher: in Germany (P = 0.0006), Poland (P < 0.0001) and Romania (P = 0.0004) compared with Turkey; in patients with alanine transaminase (ALT) 1-2 × upper limit of normal (ULN) (P = 0.0580) or >2 × ULN (P = 0.0523) compared with ALT ≤ 1 × ULN; and in patients with hepatitis B virus (HBV) DNA ≥ 2000 IU/mL (P < 0.0001) compared with HBV DNA <2000 IU/mL or undetectable. Among 567 treated patients, 87 switched treatment during follow-up. The probability of treatment switch was higher: in France (P = 0.0029), Germany (P = 0.0078) and Poland (P = 0.0329) compared with Turkey; and in patients with HBV DNA <2000 (P < 0.0001) or ≥ 2000 IU/mL (P < 0.0001), compared with undetectable. Viral load and ALT level were identified as the major drivers of treatment initiation. HBV DNA level was also a significant determinant of treatment switch. Results were statistically different across EU countries.

Impact of age on viral kinetics of peginterferon alfa-2a/ribavirin in chronic hepatitis C: final analysis from the PROPHESYS cohort.

The population of patients with chronic hepatitis C viral infection is ageing; however, elderly, hepatitis C-infected patients are understudied and less frequently treated. This subanalysis of data from the multinational PROPHESYS study examined associations between age (≤65 vs >65 years), on-treatment virological response and sustained virological response (SVR) in patients treated with peginterferon alfa-2a (40KD)/ribavirin in accordance with local licences. PROPHESYS comprised three cohorts studied in 19 countries according to country-specific legal and regulatory requirements. This subanalysis includes treatment-naive HCV mono-infected patients assigned to receive peginterferon alfa-2a (40KD)/ribavirin, with 6276 individuals aged ≤65 years and 349 aged >65 years. Rapid virological response (RVR) rates by Week 4 were consistently lower in older genotype (G) 1 (21.6% vs 27.2% in younger patients), G2 (80.7% vs 85.1%) and G3 (60.0% vs 74.2%) patients. SVR rates were significantly lower (29.8% vs 43.0%) and relapse rates significantly higher (43.1% vs 26.7%) in older G1 patients (P = 0.0002 vs ≤65 years). In contrast, SVR and relapse rates were similar in G2 and G3 patients regardless of age. The positive predictive value of RVR for SVR was comparable in older and younger G1 patients (66.7% vs 68.6%, respectively) and higher in older G2 (80.7% vs 75.6%) and G3 (77.8% vs 66.8%) patients. Virological response rates are generally lower in elderly CHC patients, and RVR is a reliable positive predictor of SVR in patients >65 years.

Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin.

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) α-2b or IFN α-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α-2b and/or PEG-IFN α-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN α-2b and 366 with SVR following treatment with PEG-IFN α-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α-2b and three patients treated with PEG-IFN α-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN α-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN α-2b. Successful treatment of hepatitis C with PEG-IFN α-2b or IFN α-2b leads to clinical cure of hepatitis C in the vast majority of cases.

Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan(®): validation in chronic hepatitis C.

A novel controlled attenuation parameter (CAP) has been developed for Fibroscan(®) to assess liver steatosis, simultaneously with liver stiffness measurement (LSM). We assessed CAP diagnostic accuracy in a large cohort of patients with chronic hepatitis C (CHC) virus. A total of 615 patients with CHC, who underwent both Fibroscan(®) and liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assessment as S(0) : steatosis in <10% of hepatocytes, S(1) : 11-33%, S(2) : 34-66% and S(3) : 67-100%. Performances of CAP and liver stiffness were determined using receiver operating characteristic (ROC) curve analysis and cross-validated using the bootstrap method. The Obuchowski measure was used to assess overall accuracy of CAP and to differentiate between steatosis grades. In multivariate analysis, CAP was related to steatosis (P < 10(-15) ) independently of fibrosis stage (which was related to LSM). The areas under ROC curves using CAP to detect steatosis were 0.80 (95% CI, 0.75-0.84) for S ≥ S(1) , 0.86 (0.81-0.92) for S ≥ S(2) and 0.88 (0.73-1) S = S(3) . CAP exhibited a good ability to differentiate steatosis grades (Obuchowski measure = 0.92). Performance of LSM for fibrosis assessment confirmed results from previous studies. CAP is a novel tool to assess the degree of steatosis and both fibrosis and steatosis can be evaluated noninvasively during the same procedure using Fibroscan(®) , in patients with CHC.

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa-2a/ribavirin.

It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800,000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400,000 IU/mL was used and 16% (59%vs 43%) when 800,000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71%vs 20%) when 400,000 IU/mL was used and 43% (61%vs 18%) when 800,000 IU/mL was used. A lower threshold (200,000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400,000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT.

Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C.

UNLABELLED: As there is currently a lack of consensus on the most appropriate dose and duration of peginterferon alfa-2a (PEG-IFNα-2a) therapy in hepatitis B e antigen (HBeAg)-positive patients, the efficacy and safety of either 24 or 48 weeks' duration and 90 µg/week or 180 µg/week doses were compared. HBeAg-positive patients (n = 544; 34% genotype B, 51% genotype C) were randomized to receive PEG-IFNα-2a (2 × 2 factorial design) for 24 or 48 weeks and at 90 µg/week or 180 µg/week and included in the per-protocol population. The primary efficacy endpoint of the noninferiority study was HBeAg seroconversion 6 months posttreatment. The prespecified odds ratio (OR) noninferiority margin was 1.88 with a one-sided significance level of 0.025. The highest rates of HBeAg seroconversion 6 months posttreatment were in the 180/48 arm (36.2% versus 14.1%-25.8% in the other arms). When the dose and duration arms were pooled, the OR for noninferiority of 24 weeks versus 48 weeks was 2.17 (95% confidence interval [CI] 1.43, 3.31; P = 0.749) and for 90 µg versus 180 µg was 1.79 (95% CI 1.18, 2.72; P = 0.410). As the upper limit of the 95% CI of the ORs were >1.88, 24 weeks were inferior to 48 weeks and 90 µg/week was inferior to 180 µg/week. The highest rates of response in the 180/48 arm were achieved by patients with HBsAg <1,500 IU/mL at Week 12 (58%) or Week 24 (57%), whereas patients with HBsAg >20,000 IU/mL did not respond. Adverse events were typical of those associated with PEG-IFNα-2a. CONCLUSION: Compared with lower doses and shorter durations, the licensed PEG-IFNα-2a treatment regimen (180 µg/48 weeks) was the most efficacious and beneficial for HBeAg-positive patients predominantly infected with hepatitis B virus genotypes B or C.

Sequential therapy with adefovir dipivoxil and pegylated interferon alfa-2a for HBeAg-negative patients.

To assess the impact of sequential therapy with adefovir dipivoxil (ADV) and pegylated interferon alfa-2a (PEG-IFN) on virological (serum HBV-DNA) and serological (serum HBsAg) response in 20 consecutive HBeAg-negative patients. Patients received ADV for 20 weeks, then ADV and PEG-IFN for 4 weeks and lastly PEG-IFN for 44 weeks. Serum HBV-DNA and HBsAg were assessed at baseline, during therapy (weeks 20, 44 and 68) and follow-up (weeks 92 and 116). Sustained virological response (SVR) was defined as serum HBV-DNA <10 000 copies/mL (partial) or <70 copies/mL (complete) 24 weeks after stopping treatment. A serological response was defined as a serum HBsAg decrease ≥1 log(10) IU/mL at the end of treatment. Baseline median serum HBV-DNA and HBsAg levels were 7.6 log(10) copies/mL and 3.8 log(10) IU/mL, respectively. Ten patients (50%) achieved SVR, six of them had partial response and four complete response. Four patients (20%) achieved serological response. Complete SVRs showed a major and steep decline in HBsAg level with a median decrease of 0.5, 1.6 and 2.0 log(10) IU/mL at treatment week 20, 44 and 68, respectively. Partial SVRs showed a slight and slow decline in serum HBsAg level (0.1, 0.4, and 0.6 log IU/mL at weeks 20, 44 and 68, respectively). On-treatment serum HBsAg decrease had a high accuracy to predict SVR (AUROC = 0.88). Our results suggest that sequential therapy might be an interesting strategy for HBeAg-negative patients. Serum HBsAg kinetics seem to be an accurate tool to predict SVR. Large clinical trials are needed to explore this strategy with more potent analogues.

The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*.

Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600,000 and 350,000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under-represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost-effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.

[HBsAg seroclearance: prognostic value for the response to treatment and the long-term outcome]. / Négativation de l'antigène HBs: valeur pronostique pour la réponse au traitement et l'évolution à long terme.

Chronic hepatitis B is a major cause of liver disease worldwide, ranking as the first cause of cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) is usually used as a qualitative marker for the diagnosis of hepatitis B virus (HBV) infection. HBsAg clearance is the closest to cure outcome as one can expect to achieve in hepatitis B. Support for this comes from natural history studies demonstrating increased length of survival, lower rates of hepatic decompensation, reduction in the frequency of hepatocellular carcinoma, and regression of liver fibrosis in patients who clear HBsAg. HBsAg seroclearance may occur spontaneously at a yearly incidence of 1-2%, preceded usually by a long period of inactive disease. Interferon treatment enhanced HBsAg seroclearance by approximately three-fold in western studies and sixfold in Asian studies compared with non-treated patients. Pegylated interferon induced a 10-15% yearly rate of HBsAg seroclearance in patients who developed sustained virological response in clinical trials. By contrast, treatment with nucleos (t) ides analogues did not significantly affect the rate of HBsAg seroclearance, especially in patients with hepatitis B e antigen (HBeAg) - negative disease. Recently, serum HBsAg has been shown to be a surrogate marker of covalently closed circular DNA (cccDNA) concentration in the liver. Quantification of serum HBsAg has also been recently shown to be a promising tool for monitoring virologic response in HBeAg-negative patients treated with pegylated interferon.

Gene expression and hepatitis C virus infection.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with about 170 million people infected worldwide. Up to 70% of patients will have persistent infection after inoculation, making this disease a significant cause of morbidity and mortality. The severity of disease varies widely, from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma. Since the discovery of HCV, the treatment of hepatitis C has considerably improved. Recently, combination of pegylated interferons with ribavirin gives a response rate of about 55%. Treatment is indicated in patients with moderate or severe fibrosis. The tolerability of combination treatment is relatively poor, with a frequent flu-like syndrome and an impaired quality of life. In addition to viral and environmental behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in HCV infection. The sequencing of the human genome, together with the development of high-throughput technologies that measure the function of the genome, have afforded unique opportunities to develop profiles that can distinguish, identify and classify discrete subsets of disease, predict the disease outcome or predict the response to treatment. This paper reviews the published literature on gene expression associated with HCV infection (HCV infection, fibrosis progression), and also according to response to treatment.

Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) genotype 4 (HCV-4) is increasing in prevalence in Western countries. However, little is known about the severity of the disease and response to treatment. The aim of this study was to assess the predictors (logistic regression) of severe fibrosis (METAVIR score F3-F4), and sustained virological response (SVR) to peginterferon and ribavirin in 226 consecutive HCV-4 patients (Egyptians 40%, Europeans 35% and Africans 24%). PATIENTS AND METHODS: Insulin resistance was assessed using the homeostasis model (HOMA-IR). Serum HCV-RNA level (bDNA) and subtypes of HCV (LiPA) were determined for all patients. RESULTS: Insulin resistance (HOMA-IR >3) was present in 105 patients (46%), and was associated with: age >45 years (OR, 2.614; 95% CI, 1.316 to 5.194), body mass index (BMI) >25 kg/m(2) (OR, 2.105; 95% CI, 1.048 to 4.229), serum HCV-RNA >800 000 IU/ml (OR, 3.143; 95% CI, 1.503 to 6.574), severe fibrosis (OR, 2.657; 95% CI, 1.214 to 5.818), and steatosis >30% (OR, 2.488; 95% CI, 1.105 to 5.602). Severe fibrosis was present in 67 patients (29%) and was associated with Egyptian origin (OR, 5.872; 95% CI, 2.747 to 12.553), excessive alcohol intake (OR, 5.311; 95% CI, 1.287 to 21.924), and HOMA-IR >3 (OR, 3.864; 95% CI, 1.859 to 8.034). 108 patients received a 48 week course of peginterferon plus ribavirin. SVR (undetectable serum HCV-RNA (TMA) 24 weeks after treatment stopping) was achieved in 59 patients (55%) and was associated with Egyptian origin (OR, 13.119; 95% CI, 3.089 to 55.706), HOMA-IR <2 (OR, 5.314; 95% CI, 1.953 to 14.459), and non-severe fibrosis (OR, 8.059; 95% CI, 2.512 to 25.855). CONCLUSION: Insulin resistance and geographical origin are major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4 patients. Insulin resistance is frequently encountered in these patients, and correlated independently with serum HCV-RNA.

Impact of adefovir dipivoxil on liver fibrosis and activity assessed with biochemical markers (FibroTest-ActiTest) in patients infected by hepatitis B virus.

SUMMARY: The aim was to assess the utility of FibroTest-ActiTest (FT-AT) as noninvasive markers of histological changes in patients with chronic hepatitis. Patients with chronic hepatitis B (HBeAg+ and HBeAg-) randomized in two trials of adefovir (ADV) vs placebo, with available paired liver biopsies and FT-AT at baseline and after 48 weeks of treatment were included. The predictive value of FT-AT was assessed using the area under the receiver operating characteristics curves (AUROCs) for the diagnosis of bridging fibrosis, cirrhosis and moderate-severe necroinflammatory activity. The impact of treatment with ADV vs placebo was assessed on liver injury according to baseline stage and virological response at 48 weeks. The analysis of 924 estimates for the diagnosis of bridging fibrosis, cirrhosis and moderate or severe necroinflammatory activity yielded FT-AT AUROCs: 0.76 +/- 0.02 (standardized 0.81 +/- 0.02), 0.81 +/- 0.02 and 0.80 +/- 0.01, respectively. Similar impacts of ADV on liver fibrosis and activity were observed both with paired biopsy (fibrosis stage from 1.6 to 1.4, activity grade from 2.5 to 1.3) and paired biomarkers (FT from 0.44 to 0.40, AT from 0.62 to 0.25) (P < 0.0001). FibroTest-ActiTest provides a quantitative estimate of liver fibrosis and necroinflammatory activity in patients with chronic hepatitis B and may be an alternative to reduce the need for liver biopsy.

[Hepatitis C: the recovery]. / Hépatite C: la guérison.

After the discovery of the hepatitis B virus in 1968 and of the hepatitis A virus in 1973, many years were needed to identify the hepatitis C virus (HCV) in 1989. The discovery of HCV was a revolution for hepatology because of the magnitude of the global burden related to HCV infection, a major cause of cirrhosis and hepatocellular carcinoma. Therapy of hepatitis C has rapidly evolved with currently nearly 60% of sustained virological response with the combination of pegylated interferon plus ribavirin. In patients with sustained virological response, viral eradication, corresponding to the cure of infection, and regression of histological liver lesions have been demonstrated. Recently, the availability of in vitro culture systems allowed to characterize viral enzymes, potential therapeutic targets. A novel therapeutic era is open with the protease and polymerase inhibitors, used as a first step in association with pegylated interferon and ribavirin, both to increase efficacy and decrease the risk of resistance. Thanks to these new molecules with a potent antiviral activity, one can reasonably predict a rapid improvement of treatments becoming more efficient and also better tolerated with the progressive replacement of interferon and ribavirin by combinations of these virus specific enzyme inhibitors.

Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C.

BACKGROUND AND AIMS: The gold standard treatment of chronic hepatitis C (CHC) is combined pegylated interferon and ribavirin. Considering side effects and treatment cost, prediction of treatment response before therapy is important. The aim of this study was to identify a liver gene signature to predict sustained virological response in patients with CHC. METHODS: Group A (training set) comprised 40 patients with CHC including 14 non-responders (NRs) and 26 sustained virological responders (SVRs). Group B (validation set) comprised 29 patients including 9 NRs and 20 SVRs. Eleven responder-relapsers were also included. A total of 58 genes associated with liver gene expression dysregulation during CHC were selected from the literature. Real-time quantitative RT-PCR assays were used to analyse the mRNA expression of these 58 selected genes in liver biopsy specimens taken from the patients before treatment. RESULTS: From the Group A data, three genes whose expression was significantly increased in NRs compared with SVRs were identified: IFI-6-16/G1P3, IFI27 and ISG15/G1P2. These three genes also showed significant differences in their expression profiles between NRs and SVRs in the independent sample (Group B). Supervised class prediction analysis identified a two-gene (IFI27 and CXCL9) signature, which accurately predicted treatment response in 79.3% (23/29) of patients from the validation set (Group B), with a predictive accuracy of 100% (9/9) and of 70% (14/20) in NRs and SVRs, respectively. The expression profiles of responder-relapsers did not differ significantly from those of NRs and SVRs, and 73% (8/11) of them were predicted as SVRs with the two-gene classifier. CONCLUSION: NRs and SVRs have different liver gene expression profiles before treatment. The most notable changes occurred mainly in interferon-stimulated genes. Treatment response could be predicted with a two-gene signature (IFI27 and CXCL9).

[Treatment of chronic hepatitis B]. / Traitement de l'hépatite chronique B.

SUMMARY: In recent years, marked progress has been made in the treatment of chronic hepatitis B. Several agents have been approved: interferon alpha-(IFN), pegylated interferon alpha2a (PEG-IFN alpha2a), lamivudine, adefovir, entecavir, telbivudine and recently, tenofovir. Each drug has advantages and limitations. IFN and PEG-IFN alpha2a have the advantage of inducing a sustained virologic response after a defined, limited course of treatment. However, these drugs are only effective in a minority of patients and have frequent side effects. Analogues have the advantage of being administered orally, with good safety profiles and a potent antiviral effect. However, these drugs need to be administered indefinitely since withdrawal of therapy is generally associated with reactivation, and a sustained response is uncommon except in HBeAg positive patients who develop HBe seroconversion. In case of HBe seroconversion, therapy should usually be continued for at least another 24 weeks. The efficacy of lamivudine is limited by the emergence of lamivudine-resistant HBV. Adefovir is associated with a moderate incidence of resistance but its antiviral effect is not optimal. Entecavir has shown to be more effective with a favourable safety profile and a low incidence of resistance. Telbivudine is more potent and has a lower rate of resistance than lamivudine but the resistance rate is significantly higher than other approved drugs. Tenofovir has a potent antiviral effect with a good resistance profile. The future of chronic hepatitis B therapy appears to be different drug combinations. Normally the advantage of drug combinations versus monotherapy should be additive or synergistic antiviral effects and a decrease in viral resistance. Unfortunately, there are few data available and none of the evaluated analogue combinations have been shown to be better than monotherapy. The only combination which has shown a synergistic effect is of pegylated interferon alpha2a with lamivudine. Therefore, combinations of pegylated interferon with the most potent analogues need to be evaluated. The ultimate goal of therapy is HBsAg seroconversion which is more often observed with interferon. Indeed, quantification of serum HBsAg will be a useful tool to predict the treatment outcome. More potent drugs and new combinations as well as understanding the mechanisms of viral resistance should be evaluated to improve the efficacy of treatment.

[Hepatitis C, cirrhosis and hepatocellular carcinoma]. / Hépatite C, cirrhose et carcinome hépatocellulaire.

The screening for the detection of hepatocellular carcinoma is based on ultrasound sonography which should be realised in patients with post-hepatitis C cirrhosis with a delay between 3 and 6 months according to the most identified risk factors, in particular age and sex male. In the case of discovery of hypoechogen nodule < or = 1cm, a follow-up is mandatory because it is usually untypical by ultrasound sonography and to propose a liver biopsy in the case of an increasing in size is shown. The ultrasound guided cutting biopsy can precise the histological characteristics of the nodule, the grade, and indicate prognostic factors. The liver biopsy is also mandatory in the case of a nodule > 2 cm and when the ultrasound sonography is not contributive, especially when the nodule is between 1 and 2 cm in size.