Olivier Lada

IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C

BACKGROUND & AIMS Polymorphisms in the region of the interleukin (IL)28B gene have been associated with pegylated-interferon (PEG-IFN) and ribavirin treatment response mainly in genotype 1 HCV infections. However, there are few data on HCV genotype 4 (HCV-4) infection. We evaluated, in a unique well-characterized cohort of HCV-4 patients, the association of IL28B polymorphism with response to treatment or liver disease severity. METHODS This study included 164 HCV-4 patients from different ethnic groups (Egyptian, European, and Sub-Saharan African). Among these patients, 82 were studied for response and 160 for disease severity. Free DNA extracted from all the 164 patients serum samples was analyzed by direct sequencing of the SNP rs12979860 of IL28B. Genetic and bio-clinical features from patients having sustained virological response (43 SVR patients) and from those who did not respond to treatment or had a relapse after the end of the treatment (39 NR patients) were compared. IL28B polymorphism was compared between the 78 patients with mild fibrosis (Metavir score F0-F1) and the 82 with advanced fibrosis (F2-F4). RESULTS Our data showed a better treatment response rate of the C allele of the IL28B gene SNP rs12979860 (p=0.0008). The response rates were 81.8%, 46.5%, and 29.4% for genotype CC, CT, and TT, respectively. No significant relationship was found between rs12979860 and the severity of the disease. CONCLUSIONS The SNP rs12979860 is strongly associated with SVR in patients infected with HCV-4, but not with liver disease severity. Analysis of IL28B genotype might be used to guide treatment for these patients.

Coexistence of Hepatitis B Surface Antigen (HBs Ag) and Anti-HBs Antibodies in Chronic Hepatitis B Virus Carriers: Influence of “a” Determinant Variants

ABSTRACT In chronic hepatitis B (CHB), the persistence of hepatitis B surface antigen (HBs Ag) is sometimes associated with antibodies (Ab) to HBs (anti-HBs). To assess the hypothesis of the selection of HBs Ag immune escape variants in CHB patients, the variability of the HBV S gene was determined for patients persistently carrying both HBs Ag and anti-HBs antibodies and patients solely positive for HBs Ag. We selected 14 patients who presented both markers (group I) in several consecutive samples and 12 patients positive for HBs Ag only (group II). The HBs Ag-encoding gene was amplified and cloned, and at least 15 clones per patient were sequenced and analyzed. The number of residue changes within the S protein was 2.7 times more frequent for group I than for group II patients and occurred mostly in the “a” determinant of the major hydrophilic region (MHR), with 9.52 versus 2.43 changes per 100 residues (P = 0.009), respectively. Ten patients (71%) from group I, but only three (25%) from group II, presented at least two residue changes in the MHR. The most frequent changes in group I patients were located at positions s145, s129, s126, s144, and s123, as described for immune escape variants. In CHB patients, the coexistence of HBs Ag and anti-HBs Ab is associated with an increase of “a” determinant variability, suggesting a selection of HBV immune escape mutants during chronic carriage. The consequences of this selection process with regard to vaccine efficacy, diagnosis, and clinical evolution remain partially unknown.

Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C

Accuracy of transient elastography (TE) in hepatitis B virus (HBV) infection has not been well established. We aimed to compare the performances of TE for the assessment of liver fibrosis in patients with chronic HBV or hepatitis C virus (HCV) infection. A secondary analysis was performed to assess whether or not alanine aminotransferase (ALT) levels would impact on the accuracy of TE.

Clinically Relevant Genotype Interpretation of Resistance to Didanosine

ABSTRACT We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as −1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E − K70R − M184V/I; P = 4.5 × 10−9) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 × 10−7). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log10 copies/ml when they were ranked as having a genotypic score II of −2, −1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI.

Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naïve, e antigen-positive patients

BACKGROUND & AIMS Little is currently known about the association between serum HBsAg or HBV DNA levels and the severity of liver disease in chronic hepatitis B (CHB) patients. Therefore, we investigated these relationships in a large cohort of unselected, well-characterized, treatment-naïve CHB patients. METHODS CHB patients were assessed at the Hôpital Beaujon in Paris, France, between 2000 and 2008. Serum samples and liver biopsies were obtained on the same day. HBsAg, HBV DNA, and HBV genotype were investigated using commercial diagnostic assays and liver histology was scored using the METAVIR system. RESULTS 406 patients were included in this cross-sectional study. Serum HBsAg and HBV DNA levels in hepatitis B e antigen-positive (HBeAg[+]) patients showed strong correlation (r=0.44, p<0.0001), as did serum HBsAg levels and fibrosis severity (r=0.43, p<0.0001). HBeAg(+) patients with moderate to severe fibrosis exhibited significantly lower serum HBsAg and HBV DNA levels compared with patients with no or mild fibrosis. Modeling analysis suggested a serum HBsAg cut-off of 3.85 logIU/ml would provide a theoretical sensitivity of 100% (95% CI: 0-100), theoretical specificity of 86% (95% CI: 50-100), and a negative predictive value of 100% (95% CI: 67-100) in HBeAg(+) patients infected with HBV genotype B or C. CONCLUSIONS We found an association between low serum HBsAg levels and moderate to severe fibrosis in HBeAg(+) CHB patients. Furthermore, we described a serum HBsAg cut-off for the prediction of fibrosis severity in CHB patients infected with HBV genotype B or C.

Reduction of MicroRNA 122 Expression in IFNL3 CT/TT Carriers and during Progression of Fibrosis in Patients with Chronic Hepatitis C

ABSTRACT The microRNA miR-122 is highly expressed in the liver and stimulates hepatitis C virus (HCV) replication in vitro. IFNL3 (lambda-3 interferon gene) polymorphisms and the expression of miR-122 have been associated with sustained virological response (SVR) to treatment with pegylated interferon plus ribavirin in patients with chronic hepatitis C (CHC). We investigated, in vivo, the relationship between miR-122 expression, IFNL3 polymorphism, fibrosis, and response to PEG-IFN plus ribavirin. Pretreatment liver biopsy specimens and serum samples from 133 patients with CHC were included. Sixty-six patients achieved SVR, and 64 failed to respond to the treatment (43 nonresponders [NR] and 21 relapsers [RR]). All stages of fibrosis were represented, with 39, 50, 23, and 19 patients, respectively, having Metavir scores of F1, F2, F3, and F4. miR-122 expression was assessed by real-time quantitative PCR (RT-qPCR) and IFNL3 rs12979860 by direct sequencing. Hepatic miR-122 expression was higher in patients with the IFNL3 CC genotype than in those with the IFNL3 CT or TT genotype, in all patients (P = 0.025), and in NRs plus RRs (P = 0.013). Increased hepatic miR-122 was more strongly associated with complete early virological response (cEVR) (P = 0.003) than with SVR (P = 0.016). In multivariate analysis, increased hepatic miR-122 was only associated with the IFNL3 CC genotype. miR-122 was decreased in patients with advanced fibrosis (Metavir scores of F3 and F4) compared to its levels in patients with mild and moderate fibrosis (F1 and F2) (P = 0.01). Serum and hepatic expression of miR-122 were not associated. The association between miR-122 and IFNL3 was stronger than the association between miR-122 and response to treatment. miR-122 may play a role in the early viral decline that is dependent on IFNL3 and the innate immune response. IMPORTANCE miR-122 plays a crucial role during HCV infection. Moreover, it was reported that miR-122 binding within the HCV genome stimulates its replication. Moreover, miR-122 is highly expressed within hepatocytes, where it regulates many cellular pathways. A reduction of miR-122 expression has been suggested to be associated with responsiveness to IFN-based therapy in patients with chronic hepatitis C. Several independent genome-wide association studies reported a strong association between IFNL3 polymorphism and responsiveness to IFN-based therapy. We report here a strong association between the expression of miR-122 and IFNL3 polymorphism that is independent of the response to the treatment. Our data suggest that modification of miR-122 expression may play an important role in the molecular mechanism associated with IFNL3 polymorphism. Moreover, we report a reduction of miR-122 at more advanced stages of fibrosis in patients with chronic hepatitis C.

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.

Treatment of chronic hepatitis B with the combination of pegylated interferon with lamivudine.

Several agents are currently approved for the treatment of chronic hepatitis B: interferon alpha (IFN), pegylated interferon‐α (PEG IFN), lamivudine, adefovir, and entecavir. Each agent has inherent limitations. IFN is effective in a minority of patients and has frequent side effects that limit its tolerability. Large randomized controlled trials have demonstrated the efficacy of PEG IFN in the treatment of chronic hepatitis B. The efficacy of lamivudine is limited by the emergence of drug‐resistant hepatitis B virus (HBV) mutants, restricting its utility as a long‐term therapy. Adefovir is well tolerated and is associated with low incidence of resistance, but its antiviral effect is not optimal. Entecavir has a high antiviral effect and is well tolerated. However, its long term efficacy and resistance profile are not yet determined. Lamivudine, adefovir and entecavir have the advantages of oral administration and excellent safety profiles. However, theyinduce a sustained response after withdrawal of therapy in only a minority of patients, and therefore, the treatment needs to be indefinitely administered in most patients. IFNs have two mechanisms of action: (i) direct antiviral effect by inhibiting synthesis of viral DNA and by activating antiviral enzymes; and (ii) exaggeration of the cellular immune response against hepatocytes infected with HBV. PEG IFN, administered for 48 weeks, gives an overall sustained response rate of approximately 30%. Two large randomized controlled trials have conducted to registration of PEG IFN‐α‐2a in the treatment of chronic hepatitis B.

Clevudine: a promising therapy for the treatment of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection, affecting ∼ 350 million people worldwide, is associated with significant morbidity and mortality. In the past 10 years, hepatitis B therapy research has led to a multitude of available antiviral therapies: IFN-α, pegylated IFN-α2a, lamivudine, adefovir, entecavir, telbivudine and tenofovir. To further improve reductions in viral load and resistance profiles, development of new HBV therapeutic strategies has been an important focus. One such therapy is clevudine, an analogue of the β-L configuration. Clevudine is already licensed in Korea for anti-HBV therapy (Bukwang Pharmaceuticals, Seoul, Korea). Unique to clevudine is its ability to maintain antiviral activity following discontinuation of therapy. Typically, hepatitis B treatment requires continuous therapy to prevent reactivation. Sustained response is uncommon except in hepatitis B antigen (HBeAg)-positive patients who developed HBeAg seroconversion. This article reviews chronic HBV and its therapy options. Specifically, it describes clevudines potent and sustained antiviral activity as observed in vitro and in vivo.

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients

ABSTRACT Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day−1) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.