Transient elastography alone and in combination with FibroTest® for the diagnosis of hepatic fibrosis in alcoholic liver disease.

BACKGROUND & AIMS: The reliability of transient elastography (TE) to assess liver fibrosis is insufficiently validated in alcoholic liver disease (ALD). We aimed to validate the diagnostic utility of TE for liver fibrosis in patients with excessive alcohol consumption and evaluate whether Fibrotest® adds diagnostic value relative to or in combination with TE. METHODS: We conducted a multicentre prospective study on a total of 217 heavy drinkers with high serum aminotransferase levels. Patients underwent liver biopsy, TE, Fibrotest® , PGAA, APRI, FIB-4 and FORNS. The overall diagnostic performance was evaluated by the area under the receiver operating characteristic (AUROC) curves and Obuchowski measures. RESULTS: TE values correlated with fibrosis stage (r=.73; P<.0001) and steatosis stage (r=.19; P<.01). Patients with alcoholic hepatitis had higher TE values than those without alcoholic hepatitis (P<.0001). In an multivariate analysis, fibrosis stage and the presence of alcoholic hepatitis were the only parameters that correlated with liver stiffness. For the diagnosis of advanced fibrosis (F≥3), the AUROC curves were 0.90, 0.85, 0.83, 0.91 and 0.90 for TE, Fibrotest® , PGAA and associations TE-Fibrotest® , TE-PGAA respectively. For the diagnosis of cirrhosis, the AUROC curves were 0.93, 0.88, 0.89, 0.94 and 0.95 respectively. The Obuchowski measures for the diagnosis of fibrosis were 0.94, 0.92, 0.91, 0.95 and 0.94 respectively. The performance of TE was not significantly different than those of Fibrotest® , PGAA and combinations TE-Fibrotest® , TE-PGAA. CONCLUSIONS: TE has excellent diagnostic value for liver fibrosis in alcoholic liver disease. The combined use of TE-Fibrotest® or TE-PGAA does not improve the performance of TE.

HCV and the kidney.

Chronic hepatitis C (CHC) is significantly associated with a risk of renal deterioration over time. Renal impairment, especially stage 4-5 chronic kidney disease, increases the risk of: (i) the prevalence and incidence (in dialysis/transplantation) of hepatitis C virus (HCV) infection; (ii) liver deterioration during kidney transplantation and (iii) allograft failure and patient mortality. HCV-infected dialysis patients have a higher mortality than non-infected dialysis patients and than HCV-infected kidney recipients. The harmful impact of HCV emphasizes the need for oral antiviral therapies in patients with chronic kidney disease. Symptomatic cryoglobulinemic vasculitis and extensive liver fibrosis are already approved indications for early access to oral antiviral treatment. Patients with stage 4-5 chronic kidney disease should also be given priority: dialysis patients (whatever the stage of fibrosis and whether or not they are candidates for kidney transplantation) as well as all kidney recipients. The results of treatment of HCV with direct-acting antiviral (DAAs) drugs in patients with late chronic kidney disease are excellent, similar to those in the general population, although additional clinical trials are definitely needed, particularly to optimize adjustment of treatment to kidney function and determine the risk of drug-drug interactions.

Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography.

BACKGROUND & AIMS: Quantitative shear wave elastography was shown to be an effective tool for the non-invasive diagnosis and staging of chronic liver diseases. The liver shear modulus, estimated from the propagation velocity of shear waves, is correlated to the degree of fibrosis and can therefore be used for the non-invasive staging of fibrosis. METHODS: We performed a clinical prospective study in a total of 120 patients with various chronic liver diseases to compare the accuracy of supersonic shear imaging (SSI), a technique based on acoustic radiation and ultrafast ultrasound imaging, to 1D transient elastography (FibroScan) for the staging and grading of fibrosis as assessed by liver biopsy. Since shear wave propagation spectroscopy can also provide additional mechanical information on soft tissues, such as viscosity, we also investigated those new mechanical parameters as possible predictors of fibrosis, steatosis, and disease activity. RESULTS: SSI was successfully performed in 98.3% of patients and it was shown to be as accurate as FibroScan for the staging of fibrosis both for the whole population (N=120) and for the subgroup with viral hepatitis (n=70) (AUC=0.85 [0.77-0.96] and 0.89 [0.81-0.97] for significant fibrosis, AUC=0.90 [0.83-0.97] and 0.87 [0.75-0.98] for cirrhosis, with respect to SSI [n=68/70] and FibroScan [n=66/68]). Viscosity could also be used to stage the degree of fibrosis (AUC=0.76 [0.64-0.87] for significant fibrosis and AUC=0.87 [0.74-0.99] for cirrhosis), for the subgroup of patients with viral hepatitis (n=67/70) but was a poor predictor of disease activity and steatosis levels. CONCLUSIONS: Supersonic shear imaging is a robust technique for the staging of liver fibrosis. Liver viscosity was found to be correlated with fibrosis but not to steatosis or disease activity.

Effect of nucleoside and nucleotide analogues on renal function in patients with chronic hepatitis B virus monoinfection.

BACKGROUND & AIMS: There is controversy regarding whether nucleos(t)ide analogues contribute to renal impairment in patients with chronic hepatitis B virus (HBV) infection. We analyzed changes in renal function in patients with chronic HBV infection and whether these were associated with treatment or comorbidities. METHODS: We performed a longitudinal observational study to investigate factors associated with renal function in 214 patients (median age, 43 y; 69.2% men) with compensated chronic HBV monoinfection treated with 343 lines of nucleos(t)ide analogues (210 monotherapies, 133 combinations) between 1990 and 2012 (median time, 2.4 y) in France. A linear mixed-effect model was used to model variations of estimated glomerular filtration rate (eGFR, computed with the Chronic Kidney Disease Epidemiology Collaboration formula), adjusting for age, sex, geographic origin, initial liver fibrosis, level of HBV DNA, and an eGFR less than 90 mL/min/1.73 m(2). RESULTS: The eGFR decreased in patients given adefovir dipivoxil as monotherapy or in a combination (P < .0001 and P < .002, respectively), and remained stable in patients given lamivudine, tenofovir disoproxil fumarate, or entecavir. The eGFR decreased in patients with a baseline eGFR of less than 90 mL/min/1.73 m2, regardless of treatment. The eGFR remained stable or increased, regardless of treatment, in patients with a baseline eGFR of 90 mL/min/1.73 m2 or greater and with an initial HBV DNA level of 100,000 IU/mL or greater. Patients born in areas of high endemicity of HBV were more prone to increases in eGFR with treatment. CONCLUSIONS: In a real-life study, the eGFR remained stable or increased over time in patients with chronic HBV monoinfection with a baseline eGFR of 90 mL/min/1.73 m2 or higher and treated with tenofovir disoproxil fumarate or entecavir. Patients born in an area of high endemicity of HBV who had initial levels of HBV DNA of 100,000 IU/mL or greater were more likely to have increased eGFR with treatment.

Treatment of hepatitis C virus genotype 3-infection.

The treatment of hepatitis C virus (HCV) infection with pegylated interferon (PEG-IFN) alfa and ribavirin (800 mg daily) (RBV) is the standard of care (SOC) for hepatitis C virus genotype 3-infection leading to a sustained virological response (SVR) in around 65% of patients. A better understanding of the HCV life-cycle has recently resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins (NS3/4A protease, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase, NS5A viral replication complex). First generation protease inhibitors in combination with PEG-IFN/RBV are not efficient in genotype 3-infected patients. The combination of PEG-IFN/RBV with Daclatasvir, a NS5A inhibitor for 12-24 weeks results in a SVR in around 75% while the triple combination of PEG-IFN/RBV with the oral nucleotidic polymerase inhibitor Sofosbuvir (GS-7977) for 12 weeks in naïve patients results in a SVR in more than 95%. The results of the first oral combination of Sofosbuvir and RBV for 12 weeks in genotype 3-infected patients have been rather disappointing with a slightly lower SVR than after 24 weeks of PEG-IFN: around 60%, and only 30% in patients with cirrhosis. Extending treatment from 12 to 16 weeks in treatment experienced patients doubled the SVR rate and an 80% SVR rate is expected by extending treatment to 24 weeks. The best oral combination of new DAAs is probably the combination of Sofosbuvir and a NS5A inhibitor (Daclatasvir, Ledipasvir…) for 24 weeks, which resulted in a 100% SVR rate in a limited series. The use of cyclophilin inhibitors, a host-targeted antiviral, in association with DAAs and/or RBV may also be of interest. The oral combination of new DAAs (dual or triple combination of different antivirals) or of DAAs and host targets such as cyclophilin will probably become the SOC for genotype 3-infected treatment-naïve or -experienced patients.

[Treatment of hepatitis C: current status and perspectives]. / Traitement de l'hépatite C: état actuel et perspectives.

The treatment of hepatitis C virus (HCV) infection has significantly improved these last two decades. For nearly 15 years, the association of pegylated interferon alfa and ribavirin (PR) has allowed a sustained virologic response (SVR), i.e., a viral cure of the infection, in 45% of genotype 1-infected patients, 65% of genotype 4-, 70% in genotype 3- and around 85% of genotype 2-infected patients. A better understanding of the HCV life-cycle has led to the development of direct-acting antiviral drugs (DAAs) targeted against viral proteins (NS3/4A protease, NS5B polymerase with nucleos(t)idic and non nucleos(t)idic inhibitors, NS5A viral replication complex). The combination of first generation protease inhibitors with PR has showed a high antiviral efficiency (75% of SVR in genotypes 1) with substantial side effects for the first generation protease inhibitors, which have obtained approval to market in 2011 (Telaprevir and Boceprevir) and recommandations of use in HCV mono-infected patients in 2012 and in HCV/HIV coinfected in 2013. Then, the combination of second generation protease inhibitors with PR has increased SVR rates from 75 to 90%, while reducing treatment duration, side effects and number of pills. Next step is now interferon and ribavirin free combination of DAAs, about to become the standard of care in 2015. These excellent results in 'easy-to-treat' patients and in small population studies has now been confirmed in phase III studies and in 'difficult-to-treat' patients (treatment - especially protease inhibitors-experienced patients, cirrhotic patients, liver and renal transplant patients, HIV co-infected patients, and subjects with polypharmacy, at increased risk of drug interaction).

Histological Characteristics and Management of Hepatitis on Immune Checkpoint Inhibitors: A Retrospective Descriptive Study.

BACKGROUND AND AIMS: the side effects of immune checkpoint inhibitors (ICI) pose a problem for the clinical management of cancer patients. There is a lack of knowledge of the value of liver biopsy in patients with ICI-related drug-induced liver injury (ICI-DILI). The aim of this study was to explore the impact of liver biopsy on clinical management and response to corticosteroids, according to histological findings. METHODS: We conducted a retrospective, single-center study to evaluate the biochemical, histological and clinical data of 35 patients with ICI-DILI between 2015 and 2021 in a university hospital in France. RESULTS: Of the 35 patients with ICI-DILI (median [interquartile range] age 62 [48-73] years, 40% males) studied, 20 underwent a liver biopsy. There was no difference in the management of ICI-DILI according to liver biopsy in terms of ICI withdrawal, reduction or rechallenge. According to the histological profile, patients with toxic and granulomatous profiles had a better response to corticosteroids, while patients with cholangitic lesions had the worst response. CONCLUSION: In ICI-DILI, liver biopsy must not delay patient care but may be useful in identifying patients with a cholangitic profile who have a poorer response to corticosteroids.

Benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection is more frequent in kidney recipients than in the general population with a higher rate of liver-related morbidity and mortality. We evaluated the benefit associated with HBV viral suppression by nucleos(t)ide analogues treatment in HBV-infected kidney recipients. METHODS: This retrospective study included 42 HBsAg-positive kidney recipients, 33 males, 9 females, median age 54 years, followed up during a mean of 15.4±11.8 years after kidney transplantation. Mean treatment duration by single or combined nucleos(t)ide analogues was 6.8±4.3 years. Fibrosis, before treatment, according to Metavir score was: F4 for 6 patients, F3 for 10, F2 for 6, and F0-F1 for 20 patients. The primary end point, the patient survival, was defined as patient death or liver transplantation, the secondary end point was graft survival. RESULTS: HBV DNA at the last evaluation was undetectable (<12 IU/ml) in 92.8% of patients. During the follow-up, 8 patients died (17.7%), death being related to hepatocellular carcinoma in 4 (9.5%), including 1 patient with baseline mild fibrosis, and to extrahepatic causes in 4. This mortality rate is strikingly lower than that previously reported in HBV-infected kidney recipients before oral antiviral therapies. Graft survival seems to be improved when compared to the former series. CONCLUSIONS: Suppression of HBV replication associated with nucleo(s)tide analogues treatment improves the survival of HBV-infected kidney recipients. Viral suppression does not exclude regular follow-up given the risk of occurrence of hepatocellular carcinoma even in non-cirrhotic patients.

Rapid decline of liver stiffness following alcohol withdrawal in heavy drinkers.

BACKGROUND: Measurement of liver stiffness (LS) using real-time elastography appears as a promising tool to evaluate the severity of chronic liver diseases. Previous studies in patients with alcoholic liver disease have suggested that fibrosis was the only histological parameter to influence LS. To challenge this hypothesis, we have prospectively tested the short-term impact of alcohol withdrawal on LS value. METHODS: Patients hospitalized for alcohol withdrawal in our Liver and Addiction Unit between 2007 and 2010 had an LS determination at entry (D0) and 7 days after alcohol withdrawal (D7). LS value was given as the median of 10 measurements performed with a FibroScan(®) device. For a given patient, variation of LS was considered as significant when the comparison of the 10 measurements at D0 and at D7 yielded a p-value under 0.05 (Wilcoxon test). RESULTS: One hundred and thirty-seven patients were included in the study (median alcohol consumption: 150 g/d; hepatitis C: n = 21 [15.6%]). Considering all patients, median LS value decreased from 7.2 to 6.1 kPa between D0 and D7 (p = 0.00001, paired Wilcoxon test). LS decreased significantly in 62 patients (45.3%), and there was a reduction in the estimated stage of fibrosis in 32 (23.3%). LS increased significantly in 16 patients (11.7%). Subgroup analyses revealed that the decrease in LS was still significant in patients with or without hepatitis C infection, and aspartate transaminase level below or above 100 UI/l. CONCLUSIONS: LS decreases significantly in nearly half of heavy drinkers after only 7 days of abstinence. This result strongly suggests that nonfibrotic lesions (such as the presence of alcoholic hepatitis) may influence LS. From a practical point of view, it also shows that variation of alcohol consumption must be taken into account for the interpretation of LS value.

Usefulness of viral kinetics for early prediction of a sustained virological response in HCV-1 non-responders re-treated with pegylated interferon and ribavirin.

BACKGROUND & AIMS: Undetectable HCV RNA at 12 weeks is the stopping rule recommended in HCV patients in whom previous treatment has failed. Whether earlier virological criteria may be useful for deciding treatment discontinuation remains subject of debate. The aim of this study was to identify, in HCV-1 non-responders and relapsers to IFN or Peg-IFN and ribavirin, the earliest and most accurate predictor of failure to respond to a new treatment combining Peg-IFN and ribavirin. METHODS: Prediction of SVR was assessed using the area under the ROC (AUROC) curve of reduction in viral load at different time points. RESULTS: This study included 151 patients (32% with extensive fibrosis or cirrhosis). A SVR was reached in 34% (21% in non-responders and 59% in relapsers). In non-responders, 1 month was the most accurate time point for predicting SVR (AUROC: 0.787 ± 0.075, p = 0.0001). Thirty-seven percent of non-responders did not have a 1-log drop in viral load at 1 month. All these patients had detectable HCV RNA at 3 months (p < 0.0001) and only 4% attained a SVR (p = 0.004). The same high negative predictive value for SVR was found in sensitivity analysis restricted to non-responders to Peg-IFN and ribavirin. In contrast, in relapsers, undetectable HCV RNA at 3 months was the earliest criterion with high negative predictive value (92%, p < 0.0001). CONCLUSIONS: All HCV-1 non-responders who did not have a 1-log drop in viral load at 1 month remained HCV-RNA-detectable at 3 months, and only 4% attained a SVR. This new criterion can be used early on as a first stopping rule.

Daclatasvir-sofosbuvir combination therapy with or without ribavirin for hepatitis C virus infection: from the clinical trials to real life.

The treatment of hepatitis C virus has changed dramatically with the rapid advent of numerous new antiviral agents, including direct-acting antivirals and agents with non-viral targets (cyclophilin inhibitors, interferon-lambda, vaccine therapy). Given the better safety profile and high antiviral potency of direct-acting antivirals, their combination in interferon-free oral regimens is becoming the standard of care for hepatitis C virus infection, tailored to individual patients according to the degree of disease progression (fibrosis), hepatitis C virus genotype and subtype, resistance profile, and prior therapeutic history. Results from clinical studies as well as preliminary real-life data regarding the combination of sofosbuvir (a nucleotide polymerase inhibitor) and daclatasvir, a first-in-class NS5A replication complex inhibitor, demonstrate that it is one of the most promising antiviral therapies, with once-daily oral dosing, a low pill burden, good tolerability, and limited drug-drug interactions, in addition to high antiviral potency, with >90% sustained virologic response rates. This combination has high pangenotypic antiviral potency regardless of the severity and patient characteristics. The combination of sofosbuvir and an NS5A inhibitor with ribavirin for 12 weeks appears to be a very good further treatment option in both cirrhotic and treatment-experienced patients whatever the stage of fibrosis.

Humoral immunity links Candida albicans infection and celiac disease.

OBJECTIVE: The protein Hwp1, expressed on the pathogenic phase of Candida albicans, presents sequence analogy with the gluten protein gliadin and is also a substrate for transglutaminase. This had led to the suggestion that C. albicans infection (CI) may be a triggering factor for Celiac disease (CeD) onset. We investigated cross-immune reactivity between CeD and CI. METHODS: Serum IgG levels against recombinant Hwp1 and serological markers of CeD were measured in 87 CeD patients, 41 CI patients, and 98 healthy controls (HC). IgA and IgG were also measured in 20 individuals from each of these groups using microchips sensitized with 38 peptides designed from the N-terminal of Hwp1. RESULTS: CI and CeD patients had higher levels of anti-Hwp1 (p=0.0005 and p=0.004) and anti-gliadin (p=0.002 and p=0.0009) antibodies than HC but there was no significant difference between CeD and CI patients. CeD and CI patients had higher levels of anti-transglutaminase IgA than HC (p=0.0001 and p=0.0039). During CI, the increase in anti-Hwp1 paralleled the increase in anti-gliadin antibodies. Microchip analysis showed that CeD patients were more reactive against some Hwp1 peptides than CI patients, and that some deamidated peptides were more reactive than their native analogs. Binding of IgG from CeD patients to Hwp1 peptides was inhibited by γIII gliadin peptides. CONCLUSIONS: Humoral cross-reactivity between Hwp1 and gliadin was observed during CeD and CI. Increased reactivity to Hwp1 deamidated peptide suggests that transglutaminase is involved in this interplay. These results support the hypothesis that CI may trigger CeD onset in genetically-susceptible individuals.

[Viral hepatitis, diagnosis, natural history and treatment]. / Hépatites virales, diagnostic, histoire naturelle et traitement.

Epidemiological, virological and therapeutic knowledge in the field of viral hepatitis is constantly growing, resulting in the improved management of the diagnosis and treatment of patients with acute or chronic hepatitis.

[Epidemiology, transmission and screening of viral hepatitis]. / Epidémiologie, transmission et dépistage des hépatites virales.

Epidemiological advances, new vaccines, early diagnosis as well as research into the ways the different forms of hepatitis are transmitted, have resulted in better prevention.The treatment of populations is more effective and faster.

Oral antiviral therapies for chronic hepatitis C infection.

The treatment of hepatitis C virus (HCV) infection with pegylated interferon alpha and ribavirin leads to a sustained virologic response in around 50% of patients with HCV genotype 1, 65% with HCV genotype 4, 75% with HCV genotype 3 and around 80% with HCV genotype 2. A better understanding of the HCV lifecycle has resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins [NS3/4A protease inhibitors, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase inhibitors, NS5A replication complex inhibitors]. This review summarizes the main clinical data for the combinations of oral DAAs. DAAs, either in combination with pegylated interferon alpha or in interferon-free regimens, have demonstrated a high level of antiviral efficacy and a generally well-tolerated safety profile in treatment-naïve patients and in prior nonresponders to pegylated interferon alpha/ribavirin. Oral combination of new DAAs is likely to become the standard of care for chronic HCV in treatment-naïve or treatment-experienced patients. However, most studies so far have included small numbers of 'easy-to-treat' patients with short post-treatment periods for defining the sustained virologic response. Extension of the number of treated patients (including 'difficult-to-treat' patients, i.e. patients infected with genotype 3, who failed to respond to first-generation protease inhibitors or with cirrhosis as well as immunocompromised patients) and of the post-treatment follow up in a real-life setting could significantly worsen the rate of recovery. In these 'difficult-to-treat' patients, the rate of virologic cure with new DAAs could be lower than expected and consequently interferons may be still necessary in combination with the new drugs.

Hepatitis C: epidemiology, diagnosis, natural history and therapy.

With an estimated prevalence of 3% in the world population (around 170 million infected individuals worldwide), hepatitis C virus (HCV) heavily burdens public health. Even though the incidence of new infections is declining, at least in industrialized countries where they are mainly restricted to intravenous drug users, morbidity and mortality (which means also HCV-induced costs) associated with HCV infection are expected to increase over the next decade. Models suggest that the incidence of hepatocellular carcinoma and HCV-related mortality will still increase until about 2015. The prevalence of the disease, the risk of progression of fibrosis to cirrhosis or hepatocellular carcinoma, mainly but not only in patients with liver comorbidities such as metabolic syndrome and/or heavy alcohol intake, evidences: (1) the need for a screening of chronic HCV infection as defined by both anti-HCV antibodies and detectable HCV RNA, (2) the evaluation of the extrahepatic (cryoglobulinemia-related vasculitis) or liver impact of chronic infection (by liver biopsy or noninvasive markers of fibrosis) and (3) the discussion of an antiviral treatment which is mainly the combination of pegylated interferon (one weekly subcutaneous injection) and ribavirin, a nucleosidic analogue with a twice daily oral intake. This 'standard of care' results in a mean of 60% of sustained virologic response corresponding to viral eradication, which allows the inactivation of necroinflammation and the remodeling of fibrosis. New antiviral treatments (direct-acting anti-virals like protease NS3/4, polymerase NS5B, NS5A, entry inhibitors or other drugs like cyclophilin inhibitors, new interferons, immune modulators or therapeutic vaccine) are being rapidly developed (the approval of the first generation protease inhibitors is expected for spring 2011). The next step appears to be the combination of these oral drugs allowing a better safety and efficacy of the treatment.

Hepatitis B virus infection and pregnancy.

Pregnancy only mildly affects that natural progression of acute and chronic infection by the hepatitis B virus (HBV) but it does bring to light three important questions. Mother to child (vertical) transmission risk is best prevented by mandatory HBs antigen testing in all pregnant women in their second trimester and by systemic serovaccination of newborns of infected mothers. In mothers with high viral load, vertical infection in utero could be prevented by lamivudine, telbivudine or tenofovir treatment. Invasive obstetric or gynecological procedures (such as amniocentesis, forceps, etc.) do not seem to increase the risk of vertical infection. Breastfeeding is not contraindicated in maternal HBV infection after serovaccination of the newborn. This holds true for mothers on active treatment with tenofovir which is not absorbed into breast milk. When it comes to managing active antiviral treatment, in absence of virosuppression with lamivudine, tenofovir remains a logical step-up treatment; in absence of virosuppression with adefovir, tenofovir also remains a logical step-up choice as do tenofovir/emtricitabine combinations or lamivudine in absence of preexisting resistance which may have been induced during combination treatment of adefovir and lamivudine. In cases of effective virosuppression with treatment by analogues, lamivudine should be continued and entecavir should eventually be replaced by lamivudine, telbivudine or tenofovir; adefovir should be replaced by tenofovir or lamivudine in absence of resistance (which would require tenofovir therapy) or adefovir which would restrict lamivudine therapy.