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Summary: Background: No prospective diagnostic studies have directly compared widespread non‐invasive liver tests in patients with type 2 diabetes (T2D) using the intention‐to‐diagnose method for each of the three main histological features of metabolic dysfunction associated steatotic liver disease ‐ namely fibrosis, metabolic dysfunction‐associated steatohepatitis (MASH), and steatosis. Aims: To compare the performance of nine tests using the intention‐to‐diagnose rather than the standard method, which would exclude non‐evaluable participants Methods: Biopsy was used as the reference with predetermined cut‐offs, advanced fibrosis being the main endpoint. The Nash‐FibroTest panel including FibroTest‐T2D, SteatoTest‐T2D and MashTest‐T2D was optimised for type 2 diabetes. FibroTest‐T2D was compared to vibration‐controlled transient elastography stiffness (VCTE), two‐dimensional shear‐wave elastography stiffness (TD‐SWE), and Fibrosis‐4 blood test. NashTest‐T2D was compared to aspartate aminotransferase. SteatoTest‐T2D was compared to the controlled attenuation parameter and the hepatorenal gradient. Results: Among 402 cases, non‐evaluable tests were 6.7% for VCTE, 4.0% for hepatorenal gradient, 3.2% for controlled attenuation parameter, 1.5% for TD‐SWE, 1.2% for NashTest‐T2D, and 0.02% for Fibrosis‐4, aspartate aminotransferase and SteatoTest‐T2D. The VCTE AUROC for advanced fibrosis was over‐estimated by 6% (0.83 [95% CI: 0.78–0.87]) by standard analysis compared to intention‐to‐diagnose (0.77 [0.72–0.81] p = 0.008). The AUROCs for advanced fibrosis did not differ significantly in intention‐to‐diagnose between FibroTest‐T2D (0.77; 95% CI: 0.73–0.82), VCTE (0.77; 95% CI: 0.72–0.81) and TD‐SWE(0.78; 0.74–0.83) but were all higher than the Fibrosis‐4 score (0.70; 95% CI all differences ≥7%; p ≤ 0.03). For MASH, MashTest‐T2D had a higher AUROC (0.76; 95% CI: 0.70–0.80) than aspartate aminotransferase (0.72; 95% CI: 0.66–0.77; p = 0.035). For steatosis, AUROCs did not differ significantly between SteatoTest‐T2D, controlled attenuation parameter and hepatorenal gradient. Conclusions: In intention‐to‐diagnose analysis, FibroTest‐T2D, TD‐SWE and VCTE performed similarly for staging fibrosis, and out‐performed Fibrosis‐4 in outpatients with type 2 diabetes. The standard analysis over‐estimated VCTE performance. ClinicalTrial.gov: NCT03634098. [ABSTRACT FROM AUTHOR]

Purpose: The impact of direct‐acting antivirals (DAAs) on extrahepatic complications in chronic hepatitis C (CHC) patients remains poorly described. We estimated the association of DAAs with cardiovascular events and extrahepatic cancers. Methods: The prospective ANRS CO22 HEPATHER cohort was enriched with individual data until December 2018 from the French Health Insurance Database (SNDS). CHC patients were enrolled between August 2012 and December 2015 in 32 French hepatology centers. A total of 8148 CHC adults were selected. Cardiovascular events (stroke, acute coronary syndrome, pulmonary embolism, heart failure, arrhythmias and conduction disorders [ACD], peripheral arterial disease [PAD]) and extrahepatic solid cancers were derived from the SNDS. Associations between DAAs and extrahepatic events were estimated using marginal structural models, with adjustments for clinical confounders. Results: Analyses of 12 905 person‐years of no DAA exposure and 22 326 person‐years following DAA exposure showed a decreased risk of PAD after DAA exposure (hazard ratio [HR], 0.54; 95% CI, 0.33–0.89), a beneficial effect of DAAs on overall cardiovascular outcomes in patients with advanced fibrosis (aHR, 0.58; 95% CI, 0.42–0.79), and an increased risk of ACD (hazard ratio [HR], 1.46; 95% CI, 1.04–2.04), predominant after the first year following DAA initiation. There was no association between DAAs and extrahepatic cancer risk (HR, 1.23; 95% CI, 0.50–3.03). Conclusions: DAAs were not associated with extrahepatic cancer development or reduction. They were associated with a decreased risk of PAD and an increased risk of ACD, supporting long‐term cardiac monitoring after DAA therapy. [ABSTRACT FROM AUTHOR]

The validity of algorithms for identifying patients with chronic hepatitis B or C virus (HBV or HCV) infection in claims databases has been little explored. The performance of 15 algorithms was evaluated. Data from HBV‐ or HCV‐infected patients enrolled between August 2012 and December 2015 in French hepatology centres (ANRS CO22 HEPATHER cohort) were individually linked to the French national health insurance system (SNDS). The SNDS covers 99% of the French population and contains healthcare reimbursement data. Performance metrics were calculated by comparing the viral status established by clinicians with those obtained with the algorithms identifying chronic HBV‐ and HCV‐infected patients. A total of 14 751 patients (29% with chronic HBV and 63% with chronic HCV infection) followed‐up until December 2018 were selected. Despite good specificity, the algorithms relying on ICD‐10 codes performed poorly. By contrast, the multi‐criteria algorithms combining ICD‐10 codes, antiviral dispensing, laboratory diagnostic tests (HBV DNA or HCV RNA detection and quantification, HCV genotyping), examinations for the assessment of liver fibrosis and long‐term disease registrations were the most effective (sensitivity 0.92, 95% CI, 0.91–0.93 and specificity 0.96, 95% CI, 0.95–0.96 for identifying chronic HBV‐infected patients; sensitivity 0.94, 95% CI, 0.94–0.94 and specificity 0.85, 95% CI, 0.84–0.86 for identifying chronic HCV‐infected patients). In conclusion, the multi‐criteria algorithms perform well in identifying patients with chronic hepatitis B or C infection and can be used to estimate the magnitude of the public health burden associated with hepatitis B and C in France. [ABSTRACT FROM AUTHOR]

Background and aims: Non‐O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non‐O group on the outcome of Child‐Pugh A cirrhotic patients. Methods: We used two prospective cohorts of Child‐Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 μmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation» or « the occurrence of one or more parameters » among: prothrombin time (PT) <45%, albumin <28 g/L, Child‐Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato‐pulmonary syndrome, (2) other events such as non‐malignant portal vein thrombosis (nmPVT), and (3) overall survival. Results: Patients (n = 1789; 59.9% Non‐O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non‐O group and 7.2% in group O (P =.27). Cumulated incidence of Disease Progression was 20.7% in Non‐O group and 18.9% in group O (P =.26). Cumulated incidence of nmPVT was 2.7% in Non‐O group and 2.8% in group O (P =.05). At 3 years overall survival was 92.4% in Non‐O group and 93.4% in group O (P = 1). Conclusion: Non‐O group does not influence disease outcome in Child‐Pugh A cirrhotic patients. Clinicals trial number NCT03342170. [ABSTRACT FROM AUTHOR]

Novel treatments for hepatitis Delta virus (HDV) infection provide promising opportunities to treat patients with hepatitis B virus (HBV) and HDV co‐infection. However, current clinical trials on HDV treatment rarely explore patients' barriers to treatments. In Europe, HDV infection mostly affects young migrants from HDV‐endemic areas who experience early liver‐related mortality. Migrants are more likely to face multiple situations of statutory and socioeconomic insecurity and structural barriers than non‐migrants. These obstacles may impact their quality of life and can (i) lead them to give secondary importance to certain HDV care options, (ii) delay treatment initiation and (iii) affect their adherence and commitment to care. Preliminary results from the ANRS CO22 HEPATHER cohort show that the majority (61.6%) of HBV‐HDV co‐infected migrants live in poverty. Moreover, half were diagnosed and a quarter of those who initiated HBV treatment had been in France for no more than two years, a period when language skills are often still poor and when knowledge of the health and administrative system may be lacking. We advocate for increased social science research, in particular qualitative studies, to investigate the effects that multiple forms of precarity (weak access to social rights, language barriers, housing insecurity, unexpected expenditures and other difficulties) may have on HDV screening opportunities, follow‐up, and treatment pathways in migrants. This will help adapt communication and care around viral hepatitis, as well as inform and orient medical services and public health actors about the difficulties that migrants encounter. [ABSTRACT FROM AUTHOR]

Background and Aims: Late presentation for care of hepatitis C virus (HCV) infection – defined as having severe liver fibrosis when first consulting a specialist for HCV care – increases morbidity and mortality. Identifying the socio‐behavioural correlates of late presentation is essential to improve HCV strategies to optimize HCV cascade of care. We investigated clinical and socio‐behavioural correlates of late presentation for care in HCV mono‐infected individuals. Methods: This study included chronic HCV mono‐infected patients participating in the French national cohort ANRS CO22 HEPATHER, starting in 2012. The correlates of late presentation were estimated using a Heckman probit selection model, which takes into account the possible selection bias because of missing data in the outcome. Results: Among the 9174 study patients, 1236 had available data on liver fibrosis stage at first presentation for HCV care. Of these, 591 (47.8%) were late presenters. In a multivariable analysis adjusted for age, sex and HCV genotype, having diabetes (adjusted coefficient [95% confidence interval]: 0.55 [0.30; 0.80]), current hazardous alcohol use (0.36 [0.03; 0.69]) and current abstinence but past hazardous alcohol use (0.42 [0.19; 0.64]) (vs. current abstinence and no past hazardous use) were all independently associated with late presentation for HCV care. Conclusions: As late presentation severely affects HCV cascade of care, our findings bring important new evidence about the need to promptly identify and target people with diabetes and/or past or current hazardous alcohol use for HCV screening and treatment within the wider context of the WHO goal to eliminate HCV by 2030. [ABSTRACT FROM AUTHOR]

Objectives: HIV‐coinfected patients experience higher incidences of non‐liver‐related cancers than HCV‐monoinfected patients. Chronic inflammation, immunosuppression, but also higher tobacco or alcohol consumption and metabolic dysregulation could explain this higher risk. We aimed to estimate the direct, indirect and total effects of HIV coinfection on the risk of non‐liver‐related cancers in HCV participants treated with direct‐acting antivirals (DAAs). Methods: Up to four HCV‐monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to HIV/HCV‐coinfected participants from the ANRS CO13 HEPAVIH cohort. Participants were followed from DAA initiation until the occurrence of a non‐liver‐related cancer. Counterfactual mediation analysis was carried out to estimate the direct (chronic inflammation and immunosuppression), indirect (tobacco and alcohol consumption and metabolic syndrome) and total effect of HIV coinfection on the risk of non‐liver‐related cancers. Results: 548 HIV/HCV‐coinfected and 2016 monoinfected participants were included. Overall, HIV coinfection was associated with a 3.7‐fold [95% confidence interval (CI): 1.7–7.0] higher risk of non‐liver‐related cancers in HCV participants. This increased risk was explained by significant direct effect [hazard ratio (HR) = 3.4, 95% CI: 1.7–6.6] but not indirect effect (HR = 1.1, 95% CI: 0.8–1.5) of HIV coinfection. Conclusions: In HCV participants treated with DAAs, the direct effect of HIV coinfection, reflecting chronic inflammation and immunosuppression, was associated with a 3.7‐fold higher risk of non‐liver‐related cancer. By contrast, the indirect effect of HIV coinfection, reflecting higher tobacco and alcohol consumption and metabolic dysregulation, was not significantly associated with the risk of non‐liver‐related cancers. [ABSTRACT FROM AUTHOR]

Despite universal health coverage in France, migrants face specific socioeconomic barriers that increase the likelihood of a suboptimal cascade of care for chronic hepatitis C virus (HCV) infection and impaired treatment effectiveness in this sub‐population. We selected data collected from 2012 to 2018 from the ANRS CO22 HEPATHER prospective cohort study for chronic HCV participants with available data on treatment failure (defined as the presence of a detectable HCV‐RNA load 12 weeks after their first DAA treatment ended). We performed multivariable Poisson regression models to test whether treatment failure rates differed significantly between HCV‐infected migrants and non‐migrants receiving DAA in France (cross‐sectional analysis), while taking into account the former's world region of birth and other potential social vulnerability factors. Among the study population's 7,879 patients, 5,829 (74%) were non‐migrants and 2,050 (26%) migrants. Median [interquartile range] age was 57 [51‐65] years, 4433 (56%) were men and 369 (5%) of the entire study population had treatment failure. After multivariable adjustment, only migrants from Central Asia were at higher risk of treatment failure than non‐migrants (aIRR = 2.83; 95% CI [1.72, 4.65]). Results from this large‐scale study performed in France suggest a higher risk of DAA treatment failure in migrants from Central Asia than in non‐migrants and confirm the overall low treatment failure rate in chronic HCV patients treated with DAA (whether migrants or not). Simplified models of care taking into account language and cultural barriers are needed to improve DAA effectiveness in migrants from Central Asia. [ABSTRACT FROM AUTHOR]

Our results confirm that diabetes is a significant risk factor for all-cause mortality in chronic HCV patients. Liver fibrosis and all-cause mortality in chronic HCV-infected diabetic patients: A paradoxical association? Further studies investigating cause-specific mortality in diabetic and non-diabetic HCV patients in the DAA era need to be conducted, in order to shed light on the respective major risk factors for mortality in these two sub-populations and adapt their clinical follow-up accordingly. [Extracted from the article]

The World Health Organization (WHO) has proposed a plan for the elimination of viral hepatitis with a goal of reducing new hepatitis infections by 30% and 90% in 2020 and 2030, and associated mortality by 10% and 65% respectively. Actions and targets to reach these goals include improving hepatitis B virus (HBV) vaccination programs, the prevention of mother‐to‐child transmission of HBV, improving the safety of blood products and injections, risk reduction policies and optimizing the diagnosis and treatment of hepatitis. The goal of eliminating hepatitis C virus (HCV) by 2030 is based on three main actions: increased screening, strengthening access to care and the prevention of infections and re‐infections. But, can this goal be reached? The answer to this question is yes in some countries, perhaps in others and no in most countries. Success will be limited by a "diagnosis burn‐out" with 5 times more new viral infections than diagnoses in 2016 and a "treatment burn‐out" with cure rates that are 5 times lower than the number of new infections. Nevertheless, France, like 10 other countries, is on track to achieve the WHO elimination plan by 2030. In France, the prioritization of oral antivirals in 2013‐2014 which was extended to high‐risk populations in 2015 (HIV‐infected patients) and 2016 (men who have sex with men, dialyzed or kidney transplant recipients), then in 2017 to universal treatment with full coverage by French national healthcare (10 to 15 000 treatments per year) has resulted in half of the 120 000 patients needed to be treated by 2022 have been treated. Renewed efforts should make it possible to reach the target announced by the French Minister of Health in May 2018 by 2025. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic hepatitis B virus (HBV) infection results in a high risk of cirrhosis and its complications: cirrhosis decompensation, hepatocellular carcinoma (HCC, the fourth most common cause of cancer‐related mortality worldwide), liver transplantation and death. It is now 40 years since development of the first plasmatic vaccine which has been proven to prevent (liver) cancer. Aims: To update firstly the molecular and epidemiological aspects of HBV‐related HCC and its natural history together with the benefits associated with viral suppression and secondly the safety, immunogenicity and efficacy of HBV vaccination. Methods: Analysis of recent published data regarding HBV replication, anti‐viral treatments and vaccination. Results: The nuclear HBV replication cycle in the hepatocyte combines two limiting steps to achievement of HBV cure during chronic infection: the formation of a minichromosome, the supercoiled cccDNA, and host‐genome integration of HBV DNA which triggers direct viral hepatocarcinogenesis. Even if specific anti‐viral treatments significantly reduce viral replication, they decrease but do not cancel the risk of liver‐related events in contrast with the prevention of HBV through HBV vaccination. Conclusions: To achieve the 2030 viral hepatitis elimination plan, the HBV vaccine is a priority tool for achieving the sustainable development goals of the World Health Organization. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic hepatitis B virus (HBV) infection results in a high risk of cirrhosis and its complications, cirrhosis decompensation (DC), hepatocellular carcinoma (HCC), liver transplantation (LT), death or any of these outcomes (composite endpoint [CE]). Nucleos(t)ide analogues (NUCs) such as tenofovir or entecavir are associated with a reduction in these complications. Aim: To compare the impact of tenofovir and entecavir on these outcomes in patients treated for HBV infection and included in the prospective Hepather cohort. Methods: All patients with HBV infection who had received tenofovir or entecavir for more than 6 months at or after entry in the ANRS CO22 cohort were selected. Patients with HDV and HCV co‐infection or prior liver event were excluded. Incidence rates of events were compared using inverse probability of treatment weighting (IPW). Results: The cohort included 1800 patients (986 tenofovir and 814 entecavir). Median follow‐up was 4.2 years. The incidences of HCC, DC, LT, ACD, LRD and CE were not different between tenofovir‐ (1.8 (0.9; 3.2), 0.6 (0.2; 1.6), 0.2 (0.0; 0.8), 1.7 (0.8; 3.0), 0.8 (0.2, 1.8) and 4.1 (3.0; 5.4) per 1000 person‐years) and entecavir‐treated patients (1.6 (0.7; 3.0), 0.7 (0.2; 1.8), 0.2 (0.0; 1.0), 3.0 (1.7, 4.8), 0.5 (0.1; 1.5) and 5.0 (3.3; 7.2)) per 1000 person‐years, respectively. Conclusion: The risk of liver‐related events or death was not different between tenofovir‐ and entecavir‐treated patients in this large prospective cohort of predominantly non‐cirrhotic French patients. Trial registration number: NCT019553458. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection is a risk factor of insulin resistance, and HCV‐infected patients are at a high risk of developing diabetes. In the general population, research has shown the potential benefit of cannabis use for the prevention of diabetes and related metabolic disorders. We aimed to test whether cannabis use is associated with a lower risk of diabetes in chronic HCV‐infected patients. Chronic HCV‐infected patients (n = 10 445) were selected from the French national, multicenter, observational ANRS CO22 Hepather cohort. Cross‐sectional data collected at cohort enrollment were used to assess the association between patients' clinical and behavioural characteristics and the risk of diabetes. Logistic regression model was performed with cannabis use as the main independent variable and a significance level set at 5%. A similar model stratified by the presence of advanced liver fibrosis (FIB‐4 > 3.25) was also run. After multivariable adjustment, current (AOR [95%CI]: 0.49 [0.38‐0.63]) and former (0.81 [0.67‐0.98], P <.001) cannabis use were both associated with a reduced odds of diabetes. Conversely, male gender, tobacco use, elevated BMI, poverty, being a migrant and advanced fibrosis were associated with increased odds of diabetes. The association between cannabis use and diabetes was maintained in the stratified analysis. In this large cross‐sectional study of chronic HCV‐infected patients, cannabis use was associated with a lower risk of diabetes independently of clinical and socio‐behavioural factors. Further studies are needed to elucidate a potential causal link and shed light on cannabis compounds and mechanisms involved in this relationship. [ABSTRACT FROM AUTHOR]

Sofosbuvir plus daclatasvir with or without ribavirin has demonstrated a high efficacy and an acceptable safety profile in clinical trials of patients infected with genotype 2 hepatitis Cvirus (HCV); however, there are currently no real‐world data available for this regimen. To evaluate the real‐life safety and efficacy of sofosbuvir/daclatasvir with or without ribavirin in genotype 2 HCV patients in the French cohort ANRS CO22 HEPATHER(NCT01953458). In this ongoing, national, multicentre, prospective, observational study, we observed patients with HCV genotype 2 infection who initiated treatment with sofosbuvir (400 mg/d) plus daclatasvir with or without ribavirin (1‐1.2 g/d). Patients were divided into two treatment groups: sofosbuvir/daclatasvir with or without ribavirin (12 weeks/24 weeks). The primary end point was a sustained virological response at week 12 following the end of therapy. Overall, 88% and 91% of patients achieved a sustained virological response following 12 and 24 weeks of treatment with sofosbuvir/daclatasvir with or without ribavirin, respectively. The most common adverse events were asthenia (29%), headache (15%) and fatigue (20%), and ribavirin addition was associated with a higher rate of adverse events and treatment discontinuation. Sofosbuvir/daclatasvir with or without ribavirin was associated with lower rates of sustained virological response in the real‐life setting compared with the clinical setting and demonstrated suboptimal efficacy for the treatment of patients with genotype 2 chronic HCV. [ABSTRACT FROM AUTHOR]

Background: Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed‐dose combination of grazoprevir‐elbasvir in treatment‐naïve patients, with non‐severe fibrosis. Methods: HCV mono‐infected and treatment naïve patients with non‐severe fibrosis (Fibroscan®<9.5 kPa and Fibrotest® < 0.59) were enrolled in a study which included 117 patients. Genotyping by sequencing identified five patients with non‐1b genotype (two GT1a, one GT1h, one GT1e and one GT1l). Thus, we included in the final analysis 112 GT1b patients. The primary end point was the proportion of patients with HCVRNA below the lower limit of quantification 12 weeks after treatment (SVR12). Findings: Mean age was 54 ± 13 years, 31% were men and viral load was higher than 800.000 IU/mL in 70 of 112 patients (63%). Using Fibroscan®, 100 had F0‐1 fibrosis score. FIB‐4 lower than 1.45 and APRI less than 1 was found in 74/112 (66%) and 107/112 (95%) patients respectively. Relapse occurred in three patients by week 12. These three patients had a viral load higher than 6 million IU/mL and NS5A Y93H RAS (resistance‐associated substitution). Then, modified intention‐to‐treat SVR12 for patients with genotype 1b was 109/112 (97%). By week 24; five relapses were observed and all had the Y93H RAS at relapse. SVR12 was achieved in 100% of patients with a baseline viral load below 6 million and decreased to 98% (98/100) by follow‐up week 24. Interpretation: Naïve patients with genotype 1b and non‐severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir‐elbasvir for 8 weeks. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatitis C virus (HCV) genotype (GT) 4 infection is prevalent in sub‐Saharan Africa and the Middle East, particularly in Egypt. This study evaluated the safety and efficacy of elbasvir/grazoprevir administered for 8 and 12 weeks in participants with HCV GT4 infection. Methods: In this partially randomized, open‐label multicentre study conducted in France (NCT03111108; Protocol MK5172‐096), treatment‐naive participants with GT4 infection and F0‐F2 fibrosis were randomized 2:1 to elbasvir (50 mg)/grazoprevir (100 mg) for 8 or 12 weeks. Treatment‐naive participants with F3‐F4 fibrosis and all treatment‐experienced participants (F0‐F4) were assigned to elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy. Results: One hundred and seventeen participants were enrolled. Among treatment‐naive participants with F0‐F2 fibrosis, SVR was achieved by 94% (50/53) and 96% (26/27) of those receiving elbasvir/grazoprevir for 8 or 12 weeks, respectively, and four participants relapsed. In the 12‐week arm, 95% (35/37) achieved SVR and two participants relapsed. NS5A resistance‐associated substitutions were present at baseline and virologic failure in five of the participants with relapse. Drug‐related adverse events occurred in 42% (n = 22) and 50% (n = 32) of participants receiving 8 and 12 weeks of treatment, respectively. No participant discontinued treatment owing to an adverse event. Conclusion: These data confirm the efficacy of elbasvir/grazoprevir administered for 12 weeks in treatment‐experienced individuals with HCV GT4 infection and those with advanced fibrosis. Treatment‐naive individuals with mild fibrosis can be treated effectively with an 8‐week regimen. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusions Conflicting results have been reported on the impact of tenofovir versus entecavir on liver‐related outcomes.To explore trends in clinical outcomes in chronic hepatitis B virus (HBV)–infected patients and compare the impact of tenofovir versus entecavir on the risk of hepatocellular carcinoma (HCC), liver transplantation (LT) and mortality.We used the French National Health Insurance Databases (SNDS) to identify HBV‐infected patients. We quantified the excess clinical burden from 2012 to 2021 by comparing the HBV‐infected cohort with a general population cohort, using 1:1 exact matching on birth date, sex, social deprivation index and follow‐up start date. The risks of mortality, HCC and LT were compared between patients treated with tenofovir and entecavir using inverse probability weighting.A total of 101,740 patients were matched to the general population. From 2012 to 2021, the average annual decreases in excess mortality, incidence of HCC and LT were 3.7%, 8.0% and 11.9%, respectively (p for trend < 0.001). During the same period, the nucleos(t)ide analog (NUC) treatment coverage significantly increased, particularly after 2016 (p < 0.001). Among 14,054 treatment‐naïve patients starting tenofovir (n = 7426) or entecavir (n = 6628), we observed no difference in the composite outcome of mortality, LT or HCC (HR, 1.09; 95% CI, 0.95–1.24). Tenofovir was associated with an increased risk of HCC compared with entecavir (HR, 1.31; 95% CI, 1.07–1.62).Tenofovir was associated with a higher risk of HCC compared with entecavir, although no difference in the composite outcome of mortality or liver‐related events was observed between the two treatments. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods and Results Conclusions Hepatitis C virus genotype 5 (HCV‐GT‐5) is found mainly in South Africa. In our area in central France, the prevalence of HCV‐GT‐5 is 14%.Here we evaluated sustained virological response at week 12 post‐treatment (SVR12) in 147 HCV‐GT‐5 patients from 14 French university hospitals (2014–2021) treated with direct‐acting antivirals (DAA) in real‐life. Patients had mainly received sofosbuvir/ledipasvir ± ribavirin, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. Overall SVR12 was 98% (144/147). Two patients experienced relapse: one was successfully retreated with the same DAAs (sofosbuvir/ledipasvir) plus ribavirin, and the other refused further DAA treatment. One patient with virological failure (sofosbuvir/velpatasvir) had received a second treatment (sofosbuvir/velpatasvir/voxilaprevir) and progressed to cure.HCV‐GT‐5 patients treated with a DAA regimen had a 99% SVR12 in intention‐to‐treat (including initial therapy and retreatment) and 100% SVR12 per protocol. Sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir show very good efficacy in real‐world HCV‐GT‐5 patients. [ABSTRACT FROM AUTHOR]

Comparisons of time‐to‐event clinical outcomes between patients with or without a sustained virological response (SVR) after treatment of chronic hepatitis C infection have been repeatedly reported in emphasizing the potential clinical impact of treatment. Combining recently published data from different therapeutic eras with simple examples, we show that comparisons of incidence rates by SVR status between patients treated with interferon‐based and interferon‐free regimens are flawed through confounding by prognosis. The relevant analysis for evaluating and comparing the clinical impact of these regimens should be a comparison between randomized treatment groups, irrespective of the SVR status. [ABSTRACT FROM AUTHOR]

Background & Aims: HCV affects about 71 million people worldwide with 1.75 million new infections a year, mainly associated with healthcare, blood transfusion before screening of donors and drug use. Hepatitis C is a systemic disease with hepatic and extrahepatic manifestations resulting in increased morbidity and mortality in HCV‐infected patients compared to cured or uninfected individuals. Results: The goal of eliminating hepatitis C by 2030 is based on the following three main actions: strengthening and increasing outreach screening; increasing access to treatment; and improving prevention. Although the tools and the targets of HCV elimination have now been well established, micro‐elimination, a cure in high‐risk populations, is possible, but has not been achieved. These populations are mainly migrants, prisoners, drug users, HIV co‐infected patients and psychiatric patients. New tools must be developed to achieve micro‐elimination, in particular, rapid diagnostic orientation tests for better screening, delocalization of healthcare services to improve access to care, and training physicians to raise awareness of the disease, increase understanding of its pathogenesis and provide information on the availability of safe and effective treatment to cure chronic infection and reverse hepatic and extrahepatic manifestations. Conclusion: Thus, while the goal of complete elimination of hepatitis C virus was feasible in Western countries, it was more difficult in high‐prevalence countries where improvement in the detection of chronic infection (with rapid serological and virological diagnostic tests), outsourcing of diagnostic and therapeutic care and access to direct oral antivirals are urgently needed. [ABSTRACT FROM AUTHOR]

There is still some controversy over a potentially increased short‐term risk of developing hepatocellular carcinoma (HCC) after the initiation of direct‐acting antiviral (DAA) therapy, even though a decreased long‐term risk of HCC has been reported following a sustained virological response in patients with chronic hepatitis C virus (HCV) infection. We characterized the time‐varying effect of DAAs on the risk of the occurrence of HCC in patients with cirrhosis and HCV infection. We analysed patients with cirrhosis and chronic HCV infection from the ANRS CO22 HEPATHER cohort study. We excluded patients with active HBV coinfection, liver transplantation or a past history of HCC. We used a flexible weighted effect cumulative exposure Cox model to characterize the time‐varying effect of DAAs on the risk of HCC. A total of 3595 patients, mean age 59.3 years old, 65% men, were eligible for the study. Median follow‐up was 36.8 months (IQR 24.6‐47.1). DAAs were started during follow‐up in 3292 patients. Three hundred and fifty‐six HCCs were reported (275 treated, 81 untreated). Overall, a constant decrease in the risk of occurrence of HCC (vs untreated) was found from the start of treatment. Results were similar in patients without a history of decompensated cirrhosis (DC). Analysis of patients with a past history of DC showed a nonsignificant increase in the occurrence of HCC over the first 6 months, while the HR was significantly decreased at 14 months. These findings support the urgent initiation of DAAs in all patients. [ABSTRACT FROM AUTHOR]

Genotype‐6 hepatitis C virus (GT6‐HCV) exhibits a high genetic diversity. GT6 prevalence, diversity and real‐life response to treatment were studied among 14 603 HCV mono‐infected patients from the French ANRS‐CO22‐Hepather cohort. NS3, NS5A and NS5B‐HCV genes were amplified and sequenced for all GT6‐infections identified in the database. Following phylogenic characterization, resistance‐associated substitution polymorphisms were identified. GT6‐infected patients (n = 36; 0.25%) did not differ from patients infected with other genotypes with regard to gender, age or liver fibrosis. GT6e was the most prevalent (27.8%), followed by 6a (22.2%), 6q (11.1%) and 6o (8.3%). Each subtype p and xc were found in two patients (5.6%) and subtypes f/h/r and t were each detected in one patient. Four strains (11.1%) clustered with unclassified reference sequences. Concordant genotype determination throughout NS3, NS5A and NS5B‐genes is consistent with lack of recombination within this genomic region. All, but three patients were born in Asia, Cambodia (44.4%), Vietnam (38.9%) or Laos (8.3%). GT6a were found in 42.8% of Vietnamese and 6e in 37.5% of Cambodian. GT6q, 6p and 6r were only found in Cambodian patients. Resistance‐associated polymorphisms for each DAA classes were identified in baseline sequences. Twenty‐seven patients were treated with sofosbuvir‐based combinations and 3 with glecaprevir/pibrentasvir. All treated patients, whether naïve or previously treated, achieved a sustained viral response. In conclusion, GT6‐infections are uncommon in France and their genetic diversity likely reflects infection within the country of origin. Despite residue variability at DAA resistance‐associated positions, sustained viral response was obtained in all treated patients. [ABSTRACT FROM AUTHOR]

Summary: Worldwide, hepatocellular carcinoma (HCC) occurs mainly in Asian patients with hepatitis B virus (HBV) infection. This study aimed to decipher the environmental and virological factors associated with HCC occurrence and validate risk scoring systems in a French multicentre prospective cohort of HBV cirrhotic patients. Patients with biopsy‐proven Child‐Pugh A viral cirrhosis included in the ANRS CO12 CirVir cohort who were HBsAg(+) without hepatitis C coinfection were selected for: (a) interview through a standardized questionnaire reporting coffee consumption and HCC familial history; (b) HBsAg quantification using baseline and sequential 2‐year frozen sera; (c) baseline HBV genotype determination; and (d) assessment of risk factors and applicability of HCC risk scores (Kaplan‐Meier analysis, Cox models). Among 317 patients studied (261 men, median age 53 years, past or ongoing antiviral treatment 93.3% and baseline detectable HBV DNA in 88 patients), the baseline and 2‐year median HBsAg levels were 810 and 463 IU/mL, respectively. After a median follow‐up of 65.2 months, 27 HCC cases were diagnosed (annual incidence: 1.6%). Three factors were independently associated with HCC occurrence: age > 50 years, platelets ≤ 150 × 103/mm3 and body mass index ≥ 30 kg/m2. Two out of five risk scores were validated, and the most accurate was PAGE‐B at 1 year. Moreover, HCC in patients without maintained virological suppression seems more aggressive and less accessible to curative treatment. In conclusion, in French patients with HBV cirrhosis mostly virally suppressed, independent HCC risk factors were host‐related (age, obesity) or linked to the severity of cirrhosis (thrombopenia), and the European PAGE‐B score was the most accurate risk score. In the French prospective multicentre ANRS CO12 CirVir cohort, among 317 patients with biopsy‐proven compensated HBV‐related cirrhosis, host conditions, comorbidities and severity of liver disease were independent predictors of HCC occurrence. Only two out of five HCC risk scores were validated in those patients and the European PAGE‐B score was the most accurate. Moreover, HCC in patients without a maintained virological suppression seem more aggressive and less accessible to curative treatment. [ABSTRACT FROM AUTHOR]

Background: Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in serum and/or liver in HBsAg‐negative patients. We investigated the prevalence of OBI in large chronic haemodialysis (CHD) and kidney transplant recipients (KTxR) cohorts, including determination of HBV DNA in peripheral blood mononuclear cells (PBMCs). Methods: HBV DNA was determined in both serum and PBMCs in 417 CHD patients, 417 KTxR, 20 HBsAg‐positive non‐CHD non‐KTx patients (positive controls) and 40 HBsAg‐negative healthy subjects (negative controls). Results: Chronic haemodialysis group: two of 376 patients were HBsAg‐positive. The 374 HBsAg‐negative patients tested negative for HBV DNA in both serum and PBMCs. KTxR group: 14 of 417 patients were HBsAg‐positive. One of 403 HBsAg‐negative patients tested positive for HBV DNA in serum but not in PBMCs. Positive controls: six of 20 patients were under antiviral therapy and had negative HBV DNA in both serum and PBMCs. In 11 of 14 remaining patients, HBV DNA was detected in serum and in both serum and PBMCs in 3 patients. Negative controls: All 34 patients were anti‐HBc‐negative and HBV DNA‐negative in both serum and PBMCs. In the long term, the only case of anti‐HBc‐negative OBI lost anti‐HBs 5 years after inclusion in the study and showed HBV reactivation with HBsAg re‐seroconversion. Conclusions: We found nil prevalence of OBI in CHD patients and a very low prevalence (<1%) in KTxR suggesting that routine screening for HBV DNA is not required in CHD population in our region. However, in KTxR, pretransplant screening with HBV DNA should be considered. Testing for HBV DNA in PBMCs does not seem to be of additional value. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Our aim was to explore a signal detection method for early identification of potential adverse drug reactions (ADRs) in a patient cohort. Methods: ANRS CO22 HEPATHER is a French multicentre prospective observational cohort started in 2012. The cohort includes patients with chronic hepatitis C virus (HCV) infection with reports of all adverse events (AEs) occurring in patients exposed to HCV drugs. We applied a disproportionality method, which calculated a measure of association, the Bayesian information component (IC), for each drug‐AE pair. Information components were continuously updated and a positive drug‐AE association was detected when the lower limit of an IC 95% credible interval (95% CI) exceeded 0. We illustrate how the method could result in timely detection of photosensitivity reaction with simeprevir use. Results: By August 28, 2016, 6600 patients with HCV infection had been treated or were undergoing current HCV treatment, and 3464 experienced at least one AE for a total of 12 720 reported AEs. We detected 52 positive drug‐AE associations, including 44 that were known ADRs based on the summary of product characteristics. The association between simeprevir and photosensitivity reaction was detected on June 4, 2014. At this date, 68 patients had received simeprevir and 6 photosensitivity reaction (4 during simeprevir treatment) had been reported for an estimated IC of 1.90, 95% CI, 0.20‐3.61. Conclusions: The disproportionality method can help with early detection of potential ADRs in patient cohorts. Detected associations need to be confirmed by a review of clinical data. [ABSTRACT FROM AUTHOR]

Abstract: Direct‐acting agents (DAAs) are highly efficient at treating hepatitis C virus (HCV) infections after kidney transplantation. Although drug agencies have recently warned of the risk of hepatitis B virus (HBV) reactivation after patients have received DAAs, reports have discrepant results in HBsAg‐positive and HBsAg‐negative patients. We report on 3 cases of HBV reactivation that were detected after achieving a DAA‐associated sustained virological response in 3 kidney‐transplant recipients initially HBsAg‐negative. In the first case, retrospective virological analysis revealed that HBsAgs had become positive and HBV DNA was detectable before initiating DAA therapy. In the second and third cases, HBV reactivation occurred 2 months and more than 1 year after stopping anti‐HCV therapy. These cases underline the discrepancies and highlight the need for comprehensive information before making definitive conclusions regarding the causal link between DAAs and HBV reactivation. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long‐term efficacy and safety of daclatasvir‐based regimens administered during clinical studies. Methods: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow‐up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non‐responders or responders who relapsed, and characterization of liver disease progression. Results: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir‐based regimens (follow‐up cut‐off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype‐1a (42%) or ‐1b (45%) infection, and 18% had cirrhosis. Median follow‐up from parent study follow‐up Week 12 was 111 (range, 11‐246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow‐up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon‐free or interferon‐containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non‐responders, emergent non‐structural protein‐5A (NS5A) and ‐3 (NS3) substitutions were replaced by wild‐type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. Conclusions: SVR12 was durable in 99% of recipients of daclatasvir‐based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non‐responders. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: The recommended combination of pangenotypic direct‐acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) associates the co‐formulation of 2 or 3 second‐generation DAAs. In the so‐called “special populations” defined as patients with chronic kidney disease (CKD), HCV/HIV co‐infection, HCV/HBV co‐infection and an unsuccessful previous DAA regimen, these combinations have a high antiviral potency (sustained virologic response (SVR) > 95%), fair tolerance and a reduced pill burden. Methods: We have taken into account the scientific evidence on the treatment of “special populations”, in particular from the RUBY 1‐2 trials, EXPEDITION 2‐4 study, C‐WORTHY trial, ASTRAL 5, POLARIS 1‐4 studies, MAGELLAN 1 and REVENGE study. Results: CKD and HCV/HIV co‐infection are not predictors of a non‐viral response. The glecaprevir/pibentrasvir (Maviret) combination appears to be the first‐line therapy for CKD patients while the sofosbuvir/vlpatasvir/voxaliprevir (Sovesi) combination is the first‐line option for DAAs failures. Both are effective in patients with HIV‐or HBV‐HCV co‐infection and should be chosen according to the potential drug‐drug interaction profile. Conclusions: The notion of “special populations” is no longer pertinent with pangenotypic DAAs combinations. International guidelines recommend treating all infected patients and the next challenge is not the therapeutic choice, but to improve the limitations for screening and access to care in HCV infection. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Interferon- and ribavirin (RBV)-free regimens can improve patient-reported outcomes (PROs) during treatment. Aim: To compare PROs during treatment with ledipasvir and sofosbuvir (LDV/SOF) to placebo and to LDV/SOF + RBV. Methods: Treatment-experienced CH-C genotype 1 patients with compensated cirrhosis (N = 154) were randomized to receive 24 weeks of LDV/SOF or 12 weeks of placebo followed by 12 weeks of LDV/SOF + RBV (the SIRIUS clinical trial). While blinded to their HCV RNA level and study treatment, patients completed PRO questionnaires (SF-36, FACIT-F, CLDQ-HCV, WPAI:SHP) at baseline, during and post-treatment. Results: Baseline PRO scores were similar between the two study arms. Patients receiving LDV/SOF showed improvement in a number of PROs (predominantly related to mental health) starting as early as 4 weeks after treatment initiation; no PRO decrement from baseline were noted, and no PRO scores were inferior to placebo (all P > 0.05). In the second 12 weeks, patients who were receiving LDV/SOF continued to improve PROs (up to +9.2% from a 100% maximum possible score, P < 0.05), while patients receiving LDV/SOF + RBV had less gains or no improvement in their PRO scores. However, regardless of the regimen, patients who successfully cleared the virus (N = 149) had significant improvement in all aspects of PROs (up to +12.2% by post-treatment week 12, up to +16.9% by week 24). Conclusions: Treatment-experienced cirrhotic patients experience a notable improvement of their PROs during treatment with LDV/SOF. Furthermore, achieving SVR-12 is associated with significant PRO improvement, which further improves at post-treatment week 24 in this difficult to treat group of patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Background & Aims To compare the management of chronic hepatitis B ( CHB) and its evolution over time in currently followed HIV-positive and HIV-negative patients. Methods A total of 709 consecutive patients with past or present positive HBs antigenemia seen in October 2012 in 19 French participating centres were included. The data were retrospectively collected from the first visit onwards through standardized questionnaires. Results Chronic hepatitis B was less often assessed in the 299 HIV-positive patients, who were older, more likely to be male, excessive alcohol drinkers and HBe antigen-, HCV- and HDV-positive. They were also followed up for a longer time (11.3 +/−8.8 vs. 8.6 +/−6.9 years, P < 10−3) and were more frequently treated for HBV (95.3% vs. 56.8%, P < 10−3). HBV was undetectable at the last visit in 80.8% of HIV-positive vs. 55.1% of HIV-negative patients ( P < 10−3). In multivariate analyses, undetectable HBV was significantly associated with older age, lower baseline HBV DNA, longer HBV therapy and no previous lamivudine monotherapy, but not with HIV. Cirrhosis was associated with age, male gender, Asian origin, alcoholism , HCV, HDV, but not with HIV infection. Hepatocellular carcinoma, less frequently observed in HIV-positive patients (0.7% vs. 4.7%, P = 0.002), was positively associated with age, male gender, cirrhosis and negatively associated with HIV infection ( OR 0.15, 95% CI 0.03-0.67, P = 0.01). Conclusions Although the assessment of CHB still has to be improved in HIV-positive patients, the negative impact of HIV on the virological, histological and clinical evolution of CHB seems to be disappearing, probably because of the immunovirological impact of HAART and the more frequent and longer use of HBV therapy. [ABSTRACT FROM AUTHOR]

Background & Aims Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin ( PR) and HCV non-structural protein 3 ( NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort. Methods We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results. Results We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR ( AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication. Conclusion These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection. [ABSTRACT FROM AUTHOR]

Background & Aims Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. Methods Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses ( n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. Results Sustained viral response ( SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio ( OR) = 2.80; 95% confidence interval ( CI), 2.13-3.69], low-density lipoprotein ( LDL) (≥2.6 mmol/L) ( OR = 2.11; 95% CI, 1.52-2.93), HCV genotype ( OR = 0.58; 95% CI, 0.36-0.93), and maximum alanine amino transferase and aspartate amino transferase ( OR = 0.62; 95% CI, 0.40-0.97). Conclusions Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy. [ABSTRACT FROM AUTHOR]

Background & Aims Few data are available on the prevalence of renal abnormalities in chronic hepatitis B virus ( HBV)-infected patients. The multicentric cross-sectional HARPE study evaluated the prevalence of kidney disease indicators, in chronic HBV surface antigen carriers patients ( HBsAg+) with active or inactive infection. Patients and methods Two hundred and sixty-eight HBsAg+ adult patients, naïve of any oral antihepatitis B virus treatment were prospectively included over 2 years. Data for renal assessment were collected once from patient files. Univariate tests and multiple linear regressions were performed with the SAS software, version 8.02 ( SAS, Inc., Cary, NC, USA). Results Among the 260 patients analysed, 58% were men, the mean age was 42 ± 14 years, 59.6% were inactive carriers whereas 47 patients, mostly active, were about to start an antiviral therapy. Prevalence of proteinuria, haematuria, glycosuria, uninfectious leukocyturia was 38.1%, 20.6%, 3.9% and 9% respectively. According to the international definition, a total of 64.6% of patients were found to have kidney disease. Diabetes, hypertension and dyslipidaemia were observed, respectively, in 4.6%, 9.2% and 38.8% patients. There were no significant differences in these results within the three subgroups. Conclusion Renal abnormalities are highly prevalent in our population and pre-exist before the initiation of any antihepatitis B virus treatment. This emphasizes the need for: (i) a baseline renal evaluation in all HBs antigen-positive patients; (ii) a regular renal monitoring before and during antihepatitis B virus treatment to diagnose and manage renal impairment and adjust antihepatitis B virus treatment doses to renal function when necessary. [ABSTRACT FROM AUTHOR]

Background In HCV genotype 1-infected patients with HIV co-infection, tritherapy [ HCV protease inhibitors ( PIs) plus peg-interferon and ribavirin] has been shown to have an increased rate of sustained virological response. However, complex drug-to-drug interactions and tolerability issues remain a concern. Methods Under the auspices of four French scientific societies of medicine, a committee was charged of establishing guidelines on the use of first-generation HCV PIs in these patients. This scientific committee based its work on preliminary results from tritherapy clinical trials in co-infected patients and, since data on these patients are still scarce, on the statements already made by the French Association for the Study of the Liver ( AFEF) on the use of tritherapy in HCV mono-infected patients, written in May 2011 and updated in 2012. Each AFEF guideline concerning HCV monoinfection was examined to determine whether it could be used in the context of HIV/ HCV coinfection. Results These guidelines are addressed for the treatment of coinfected patients with various profiles, including treatment-naïve or patients with failure to previous bitherapy and mention those patients for whom tritherapy should start or those for whom it should be delayed. Preliminary results of triple therapy as well as factors associated to virological response are also discussed. Other issues include virological monitoring, clinical and virological criteria to stop therapy, practical treatment management, treatment adherence and the management of side effects and interactions with antiretroviral drugs. These guidelines were submitted for critical review to independent experts. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hepatitis B virus ( HBV) infection is more frequent in immune deficient populations than in the general population with lower rates of spontaneous recovery in acute cases, thus explaining the high rate of chronic infection and the increased risk of cirrhosis and hepatocellular carcinoma, resulting in increased morbidity-mortality in these patients. The negative impact of immune deficiency on chronic HBV infection is related to two non-exclusive factors: (i) high viral load enhances the progression of fibrosis and may result in a rare severe liver disease called fibrosing cholestatic hepatitis, which reflects the direct toxicity of high levels of HBV proteins; (ii) The pathobiology of HBV infection is mainly immune-mediated via HBV-specific T lymphocytotoxicity. The reduction or discontinuation of immune deficiency may result in severe liver disease including fulminant hepatitis from immune restoration. Thus, immune deficiency enhances the hepatitis B viral load, which results in the progression of fibrosis and/or acute exacerbation of underlying liver disease ( HBV reactivation) on one hand, whereas reduction in immune deficiency may also be harmful because of immune restoration on the other hand. This double-edged sword explains why the diagnosis and evaluation of the impact of HBV infection on the liver must be especially rigorous in cases of immune deficiency whatever the cause: transplantation, oncology, haematology, internal medicine (rheumatology, gastroenterology ...) or HIV infection, and why pre-emptive therapy by HBV nucleos(t)ide analogues should be considered for all HBV-infected patients. [ABSTRACT FROM AUTHOR]

Of all hepatitis C virus patients, those with cirrhosis are most in need of treatment owing to increased morbidity and mortality. Treatment with pegylated interferon and ribavirin (PEG-IFN/RBV) has clearly shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response ( SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PEG-IFN/RBV are a major advancement in the treatment of both naïve and treatment-experienced genotype 1 patients. In naïve patients, the SVR rate with the triple regimen with boceprevir increased by 14% in patients with severe fibrosis or cirrhosis compared to PEG- IFN/ RBV compared by 30% in patients with mild or moderate fibrosis. The SVR rate of the triple regimen with telaprevir increased by 10-30% compared to PEG- IFN/ RBV in patients with severe fibrosis or cirrhosis and by nearly 30% in patients with mild or moderate fibrosis. The greatest benefits seem to be found in patients with cirrhosis who have relapsed, and is limited in prior non-responder patients. Thus, the choice of triple therapy in the latter should be considered in relation to the increase in side effects. There are no data on the efficacy of the triple regimen in patients with decompensated cirrhosis. Results in real-life settings show that patients with cirrhosis need to be carefully followed-up during treatment due to the increase in side effects that are greater than in clinical studies. Next generation DAAs and PEG- IFN/ RBV appear to be more effective and have fewer side effects in patients with cirrhosis. Ultimately, an interferon-free regimen of DAAs combinations will probably provide a SVR in patients with cirrhosis and will probably be proposed in patients with more advanced or decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

The recent marketing authorizations and hence availability of the new protease inhibitors, telaprevir and boceprevir, have profoundly changed the management of chronic hepatitis C patients. Guidelines for the use of these new drugs as part of a triple therapy, in combination with the standard therapy of peginterferon plus ribavirin, are proposed. The guidelines have been drawn up and evaluated by a meeting of the French Association for the Study of the Liver, posted online for comments, and extensively reviewed by international experts. The current published data on the various treatment strategies are reviewed. The guidelines address the majority of patient profiles including treatment-naïve patients and patients with failure of previous treatment. They recommend which patients should be treated with triple therapy and consider the results of triple therapy including the factors that are predictive of response. They consider the circumstances in which the length of triple therapy can be shortened and the advantages of a peginterferon plus ribavirin lead-in phase. Virological monitoring, stopping criteria, the evaluation of resistance to protease inhibitors, practical treatment management, treatment adherence and the management of side effects are discussed and simple guidelines proposed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An association between variations at the IL28B gene locus and HCV clearance (spontaneous recovery or sustained virological response under pegylated interferon ( PEG- IFN) and ribavirin ( RBV) has been extensively described. In genotype 1-infected patients, the new direct antiviral agents ( DAA) including the two approved protease inhibitors boceprevir and telaprevir, in association with the PEG- IFN/ RBV combination is the new standard of care making it necessary to redefine the interest of the IL28B genotype in the decision to treat and how to treat genotype 1-infected patients. In treatment-naïve patients, IL28B status can certainly identify those with a high probability of achieving SVR with response guided therapy and probably in whom the duration of treatment can be markedly reduced. In experienced patients, the impact of IL28B genotypes is limited and cancelled by early viral kinetics. However, the decision to initiate or withhold therapy remains a clinical one. In summary, although it was a major milestone in the treatment of patients with PEG- IFN/ RBV, IL28B polymorphism testing entered the clinical arena almost 10 years too late. [ABSTRACT FROM AUTHOR]

The study evaluated whether a liquid suspension of adefovir dipivoxil (ADV) is effective and safe when dose adjusted based on varying degrees of renal impairment in patients with chronic hepatitis B. Patients had stable mild, moderate, or severe renal impairment or end-stage renal disease. Twenty-eight patients were enrolled: 10 (mild), 12 (moderate), and 6 severe renal impairment or end-stage renal disease with hemodialysis. Statistical testing demonstrated that daily dosages of ADV liquid suspension at 10 mg and 5 mg in the mild and moderate renal impairment groups, respectively, were clinically similar to ADV 10-mg tablets. However, the antiviral effect observed with the 5-mg/d dose was clearly numerically less than that observed with the 10-mg/d dose. Steady-state adefovir plasma exposures after administration of the ADV liquid suspension were generally within the ranges observed in patients with normal renal function. Treatment with ADV liquid suspension for up to 48 weeks was generally well tolerated. The daily dose-adjustment approach was not clearly safer or more efficacious than the dosing-interval adjustment. Therefore, the results do not support daily ADV dosing using a liquid suspension over the current strategy of adjustment of the ADV dosing interval in patients with impaired renal function. [ABSTRACT FROM PUBLISHER]

Hepatitis C virus (HCV) infection is associated with chronic progressive liver disease. Its global epidemiology is still not well ascertained and its impact will be confronted with a higher burden in the next decade. The goal of this study was to develop a tool that can be used to predict the future prevalence of the disease in different countries and, more importantly, to understand the cause and effect relationship between the key assumptions and future trends. A system approach was used to build a simulation model where each population was modeled with the appropriate inflows and outflows. Sensitivity analysis was used to identify the key drivers of future prevalence. The total HCV-infected population in the US was estimated to decline 24% from 3.15 million in 2005 to 2.47 million in 2021, while disease burden will increase as the remaining infected population ages. During the same period, the mortality rate was forecasted to increase from 2.1 to 3.1%. The diagnosed population was 50% of the total infections, while less than 2% of the total infections were treated. We have created a framework to evaluate the HCV-infected populations in countries around the world. This model may help assess the impact of policies to meet the challenges predicted by the evolution of HCV infection and disease. This prediction tool may help to target new public health strategies. [ABSTRACT FROM AUTHOR]

The combination of antiretroviral (ARV) therapies introduced at the end of the 1990s profoundly changed the natural history of human immunodeficiency virus (HIV) infection. Liver diseases are one of the three primary causes of 'non-AIDS-related' death in people living with HIV for three reasons: the high prevalence of hepatotropic viral co-infections, the hepatotoxicity of ARV drugs and new emerging liver diseases, including nodular regenerative hyperplasia and hepatitis E virus infection. The impact of HIV infection on the natural history of hepatitis C virus (HCV) or hepatitis B virus (HBV)/HIV co-infection has markedly changed in the past few decades with the progress made in ARV treatment and the improved definition of therapeutic strategies for HCV or HBV. Initially, HIV had a negative impact on hepatotropic infections. Today, HIV does not appear to significantly modify the natural history of HCV and HBV infection. This is associated with fair immune restoration, viral suppression associated with analogues having dual activity against HBV and HIV and with the increasing efficacy of antiviral treatments against HCV. A significant decline is expected in the morbidity and mortality associated with chronic liver infection in co-infected patients. Nevertheless, today, there are three major issues: (i) improving preventive measures including vaccination and risk reduction; (ii) screening patients infected with HBV or HCV and evaluating the impact of chronic infection on the liver and finally; (iii) early screening of hepatocellular carcinoma whose occurrence is higher and that evolves more rapidly in co-infected than in mono-infected patients. [ABSTRACT FROM AUTHOR]

The safety and efficacy of pegylated interferon (PEG-IFN) alfa-2a and ribavirin were studied among patients treated for genotype 4 chronic hepatitis C. Ninety-five patients with chronic hepatitis C genotype 4 were treated with PEG-IFN alfa-2a (180 µg/week) plus ribavirin (≥11 mg/kg/day) for 48 weeks. The primary end point was sustained virological response, defined as non-detectable levels of HCV RNA at the end of follow up (week 72). The proportion with sustained virological response was 58/95 = 61.1% (95% CI = 50.5-70.9%). Side effects were generally mild, well managed by dose reductions (in 62% of patients); in only two patients were side effects sufficiently severe to require treatment interruption. Ninety percent of patients adhered to treatment up to week 12, and their sustained virological response rate was higher compared to non-adherent (65% vs. 22%, respectively, P = 0.012). None of the patients who failed to achieve 1 log reduction of viral load by week 8 (n = 15), or 2 log reduction by week 12 (n = 17), had a sustained virological response. In conclusion, sustained virological response in genotype 4 Egyptian patients treated with PEG-IFN alfa-2a and ribavirin was estimated around 60%, intermediate between sustained virological response observed in genotype 1 and genotype 2-3 patients in Western countries. The early virological response (week 4 or week 8) should be investigated as a criterion to decide whether the patient may benefit from a shorter duration of therapy. J. Med. Virol. 81:1576-1583, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]