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The benefits of direct-acting antivirals towards the elimination of hepatitis C virus (HCV) in people living with HIV are decreased when individuals are reinfected with HCV following treatment. We aimed to systematically review the existing evidence of HCV reinfection risk after treatment among people living with HIV, including people who inject drugs and men who have sex with men (MSM), and to identify the factors that explain heterogeneity in the incidence of HCV reinfection.For this systematic review and meta-analysis, we searched PubMed, Scopus, Web of Science, Cochrane, PsycINFO, and conference presentations from date of database inception to Jan 10, 2022, for clinical trials and cohort studies providing data that could be used to calculate the incidence of HCV reinfection following HCV treatment. Random-effect meta-analysis models were used to calculate rate estimates. Study-level factors contributing to heterogeneity of reinfection estimates were assessed using meta-regression. This study is registered with PROSPERO, CRD42019146973.41 studies, predominantly conducted in Europe, were included, with a total of 9024 participants. The incidence of reinfection was 3·76 cases per 100 person-years of follow-up (95% CI 2·80-5·05; IRisk of HCV reinfection following treatment in people living with HIV was highest among MSM and those with recent HCV infection. Continued scale-up of HCV treatment and ongoing HCV screening and treatment of infection in this patient population should reduce viraemic burden and risk of reinfection.None.

Objectives To describe the characteristics of a large hepatitis A virus (HAV) outbreak among men who have sex with men (MSM) in Berlin and to assess the impact of measures implemented. Methods Cases of laboratory-confirmed, symptomatic HAV infection notified in Berlin, Germany between August 2016 and February 2018 were analysed using routine and enhanced surveillance data including genotyping results. Several studies involving different groups of participants were conducted to further investigate the outbreak, including surveys on knowledge and practices of HAV vaccination among physicians and vaccination coverage and determinants of vaccination status among MSM. The measures implemented were categorized by target group in a Gantt chart. To assess their impact, health insurance data on HAV vaccination uptake were analysed, comparing Berlin and other federal states. Results During the outbreak period, a total of 222 cases were reported (of which 91 were sequence-confirmed), with a peak in case numbers in January 2017. Physicians were aware of the existing vaccination recommendations, but vaccination coverage among 756 MSM was low, with 32.7% being completely vaccinated and 17.3% being incompletely vaccinated before 2017. HAV vaccination before 2017 was associated with being born in Germany (odds ratio 2.36) and HIV-positive (odds ratio 1.80). HAV monovalent vaccination uptake increased by 164% from 2016 to 2017 among males in Berlin, compared to 7% in other federal states. Conclusions Multiple measures targeting the MSM community, physicians, and public health to increase HAV vaccination uptake were successfully implemented. To prevent future HAV outbreaks, we recommend monitoring vaccination coverage among MSM, promoting awareness of existing recommendations among physicians, and ensuring access for foreign-born and young MSM.

Using direct acting antivirals (DAA) for recently acquired hepatitis C virus (RAHCV-) infections, particularly in HIV-positive men having sex with men (MSM), dramatically reduced hepatitis C incidence. However, implementation into clinical practice is challenging. The aim of this study was to analyse spontaneous clearance (SC) rates of RAHCV and to identify predictors of SC.The PROBE-C study is an observational European cohort on RAHCV-infections in HIV-positive MSM. Between 2007 and 2017, RAHCV-infections were documented with at least 12 months of follow-up. Fisher's exact, chi-square and Mann-Whitney U test were used for statistical analysis.464 RAHCV-infections were documented. 457/464 (98%) cases were male, median age was 41 years (IQR 38-46). Main risk groups for HCV-transmission were MSM (98.9%). Most participants were infected with HCV-genotype (GT) 1 (78.3%). Median baseline HCV-RNA was 230,000 (135,000-474,432) IU/mL, median CD4+-T cell count was 574 (547-604) cells/µL. 92% of all cases received combination antiretroviral therapy with 91% showing suppressed HIV-RNA (200 copies/mL). Median maximum alanine aminotransferase was 445 (402-522) U/L.SC of RAHCV-infection occurred in 55/464 (11.9%) cases. A2log decline in HCV-RNA four weeks after diagnosis of RAHCV infection was the strongest predictor of SC (p 0.001, sensitivity 96.4%, specificity 97.5%, PPV 84.1%, NPV 99.5%).SC of RAHCV in HIV-positive MSM is only found in 11.9% of cases and a2log drop in HCV-RNA at week four after diagnosis should prompt for early DAA-based treatment. However, immediate DAA treatment for RAHCV-infection may also be favoured in patients with ongoing transmission risk behaviour.

International guidelines recommend prioritized treatment initiation in hepatitis C virus (HCV)-infected patients with advanced liver disease. We aimed to evaluate whether the widespread usage of direct acting antivirals (DAAs) has led to a decrease in late presentation for care.Data derived from the multicenter German Hepatitis C Cohort (GECCO) was analyzed. Treatment naive HCV-infected patients initiating DAA-based treatment between January 2014 and September 2017 were included. Advanced liver disease was defined by aspartate aminotransferase to platelet ratio index score ≥1.5, METAVIR≥F3, or FibroScan ≥9.5 kPa. Period prevalence and risk factors for late presentation were evaluated.Six hundred fifty-three HCV-monoinfected and 210 HIV/HCV-coinfected patients (mean age, 48.6±12.7 y; 65.5% male) were included. Overall 32.5% of patients had advanced liver disease. In 2014 39.4% of patients presented with advanced liver disease, decreasing to 30.1%, 34.4%, and 26.4% in the years 2015, 2016, and 2017 (P=0.057), respectively. Patients with and without advanced liver disease differed in age (P0.0001), CD4 ≤350/µL (P=0.027), genotype (P=0.005), transmission route (P=0.047), body mass index (P0.001), and time since diagnosis (P=0.007). In the multivariable binary logistic regression analysis GT3, age above 45 years and being diagnosed2 years ago were positively and HCV transmission through men who have sex with men was negatively associated with advanced liver disease.Overall 32.5% of patients presented with advanced liver disease. We observed a trend toward a lower proportion of patients starting treatment late.GT3, age, years since HCV diagnosis and HCV transmission route were identified as risk factors for presentation with advanced liver disease.

Background Prior to direct-acting antivirals (DAAs), HCV incidence rose among men who have sex with men (MSM) living with HIV infection in Germany despite high hepatitis C virus (HCV) treatment rates. We establish a HCV elimination modeling framework to evaluate whether existing treatment rates can achieve the World Health Organization (WHO) incidence target among MSM living with HIV in Germany. Methods To evaluate progress towards HCV elimination in Germany, we adapted a previously published HCV transmission model among MSM living with diagnosed HIV. We modelled HCV incidence and prevalence until 2030 (relative to 2015) under existing treatment and DAA scale-up and explored potential impacts of disruptions in treatment and behavioral risk reduction due to the COVID-19 pandemic. Results Continuing current treatment rates will result in stable HCV incidence among MSM living with HIV in Germany between 2015–2030. The WHO HCV incidence target is achievable under DAA scale-up to 100% treatment combined with treatment of those previously diagnosed and untreated (at a rate of 15%/year) and would result in greater reductions with early treatment (3 vs 6 months) reducing incidence from 4.0/100person-years to 0.8/100person-years by 2030. A 12-month disruption to HCV treatment (20% reduction) and risk behaviors (25%,50%,75% reduction) during the COVID-19 pandemic would result in a 15% relative increase in total HCV incidence in 2030 compared to that expected under the status quo. Conclusions HCV elimination among MSM living with HIV in Germany requires further DAA scale-up among those newly diagnosed combined with efforts to treat those previously diagnosed but untreated. Prospective monitoring will establish whether Germany is on track for HCV microelimination.

Poster-Abstract

Background & Aims Shortened duration therapy for acute and recent HCV infection has been shown to be highly effective in several small non-randomised studies with direct-acting antiviral regimens; however, large randomised studies are lacking. Methods REACT was an NIH-funded multicentre international, open-label, randomised, phase IV non-inferiority trial examining the efficacy of short course (6-week) vs. standard course (12-week) therapy with sofosbuvir-velpatasvir for recent HCV infection (estimated duration of infection ≤12 months). Randomisation occurred at week 6. The primary endpoint was sustained virological response 12 weeks after treatment end (SVR12) in the intention-to treat (ITT) population. A total of 250 participants were due to be enrolled, but on advice of the data safety and monitoring board the study was halted early. Results The primary analysis population consisted of 188 randomised participants at termination of study enrolment; short arm (n = 93), standard arm (n = 95). Ninety-seven percent were male and 69% HIV positive. ITT SVR12 was 76/93, 81.7% (95% CI 72.4–89.0) in the short arm and 86/95, 90.5% (95% CI 82.7–95.6) in the standard arm. The difference between the arms was -8.8 (95% CI -18.6 to 1.0). In modified ITT analysis, wherein non-virological reasons for failure were excluded (death, reinfection, loss to follow-up), SVR12 was 76/85, 89.4% (95% CI 80.8–95.0) in the short arm and 86/88, 97.7% in the standard arm (95% CI 92.0–99.7; difference -8.3%, p = 0.025). Conclusions In this randomised study in recent HCV infection, a 6-week course of sofosbuvir-velpatasvir did not meet the criteria for non-inferiority to standard 12-week therapy. Lay summary In this randomised trial, 188 people with recently acquired hepatitis C infection were randomly assigned to treatment using either a short 6-week course (93 people) or standard 12-week course (95 people) of the hepatitis C treatment sofosbuvir/velpatasvir. There were 9 cases of relapse after treatment with the short course and 2 following the standard course. A shortened course of 6-week therapy for hepatitis C infection appeared to be less effective than a standard 12-week course in people with recently acquired hepatitis C infection. ClinicalTrials.gov Identifier NCT02625909 .

Nonalcoholic fatty liver disease (NAFLD) is a growing concern in the aging population with human immunodeficiency virus (HIV). Screening for NAFLD is recommended in patients with metabolic risk factors or unexplained transaminitis. This study aimed to prospectively assess the prevalence and associated factors of liver steatosis and advanced fibrosis (AF) in HIV-monoinfected patients at risk of NAFLD.We conducted a multicenter study in HIV-monoinfected patients, nonexcessive drinkers with metabolic syndrome, and/or persistently elevated liver enzymes, and/or clinical lipodystrophy. All participants had magnetic resonance imaging proton density fat fraction (MRI-PDFF), Fibroscan/controlled attenuation parameter (CAP), and cytokine and genetic analysis.From March 2014 to November 2015, we enrolled 442 participants and analyzed 402: male (85%); median age, 55 years (interquartile range [IQR], 50-61 years); body mass index, 27.0 kg/mIn a large cohort of HIV-moninfected patients at risk of NAFLD, steatosis is present in two-thirds of cases, and around 10% have AF. The CAP technique is accurate for screening steatosis in this population.

Disease activity, but also demographics, lifestyle, and comorbidities, may influence alanine aminotransferase (ALT) levels in hepatitis C virus (HCV)-infected patients. Direct-acting antiviral agents (DAA) achieve virological cure in 90 % of patients, regardless of HCV genotype and fibrosis stage. This allows assessing determinants for ALT levels before and after elimination of HCV. Our prospective cohort included HCV- and HIV/HCV-infected patients treated with DAA at 9 German centers (GECCO cohort). We analyzed all consecutive patients with sustained virological response (SVR) at week 12 (SVR12) and/or 24. Normal ALT was defined as ≤ 35 U/L, regardless of sex. At baseline, 1477 out of 1774 patients (83 %) had ALT 35 U/L, and 297 (17 %) had ALT ≤ 35 U/L. Baseline ALT 35 U/L was independently associated with male sex, higher body mass index (BMI), liver cirrhosis, and not being on opioid substitution. After SVR, 80 % of patients normalized ALT, and even patients with low baseline ALT further reduced ALT levels. However, ALT remained 35 U/L in 15 % (221/1477) after SVR12. By multivariate analysis, ALT 35 U/L at SVR12 was associated with male sex, higher BMI, liver cirrhosis, baseline ALT, HCV genotype 2, and younger age. Obesity, cirrhosis, and ALT were also independent factors associated with ALT 15 U/L at SVR12 in patients with normal ALT at baseline. Male sex, advanced liver fibrosis, and obesity are main risk factors for the lack of ALT normalization and/or ALT decline after SVR, indicative of fatty liver disease as a relevant comorbidity in hepatitis C. Alanin-Aminotransferase (ALT)-Spiegel bei Hepatitis-C-Virus (HCV) infizierten Patienten werden durch die Krankheitsaktivität der Hepatitis C, aber auch durch Demografie, Lebensstil und Komorbiditäten beeinflusst. Direkt wirkende antivirale Agenzien (DAA) erzielen eine virologische Ausheilung in 90 % der Patienten, unabhängig von HCV-Genotyp und Fibrose-Stadium. Dies ermöglicht festzustellen, welche Faktoren ALT-Spiegel vor und nach der Eliminierung von HCV determinieren. Die GECCO-Kohorte ist eine prospektive Kohorte aus HCV- und HIV/HCV-infizierten Patienten, die in neun deutschen Zentren mit DAA behandelt wurden. Wir analysierten alle konsekutiven Patienten mit anhaltender virologischer Remission (SVR) in Woche 12 (SVR12) und/oder 24. Eine normale ALT wurde definiert als ≤ 35 U/L, unabhängig vom Geschlecht. Zu Studienbeginn hatten 1477 von 1774 Patienten (83 %) eine ALT 35 U/L, und 297 (17 %) zeigten eine ALT ≤ 35 U/L. Baseline ALT 35 U/L war unabhängig mit männlichem Geschlecht, höherem Body-Mass-Index (BMI), Leberzirrhose und fehlender Opiat-Substitution assoziiert. Nach der SVR normalisierten 80 % der Patienten die ALT, und sogar Patienten mit niedriger Baseline-ALT senkten die ALT-Werte weiter. ALT blieb jedoch nach SVR12 bei 15 % (221/1477) bei 35 U/L. In einer multivariaten Analyse war ALT 35 U/L nach SVR12 mit männlichem Geschlecht, höherem BMI, Leberzirrhose, Ausgangs-ALT, HCV-Genotyp 2 und jüngerem Alter assoziiert. Adipositas, Zirrhose und ALT waren bei Patienten mit normaler ALT zu Studienbeginn ebenfalls unabhängige Faktoren, die mit ALT 15 U/L bei SVR12 assoziiert waren. Männliches Geschlecht, fortgeschrittene Leberfibrose und Adipositas sind Hauptrisikofaktoren für das Fehlen von ALT Normalisierung und/oder ALT Rückgang nach SVR, was auf eine Fettleber als relevante Komorbidität bei Hepatitis C hinweist.

The course of the COVID-19 infection has been better understood since the first identification of a novel beta-coronavirus (SARS-CoV-2) in early January 2020 in Wuhan, China [1]. Some individuals w...

In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies.

Background & Aims Chronic hepatitis D (delta) is a major global health burden. Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world-wide are poorly defined. Methods The Hepatitis Delta International Network (HDIN) registry was established in 2011 with centres in Europe, Asia, North- and South America. Here, we report on clinical/ virological characteristics of the first 1576 patients with ongoing or past HDV infection included in the database until October 2016 and performed a retrospective outcome analysis. The primary aim was to investigate if the region of origin was associated with HDV replication and clinical outcome. Results The majority of patients was male (n = 979, 62%) and the mean age was 36.7 years (range 1-79, with 9% of patients younger than 20 years). Most patients were HBeAg-negative (77%) and HDV-RNA positive (85%). Cirrhosis was reported in 48.7% of cases which included 13% of patients with previous or ongoing liver decompensation. Hepatocellular carcinoma (HCC) developed in 30 patients (2.5%) and 44 (3.6%) underwent liver transplantation. Regions of origin were independently associated with clinical endpoints and detectability of HDV RNA. Antiviral therapy was administered to 356 patients with different treatment uptakes in different regions. Of these, 264 patients were treated with interferon-a and 92 were treated with HBV-Nucs only. Conclusions The HDIN registry confirms the severity of hepatitis delta but also highlights the heterogeneity of patient characteristics and clinical outcomes in different regions. There is an urgent need for novel treatment options for HDV infection.

Background & Aims Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have strongly improved treatment options since 2014, but it is unclear if treatment numbers have increased. We aimed to estimate the number of treatment regimens per month from 2010–2015 and the number of patients treated and cured with DAAs since 2014, as well as the associated costs. Methods Drug prescription data of hepatitis C virus (HCV) antivirals for patients with statutory health insurance in Germany (∼85% of population) from January 2010–December 2015 were evaluated. Standard 28-day prescriptions of pegylated interferon (PegIFN) and 1st/2nd generation DAAs were combined according to treatment guidelines and analysed. Drug costs were calculated from pharmacy sales prices. Mean treatment durations/regimen from real-world data were used to calculate drug costs/regimen and numbers of DAA-treated persons in 2014/15. Results From January 2010–December 2015 PegIFN/ribavirin-treatments/month decreased from ∼6500 to ∼650. Monthly HCV-prescriptions rose with the approval of 1st generation DAAs (2011), and decreased at the end of 2013. With the approval of 2nd generation DAAs, prescriptions/month increased (peak: ∼6600; March 2015), and subsequently decreased (∼4000; December 2015). In 2014, ∼7000 patients were treated with DAAs, and ∼20,100 in 2015. Treatment costs/month were stable at 12 million EUR (2010–2011), increased to ∼38 million EUR (March 2012), and peaked to 150 million EUR (March 2015). DAA-drug costs/year added up to ∼664million EUR (2014) and ∼1.3billion EUR (2015). Conclusions Despite an increase in DAA prescriptions, in December 2015 less persons/month were under treatment compared to January 2010, even though access to DAAs is not limited. However, yearly treatment numbers increased from 2014–2015. Under observed conditions, ∼18,000 patients/year can be cured, making substantial reduction of the estimated 160,000 diagnosed patients realizable. Political commitment to achieve further reduce DAA-prices and increase treatment numbers is recommended. Lay summary New treatment options with all-oral second generation direct-acting antivirals (DAAs) have resulted in the potential to cure chronic hepatitis C infection, but at high costs. Analyses from HCV drug prescription data of patients with statutory health insurance in Germany from 2010–2015, showed that DAAs replaced treatments with pegylated interferon and ribavirin, but accompanied by a disproportionate rise in costs. Although the monthly number of patients under treatment did not increase over time, the total number of patients yearly treated with DAAs increased from ∼7000 patients in 2014 to ∼20,100 in 2015, with a trend to shorter treatment regimens. Under observed conditions ∼18,000 patients can be cured yearly, making a substantial reduction of the estimated 160,000 diagnosed patients in Germany achievable.

Summary Background The latest European Association for the Study of the Liver (EASL) guidelines now recommend that patients with acute hepatitis C virus (HCV) infection should be treated with a combination of sofosbuvir and an NS5A inhibitor for 8 weeks. However, the ideal duration of treatment with interferon-free regimens, particularly in HIV-coinfected individuals, remains unknown. We assessed the efficacy and safety of 6 weeks of ledipasvir–sofosbuvir for acute genotype 1 or 4 HCV in HIV-1-coinfected patients. Methods This open-label, single-arm trial, done in Germany and the UK, included patients with acute HCV genotype 1 or 4 and HIV-1. At screening, patients were either receiving HIV antiretrovirals and had HIV RNA less than 200 copies per mL, or not receiving antiretrovirals and had a CD4 T-cell count of greater than 500 cells per μL. All patients received ledipasvir–sofosbuvir once daily for 6 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12). This study is registered with ClinicalTrials.gov, number NCT02457611. Findings Between June 11, 2015, and Jan 8, 2016, we enrolled and treated 26 patients. All (100%) were men, 24 (92%) were white, and 25 (96%) were receiving antiretroviral treatment. 19 (73%) had genotype 1a and seven (27%) had genotype 4 HCV. Overall, 20 (77%; 95% CI 56–91) of 26 patients achieved SVR12: 15 (79%) of 19 with genotype 1a, and five (71%) of seven with genotype 4. Of six patients not achieving SVR12, three relapsed, two achieved sustained virological response 4 weeks after the end of treatment but were lost to follow-up, and one was reinfected. The most common adverse events were fatigue (seven participants [27%]), nasopharyngitis (seven [27%]), and headache (six [23%]). No patient discontinued or interrupted therapy due to adverse events. No HIV rebound occurred during the study. Interpretation The rate of cure with a fixed-dose combination of ledipasvir–sofosbuvir for patients with acute genotype 1 or 4 HCV infection and HIV-1 coinfection is similar to historic rates with interferon-based treatment, but with shorter treatment duration and more favourable safety outcomes. Funding Gilead Sciences.

Several cohorts have shown that long-term tenofovir-containing combination antiretroviral therapy (cART) leads to higher HBsAg seroclearance rates in HIV/HBV coinfected patients vs HBV-monoinfected patients under tenofovir disoproxil fumarate (TDF)-based therapy. We have analysed data on determinants of HBsAg loss in a retrospective multicentric cohort of 359 HIV/HBV coinfected patients. Median CD4 T-cell count at baseline was 359/ul (321-404), CDC stage was C in 20% (n = 70). Most patients (68%) were ART-naïve when TDF- or tenofovir alafenamide (TAF)-containing cART was initiated (baseline). After a median follow-up of 11 years HBsAg loss had occurred in 66/359 (18%) patients. However, patients with stage CDC C (P ≤ .001), lower CD4 gain (P = .043) and not receiving TDF/FTC (P = .008) were less likely to lose HBsAg. Long-term TDF-containing cART appears to achieve higher rates of HBsAg seroclearance compared to published data for HBV monoinfected subjects. However, late presentation for HIV and poor immune recovery significantly impair HBV seroconversion rates.

International audience; Background and aims: The prevalence of chronic hepatitis B virus (HBV) infection in Europe is poorly defined. Data on the proportion of patients eligible for therapy are lacking but are crucial to meet WHO elimination goals. The aims of our study were to provide an estimate of the need for antiviral treatment and to assess the prevalence of advanced liver disease in treatment-naive, chronic HBV-infected patients.Patients and methods: We performed a retrospective, cross-sectional analysis of all treatment-naive HBV-infected patients. Baseline clinical assessments included sociodemographic data, hepatitis B-specific analyses, and liver stiffness measurement (LSM).Results: Between 2010 and 2017, 465 patients with chronic HBV infection were referred, with 301 (64.7%) being eligible for our analysis. Overall, 40% were female, and the mean age was 39.3±13.1 years. Moreover, 61% of patients were born outside Europe, predominantly in the Asia-Pacific region. The median HBV viral load was 1630 IU/ml (interquartile range: 240-35 000 IU/ml), 145 (48.2%) patients had an HBV viral load above 2000 IU/ml, and 14.3% were HBeAg positive.Median LSM was 5.2 kPa (interquartile range: 4.2-6.6 kPa). LSM indicating clinically significant fibrosis (≥F2) was found in 96/271 (35.0%) patients, including 20/271 (7.4%) patients with suspected advanced fibrosis/cirrhosis. Overall, 26% of patients met EASL 2017 treatment criteria.Conclusion: In HBV-infected patients referred to one of the largest ID clinics in Berlin, only 26% met EASL treatment criteria and 7% had suspected cirrhosis at presentation. Only in 4% of all patients, a treatment indication could not be determined by a noninvasive approach.

Background HIV–HCV-coinfected patients respond just as well to modern direct-acting antiviral HCV therapy as HCV-monoinfected patients. However, clinical data for all-oral HCV treatments are sparse in HIV–HCV-coinfected patients with an advanced stage of liver cirrhosis. Methods A subanalysis of efficacy and safety for a daclatasvir (DCV) and sofosbuvir (SOF) regimen, with or without ribavirin (RBV), was undertaken in HIV–HCV-coinfected patients with advanced liver disease and no other treatment options enrolled into a European DCV compassionate use programme. Results Fifty five HIV–HCV (mostly genotypes 1, 3, 4) coinfected patients were treated with DCV+SOF with ( n=16) or without RBV ( n=39), mostly for 24 weeks. Patients were predominantly (95%) cirrhotic (50% were Child–Pugh class B or C) and were receiving a wide range of antiretrovirals; 40% were injection drug users and 25% were receiving oral opioid substitution. Sustained virological response at post-treatment week 12 (SVR12) by modified intention-to-treat analysis ( n=52) was 92% overall (95% CI 81.5, 97.9), and was similar with (94% [95% CI 69.8, 99.8]) or without RBV (92% [95% CI 77.5, 98.2]). Only one patient relapsed (Child–Pugh class B). The overall SVR12 rate after excluding non-virologi-cal failures ( n=49) was 98% (95% CI 89.1, 99.9). Four patients discontinued treatment for adverse events and one died during treatment (not treatment-related). No patient lost opioid maintenance or required a change of antiretrovirals due to drug–drug interactions. Conclusions DCV+SOF, with or without RBV, showed high SVR12 rates and was well tolerated in this real-world cohort of HIV–HCV-coinfected patients with very advanced liver disease. ClinicalTrials.gov ID NCT02097966 (Study AI444-237).

Background & Aims NAFLD is a growing health concern. The aim of the Fatty Liver Assessment in Germany (FLAG) study was to assess disease burden and provide data on the standard of care from secondary care. Methods The FLAG study is an observational real-world study in patients with NAFLD enrolled at 13 centres across Germany. Severity of disease was assessed by non-invasive surrogate scores and data recorded at baseline and 12 months. Results In this study, 507 patients (mean age 53 years; 47% women) were enrolled. According to fibrosis-4 index, 64%, 26%, and 10% of the patients had no significant fibrosis, indeterminate stage, and advanced fibrosis, respectively. Patients with advanced fibrosis were older, had higher waist circumferences, and higher aspartate aminotransferase and gamma-glutamyltransferase as well as ferritin levels. The prevalence of obesity, arterial hypertension, and type 2 diabetes increased with fibrosis stages. Standard of care included physical exercise >2 times per week in 17% (no significant fibrosis), 19% (indeterminate), and 6% (advanced fibrosis) of patients. Medication with either vitamin E, silymarin, or ursodeoxycholic acid was reported in 5%. Approximately 25% of the patients received nutritional counselling. According to the FibroScan-AST score, 17% of patients presented with progressive non-alcoholic steatohepatitis (n = 107). On follow-up at year 1 (n = 117), weight loss occurred in 47% of patients, of whom 17% lost more than 5% of body weight. In the weight loss group, alanine aminotransferase activities were reduced by 20%. Conclusions This is the first report on NAFLD from a secondary-care real-world cohort in Germany. Every 10th patient presented with advanced fibrosis at baseline. Management consisted of best supportive care and lifestyle recommendations. The data highlight the urgent need for systematic health agenda in NAFLD patients. Lay summary FLAG is a real-world cohort study that examined the liver disease burden in secondary and tertiary care. Herein, 10% of patients referred to secondary care for NAFLD exhibited advanced liver disease, whilst 64% had no significant liver scarring. These findings underline the urgent need to define patient referral pathways for suspected liver disease., Graphical abstract, Highlights • This is the first report on NAFLD from a secondary-care real-world cohort in Germany. • In this outpatient cohort, diagnostics rely heavily on non-invasive surrogate scores and elastography to stage NAFLD. • Every 10th patient presents with advanced fibrosis at baseline. • Management of NAFLD in Germany consists predominantly of general lifestyle recommendations and best supportive care. • The study underlines the applicability of non-invasive tests to identify patients at risk of advanced fibrosis in secondary care in Germany.

Introduction Le 10 mars 2020, l’OMS a déclaré pandémique la diffusion du SARS-CoV2 en recommandant de pratiquer de façon massive le dépistage du virus. Cette épidémie s’est installée alors que les épidémies hivernales de virus respiratoires n’étaient pas encore achevées. Afin de mieux comprendre les étiologies des syndromes grippaux en période COVID-19, nous avons analysé les prélèvements effectués dans un centre de dépistage hospitalier Francilien au tout début de l’épidémie. Matériels et méthodes La période d’étude s’est étendue du 28 février au 27 mars 2020. Tout patient consultant pour une recherche de SARS-CoV2 par RT-PCR dans le cadre d’un syndrome grippal a bénéficié d’une PCR multiplex pour les autres virus respiratoires. Les caractéristiques démographiques, cliniques et virologiques des consultants ont été analysées et les variables associées aux prélèvements positifs pour le SARS-CoV ou les autres virus ont été recherchées par régression logistique. Résultats Au total 707 patients ont consulté pendant la période d’étude et 468 patients ont bénéficié de la recherche de SARS-CoV2 et autres virus respiratoires. L’âge médian (IQR) était de 37 ans (29–50) avec 139 hommes (29,7 %). La prévalence du SARS-CoV2 était de 37,4 % (IQR : 33,01–41,8), et 37 sujets (7,9 %) étaient positifs pour d’autres pathogènes : Influenza A – 6 (1,3 %), Influenza B – 7 (1,5 %), Metapneumovirus – 5 (1,1 %), Rhinovirus – 4 (0,9 %), Coronavirus (229E, HKU1) – 3 (0,6 %), Adenovirus – 2 (0,4 %), Enterovirus – 4 (0,9 %), M. pneumoniae – 1 (0,2 %), Virus Respiratoire syncytial – 1 (0,2 %), infection mixte hors SARS-CoV-2 – 4 (0,9 %). À noter qu’aucun agent pathogène n’a été retrouvé chez 256 consultants. Les symptômes d’anosmie, fièvre et céphalées étaient plus fréquemment présents chez les sujets avec SARS-CoV2 comparés aux autres pathogènes (respectivement 26,3 % vs 2,7 %, p

The efficacy and safety of interferon-free therapies for hepatitis C virus (HCV) infection have been reported. Considering the accumulating evidence for a direct central nervous system infection by HCV, we aim to evaluate the effect of direct acting antivirals (DAA) therapy on cognitive function in HCV patients. We conducted a longitudinal analysis of the cognitive performance of 22 patients (8 HCV+, 14 HCV+/HIV+) who completed neuropsychological testing at baseline and at week 12 after DAA therapy. In 20 patients, we analyzed specific attention parameters derived from an experimental testing based on the Theory of Visual Attention (TVA). Depression, fatigue, and mental health were assessed as patient reported outcomes. At baseline, 54.5% of the patients met the criteria for cognitive impairment and 40% showed impairment in TVA parameters. Follow-up analysis revealed significant improvements in the domains of visual memory/learning, executive functions, verbal fluency, processing speed, and motor skills but not in verbal learning and attention/working memory. We did not observe significant improvement in visual attention measured by TVA. Fatigue and mental health significantly improved at follow-up. Our findings indicate that successful DAA treatment leads to cognitive improvements in several domains measured by standard neuropsychological testing. The absence of improvement in TVA parameters and of significant improvement in the domain of attention/working memory might reflect the persistence of specific cognitive deficits after HCV eradication. In summary, DAA treatment seems to have a positive effect on some cognitive domains and leads to an improvement in mental health and fatigue in HCV-infected patients.

Background & Aims To eliminate hepatitis B virus (HBV) infection, it is essential to scale up antiviral treatment through decentralized services. However, access to the conventional tools to assess treatment eligibility (liver biopsy/Fibroscan®/HBV DNA) is limited and not affordable in resource-limited countries. We developed and validated a simple score to easily identify patients in need of HBV treatment in Africa. Methods As a reference, we used treatment eligibility determined by the European Association for the Study of the Liver based on alanine aminotransferase (ALT), liver histology and/or Fibroscan and HBV DNA. We derived a score indicating treatment eligibility by a stepwise logistic regression using a cohort of chronic HBV infection in The Gambia (n = 804). We subsequently validated the score in an external cohort of HBV-infected Africans from Senegal, Burkina Faso, and Europe (n = 327). Results Out of several parameters, two remained in the final model, namely HBV e antigen (HBeAg) and ALT level, constituting a simple score (treatment eligibility in Africa for the hepatitis B virus: TREAT-B). The score demonstrated a high area under the receiver operating characteristic curve (0.85, 95% CI 0.79–0.91) in the validation set. The score of 2 and above (HBeAg-positive and ALT ≥20 U/L or HBeAg-negative and ALT ≥40 U/L) had a sensitivity and specificity for treatment eligibility of 85% and 77%, respectively. The sensitivity and specificity of the World Health Organization criteria based on the aspartate aminotransferase-to-platelet ratio index (APRI) and ALT were 90% and 40%, respectively. Conclusions A simple score based on HBeAg and ALT had a high diagnostic accuracy for the selection of patients for HBV treatment. This score could be useful in African settings. Lay summary Limited access to the diagnostic tools used to assess treatment eligibility (liver biopsy/Fibroscan/hepatitis B virus DNA) has been an obstacle to the scale up of hepatitis B treatment programs in low- and middle-income countries. Using the data from African patients with chronic HBV infection, we developed and validated a new simple diagnostic score for treatment eligibility, which only consists of hepatitis B virus e antigen and alanine aminotransferase level. The diagnostic accuracy of the score for selecting patients for HBV treatment was high and could be useful in African settings.

OBJECTIVE To analyze the role of CD3(+)CD56(+) natural killer (NK)-like T cells in HIV(+) patients with acute hepatitis C. DESIGN Frequency, phenotype, and anti-hepatitis C virus (HCV) activity of CD3(+)CD56(+) NK-like T cells were studied in 36 HIV(+) patients with acute hepatitis C. As controls, 12 patients with chronic HCV/HIV coinfection, 8 HIV monoinfected patients, and 12 healthy donors were enrolled in this study. METHODS CD3(+)CD56(+) NK-like T-cell-mediated inhibition of HCV replication was analyzed using the HuH7A2HCVreplicon model. The CD3(+)CD56(+) NK-like T-cell phenotype and interferon (IFN)-γ secretion were studied by flow cytometry. RESULTS Interleukin 12/interleukin 15 stimulated CD3(+)CD56(+) NK-like T cells from healthy donors effectively block HCV replication in vitro in an IFN-γ dependent manner. Accordingly, we found that blocking of IFN-γ with a specific antibody significantly reduced the antiviral activity of CD3(+)CD56(+) NK-like T cells. However, when CD3(+)CD56(+) NK-like T cells from HIV(+) patients were studied, we found HIV infection to be associated with a significantly impaired IFN-γ production, irrespective of HCV coinfection. Accordingly, CD3(+)CD56(+) NK-like T cells from HIV(+) patients were significantly less effective in blocking HCV replication in vitro than cells from healthy individuals. CONCLUSIONS Taken together, our data indicate that HIV infection is associated with an impaired anti-HCV activity of CD3(+)CD56(+) NK-like T cells, which might represent a novel mechanism of dysregulated immune response in HIV/HCV-coinfected patients.

Approval of direct-acting antivirals against the hepatitis C virus (HCV) has dramatically changed the management of HCV infection due to high cure rates and a favorable safety profile. Their influence on neurologic aspects is notably relevant, as studies demonstrated active HCV replication within the CNS1 and alterations in cerebral metabolism consistent with neuroinflammatory conditions.2 These findings may be causative for cognitive deficits in HCV-infected patients.3 Similar impairment has been demonstrated in patients coinfected with HIV, with a prevalence as high as 60%.4 Therefore, these patients may particularly benefit from HCV eradication. To date, studies addressing the issue of reversibility of cognitive deficits after HCV therapy are based on interferon treatment, which itself can cause continuing cognitive impairment.5 The important question whether these deficits are indeed reversible after HCV eradication remains unsolved to date. Acknowledgment: The authors thank Ute Kopp for neuropsychological advice.

Background Twelve weeks of the pangenotypic direct-acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL-3 approval study. However, presence of resistance-associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response. Aim To assess the efficacy and safety of SOF/VEL ± ribavirin (RBV) and the impact of NS5A RASs and RBV use on treatment outcome in HCV GT3 infection in a real-world setting. Methods In this multicentre cohort study, GT3 patients from ten treatment centres across Germany were included. Sustained virological response was assessed 12 weeks after end-of-treatment (SVR12) in modified intention-to-treat (mITT) and per-protocol analysis (PP). NS5A RASs were tested by population-based sequencing. Results A total of 293 GT3 patients were included. The median age was 48 years, 70% were male, 25.3% were cirrhotic, 9.2% were HCV/HIV co-infected and 21.8% were treatment-experienced, including 4.1% with DAA experience. Baseline NS5A RASs (Y93H, A30K, L31M) were detected in 11.2%. RBV was added in 5% of noncirrhotic and 58.9% of cirrhotic patients, respectively. SVR12 rates for SOF/VEL±RBV were 95.9% (mITT) and 99.5% (PP), respectively. Only 1 virological relapse occurred in a cirrhotic patient previously treated with SOF/RBV. No treatment-related major adverse events occurred. Conclusion Twelve weeks of SOL/VEL±RBV was safe and highly efficient in HCV GT3 across a diverse patient population. Baseline NS5A RASs were rarely observed and presence did not seem to impact SVR, regardless of the use of RBV.

Current hepatitis C virus (HCV) treatment guidelines recommend treating HCV/human immunodeficiency virus (HIV)-coinfected individuals similar to HCV-monoinfected individuals. Recently inferior response rates to direct acting antiviral (DAA) therapy in HCV/HIV coinfection have been reported. Our German hepatitis C cohort (GECCO) cohort data show that coinfected patients with liver cirrhosis are less likely to achieve viral eradication.

There are limited data regarding the real world effectiveness of direct acting antivirals (DAA) for the therapy of chronic genotype 3 hepatitis C virus (HCV) infection. All HCV genotype 3 infected patients from the German hepatitis C cohort (GECCO), which is a prospective database of nine German hepatitis C treatment centers, were included in the study. 342 chronically infected HCV genotype 3 patients were analyzed (253 males [74.0%], mean age 47.3 years, 127 cirrhotic patients [37.1%] mostly with Child A cirrhosis, 113 treatment experienced patients [37.1%], 38 HCV/HIV co-infected patients [11.1%]). SVR12 rates in the “intention-to-treat” analysis were as follows: sofosbuvir/ribavirin 69.4% (75/108), sofosbuvir/peginterferon/ribavirin 80.6% (58/72), sofosbuvir/daclatasvir ± ribavirin for 12 weeks 88.3% (53/63), sofosbuvir/daclatasvir ± ribavirin for 24 weeks 79.3% (23/29), sofosbuvir/ledipasvir ± ribavirin for 12 weeks 71.4% (10/14) and sofosbuvir/ledipasvir ± ribavirin for 24 weeks 86.7% (26/30). Forty patients were lost to follow-up, 23 patients had a relapse, 4 patients stopped treatment prematurely and 1 patient died. Female sex (P = 0.038) and treatment with two different DAAs (P = 0.05) were predictors for SVR12 in the multivariate analysis. In conclusion, sofosbuvir/daclatasvir ± ribavirin for 12 weeks and sofosbuvir/ledipasvir ± ribavirin for 24 weeks are effective for the treatment of HCV genotype 3 infected patients including cirrhotic, treatment-experienced or HIV/HCV co-infected patients. This article is protected by copyright. All rights reserved

Background No published randomized controlled data on the use of direct-acting antivirals (DAA) in acute hepatitis C (AHC) coinfection exist. However, with the AHC epidemic ongoing among men who have sex with men (MSM) these are urgently needed. Methods The CHAT study is a randomized controlled trial of pegylated interferon + ribavirin (PR) plus telaprevir (TVR) for 12–24 weeks versus PR alone for 24–48 weeks in the response-guided treatment of patients with AHC genotype (GT) 1 infection and HIV-1 coinfection in Germany and Great Britain. Results 34 patients were included: 15 were randomized to the PR arm (arm 1), 19 to the TVR + PR arm (arm 2). All patients were MSM, median age was 40 years. 55% had IL28B C/C GT. Median baseline HCV RNA was 291,227 IU/ml, median alanine aminotransferase was 105 U/l. 85% received cART, all had baseline HIV RNA 12) rate was 79.4% (27/34). SVR12 was seen in 12/15 (80%) in arm 1 and in 15/19 (79.8%) in arm 2. Of the four patients without SVR in arm 2, one experienced viraI breakthrough, two were non-responders; in one case HCV protease inhibitor (PI)-associated mutations were selected under TVR (V36M, R155K). Conclusions Due to moderate response rates and additional toxicities 1st generation HCV PIs should not be used in treating acute HCV. While not being licensed, recent study data and guidelines support the use of dual DAA therapy but optimal treatment duration in acute HCV needs further investigation.

Background & Aims Moderate cure rates of acute hepatitis C virus (HCV) infections with pegylated interferon and ribavirin have been described in the last decade in men who have sex with men (MSM), who are also coinfected with the human immunodeficiency virus (HIV). However, a subsequent high incidence of HCV reinfections has been reported regionally in men who both clear the infection spontaneously or who respond to treatment. Methods Retrospective analysis of reinfections in HIV infected MSM in eight centers from Austria, France, Germany, and the UK within the NEAT network between May 2002 and June 2014. Results Of 606 individuals who cleared HCV spontaneously or were successfully treated, 149 (24.6%) presented with a subsequent HCV reinfection. Thirty out of 70 (43%) who cleared again or were successfully treated, presented with a second reinfection, 5 with a third, and one with a fourth reinfection. The reinfection incidence was 7.3/100 person-years (95% CI 6.2–8.6). We found a trend for lower incidence among individuals who had spontaneously cleared their incident infection than among individuals who were treated (Hazard ratio 0.62, 95% CI 0.38–1.02, p =0.06). Spontaneous clearance of reinfection was associated with ALT levels >1000IU/ml and spontaneous clearance of a prior infection. Conclusions HCV reinfection is an issue of major concern in HIV-positive MSM. Prevention strategies are needed for high risk groups to reduce morbidity and treatment costs. HIV-positive MSM with a prior HCV infection should be tested every 3 to 6months for reinfection. Those who had achieved a reinfection should be tested every 3months. Lay summary We evaluated the occurrence of HCV reinfection in HIV-positive men who have sex with men. We found an alarming incidence of 7.3/100 person-years. Prevention measures need to address this specific subgroup of patients at high risk for HCV.

Background IL28B genotype predicts response to treatment against HCV with pegylated interferon/ribavirin (PR) and impacts on the outcome of therapy including telaprevir (TVR). This study aimed to determine the influence of the favourable IL28B genotype on early viral kinetics during therapy with TVR/PR in HIV–HCV-coinfected patients. Methods All HIV–HCV genotype 1 coinfected subjects who received TVR/PR for at least 4 weeks were included from populations prospectively followed in 22 centres throughout Germany, Switzerland and Spain. Results Of the 129 subjects included, 38 (29.5%) presented with IL28B genotype CC and 94 (72.9%) were treatment-experienced. A total of 96 (73.8%) patients showed undetectable plasma HCV RNA at treatment week (W)4: 30 (78.9%) of the IL28B-CC carriers and 65 (71.4%) of the non-CC carriers ( P=0.377). Among treatment-naive patients, proportions of undetectable HCV RNA among IL28B-CC versus non-CC carriers were 8/9 (88.9%) versus 3/9 (33.3%; P=0.016) and 14/17 (82.4%) versus 11/18 (61.1%; P=0.164) at W2 and W4. The decrease of HCV RNA at W2 and W4 was similar among the IL28B carriers. Conclusions IL28B genotype does not predict W4 response to TVR/PR in HIV–HCV-coinfected patients, regardless of their treatment history. However, there is evidence of an impact on response during the first weeks in treatment-naive patients.

The licensing of the first HCV protease inhibitors will lead to a dramatic increase in cure rates for patients with chronic genotype 1 hepatitis C. The addition of a third drug, such as telaprevir, to the standard treatment with pegylated interferon and ribavirin has become the new standard of care in the western world. While a shortening of the treatment duration is often possible, side effects are likely to increase with these products. The experience with telaprevir in HIV/HCV-coinfected patients is limited to one Phase II trial. Nevertheless, HIV-positive patients are in urgent need for new treatment options, as they often have more aggressive liver disease and lower reponse rates with the current standard treatments. These initial results are very promising, and HIV/HCV-coinfected patients seem to now have equal response rates as monoinfected patients, as long as drug–drug interactions remain under control.