[The status of national and global hepatitis C elimination]. / Stand der nationalen und globalen Hepatitis-C-Elimination.

BACKGROUND: In 2016, the World Health Organization propagated the elimination of hepatitis C virus (HCV) by 2030 in order to address the public health threat posed by viral hepatitis. This article looks at the progress that has been made globally and in Germany since 2016. METHODS: A selective literature search was conducted, with particular focus on studies and reviews relating to the elimination of hepatitis C infection both globally and in Germany. RESULTS: In 2020, 56.8 million HCV infections were counted worldwide, which corresponds to a decline of 6.8 million since 2015. Countries that made a significant contribution to the elimination figures during this period included Egypt, Georgia, and Iceland, which were able to drastically reduce the number of HCV infections by means of national commitment in politics and healthcare. With regard to the status of elimination in Germany, the inclusion of screening for viral hepatitis in the general health check-up ("Check-up 35") in 2022/2023 has led to a significant increase in HCV case numbers. Globally and in Germany, men who have sex with men, intravenous drug users, migrants, and prison inmates are particularly vulnerable groups with regard to HCV infection. CONCLUSION: In order to sustainably eliminate HCV, it is necessary to optimize education and prevention strategies in risk groups. With regard to the subgroup of prison inmates, political measures must be used to create a standardized approach in prison medicine. At a global level, elimination in low- and middle-income countries needs to be promoted in the future.

Real-world effectiveness of voxilaprevir/velpatasvir/sofosbuvir in patients following DAA failure.

Background & Aims: Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is highly effective for re-treatment of direct-acting antiviral (DAA)-experienced patients with chronic HCV infection. In the present study, predictors of virologic treatment response were analyzed in an integrative analysis of three large real-world cohorts. Methods: Consecutive patients re-treated with VOX/VEL/SOF after DAA failure were enrolled between 2016 and 2021 in Austria, Belgium, Germany, Italy, Spain and Switzerland. Results: A total of 746 patients were included: median age was 56 (16-88) years and 77% were male. Most patients were infected with HCV genotype 1 (56%) and 3 (32%). 86% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Overall, 95.4% (683/716) of patients achieved a sustained virologic response. Treatment effectiveness was significantly affected by advanced liver disease (p <0.001), hepatocellular carcinoma (p <0.001), higher baseline ALT levels (p = 0.02), HCV genotype 3 (p <0.001), and prior VEL/SOF treatment (p = 0.01). In a multivariate analysis, only HCV genotype 3, hepatocellular carcinoma and cirrhosis turned out to be independent predictors of treatment failure. Resistance-associated substitutions, as well as the presence of rare genotypes, did not impact treatment outcome. The effectiveness of rescue therapy with glecaprevir/pibrentasvir and SOF, with or without ribavirin, for 12 to 24 weeks was found to be high (100%). Conclusions: Infection with HCV genotype 3, the presence of liver cancer and cirrhosis are independently associated with failure of VOX/VEL/SOF re-treatment. It is unclear whether the addition of ribavirin and/or extension of treatment duration may be effective to avoid virologic relapse on VOX/VEL/SOF. However, rescue treatment with glecaprevir/pibrentasvir+SOF seems to be effective. Impact and implications: Representative data on the effectiveness of voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) in clinical practice are still scarce and the collection of a larger number of patients with difficult-to-treat cofactors including the assessment of resistance-associated substitution profiles is required before more specific recommendations for optimal re-treatment in these patients can be given. Thus, we aimed to analyze treatment effectiveness and predictors of virologic response to VOX/VEL/SOF in an integrative analysis of three large real-word cohorts. The study results, derived from a multicenter cohort consisting of 746 patients, demonstrated that re-treatment with VOX/VEL/SOF is an effective salvage therapy associated with an overall per protocol sustained virologic response rate of 95%. Hepatocellular carcinoma onset, cirrhosis and HCV genotype 3 were identified as independent negative predictors of treatment response, whereas resistance-associated substitutions, as well as rare genotypes and chimera, did not impact sustained virologic response rates following re-treatment with VOX/VEL/SOF.

Expanding epidemic of recently acquired HCV in HIV-coinfected patients over a period of 10 years.

Background & Aims: Ongoing transmission of HCV infections is associated with risk factors such as drug injection, needlestick injuries, and men who have sex with men (MSM). Ways of transmission, the course of acute infection, changes of virologic features, and incidence over time are not well known. Methods: Over a period of 10 years, n = 161 patients with recently acquired HCV infection (RAHC) (median follow-up 6.8 years) were prospectively enrolled. NS5B sequencing was performed to re-evaluate the HCV genotype (GT) and for phylogenetic analyses. Results: Patients with RAHC were mainly male (92.5%), MSM (90.1%), and HIV-coinfected (86.3%). Transmission risk factors for MSM and non-MSM were sexual risk behaviour (100 and 6.3%, respectively), injection drug use (9.7 and 37.5%, respectively), and nasal drug use (15.2 and 0%, respectively). Spontaneous and interferon- or direct-acting antiviral-based clearance rates were 13.6, 84.3 and 93.4%, respectively. Mean RAHC declined from 19.8 in the first to 13.2 in the past five study years. Although the majority of infections was caused by HCV GT1a, the frequency of HCV GT4d and slightly HCV GT3a increased over time. No relevant clustering of HCV isolates was observed in non-MSM. However, 45% of HCV GT1a and 100% of HCV GT4d MSM cases clustered with MSM isolates from other countries. Travel-associated infections were supported by personal data in an MSM subgroup. No international clustering was detected in MSM with HCV GT1b or HCV GT3a. Conclusions: RAHCs were mainly diagnosed in HIV-coinfected MSM patients and were associated with sexual risk behaviour. Spontaneous clearance rates were low, and phylogenetic clusters were observed in the majority of patients. Impact and Implications: We evaluated the occurrence and transmission of recently acquired HCV infections (RAHCs) over a period of 10 years. Our data demonstrate that the presence of RAHC was mainly found in HIV-coinfected MSM, with internationally connected transmission networks being observed in the majority of patients. Spontaneous clearance rates were low, and reinfection rates increased mainly driven by a small subset of MSM patients with high-risk behaviour.

[Intersectoral management of patients with abnormal liver enzymes and non-alcoholic fatty liver disease (NAFLD)]. / Intersektorales Management von Patienten mit unklarer Leberwerterhöhung und nichtalkoholischer Fettlebererkrankung (NAFLD).

The prevalence of fatty liver disease has increased significantly in Germany in recent years. With an estimated 18 million German citizens being affected, it is now among the most prevalent diseases. Furthermore, it is also considered a relevant and independent risk factor for other common cardiovascular diseases such as heart attack or stroke. Finally, diabetes mellitus promotes the development of and an unfavorable course of fatty liver disease. Given the high prevalence and complications, the German healthcare system is reaching its limits.Therefore, close coordination of all healthcare providers and specialists involved in the treatment of these patients is essential. In an expert consensus involving private practice and hospital doctors from the fields of gastroenterology, endocrinology, cardiology, general practitioners and laboratory physicians, as well as in close coordination with patient representatives, we have designed a concept for the care of these patients in the German healthcare system. Necessary developments are also addressed. In addition to being useful as a practical guideline, this should also support health policy work, especially in the development of practical care solutions at the medical level.

SARS-CoV-2 neutralizing antibody therapies: an early retrospective cohort study of 26 hospitalized patients treated with bamlanivimab or casirivimab/imdevimab.

OBJECTIVES: In this early retrospective cohort study, a total of 26 patients with SARS-CoV-2 were treated with bamlanivimab or casirivimab/imdevimab, and the reduction of the viral load associated with the developed clinical symptoms was analyzed. METHODS: Patients in the intervention groups received bamlanivimab or casirivimab/imdevimab. Patients without treatment served as control. Outcomes were assessed by clinical symptoms and change in log viral load from baseline based on the cycle threshold over a period of 18 days. RESULTS: Median log viral load decline was higher in both intervention groups after 3 and 6 days compared to control. However, at later time points, the decline of the viral load was more distinct in the control group. Mild symptoms of COVID-19 were observed in 6.3% of the intervention groups and in no patient of the control. No patients treated with bamlanivimab, 18.8% treated with casirivimab/imdevimab, and 14.2% in the control group developed moderate symptoms. Severe symptoms were recorded only in the control group (14.2%), including one related death. CONCLUSION: Treatment with monoclonal SARS-CoV-2 antibodies seems to accelerate decline of virus loads, especially in the first 6 days after administration, compared to control. This may be associated with a reduced likeliness of a severe course of COVID-19.

The role of serum sphingolipids as potential biomarkers of non-response to direct acting antiviral therapy in chronic hepatitis C virus infection.

Elimination strategies of chronic hepatitis C virus (HCV) infection aim to optimize the high antiviral potency of direct-acting antivirals (DAAs). Sphingolipids (SLs) constitute bioactive lipid compounds with a remarkable second messenger potential. SL levels associate with responsiveness to interferon treatment in HCV-patients, thus prompting the question whether failure to DAAs can be predicted by the serologic sphingolipidomic profile. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to retrospectively quantify various sphingolipid metabolites in baseline serum samples of 97 chronic HCV patients with DAA failure compared with an age-matched cohort of 95 HCV-patients with sustained virological response (SVR). Sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) serum concentrations were significantly upregulated at baseline in patients with DAA failure compared to patients with SVR. Similarly, GluC24:1Cer baseline levels were significantly upregulated in patients with DAA failure compared to the patients with SVR. However, GluC18Cer serum levels showed decreased baseline levels for patients with DAA failure compared to patients with SVR. In multivariate analysis sphinganine (OR 0.08494, CI 0.07393-0.9759, p = .021223), SA1P (OR 0.9818, CI 0.9653-0.9987, p = .034801), GluCerC18 (OR 1.0683, CI 1.0297-1.1104, p = .000786) and GluCer24:1 (OR 0.9961, CI 0.994-0.998, p = .000294) constituted independent predictors of treatment response. In conclusion, serum sphingolipid concentrations, in particular sphingosine, sphinganine and their derivatives S1P and SA1P as well as glucosylceramides may identify at baseline the minority of HCV patients with DAA failure. Serum sphingolipids could constitute additional biomarkers for national treatment strategies aiming to eliminate HCV infection.

Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure.

BACKGROUND & AIMS: Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT). METHODS: We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated. RESULTS: A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H. CONCLUSIONS: We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. IMPACT AND IMPLICATIONS: There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

Elevated liver enzymes predict morbidity and mortality despite antiviral cure in patients with chronic hepatitis C: Data from the German Hepatitis C-Registry.

While direct-acting antivirals (DAAs) cure chronic hepatitis C virus (HCV) infection in almost all patients, some patients remain at risk of liver disease despite HCV cure. In order to identify risk factors indicating liver-related morbidity and death after viral cure, we included 6982 patients from the national multicenter real-world German Hepatitis C Registry with regular follow-up visits for up to 7 years after DAA therapy. Definitions for normal liver function tests (in women/men) were alanine aminotransferase (ALT; ≤35/≤50 U/L), ALT according to American Association for the Study of Liver Diseases (AASLD; ≤19/≤30 U/L), and gamma-glutamyltransferase (GGT; ≤40/≤60 U/L). In our cohort, 97.4% of patients achieved sustained virologic response (SVR). At 24 weeks after SVR (SVR24), elevated ALT occurred in 657/6982 (9.4%), elevated ALT (AASLD) in 2609/6982 (37.4%), and elevated GGT in 1777/6982 (25.5%) patients. Risk factors for increased ALT at SVR24 were obesity, alcohol, cirrhosis, elevated baseline ALT, and non-SVR. Increased GGT at SVR24 was significantly (p < 0.05) and independently associated with male sex (odds ratio [OR], 2.12), higher body mass index (OR, 1.04), age >50 years (OR, 1.60), liver cirrhosis (OR, 3.97), alcohol consumption (OR, 2.99), diabetes (OR, 1.63), non-SVR (OR, 8.00), and elevated GGT at baseline (OR, 17.12). In multivariate regression analysis, elevated GGT at SVR24, particularly in combination with cirrhosis, was the best predictor for hepatic decompensation, hepatocellular carcinoma development, and death, followed by elevated ALT (AASLD) and standard ALT, which predicted hepatic decompensation. Despite successful HCV therapy, elevated GGT at SVR24 and to a lesser extent ALT are predictive of the future clinical outcome and linked with liver-associated comorbidities. This may highlight the relevance of nonalcoholic fatty liver disease, diabetes mellitus, alcohol, and cirrhosis for the clinical outcome in a vulnerable population, even after HCV cure.

Safety and Effectiveness Using 8 Weeks of Glecaprevir/Pibrentasvir in HCV-Infected Treatment-Naïve Patients with Compensated Cirrhosis: The CREST Study.

INTRODUCTION: In clinical trials with hepatitis C virus-infected treatment-naïve (TN) patients with compensated cirrhosis (CC), glecaprevir/pibrentasvir (G/P), a fixed-dose, once-daily, pangenotypic regimen, has demonstrated sustained virologic response at posttreatment Week 12 (SVR12) > 95%. We evaluated the real-world safety and effectiveness of 8-week G/P therapy in TN patients with CC, including certain subgroups of interest. METHODS: The CREST study is a real-world, noninterventional, multicenter study retrospectively assessing data from Canada, Germany, Israel, Italy, and Spain. The full analysis set (FAS) designated all patients in the study; the modified analysis set (MAS) excluded patients who discontinued G/P for nonvirologic failure or who had missing SVR12 data. The primary endpoint was SVR12; safety endpoints were also assessed. RESULTS: A total of 386 patients were included in the FAS, 375 patients completed the study, and 325 patients were included in the MAS; 51 patients had missing SVR12 data. Overall, in the MAS and FAS, SVR12 was achieved in 99.1% and 84.2% of patients, respectively. In subgroups of interest, the percentage of patients achieving SVR12 in the MAS (and FAS) was: genotype (GT)3: 97.5% (80.6%); FibroScan® ≥ 12.5 kPa: 98.9% (89.3%); platelet count < 100 × 109/l: 100% (88.2%); both platelets < 150 × 109/l and FibroScan® > 20 kPa: 100% (88.9%); aspartate aminotransferase-to-platelet ratio index > 1.09: 98.7% (83.1%); fibrosis-4 index > 3.25: 98.6% (84.0%); albumin < 3 g/dl: 100% (91.7%); people who use drugs: 97.7% (84.3%); psychiatric disorders: 96.6% (84.8%); and human immunodeficiency virus coinfection: 100% (95.0%). Overall, 26.9% (104/386) of patients experienced an adverse event, none of which were classed as serious. CONCLUSION: In this real-world cohort, 8 weeks of G/P therapy was well tolerated in TN patients with CC. SVR12 rates were similar to clinical trials, supporting 8-week treatment in TN patients with CC, including those with signs of advanced liver disease and GT3 infection.

Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals.

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.

Efficacy and Safety of ELOM-080 as Add-On Therapy in COVID-19 Patients with Acute Respiratory Insufficiency: Exploratory Data from the Prospective Placebo-Controlled COVARI Trial.

INTRODUCTION: Enhancement of mucociliary clearance (MCC) might be a potential target in treating COVID-19. The phytomedicine ELOM-080 is an MCC enhancer that is used to treat inflammatory respiratory diseases. PATIENTS/METHODS: This randomised, double-blind exploratory study (EudraCT number 2020-003779-17) evaluated 14 days' add-on therapy with ELOM-080 versus placebo in patients with COVID-19 hospitalised with acute respiratory insufficiency. RESULTS: The trial was terminated early after enrolment of 47 patients as a result of poor recruitment. Twelve patients discontinued prematurely, leaving 35 in the per-protocol set (PPS). Treatment with ELOM-080 had no significant effect on overall clinical status versus placebo (p = 0.49). However, compared with the placebo group, patients treated with ELOM-080 had less dyspnoea in the second week of hospitalisation (p = 0.0035), required less supplemental oxygen (p = 0.0229), and were more often without dyspnoea when climbing stairs at home (p < 0.0001). CONCLUSION: These exploratory data suggest the potential for ELOM-080 to improve respiratory status during and after hospitalisation in patients with COVID-19.

Updated epidemiology of hepatitis C virus infections and implications for hepatitis C virus elimination in Germany.

In 2014, an analysis was conducted to evaluate the hepatitis C virus (HCV) epidemiology and disease burden in Germany. Since then, there have been considerable developments in HCV management such as the implementation of direct acting antivirals. The aim of this analysis was to assess the recent data available for Germany, establish an updated 2020 HCV prevalence and cascade of care and evaluate the impact of what-if scenarios on the future burden of disease using modelling analysis. A dynamic Markov model was used to forecast the HCV disease burden in Germany. Model inputs were retrieved through literature review, unpublished sources and expert input. Next, three "what-if" scenarios were developed to evaluate the status quo, COVID-19 pandemic, and steps needed to achieve the WHO targets for elimination. At the beginning of 2020, there were 189,000 (95% UI: 76,700-295,000) viremic infections in Germany, a decline of more than 85,000 viremic infections since 2012. Annual treatment starts went down since 2015. Compared with 2019, the COVID-19 pandemic resulted in a further 11% decline in 2020. If this continues for two years, it could result in 110 excess HCC cases and 200 excess liver related deaths by 2030. To achieve the WHO targets, 81,200 people need to be diagnosed, with 118,600 initiated on treatment by 2030. This could also avert 1,020 deaths and 720 HCC cases between 2021 and 2030. Germany has made strides towards HCV elimination, but more efforts are needed to achieve the WHO targets by 2030.

[Treatment of parenterally transmittable viral hepatitis]. / Therapie der parenteral übertragbaren Virushepatitiden.

The parenterally transmittable hepatitides B, D and C and their complications are a problem worldwide and also in Germany that should not be underestimated. Due to the estimated high gray area, a broad distribution, particularly by drug abuse, increasing prevalence due to immigration and a pandemic-related delay in the diagnostics, the identification of affected persons and therefore potentially infectious patients represents a great challenge for the healthcare system. Highly effective treatment concepts with practically no side effects and a tablet ingestion once daily are available for hepatitis B and also hepatitis C. For hepatitis B this involves long-term treatment for suppression of replication, whereas for hepatitis C virus elimination occurs within a few weeks. A new treatment concept with inhibition of virus uptake for treatment of hepatitis D first became available in September 2020. For all patients a long-term further monitoring is necessary when advanced liver damage or even liver cirrhosis occurs, especially for the exclusion of liver cell carcinoma.

Association of Alpha-1 Antitrypsin Pi*Z Allele Frequency and Progressive Liver Fibrosis in Two Chronic Hepatitis C Cohorts.

(1) Background: The inherited alpha-1 antitrypsin (A1AT) deficiency variant 'Pi*Z' emerged as a genetic modifier of chronic liver disease. Controversial data exist on the relevance of heterozygous Pi*Z carriage ('Pi*MZ' genotype) as an additional risk factor in patients with chronic viral hepatitis C to develop progressive liver fibrosis. (2) Methods: Two prospectively recruited cohorts totaling 572 patients with therapy-naïve chronic viral hepatitis C (HCV) were analyzed. The Frankfurt cohort included 337 patients and a second cohort from Leipzig included 235 patients. The stage of liver fibrosis was assessed by liver biopsy, AST-to-platelet ratio index (APRI) score and Fibrosis-4 (FIB-4) score (Frankfurt) as well as liver stiffness measurement (LSM) via transient elastography (Leipzig). All patients were genotyped for the Pi*Z variant (rs28929474) of the SERPINA1 gene. (3) Results: In the Frankfurt cohort, 16/337 (4.7%) patients carried the heterozygous Pi*Z allele while 10/235 (4.3%) in the Leipzig cohort were Pi*Z carriers. In both cohorts, there was no higher proportion of Pi*Z heterozygosity in patients with cirrhosis compared to patients without cirrhosis or patients with cirrhosis vs. no liver fibrosis. Accordingly, Pi*Z frequency was not different in histological or serological stages of liver fibrosis (F0-F4) and showed no clear association with LSM. (4) Conclusions: Evaluation in two representative HCV cohorts does not indicate Pi*Z heterozygosity as a clinically relevant disease modifier in chronic HCV infection. However, validation in even larger cohorts with longitudinal follow-up is warranted.

Weight Gain after Interferon-Free Treatment of Chronic Hepatitis C-Results from the German Hepatitis C-Registry (DHC-R).

Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (-0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

BACKGROUND & AIMS: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 µg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Non-invasive assessment of fibrosis regression and portal hypertension in patients with advanced chronic hepatitis C virus (HCV)-associated liver disease and sustained virologic response (SVR): 3 years follow-up of a prospective longitudinal study.

Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1-75) kPa] and EOT [21.3(6.7-73.5) kPa; p < .0001] and EOT and FU144 [16(4.1-75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2-4.1) m/s] and FU144 [1.7(0.9-4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.

Epistatic interactions promote persistence of NS3-Q80K in HCV infection by compensating for protein folding instability.

The Q80K polymorphism in the NS3-4A protease of the hepatitis C virus is associated with treatment failure of direct-acting antiviral agents. This polymorphism is highly prevalent in genotype 1a infections and stably transmitted between hosts. Here, we investigated the underlying molecular mechanisms of evolutionarily conserved coevolving amino acids in NS3-Q80K and revealed potential implications of epistatic interactions in immune escape and variants persistence. Using purified protein, we characterized the impact of epistatic amino acid substitutions on the physicochemical properties and peptide cleavage kinetics of the NS3-Q80K protease. We found that Q80K destabilized the protease protein fold (p < 0.0001). Although NS3-Q80K showed reduced peptide substrate turnover (p < 0.0002), replicative fitness in an H77S.3 cell culture model of infection was not significantly inferior to the WT virus. Epistatic substitutions at residues 91 and 174 in NS3-Q80K stabilized the protein fold (p < 0.0001) and leveraged the WT protease stability. However, changes in protease stability inversely correlated with enzymatic activity. In infectious cell culture, these secondary substitutions were not associated with a gain of replicative fitness in NS3-Q80K variants. Using molecular dynamics, we observed that the total number of residue contacts in NS3-Q80K mutants correlated with protein folding stability. Changes in the number of contacts reflected the compensatory effect on protein folding instability by epistatic substitutions. In summary, epistatic substitutions in NS3-Q80K contribute to viral fitness by mechanisms not directly related to RNA replication. By compensating for protein-folding instability, epistatic interactions likely protect NS3-Q80K variants from immune cell recognition.

Hepatitis C virus: Current steps toward elimination in Germany and barriers to reaching the 2030 goal.

Hepatitis C virus (HCV) affects over 70 million people globally, with an estimated 399 000 HCV-related deaths in 2016. The World Health Organization (WHO) has set a goal to eliminate HCV by 2030. Despite the availability of direct-acting antivirals-highly effective and well-tolerated therapies for HCV-many patients infected with HCV in Germany have not initiated treatment, including a majority of those who are aware of their positive diagnosis. Barriers to screening, diagnosis, and treatment are major factors taking many countries off track for HCV elimination by 2030. Identifying country-specific barriers and challenges, particularly in at-risk populations such as people who inject drugs or men who have sex with men, has the potential to create tailored programs and strategies to increase access to screening or treatment and engage at-risk populations. This review aims to report the current steps toward HCV elimination in Germany, the country-specific barriers and challenges that will potentially prevent reaching the 2030 HCV elimination goal and describe good practice examples to overcome these barriers.