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Background & Aims: Interferon(IFN)-based hepatitis C virus (HCV) therapy has been replaced by direct-acting antivirals (DAAs). We assessed temporal trends in patient characteristics, transmission risks, treatment initiation, and cure rates in eras of IFN, restricted DAA-access, and unrestricted DAA-access in Viennese HCV/HIV-coinfected patients (HIV/HCV)., Methods: Consecutive HIV/HCV-coinfected patients starting HCV treatment at the Vienna General Hospital between 2002 and 2020 were retrospectively enrolled., Results: Of all N  = 508 HIV/HCV, 78% (398/508) were male and the mean age was 41.8 ± 9.5 years. 'People-who-inject-drugs' (PWID) accounted for 61% (311/508), while 31% (156/508) were 'men who have sex with men' (MSM). In the IFN-era, restricted DAA-era and unrestricted DAA-era, N  = 152, N  = 129, and N  = 227 HCV treatments were started and 49% (74/152), 95% (122/129), and 88% (200/227) achieved sustained virologic response, respectively. Treatment during the IFN-era was a strong predictor for virologic non-response (aOR 12.69; 6.93-23.24) and loss-to-follow-up (aOR 6.12; 2.99-12.54), while virologic non-response was less common in 'MSM' (aOR 0.28; 0.13-0.62). Ninety three percent (50/54) of the observed HCV reinfections occurred in the unrestricted DAA-era. A substantial increase in 'MSM' transmission was observed since 2010 with 66% (107/161) in the DAA-era versus 15% (49/330) prior to the DAA-era., Conclusions: HCV cure rates in Viennese HIV patients increased from 49% in the IFN-era to 88-95% in the DAA-era. MSM-related risk behaviour and reinfections became the key challenges towards HCV elimination in HIV-coinfected patients.

Background & Aims: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting., Methods: A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort)., Results: HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843-0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%)., Conclusions: NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment., Lay Summary: Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden., Competing Interests: Conflict of interest G.S. received travel support from Gilead. S.L. received grant support from Gilead and served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD. E.L.M. received grant support from Novartis. A.B. has nothing to disclose. E.A. has nothing to disclose. E.L. has nothing to disclose. L.T. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, Bayern, Janssen, and W. L. Gore & Associates, and received travel support from AbbVie, MSD, and Gilead. P.S. served as a consultant for PharmaIN. E.M. has nothing to disclose. L.E. has nothing to disclose. C.D. has nothing to disclose. L.I.-M. has nothing to disclose. A.P. has nothing to disclose. J.I.F. has nothing to disclose. M.A. has nothing to disclose. A.Z. has nothing to disclose. A.C. has nothing to disclose. H.H.-E. has nothing to disclose. I.S.L.S. has nothing to disclose. J.J. has nothing to disclose. H.Y. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, Otuka, Asuka, and MSD. S.M.F. has nothing to disclose. E.A.T. served as a speaker and/or consultant and/or advisory board member for Intercept, Gilead, Pfizer, NovoNordisk and Orphalan. F.P.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Biotest, Gilead, and MSD, and received travel support from AbbVie, Biotest, and Gilead. G.C. has nothing to disclose. X.F. served as a speaker and/or consultant for AbbVie and Gilead. R.B. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and Janssen. C.V. has nothing to disclose. V.H.-G. served as a speaker and/or consultant and/or advisory board member for W. L. Gore & Associates. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, MSD, Philips, and W. L. Gore & Associates as well as travel support from Boehringer Ingelheim and Gilead. J.B. served as a lecturer or consultant for W. L. Gore & Associates, Actelion and Surrozen, and received grants from the ‘Siftung für Leberkrankheiten Bern’. J.C.G.-P. served as a speaker and/or consultant and/or advisory board member for Cook and W. L. Gore & Associates and received grants/research support from Conatus, Exalenz, Novartis, and Theravance. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Portal hypertension (PH) does not resolve in a considerable proportion of patients who achieved HCV-cure., Aims: To investigate (i)whether HCV-cure impacts cytokines that orchestrate angiogenesis (i.e.,Ang1/Ang2/VEGF) and fibrogenesis (i.e.,PDGF/TGF-β) and (ii)whether their changes reflect PH-evolution and its complications., Methods: We measured plasma levels of cytokines and von Willebrand factor (VWF) and assessed hepatic venous pressure gradient (HVPG) before/after HCV-cure in 66 patients with pre-treatment PH and 23 patients without advanced disease, who served as controls., Results: Following HCV-cure, we observed a decrease in Ang2/TGF-β, but no changes in the other cytokines. The differences in circulating cytokine profiles in PH patients persisted after removing the primary etiological factor. Patients with pre-treatment HVPG≥10 mmHg with HVPG-reduction≥10% had a more pronounced relative decrease in Ang2. Finally, post-treatment Ang2 predicted FU-HVPG≥16 mmHg/decompensation with AUROC-values of 0.804/0.835., Conclusions: HCV-cure decreases circulating Ang2 - a mediator/indicator of dysangiogenesis/endothelial dysfunction, as well as TGF-β - a profibrogenic cytokine. The dynamics of Ang2 mirrored those of PH, rendering FU-Ang2 a non-invasive test for pronounced PH at FU that also predicts hepatic decompensation. The pathophysiological significance of the persistently altered cytokine levels for mechanisms that hinder the PH-regression warrants further study., Competing Interests: Conflict of interest D.B. served as speaker and/or consultant and/or advisory board member for AbbVie and received travel support from AbbVie and Gilead. K.K. received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. P.S. served as speaker and/or consultant and/or advisory board member for Bristol-Myers Squibb and Boehringer Ingelheim and received travel support from Falk and Gilead. D.C. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD and received travel support from AbbVie, MSD, ViiV Healthcare, and Gilead. B.Si. received travel support from AbbVie and Gilead. A.F.S. served as a speaker and/or consultant and/or advisory board member for Boehringer Ingelheim, Gilead, and MSD. M.P. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Ipsen, Eisai, Lilly, MSD, and Roche and received travel support from and Bristol-Myers Squibb. P.S.-M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, Intercept, and MSD and received travel support from , Gilead, and Falk. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, Regulus, and Shire and received travel support from , Falk, Gilead, and Intercept as well as grants/research support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. P.F. has served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol Myer-Squibb, Gilead, and MSD and has received research funding from Gilead. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, MSD, Philips, and W. L. Gore & Associates as well as travel support from Boehringer Ingelheim and Gilead. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead, (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The recently reported epidemic of acute hepatitis C virus (HCV) infections -observed predominantly among men who have sex with men (MSM)-may now decline due to wide availability of direct-acting antivirals (DAAs). This study aimed to investigate the current trends of acute hepatitis C in Vienna. Patients presenting with acute hepatitis C between 01/2007 and12/2020 at the Vienna General Hospital were retrospectively enrolled and followed after virologic clearance/eradication. The introduction of unrestricted DAA access after 09/17 defined the 'DAA era', as compared to the 'pre-DAA era' prior to 09/17. We identified 134 acute hepatitis C cases in 119 patients with a mean age of 39 ± 9 years at inclusion. The majority of patients were male (92%), HIV-positive (88%) and MSM (85%). In the DAA era, a history of prior chronic HCV infection at inclusion was found in 24% (11/46) compared to 7% (5/73) in the pre-DAA era (p = .012). The annual rate of acute hepatitis C cases increased in the DAA era (17.11 per year) compared to the pre-DAA era (7.76 per year). The DAA era included an AHC-genotype-2 cluster and more HIV-negative acute hepatitis C cases (0% (0/73) vs. 30% (14/46), p < .001). Patients were followed after spontaneous clearance or sustained virologic treatment response (SVR) for a total of 251.88 patient-years (median 1.39 years per patient). In the DAA era, we recorded 15 acute hepatitis C-reinfections - corresponding to an incidence rate of 5.96 (95% CI: 3.57-9.66) reinfections per 100-patient-years. We continue to observe a high incidence of acute hepatitis C in Vienna in the DAA era-primarily among HIV-positive MSM, but increasingly also in HIV-negative MSM., (© 2022 John Wiley & Sons Ltd.)

Background & Aims: Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) caused by chronic hepatitis C who have achieved sustained virologic response (SVR). We developed risk stratification algorithms for de novo HCC development after SVR and validated them in an independent cohort., Methods: We evaluated the occurrence of de novo HCC in a derivation cohort of 527 patients with pre-treatment ACLD and SVR to interferon-free therapy, in whom alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. We validated our results in 1,500 patients with compensated ACLD (cACLD) from other European centers., Results: During a median follow-up (FU) of 41 months, 22/475 patients with cACLD (4.6%, 1.45/100 patient-years) vs. 12/52 decompensated patients (23.1%, 7.00/100 patient-years, p <0.001) developed de novo HCC. Since decompensated patients were at substantial HCC risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de novo HCC development during FU than pre-treatment values or absolute/relative changes. Models based on post-treatment AFP, alcohol consumption (optional), age, LSM, and albumin, accurately predicted de novo HCC development (bootstrapped Harrel's C with/without considering alcohol: 0.893/0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low- (~2/3 of patients) and high-risk (~1/3 of patients) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk: 0% vs. 16.5%) and validation (3.3% vs. 17.5%) cohorts. An alternative approach based on alcohol consumption (optional), age, LSM, and albumin (i.e., without AFP) also showed a robust performance., Conclusions: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol consumption, accurately stratified patients with cACLD based on their risk of de novo HCC after SVR. Approximately two-thirds were identified as having an HCC risk <1%/year in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC surveillance., Lay Summary: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately two-thirds) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound., Competing Interests: Conflict of interest G.S. has nothing to disclose. E.M. received grants from Novartis. K.K. received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. P.Sc. received consulting fees from PharmaIN, and travel support from Falk and Phenex Pharmaceuticals; S.H.-S. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Eisai, Gilead, and Intercept and received travel support from AbbVie and Gilead; A.Z. has nothing to disclose; D.B. received travel support from AbbVie and Gilead; D.C. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD, and received travel support from AbbVie, MSD, ViiV Healthcare and Gilead; B.Si. received travel support from AbbVie and Gilead. B.Sch. received travel support from AbbVie, Ipsen and Gilead. A.F.S. served as a speaker and/or consultant and/or advisory board member for Boehringer Ingelheim, Gilead, and MSD. M.Pi. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Ipsen, Eisai, Lilly, MSD, and Roche, and received travel support from Bayer and Bristol-Myers Squibb. R.S. has nothing to disclose. F.P.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Biotest, Gilead, and MSD, and received travel support from AbbVie, Biotest, and Gilead. H.G. has nothing to disclose. M.S. received speaking honoraria from BMS and travel support from Bristol-Myers Squibb, AbbVie, and MSD. C.S. has nothing to disclose. M.G. received grants from AbbVie, Gilead, and MSD; speaking honoraria/advisory board fees from AbbVie, Gilead, MSD, Janssen, Roche, Intercept, Norgine, AstraZeneca, Falk, and Shionogi. S.A.L. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD and received grants from AbbVie and Gilead. M.L.M. has nothing to disclose. A.A. received consulting and speaker fees from Abbvie and Gilead. R.B. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and Janssen. M.Po. has nothing to disclose. S.R.-T. has nothing to disclose. J.G. has nothing to disclose. S.L. received grants from Gilead, speaker and advisory fees from Gilead, Abbvie and MSD. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, Regulus and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept, as well as grants/research support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. P.F. has served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol Myer-Squibb, Gilead, and MSD and has received research funding from Gilead. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, MSD, Philips, and W. L. Gore & Associates as well as travel support from Boehringer Ingelheim and Gilead. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite the availability of effective and well-tolerated direct acting antivirals (DAAs) against hepatitis C virus (HCV) infection, a substantial number of HCV patients remain untreated. Novel strategies targeting HCV patients with poor adherence are urgently needed to enable HCV elimination., Methods: We implemented a physician-operated HCV hotline (HCV-Phone) that was promoted within the patient community and referral networks. Previously diagnosed HCV patients were contacted via the HCV-Phone and offered low-barrier access to DAA therapy. Patients/referring physicians could directly call or send messages to the HCV-Phone. The HCV-Phone related and unrelated visits as well as DAA treatment initiations throughout 2019 were documented. Patients were followed until October 2020. This study analyzed treatment initiation, adherence to scheduled visits and outcomes in patients in whom management was assisted by the HCV-Phone., Results: Out of 98 patient contacts via the HCV-Phone 74 attended treatment assessment at our clinic. While 15 (20%) patients were HCV-RNA negative and 1 (1%) patient did not initiate therapy, 58 patients were recruited for DAA therapy via the HCV-Phone. A total of 21 additional patients who started DAAs without HCV-Phone assistance required the use of the HCV-Phone infrastructure later on during treatment, resulting in a total of 79 HCV-Phone related DAA therapies. The poor adherence of patients previously diagnosed with HCV at our clinic is underlined by the long duration from HCV diagnosis to DAA therapy of median 37.0 months (IQR 2.7-181.1 months). A total of 55 (70%) HCV patients achieved a sustained virological response (SVR), 5 (6%) discontinued therapy, 1 (1%) had a reinfection, while 10 (13%) and 8 (10%) patients were lost during DAA therapy or follow-up, respectively., Conclusion: The implementation of a physician-operated phone hotline for patients with HCV infection facilitated treatment initiation in an HCV population with poor adherence. Mainly due to losses to follow-up, the SVR rate remained suboptimal with 70%.

Background and Aims: Risk stratification after cure from hepatitis C virus (HCV) infection remains a clinical challenge. We investigated the predictive value of noninvasive surrogates of portal hypertension (liver stiffness measurement [LSM] by vibration-controlled transient elastography and von Willebrand factor/platelet count ratio [VITRO]) for development of hepatic decompensation and hepatocellular carcinoma in patients with pretreatment advanced chronic liver disease (ACLD) who achieved HCV cure., Approach and Results: A total of 276 patients with pretreatment ACLD and information on pretreatment and posttreatment follow-up (FU)-LSM and FU-VITRO were followed for a median of 36.6 months after the end of interferon-free therapy. FU-LSM (area under the receiver operating characteristic curve [AUROC]: 0.875 [95% confidence interval [CI]: 0.796-0.954]) and FU-VITRO (AUROC: 0.925 [95% CI: 0.874-0.977]) showed an excellent predictive performance for hepatic decompensation. Both parameters provided incremental information and were significantly associated with hepatic decompensation in adjusted models. A previously proposed combined approach (FU-LSM < 12.4 kPa and/or FU-VITRO < 0.95) to rule out clinically significant portal hypertension (CSPH, hepatic venous pressure gradient ≥10 mm Hg) at FU assigned most (57.3%) of the patients to the low-risk group; none of these patients developed hepatic decompensation. In contrast, in patients in whom FU-CSPH was ruled in (FU-LSM > 25.3 kPa and/or FU-VITRO > 3.3; 25.0% of patients), the risk of hepatic decompensation at 3 years following treatment was high (17.4%). Patients within the diagnostic gray-zone for FU-CSPH (17.8% of patients) had a very low risk of hepatic decompensation during FU (2.6%). The prognostic value of this algorithm was validated in an internal (n = 86) and external (n = 162) cohort., Conclusion: FU-LSM/FU-VITRO are strongly and independently predictive of posttreatment hepatic decompensation in HCV-induced ACLD. An algorithm combining these noninvasive markers not only rules in or rules out FU-CSPH, but also identifies populations at negligible versus high risk for hepatic decompensation. FU-LSM/FU-VITRO are readily accessible and enable risk stratification after sustained virological response, and thus facilitate personalized management., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Increasing numbers of hepatitis C virus (HCV) infections among men who have sex with men (MSM) are being observed in the Western world. The actual routes of HCV transmission during high-risk sex practices and associated drug use remain poorly understood., Methods: Forty-seven patients with HCV were prospectively enrolled. Rectal and nasal swabs were collected to quantify HCV-RNA levels within rectal and nasal fluids. Contamination by occult rectal bleeding was excluded by guaiac paper test. Risk behavior was assessed by standardized questionnaires., Results: Median age was 41.9 years, 89% were HIV positive (+) (42/47) and 85% (40/47) were male, 58% (23/40) of whom were MSM. Acute HCV infection was diagnosed in 32% (15/47) ,with all patients being HIV+MSM and 93% (14/15) having a documented history of sexually transmitted disease. Thirty-three (70%) patients had ≥1 HCV+ swab sample (HCV+SS; 48%, 22/46 rectal; 62%, 29/47 nasal), and contamination with blood was excluded in all patients. Individuals with HCV+SS had significantly higher serum HCV-RNA levels than patients with HCV-negative SS (6.28 [IQR, 0.85] log IU/mL vs 4.08 [2.45] log IU/mL; P < .001). Using ROC-curve analysis, serum HCV-RNA cutoffs for ruling in/out any HCV+SS were established at 6.02 log IU/mL and 4.02 log IU/mL, respectively., Conclusions: HCV-RNA is commonly detectable in rectal and nasal fluids of both HIV+ and HIV-negative HCV patients with high serum HCV-RNA, independently of the suspected route of HCV transmission. Accordingly, high-risk sex practices and sharing of nasal drug-sniffing "tools" might be important HCV transmission routes, especially in patients with high serum HCV-RNA., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The treatment of acute hepatitis C (AHC) with direct-acting antiviral agents (DAAs) is considered a cornerstone of hepatitis C virus (HCV) elimination strategies, especially in human immunodeficiency virus (HIV)-infected individuals at high risk of onward transmission., Objective: Optimal treatment regimens and duration for AHC in HIV-coinfected patients remain to be established. Thus, we aimed to evaluate the efficacy and safety of DAA treatment regimens in the setting of AHC., Methods: All HIV-positive patients with a diagnosis of AHC according to the European AIDS Treatment Network (NEAT) consensus attending our clinic after 2014 were included. DAA treatment regimens and duration were based on current recommendations for chronic hepatitis C (CHC) at treatment initiation., Results: Thirty-eight HIV/AHC patients (median age 42.0 years), mostly men who have sex with men (92%), were started on interferon-free regimens. HCV-genotype (GT) was predominately GT-1a (65%). The following DAA regimens were prescribed: ombitasvir/paritaprevir/ritonavir/dasabuvir (42%; 16/38), glecaprevir/pibrentasvir (29%; 11/38), sofosbuvir/ledipasvir (13%; 5/38), ombitasvir/paritaprevir/ritonavir (5%; 2/38), grazoprevir/elbasvir (5%; 2/38) and sofosbuvir/velpatasvir (5%; 2/38). All HIV/AHC patients achieved sustained virologic response 12 weeks after end of treatment (SVR12) (100%; 38/38). DAA-related adverse events were rare., Conclusion: Interferon-free DAA regimens (including 34% pan-genotypic regimens) yielded 100% SVR12 in HIV/AHC individuals if treatment durations similar to CHC are applied.

Human immunodeficiency virus (HIV)-induced metabolic abnormalities and antiretroviral therapy (ART), genetic factors, most importantly the rs738409 C > G p.I148M variant in the patatin-like phospholipase domain containing 3 (PNPLA3)-gene, as well as hepatitis C virus (HCV) coinfection may all cause hepatic steatosis (HS). However, recent studies suggest a protective effect of HCV infection on HS. Thus, we evaluated HS prior and after HCV eradication in an HIV/HCV-coinfected cohort at the Medical University of Vienna between January 2014 and June 2017. Two hundred forty-seven patients underwent liver stiffness measurement and controlled attenuation parameter (CAP)-based steatosis assessment. A subcohort of 138 patients also had follow-up CAP measurement after HCV eradication by direct-acting antivirals (DAAs). A CAP value ≥248 dB/m defined HS and all CAP values were adapted to compensate for body mass index (BMI) and diabetes mellitus. Among all 247 HIV/HCV-coinfected patients, HS was prevalent in 31%, mean age was 43.3 years, 75% were male, the main ethnicity was Caucasian (96%), and mean BMI was 23.33 kg/m 2 . Independent risk factors for HS were BMI, years exposed to HIV, PNPLA3 G-alleles, and protease inhibitor (PI) intake. Notably, a significant increase in CAP (from 225 ± 52.9 to 235 ± 50.7 dB/m; p  = 0.047) was observed after HCV eradication, whereas patients on PI-containing ART experienced a significant decrease in CAP. Overall, one-third of HIV/HCV-coinfected patients are affected by HS with PI-based ART and PNPLA3 impacting on HS prevalence. While HCV eradication by DAAs increased HS, as assessed by CAP, future studies should account for metabolic syndrome and evaluate whether changes in CAP-based steatosis assessments correspond to a clinically relevant outcome.

Background and Aim: Hepatitis C virus (HCV) therapy should be considered without delay in all patients with significant (SIGFIB) or advanced liver fibrosis (ADVFIB). We aimed to investigate the rates of treatment initiation with interferon-free regimens within a screening program for SIGFIB/ADVFIB in human immunodeficiency virus/HCV coinfected patients (HIV/HCV)., Methods: The FIB-4 was calculated in all HIV/HCV from 2014-2016. HIV/HCV were counselled by the HIV clinic and referred to the Division of Gastroenterology and Hepatology for transient elastography (TE) and evaluation for HCV therapy. Patients were stratified by FIB-4 of 7.1 kPa/>9.5 kPa, respectively., Results: Among 1348 HIV+ patients, 16% (210/1348) had detectable HCV-RNA. One hundred HIV/HCV had a FIB-4 ≥1.45. Among these, 57% (57/100) underwent TE. The majority of these patients had SIGFIB (75%; 43/57) or ADVFIB (37%; 21/57), however, interferon-free treatment was initiated in only 56% (24/43). In addition, fifty-two percent (57/110) of HIV/HCV with FIB-4 <1.45 underwent TE. Interestingly, 40% (23/57) and 18% (10/57) of these patients showed SIGFIB or even ADVFIB, respectively, and 78% (18/23) finally received interferon-free treatment. Overall, only 20% (42/210) of HIV/HCV received interferon-free treatment., Conclusion: FIB-4 was not useful for ruling out SIGFIB/ADVFIB in our cohort of HIV/HCV. Treatment was initiated only in a small proportion (20%) of HIV/HCV during the first 2 years of interferon-free treatment availability, although the observed proportion of patients with SIGFIB (assessed by TE) was considerably higher (58%). Thus, it requires the ongoing combined efforts of both HIV and HCV specialists to increase treatment uptake rates in this special population.

Background: According to current guidelines, the universal use of direct-acting antiviral agents in HIV-positive patients with acute hepatitis C (AHC) is not recommended. We aimed to evaluate the concept of treatment intensification with boceprevir (BOC) in HIV-positive patients with HCV-genotype 1 AHC (HIV/AHC-GT1) at high risk for failure to pegylated interferon/ribavirin therapy (PEGIFN/RBV)., Methods: Nineteen consecutive HIV-positive patients with HIV/AHC-GT1 who underwent antiviral therapy were studied retrospectively. Patients were treated with PEGIFN/RBV for 24 or 48 weeks, depending on rapid virologic response (RVR; undetectable HCV-RNA at treatment week [W] 4). Patients without complete early virologic response (cEVR; undetectable HCV-RNA at W 12) were offered treatment intensification with BOC at W 12, resulting in 36 weeks of BOC/PEGIFN/RBV triple therapy (total treatment duration: 48 weeks)., Results: Thirty-seven percent (7/19) of patients had an RVR and 74 % (14/19) of patients had a cEVR. BOC was used in four out of five patients who did not achieve cEVR and one patient elected to proceed with PEGIFN/RBV. Sustained virologic response (SVR; undetectable HCV-RNA 24 weeks after the end of treatment) rates were 100 % (14/14) among patients with cEVR treated with PEGIFN/RBV and 75 % (3/4) among patients without cEVR receiving BOC add-on. The patient without cEVR who preferred to continue with PEGIFN/RBV did not achieve SVR. Thus, the overall SVR rate was 89 % (17/19) in intention to treat analysis., Conclusions: BOC add-on in selected HIV/AHC-GT1 resulted in a high overall SVR rate. If 2nd generation direct-acting antiviral agents (DAAs) are not available, treatment intensification with BOC can be considered in HIV/AHC-GT1 at high risk for failure to PEGIFN/RBV.

HCV coinfection has emerged as a major cause of non-AIDS-related morbidity and mortality in HIV-positive patients. As a consequence of the availability of modern combined antiretroviral therapy regimens, for optimally managed HIV/HCV-coinfected patients, the rates of liver fibrosis progression and the risk of liver-related events are increasingly similar to those of HCV-monoinfected patients. Moreover, our understanding of modulators of liver disease progression has greatly improved. In addition to immune status, endocrine, metabolic, genetic and viral factors are closely interrelated and might be important determinants of liver disease progression. In the last decade, a variety of serologic and radiographic tests for noninvasive liver disease staging have been extensively validated and are commonly used in HIV/HCV-coinfected patients. Sustained virologic response prevents end-stage liver disease, hepatocellular carcinoma, and death, with an even greater effect size in HIV-positive compared to HIV-negative patients. As interferon-free regimens achieve comparable rates of sustained virologic response in HIV-negative and HIV-positive patients, HIV/HCV-coinfected patients should from now on be referred to as a special, rather than a difficult-to-treat, population. Our comprehensive review covers all relevant aspects of HIV/HCV coinfection. Beginning with the changing epidemiology, it also provides new insights into the natural history of this condition and gives an overview on non-invasive techniques for the staging of liver disease. Furthermore, it outlines current recommendations for the treatment of acute hepatitis C and summarizes the unprecedented advances in the field of chronic hepatitis C therapy.

Background: Introduction of combined antiretroviral therapy (cART) has improved survival of HIV infected individuals, while the relative contribution of liver-related mortality increased. Especially in HIV/HCV-coinfected patients hepatic fibrosis and portal hypertension represent the main causes of liver-related morbidity and mortality. Circulating miRNA-122 levels are elevated in HIV patients and have been shown to correlate with severity of liver injury. However, the association of miRNA-122 levels and hepatic fibrosis and portal hypertension remains to be explored in HIV/HCV coinfection., Methods: From a total of 74 (31% female) patients with HIV/HCV coinfection were included. Serum levels of miRNA-122 were analyzed by quantitative polymerase chain reaction (PCR) and normalized to SV-40 spike-in RNA. Hepatic venous pressure gradient (HVPG) was measured in 52 (70%) patients and the fibrosis stage was determined in 63 (85%) patients using transient elastography., Results: The levels of circulating miRNA-122 were increased in HIV/HCV coinfected patients and significantly correlated with the alanine aminotransferase (ALT) (rs = 0.438; p<0.001) and aspartate transaminase AST values (rs = 0.336; p = 0.003), but not with fibrosis stage (p = n.s.). Interestingly, miRNA-122 levels showed an inverse correlation with hepatic venous pressure gradient (HVPG) (rs = -0.302; p = 0.03)., Conclusion: Elevated miRNA-122 levels are associated with liver injury, and with low HVPG. Though, miRNA-122 levels are not suitable to predict the degree of fibrosis, they might function as indicators for portal hypertension in HIV/HCV coinfected patients.

Background. The HIVCOBOC-RGT study (NCT01925183) was the first study to evaluate response-guided shortening of the duration of boceprevir (BOC)-based triple therapy in human immunodeficiency virus (HIV)/hepatitis C virus genotype 1-coinfected patients (HIV/HCV-GT1).Methods. After 4 weeks of pegylated interferon-α-2a/ribavirin (PEGIFN/RBV) lead-in, patients with target-not-detectable HCV-RNA at week 8 (rapid virologic response; LI4W-W8UTND) received 24 weeks of BOC/PEGIFN/RBV (total: 28 weeks [W28]). Patients with target-detectable HCV-RNA at week 8 received 44 weeks of BOC/PEGIFN/RBV (total: 48 weeks [W48]).Results. Fourteen patients (67%) had LI4W–W8UTND and were eligible for the shortened W28 arm, while 7 (33%) patients were allocated to the W48 arm. No breakthrough or relapse occurred in the W28 arm, resulting in a sustained virologic response (SVR12TND) rate of 100% (12/12). In the W48 arm, the SVR12TND was 50% (3/6), with 3 patients meeting the futility rule at treatment week 12. The preliminary overall SVR12TND rate was 83% (15/18). Serious adverse events were observed in 5 (24%) patients, with 2 (10%) patients requiring surgical treatment of abscesses.Conclusions. The majority of HIV/HCV-GT1 were eligible for response-guided shortening of treatment duration to W28 and all of these patients had a SVR12TND. If second-generation direct-acting antivirals are not available, W28 of BOC-based triple therapy may be recommended. [ABSTRACT FROM PUBLISHER]

Background: Liver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) derived degradation fragments in peripheral blood as biomarkers for fibrosis and portal hypertension in patients with HIV/HCV co-infection. Methods: Fifty-eight patients (67% male, mean age: 36.5 years) with HIV/HCV-co-infection were included in the study. Hepatic venous pressure gradient (HVPG) was measured in forty-three patients. The fibrosis stage was determined using FIB4 -Score. ECM degraded products in peripheral blood were measured using specific ELISAs (C4M, MMP-2/9 degraded type IV collagen; C5M, MMP-2/9 degraded type V collagen; PRO-C3, MMP degraded n-terminal propeptide of type III collagen). Results: As expected, HVPG showed strong and significant correlations with FIB4-index (rs = 0.628; p = 7*10−7). Interestingly, PRO-C3 significantly correlated with HVPG (rs = 0.354; p = 0.02), alanine aminotransferase (rs = 0.30; p = 0.038), as well as with FIB4-index (rs = 0.3230; p = 0.035). C4M and C5M levels were higher in patients with portal hypertension (HVPG>5 mmHg). Conclusion: PRO-C3 levels reflect liver injury, stage of liver fibrosis and degree of portal hypertension in HIV/HCV-co-infected patients. Furthermore, C4M and C5M were associated with increased portal pressure. Circulating markers of hepatic ECM remodeling might be helpful in the diagnosis and management of liver disease and portal hypertension in patients with HIV/HCV coinfection. [ABSTRACT FROM AUTHOR]

Genetic variants including PNPLA3-rs738409 C>G, TM6SF2-rs58542926 C>T, MBOAT7-rs641738 C>T, and HSD17B13-rs72613567 T>TA have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)]) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the PNPLA3 minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, PNPLA3/TM6SF2/MBOAT7/HSD17B13 genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the PNPLA3 G-allele in the overall cohort. Finally, carriage of PNPLA3 G-allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in PNPLA3/TM6SF2/MBOAT7/HSD17B13 do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure. [ABSTRACT FROM AUTHOR]

Background & Aims We aimed to investigate the impact of sustained virologic response (SVR) to interferon (IFN)-free therapies on portal hypertension in patients with paired hepatic venous pressure gradient (HVPG) measurements. Methods One hundred and four patients with portal hypertension (HVPG ⩾6 mmHg) who underwent HVPG and liver stiffness measurement before IFN-free therapy (baseline [BL]) were retrospectively studied. Among 100 patients who achieved SVR, 60 patients underwent HVPG and transient elastography (TE) after antiviral therapy (follow-up [FU]). Results SVR to IFN-free therapies significantly decreased HVPG across all BL HVPG strata: 6–9 mmHg (BL: 7.37 ± 0.28 vs. FU: 5.11 ± 0.38 mmHg; −2.26 ± 0.42 mmHg; p <0.001), 10–15 mmHg (BL: 12.2 ± 0.4 vs. FU: 8.91 ± 0.62 mmHg; −3.29 ± 0.59 mmHg; p <0.001) and ⩾16 mmHg (BL: 19.4 ± 0.73 vs. FU: 17.1 ± 1.21 mmHg; −2.3 ± 0.89 mmHg; p = 0.018). In the subgroup of patients with BL HVPG of 6–9 mmHg, HVPG normalized (<6 mmHg) in 63% (12/19) of patients, while no patient progressed to ⩾10 mmHg. Among patients with BL HVPG ⩾10 mmHg, a clinically relevant HVPG decrease ⩾10% was observed in 63% (26/41); 24% (10/41) had a FU HVPG <10 mmHg. Patients with Child-Pugh stage B were less likely to have a HVPG decrease (hazard ratio [HR]: 0.103; 95% confidence interval [CI]: 0.02–0.514; p = 0.006), when compared to Child-Pugh A patients. In the subgroup of patients with BL CSPH, the relative change in liver stiffness (per %; HR: 0.972; 95% CI: 0.945–0.999; p = 0.044) was a predictor of a HVPG decrease ⩾10%. The area under the receiver operating characteristic curve for the diagnosis of FU CSPH by FU liver stiffness was 0.931 (95% CI: 0.865–0.997). Conclusions SVR to IFN-free therapies might ameliorate portal hypertension across all BL HVPG strata. However, changes in HVPG seemed to be more heterogeneous among patients with BL HVPG of ⩾16 mmHg and a HVPG decrease was less likely in patients with more advanced liver dysfunction. TE might be useful for the non-invasive evaluation of portal hypertension after SVR. Lay summary We investigated the impact of curing hepatitis C using novel interferon-free treatments on portal hypertension, which drives the development of liver-related complications and mortality. Cure of hepatitis C decreased portal pressure, but a decrease was less likely among patients with more pronounced hepatic dysfunction. Transient elastography, which is commonly used for the non-invasive staging of liver disease, might identify patients without clinically significant portal hypertension after successful treatment. [ABSTRACT FROM AUTHOR]