Kinetics of emergence of liver complications in hepatitis C virus infected patients and advanced fibrosis, with and without HIV-coinfection, after sustained virological response.

OBJECTIVE: There is scarce available evidence on the distribution over time of liver complications emergence in hepatitis C virus (HCV)-infected patients who achieve sustained virological response (SVR) with direct-acting antiviral (DAA)-based therapy. Therefore, we aimed at describing the kinetics of liver-related events appearance in this setting. DESIGN: A multicentric prospective cohort study. METHODS: HCV-monoinfected and HIV/HCV-coinfected patients from GEHEP-011 cohort, whose inclusion criteria were had achieved SVR with DAA-based therapy; liver stiffness prior to starting treatment at least 9.5 kPa; and available liver stiffness measurement at SVR. SVR was considered as the baseline time-point. RESULTS: One thousand and thirty-five patients were included, 664 (64%) coinfected with HIV. Before DAA-based therapy, 63 (6.1%) individuals showed decompensated cirrhosis. After SVR, 51 (4.9%) patients developed liver complications. Median (Q1-Q3) time to the emergence of hepatic events was hepatic encephalopathy 11 (7-24) months, ascites 14 (6-29) months, hepatocellular carcinoma (HCC) 17 (11-42) months and portal hypertension gastrointestinal bleeding (PHGB) 28 (22-38) months (P = 0.152). We define two profiles of liver complications: those emerging earlier (encephalopathy and ascites) and, those occurring continuously during the follow-up (HCC, PHGB) [median (Q1-Q3) time to emergence 12.7 (6.6-28.2) months vs. 25.4 (12.5-41.53) months, respectively (P = 0.026)]. CONCLUSION: The vast majority of HCV-infected patients who develop liver complications after reaching SVR with DAA do it within 3 years after SVR time-point. Specifically, hepatic encephalopathy and ascites do not usually emerge after this period. Conversely, HCC and PHGB may occur in longer term. It is critical to identify patients at risk of developing hepatic events to continue performing surveillance for them.

Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower Risk of Hepatocellular Carcinoma After Sustained Virological Response to Direct-acting Antivirals in Hepatitis C Infected Patients With Advanced Fibrosis.

BACKGROUND: The aim of this study was to assess the impact of human immunodeficiency virus (HIV) infection on the risk of developing hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV) who achieve sustained virological response (SVR) with direct-acting antiviral (DAA). METHODS: Multisite prospective cohort study, where HCV-monoinfected patients and HIV/HCV-coinfected individuals were included if they met: (1) SVR with DAA-based combination; (2) liver stiffness (LS) ≥9.5 kPa previous to treatment; (3) LS measurement at the SVR time-point. The main endpoint was the occurrence of HCC. Propensity score (PS) was calculated to address potential confounders due to unbalanced distribution of baseline characteristics of HIV/HCV-coinfected and HCV-monoinfected patients. RESULTS: In total, 1035 HCV-infected patients were included, 667 (64%) coinfected with HIV. After a median (Q1-Q3) follow-up time of 43 (31-49) months, 19 (1.8%) patients developed HCC (11 [3.0%]; HCV-monoinfected, 8[1.2%]; HIV/HCV-coinfected individuals; P = .013). In the multivariable analysis, HIV coinfection was associated with a lower adjusted risk of developing HCC (subhazard ratio [sHR] = 0.27, 95% confidence interval [CI]: .08-.90; P = .034). Predictors of HCC emergence were: HCV genotype 3 (sHR = 7.9, 95% CI: 2.5-24.9; P < .001), MELD score at SVR >10 (sHR = 1.37, 95% CI: 1.01-1.86; P = .043) and LS value at SVR (sHR = 1.03, 95% CI: 1.01-1.06, for 1 kPa increase; P = .011). Using inverse probability weighting method on the PS, HIV-infected patients had a lower risk of HCC (powered HR = 0.33, 95% CI: .11-.85). CONCLUSIONS: Among HCV-infected patients with advanced fibrosis, who achieve SVR with DAA, HIV coinfection seems to be associated with a lower risk of HCC occurrence. The underlying causes for this finding need to be investigated.

High efficacy of resistance-guided retreatment of HCV patients failing NS5A inhibitors in the real world.

BACKGROUND & AIMS: Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available. METHODS: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded. RESULTS: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin. CONCLUSIONS: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited. LAY SUMMARY: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.

HIV infection does not increase the risk of liver complications in hepatitis C virus-infected patient with advanced fibrosis, after sustained virological response with direct-acting antivirals.

OBJECTIVE: To assess the impact of HIV coinfection on the risk of developing liver-related complications in HCV-infected patients with advanced fibrosis treated with direct-acting antivirals (DAA) after sustained virological response (SVR). DESIGN: Prospective cohort study. SETTING: Multicenter. SUBJECTS: Patients from the GEHEP and HEPAVIR cohorts were selected if they fulfilled the following criteria: treatment against HCV with all oral DAA combination; SVR achievement, defined as undetectable plasma HCV RNA 12 weeks after the end of therapy; pretreatment liver stiffness equal to or higher than 9.5 kPa; liver stiffness measurement at the time of SVR. MAIN OUTCOME MEASURE(S): The primary variable was the time until the development of a liver complication or requiring liver transplant. RESULTS: Seven hundred and seventeen patients were included and 507 (71%) were coinfected with HIV. After a median follow-up time of 21 (14-25) months, 15 (2.1%) patients developed a liver complication and/or underwent a liver transplant and 15 (2.0%) died. The probability of remaining free of hepatic complications or transplant at 1 and 2 was, respectively, 99 and 96% in HCV-monoinfected patients and 99 and 98% in coinfected patients (P = 0.648). In a multivariate analysis, in which nonliver-related death was considered as a competing event, HIV coinfection was not associated with the appearance of hepatic complications or requiring liver transplant [hazard ratio = 0.24; 95% CI (0.03-1.93), P = 0.181]. Having presented hepatic decompensation prior to SVR [hazard ratio = 29.06; 95% CI (3.91-216.16), P < 0.001] and the value of liver stiffness at the SVR time-point (hazard ratio = 1.12; 95% CI (1.07-1.18), P < 0.001] were associated with a higher probability of development of liver events. CONCLUSION: HIV coinfection is not associated with a higher probability of developing liver complications in HCV-infected patients with advanced fibrosis, who achieved SVR with interferon-free regimens.

Tratamiento de la hepatitis crónica por virus C en pacientes coinfectados por el virus de la inmunodeficiencia humana / Chronic hepatitis C treatment in human infection virus coinfected patients

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Síndrome del ¿pulmón pequeño¿, una rara manifestación del lupus eritematoso sistémico / Shrinking lung syndrome: a rare manifestation of systemic Lupus Erythematosus

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