Long-term follow-up of HCV-infected patients with end-stage chronic kidney disease after sustained virological response with direct-acting antiviral therapy.

BACKGROUND AND AIM: Patients with chronic kidney disease (CKD) and hepatitis C infection can be safely and effectively treated with direct-acting antivirals (DAAs). However, there is scarce data on the long-term impact of hepatitis C cure on CKD. The aim of this study was to assess the long-term mortality, morbidity and hepatic/renal function outcomes in a cohort of HCV-infected individuals with CKD treated with DAAs. METHODS: 135 HCV patients with CKD stage 3b-5 who received ombitasvir/paritaprevir/ritonavir±dasabuvir in a multicenter study were evaluated for long-term hepatic and renal outcomes and their associated mortality. RESULTS: 125 patients achieved SVR and 66 were included. Prior to SVR, 53 were under renal replacement therapy (RRT) and 25 (37.8%) had liver cirrhosis. After a follow-up of 4.5 years, 25 (38%) required kidney transplantation but none combined liver-kidney. No changes in renal function were observed among the 51 patients who did not receive renal transplant although eGFR values improved in those with baseline CKD stage 3b-4. Three (5.6%) subjects were weaned from RRT. Eighteen (27.3%) patients died, mostly from cardiovascular events; 2 developed liver decompensation and 1 hepatocellular carcinoma. No HCV reinfection was observed. CONCLUSIONS: Long-term mortality remained high among end-stage CKD patients despite HCV cure. Overall, no improvement in renal function was observed and a high proportion of patients required kidney transplantation. However, in CKD stage 3b-4 HCV cure may play a positive role in renal function.

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.

Liver Stiffness-Based Strategies Predict Absence of Variceal Bleeding in Cirrhotic Hepatitis C Virus-Infected Patients With and Without Human Immunodeficiency Virus Coinfection After Sustained Virological Response.

BACKGROUND: In the setting of hepatitis C virus (HCV) active infection, liver stiffness (LS)-based strategies identify patients with low risk of developing esophageal variceal bleeding (VB) episodes, in whom unnecessary upper esophagogastroduodenoscopy (UGE) screening can be safely avoided. However, after sustained virological response (SVR), data on the accuracy of the criteria predicting this outcome in HCV-infected patients with cirrhosis, with or without human immunodeficiency virus (HIV) coinfection, are very limited. METHODS: This was a multicenter prospective cohort study, where HCV-monoinfected patients and HIV/HCV-coinfected individuals were included if they had (1) SVR with direct-acting antiviral-based therapy; (2) LS ≥9.5 kPa previous to treatment; and (3) LS measurement at the SVR time-point ≥14 kPa. Diagnostic accuracy of HEPAVIR, expanded Baveno VI, and HIV cirrhosis criteria, at the time of SVR, was evaluated. Missed VB episodes, negative predictive values (NPVs), and number of spared UGEs were specifically assessed. RESULTS: Four hundred thirty-five patients were included, 284 (65%) coinfected with HIV. Seven (1.6%) patients developed a first episode of VB after SVR. In patients without a previous VB episode, HEPAVIR, expanded Baveno VI and HIV cirrhosis criteria achieved NPV for first VB episode after SVR of 99.5% (95% confidence interval [CI], 97.1%-100%), 100% (95% CI 97.8%-100%), and 100% (95% CI 98%-100%) while sparing 45%, 39%, and 44% of UGEs, respectively. When considering HIV coinfection, the performance of the 3 criteria was similar, both in HCV-monoinfected and HIV/HCV-coinfected individuals. CONCLUSIONS: After SVR, predictive LS-based strategies accurately identify HCV-infected patients, HIV coinfected or not, with low risk of developing VB during follow-up. In these specific patients, using HIV cirrhosis criteria maximize the number of spared UGEs while missing no VB episode.

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.

Executive summary: Consensus document of GEHEP of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), along with SOCIDROGALCOHOL, SEPD and SOMAPA on hepatitis C virus infection management in drug users.

The micro-elimination of HCV infection in drug users (DU) in our area is a priority in order to achieve the overall elimination of this disease. Coordinated action between specialists in addiction treatment, microbiologists and physicians who treat HCV infection is required to implement infection screening, to achieve universal access to treatment and to prevent new infections and reinfections. The objective of this document was to come to a consensus on the screening, hospital referral, treatment, follow-up and prevention of HCV infection in DU by an expert panel from GEHEP/SEIMC and three scientific societies of addiction treating physicians: SEPD, SOCIDROGALCOHOL and SOMAPA.

Liver-related events and mortality among elderly patients with advanced chronic hepatitis C treated with direct-acting antivirals.

BACKGROUND: Direct-acting antivirals (DAAs) are effective in patients aged ≥65 years. However, little is known about the effects of DAAs on survival, liver decompensation and development of hepatocellular carcinoma (HCC). OBJECTIVE: To compare the incidence of liver-related events and mortality between patients aged ≥65 and <65 years. METHODS: Prospective study comparing patients aged ≥65 and <65 years treated with DAAs. The incidence of liver-related events and mortality, and HCC was compared between age groups. RESULTS: Five hundred patients (120 aged ≥65 and 380 aged <65 years) were included. The incidence of liver-related events was 2.62 per 100 patient-years (py) in older and 1.41/100 py in younger patients. All-cause mortality was 3.89 and 1.27/100 py in older and younger patients, respectively. The respective liver-related mortality rates were 1.12 and 0.31/100 py. In patients with cirrhosis (stage F4), all-cause mortality (P = 0.283) and liver-related mortality (P = 0.254) did not differ between groups. All five liver-related deaths were related to multifocal HCC. The incidence of HCC was 1.91 and 1.43 per 100 py in the older and younger groups, respectively (P = 0.747). The diagnosis of HCC was 8 months after the end of treatment. CONCLUSIONS: The incidence of liver-related events and liver-related mortality was low in older people treated with DAAs and was similar to that in younger patients. The extra mortality in people aged ≥65 years treated with DAAs seems to be secondary to non-liver-related causes. These results support the utilization of DAAs in patients aged ≥65 years.

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.

Correction: Randomized prospective study evaluating tenofovir disoproxil fumarate prophylaxis against hepatitis B virus reactivation in anti-HBc-positive patients with rituximab-based regimens to treat hematologic malignancies: The Preblin study.

[This corrects the article DOI: 10.1371/journal.pone.0184550.].

Randomized prospective study evaluating tenofovir disoproxil fumarate prophylaxis against hepatitis B virus reactivation in anti-HBc-positive patients with rituximab-based regimens to treat hematologic malignancies: The Preblin study.

BACKGROUND: Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy. METHODS: PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc-positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I to investigate TDF safety. RESULTS: Sixty-one patients were enrolled in the study, 33 in the TDF treatment group and 28 in the observation group. By ITT analysis, HBV reactivation was 0% (0/33) in the study group and 10.7% (3/28) in the observation group (p = 0.091). None of the patients in either group showed significant differences in liver function parameters between baseline and the last follow-up sample. TDF was generally well tolerated and there were no severe treatment-related adverse events. CONCLUSION: In patients with hematological malignancy and resolved hepatitis B infection receiving RTX-based regimens, HBV reactivation did not occur in patients given TDF prophylaxis.

Acute hepatitis C in Spain: a retrospective study of 131 cases.

BACKGROUND AND AIMS: The management of acute hepatitis C (AHC) is controversial. We have conducted a retrospective study to determine the epidemiological and biochemical aspects, the genotypes, the spontaneous clearance of HCV (SVC), and the treatment responses in patients with AHC. METHODS: We have retrospectively collected data from 131 patients with AHC from 18 Spanish hospitals. RESULTS: The mean age was 43 ± 16 years (17-83), 69% were symptomatic. The causes of infection were nosocomial in 40% and intravenous drug users in 20%. Eighty two percent had genotype 1. The delay from symptoms-onset to HCV-RNA confirmation was 50 ± 68 days (range, 11-350 days) and to treatment (in 59%) 14±1 3 weeks (range, 2-58 days). In the treated group, 80% achieved sustained virological response (SVR) versus 57% SVC in untreated patients (p = 0.004). Up to 96% of those treated within the first 12 weeks had SVR versus 86% of those treated later (p = 0.04). Patients with HCV-RNA(-) at week 4 resolved with or without treatment more frequently than those HCV-RNA(+) (98% versus 69%, p = 0.005). The treatment was not beneficial if HCV-RNA was undetectable at week 12. No differences in SVR were found in genotype 1 patients treated for 24 or 48 weeks. Patients with low baseline viral load achieved higher SVC and SVR. The SVC in patients with bilirubin > 5 mg/dL was 78 versus 40% in those with lower values (p = 0.004). CONCLUSIONS: The most common transmission route was nosocomial. SVR was higher in patients treated than SVC in non-treated.Early treatment (before week 12) achieved the highest response rate. SVC and SVR were more common in patients with a low baseline viral load. Undetectable HCV-RNA at week 4 was associated with high SVR and SVC rates. Jaundice was related with SVC.