Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Impact of HIV on the survival of hepatocellular carcinoma in hepatitis C virus-infected patients.

BACKGROUND: Previous studies have suggested that hepatocellular carcinoma (HCC) has an aggressive presentation and a shorter survival in people with HIV (PWH). This could be due to later diagnosis or lower rates of HCC treatment, and not to HIV infection itself. AIM: :: To assess the impact of HIV on HCC survival in hepatitis C virus (HCV)-infected patients. METHODS: Multicenter cohort study (1999-2018) of 342 and 135 HCC cases diagnosed in HIV/HCV-infected and HCV-monoinfected patients. Survival after HCC diagnosis and its predictors were assessed. RESULTS: HCC was at Barcelona-Clinic Liver-Cancer (BCLC) stage 0/A in 114 (33%) HIV/HCV-coinfected and in 76 (56%) HCV-monoinfected individuals (P < 0.001). Of them, 97 (85%) and 50 (68%) underwent curative therapies (P = 0.001). After a median (Q1-Q3) follow-up of 11 (3-31) months, 334 (70%) patients died. Overall 1 and 3-year survival was 50 and 31% in PWH and 69 and 34% in those without HIV (P = 0.16). Among those diagnosed at BCLC stage 0/A, 1 and 3-year survival was 94 and 66% in PWH whereas it was 90 and 54% in HIV-negative patients (P = 0.006). Independent predictors of mortality were age, BCLC stage and α-fetoprotein levels. HIV infection was not independently associated with mortality [adjusted hazard ratio (AHR) 1.57; 95% confidence interval: 0.88-2.78; P = 0.12]. CONCLUSION: HIV coinfection has no impact on the survival after the diagnosis of HCC in HCV-infected patients. Although overall mortality is higher in HIV/HCV-coinfected patients, this seem to be related with lower rates of early diagnosis HCC in HIV-infected patients and not with HIV infection itself or a lower access to HCC therapy.

Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs.

BACKGROUND & AIMS: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. METHODS: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. RESULTS: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. CONCLUSION: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. LAY SUMMARY: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.

Response to direct-acting antiviral therapy among ongoing drug users and people receiving opioid substitution therapy.

BACKGROUND & AIMS: People who inject drugs (PWID) and are on opioid agonist therapy (OAT) might have lower adherence to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) and, therefore, lower rates of sustained virologic response (SVR). Because of this, we compared the SVR rates to interferon-free DAA combinations in individuals receiving OAT and those not receiving OAT in a real-world setting. METHODS: The HEPAVIR-DAA cohort, recruiting HIV/HCV-coinfected patients (NCT02057003), and the GEHEP-MONO cohort (NCT02333292), including HCV-monoinfected individuals, are ongoing prospective multicenter cohorts of patients receiving DAAs in clinical practice. We compared SVR 12 weeks after treatment (SVR12) in non-drug users and PWID, including those receiving or not receiving OAT. Intention-to-treat and per protocol analyses were performed. RESULTS: Overall, 1,752 patients started interferon-free DAA treatment. By intention-to-treat analysis, 778 (95%, 95% CI 93%-96%) never injectors, 673 (92%, 95% CI 89%-93%) PWID not on OAT and 177 (89%, 95% CI 83%-92%) PWID on OAT achieved SVR12 (p = 0.002). SVR12 rates for ongoing drug users (with or without OAT) were 68 (79%) compared with 1,548 (95%) for non-drug users (p <0.001). Among ongoing drug users, 15 (17%) were lost-to-follow-up, and 3 (3.5%) became reinfected. In the per protocol analysis, 97% never injectors, 95% PWID not on OAT and 95% PWID on OAT achieved SVR12 (p = 0.246). After adjustment, ongoing drug use was associated with SVR12 (intention-to-treat) and OAT use was not. CONCLUSIONS: HCV-infected PWID achieve high SVR12 rates with DAAs whether they are on OAT or not, but their response rates are lower than those of patients who never used drugs. This is mainly attributable to more frequent loss to follow-up. Accounting for active drug use during DAA therapy nearly closed the gap in SVR rates between the study groups. LAY SUMMARY: Patients with hepatitis C virus infection who are on opioid agonist therapy can achieve high cure rates with current treatments. The use of illicit drugs during treatment can drive drop-outs and reduce cure rates. However, hepatitis C can be cured in most of those using drugs who complete treatment and follow-up. Clinical trial number: HEPAVIR-DAA cohort, NCT02057003; GEHEP-MONO cohort, NCT02333292.

Low performance of ultrasound surveillance for the diagnosis of hepatocellular carcinoma in HIV-infected patients.

OBJECTIVE: To assess the performance of ultrasound surveillance for the diagnosis of hepatocellular carcinoma (HCC) in HIV-infected patients. METHODS: The GEHEP-002 cohort recruits HCC cases diagnosed in HIV-infected patients from 32 centers across Spain. The proportion of 'ultrasound lack of detection', defined as HCC diagnosed within the first 3 months after a normal surveillance ultrasound, and the proportion of 'surveillance failure', defined as cases in which surveillance failed to detect HCC at early stage, were assessed. To assess the impact of HIV, a control population of 104 HCC cases diagnosed in hepatitis C virus-monoinfected patients during the study period was used. RESULTS: A total of 186 (54%) out of 346 HCC cases in HIV-infected patients were diagnosed within an ultrasound surveillance program. Ultrasound lack of detection occurred in 16 (8.6%) of them. Ultrasound surveillance failure occurred in 107 (57%) out of 186 cases diagnosed by screening, whereas this occurred in 18 (29%) out of 62 diagnosed in the control group (P < 0.0001). HCC cases after ultrasound surveillance failure showed a lower frequency of undetectable HIV viral load at diagnosis. The probability of 1-year and 2-year survival after HCC diagnosis among those diagnosed by screening was 56 and 45% in HIV-infected patients, whereas it was 79 and 64% in HIV-negative patients (P = 0.038). CONCLUSION: The performance of ultrasound surveillance of HCC in HIV-infected patients is very poor and worse than that shown outside HIV infection. A HCC surveillance policy based on ultrasound examinations every 6 months might be insufficient in HIV-infected patients with cirrhosis.

Effectiveness and safety of elbasvir/grazoprevir therapy in patients with chronic HCV infection: Results from the Spanish HEPA-C real-world cohort.

In randomized controlled trials of patients with chronic HCV infection, elbasvir/grazoprevir (EBR/GZR) demonstrated high cure rates and a good safety profile. This study assessed the effectiveness and safety of EBR/GZR, with and without ribavirin, in a real-world HCV patient cohort. HEPA-C is a collaborative, monitored national registry of HCV patients directed by the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for Hepatic and Digestive Diseases. Patients entered into HEPA-C between December 2016 and May 2017, and treated with EBR/GZR with at least end-of-treatment response data, were included. Demographic, clinical and virologic data were analysed, and adverse events (AEs) recorded. A total of 804 patients were included in the study. The majority were male (57.9%), with a mean age of 60 (range, 19-92) years. Genotype (GT) distribution was GT 1, 86.8% (1a, 14.3%; 1b, 72.5%); GT 4, 13.2% and 176 patients (21.9%) were cirrhotic. Overall, among 588 patients with available data, 570 (96.9%) achieved sustained virologic response at 12 weeks post-treatment (SVR12). SVR12 rates by genotype were GT 1a, 97.7%; GT 1b, 98.6%; and GT 4, 98.1%. No significant differences in SVR12 according to fibrosis stage were observed. Eighty patients experienced an AE, resulting in treatment discontinuation in three. In this large cohort of patients with chronic HCV managed in a real-world setting in Spain, EBR/GZR achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with a similarly good safety profile.

Hepatitis B surface antigen loss after discontinuing nucleos(t)ide analogue for treatment of chronic hepatitis B patients is persistent in White patients.

OBJECTIVE: The objective of this study was to determine the long-term clinical outcome and persistence of hepatitis B surface antigen (HBsAg) loss after discontinuation of treatment. BACKGROUND: The prognosis of patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs) who discontinue treatment after loss of HBsAg remains largely unknown, particularly in White patients. PATIENTS AND METHODS: We analysed a cohort of patients with CHB who discontinued NA treatment after loss of HBsAg. A total of 69 patients with hepatitis-B-e antigen-positive or hepatitis-B-e antigen-negative CHB with undetectable HBsAg during NA treatment were included after discontinuation of treatment, and followed up for a median period of 37.8 months (interquartile range: 23.8-54.6 months). RESULTS: At the end of follow-up, none of the patients showed spontaneous reappearance of HBsAg and only one patient had detectable hepatitis B virus DNA (22 IU/ml). Another patient negative for HBsAg and anti-HBs developed hepatitis B virus reactivation without elevated transaminases after treatment with corticosteroids and vincristine for dendritic cell neoplasm, 38 months after withdrawal of the antiviral treatment. Regarding clinical outcome, a patient with cirrhosis developed hepatocellular carcinoma, 6.6 years after discontinuing treatment. None of the patients had hepatic decompensation or underwent liver transplantation. CONCLUSION: HBsAg clearance after discontinuing NAs in patients with CHB is persistent and associated with good prognosis. The risk for developing hepatocellular carcinoma persists among patients with cirrhosis.

Hepatitis C virus deep sequencing for sub-genotype identification in mixed infections: A real-life experience.

BACKGROUND: The effectiveness of the new generation of hepatitis C treatments named direct-acting antiviral agents (DAAs) depends on the genotype, subtype, and resistance-associated substitutions present in individual patients. The aim of this study was to evaluate a massive sequencing platform for the analysis of genotypes and subtypes of hepatitis C virus (HCV) in order to optimize therapy. METHODS: A total of 84 patients with hepatitis C were analyzed. The routine genotyping methodology for HCV used at the study institution (Versant HCV Assay, LiPA) was compared with a deep sequencing platform (454/GS-Junior and Illumina MiSeq). RESULTS: The mean viral load in these HCV patients was 6.89×106±7.02×105. Viral genotypes analyzed by LiPA were distributed as follows: 26% genotype 1a (22/84), 55% genotype 1b (46/84), 1% genotype 1 (1/84), 2.5% genotype 3 (2/84), 6% genotype 3a (5/84), 6% genotype 4a/c/d (5/84). When analyzed by deep sequencing, the samples were distributed as follows: 27% genotype 1a (23/84), 56% genotype 1b (47/84), 8% genotype 3a (7/84), 5% genotype 4d (4/84), 2.5% genotype 4f (2/84). Six of the 84 patients (7%) were infected with more than one subtype. Among these, 33% (2/6) failed DAA-based triple therapy. CONCLUSIONS: The detection of mixed infection could explain some treatment failures. Accurate determination of viral genotypes and subtypes would allow optimal patient management and improve the effectiveness of DAA therapy.

Impact of comorbidities on patient outcomes after interferon-free therapy-induced viral eradication in hepatitis C.

BACKGROUND & AIMS: Patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and those with severe comorbidities may not benefit from hepatitis C (HCV) eradication. We aimed to collect data on all-cause mortality and relevant clinical events within the first two years of direct-acting antiviral therapy, whilst determining the prognostic capability of a comorbidity-based model. METHODS: This was a prospective non-interventional study, from the beginning of direct-acting antiviral therapy to the event of interest (mortality) or up to two years of follow-up, including 14 Spanish University Hospitals. Patients with HCV infection, irrespective of liver fibrosis stage, who received direct-acting antiviral therapy were used to build an estimation and a validation cohort. Comorbidity was assessed according to Charlson comorbidity and CirCom indexes. RESULTS: A total of 3.4% (65/1,891) of individuals died within the first year, while 5.4% (102/1,891) died during the study. After adjusting for cirrhosis, platelet count, alanine aminotransferase and sex, the following factors were independently associated with one-year mortality: Charlson index (hazard ratio [HR] 1.55; 95% CI 1.29-1.86; p = 0.0001), bilirubin (HR 1.39; 95% CI 1.11-1.75; p = 0.004), age (HR 1.06 95% CI 1.02-1.11; p = 0.005), international normalized ratio (HR 3.49; 95% CI 1.36-8.97; p = 0.010), and albumin (HR 0.18; 95% CI 0.09-0.37; p = 0.0001). HepCom score showed a good calibration and discrimination (C-statistics 0.90), and was superior to the other prognostic scores (model for end-stage liver disease 0.81, Child-Pugh 0.72, CirCom 0.68) regarding one- and two-year mortality. HepCom score identified low- (≤5.7 points: 2%-3%) and high-risk (≥25 points: 56%-59%) mortality groups, both in the estimation and validation cohorts. The distribution of clinical events was similar between groups. CONCLUSIONS: The HepCom score, a combination of Charlson comorbidity index, age, and liver function (international normalized ratio, albumin, and bilirubin) enables detection of a group at high risk of one- and two-year mortality, and relevant clinical events, after starting direct-acting antiviral therapy. LAY SUMMARY: The prognosis of patients with severe comorbidities may not benefit from HCV viral clearance. An algorithm to decide who will benefit from the treatment is needed to manage the chronic HCV infection better.

Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy.

BACKGROUND & AIMS: Minimal hepatic encephalopathy is associated with poor prognosis and mortality in patients with cirrhosis. We aimed at investigating whether bacterial-DNA translocation affects hyperammonaemia and neurocognitive scores in patients with mHE according to the use of lactulose. METHODS: Observational study including 72 mHE cirrhotic patients, as defined by a psychometric hepatic encephalopathy score (PHES)<-4 and/or a critical flicker frequency (CFF)<39 Hz. Bacterial-DNA, serum ammonia, pro-inflammatory cytokines and nitric oxide levels were evaluated. A second cohort of 40 lactulose-untreated patients were evaluated before and 6-month after lactulose administration (30-60 mL/d). RESULTS: In the first cohort, bacterial-DNA rate was significantly higher in patients without lactulose (39% vs 23%, P=.03). Serum ammonia and inflammatory markers were significantly increased in patients with bacterial-DNA, regardless the use of lactulose, and correlated with the amount of amplified bacterial-DNA. Neurocognitive scores were significantly worse in bacterial-DNA positive vs negative patients (PHES -7.6±1.1 vs -5.5±1.0; CFF 32.5±2.6 vs 36.2±2.8, P=.01). Lactulose was associated with improved neurocognitive scores in patients without bacterial-DNA. Serum ammonia levels inversely correlated with neurocognitive scores in patients with bacterial-DNA (PHES r=-.84; CFF r=-.72, P=.001). In the second cohort, lactulose reduced bacterial-DNA translocation (36%-16%, P=.02). Neurocognitive scores were significantly improved in bacterial-DNA positive patients who cleared bacterial-DNA during the period on lactulose. Serum ammonia levels correlated with both neurocognitive scores in patients with bacterial-DNA, either before or after lactulose. CONCLUSION: Bacterial-DNA translocation worsens neurocognitive scores in mHE patients and it is reduced by lactulose, enhancing the relevance of controlling bacterial antigen translocation in these patients.

Metformin inhibits glutaminase activity and protects against hepatic encephalopathy.

AIM: To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro. METHODS: Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizers experienced (metformin) and 41 as controls (cirrhotic patients with type 2 diabetes mellitus without metformin treatment). Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutations in glutaminase gene. We performed an experimental study in vitro including an enzymatic activity assay where glutaminase inhibition was measured according to different metformin concentrations. In Caco2 cells, glutaminase activity inhibition was evaluated by ammonia production at 24, 48 and 72 hours after metformina treatment. RESULTS: Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82): 4.9% (2/41) in patients receiving metformin and 41.5% (17/41) in patients without metformin treatment (logRank 9.81; p=0.002). In multivariate analysis, metformin use [H.R.11.4 (95% CI: 1.2-108.8); p=0.034], age at diagnosis [H.R.1.12 (95% CI: 1.04-1.2); p=0.002], female sex [H.R.10.4 (95% CI: 1.5-71.6); p=0.017] and HE risk [H.R.21.3 (95% CI: 2.8-163.4); p=0.003] were found independently associated with hepatic encephalopathy. In the enzymatic assay, glutaminase activity inhibition reached 68% with metformin 100 mM. In Caco2 cells, metformin (20 mM) decreased glutaminase activity up to 24% at 72 hours post-treatment (p<0.05). CONCLUSIONS: Metformin was found independently related to overt hepatic encephalopathy in patients with type 2 diabetes mellitus and high risk of hepatic encephalopathy. Metformin inhibits glutaminase activity in vitro. Therefore, metformin use seems to be protective against hepatic encephalopathy in diabetic cirrhotic patients.

[Virological response to adefovir dipivoxil predicts the long-term development of resistance in previously untreated patients with HBeAg-negative chronic hepatitis B]. / La respuesta virológica al tratamiento con adefovir dipivoxil predice el desarrollo de resistencias a largo plazo en pacientes con hepatitis crónica B HBeAg negativo previamente no tratados.

BACKGROUND AND OBJECTIVE: Adefovir dipivoxil monotherapy in lamivudine-resistant patients is associated with more frequent development of resistance than in naïve patients. The virological response during treatment predicts the risk of developing resistance. The aims of this study were to assess the efficacy of adefovir dipivoxil treatment in naïve and lamivudine-resistant patients and to determine whether virological response predicts the development of adefovir resistance. PATIENTS AND METHOD: This study included 82 patients with HBeAg-negative chronic hepatitis B (CHB) who received adefovir dipivoxil therapy. During active treatment, HBV-DNA values were determined by polymerase chain reaction; in addition, the presence of adefovir resistance-associated mutations was studied in cases of virological breakthrough. RESULTS: Virological response at 12 and 24 months was 59% and 73% in naive patients compared with 40% and 67% in lamivudine-resistant patients, whereas virological breakthrough at 24 months was 9.5% in naïve patients compared with 20% in lamivudine-resistant patients. A small percentage (4%) of patients with virological response at 12 months showed virological breakthrough between 12 and 40 months versus 29.4% of patients without virological response (P=.03). In lamivudine-resistant patients, virological response at 12 months was not a predictive factor for the development of virological breakthrough. CONCLUSIONS: Adefovir dipivoxil monotherapy in lamivudine-resistant patients is associated with an increased tendency to develop virological breakthrough, which cannot be predicted by virological response at 12 months of treatment. In naive patients, an undetectable viral load at 12 months of treatment ensures the absence of virological breakthrough at 40 months of treatment.