Worsening of Serum Lipid Profile after Direct Acting Antiviral Treatment.

INTRODUCTION: Host lipid metabolism influences viral replication and lifecycle of hepatitis C virus. Our aim was to evaluate changes in glucose and lipid metabolism of patients with chronic hepatitis C after therapy with direct acting antivirals (DAA). MATERIAL AND METHODS: We considered patients consecutively treated between January and November 2015 recording clinical data at baseline and week 24 of follow-up. Frozen serum samples were used for apolipoprotein A1 (apoA1), apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)]. Wilcoxon test was utilized to estimate trends and Logistic Regression for predictors of lipid changes. RESULTS: We enrolled 100 patients, mostly cirrhotic (81%) and with genotype 1b (59%). Ninety-three patients achieved sustained virological response (SVR), while 7 relapsed. Homeostasis model assessment of insulin resistance declined (from 3 to 2.7, p < 0.001); non-high density lipoprotein (HDL) cholesterol increased from 102 ± 29 to 116 ± 35 (p < 0.001), and Lp(a) from 5.6 ± 6.5 to 9.8 ± 11.5 mg/dL (p < 0.001). Rise of low-density lipoprotein/HDL and apoB/apoA1 ratio were registered (from 1.79 ± 1.10 to 2.08 ± 1.05 and from 0.48 ± 0.18 to 0.53 ± 0.18 mg/dL, p < 0.001). We conducted a subanalysis on patients with relapse. In this subgroup, no change of lipid profile was recorded. At multivariate analysis emerged that the addition of ribavirin to DAA, represented an independent predictor of increased Lp(a) (OR 3.982, 95% CI 1.206-13.144, p = 0.023). CONCLUSION: DAA therapy led to reduction of insulin resistance. In contrast, pro-atherogenic lipid changes were observed in patients with SVR. Further studies will be necessary to evaluate the cardiovascular balance between amelioration of glucose metabolism and negative changes of lipid profile.

Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA. METHODS: We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24weeks. Fifty-nine patients had previous HCC. RESULTS: DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99-10.84): 17 of 59 patients (28.81%, 95% CI: 17.76-42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45-5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p=0.03, OR: 4.18, 95% CI: 1.17-14.8) and history of HCC (p<0.0001, OR: 12.0, 95% CI: 4.02-35.74) resulted independently associated with HCC development. Among the 59 patients with previous HCC, younger age and more severe liver fibrosis were significantly associated with HCC recurrence, both at univariate and at multivariate analysis. CONCLUSIONS: In patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumour recurrence, in the short term. For these reasons, all cirrhotic patients should be closely monitored and followed during and after antiviral therapy. LAY SUMMARY: New direct-acting antivirals are able to eradicate HCV infection in over 90% of patients with advanced liver disease. Unfortunately, the occurrence of liver cancer is not reduced in effectively treated cirrhotic patients. In addition, patients previously treated for HCC have still a high risk of tumour recurrence in the short term, despite DAA treatment.

Increase of ribavirin dose improves sustained virological response in HCV-genotype 1 patients with a partial response to peg-interferon and ribavirin.

BACKGROUND AND AIM: In patients with chronic hepatitis C receiving Peg interferon/ribavirin (PEG-IFN/RBV) who do not achieve ≥ 2 log-reduction in HCV-RNA at week 12 (null responders, NR) and in those with ≥ 2 log-decrease but detectable at week 24 (partial responders, PR) the probability to achieve the sustained virological response (SVR) is almost null. The aim of this study was to investigate the efficacy of individualized schedule of progressively increased RBV doses in the setting of PEG-IFN/RBV treatment. MATERIAL AND METHODS: PR or NR to PEG-IFN/RBV instead of discontinuing treatment were enrolled to receive increasing doses of RBV until a target theoretical concentration ([tRBV]) of ≥ 15 µmol/L (by pharmacokinetic formula based on glomerular filtration rate). HCV-RNA was assessed every 4 weeks and, if detectable, RBV dose was gradually increased until negativization. Twelve weeks later, patients with detectable HCV-RNA discontinued therapy while those with undetectable HCV-RNA continued for further 48 weeks. RESULTS: Twenty genotype-1 patients (8 NR and 12 PR) were enrolled. After 12 weeks 9 (45%) were still HCV-RNA positive and were discontinued, while remaining 11 had undetectable HCV-RNA. One stopped treatment for side effects. Ten completed treatment. Five (all PR) achieved SVR. Side effects incidence was similar to that observed during PEG-IFN/RBV. CONCLUSIONS: In conclusion, RBV high doses, according to individualized schedule, increase SVR in PR on a similar extent to that of triple therapy but without increase of side effects. Such treatment should be considered in PR with no access or intolerant to protease inhibitors (PI).

Two yr mycophenolate mofetil plus low-dose calcineurin inhibitor for renal dysfunction after liver transplant.

We assessed the efficacy and outcome of low through level of calcineurin inhibitors (CNI) and introducing mycophenolate mofetil (MMF) in liver transplant (LT) patients with CNI-related renal dysfunction. Thirty LT patients were converted to combined therapy and compared with 30 patients used as a contemporary control group receiving CNI only. The two groups were matched for sex, age, months after LT, immunosuppressive treatment, creatinine level, presence of diabetes and calculated glomerular filtration rate (GFR) via Cockroft-Gault method. After two years, in the MMF serum creatinine decreased from 1.65 mg/dL (range 1.33-3.5) to 1.4 mg/dL (range 0.9-4.7) (p = 0.002) and GFR increased from 51 mL/min (range 18.9-72.2) to 57.6 mL/min (range 16-92.2) (p < 0.001), whereas the controls not showed any improvement. The logistic regression models employing improvement of creatinine and GFR of at least 10% with respect to baseline as dependent variables showed the use of MMF (p = 0.004 and p = 0.019, respectively) as the only statistically significant parameter. Multiple linear regression analysis identified only MMF as independent predictor of Deltacreatinine and DeltaGFR (p = 0.002 and p < 0.001, respectively). No rejection episode was observed (three in controls). This study demonstrates the medium-term efficacy and safety of MMF plus low dose CNI in reducing nephrotoxicity in LT recipients.

Hepatocellular carcinoma appearance in patients with hepatitis C virus-related chronic liver disease 90 and 70 months after sustained virological response to interferon and ribavirin.

We report here two cases of hepatocellular carcinoma (HCC) 90 and 70 months, respectively, after successful treatment with interferon (IFN) and ribavirin for hepatitis C virus (HCV)-related cirrhosis. A 50-year-old Caucasian man and a 66-year-old Caucasian woman with HCV-related cirrhosis were treated with IFN and ribavirin and in both cases a sustained virological response (SVR) was obtained with persistent normalization of serum aminotransferases and continuous disappearance of serum HCV-RNA. Both patients were subsequently followed up within an HCC surveillance programme based on biochemical and ultrasound (US) evaluation every 6 months and the appearance of HCC was detected 90 and 70 months, respectively, after discontinuation of therapy. We introduce these two cases to call attention to the importance of not underestimating the risk of HCC development even many years after complete HCV eradication, especially in the presence of established cirrhosis and concomitance of other risk factors for HCC.

Hepatitis B virus reactivation among hepatitis C patients treated with direct-acting antiviral therapies in routine clinical practice.

BACKGROUND: Hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients treated with IFN-free direct acting antiviral (DAA) therapies has recently emerged as a potential risk. Given the potential burden of this issue, further data are needed to establish its actual clinical impact. OBJECTIVES: The aim of the present study was to analyze the occurrence of HBV reactivation in a cohort of CHC patient treated with DAAs in routine clinical practice. STUDY DESIGN: Consecutive CHC patients with different genotypes, treated with DAA between January 2015 and January 2016 were included in the study. Subjects had been tested for HBsAg and anti-HBc antibodies before antiviral therapy. HBV-DNA levels were examined in anti-HBc positive patients at baseline and 24 weeks after the end of treatment. Post-treatment HBsAg determination was performed in case of HBV-DNA positivity. Serum anti-HBs kinetics was analysed in anti-HBs and anti-HBc positive subjects. RESULTS: A cohort of 137 consecutive HCV patients treated with IFN-free regimens in routine clinical practice was evaluated. From this cohort, plasma samples of 44 subjects with positive serology for HBV (anti-HBc positive) were tested for HBV-DNA levels at baseline and 24 weeks after the end of treatment. Two of them were HBsAg-positive, while the others had signs of a past HBV exposure (HBsAg-negative±HBsAb-positive). No reactivation was found in HBcAb-positive and HBsAg-negative subjects. In the two HBsAg-positive, one experienced an increase in HBV-DNA levels of ≥2 log10 IU/mL during treatment. However, the reactivation was without clinical impact and, most important, was followed by HBsAg loss. CONCLUSIONS: Based on our experience, a past HBV infection seems not to be a condition predisposing to HBV reactivation. On the contrary, in HBsAg-positive subjects not in suppressive treatment with nucleos(t)ide analogs, regular monitoring of HBV-DNA during and after DAA treatment should be considered.

A Case of Acute Liver Failure during Ritonavir-Boosted Paritaprevir, Ombitasvir and Dasabuvir Therapy in a Patient with HCV Genotype 1b Cirrhosis.

BACKGROUND: Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin is one of the current recommended therapies for HCV genotype 1b monoinfected patients in compensated (Child-Pugh A) cirrhosis. Whether it is known that the worsening of liver function is a rare but possible complication of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir therapy, to our knowledge no description of treatment-related acute liver failure is available in the literature. CASE PRESENTATION: An 84-year-old Caucasian man with chronic compensated HCV genotype 1b cirrhosis received Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy. After 13 days he developed grade 4 hyperbilirubinaemia and ascites. Even though treatment was promptly stopped, patient's clinical condition worsened, and he underwent hospitalization, several paracentheses, and developed sub-acute kidney injury. The bilirubinemia returned under three times the upper normal limit only after five months. Notably, he achieved sustained virological response despite the very short duration of therapy. CONCLUSION: Hepatic decompensation and acute liver failure are rare but severe complications of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy in patients with compensated cirrhosis. Close monitoring for signs or symptoms of worsening of liver disease is mandatory, and further research for stratifying risk factors are required.

Patterns of HCV-RNA and HCV core antigen in the early monitoring of standard treatment for chronic hepatitis C.

BACKGROUND: An early drop of HCV-RNA levels is useful in assessing response to antiviral treatment in chronic hepatitis C; the first recommended time point is 4 weeks after the start of therapy. OBJECTIVES: We evaluated retrospectively HCV-RNA and HCVAg levels at different time points to assess the clinical value of an early monitoring. STUDY DESIGN: Thirty-five patients with chronic hepatitis C infected by genotype 1b and consecutively enrolled in an open-label study on PegIFN plus Ribavirin and/or ketoprofene were tested for HCV-RNA (real-time PCR) and HCVAg (ARCHITECT) at baseline and after 1 and 2 days and 1, 2, 4 and 12 weeks after the start of treatment. Treatment response was assessed according to the EASL consensus criteria. RESULTS: In the 17 sustained responders (SR) the median log decrease of HCV-RNA and HCVAg at the different time points was 0.40 and 0.37; 1.36 and 0.84; 1.47 and 0.97; 2.34 and 1.86; 2.51 and 2.32; 3.28 and 2.61, respectively. The best time point to predict SR was 2 weeks after the start of therapy, with a sensitivity, specificity and overall accuracy of 76.9%, 86.7% and 82.1% for HCV-RNA and 81.8%, 75.0% and 76.8% for HCVAg, respectively. DISCUSSION: An early monitoring is at least equally effective than standard monitoring in predicting response to hepatitis C therapy. The similarity of HCV-RNA and HCVAg kinetics suggests that HCVAg may be useful in the early phases as a trigger to evaluate HCV-RNA levels at earlier time points for a personalized approach to therapy monitoring.

Evaluation of the effects of human leukocyte IFN-alpha on the immune response to the HBV vaccine in healthy unvaccinated individuals.

HBV vaccine needs 3 injections over 6 months to induce immunity. Thus, the use of adjuvants capable of inducing earlier immune protection would be highly desirable. Most adjuvants may act by inducing cytokines, and among them, type I interferons (IFNs), deserve a special attention in view of the potent immunomostimulatory activity observed in mouse models and on dendritic cell functions. The aim of the present trial was to evaluate the effects of IFN-alpha administered as an adjuvant of HBV vaccine in healthy unvaccinated individuals. No significant enhancing effect on the antibody response was observed, in spite of an early and transient upregulation of costimulatory molecule expression on peripheral blood mononuclear cells, which may be suggestive of an IFN-mediated activation of antigen presenting cells. We conclude that, under the conditions used in this trial, natural IFN-alpha does not act as an adjuvant of the HBV vaccine in healthy unvaccinated individuals.