Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study.

BACKGROUND & AIMS: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. METHODS: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ±â€¯197.6 days. RESULTS: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. CONCLUSIONS: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors. LAY SUMMARY: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Increased incidence of liver cancer after successful DAA treatment of chronic hepatitis C: Fact or fiction?

Therapy of hepatitis C has been revolutionized by Direct Antiviral Agents. These drugs are safe and efficacious in all infected patients, including those with advanced, or decompensated cirrhosis, and are currently largely used in such cases in clinical practice worldwide. It was therefore cause of great concern the publication of two reports suggesting that treatment with DAAs could increase the risk of hepatocellular carcinoma in cirrhotic patients, particularly in those receiving antiviral therapy after having been cured for an HCC. These reports have generated a great and controversial debate and have been followed by a series of other publications not confirming such increased risk. This article summarizes published studies assessing the relation between DAA therapy and HCC in two different clinical setting: HCC recurrence in patients with an history of cured HCC and "de novo" HCC occurrence in patients without previous HCC. Rates of HCC recurrence after DAAs were extremely variable in different studies, reflecting great heterogeneity of this clinical setting. Data on "de novo" HCC incidence were more homogeneous and suggest that treatment with DAAs is not modifying the risk of developing HCC in the first 6-12 months. The possibility that treatment with DAAs may favour tumour growth and spread in individual patients with active HCC foci is suggested by some observations but remains unproven. There is clearly a need for prospective studies designed to better define these issues.

Protease inhibitors-based therapy induces acquired spherocytic-like anaemia and ineffective erythropoiesis in chronic hepatitis C virus patients.

BACKGROUND & AIMS: The addition of protease inhibitors, boceprevir (BOC) or telaprevir (TRV), to peg-interferon and ribavirin (PR) increases the incidence of anaemia in patients with chronic hepatitis C virus (HCV) infection. Although genetic variants in inosine triphosphatase (ITPA) gene have been linked to the haemolytic anaemia induced by PR, the mechanism sustaining severe anaemia during triple therapy is still unknown. This study aims to elucidate the molecular mechanisms underlying anaemia in chronic HCV patients with combined therapy. METHODS: We studied 59 patients with chronic HCV genotype-1: 29 treated with TRV/PR and 30 with BOC/PR. We evaluated biochemical and haematological parameters, red cell index at baseline, 4, 12, 16 and 24 weeks of treatment; in a subgroup, we performed functional studies: osmotic fragility, red cell membrane protein separation, mass spectrometry analysis, quantification of erythroid microparticles release. IL28B and ITPA polymorphisms were also evaluated. RESULTS: We found early acute normochromic normocytic haemolytic anaemia (4-8 weeks) followed by a late macrocytic hypo-regenerative anaemia with inappropriate low reticulocyte count (12-24 weeks). Studies on red cells revealed: (i) presence of spherocytes; (ii) increased osmotic fragility; (iii) abnormalities in red cell membrane protein composition; (iv) reduced membrane-cytoskeleton stability; (v) increased release of erythroid microparticles. ITPA polymorphisms impacted only the early phase of anaemia. CONCLUSIONS: The bimodal pattern of anaemia in chronic HCV patients on triple therapy might be because of acquired spherocytic-like anaemia in the early phase, followed by hyporegenerative anaemia, most likely related to the combined effects of PR and TRV or BOC on erythropoiesis.

Novel biocompatible chitosan decorated single-walled carbon nanotubes (SWNTs) for biomedical applications: theoretical and experimental investigations.

Molecular mechanics and molecular dynamics simulations have been employed to characterise the interactions between SWNTs and biocompatible amphililic derivatives of chitosan, namely N-butyl-O-sulfate chitosan (NBSC), N-octyl-O-sulfate chitosan (NOSC) and N-palmitoyl-O-sulfate chitosan (NPSC). The computational simulations have shown that the affinity of the polymer for the hydrophobic surface of the nanotubes depends on the length of the chitosan hydrophobic pendant chain. Longer chains have a higher flexibility and therefore a better ability to wrap around the nanotubes. To underpin the theoretical calculations, experimental studies revealed that NPSC exhibits highest affinity for SWNTs with up to 66.9 ± 19.7% SWNTs stably suspended in an aqueous environment; this affinity was confirmed by the calculated binding energy of five polymer chains with a SWNT that was found to be -300.93 kcal mol(-1), the highest amongst the three polymers studied. Furthermore, the high value of cell viability after incubation with NPSC indicates that this is a good candidate for the preparation of biocompatible SWNTs dipersions that could be used in biomedical and pharmaceutical applications.

Liver stiffness is not associated with short- and long-term plasma HIV RNA replication in immunocompetent patients with HIV infection and with HIV/HCV coinfection.

BACKGROUND: Human immunodeficiency virus (HIV) may be directly responsible for liver damage but there are contrasting data regarding the influence of detectable plasma viremia. We analyzed the influence of plasma HIV RNA (pHIV) detectability and of other clinical and viro-immunological variables on liver stiffness (LS) measurement in adult immunocompetent HIV-monoinfected patients and in patients coinfected with hepatitis C virus (HCV). METHODS: Logistic regression analysis was performed using the value of LS>7.1 kPa as the dependent variable. A linear regression model was applied using LS measurement after log10 transformation (lkpa) as the dependent variable and we analyzed the predicted values versus the observed lkpa values; pHIV was classified as detectable or undetectable in the 12- and 36-month study periods before LS measurement. RESULTS: We studied 251 patients (178 with HIV monoinfection), most of whom were on antiviral treatment; 36-month study time was available for 154 subjects. The mean CD4+ cell count was 634 cells/mm3 in HIV-monoinfected patients and 606 cells/mm3 in coinfected patients. No difference in LS was found between patients with detectable or undetectable pHIV in either the 12- or the 36-month study period before transient elastography. The mean LS was higher in HIV/HCV coinfected patients (P<0.0001) than in the HIV-monoinfected subjects; lkpa was positively correlated with HCV coinfection (P<0.0001) and aspartate aminotransferase levels (P<0.0001). Detectable pHIV failed to reach significance. Eight HIV-monoinfected patients had a predicted LS measurement lower than the observed one, while eight patients had the opposite result. CONCLUSION: LS was not correlated with ongoing HIV replication during the 12- and 36-month study periods in immunocompetent HIV-monoinfected and HIV/HCV-coinfected patients.

The evolution of the therapeutic strategy in hepatitis C: features of sofosbuvir and indications.

The treatment of chronic hepatitis C virus infection is rapidly evolving with the entry into the therapeutic armamentarium of a series of new and highly effective direct antiviral agents, targeted to the different virus structures involved in hepatitis C virus replication and assembly. Sofosbuvir is considered, without controversies, the most promising single direct antiviral agent in the current scenario. The pharmacological properties of sofosbuvir allow a single oral daily administration and ensure a favourable drug-drug interaction profile, compared to other direct antiviral agents. Clinical development of sofosbuvir has been conducted with the strategy of positioning it as the backbone drug of several combination regimes, including triple therapy with pegylated interferon and ribavirin, but also IFN-free regimen with ribavirin alone as well as with complementary direct antiviral agents directed against other virus targets. Based on available data and International guidelines sofosbuvir is indicated in combination with pegylated interferon and ribavirin in patients infected with hepatitis C virus 1 to 6 that can take interferon, and this regimen is particularly efficacious in those who have not received any previous antiviral treatment. The pangenotypic activity, excellent safety (even in advanced liver disease) make sofosbuvir the ideal backbone for combination therapy in all hepatitis C virus patients subgroups, the limiting factors being safety and tolerability of the combined direct antiviral agent rather than those of sofosbuvir itself.