Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.

The present paper evaluates the genetic variability of HCV in patients with hepatocellular carcinoma (HCC).

Amino acid substitutions (aas) in NS3, NS5A and core regions were analyzed in 17 patients with HCC (Cases) and 13 without HCC (Controls), all naïve to DAAs. For the Cases, a sample of neoplastic liver tissue, non-neoplastic liver tissue and a serum sample were collected; for the Controls, a sample of liver tissue was collected. Sanger sequencing of three regions was performed using homemade protocols.

Phylogenetic trees showed that there was no difference in the virus populations in the three compartments analyzed for the three HCV regions in patients with HCC. Low variability and no difference between the Cases and Controls were observed in the core and NS5A regions; however, in the NS3 region, a higher variability was observed in the Cases. No difference was observed in the core region between Cases and Controls. In NS3, aa substitutions at positions 103 and 122 were more frequently found in Cases than Controls (in both cases 50% vs 9.1%, p<0.05); moreover, aas in positions 32, 44 (p=0.035 for both), 79 (p=0.008) and 121 (p=0.018) were observed in the Cases and absent in the Controls. Finally, considering the NS5A region, aa substitutions at positions 37 and 54 were more frequently identified in the Cases than the Controls, but without statistical significance.

These data may suggest a higher aa variability in patients with HCC than in those without, especially in the NS3 region.

There are few data on the virological characterisation of patients with failure to current-generation direct-acting antivirals (DAAs), namely elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir. This study aimed to characterise virological patterns in patients with failure to current DAA regimens as well as the efficacy of re-treatment. All 61 consecutive hepatitis C virus (HCV) treatment-naïve patients with failure to current DAAs from January 2018 to February 2019 were enrolled. Sanger sequencing of NS3, NS5A and NS5B proteins was performed using homemade protocols. NS5A resistance-associated substitutions (RASs) were more frequent in the 17 patients treated with sofosbuvir/velpatasvir (89.5%) and 33 patients treated with elbasvir/grazoprevir (97%) compared with the 11 patients treated with glecaprevir/pibrentasvir (18.2%) (P = 0.002 and 0.000, respectively). NS3 RASs were more often detected in the 33 patients with failure to elbasvir/grazoprevir (30.3%) than in the 11 patients treated with glecaprevir/pibrentasvir (9.1%). NS3 RASs were also detected in 12% of sofosbuvir/velpatasvir-treated patients. NS5B RASs were infrequently identified. Of the glecaprevir/pibrentasvir-treated patients, 73% did not show RASs in any HCV regions, a prevalence higher than that observed in those treated with elbasvir/grazoprevir (0%; P < 0.05) or sofosbuvir/velpatasvir (12%; P < 0.05). Of the 61 patients, 21 (34.4%) were re-treated with sofosbuvir/velpatasvir and voxilaprevir. All patients achieved sustained virological response at 12 weeks (SVR12). To our knowledge, this is one of the first real-life studies describing patients who failed current-generation DAAs; the prevalence of RASs differed according to the DAA regimen used, and the efficacy of re-treatment was high.

The aim of the present study was to evaluate in HIV-infected patients treated with a direct-acting antiviral agent (DAA)-based regimen the variables associated with sustained virological response (SVR) and the trend in biochemical parameters and clinical events during and after DAA regimen.

We performed a multicentre retrospective cohort study, enrolling all 243 HIV-HCV-coinfected adult patients treated with DAAs between January 2015 and December 2018 in one of the nine participating Infectious Disease Centers in southern Italy, eight in Campania and one in Apulia.

Of the 243 patients enrolled, 233 (95.9%) obtained an SVR at 12 weeks (SVR12). Of the 10 patients with non-SVR, 7 were tested for NS3, NS5A and NS5B resistance-associated substitutions (RASs) by sequencing analysis and 6 showed at least 1 major RAS in 1 HCV region (all in NS5A, 2 in NS5B and 1 in NS3). Comparing the 233 patients achieving SVR and the 10 non-achievers, no variable was independently associated with non-SVR. During and after DAA regimen, no modification in the biochemical parameters and clinical events was observed; however, the serum cholesterol and low-density lipoprotein (LDL) levels showed an increase (from 159 ±41.3 mg/dl at baseline to 174 ±44.5 mg/dl at week 12 after stopping treatment, P<0.001, and from 92 ±34.6 mg/dl to 109.4 ±73.7 mg/dl, P=0.002, respectively).

The treatment with DAAs led to a high SVR12 rate in HIV-HCV-coinfected subjects, irrespective of epidemiological, clinical or virological characteristics. However, the DAA regimen was associated with an increase in total- and LDL-cholesterol, to be taken into account in the management of HIV infection.