Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.

Previous studies reported that the hepatitis C virus (HCV) could help disseminate the hepatitis D virus (HDV) in vivo through the unrelated hepatitis B virus (HBV), but with essentially inconclusive results. To try to shed light on this still-debated topic, 146 anti-HCV-positive subjects (of whom 91 HCV/HIV co-infected, and 43 with prior HCV eradication) were screened for anti-HDV antibodies (anti-HD), after careful selection for negativity to any serologic or virologic marker of current or past HBV infection. One single HCV/HIV co-infected patient (0.7%) tested highly positive for anti-HD, but with no positive HDV-RNA. Her husband, in turn, was a HCV/HIV co-infected subject with a previous contact with HBV. While conducting a thorough review of the relevant literature, the authors attempted to exhaustively describe the medical history of both the anti-HD-positive patient and her partner, believing it to be the key to dissecting the possible complex mechanisms of HDV transmission from one subject to another, and speculating that in the present case, it may have been HCV itself that behaved as an HDV helper virus. In conclusion, this preliminary research, while needing further validation in large prospective studies, provided some further evidence of a role of HCV in HDV dissemination in humans.

The effects of a concomitant infection of hepatitis B virus (HBV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still debated, with a recognized major risk of HBV reactivation during immune-suppressive treatments. The aim of this study was to determine the prevalence and predictive factors of HBV reactivation in a cohort of hospitalized patients with coronavirus disease 2019 (COVID-19) and a current or past hepatitis B infection. In a monocentric retrospective observational study, we enrolled all consecutive hospital admitted patients with COVID-19 pneumonia and a positive HBV serology (N = 84) in our Infectious Diseases Unit from April 2021 to December 2023. We identified 18 (21%) HBsAg-positive/anti-HBc-positive, 41 (49%) HBsAg-negative/anti-HBc-positive/anti-HBs-positive, and 25 (30%) HBsAg-negative/anti-HBc-positive/anti-HBs-negative subjects. The overall rate of hepatitis flare was 10.7%, without any HBsAg seroreversion, severe HBV reactivation, and/or need for new HBV antiviral therapy introduction. Systemic corticosteroid treatment for COVID-19 and baseline anti-HBsAg status were associated with this risk of HBV reactivation. In conclusion, the overall risk of hepatitis flares in hospitalized COVID-19 was reasonably low, with higher doses of corticosteroids treatment being the major risk factor for HBV reactivation, and anti-HBs-positive serological status as a protective element.

Some studies suggested a high incidence of human herpesvirus (HHV) reactivation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To evaluate the prevalence of HHV reactivations in a population with various severity degrees of coronavirus disease 2019 (COVID-19), we analyzed 102 individuals and compared them with 51 SARS-CoV-2-negative subjects admitted in the same period (January–July 2022) for acute respiratory failure. Positivity was found in 76% of subjects for at least one HHV, and in 46% for ≥2 HHV. These proportions were more prevalent in SARS-CoV-2-positive than in negative patients (83% vs. 61%; 56% vs. 27%, respectively). The most common HHV was HHV-7 both in the whole population (51%) and in SARS-CoV-2-positive and -negative subjects (57% and 39%, respectively); human cytomegalovirus, herpes simplex virus-1, Epstein–Barr virus, and HHV-6 were more represented in SARS-CoV-2-positive individuals. No single or combined HHV reactivation was associated with the 60-day mortality rate. However, cytomegalovirus reactivation was an independent predictor of COVID-19 severity and longer hospitalizations, while the occurrence of ≥3 any HHV reactivations was independently associated with the aforementioned outcomes and ventilatory support need. Taken together, our data suggest that in patients with moderate-to-severe COVID-19, the diagnosis of HHV coinfections can add useful prognostic information.

Following the advent of direct-acting antivirals (DAAs), the treatment of hepatitis C virus (HCV) infection is now rarely challenging. However, data are still limited concerning DAA use in patients affected by glucose-6-phosphate dehydrogenase deficiency (G6PDd). Based on these considerations, the goal of this study was to evaluate the effectiveness and safety of DAAs in this subpopulation. A retrospective multicenter observational study (2015–2023) was conducted on all 2754 consecutive HCV-positive patients treated with first- and second-generation all-oral DAAs, and with a G6PDd diagnosis confirmed by quantitative testing (n = 38). At the treating clinician’s discretion, an enhanced clinical and laboratory follow-up was performed, generally on a monthly basis both during treatment and up to six months after the end of it. Concerning hematochemical parameters, no significant differences were found between any considered time point. In all cases, no treatment-related adverse events were reported, and virologic response rates were as expected without G6PDd. In conclusion, in a large experience which, to the best of our knowledge, is unprecedented in the literature, the treatment of HCV hepatitis with nearly all available DAAs in patients with G6PDd as a comorbidity—a common occurrence in countries such as Italy—proved to be highly effective and safe.

Herpes simplex virus 1 (HSV-1) is a rare cause of acute hepatitis, especially in patients with chronic immunosuppression. We performed whole-genome HSV-1 sequencing with a metagenomics approach on peripheral blood samples from an Italian case of fatal acute liver failure with high circulating HSV-1 (1,129,900,000 copies/mL), followed by phylogenetic analysis. After multiple sequence alignment, a final dataset of 182 whole-genome sequences was selected. The sequenced HSV-1 strain belonged to a phylogenetic clade isolated in Florida in 2002 (OQ724868.1). A characterization of single nucleotide polymorphisms and indels was performed to determine their effects on the viral genome: only one variant, classified as an indel, was detected with a high impact effect (c.905_906insGTTTT) in the UL49A gene, which is known to encode a membrane protein regulating virion morphogenesis, replication and assembly. In addition, this study also detected variants in other genes involved in crucial steps of the HSV-1 life cycle, like alpha-regulation (US7), capsid transport (UL36) and viral polymerase function (UL30). In conclusion, the results of this variant analysis confirmed that in HSV-1 hepatitis, some viral regions may be hotspots for adaptive mutations with a substantial impact on viral replication or immune evasion.