Effect of Antiviral Treatment on Hepatitis B Virus Integration and Hepatocyte Clonal Expansion.

BACKGROUND: This study investigated the effect of nucleos(t)ide analogue (NUC) treatment on hepatitis B virus (HBV) DNA integration and hepatocyte clonal expansion, both of which are implicated in hepatocellular carcinoma (HCC) in chronic hepatitis B. METHODS: Twenty-eight patients receiving NUCs (11 lamivudine, 7 telbivudine, 10 entecavir) were included. All had liver biopsies at baseline and year 1, and 7 had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse polymerase chain reaction. RESULTS: All patients had detectable HBV integration at baseline, with a median integration frequency of 1.01 × 109 per liver and hepatocyte clone size of 2.41 × 105. Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After 1 year of treatment, HBV integration was still detectable in all patients, with a median of 5.74 × 108 integration per liver (0.22 log reduction; P = .008) and hepatocyte clone size of 1.22 × 105 (0.40 log reduction; P = .002). HBV integration remained detectable at year 10 of treatment, with a median integration frequency of 4.84 × 107 integration per liver (0.93 log reduction from baseline) and hepatocyte clone size of 2.55 × 104 (1.02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (P = .066 and.018, respectively). CONCLUSIONS: NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings supported the notion for a long-term NUC treatment to prevent HCC.

Successful Eradication of Hepatitis-C Virus with Sofosbuvir based Antiviral treatment results in improvement in quality of life in cirrhotic patients.

Objectives: To document improvement in quality of life in patients with Hepatitis-C related cirrhosis after successful eradication of the virus. Methods: In this observational cohort study conducted at Fatima Memorial Hospital from September 2015 to July 2017, patients with HCV were assessed for improvement in quality of life by using FACIT-F questionnaire. We compared the Quality of life (QOL) score before the start of treatment with DAAs and after achieving SVR12 in various aspects of quality of life including physical, emotional, functional and social well-being. Results: A total of 71 patients, 52 (73%) were CTP class A, 18 (25%) in B and one (1.4%) in C. The mean score of QOL before AVT was 23.93±7.04 and after achieving SVR it was 36.83±6.36 (P-value <0.001). In the subcategories, score of functional wellbeing, physical well-being and social wellbeing were significantly improved except emotional wellbeing scores. All scores improved across the spectrum of patients in the CTP class A and B. There was only one patient in the CTP-C class. Conclusion: Chronic HCV infection complicated by cirrhosis causes a significant decline in quality of life. There was a marked improvement in the functional, social and physical health of the patients after eradication of Hepatitis-C with anti-viral therapy except emotional health of the individuals.

Prevalence and outcome of post-transfusion hepatitis C acquired at different ages and detected in look-back screening.

OBJECTIVES: The prevalence of hepatitis C virus (HCV) infection in Sweden is estimated to 0.5%. Before 1992, blood transfusion posed a risk of HCV transmission. The primary aim of this study was to estimate anti-HCV prevalence in Stockholm County among individuals receiving blood transfusions 1965-1991. The secondary aim was to study the effect of age at transfusion on the development of liver disease and treatment outcome. MATERIALS AND METHODS: This is a retrospective analysis of individuals found to be anti-HCV tested positive in Stockholm County during a national screening campaign in Sweden 2008-2010. All anti-HCV-positive individuals were also HCV RNA tested. Data on age at transfusion, age at diagnosis, HCV genotype, viral load, fibrosis score, liver histology and antiviral treatment were recorded. RESULTS: Out of 7473, 134 (1.8%) tested individuals were anti-HCV positive and 102 were HCV RNA positive resulting in a prevalence of chronic hepatitis C (CHC) of 1.4%. The rate of advanced liver damage was 18% (10/56). Patients younger than 19 years of age at transfusion were significantly more often started on antiviral treatment compared to adult patients, 65% vs 29% p < .001. No significant correlation was found between treatment outcome and gender or age at transfusion. CONCLUSIONS: In this study, we found an anti-HCV prevalence of 1.8% which is considerably higher than the estimated prevalence in the Swedish general population (0.5%), and patients infected during childhood were more likely to receive antiviral treatment. Additional data on the HCV epidemic in Sweden are needed regarding prevalence and age distribution.

Veritable antiviral capacity of natural killer cells in chronic HBV infection: an argument for an earlier anti-virus treatment.

BACKGROUND: There is limited information on innate immunity, especially natural killer (NK) cell function, in different chronic hepatitis B (CHB) stages. Therefore, we examined whether the clinical staging strategy accurately reflects veritable NK cell immunity. METHODS: A total of 237 eligible CHB patients and 22 healthy controls were enrolled in our study. Demographic and clinical data were collected, and the CHB phases (immune active-IA, immune tolerant phase-IT, inactive CHB-IC, and grey zone-GZ) were classified according to the latest American Association for the Study of Liver Disease guidelines. Peripheral blood mononuclear cells from patients and healthy controls were tested for NK cell frequency, phenotype and function using flow cytometry. RESULTS: A significant decrease in activating receptor NKp44 and NKp46 expression and significant increase of exhaustion molecule Tim-3 expression were observed in NK cells from CHB patients. Reduced cytokine secretion and preserved or elevated cytotoxic function were also observed. Patients in the IT group exhibited comparable cytokine secretion and cytolytic capacity as age-matched IA patients. NK cell anti-viral functions were preserved in GZ patients. Some of the NK cell function in patients who were excluded from treatment by the current treatment guidelines was less compromised than patients who qualified for treatment. CONCLUSION: Our findings provide evidence of veritable NK cell immunity during different natural history phases in treatment-naïve patients with chronic HBV Infection. Chronic HBV infection hindered NK cell function in CHB patients. However, the presumed IT and GZ statuses of CHB patients based on the clinical parameters may not accurately reflect the inner immune status of these patients and should be reconsidered. Some patients excluded from treatment by the current treatment guidelines may be able to be selected as candidates for treatment.

Hepatitis B virus infection and active replication promote the formation of vascular invasion in hepatocellular carcinoma.

BACKGROUND: Vascular invasion, including microvascular invasion (MVI) and portal vein tumor thrombus (PVTT), is associated with the postoperative recurrence of hepatocellular carcinoma (HCC). We aimed to investigate the potential impact of hepatitis B virus (HBV) activity on the development of vascular invasion. METHODS: Patients with HBV and tumor-related factors of HCC who had undergone hepatectomy were retrospectively enrolled and analyzed to identify the risk factors for developing vascular invasion. RESULTS: A total of 486 patients were included in this study. The overall proportion of patients with vascular invasion, including MVI and PVTT, was 60.3% (293/486). The incidence of MVI was 58.2% (283/486) whereas PVTT was 22.2% (108/486). Univariate analysis revealed that positive Hepatitis B virus surface Antigen (HBsAg) was significantly associated with the presence of vascular invasion. In a multivariate regression analysis carried out in patients with HBV-related HCC, positive Hepatitis B virus e Antigen (HBeAg)(OR = 1.83, P = 0.019) and a detectable seral HBV DNA load (OR = 1.68, P = 0.027) were independent risk factors of vascular invasion. The patients in the severe MVI group had a significantly higher rate of positive seral HBsAg (P = 0.005), positive seral HBeAg (P = 0.016), a detectable seral HBV DNA load (> 50 IU/ml) (P < 0.001) and a lower rate of anti-viral treatment (P = 0.002) compared with those in the mild MVI group and MVI-negative group. Whereas, HCC with PVTT invading the main trunk showed a significantly higher rate of positive HBsAg (P = 0.007), positive HBeAg (P = 0.04), cirrhosis (P = 0.005) and a lower rate of receiving antiviral treatment (P = 0.009) compared with patients with no PVTT or PVTT invading the ipsilateral portal vein. Patients with vascular invasion also had a significantly higher level of seral HBV DNA load than patients without vascular invasion (P = 0.008). CONCLUSIONS: In HCC patients, HBV infection and active HBV replication were associated with the development of vascular invasion.

Effects of bamlanivimab alone or in combination with etesevimab on subsequent hospitalization and mortality in outpatients with COVID-19: a systematic review and meta-analysis.

Background: Coronavirus disease 2019 (COVID-19) has caused an enormous loss of life worldwide. The spike protein of the severe acute respiratory syndrome coronavirus 2 is the cause of its virulence. Bamlanivimab, a recombinant monoclonal antibody, has been used alone or in combination with etesevimab to provide passive immunity and improve clinical outcomes. A systematic review and meta-analysis was conducted to investigate the therapeutic effects of bamlanivimab with or without etesevimab (BAM/ETE) treatment. Methods: Our study was registered in PROSPERO (registry number CRD42021270206). We searched the following electronic databases, without language restrictions, until January 2023: PubMed, Embase, medRxiv, and the Cochrane database. A systematic review and meta-analysis was conducted based on the search results. Results: Eighteen publications with a total of 28,577 patients were identified. Non-hospitalized patients given bamlanivimab with or without etesevimab had a significantly lower risk of subsequent hospitalization (18 trials, odds ratio (OR): 0.37, 95% confidence interval (CI): [0.29-0.49], I2: 69%; p < 0.01) and mortality (15 trials, OR: 0.27, 95% CI [0.17-0.43], I2: 0%; p = 0.85). Bamlanivimab monotherapy also reduced the subsequent risk of hospitalization (16 trials, OR: 0.43, 95% CI [0.34-0.54], I2: 57%; p = 0.01) and mortality (14 trials, OR: 0.28, 95% CI [0.17-0.46], I2: 0%; p = 0.9). Adverse events from these medications were uncommon and tolerable. Conclusions: In this meta-analysis, we found the use of bamlanivimab with or without etesevimab contributed to a significantly-reduced risk of subsequent hospitalization and mortality in non-hospitalized COVID-19 patients. However, resistance to monoclonal antibodies was observed in COVID-19 variants, resulting in the halting of the clinical use of BAM/ETE. Clinicians' experiences with BAM/ETE indicate the importance of genomic surveillance. BAM/ETE may be repurposed as a potential component of a cocktail regimen in treating future COVID variants.

Time to negative PCR conversion amongst high-risk patients with mild-to-moderate Omicron BA.1 and BA.2 COVID-19 treated with sotrovimab or nirmatrelvir.

OBJECTIVES: Our aim was to compare the clinical and virological outcomes in Omicron BA.1- and BA.2-infected patients who received sotrovimab with those in patients who received nirmatrelvir for the prevention of severe COVID-19. METHODS: In this multi-centric, prospective ANRS 0003S CoCoPrev cohort study, patients at a high risk of progression of mild-to-moderate BA.1 or BA.2 COVID-19 who received sotrovimab or nirmatrelvir were included. The proportion of patients with progression to severe COVID-19, time between the start of treatment to negative PCR conversion, SARS-CoV-2 viral decay, and characterization of resistance variants were determined. A multi-variable Cox proportional hazard model was used to determine the time to negative PCR conversion and a mixed-effect model for the dynamics of viral decay. RESULTS: Amongst 255 included patients, 199 (80%) received ≥3 vaccine doses, 195 (76%) received sotrovimab, and 60 (24%) received nirmatrelvir. On day 28, new COVID-19-related hospitalization occurred in 4 of 193 (2%; 95% CI, 1-5%) sotrovimab-treated patients and 0 of 55 nirmatrelvir-treated patients (p 0.24). One out of the 55 nirmatrelvir-treated patients died (2%; 95% CI, 0-10%). The median time to negative PCR conversion was 11.5 days (95% CI, 10.5-13) in the sotrovimab-treated patients vs. 4 days (95% CI, 4-9) in the nirmatrelvir-treated patients (p < 0.001). Viral decay was faster in the patients who received nirmatrelvir (p < 0.001). In the multi-variable analysis, nirmatrelvir and nasopharyngeal PCR cycle threshold values were independently associated with faster conversion to negative PCR (hazard ratio, 2.35; 95% CI, 1.56-3.56; p < 0.0001 and hazard ratio, 1.05; 95% CI, 1.01-1.08; p 0.01, respectively). CONCLUSIONS: Early administration of nirmatrelvir in high-risk patients compared with that of sotrovimab was associated with faster viral clearance. This may participate to decrease transmission and prevent viral resistance.

Human Monkeypox Virus: Current State of Knowledge and Implications for the Imminent Days.

Monkeypox, a zoonotic orthopoxvirus, unintentionally infects humans and causes a condition resembling smallpox with noticeably reduced fatality. Despite the name monkeypox, the virus did not originate in monkeys. The virus has been linked to several rodents and small mammals, but the real source of monkeypox is still unknown. It was first noticed in macaque monkeys; hence it is named monkeypox. Although monkeypox transmission from person to person is extremely uncommon, it is frequently linked to respiratory droplets or close contact with mucocutaneous lesions of an infected person. This virus is indigenous to western and central Africa, with outbreaks in the Western Hemisphere linked to the exotic pet trade and international travel, making it clinically significant. The immunization against vaccinia virus provided coincidental immunity to monkeypox, but the eradication of smallpox and the consequent lack of vaccination campaigns allowed monkeypox to become clinically relevant. Even though the smallpox vaccine offers protection against the monkeypox virus, the incidence is increasing because of newly non-immunized generations. There is currently no designated treatment for infected individuals; however, supportive treatments are used to relieve symptoms. In extremely severe cases, medications such as tecovirimat may be effective and are used in Europe. Because there are no precise recommendations for symptom alleviation, many treatments are on trial. Smallpox immunizations like JYNNEOS and ACAM2000 are also used as prophylactic measures in the case of the monkeypox virus. This article describes the assessment and treatment of monkeypox infections in humans and emphasizes the need for a multidisciplinary team to treat patients with this condition and prevent disease outbreaks.

SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial.

Background: Additional outpatient therapies which are readily accessible will be essential to reduce COVID-19 illness progression in high risk individuals. Especially as the virus continues to mutate with greater transmissibility despite increased global vaccination. Methods: A randomized, double-blind, multicentre, parallel group, placebo-controlled phase III clinical trial evaluated the ability of nitric oxide (NO) to rapidly eradicate nasal SARS-CoV-2 RNA. Adults (18-70 years) with mild symptomatic COVID-19 were randomized, confirmed by laboratory SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) nasal swab. Randomisation was 1:1, NONS (N = 153) vs placebo (N = 153). NO generated by a nasal spray (NONS) was self-administered six times daily as two sprays per nostril (0⋅45 mL of solution/dose) for seven days. Patients at high risk of illness progression, defined as unvaccinated, ≥ 45 years of age or having comorbidities, were the primary analysis population. Findings: Overall, mean SARS-CoV-2 RNA concentrations (6·96 log10 copies/mL in the NONS group and 7·16 log10 copies/mL in the placebo group) were comparable at baseline. Primary endpoint mean treatment difference SARS-CoV-2 RNA change from baseline to the end of treatment (EOT) was -0·52 copies/mL (SE 0·202, 95% CI -0·92 to -0·12; p = 0·010) with NONS compared to placebo. Secondary endpoint assessments demonstrated a greater proportion of patients receiving NONS (82·8%) cleared SARS-CoV-2 (RT-PCR negative) by EOT compared to placebo (66·7%, p = 0·046), with no virus RNA detected a median of four days earlier compared to placebo (three vs seven days; p = 0·044). Interpretation: Use of NONS in patients recently infected with SARS-CoV-2 accelerates nasal virus clearance. Funding: Funding provided by Glenmark Pharmaceuticals Limited. Study medication provided by SaNOtize.

Distinct Impacts of Pre-Operative Antiviral Treatment on Post-Operative Outcomes of HBV-related Hepatocellular Carcinoma: A Landmark Analysis.

Background: The effect of anti-viral treatment (AVT) initiated before surgery (pre-operative AVT) on HBV-related hepatocellular carcinoma (HCC) has been controversial. This study aimed to elucidate the prognostic significance of pre-operative AVT for HCC patients who received hepatectomy. Materials and Methods: A large-scale retrospective study was conducted based on a cohort consisting of 1937 HBV-related HCC patients who underwent R0 liver resection between January 2011 and December 2012. Propensity score matching (PSM) method was adopted to balance covariates and landmark survival analyses were performed to visualize effects in different phases after surgery. Results: After PSM, a total of matched 744 patients (372 in each group) were recruited. The patients in the pre-operative AVT group had lower HBV-DNA loading levels and better recurrence-free survival (RFS) than those in the non-AVT group. The 1, 3, 5-year RFS rates of two groups were 67.3%, 49.0%, and 43.1% vs. 66.7%, 41.1% and 18.5%, respectively (P<0.001). Landmark survival analyses demonstrated that pre-operative AVT could improve RFS, and the effect was beginning to show after the first 12 months. There was no significant difference of overall survival (OS) between the two groups (P=0.543), and the landmark survival analyses indicated that pre-operative AVT could improve OS and this effect was beginning to show after 36 months. Additionally, multivariate Cox regression analyses revealed that larger tumor (>5cm), esophageal and gastric varices, lymph node metastasis were independent risk factors of RFS, and larger tumor (>5cm) and ascites were independent risk factors of OS. Conclusions: Pre-operative AVT could significantly improve the RFS, and could not improve short-term OS (< 36 months) but could better long-term survival of the patients with HBV-HCC after surgery.

Outcome of hepatitis C-related liver transplantation in direct-acting antiviral era.

BACKGROUND: Hepatitis C virus (HCV) has become an easily treatable disease after the introduction of sofosbuvir-based direct-acting antiviral (DAA) regimens. This is a large single center experience of changing severity and outcome profile of HCV-related liver disease after availability of DAAs. METHODS: A retrospective analysis of prospectively collected liver transplantation (LT) database of adults (age > 18 years at the time of LT) was performed from June 2010 to July 2018. A total of 410 patients (including 26 co-infection with hepatitis B) underwent LT for hepatitis C-related decompensated cirrhosis and/or hepatocellular carcinoma (HCC) out of 1754 adult transplantation in the defined period. RESULTS: The study group comprised of 296 males and 114 females aged 52.1 ± 7.9 years. HCV-related decompensated cirrhosis and/or HCC as indication of LT was present in 289/1016 (28.4%) during 2010-2014, which was reduced to 121/738 (16.3%) during 2015-2018 (p = 0.000). The LT recipients for HCV-related cirrhosis had significantly lower Child's and model for end-stage liver disease (MELD) score during 2015-2018 as compared to that during 2010-2014; Child's score was 7.9 ± 2.2 vs. 8.6 ± 2.1, p = 0.003; MELD score was 13.9 ± 5.3 vs. 17.1 ± 5.8, p = 0.000, respectively. There was a trend towards better survival in HCV patients during 2015-2018 as compared to that during 2010-2014. Significantly more patients had HCV RNA negative status before LT during 2015-2018 (38.8% vs. 13%, p = 0.000); moreover, the proportion of LT for decompensated cirrhosis (without HCC) decreased significantly in the latter period, 64.0% vs. 42.1% (p = 0.000). CONCLUSION: In the DAA era, HCV as an indication for LT has decreased and patients have less severe disease at transplantation. There is a trend towards better patient survival.

The rabbit papillomavirus model: a valuable tool to study viral-host interactions.

Cottontail rabbit papillomavirus (CRPV) was the first DNA virus shown to be tumorigenic. The virus has since been renamed and is officially known as Sylvilagus floridanus papillomavirus 1 (SfPV1). Since its inception as a surrogate preclinical model for high-risk human papillomavirus (HPV) infections, the SfPV1/rabbit model has been widely used to study viral-host interactions and has played a pivotal role in the successful development of three prophylactic virus-like particle vaccines. In this review, we will focus on the use of the model to gain a better understanding of viral pathogenesis, gene function and host immune responses to viral infections. We will discuss the application of the model in HPV-associated vaccine testing, in therapeutic vaccine development (using our novel HLA-A2.1 transgenic rabbits) and in the development and validation of novel anti-viral and anti-tumour compounds. Our goal is to demonstrate the role the SfPV1/rabbit model has played, and continues to play, in helping to unravel the intricacies of papillomavirus infections and to develop tools to thwart the disease. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.

A MULTICENTER, LONGITUDINAL, INTERVENTIONAL, DOUBLE BLIND RANDOMIZED CLINICAL TRIAL IN HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS RESIDING IN REMOTE AREAS: LESSONS LEARNED FROM THE LATE CYTOMEGALOVIRUS PREVENTION TRIAL.

PURPOSE: The logistics of conducting double-blinded phase III clinical trials with participants residing in remote locations are complex. Here we describe the implementation of an interventional trial for the prevention of late cytomegalovirus (CMV) disease in hematopoietic cell transplantation (HCT) subjects in a long-term follow-up environment. METHODS: A total of 184 subjects at risk for late CMV disease surviving 80 days following allogeneic HCT were randomized to receive six months of valganciclovir or placebo. Subjects were followed through day 270 post-transplant at their local physician's office within the United States. Anti-viral treatment interventions were based on CMV DNAemia as measured by polymerase chain reaction (PCR) (>1000 copies/mL) and granulocyte colony stimulating factor (G-CSF) was prescribed for neutropenia (absolute neutrophil count (ANC <1.0 × 109 cells/L). Blood samples for viral testing and safety monitoring were shipped to a central laboratory by overnight carrier. Real-time communication was established between the coordinating center and study sites, primary care physicians, and study participants to facilitate starting, stopping and dose adjustments of antiviral drugs and G-CSF. The time required to make these interventions was analyzed. RESULTS: Of the 4169 scheduled blood specimens, 3832 (92%) were received and analyzed; the majority (97%) arriving at the central site within 2 days. Among subjects with positive CMV DNAemia (N=46), over 50% received open label antiviral medication within one day. The median time to start G-CSF for neutropenia was <1 day after posting of laboratory results (range 0-6; N=38). Study drug dose adjustments for abnormal renal function were implemented 203 times; within one day for 48% of cases and within 2 days for 80% of cases. CONCLUSION: Complex randomized, double-blind, multicenter interventional trials with treatment decisions made at a central coordinating site can be conducted safely and effectively according to Good Clinical Practice (GCP) guidelines over a large geographic area.

Acute Retinal Necrosis with Multiple Viral Infections: A Case Report.

A 52-year-old male presented with acute retinal necrosis in his left eye. Slit lamp examination revealed stellate keratic precipitates and cells in the anterior chamber and vitreous. Funduscopy of his left eye revealed multiple yellow deposits. Pathological examination of the vitreous showed both small, reactive lymphocytes and a few macrophages. IL-6 and IFN-γ were elevated in the vitreous. Microdissected macrophages from the vitreous revealed DNAs from multiple viruses. The patient responded to oral valacyclovir. We conclude that multiple viral infections can be involved in the pathogenesis of acute retinal necrosis and that adequate anti-viral therapy has a beneficial effect on disease progression. However, retinal detachment can be a consequence for a poor visual outcome.