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ObjectiveThe involvement of HBV DNA integration in promoting hepatocarcinogenesis and the extent to which the intrahepatic HBV reservoir modulates liver disease progression remains poorly understood. We examined the intrahepatic HBV reservoir, the occurrence of HBV DNA integration and its impact on the hepatocyte transcriptome in hepatitis B ‘e’ antigen (HBeAg)-negative chronic hepatitis B (CHB).DesignLiver tissue from 84 HBeAg-negative patients with CHB with low (n=12), moderate (n=25) and high (n=47) serum HBV DNA was analysed. Covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) were evaluated by quantitative PCR, whole exome and transcriptome sequencing was performed by Illumina, and the burden of HBV DNA integrations was evaluated by digital droplet PCR.ResultsPatients with low and moderate serum HBV DNA displayed comparable intrahepatic cccDNA and pgRNA, significantly lower than in patients with high HBV DNA, while hepatitis B core-related antigen correlated strongly with the intrahepatic HBV reservoir, reflecting cccDNA quantity. Whole exome integration was detected in a significant number of patients (55.6%, 14.3% and 25% in high, moderate and low viraemic patients, respectively), at a frequency ranging from 0.5 to 157 integrations/1000 hepatocytes. Hepatitis B surface antigen >5000 IU/mL predicted integration within the exome and these integrations localised in genes involved in hepatocarcinogenesis, regulation of lipid/drug metabolism and antiviral/inflammatory responses. Transcript levels of specific genes, including the proto-oncogene hRAS, were higher in patients with HBV DNA integration, supporting an underlying oncogenic risk in patients with low-level to moderate-level viraemia.ConclusionsHBV DNA integration occurs across all HBeAg-negative patients with CHB, including those with a limited HBV reservoir; localising in genes involved in carcinogenesis and altering the hepatocyte transcriptome.

Post COVID-19 condition (PCC) is defined as ongoing symptoms at ≥1 month after acute COVID-19. We investigated the risk of PCC in an international cohort according to viral variants. We included 7699 hospitalized patients in six centers (January 2020–June 2023); a subset of participants with ≥1 visit over the year after clinical recovery were analyzed. Variants were observed or estimated using Global Data Science Initiative (GISAID) data. Because patients returning for a post COVID-19 visit may have a higher PCC risk, and because the variant could be associated with the probability of returning, we used weighted logistic regressions. We estimated the proportion of the effect of wild-type (WT) virus vs. Omicron on PCC, which was mediated by Intensive Care Unit (ICU) admission, through a mediation analysis. In total, 1317 patients returned for a post COVID visit at a median of 2.6 (IQR 1.84–3.97) months after clinical recovery. WT was present in 69.6% of participants, followed by the Alpha (14.4%), Delta (8.9%), Gamma (3.9%) and Omicron strains (3.3%). Among patients with PCC, the most common manifestations were fatigue (51.7%), brain fog (32.7%) and respiratory symptoms (37.2%). Omicron vs. WT was associated with a reduced risk of PCC and PCC clusters; conversely, we observed a higher risk with the Delta and Alpha variants vs. WT. In total, 42% of the WT effect vs. Omicron on PCC risk appeared to be mediated by ICU admission. A reduced PCC risk was observed after Omicron infection, suggesting a possible reduction in the PCC burden over time. A non-negligible proportion of the variant effect on PCC risk seems mediated by increased disease severity during the acute disease.

In vitro, gp120 of both X4 and R5 HIV-1 strains activates human hepatic stellate cells, but if it can promote liver fibrosis in vivo is unknown. We aimed to evaluate if patients carrying X4 or R5 strains have a different liver fibrosis (LF) progression over time. A total of 1,137 HIV-infected patients in ICONA cohort (21% females, 7% HCV co-infected) with an available determination of HIV-1 co-receptor tropism (CRT), a Fibrosis-4 Index for Liver Fibrosis (FIB-4) <3.25 and at least one-year follow-up were included. CRT was assessed by gp120 sequencing on plasma RNA and geno2pheno algorithm (10% false positive rate) or by Trofile. LF was assessed by means of FIB-4. LF progression was defined as an absolute score increase or a transition to higher fibrosis stratum and/or occurrence of liver-related clinical events. A total of 249 (22%) patients carried X4 strains, which were associated with older age, lower CD4 count, lower nadir CD4, and intravenous drug use. Overall, X4 and R5 patients had similar baseline FIB-4 scores and similar mean FIB-4 slope after a median follow-up of 35 months. There was no difference between X4 and R5 for time to LF progression (p = 0.925). Estimated risk of LF at 24 months (95% CI) after baseline in X4 and R5 was 10.6% (8.3-12.9) and 9.9% (5.9-14.0), respectively. Age, HCV co-infection, diabetes, HIV-duration, HIV-RNA>100.000 cp/mL, antiretroviral therapy exposure were associated with LF progression at multivariate analysis. A slight LF progression over time was observed in HIV-infected patients. No difference was demonstrated for X4 and R5 HIV-1 strains in accelerating LF evolution.

To evaluate incidence rates of and predictors for any antiretroviral (ART) drug discontinuation by HCV infection status in a large Italian cohort of HIV infected patients. All patients enrolled in ICONA who started combination antiretroviral therapy (cART) containing abacavir or tenofovir or emtricitabine or lamivudine plus efavirenz or rilpivirine or atazanavir/r or darunavir/r (DRV/r) or lopinavir/r or dolutegravir or elvitegravir or raltegravir were included. Multivariate Poisson regression models were used to determine factors independently associated with single ART drug discontinuation. Inverse probability weighting method to control for potential informative censoring was applied. Data from 10,637 patients were analyzed and 1,030 (9.7%) were HCV-Ab positive. Overall, there were 15,464 ART discontinuations due to any reason in 82,415.9 person-years of follow-up (PYFU) for an incidence rate (IR) of 18.8 (95% confidence interval [95%CI] 18.5–19.1) per 100 PYFU. No difference in IR of ART discontinuation due to any reason between HCV-infected and -uninfected patients was found. In a multivariable Poisson regression model, HCV-infected participants were at higher risk of darunavir/r discontinuation due to any reason (adjusted incidence rate ratio = 1.5, 95%CI 1.01–2.22, p value = 0.045) independently of demographics, HIV-related, ART and life-style factors. Among DRV/r treated patients, we found that HCV-viremic patients had twice the risk of ART discontinuation due to any reason than HCV-aviremic patients. In conclusion, HIV/HCV coinfected patients had a marginal risk increase of DRV/r discontinuation due to any reason compared with those without coinfection.

The significance of the clinical impact of direct‐acting antiviral (DAA) resistance‐associated substitutions (RASs) in hepatitis C virus (HCV) on treatment failure is unclear. No standardized methods or guidelines for detection of DAA RASs in HCV exist. To facilitate further evaluations of the impact of DAA RASs in HCV, we conducted a systematic review of RAS sequencing protocols, compiled a comprehensive public library of sequencing primers, and provided expert guidance on the most appropriate methods to screen and identify RASs. The development of standardized RAS sequencing protocols is complicated due to a high genetic variability and the need for genotype‐ and subtype‐specific protocols for multiple regions. We have identified several limitations of the available methods and have highlighted areas requiring further research and development. The development, validation, and sharing of standardized methods for all genotypes and subtypes should be a priority. (Hepatology Communications 2017;1:379–390)

The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5′ to 3′ direction and acts in concert with the replication–transcription complex (nsp7/nsp8/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme’s binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range.

Background Post COVID-19 condition (PCC) affects 10–40% of patients and is characterized by persisting symptoms at ≥ 4 weeks after SARS-CoV-2 infection. Symptoms can last 7 or even more months. How long PCC persists and any changes in its clinical phenotypes over time require further investigation. We investigated PCC trajectories and factors associated with PCC persistence. Material and methods We included both hospitalized COVID-19 patients and outpatients from February 2020 to June 2023, who underwent at least one follow-up visit after acute infection at San Paolo Hospital, University of Milan. Follow-up visits were conducted at the post COVID-19 clinic or via telemedicine. During each follow-up examination, patients completed a short version of the World Health Organization (WHO) Case Report Form (CRF) for ongoing symptoms, the Hospital Anxiety and Depression Scale (HADS), and a screening tool for Post-Traumatic Stress Disorder (PTSD). Statistical analyses involved Chi-square, Mann–Whitney, Kruskal–Wallis tests, and logistic regression analysis. Results We enrolled 853 patients (median age 62, IQR 52–73; 41% females). 551/853 (64.6%), 152/418 (36.4%) and 21/69 (30.4%) presented PCC at median follow up of 3 (IQR 2–3), 7 (IQR 6–10) and 26 (IQR 20–33) months, respectively ( p  < 0.001). The main clinical phenotypes were fatigue, respiratory sequelae, brain fog and chronic pain; anosmia/dysgeusia was observed mostly in the first post-acute period. Female sex, acute disease in 2020, a longer hospital stay and no COVID-19 vaccination were associated with persistence or resolution of PCC compared to never having had PCC. Anxiety, depression and PTSD were more common in PCC patients. By fitting a logistic regression analysis, acute infection in 2020 remained independently associated with persistent PCC, adjusting for age, sex, preexisting comorbidities and disease severity (AOR 0.479 for 2021 vs 2020, 95%CI 0.253–0.908, p  = 0.024; AOR 0.771 for 2022 vs 2020, 95%CI 0.259–2.297, p  = 0.641; AOR 0.086 for 2023 vs 2020, 95%CI 0.086–3.830, p  = 0.565). Conclusions There was a reduction in the PCC burden 7 months following the acute phase; still, one third of patients experienced long-lasting symptoms. The main clinical presentations of PCC remain fatigue, respiratory symptoms, brain fog, and chronic pain. Having had SARS-CoV-2 infection during the first pandemic phases appears to be associated with persistent PCC.

Background Post-COVID-19 condition refers to persistent or new onset symptoms occurring three months after acute COVID-19, which are unrelated to alternative diagnoses. Symptoms include fatigue, breathlessness, palpitations, pain, concentration difficulties (\"brain fog\"), sleep disorders, and anxiety/depression. The prevalence of post-COVID-19 condition ranges widely across studies, affecting 10–20% of patients and reaching 50–60% in certain cohorts, while the associated risk factors remain poorly understood. Methods This multicentre cohort study, both retrospective and prospective, aims to assess the incidence and risk factors of post-COVID-19 condition in a cohort of recovered patients. Secondary objectives include evaluating the association between circulating SARS-CoV-2 variants and the risk of post-COVID-19 condition, as well as assessing long-term residual organ damage (lung, heart, central nervous system, peripheral nervous system) in relation to patient characteristics and virology (variant and viral load during the acute phase). Participants will include hospitalised and outpatient COVID-19 patients diagnosed between 01/03/2020 and 01/02/2025 from 8 participating centres. A control group will consist of hospitalised patients with respiratory infections other than COVID-19 during the same period. Patients will be followed up at the post-COVID-19 clinic of each centre at 2–3, 6–9, and 12–15 months after clinical recovery. Routine blood exams will be conducted, and patients will complete questionnaires to assess persisting symptoms, fatigue, dyspnoea, quality of life, disability, anxiety and depression, and post-traumatic stress disorders. Discussion This study aims to understand post-COVID-19 syndrome's incidence and predictors by comparing pandemic waves, utilising retrospective and prospective data. Gender association, especially the potential higher prevalence in females, will be investigated. Symptom tracking via questionnaires and scales will monitor duration and evolution. Questionnaires will also collect data on vaccination, reinfections, and new health issues. Biological samples will enable future studies on post-COVID-19 sequelae mechanisms, including inflammation, immune dysregulation, and viral reservoirs. Trial registration This study has been registered with ClinicalTrials.gov under the identifier NCT05531773.

A growing number of emerging SARS-CoV-2 variants is being identified worldwide, potentially impacting the effectiveness of current vaccines. We report the data obtained in several Italian regions involved in the SARS-CoV-2 variant monitoring from the beginning of the epidemic and spanning the period from October 2020 to March 2021.

Introduction We aimed at evaluating the efficacy and durability of a lopinavir/ritonavir‐based dual regimen (LPV/r‐DR) in virologically controlled HIV‐infected individuals in current clinical practice. Methods Patients who have initiated for the first time a LPV/r‐DR with HIV‐RNA<50 copies/mL were included in this observational study. The main endpoints were: time to virological rebound [VR=time of first of two consecutive viral loads (VL)>50 copies/mL] and time to experience either a single VL>200 copies/mL or discontinuation/intensification (= treatment failure, TF). Individuals’ follow‐up accrued from the date of starting the LPV/r‐DR to event or last available VL. Kaplan‐Meier curves and Cox regression analysis were used. Covariates included in the multivariable analysis were gender, age, route of transmission, hepatitis co‐infection, calendar year of starting the DR, nadir CD4+ count, VL at initiation of first cART, previous failures to protease inhibitors (PIs), time with undetectable VL before starting the DR and the type of DR [nucleoside reverse transcriptase (NRTI), non‐NRTI (NNRTI), raltegravir or maraviroc, with NRTI as reference group]. Results are presented as median (Q1, Q3) or frequency (%) as appropriate. Results 108 individuals followed for 18 (7, 30) months were included; baseline (BL) characteristics are detailed in Table 1. LPV/r was associated with a NRTI in 51, with a NNRTI in 10, with raltegravir in 29, and with maraviroc in 18 individuals. By 36 months from switching to the LPV/r‐DR, the proportion of individuals with VR and TF was 10% (95% CI 3–17%) and 36% (95% CI 22–50%), respectively. We did not find any factor independently associated with the risk of VR. Older age (ARH=0.49 (95% CI 0.30–0.78) per 10 years older; p=0.003) was found to be protective from TF. Mean (SE) CD4+ cells/µL increase from BL to month 36 resulted significant: 195 (40.1) cells/µL (p=0.0028). We did not observe significant changes in AST, ALT, eGFR (MDRD formula), triglycerides and both total and HDL‐cholesterol. Conclusions A LPV/r‐DR can be considered a valuable option in patients with HIV‐RNA<50 copies/mL and ongoing toxicity from the third drug of the regimen, although up to 17% of patients showed viral rebound by 3 years. Older patients are at lower risk of failure with this strategy, but larger sample size is needed to identify who might benefit from this strategy instead of others.