Sustained Virological Response Research Articles

Directly Acting Anti-Viral Drugs and Its Metabolic Side Effects in Patients with Chronic HCV

Abstract Background Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide. Treatment of hepatitis C virus has traditionally been difficult because of low rates of treatment success and high rates of treatment discontinuation due to side effects. Aim of the Work The aim of this work is to study side effects of directly acting anti HCV drug (DAA) and its progression in metabolism of lipid profile, blood sugar level, and renal function. Patients and Methods This case study had been carried out on 200 subjects presented to Department of Internal Medicine at Kobbri ELkobba hospital inpatient and outpatient clinics between March 2016 and September 2016. Results sustained virological response (12 weeks) after end of the treatment in more than 90% of patients, Liver function parameters including albumin, bilirubin, and prothrombin time and liver enzymes Ast, Alt improved in the majority of patients during and after the end of therapy,but there is significant increase in urea level, serum creatinin and HbA1C. There is significant decrease in LDL and mild increase in TG level. Conclusion Once-daily oral daclatasvir plus sofosbuvir with or without Ribavirin was associated with high rates of sustained virologic response among patients infected with HCV, including chronic cirrhotic patients and relapsers, successful treatment associated with Improvement of liver function parameters in the majority of patients, Increase in urea level, serum creatinin and HbA1C. There is significant decrease in LDL and mild increase in TG level.

Safety and Efficacy of Directly Acting Antivirals (Sofosbuvir & Daclatasvir) in Treatment of Chronic HCV

Abstract Background The introduction of direct-acting antiviral agents, has revolutionized the treatment for chronic HCV with higher cure rates, shorter duration of treatment and more tolerability have been achieved. Aim of the Work The aim of our study is to estimate the efficacy and safety of DAAs in treatment of chronic HCV in patients co-infected with HIV. Patients and Methods This study of previously untreated HCV infection in patients with HCV and HIV co-infection conducted at Abbasia Fever Hospital, from July 2019 to February 2020. Patients included are chronic HCV infection and were receiving antiretroviral therapy for the HIV with a CD4 T-lymphocyte count of 200 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed during treatment by combination of daclatasvir 90mg and sofosbuvir 400mg+/- ribavirin 800mg daily for 12 weeks. Results In this study, the rate of a sustained virologic response (SVR) at post-treatment week 12 (SVR 12) were high (29/30, 96.67%). The most common adverse events were fatigue (73.33%), headache (46.67%), and there was a high safety profile on using DAAs. No patient discontinued treatment because of adverse events. No serious adverse events or mortality were reported. In this study, AST & ALT were significantly decreased at end of treatment and 12 weeks after treatment, CD4 count was significantly increased. Otherwise there are no significant changes in both hematological and biochemical laboratory results. Conclusion Combination of daclatasvir and sofosbuvir have showed 96.67% sustained virologic response at 12 weeks after treatment (SVR 12) among HIV/HCV co-infected patients, with a very good safety profile. Moreover, the treated patients showed a significant increase in CD4 count. Accordingly, HIV/HCV co-infected patients should be treated with sofosbuvir and daclatesvir containing regimens.

632 Hepatitis C Positive Organ Donation and Direct Acting Antivirals in Pancreas Transplantation: A Systematic Review

Abstract Background Pancreas transplantation (PT) provides diabetic cure for patients with complicated diabetes mellitus. However, there is a paucity of suitable donor organs to fulfil requirements resulting in deaths on the waiting list. Organs from otherwise suitable hepatitis C virus positive (HCV+) donors alongside direct-acting antiviral agents (DAAs) have been used in kidney and liver transplants in small trials. We aimed to review this strategy in PT. Method A literature search was conducted on OVID MedLINE, PubMed and EMBASE to evaluate evidence on the use of HCV+ organ donors for PT in HCV- recipients alongside DAA therapy. Results Database analysis produced 5 articles (4 single centre retrospective, 1 case report). This included a total of 65 patients, 15 of which received PT. Two studies examined multiple organ transplants whilst 3 evaluated PT alone. Three studies employed prophylactic perioperative therapy, while 2 examined treatment post-transplantation. 100% of patients achieved a sustained virological response (SVR) at 12 weeks across all 5 studies. There were no episodes of acute rejection or complications directly associated with DAA therapy or HCV infection. HCV transmission occurred in only 1 of 15 patients, which was successfully treated. Pancreatic graft function and outcome after 7-12 months was good. Conclusions The use of DAA therapy is safe and effective for HCV+ donors to HCV- transplant in early reported studies. This approach could facilitate the successful utilisation of HCV+ organs for transplantation thereby minimising impact on supply and demand disparities. Pancreas transplantation specific studies are required to further analyse outcomes.

New incidence or recurrence hepatocellular carcinoma (HCC) in genotype 4 hepatitis C virus treated with sofosbuvir/daclatasvir with or without ribavirin

Background: Several studies have resulted in controversial data about the recurrence or new incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C who were treated with direct-acting antivirals (DAAs). Aim: This observational study aimed to assess the occurrence rate of HCC in patients who developed a sustained virological response (SVR). METHOD: A six-month prospective study was done at the National Hepatology and Tropical Medicine Research Institute [NHTMRI] in Cairo, Egypt on 150 chronic hepatitis C (CHC) patients treated with sofosbuvir and daclatasvir with or without ribavirin. Patients were assigned into two groups according to their laboratory values to either receive sofosbuvir/daclatasvir and ribavirin (S/D/R) or receive only sofosbuvir/daclatasvir (S/D). The main outcome measure was the occurrence of HCC. Results: SVR-12 was 100%. 8.5% of patients developed HCC in the S/D/R group, while 0% in the S/D group. Conclusion: New incidence or recurrence of HCC may occur in CHC genotype 4 cirrhotic patients receiving sofosbuvir/daclatasvir and ribavirin (difficult to treat) although achieving SVR. The cause of HCC development in this study is cirrhosis, not the administered DAAs.

Cytokines assets in PLWH in two-drug dolutergravir based or three-drug antiretroviral regimen

To minimize the toxicity and impact of combined antiretroviral therapy (cART) on the lifestyle of people living with Human Immunodeficiency Virus (PLWH), scientific community evaluated the efficacy, safety and sustained virologic response of two drugs antiretroviral regimens, in particular dolutegravir (DTG). The effects of deintensification therapy on inflammatory settings are currently unknown in PLWH. Thus, our study explored the inflammatory state in virologically suppressed HIV individuals between patients in treatment with a DTG-containing dual therapy (2DR) versus triple regimen therapies (3DR). We enrolled a total of 116 subjects in 2DRs or 3DRs regimens, and the plasma levels of pro- and anti-inflammatory cytokines (in particular IL-1β, IL-10, IL-18, IL-33, IL-36 and IFN-γ) have been evaluated. CD4 + cell’s median value was 729.0 cell/µL in the 3DR group and 771.5 cell/µL in 2DR group; the viral load was negative in all patients. Significant differences were found in levels of IL-18 (648.8 cell/µL in 3DR group vs. 475.0 cell/µL in 2DR group, p = 0.034) and IL-36 (281.7 cell/µL in 3DR group vs. 247.0 cell/µL in 2DR group, p = 0.050), and a correlation between IL-18 and IL-36 was found in 3DR group (rho = 0.266, p = 0.015). This single-center retrospective pharmacological study confirms the absence of significant differences in IL-1β, IL-10, IL-33, and IFN-γ levels between patients on two-drug antiretroviral regimens compared to patients on 3DR antiretroviral regimens. Patients in 2DR show greater control over IL-18 and IL-36 serum levels, cytokines related to an increased cardiovascular risk and development of age-related chronic diseases. Based on our results, we suggest that DTG-based 2DR antiretroviral regimens could be associated with better control of the chronic inflammation that characterizes the population living with HIV in effective ART.

Taurine-conjugated bile acids and their link to hepatic S1PR2 play a significant role in hepatitis C-related liver disease.

Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease. Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids. Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2). Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.

Hepatocyte transformation is induced by laminin γ2 monomer.

Serum laminin-γ2 monomer (Lm-γ2m) is a potent predictive biomarker for hepatocellular carcinoma (HCC) onset in patients with hepatitis C infection who achieve a sustained virologic response with liver cirrhosis (LC) and for the onset of extrahepatic metastases in early-stage HCC. Although Lm-γ2m involvement in late-stage cancer progression has been well investigated, its precise roles in HCC onset remain to be systematically investigated. Therefore, we analyzed an HCC model, human hepatocytes and cholangiocytes, and surgically resected liver tissues from patients with HCC to understand the roles of Lm-γ2m in HCC onset. Ck-19- and EpCAM-positive hepatic progenitor cells (HPCs) in the liver of pdgf-c transgenic HCC mouse model with ductular reaction showed ectopic expression of Lm-γ2m. Forced expression of Lm-γ2m in hepatocytes adjacent to HPCs resulted in enhanced tumorigenicity, cell proliferation, and migration in immortalized hepatocytes, but not in cholangiocytes invitro. Further, pharmacological inhibition of epidermal growth factor receptor (EGFR) and c-Jun activator JNK suppressed Lm-γ2m-induced hepatocyte transformation, suggesting the involvement of EGFR/c-Jun signaling in the transformation, leading to HCC development. Finally, immunohistochemical staining of HCC tissues revealed a high level of Lm-γ2 expression in the HPCs of the liver with ductular reaction in normal liver adjacent to HCC tissues. Overall, HPC-derived Lm-γ2m in normal liver with ductular reaction acts as a paracrine growth factor on surrounding hepatocytes and promotes their cellular transformation through the EGFR/c-Jun signaling pathway. Furthermore, this is the first report on Lm-γ2m expression detected in the normal liver with ductular reaction, a human precancerous lesion of HCC.

Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir in Treating HCV Genotypes 1 and 4 in Patients with Advanced Chronic Kidney Disease

ABSTRACT This study assessed the efficacy and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) combined with dasabuvir (DSV) for treating hepatitis C genotype 4 (GT4) and genotype 1 (GT1) in patients with stage 4 or 5 chronic kidney disease (CKD). Among 88 patients, including treatment-naïve and Peginterferon/Ribavirin (RBV)-experienced, treated with OBV/PTV/r±RBV (dosed between 200 mg per week to daily) and additional DSV for GT1, 94.3% achieved sustained virologic response at 12 weeks (SVR12), demonstrating high efficacy. RBV was used at the discretion of the treating physician. The treatment was well-tolerated, with two non-treatment-related deaths reported. The findings suggest that a 12-week regimen of OBV/PTV/r±DSV is highly effective and safe for GT1 and GT4 patients with advanced CKD, regardless of baseline characteristics.

Liver Fibrosis Stages Affect Organic Cation Transporter 1/2 Activities in Hepatitis C Virus-Infected Patients.

This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0-24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61-0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66-0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97-1.24), p > 0.05) and 2 (ratio 1.03 (0.94-1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.

Changes in the Lipid Asset of HIV/HCV Patients after a Successful Course of Direct-Acting Antivirals.

Background: Highly Active Antiretroviral Therapy (HAART) for HIV infection and Direct-Acting Antivirals (DAA) for HCV infection currently represent the main treatment options for HIV/HCV co-infected patients. However, HAART has been associated with increased lipids. This study aimed to evaluate lipid profile changes after the DAA cycle in HIV/HCV co-infected patients undergoing HAART/DAA therapy. Methods: A prospective, longitudinal, observational study among HIV/HCV co-infected patients undergoing HAART/DAA treatment was conducted at the Infectious Diseases Unit of the University Hospital of Salerno. Inclusion criteria were age > 18 years, written informed consent, completion of the DAA cycle, and virologic suppression on HAART. Changes in the lipid profile were analyzed from baseline during and after DAA therapy at 12, 24, and 48 weeks after the sustained virologic response (SVR). A t-test was used to compare continuous variables. An analysis of variance was performed for each antiretroviral drug and genotype. Results: Fifty-four HIV/HCV patients (men/women n. 34/20 [68/32%], median age 56 years), all naïve to HCV therapy, were enrolled. HCV infection was caused by genotype 1 in 55% of cases and by genotype 3 in 29%. An increase in total cholesterol was recorded after the DAA treatment (from 165.03 ± 46.5 to 184.7 ± 44.9 mg/dL, p < 0.0001), after 12, 24, and 48 weeks, and in LDL-C at 24 weeks follow-up (at baseline 86.7 ± 34 mg/dL to 103.4 ± 41.38 mg/dL, p < 0.0001). Conclusions: Changes in the lipid profile after combined DAA/HAART treatment represent an important prognostic index. Further evaluation of cardiovascular-associated risk is necessary to implement appropriate prevention strategies.

Evaluation of direct-acting antiviral agents impact on liver biomarkers in patients with type-2 diabetes and hepatitis C virus infection

Objectives. Chronic hepatitis C (CHC) infection still affects a significant portion of the global population. Despite efforts to combat it, the global prevalence remains high. The use of direct antiviral therapy (DAA) has significantly improved cure rates. The study aimed to assess liver parameters and body mass index (BMI dynamics in type 2 diabetes mellitus (T2DM) patients compared to non-diabetics, after obtaining sustained viral response (SVR) under DAA. Material and methods. We conducted a retrospective study on 100 CHC infected patients treated with DAAs between September 2016 and August 2019 at “Prof. Dr. Matei Bals” National Institute for Infectious Diseases, Bucharest (INBI MB). The study group was divided into 2 subgroups according to the presence of diabetes. All patients were evaluated at initiation of treatment and one year after. FibroMax parameters and BMI were monitored. Outcomes. The study found improvements in liver fibrosis, necroinflammatory activity, and steatosis in both groups after treatment. Notably, T2DM patients experienced a more significant decrease in necroinflammatory activity. Moreover, weight gain post-SVR was observed, potentially impacting liver health. Conclusions. Post-SVR, CHC patients showed improvements in liver health markers, emphasizing the importance of early treatment to prevent severe liver complications. Future research should focus on long-term outcomes post-treatment.

Evaluation of direct-acting antiviral agents impact on liver biomarkers in patients with type-2 diabetes and hepatitis C virus infection

Objectives. Chronic hepatitis C (CHC) infection still affects a significant portion of the global population. Despite efforts to combat it, the global prevalence remains high. The use of direct antiviral therapy (DAA) has significantly improved cure rates. The study aimed to assess liver parameters and body mass index (BMI dynamics in type 2 diabetes mellitus (T2DM) patients compared to non-diabetics, after obtaining sustained viral response (SVR) under DAA. Material and methods. We conducted a retrospective study on 100 CHC infected patients treated with DAAs between September 2016 and August 2019 at “Prof. Dr. Matei Bals” National Institute for Infectious Diseases, Bucharest (INBI MB). The study group was divided into 2 subgroups according to the presence of diabetes. All patients were evaluated at initiation of treatment and one year after. FibroMax parameters and BMI were monitored. Outcomes. The study found improvements in liver fibrosis, necroinflammatory activity, and steatosis in both groups after treatment. Notably, T2DM patients experienced a more significant decrease in necroinflammatory activity. Moreover, weight gain post-SVR was observed, potentially impacting liver health. Conclusions. Post-SVR, CHC patients showed improvements in liver health markers, emphasizing the importance of early treatment to prevent severe liver complications. Future research should focus on long-term outcomes post-treatment.

Measures of insulin resistance and beta cell function before and after treatment of HCV infection

The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on β-cell function particularly in the pre-diabetic population. Here, we evaluated indices of β-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate β-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and β-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of β-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.

Supporting direct acting antiviral medication adherence and treatment completion in a sample of predominantly rural veterans with hepatitis C and substance use disorders

BackgroundClinic-based interventions are needed to promote successful direct acting antiviral (DAA) treatment for chronic hepatitis C virus (HCV) infection in patients with substance use disorders (SUDs) among rural Veterans.MethodsWe implemented a clinic-based intervention which used motivational interviewing (MI) techniques to promote medication adherence and treatment completion with 12 weeks of DAA treatment among rural Veterans with chronic HCV and SUDs. Patients received an MI session with a licensed psychologist at baseline and at each two-week follow-up visit during DAA treatment. Patients received $25 per study visit completed. Patients were to attend a laboratory visit 12 weeks after treatment completion to assess for sustained virologic response (SVR).ResultsOf the 20 participants who enrolled, 75% (n = 15) completed the planned 12-week course of treatment. Average adherence by pill count was 92% (SD = 3%). Overall SVR was 95% (19/20).ConclusionsWe demonstrated that a clinic-based intervention which incorporated frequent follow up visits and MI techniques was feasible and acceptable to a sample of predominantly rural Veterans with chronic HCV and SUDs.Clinical trial registrationRegistered at ClinicalTrials.gov (NCT 02823457) on July 1, 2016. https://clinicaltrials.gov.

Real-life experience of chronic hepatitis C treatment in Switzerland: a retrospective analysis.

Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C. We analysed the use of different generations of DAAs over time in Switzerland and investigated factors predictive of treatment failure. This retrospective study was conducted within the framework of the Swiss Association for the Study of the Liver and the Swiss Hepatitis C Cohort Study; it included all patients with chronic hepatitis C treated with DAAs between January 2015 and December 2019 at eight Swiss referral centres. A total of 3088 patients were included; 57.3% were male, and the median age was 54 years. Liver cirrhosis was present in 23.9% of the cohort, 87.8% of whom were compensated. The overall sustained virological response (SVR) rate (defined as undetectable HCV RNA at week 12 after the first course of DAA-based treatment) was 96.2%, with an increase over time. The rate of treatment failure dropped from 8.3% in 2015 to 2.5% in 2019. Multivariable analysis revealed that female sex, the use of the latest generation of pangenotypic DAA regimens, Caucasian origin, and genotype (gt) 1 were associated with SVR, whereas the presence of active hepatocellular carcinoma (HCC), gt 3, and increasing liver stiffness were associated with treatment failure. Notably, the presence of active HCC during treatment increased the risk of DAA failure by a factor of almost thirteen. SVR rates increased over time, and the highest success rates were identified after the introduction of the latest generation of pangenotypic DAA regimens. Active HCC, gt 3 and increasing liver stiffness were associated with DAA failure.

Real-world Effectiveness and Tolerability of Interferon-free Direct-acting Antiviral for 15,849 Patients with Chronic Hepatitis C: A Multinational Cohort Study.

As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

Hepatitis C virus diversity and treatment outcomes in Benin: a prospective cohort study

10 million people are chronically infected with the hepatitis C virus (HCV) in sub-Saharan Africa. The assessment of viral genotypes and treatment response in this region is necessary to achieve the WHO target of worldwide elimination of viral hepatitis by 2030. We aimed to investigate the prevalence of HCV genotypes and outcomes of treatment with direct-acting antiviral agents in Benin, a country with a national HCV seroprevalence of 4%. This prospective cohort study was conducted at two referral hospitals in Benin. Individuals were eligible for inclusion if they were seropositive for HCV and willing to consent to participation in the study; exclusion criteria were an inability to give consent or incarceration. Viraemia was confirmed by PCR. The primary outcomes were to identify HCV genotypes and measure sustained virological response rates 12 weeks after completion of treatment (SVR12) with a 12-week course of sofosbuvir-velpatasvir or sofosbuvir-ledipasvir, with or without ribavirin. We conducted phylogenetic and resistance analyses after the next-generation sequencing of samples with a cycle threshold (Ct) value of 30 or fewer cycles. The in-vitro efficacy of NS5A inhibitors was tested using a subgenomic replicon assay. Between June 2, 2019, and Dec 30, 2020, 148 individuals were screened for eligibility, of whom 100 were recruited prospectively to the study. Plasma samples from 79 (79%) of the 100 participants were positive for HCV by PCR. At the time of the study, 52 (66%) of 79 patients had completed treatment, with an SVR12 rate of 94% (49 of 52). 57 (72%) of 79 samples had a Ct value of 30 or fewer cycles and were suitable for whole-genome sequencing, from which we characterised 29 (51%) samples as genotype 1 and 28 (49%) as genotype 2. Three new genotype 1 subtypes (1q, 1r, and 1s) and one new genotype 2 subtype (2xa) were identified. The most commonly detected subtype was 2d (12 [21%] of 57 samples), followed by 1s (eight [14%]), 1r (five [9%]), 1b (four [7%]), 1q (three [5%]), 2xa (three [5%]), and 2b (two [3%]). 20 samples (11 genotype 2 and nine genotype 1) were unassigned new singleton lineages. 53 (93%) of 57 sequenced samples had at least two resistance-associated substitutions within the NS5A gene. Subtype 2d was associated with a lower-than-expected SVR12 rate (eight [80%] of ten patients). For one patient, with subtype 2b, treatment was not successful. This study revealed a high SVR rate in Benin among individuals treated for HCV with sofosbuvir-velpatasvir, including those with highly diverse viral genotypes. Further studies of treatment effectiveness in genotypes 2d and 2b are indicated. Medical Research Council, Wellcome, Global Challenges Research Fund, Academy of Medical Sciences, and PHARMBIOTRAC.

Implementing a new HCV model of care for people who use drugs

Background and AimsAn estimated 58 million individuals have chronic hepatitis C virus (HCV) infection worldwide and people who use drugs (PWUD) are disproportionately affected. Persistent stigma and discrimination make it challenging for PWUD to access healthcare, potentially hindering HCV elimination progress in this population. To mitigate healthcare access barriers in PWUD, an HCV care model that simplified screening and linkage to care pathways was developed and rolled out in the Balearic Islands, Spain. MethodsThe prospective multicentre community model of care was implemented in 21 centres serving PWUD. This model involved: 1) participant recruitment and HCV antibody screening onsite via a point-of-care anti-HCV test, phlebotomy, or laboratory records; 2) HCV RNA, hepatitis B virus and anti-HIV testing via a dried blood spot or phlebotomy; 3) linkage to specialist care and treatment prescription via telemedicine, when required; and 4) onsite monitoring of: (a) sustained virologic response (SVR) 4 and ≥12 weeks after treatment completion; and (b) potential new HCV infection or reinfection about one year after phase 1 or SVR≥12 monitoring. Care model acceptability was assessed. ResultsBetween April 2021 and April 2023, 1,423 participants were recruited, of whom 464 (33%) were anti-HCV+ and 170 (12%) had detectable HCV RNA. Of the latter, 147 (86%) initiated therapy, of whom 124 (84%) completed it. SVR≥12 monitoring was performed in 95 (77%) of these, of whom 88 (93%) had undetectable HCV RNA. Upon re-screening, four HCV reinfections were detected. Over 90% accepted study participation and screening and treatment decentralisation. ConclusionsThis adapted care model, which decentralised screening, diagnosis, and treatment, effectively increased healthcare access among PWUD, improving progress towards HCV elimination in this population in Spain. Impact and implicationsPeople who use drugs (PWUD) are among the most affected by chronic hepatitis C virus (HCV) infection globally. A simplified model of care was implemented in 21 centres serving this population across the Balearic Islands, Spain, to offer HCV care to 1,423 PWUD in 2021-2023. This decentralised screening, diagnosis, and treatment model resulted in an HCV cure rate of 93% of those who both completed therapy and were monitored post treatment completion. The Hepatitis C Free Balears model can guide the HCV elimination efforts of regional health authorities and other stakeholders in the rest of Spain and other parts of the world.

Epigenetic scars in regulatory T cells are retained after successful treatment of chronic hepatitis C with direct-acting antivirals

Chronic HCV infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Herein, we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (Treg) cells from patients with chronic HCV infection before, during, and after DAA treatment. Patients with chronic genotype 1b HCV infection who achieved sustained virologic response by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of Treg cells were investigated through flow cytometry analysis. Moreover, the transcriptomic and epigenetic landscapes of Treg cells were analyzed using RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin with sequencing) analysis. The Treg cell population - especially the activated Treg cell subpopulation - was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA sequencing analysis revealed that viral clearance did not abrogate the inflammatory features of these Treg cells, such as Treg activation and TNF signaling. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of Treg cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that Treg cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance. Overall, our results showed that during chronic HCV infection, the expanded Treg cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the Treg cell population after recovery from chronic HCV infection. During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of direct-acting antivirals has led to high cure rates. Nevertheless, we have demonstrated that inflammatory features of Treg cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection.

Endothelial dysfunction and persistent inflammation in severe post-COVID-19 patients: implications for gas exchange

BackgroundUnderstanding the enduring respiratory consequences of severe COVID-19 is crucial for comprehensive patient care. This study aims to evaluate the impact of post-COVID conditions on respiratory sequelae of severe acute respiratory distress syndrome (ARDS).MethodsWe examined 88 survivors of COVID-19-associated severe ARDS six months post-intensive care unit (ICU) discharge. Assessments included clinical and functional evaluation as well as plasma biomarkers of endothelial dysfunction, inflammation, and viral response. Additionally, an in vitro model using human umbilical vein endothelial cells (HUVECs) explored the direct impact of post-COVID plasma on endothelial function.ResultsPost-COVID patients with impaired gas exchange demonstrated persistent endothelial inflammation marked by elevated ICAM-1, IL-8, CCL-2, and ET-1 plasma levels. Concurrently, systemic inflammation, evidenced by NLRP3 overexpression and elevated levels of IL-6, sCD40-L, and C-reactive protein, was associated with endothelial dysfunction biomarkers and increased in post-COVID patients with impaired gas exchange. T-cell activation, reflected in CD69 expression, and persistently elevated levels of interferon-β (IFN-β) further contributed to sustained inflammation. The in vitro model confirmed that patient plasma, with altered levels of sCD40-L and IFN-β proteins, has the capacity to alter endothelial function.ConclusionsSix months post-ICU discharge, survivors of COVID-19-associated ARDS exhibited sustained elevation in endothelial dysfunction biomarkers, correlating with the severity of impaired gas exchange. NLRP3 inflammasome activity and persistent T-cell activation indicate on going inflammation contributing to persistent endothelial dysfunction, potentially intensified by sustained viral immune response.