Direct-acting Antivirals Research Articles

Trends in candidate HCV NAT+ listing and associated impacts on liver transplantation waitlist outcomes

Direct-acting antiviral agents have facilitated the utilization of hepatitis C virus (HCV)+ organs in HCV nucleic acid amplification test (NAT)- recipients. We evaluated trends in HCV NAT+ listing and impact on transplant probability, waitlist mortality, and likelihood of receiving HCV NAT+ organs using the United Network for Organ Sharing dataset of adult patients waitlisted for liver transplantation from 1/2016-9/2023. Multivariable regression models accounting for competing risks were fit to study waitlist outcomes. 21,776 patients were initially listed for HCV NAT+ organs while 45,378 were not. The percentage of waitlisted patients listed for these organs increased significantly from 2016 to 2023 (8.8% to 60.8%, p<0.001). Initial HCV NAT+ listing was associated with a waitlist mortality benefit in 2021-2023 (SHR 0.73, 95% CI 0.68-0.79, p<0.001) and 17% reduced hazard of overall mortality (HR 0.83, 95% CI 0.78-0.89, p<0.001). 16.0% of the total protective effect associated with HCV NAT+ listing on overall survival was mediated through actual receipt of HCV NAT+ organs (TERERI of -0.160 and a PIE of -0.026; p<0.001). Patients not listed for HCV NAT+ organs in the modern era are relatively disadvantaged in terms of waitlist outcomes. While listings have risen over time, there remains center-level and geographic variation.

S1997 Trends in Prescriber Characteristics of Hepatitis C Direct-Acting Antivirals in the United States

S1997 Trends in Prescriber Characteristics of Hepatitis C Direct-Acting Antivirals in the United States

Diversity, Geographical Distribution and Predictive Factors of Hepatitis C Virus Genotypes and Subtypes in Rwanda

Existing data on the prevalence of hepatitis C virus (HCV) genotypes and subtypes in Rwanda need to be strengthened. The aim of this study was to identify HCV genotypes and subtypes among HCV-infected patients, as well as their geographical distribution in Rwanda, and to identify the social and economic factors that could influence HCV epidemiology which would make it possible to target national preventive and management actions for infected patients. This study included 560 patients with confirmed chronic HCV infection. Patients were recruited from various health facilities in the four provinces of Rwanda as well as in the City of Kigali and had never received treatment with direct-acting antiviral (DAAs). HCV viral loads were measured using Cobas® AmpliPrep/Cobas® TaqMan® HCV Quantitative Test, version 2.0. HCV genotyping was performed using an in-house sequencing protocol targeting the NS5B central region. Genotypic HCV prevalence was correlated with patient geographic location, sociodemographic, behavioral, lifestyle, and clinical factors. HCV genotype 4 was detected in 99.3% of the patients, while genotype 3 was identified in 0.7%. A total of eight (8) HCV subtypes were detected, with 4k being the predominant subtype nationwide (49.5%), followed by subtypes 4r (21.2%), 4q (16.2%), 4v (7.9%), 4b (2.0%), 4l (1.8%), 4c and 3h represent 0.7% each. Our findings reveal subtype distribution variations among provinces. Subtype 4k was prevalent across regions, particularly in Kigali (64.0%) and the Eastern Province (61.6%). Subtype 4q was more common in the northern province (40.7%), 4r in the southern (43.9%) and western provinces (37.1%), and 4v in the eastern province (17.8%). Farmers exhibit a distinct infection profile compared to other occupations, showing a lower prevalence of subtype 4k but a higher prevalence of subtype 4r. Our study revealed that HCV infection is unevenly distributed in Rwanda, dominated by HCV genotype 4, with considerable heterogeneity in the repartition of the different subtypes. We found potential associations between rural/urban lifestyles and HCV subtype profiles. Determined HCV distribution and diversity can serve as basis not only for HCV infection awareness and prevention campaigns, but also success and guidance for personalized treatment.

S1710 Evolving Patterns of Cirrhosis Etiology in the Era of Direct-Acting Antivirals on in a Predominately African American Population

S1710 Evolving Patterns of Cirrhosis Etiology in the Era of Direct-Acting Antivirals on in a Predominately African American Population

Efficacy and safety of direct-acting antiviral regimen for patients with hepatitis C virus genotype 2: a systematic review and meta-analysis.

Direct-acting antivirals (DAAs) show high cure rates in treating chronic hepatitis C virus (HCV). However, the effect of DAAs on patients infected with genotype 2 (GT2) is difficult to determine despite the availability of several DAA regimens. A systematic search of six databases (PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Clinicaltrial.gov) was conducted through April 20, 2022. We considered the sustained virological response 12 weeks after treatment (SVR12) as the efficacy outcome, and adverse events (AEs) as the safety outcome. By calculating the mean SVR12 and the proportion of AEs among patients, we considered the intervention effect for each DAA regimen. The random effect model was then used in all meta-analyses. This systematic review and meta-analysis aimed to summarize the evidence on efficacy and safety of DAAs in patients infected with HCV GT2. The Bayesian Markov Chain Monte Carlo (MCMC) network metanalysis was used to indirectly compare regimen in GT2 patients. Among 31 articles included (2,968 participants), consisting of 1,387 treatment-naive patients and 354 patients with cirrhosis. The overall pooled SVR12 rate was 94.62% (95% CI: 92.43-96.52%) among the participants who received all doses of treatment. Meta-analysis results of AEs revealed that fatigue was the most common AE (14.0%, 95% CI: 6.4-21.6%), followed by headache (13.1%, 95% CI: 9.2-17.1%), whereas death and serious adverse events were uncommon. We compared DAA-based treatments indirectly using meta-analysis and found the combination of Sofosbuvir plus Velpatasvir and Glecaprevir plus Pibrentasvir, each administered over a 12-week period, were identified as the most effective and relatively safe in managing chronic hepatitis C virus genotype 2 (HCV GT2) infection. Both treatments achieved a SVR12 of 100% (95% CI 99-100%).

Successful management of hepatitis B and C coinfection: a case report

We report the case of a patient with chronic hepatitis B and C managed with direct-acting antivirals in an outpatient setting. Chronic hepatitis B was first treated with entecavir before initiating treatment for chronic hepatitis C. The patient achieved viral suppression for hepatitis B and sustained virological response for hepatitis C. As direct-acting antivirals become more available, healthcare practitioners should be familiar with managing patients with chronic coinfection.

Follow-up post-HCV virological response to DAA in advanced chronic liver disease.

Direct-acting antivirals (DAA) achieve high virological response rates with minimal side effects for many patients. Despite their significant impact on the progression and epidemiology of hepatitis C virus (HCV) associated liver disease, the global annual incidence of chronic infections is expected to remain relatively constant, averaging 1.42 million new cases each year until 2030. Furthermore, by 2030, there will be a 14-17% increase in end-stage liver disease outcomes such as liver-related deaths, hepatocellular carcinoma (HCC), and decompensated cirrhosis in adults aged 18 years and over. Although reductions in liver decompensation, HCC occurrence, and mortality have been shown in patients with advanced liver disease who achieved sustained virological response (SVR) with DAA, these benefits may be less significant in those with decompensated liver cirrhosis. This review aims to summarise the impact of the virological response to DAA on liver disease progression and outcomes in patients with advanced chronic liver disease, which appears to be crucial for defining patient-specific follow-up.

Chronic Viral Infections and Hepatic Oncogenesis

Hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV) are major contrib¬utors to chronic liver disease and hepatocellular carcinoma (HCC) worldwide. Discovered in the 1960s and 1980s, these viruses are associated with significant global health burdens. HBV, a member of the He¬padnaviridae family, is a partially double-stranded DNA virus responsible for chronic liver infections that can lead to HCC. Despite the success of HBV vaccination, challenges such as vaccine escape mutants and non-responders persist. HCV, a member of the Flaviviridae family and a positive-sense single-stranded RNA virus, affects millions globally. While direct-acting antivirals (DAAs) can achieve high rates of viral clearance, vaccine development remains hindered by genetic diversity and immune evasion. HDV, the smallest known human virus, relies on HBV for its propagation. It exacerbates liver disease and increases HCC risk, particularly in co-infected individuals. HDV does not integrate into the host genome, suggesting indirect mechanisms of carcinogenesis, potentially through interactions with HBV. Addressing these chal¬lenges requires enhanced vaccination strategies, improved antiviral therapies, and continued research to understand the complex interplay between these viruses and liver cancer development.

Hepatitis C Virus Infection in Europe.

The Hepatitis C Virus (HCV) is a significant public health challenge in European countries. Historically, healthcare-related procedures were the primary source of HCV infection in Europe. However, with the implementation of blood safety programs, injection drug use has become the main transmission route. The infection's distribution and genotype prevalence vary widely across the continent. Even with the availability of highly effective direct-acting antiviral (DAA) therapies, HCV infection is far from being controlled. A significant proportion of patients remain undiagnosed, contributing to the ongoing transmission of the virus. Additionally, several barriers hinder the widespread use of DAAs, including high treatment costs, stigma, poor linkage to care, and considerable geographical variations in prevalence and transmission routes. The World Health Organization has set ambitious targets to reduce liver-related deaths, decrease new viral hepatitis infections, and ensure that 90% of infected individuals are diagnosed by 2030. However, most European countries face challenges, highlighting the need for screening programs, funding mechanisms, and public health strategies to effectively control HCV infection in Europe.

Prevalence, treatment, and outcomes of hepatitis C in an MDR/RR-TB trial cohort.

Tuberculosis (TB) and chronic hepatitis C virus infection (HCV) remain significant global health challenges, especially in low- and middle-income countries. In Eastern Europe, a considerable percentage of multi-drug resistant (MDR) and rifampicin resistant (RR) TB populations show high HCV prevalence. Current WHO guidelines do not routinely advise HCV testing during MDR-TB treatment, despite HCV being a risk factor for drug-induced liver complications in TB patients. This study investigates the co-treatment of MDR/RR-TB and HCV, using data from the TB-PRACTECAL trial. Data were collected as part of the TB-PRACTECAL clinical trial. All participants were screened for HCV at baseline. Participants who were HCV antibody positive and those who were treated for hepatitis C with Direct Acting Antivirals (DAAs) were extracted and compared to overall cohort characteristics. The characteristics of participants concomitantly treated with direct-acting antivirals are described including hepatitis treatment outcomes and adverse events. Among 552 participants from Belarus, Uzbekistan, and South Africa, 24 (4.3%) were HCV antibody positive. Unfavourable TB treatment outcomes were noted in 106/523 (22%) of the HCV-negative, 8/18 (44%) of the HCV-seropositive, and 2/7 (29%) of HCV-confirmed participants treated with DAAs. Of the six participants who received concurrent HCV and MDR/RR TB treatment, three were cured of HCV and three had no post-treatment HCV RNA test, five completed TB treatment and one discontinued treatment due to a severe adverse reaction. Concurrent treatment of MDR-TB and HCV, including in HIV patients, showed promising outcomes with no significant adverse events. The findings support the potential benefits of integrating HCV care into MDR-TB management.

Extrahepatic Cancer Risk in Patients with Hepatitis C Virus Infection Treated with Direct-Acting Antivirals.

Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.

Hepatocellular Carcinoma Incidences and Risk Factors in Hepatitis C Patients: Interferon versus Direct-Acting Agents.

Hepatocellular carcinoma (HCC) remains a significant concern for patients with chronic hepatitis C (HCV), even after achieving a sustained virological response (SVR) with direct-acting antivirals (DAAs) or interferon (IFN)-based therapies. This study compared the risk of HCC in patients with HCV who achieved SVR through the DAA versus IFN regimens. A retrospective analysis was conducted on 4806 HCV patients, without coinfection nor prior HCC history, treated at the Chang Gung Memorial Hospital, Taiwan (DAA: 2825, IFN: 1981). Kaplan-Meier and Cox regression analyses with propensity score matching (PSM) were used to adjust for baseline differences. DAA-treated patients exhibited a higher incidence of HCC than IFN-treated patients before and after PSM (after PSM: annual: 1% vs. 0.5%; 6-year: 6% vs. 3%, p = 0.01). Both DAA and IFN patients had a decreased HCC incidence during follow-up (>3 vs. <3 years from the end of treatment: DAA: 1.43% vs. 1.00% per year; IFN: 0.47% vs. 0.36% per year, both p < 0.05). HCC incidence was higher in the first three years post-SVR in DAA-treated ACLD patients and then decreased (3.26% vs. 1.39% per year, p < 0.01). In contrast, HCC incidence remained constant in the non-ACLD and IFN-treated groups. Multivariate Cox regression identified age ≥ 60, male sex, BMI, AFP ≥ 6 ng/mL, FIB-4, and ACLD status as independent risk factors for HCC, but antiviral regimens were not an independent factor for HCC. DAA treatment significantly affects HCC risk primarily within three years post-treatment, especially in younger HCV patients with ACLD. HCC incidence was reduced after three years in ACLD patients treated by DAA, but continued surveillance was still necessary. However, patients under 60 without advanced liver disease may require less intensive follow-up.

Renal Manifestations of Chronic Hepatitis C: A Review.

Hepatitis C virus (HCV) has emerged as a major global health concern and, if left untreated, can lead to significant liver damage, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Approximately 40% of patients with HCV infection experience extrahepatic manifestations, including renal involvement. HCV-related renal disease is of significant importance among patients with chronic kidney disease (CKD), leading to higher morbidity and mortality. The renal damage due to HCV infection primarily results from cryoglobulinemia and glomerulonephritis, with conditions such as membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) being most prevalent. Despite advancements in treatment, including the use of directly acting antiviral agents (DAAs), renal complications remain a significant burden in untreated patients. HCV-positive patients on hemodialysis (HD) or those who have undergone kidney transplantation face increased mortality rates compared to their HCV-negative counterparts. Managing HCV infection before kidney transplantation is crucial to mitigate the risk of HCV-related renal complications. Conversely, kidney transplantation from HCV-infected donors is well established, as post-transplant treatment for HCV is safe and effective, potentially reducing mortality and morbidity for patients on transplant waiting lists. This review aims to provide a comprehensive analysis of the renal manifestations of HCV, emphasizing the importance of early diagnosis and treatment to improve patient outcomes.

No impact of HIV coinfection on the mortality in patients with hepatitis C virus infection after sustained virological response.

In patients with hepatitis C virus (HCV) chronic infection and advanced liver disease, the impact of human immunodeficiency virus (HIV) coinfection on the clinical outcome after sustained virological response (SVR) has not been sufficiently clarified. The aim of this study was to compare the mortality after SVR of patients bearing HCV chronic infection and advanced liver fibrosis, with and without HIV-coinfection after a prolonged follow-up. This was a prospective multicenter cohort study including individuals with HIV/HCV-coinfection and patients with HCV-monoinfection from Spain, fulfilling: 1) Liver stiffness (LS) ≥9.5 kPa before treatment; 2) SVR with a direct-acting antiviral (DAA) based regimen; 3) LS measurement available at SVR. The main outcome was overall survival. Mortality attributable to liver disease and non-hepatic causes was also assessed. 1,118 patients were included, of whom 676 (60.5%) were living with HIV. The median (Q1-Q3) follow-up was 76 months (57-83). After SVR, 46 (10%) HCV-monoinfected and 74 (11%) HIV/HCV-coinfected patients died. The overall mortality rate (95% CI) was 1.9 (1.6-2.2) per 100 person-years, 1.9 (1.4-2.5) per 100 person-years in patients with HCV-monoinfection and 1.8 (1.6-2.3) per 100 person-years in people living with HIV. In the multivariable analysis, HIV-coinfection was not associated with a shorter survival [0.98 HR (95% confidence interval, CI) = (0.61-1.58), p=0.939]. In patients with HCV chronic infection and advanced fibrosis, HIV-coinfection does not reduce the overall survival after SVR.

Efficacy of late-onset antiviral treatment in immunocompromised hosts with persistent SARS-CoV-2 infection.

Four years after the onset of the global coronavirus disease 2019 (COVID-19) pandemic, the immunocompromised are at greatest risk of developing life-threatening severe disease. However, specific treatment plans for this most vulnerable patient group have not yet been developed. Employing a CD4+ and CD8+ T cell-depleted immunocompromised mouse model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we explored therapeutic options of persistent infections with standard-of-care paxlovid, molnupiravir, and the experimental therapeutic 4'-fluorouridine (4'-FlU). Late-onset treatment initiated 14 days after infection was efficacious, but only 4'-FlU was rapidly sterilizing. No treatment-experienced viral variants with reduced susceptibility to the drugs emerged, albeit virus replication rebounded in animals of the paxlovid group after treatment end. This study supports the use of direct-acting antivirals (DAAs) for late-onset management of persistent SARS-CoV-2 infection in immunocompromised hosts. However, treatment courses likely require to be extended for maximal therapeutic benefit, calling for appropriately powered clinical trials to meet the specific needs of this patient group.

Viral hepatitis in persons living with HIV in the post-COVID era.

Coinfection with hepatitis viruses A to E is frequent in persons living with HIV (PLWH) and causes significant morbidity and mortality. Oro-fecal transmissible hepatitis A and E mostly produce acute self-limited episodes in poor income regions and in non-vaccinated travelers. In high-income countries, outbreaks of hepatitis A occur in men having sex with men (MSM) and chronic hepatitis E is occasionally reported among PLWH with severe immunodeficiency. Chronic hepatitis B, C, and D are frequent in PLWH in highly endemic regions and globally in persons who inject drugs (PWID) and MSM. Progression to liver cirrhosis and development of hepatocellular carcinoma (HCC) is major clinical complications in coinfected patients. Current estimates for PLWH are of 38 million worldwide. Roughly 12% have chronic viral hepatitis (5 million). Coinfection figures are of 5-10% for HBV (2-4 million), 4% for HCV (1.5 million), and 15% of HBsAg+ for HDV (0.5 million). Oral direct-acting antivirals (DAA) cure almost all treated patients with hepatitis C. However, given that there is no protective HCV immunity, PLWH with high-risk behaviors may experience HCV reinfection episodes. Tenofovir is the drug of choice in PLWH with chronic hepatitis B, given its dual effect on HIV and HBV. Lifelong oral tenofovir suppresses HBV replication and ameliorate liver damage. However, the risk of HCC persists even in the absence of cirrhosis. Finally, HDV causes the worst of viral hepatitis with faster progression to cirrhosis and HCC. An entry inhibitor, bulevirtide, has recently been approved and another drug, lonafarnib, is completing Phase 3 trials. Combination antiviral therapy for hepatitis D could improve dramatically the poor prognosis of HIV-HDV coinfected patients. The resumption of good medical practices in PLWH after the big disruption caused by COVID-19 will reduce the burden of viral hepatitis coinfections. Renewed efforts on HAV and HBV vaccination of susceptible individuals and earlier and wider prescription of antiviral therapy for HBV, HCV, and/or HDV coinfection should be prioritized in PLWH. The benefits of innovative strategies for viral hepatitis, including pre-exposure prophylaxis or use of long-acting antivirals, warrant further consideration in PLWH.

High efficacy and safety of direct-acting antivirals for the treatment of chronic hepatitis C: A cohort study conducted in Vietnam.

Direct-acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) treatment through their high cure rates and improved safety profiles. We aimed to evaluate the efficacy and safety, and identify the optimal combination, of DAAs for the treatment of chronic HCV. A retrospective study was conducted of 613 patients with chronic HCV who were treated with DAAs. Demographic, HCV genotype, treatment regimen, virological response, and adverse drug event (ADE) data were collected at the initial visit and 4, 8, 12, and 24 weeks later. The rapid virologic response (RVR) and sustained virologic response (SVR) rates were 90.4% and 97.8% for HCV genotype 1, 89.2% and 98.7% for genotype 6, 92.8% and 99% for genotype 2, and 90.9% and 100% for mixed genotype 2/6 or unspecified genotypes, respectively. There were no significant differences in the RVR and SVR rates for the various DAA regimens. The mean ALT, AST, and GGT activities decreased, and the PLT count increased during the treatments. ADEs occurred in 8% of the patients. The commonest ADEs were itching (3.1%), fatigue (1.8%), and dizziness (1.1%). None of the patients discontinued treatment because of an ADE. Posttreatment disease progression occurred in 7.7% of the patients, including liver fibrosis (3.6%), cirrhosis (1.1%), hepatocellular carcinoma (1.1%), and high alpha-fetoprotein (AFP) (1%). The factors associated with the achievement of RVR were low viral load, the use of sofosbuvir/ledipasvir or sofosbuvir/daclatasvir regimens, and a treatment duration of 12 weeks. No specific factors were found to be associated with the achievement of SVR. Posttreatment disease progression was associated with a high AFP and the use of sofosbuvir/ledipasvir. Thus, DAAs are highly effective and well-tolerated means of treating chronic HCV, and significantly improve patient outcomes. Their high efficacy and favorable safety profiles highlight the importance of early diagnosis and the use of personalized treatment strategies.

Late Hepatocellular Carcinoma Occurrence in Patients Achieving Sustained Virological Response After Direct-Acting Antiviral Therapy: A Matter of Follow-Up or Something Else?

Background: Despite achieving a sustained virological response (SVR) with direct-acting antivirals (DAAs), an unexpected increase in the occurrence rate of hepatocellular carcinoma (HCC) has been observed among HCV-treated patients. This study aims to assess the long-term follow-up of HCV patients treated with DAAs who achieved an SVR to investigate the potential for late-onset HCC. Methods: In this prospective multicenter study, we enrolled consecutive HCV patients treated with DAAs following Italian ministerial guidelines between 2015 and 2018. Exclusion criteria included active HCC on imaging, prior HCC treatment, HBV or HIV co-infection, or liver transplant recipients. Monthly follow-ups occurred during treatment, with subsequent assessments every 3 months for at least 48 months. Abdominal ultrasound (US) was performed within two weeks before starting antiviral therapy, supplemented by contrast-enhanced ultrasonography (CEUS), dynamic computed tomography (CT), or magnetic resonance imaging (MRI) to evaluate incidental liver lesions. Results: Of the 306 patients completing the 48-months follow-up post-treatment (median age 67 years, 55% male), all achieved an SVR. A sofosbuvir-based regimen was administered to 72.5% of patients, while 20% received ribavirin. During follow-up, late-onset HCC developed in 20 patients (cumulative incidence rate of 6.55%). The pattern of HCC occurrence varied (median diameter 24 mm). Multivariate and univariate analyses identified liver stiffness, diabetes, body mass index, and platelet levels before antiviral therapy as associated factors for late HCC occurrence. Conclusions: Our findings suggest that late HCC occurrence may persist despite achieving SVR. Therefore, comprehensive long-term follow-up, including clinical, laboratory, and expert ultrasonography evaluations, is crucial for all HCV patients treated with DAAs.

Socioeconomic Deprivation Weighs Heavily on Liver Fibrosis and Mortality After Hepatitis C Cure (ANRS CO22Hepather).

Although Hepatitis C virus (HCV) infection can be cured with direct-acting antivirals (DAA), some cured patients face a serious risk of advanced liver damage and early mortality. In order to avoid these two negative health outcomes, it is important to identify and assess related risk factors. Little is currently known about socioeconomic and behavioural factors in this context. Using data from the ANRS CO22 Hepather cohort, we tested for associations between socioeconomic and behavioural factors and (i) advanced liver fibrosis (defined as an FIB-4 > 3.25) assessed longitudinally using a mixed-effects logistic regression model (both the whole population and stratified on advanced liver fibrosis status at the time of HCV cure) and (ii) all-cause mortality (Cox proportional hazards model), during post-HCV cure follow-up. Among 5833 participants cured of HCV, living in poverty was associated with postcure advanced liver fibrosis in participants without this diagnosis at the time of HCV cure (population attributable fraction-PAF-of 8.6%) and with mortality in the whole study population (PAF of 10.6%). The detrimental effects of unhealthy alcohol use and heavy tobacco smoking, as well as the beneficial effect of living with a stable partner were also highlighted. We highlighted the major role of poverty and behavioural factors in advanced liver fibrosis and all-cause mortality in patients cured of HCV. Encouraging linkage to social support services and healthy behaviours after successful DAA treatment could limit morbidity and increase survival in this population. Clinical Trial Registration: ClinicalTrials.gov: NCT01953458.

Inhibition of SARS-CoV-2 growth in the lungs of mice by a peptide-conjugated morpholino oligomer targeting viral RNA

Further development of direct-acting antiviral agents against human SARS-CoV-2 infections remains a public health priority. Here, we report that an antisense peptide-conjugated morpholino oligomer (PPMO), named 5’END-2, targeting a highly conserved sequence in the 5’UTR of SARS-CoV-2 genomic RNA, potently suppressed SARS-CoV-2 growth in vitro and in vivo. In Hela-ACE 2 cells, 5’END-2 produced IC50 values of between 40 nM and 1.15 μM in challenges using six genetically disparate strains of SARS-CoV-2, including JN.1. In vivo, using K18-hACE2 mice and the WA-1/2020 virus isolate, two doses of 5’END-2 at 10 mg/kg, administered intranasally on the day before and the day after infection, produced approximately 1.4 log10 virus titer reduction in lung tissue at 3 days post-infection. Under a similar dosing schedule, intratracheal administration of 1.0 to 2.0 mg/kg 5’END-2 produced over 3.5 log10 virus growth suppression in mouse lungs. Electrophoretic mobility shift assays characterized specific binding of 5’END-2 to its complementary target RNA. Further, using reporter constructs containing SARS-CoV-2 5’UTR leader sequence, in an in-cell system, we observed that 5’END-2 could interfere with translation in a sequence-specific manner. The results demonstrate that direct pulmonary delivery of 5’END-2 PPMO is a promising antiviral strategy against SARS-CoV-2 infections and warrants further development.