Direct-acting Antivirals Research Articles

HCV drug resistance mutations in HIV-infected patients

The aim of our work was to assess prevalence in the HCV drug resistance mutations in the NS3, NS5A, NS5B genes in HIV-infected patients. The material of the study was 157 blood plasma samples collected from HIV patients living in the Leningrad Region, with virological inefficiency of antiretroviral therapy. Samples were examined for the presence of anti-HCV antibodies and HCV RNA using commercial test systems in accordance with the manufacturer’s recommendations. In the case of detecting HCV RNA, amplification reaction was carried out using a set of primers co-flanking the NS3, NS5A, and NS5B genes. After sequencing the nucleotide sequences of the above genes, the virus subtype was determined. To assess HCV drug resistance mutations to direct-acting antiviral agents (DAAs), the Geno2pheno HCV resistance software (https:// hcv.geno2pheno.org) was used. The age of the patients varied from 18 to 65 and averaged 34.3±7.27 years. The number of males vs females prevailed comprising 71% and 28%, respectively. Antibodies against HCV were detected in 94.2% cases, whereas HCV RNA — in 98 (61.7%) HIV-infected persons. The distribution of HCV genotypes in this group was as follows: 1a — 7% (n = 7), 1b — 53% (n = 52), 2 — 2% (n = 2), 3a — 38% (n = 37). The results of determining the viral load varied from 5.3 × 103 to 2.3 × 108 IU/ml. The nucleotide sequence of all three regions NS3, NS5A, NS5B was determined in 73 samples. Analysis of drug resistance mutations in the NS3 region was performed for 82 HCV isolates of genotypes 1b (n = 46), 3a (n = 31), 1a (n = 4), 2 (n = 1). In total, the proportion of strains containing mutations in the NS3 region was 9.8%. The presence of significant amino acid substitutions in the NS5A region was tested for 83 HCV isolates of genotypes 1b (n = 47), 3a (n = 30), 1a (n = 6). The percentage of strains containing mutations in the NS5A region was 19.3%. Resistance mutations in the NS5B region were analysed for 87 HCV isolates of genotypes 1b (n = 48), 3a (n = 32), 2 (n = 2), 1a (n = 5). The proportion of strains containing mutations in the NS5B region was 11.5%. In the study group, mutations associated with hepatitis C virus resistance to DAAs in all regions were found in 16.6% (95% CI: 11.11–23.32%) cases (n = 26). In the NS3, NS5A and NS5B, there have been identified 6, 15 and 10 significant amino acid substitutions, respectively.

Barriers to access to hepatitis C treatment with direct-acting antivirals in people who inject drugs in the community setting

Barriers to access to hepatitis C treatment with direct-acting antivirals in people who inject drugs in the community setting. Qualitative study with prison population. Hepatitis C (HCV) treatments with direct-acting antiviral therapy (DAA) are an easy and effective option among people who inject drugs (PWID). However, difficulties in accessing and monitoring treatment in community services and dropouts on release from prison are detected among PWID. For this reason, the aim of the study is to know the access barriers in the diagnosis and treatment of HCV in community health services. An exploratory qualitative study was carried out through semi-structured interviews with 33 PWID recruited in a pre-trial detention prison in Barcelona. The information obtained was analysed using grounded theory. Among PWID sub-population entering prison, personal barriers are related to intense drug use, lack of interest and ignorance of HCV infection and treatment, as well as being in a situation of social exclusion. In relation to health providers, they reported receiving little information, the existence of language barriers in migrants, not receiving screening and treatment proposals, and having poor interactions with some professionals. Systemic barriers were expressed related to the health system circuit being complicated, perceiving little comprehensive care and lack of community support. It is recommended to intensify prevention and treatment campaigns, promoting drug substitution programmes than current ones, improve health education, make the diagnosis and treatment process more flexible, and promote social policies and holistic care for greater coverage of the needs of PWID.

Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV).

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan-Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23-0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16-0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02-2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

Unmet needs in the post-direct-acting antivirals era: The risk and molecular mechanisms of hepatocellular carcinoma after hepatitis C virus eradication.

Hepatitis C virus (HCV) infection is one of the major etiologies of hepatocellular carcinoma (HCC) with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in chronic hepatitis C (CHC) patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the direct-acting antiviral (DAA) era and might be due to preexisting inflammatory and fibrotic liver backgrounds, immune dysregulation between host and virus interactions, as well as host epigenetic scars, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication in CHC patients.

TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism

ObjectiveAchieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical...

Estimating the Allocation of the Economic Value Generated by Utilization of All-Oral Direct-Acting Antivirals for Hepatitis C in the United States, 2015 to 2019

ObjectivesBetween 2013 to 2019, several all-oral direct-acting antivirals (DAAs) were launched with the potential to cure patients with hepatitis C virus (HCV). They generated economic value in terms of the health gains for patients and cost-savings for the US healthcare system. We estimated the share of this value allocated to 4 manufacturers vs society. MethodsFor 2015 to 2019, we estimated the incremental impact of DAAs on HCV health outcomes and costs. We used the Center for Disease Analysis Foundation Polaris Observatory database to estimate utilization. Per-patient projections of lifetime quality-adjusted life-years (QALYs) gained and medical costs avoided were based on a standard 9-state HCV disease-progression model for DAA treatment vs alternatives. Annual QALY gains were valued at $114 000 per QALY. Outcomes and costs were discounted at 3%. Estimated revenues were based on reported sales. ResultsAn estimated 1 080 000 patients received DAAs: 81.5% would not have received the pre-DAA standard of care. On average, these patients were projected to gain 4.4 QALYs and save $104 400 in lifetime healthcare costs, generating $531.8 billion in value. Those who would have received treatment gained 1.7 QALYs and saved $41 500 in lifetime costs, generating $47.4 billion in economic value. As treatment costs fell nearly 75%, the 4 manufacturers reported $37.4 billion from DAA sales—an allocation of 6.5% of the total value. ConclusionsThe significant majority (∼90%) of the economic value of curing HCV with DAAs were health benefits to patients and net cost-savings to society. DAA manufacturers received a minority share (6.5%) of the aggregate economic value generated.

Spontaneous clearance of serum HCV-RNA after splenectomy in a patient with HCV-related liver cirrhosis and portal hypertension: a case report

BackgroundSpontaneous clearance of chronic hepatitis C virus (HCV) is rare in adults. A T-lymphocyte response is thought to be involved in HCV-RNA clearance. Splenectomy reportedly has a beneficial effect on T cell immune function in patients with cirrhosis. To the best of our knowledge, the present report is the first to describe spontaneous clearance of serum HCV-RNA within 1 year after splenectomy in a patient with cirrhosis.Case presentationA 55-year-old man with HCV cirrhosis was transferred to our institution with advanced pancytopenia, splenomegaly, and gastric varices. He had a 1-year history of ascites, edema, and general fatigue. The patient had a Child–Pugh score of 8 and serological type 1 HCV; the HCV-RNA level was 4.7 log IU/mL. Contrast-enhanced computed tomography showed gastric varices and marked splenomegaly (estimated spleen volume of 2175 mL). Esophagogastroduodenoscopy revealed enlarged gastric varices with no red color sign, and the varices were larger than those 1 year prior. He was diagnosed with decompensated HCV-related liver cirrhosis and portal hypertension. We considered direct-acting antiviral (DAA) therapy; however, DAA therapy was not approved in Japan for patients with decompensated cirrhosis at that time. Hand-assisted laparoscopic splenectomy was performed to improve the worsening portal hypertension. Further, we planned the initiation of DAA therapy after surgery, when such therapy would become available. DAA therapy was approved 1 year after splenectomy. At that time, we measured the HCV-RNA level before the initiation of DAA therapy; unexpectedly, however, serum HCV-RNA was not detectable, and the virus continued to disappear during the following 4 years. His liver function (total bilirubin, albumin, and prothrombin time) and pancytopenia improved during the 5 years postoperatively. The serum aspartate and alanine aminotransferase levels normalized between 1 and 5 years postoperatively. Esophagogastroduodenoscopy showed no change in the gastric varices during the 5 years after surgery. The patient remained asymptomatic and continued to do well.ConclusionsWe have presented a case of spontaneous clearance of HCV-RNA after splenectomy in a patient with cirrhosis and portal hypertension. Splenectomy may be associated with disappearance of HCV-RNA based on previous reports. More cases should be accumulated and evaluated.

Chronic Hepatitis C Virus Infection, Extrahepatic Disease and the Impact of New Direct-Acting Antivirals.

Chronic hepatitis C virus infection is an important cause of liver cirrhosis, hepatocellular carcinoma and death. Furthermore, it is estimated that about 40-70% of patients develop non-hepatic alterations in the course of chronic infection. Such manifestations can be immune-related conditions, lymphoproliferative disorders and metabolic alterations with serious adverse events in the short and long term. The introduction of new Direct-Acting Antivirals has shown promising results, with current evidence indicating an improvement and remission of these conditions after a sustained virological response.

Biomarkers in Detection of Hepatitis C Virus Infection.

The hepatitis C virus (HCV) infection affects 58 million people worldwide. In the United States, the incidence rate of acute hepatitis C has doubled since 2014; during 2021, this increased to 5% from 2020. Acute hepatitis C is defined by any symptom of acute viral hepatitis plus either jaundice or elevated serum alanine aminotransferase (ALT) activity with the detection of HCV RNA, the anti-HCV antibody, or hepatitis C virus antigen(s). However, most patients with acute infection are asymptomatic. In addition, ALT activity and HCV RNA levels can fluctuate, and a delayed detection of the anti-HCV antibody can occur among some immunocompromised persons with HCV infection. The detection of specific biomarkers can be of great value in the early detection of HCV infection at an asymptomatic stage. The high rate of HCV replication (which is approximately 1010 to 1012 virions per day) and the lack of proofreading by the viral RNA polymerase leads to enormous genetic diversity, creating a major challenge for the host immune response. This broad genetic diversity contributes to the likelihood of developing chronic infection, thus leading to the development of cirrhosis and liver cancer. Direct-acting antiviral (DAA) therapies for HCV infection are highly effective with a cure rate of up to 99%. At the same time, many patients with HCV infection are unaware of their infection status because of the mostly asymptomatic nature of hepatitis C, so they remain undiagnosed until the liver damage has advanced. Molecular mechanisms induced by HCV have been intensely investigated to find biomarkers for diagnosing the acute and chronic phases of the infection. However, there are no clinically verified biomarkers for patients with hepatitis C. In this review, we discuss the biomarkers that can differentiate acute from chronic hepatitis C, and we summarize the current state of the literature on the useful biomarkers that are detectable during acute and chronic HCV infection, liver fibrosis/cirrhosis, and hepatocellular carcinoma (HCC).

Improvement in Thrombocytopenia after Direct Acting Anti-Viral (DAA)Therapy in Patients with Hepatitis C Virus-Related Chronic Liver Disease in Pakistani Population-A Single Centered Study

Background: Hepatitis C Virus (HCV) infection remains a significant global health challenge, often leading to chronic liver diseases such as cirrhosis and associated complications like thrombocytopenia. Directly acting antivirals (DAAs) have revolutionized HCV treatment due to their high efficacy and favorable safety profiles but the impact on thrombocytopenia, particularly in the Pakistani population, has been less studied. Objective: This study aimed to evaluate the effects of DAA therapy on platelet count and other laboratory parameters in chronic HCV patients with thrombocytopenia in Pakistan and to establish correlations between treatment outcomes and baseline laboratory values. Methods: A retrospective observational study was conducted at the Sindh Institute of Urology and Transplantation from January 2018 to December 2022. Patients with chronic HCV genotype 3a infection, compensated cirrhosis, and a baseline platelet count of less than 150 × 10^9/L were included. Exclusion criteria encompassed decompensated liver disease, liver cancer, and other specific conditions. The treatment regimens were Sofosbuvir plus Daclatasvir or Velpatasvir plus Ribavirin over three months. Parameters such as complete blood counts, serum creatinine, liver enzymes, and Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores were recorded at baseline and post-treatment. Statistical analysis was performed using SPSS version 25, employing paired t-tests and Pearson correlation coefficients. Results: A total of 195 patients were studied, with a mean baseline platelet count of 100.7 × 10^9/L, which significantly increased to 122.2 × 10^9/L post-treatment (p < 0.001). Improvements were also noted in mean serum creatinine (0.96 mg/dL to 0.87 mg/dL; p = 0.009), total bilirubin (1.6 mg/dL to 1.2 mg/dL; p < 0.001), liver enzymes (ALT from 63.9 IU to 45.9 IU; p < 0.001 and AST from 86.8 IU to 59.5 IU; p < 0.001), and MELD scores (11.5 to 9.3; p < 0.001). Hemoglobin levels and total leukocyte counts also showed significant improvements. Conclusion: DAA therapy significantly improves platelet counts and other laboratory parameters in chronic HCV patients with thrombocytopenia, suggesting a positive impact on liver function and patient management. This study highlights the importance of DAAs in the therapeutic regimen for HCV in the Pakistani population, contributing to better clinical outcomes and healthcare practices.

Molecular characterization of the nonstructural 5A (NS5A) region of hepatitis C virus in Thai blood donors.

Direct acting antivirals (DAAs) have been developed for hepatitis C virus (HCV) therapy, and they are usually effective, however resistance to DAA regimens has also been reported to have a significant impact. Resistance associated substitutions (RASs) in the NS5A region are known to be correlated with failure of DAA therapy. HCV genotypes 3a and 1 are the most prevalent genotypes in Thailand. This study analyzed the type and frequency of RASs associated with DAA failure, focusing on the NS5A region. Serum samples of HCV genotype 3a, 1a, and 1b infection from Thai blood donors were selected. The NS5A region was amplified using reverse transcription-polymerase chain reaction (RT-PCR). A phylogenetic tree was constructed to identify the genotypes of HCV. Nucleotide sequencing and amino acid sequencing were conducted to determine the prevalence of RASs. Construction of the phylogenetic tree indicated that 29 samples were genotype 3a, 11 samples were genotype 1a, and 9 were genotype 1b. Both HCV genotypes 1a and 3a can be categorized into two subclades. Results showed that the NS5A substitutions A30V/K, A62T/V/I/M/P/S/L, and S98G were present in HCV genotype 3a. In HCV genotype 1a, only NS5A RASs H54Y was detected. NS5A amino acid substitutions Q54H and P58L were found in HCV genotype 1b. In conclusion, NS5A RASs at amino acid positions 30, 62, 54, 58, and 98 are present within HCV genotypes 3a and 1. While keeping in mind that additional information was not available on the anonymous blood donors tested in this study, these findings can contribute to understand the NS5A mutation. Further study with known patients under drug treatment is recommended.

Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (Mpro) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 μM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 Mpro. In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.

Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review.

Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.

Risk Factors Associated With Unsuccessful Linkage to Outpatient Hepatitis C Care.

Background Modern direct-acting antivirals (DAAs) can treat and cure hepatitis C virus (HCV) infection. Treatment of HCV at a population level has the potential to decrease the prevalence of chronic HCV infection and sequela. Unfortunately, many patients fall off the HCV treatment cascade and do not complete HCV treatment. As social determinants of health (SDHs) affect HCV acquisition, we sought to evaluate factors that may limit successful linkage to outpatient HCV care. Methods We conducted a case-controlstudy by matching patients who missed and those who attended their outpatient HCV visits in 2018. We matched cases in a 1:1 ratio using propensity scores. Results Of 1,539 patients,161 (10.5%) did not attend their HCV clinic appointment. Factors associated with a missed HCV visit on bivariate testing included identifying as Black (p=0.03), housing instability (p<0.001), transportation difficulty (p<0.001), history of medication non-adherence (p<0.001), and undergoing screening during an inpatient admission (p<0.001). Multivariate testing found transportation difficulty (p<0.001) and inpatient admission (p=0.002) to be associated with missing their HCV appointment. Patients who attended their HCV visit were more likely to be alive by the end of 2018 (p=0.07). Conclusion Patients who missed an initial scheduled infectious disease (ID) clinic appointment for HCV treatment had higher rates of housing instability, transportation difficulties, and medication non-adherence. Patients diagnosed with HCV infection should be provided additional support as appropriate to address the social determinants of health that may limit linkage to outpatient HCV care.

Hepatitis C screening in Lithuania: first-year results and scenarios for achieving WHO elimination targets.

The World Health Organization (WHO) has outlined a set of targets to achieve eliminating hepatitis C by 2030. In May 2022, Lithuanian health authorities initiated a hepatitis C virus (HCV) screening program to start working towards elimination. In the program, bonus was given to general practitioners (GPs) to promote and conduct anti-HCV tests for two situations: (1) one time testing for individuals born in 1945-1994 and (2) annual HCV testing for persons who inject drugs or are living with human immunodeficiency virus (HIV) regardless of age. This study aimed to model the current viral hepatitis C epidemiological status in Lithuania and to outline the requirements for WHO elimination targets using the first-year HCV screening results. Individuals were invited to participate in the anti-HCV screening by GPs during routine visits. Patients who tested positive were then referred to a gastroenterologist or infectious disease doctor for further confirmatory testing. If a patient received a positive RNA test and a fibrosis staging result of ≥ F2, the doctor prescribed direct-acting antivirals. Information on the patients screened, diagnosed, and treated was obtained from the National Health Insurance Fund. The Markov disease progression model, developed by the CDA Foundation, was used to evaluate the screening program results and HCV elimination progress in Lithuania. Between May 2022 and April 2023, 790,070 individuals underwent anti-HCV testing, with 11,943 individuals (1.5%) receiving positive results. Anti-HCV seroprevalence was found to be higher among males than females, 1.9% and 1.2%, respectively. Within the risk population tested, 2087 (31.1%) seropositive individuals were identified. When comparing the screening program results to WHO elimination targets through modelling, 2180 patients still need to be treated annually until 2030, along with expanding fibrosis restrictions. If an elimination approach was implemented, 1000 new infections would be prevented, while saving 150 lives and averting 90 decompensated cirrhosis cases and 110 hepatocellular carcinoma cases. During the first year of the Lithuanian screening program, GPs were able to screen 44% of the target population. However, the country will not meet elimination targets as it currently stands without increasing treatment levels and lifting fibrosis restrictions.

Dynamic change of metabolic dysfunction-associated steatotic liver disease in patients with hepatitis C virus infection after achieving sustained virologic response with direct-acting antivirals.

Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited. We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248dB/m utilizing vibration-controlled transient elastography in conjunction with presence of ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD. The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13-2.65, p = 0.011], age > 50years (OR: 1.73, 95% CI: 1.11-2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03-2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51-22.56, p = 0.011). The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12.

Elevation of S2-bound α1-acid glycoprotein is associated with chronic hepatitis C virus infection and hepatocellular carcinoma.

There is an urgent need for new high-quality markers for the early detection of hepatocellular carcinoma (HCC). Åström etal. suggested that S2-bound α1-acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated the predictive advantage of S2-bound AGP in the early detection of HCC. In a retrospective case-control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct-acting antiviral agents (n = 93), we measured S2-bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at the start of treatment, end of treatment and follow-up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). Thirty-one patients chronically infected with HCV developed HCC after a sustained virological response, while 62 did not. In addition, samples of patients with chronic hepatitis B virus infection, metabolic dysfunction-associated steatotic liver disease and HCC of different etiologies were analysed. S2-bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2-bound AGP for the early detection of HCC during treatment and follow-up. Interestingly, S2-bound AGP levels correlated with aspartate aminotransferase (ρ = .56, p = 9.5×10-15) and liver elastography (ρ = .67, p = 2.2×10-16). Of note, S2-bound AGP decreased in patients chronically infected with HCV after treatment-induced HCV clearance. Fucosylated S2-bound AGP levels were elevated in patients with chronic HCV and HCC. The potential role of S2-bound AGP as a novel tumour marker requires further investigation.

Changes in clinical outcomes in Japanese patients with hepatocellular carcinoma due to hepatitis C virus following the development of direct-acting antiviral agents.

Direct-acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCV-HCC) changed before and after DAA development. A retrospective analysis of 1949 Japanese HCV-HCC patients from January 2000 to January 2023 categorized them into pre-DAA (before 2013, n=1169) and post-DAA (after 2014, n=780) groups. Changes in clinical features and prognosis were assessed. Despite no significant differences in BCLC stage between groups, the post-DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69years), lower levels of AST (40 vs 56IU/L), ALT (31 vs 46IU/L), and AFP (11.7 vs 23.6ng/mL), higher platelet count (13.5 vs 10.8×104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (-2.54 vs -2.36) (all P<0.001). The post-DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence-free survival (median 2.8 vs 2.1years). Adjusted for inverse probability weighting, overall survival was superior in the post-DAA group (median 7.4 vs 5.6years, P<0.001). Subanalysis within the post-DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8years vs NA vs NA) compared to pre-SVR or post-SVR patients (both P<0.001). No significant difference in OS was observed between the pre-SVR and post-SVR groups (P=1.0). The development of DAA therapy has dramatically improved the prognosis of HCV-HCC patients.

Efficacy of assisted partner services for people who inject drugs in Kenya to identify partners living with HIV and hepatitis C virus infection: a prospective cohort study

People who inject drugs are at increased risk of both HIV and hepatitis C virus (HCV) infections but face barriers to testing and engagement in care. Assisted partner services are effective in locating people with HIV but are understudied among people who inject drugs. We assessed whether assisted partner services could be used to find, test for HIV and HCV infections, and link to care the partners of people who inject drugs in Kenya. In this prospective study at eight sites offering harm-reduction services in Kenya, we enrolled people aged 18 years or older who inject drugs and were living with HIV (index participants) between Feb 27, 2018, and Nov 1, 2021. Index participants provided information about their sexual and injecting partners (ie, anyone with whom they had had sexual intercourse or injected drugs in the previous 3 years), and then community-embedded peer educators located partners and referred them for enrolment in the study (partner participants). All participants underwent testing for HCV infection, and partner participants also underwent HIV testing. Index and partner participants with HIV but who were not on antiretroviral therapy (ART) were linked with treatment services, and those positive for HCV were linked to treatment with direct-acting antivirals. We calculated the number of index participants whom we needed to interview to identify partner participants with HIV and HCV infection. We enrolled 989 people living with HIV who inject drugs, who mentioned 4705 sexual or injecting partners. Of these 4705 partners, we enrolled 4597 participants, corresponding to 3323 unique individuals. 597 (18%) partner participants had HIV, of whom 506 (85%) already knew their status. 358 (71%) of those who knew they were HIV positive were virally suppressed. 393 (12%) partner participants were HCV antibody positive, 213 (54%) of whom had viraemia and 104 (26%) of whom knew their antibody status. 1·66 (95% CI 1·53-1·80) index participants had to be interviewed to identify a partner with HIV, and 4·24 (3·75-4·85) had to be interviewed to find a partner living with HIV who was unaware of their HIV status, not on ART, or not virally suppressed. To find a partner seropositive for HCV who did not know their antibody status, 3·47 (3·11-3·91) index participants needed to be interviewed. Among the 331 index and partner participants living with HIV who were not on ART at enrolment, 238 (72%) were taking ART at 6-month follow-up. No adverse events were attributed to study procedures. Use of assisted partner services among people with HIV who inject drugs was safe and identified partners with HIV and HCV infections. Assisted partner services was associated with increased uptake of ART for both index participants and partners. US National Institutes of Health.

Sex and gender differences in hepatitis C virus risk, prevention, and cascade of care in people who inject drugs: systematic review and meta-analysis

People who inject drugs (PWID) are a priority population in HCV elimination programming. Overcoming sex and gender disparities in HCV risk, prevention, and the cascade of care is likely to be important to achieving this goal, but these have not yet been comprehensively reviewed. Systematic review and meta-analysis. We searched Pubmed, EMBASE and the Cochrane Database of Systematic Reviews 1 January 2012-22 January 2024 for studies of any design reporting sex or gender differences among PWID in at least one of: sharing of needles and/or syringes, incarceration history, injection while incarcerated, participation in opioid agonist treatment or needle and syringe programs, HCV testing, spontaneous HCV clearance, direct-acting antiviral (DAA) treatment initiation or completion, and sustained virological response (SVR). Assessment of study quality was based on selected aspects of study design. Additional data were requested from study authors. Data were extracted in duplicate and meta-analysed using random effects models. PROSPERO registration CRD42022342806. 9533 studies were identified and 92 studies were included. Compared to men, women were at greater risk for receptive needle and syringe sharing (past 6-12 months: risk ratio (RR) 1.12; 95% confidence interval (CI) 1.01-1.23; <6 months: RR 1.38; 95% CI 1.09-1.76), less likely to be incarcerated (lifetime RR 0.64; 95% CI 0.57-0.73) more likely to be tested for HCV infection (lifetime RR 1.07; 95% CI 1.01, 1.14), more likely to spontaneously clear infection (RR1.58; 95% CI 1.40-1.79), less likely to initiate DAA treatment (0.84; 95% CI 0.78-0.90), and more likely to attain SVR after completing DAA treatment (RR 1.02; 95% CI 1.01-1.04). There are important differences in HCV risk and cascade of care indicators among people who inject drugs that may impact the effectiveness of prevention and treatment programming. Developing and assessing the effectiveness of gender-specific and gender-responsive HCV interventions should be a priority in elimination programming. Réseau SIDA-MI du Québec.