DAA treatment for HCV reduce risk of hepatocellular carcinoma: a 10-years follow-up study based on Chinese patients with hepatitis C.

The long-term benefits of direct-acting antiviral (DAA) therapy after achieving sustained virological response (SVR) remain uncertain in the Chinese population. This study evaluates the incidence of hepatocellular carcinoma (HCC), hepatic decompensation, and all-cause mortality among Chinese hepatitis C patients treated with DAAs. We included patients diagnosed since 2011 and followed them until November 1, 2022. The primary outcomes were HCC, hepatic decompensation, and mortality. Multivariable proportional hazards model was used to assess the impact of SVR and cirrhosis status. The cohort consisted of 1272 patients with SVR (92.1%) and 109 without SVR (7.9%), with a median follow-up of 61 months. The incidence of HCC was significantly lower in the SVR group (5.1 per 1000 person-years) compared to the no-SVR group (15.0 per 1000 person-years). Achieving SVR was associated with a significantly reduced risk of HCC (adjusted hazard ratio: 0.32; 95% CI 0.16-0.67). Cirrhosis was linked to an increased risk of developing HCC and hepatic decompensation. These findings highlight the importance of early DAA treatment, particularly for patients with cirrhosis.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Real-world experience with direct-acting antiviral therapy in HCV-infected patients with cirrhosis and esophageal varices.

BACKGROUND: Hepatitis C virus (HCV) infection affects 50 million people worldwide with around 242,000 deaths annually, mainly due to complications such as cirrhosis and hepatocellular carcinoma (HCC). Portal hypertension (PH) caused by cirrhosis leads to severe consequences, including esophageal varices (EV). This study aimed to evaluate the effectiveness and safety of direct-acting antiviral (DAA) treatment in patients with and without EV. METHODS: This retrospective analysis involved consecutive HCV-infected adults undergoing DAA therapy at 22 Polish hepatology centers from July 1, 2015, to December 31, 2022. Patients with cirrhosis were categorized based on the presence of EV diagnosed by gastroscopy. Treatment effectiveness was measured by sustained virologic response (SVR), with safety outcomes monitored for 12 weeks post-treatment. RESULTS: A population of 3393 HCV-infected patients with cirrhosis was divided into groups with (A, n = 976) and without (B, n = 2417) EV. Group A showed a significantly higher prevalence of comorbidities and concomitant medications. Genotype (GT)1b infections predominated in both groups, and GT3 infections were more common in the EV group. Group A exhibited more severe liver disease, and higher rates of decompensation, HCC, and HBV co-infection. SVR was significantly higher in group B (91.5% vs. 96.3%, p < 0.0001). Male gender, GT3, EV presence, and Child-Pugh grade B were identified as independent negative SVR predictors. Group A had a worse safety profile, with notably higher adverse event incidence and mortality. CONCLUSIONS: DAA therapies are highly effective and well tolerated in patients with cirrhosis, but EV presence predicts poorer virologic responses.

Predictive Value of Interleukin 6 and Interleukin 8 in Response to Treatment of Hepatitis C Virus.

BACKGROUND: Chronic hepatitis C (CHC) infection is a major public health problem in many low- and middle-income countries. The study aimed to find out how interleukin IL-6 and IL-8 levels in the blood affect the virological response to directacting antivirals (DAAs) and to find useful clinical or immunological markers for the response to HCV treatment. METHODS: CHC patients from a real Egyptian population (n = 4,300), who were treated during the Egyptian national initiative to eliminate HCV at the Sherbin Central Hospital, Dakahlia Governorate, Ministry of Health, Egypt, were enrolled in our study. They were all patients who did not obtain a sustained virological response (SVR) (n = 75; non-responder; the response rate was 98.26%), and a total of 100 patients were randomly selected from patients who obtained SVR (responder) and were age- and gender-matched (p > 0.05) with non-responder patients. Serum levels of IL-6 and IL-8 were measured by commercial ELISA kits. RESULTS: Non-responder patients were associated with significantly high levels of ALT, AST, ALP, and total bilirubin. Non-responders had significantly (p < 0.05) higher baseline IL-6 (16.7 ± 4.92 pg/mL) and IL-8 (37.81 ± 10.55 pg/mL) levels compared to responders (12.68 ± 2.06, 29.06 ± 5.94 pg/mL, respectively). There was a substantial (p < 0.05) association between the combination of two cytokines and a high likelihood of treatment failure, as indicated by all parameters examined, with the highest correlation values seen. CONCLUSIONS: The present study showed that increased IL-6 and IL-8 were associated with HCV treatment failure. Also, IL8 was associated with hepatic fibrosis.

Rationale for Hepatitis C Virus Treatment During Hematopoietic Stem Cell Transplant in the Era of Novel Direct-Acting Antivirals.

BACKGROUND AND AIMS: Untreated hepatitis C (HCV) infection in patients undergoing hematopoietic stem cell transplantation (HSCT) can lead to worse outcomes. Traditionally, HSCT patients infected with HCV would wait until after immune reconstitution to receive HCV therapy, as the oncologic urgency of transplant would not allow time for a full preceding treatment course of HCV therapy. However, in the era of newer direct-acting antivirals (DAAs), we propose that concomitant treatment of HCV while undergoing HSCT is safe and feasible, while keeping in mind potential drug-drug interactions. METHODS: A literature review was performed to summarize the available data on the impact of HCV on patients undergoing HSCT. Drug-drug interactions for DAA's and pertinent HSCT drugs were evaluated using Lexicomp online® and http://hep-druginteractions.org . RESULTS: During HSCT, HCV appears to be a conditional risk factor for sinusoidal obstruction syndrome and a potential risk factor for graft versus host disease, both of which are associated with increased mortality. HCV reactivation and exacerbation may impact the use of chemotherapeutics, but available studies haven't shown impact specifically on HSCT. Limited case reports exist but demonstrate safe and effective use DAAs during HSCT. These, along with a drug-drug interaction review demonstrate agents such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are promising DAAs for use in HSCT. CONCLUSION: HCV infection may worsen outcomes for patients undergoing HSCT. Concomitant treatment of HCV during HSCT using newer DAAs appears feasible and may improve patient morbidity and mortality, however large-scale studies are needed to further support this practice.

HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1.

Hepatitis C virus (HCV) is a positive-stranded RNA virus that mainly causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Recently we confirmed m5C modifications within NS5A gene of HCV RNA genome. However, the roles of the m5C modification and its interaction with host proteins in regulating HCV's life cycle, remain unexplored. Here, we demonstrate that HCV infection enhances the expression of the host m5C reader YBX1 through the transcription factor MAX. YBX1 acts as an m5C reader, recognizing the m5C-modified NS5A C7525 site in the HCV RNA genome and significantly enhancing HCV RNA stability. This m5C-modification is also required for YBX1 colocalization with lipid droplets and HCV Core protein. Moreover, YBX1 facilitates HCV RNA replication, as well as viral assembly/budding. The tryptophan residue at position 65 (W65) of YBX1 is critical for these functions. Knockout of YBX1 or the application of YBX1 inhibitor SU056 suppresses HCV RNA replication and viral protein translation. To our knowledge, this is the first report demonstrating that the interaction between host m5C reader YBX1 and HCV RNA m5C methylation facilitates viral replication. Therefore, hepatic-YBX1 knockdown holds promise as a potential host-directed strategy for HCV therapy.

Hepatitis C virus-induced differential transcriptional traits in host cells after persistent infection elimination by direct-acting antivirals in cell culture.

Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to the development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct-acting antiviral drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection. Combining differential transcriptomes from two different persistent infection models, we observed a major reversion of infection-related transcripts after complete infection elimination. However, a small number of transcripts were abnormally expressed in formerly infected cells. Comparison of the results obtained in proliferating and growth-arrested cell culture models suggest that permanent transcriptional alterations may be established by several mechanisms. Interestingly, some of these alterations were also observed in the liver biopsies of virologically cured patients. Overall, our data suggest a direct and permanent impact of persistent HCV infection on the host cell transcriptome even after virus elimination, possibly contributing to the development of HCC.

EASL position paper on clinical follow-up after HCV cure.

Following the advent of direct-acting antivirals (DAAs), hepatitis C virus (HCV) infection can be cured in almost all infected patients. This has led to a number of clinical questions regarding the optimal management of the millions of patients cured of HCV. This position statement provides specific guidance on the appropriate follow-up after a sustained virological response in patients without advanced fibrosis, those with compensated advanced chronic liver disease, and those with decompensated cirrhosis. Guidance on hepatocellular carcinoma risk assessment and the management of extrahepatic manifestations of HCV is also provided. Finally, guidance is provided on the monitoring and treatment of reinfection in at-risk patients. The recommendations are based on the best available evidence and are intended to help healthcare professionals involved in the management of patients after treatment for HCV.

Synergistic interaction between pay-it-forward incentives and recreational drug use on hepatitis B virus and hepatitis C virus testing among men who have sex with men in China.

OBJECTIVES: Pay-it-forward incentives effectively promote hepatitis B virus (HBV) and hepatitis C virus (HCV) testing among men who have sex with men (MSM) by offering free testing and donation opportunities. This study aims to explore the interaction between pay-it-forward incentives and recreational drug use on HBV and HCV testing uptake among Chinese MSM. METHODS: We pooled data from two pay-it-forward studies that aimed to promote dual HBV and HCV testing among MSM in Jiangsu, China. We explored factors associated with hepatitis testing uptake in the two study groups and examined the interaction between pay-it-forward incentives and recreational drug use on hepatitis testing uptake. RESULTS: Overall, 511 MSM participated in these two studies, with 265 participants in the pay-it-forward incentives group and 246 participants in the standard-of-care group. Among these participants, 59.3% in the pay-it-forward incentive group and 24.8% in the standard-of-care group received dual HBV and HCV testing, respectively. In the pay-it-forward incentives group, participants who used recreational drugs in the past 12 months (adjusted OR (AOR)=1.83, 95% CI 1.09 to 3.06) were more likely to receive dual HBV and HCV testing, compared with those who never used recreational drugs, whereas in the standard-of-care group, those who used recreational drugs were less likely to receive dual HBC and HCV testing (AOR=0.38, 95% CI 0.18 to 0.78). MSM with higher community connectedness (AOR=1.10, 95% CI 1.00 to 1.21) were also more likely to receive hepatitis testing with pay-it-forward incentives. There was a synergistic interaction on both the multiplicative (ratio of ORs=4.83, 95% CI 1.98 to 11.7) and additive scales (the relative excess risk of interaction=2.97, 95% CI 0.56 to 5.38) of pay-it-forward incentives and recreational drug use behaviours on dual HBV and HCV testing uptake among MSM. CONCLUSION: Pay-it-forward incentives may be particularly useful in promoting hepatitis testing among MSM who use recreational drugs.

Hepatitis C virus and hepatocellular carcinoma: carcinogenesis in the era of direct-acting antivirals.

Chronic hepatitis C virus (HCV) infection is a major cause of hepatic fibrosis and cirrhosis, with a risk for the development of hepatocellular carcinoma (HCC). Although highly effective direct-acting antivirals (DAAs) are available, the incidence, morbidity, and mortality of HCV-associated HCC are still high. This article reviews the current knowledge of the mechanisms of HCV-induced carcinogenesis with a special focus on those processes that continue after virus clearance and outlines implications for patient surveillance after DAA treatment.

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.

Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV's imprint on cell metabolism.

Effectiveness of test-and-treat model with direct-acting antiviral for hepatitis C virus infection in migrants: a prospective interventional study in Italy.

BACKGROUND: Migrants, mainly undocumented and low-income refugees, are at high risk of hepatitis C virus (HCV) infection, but are a difficult-to-reach and to-treat population. The aim of the study was to evaluate the effectiveness of a test and treat model with direct-acting antiviral for HCV infection in these migrants coming from low-income and living in southern Italy. METHODS: A prospective, multicenter, collaborative study based on a four-phase-program (educational counseling, screening, linkage-to-care and treatment) was designed in southern Italy; the study started in June 2018, was stopped in February 2020 because of the outbreak of SARS-CoV2 infection in Italy and was resumed in February 2021 until November 2021. After educational counseling on infectious diseases that are transmitted through blood or sexually pseudonymized HCV screening was offered to all undocumented migrants and low-income refugees observed at one of the 1st level clinical centers. The HCV-RNA-positive subjects were referred to one of the 3rd level units of Infectious Diseases (ID) and treated with a 12-week course of sofosbuvir-velpatasvir and observed for 12 weeks after the end of direct antiviral agents (DAA) treatment. STATISTICAL ANALYSIS: For the descriptive analysis, the categorical variables were reported as absolute numbers and relative frequencies. Continuous variables were summarized as mean and standard deviation (SD) if normally distributed, or as a median and interquartile range (IQR) if not normally distributed. We used Pearson chi-square or Fisher's exact test for categorical variables and Student's t test or Mann-Whitney test for continuous variables. A P value < 0.05 was considered to be statistically significant. Analyses were performed with SPSS 21.0. RESULTS: Of the 3501migrants observed in the study period, 3417 (97.6%) agreed to be screened; 185 (4.7%) were anti-HCV-positive and, of these, 53 (28.6%) were HCV-RNA-positive. Of these 53 subjects, 48 (90.5%) were referred to an ID unit and started DAA treatment. The HCV-RNA-positive-subjects were older [median 36 years (IQR: 32-21) vs 27.19 (IQR: 30.5-19.25); P = 0.001], and less frequently males [35 (66.03 %) vs 119 (90.1%), P < 0 .0001] than seronegative participants. They more frequently came from Eastern Europe (70.8%) stayed longer in Italy [months of stay in Italy, mean ± SD: 51.02 ± 52.84 vs 25.7 ± 42.65, P = 0.001], and had more years of schooling [years of schooling, mean ± SD: 9.61±2.81 vs 7.10 ± 4, P = 0.0001]. HCV-RNA-positive-subjects less frequently reported piercing, tattoos and tribal scars as risk factors (23.6%). Of these 48 HCV RNA positive subjects who started DAA, 47 (97.9%) showed a sustained virological response and one dropped-out in follow-up after DAA treatment. No subject had any adverse event. CONCLUSIONS: This model of HCV screening and linkage to care seems effective to eliminate HCV infectionin a difficult-to-reach and to-treat population, such as undocumented migrants and low-income refugees. The participation of cultural mediators in the study made possible a better interaction between migrants and physicians, as is evident from the large number of subjects enrolled. Eliminating HCV among migrants will have a long-term positive impact from a public health and healthcare perspective by reducing the number of individuals who potentially develop HCV-related complications such as liver cirrhosis and hepatocellular carcinoma and reducing the circulation of HCV in the regions that host them which often, as in the case of Italy, are low endemic for HCV infection.

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.

Natural History and Management of Hepatitis C in Children: 25 Years Experience of a Reference Center in Northern Italy.

Hepatitis C virus (HCV) infection natural history and management in the pediatric population are still debated. We retrospectively evaluated the outcome of a HCV pediatric population managed at the Pediatric Infectious Disease Unit of Luigi Sacco Hospital (Milan, Italy) from January 1997 to January 2022 (median follow-up 10 years) and we focused on the role of new drugs and transient elastography. Fifty-seven patients were enrolled: 8 (14%) had a spontaneous clearance, 33 were treated (58%), 7 (12%) were not treated because they were under 12 years old and 9 were lost at follow-up. HCV RNA was undetectable in all treated patients at the end of therapy, after 12 weeks (SVR12) and for the rest of their follow-up. All patients treated underwent elastography before and 1 year after therapy. Median stiffness pretherapy was 5.6 kPa, and 9 patients (16%) had abnormal transient elastography (>7 kPa, median 8.7 kPa). Median stiffness after treatment in the abnormal group was 6.8 kPa. Direct-acting antiviral agents are a safe and effective therapy for HCV chronic infection in the pediatric population. Liver elastography is normal in many vertically infected children before 12 years, but, when abnormal, it shows a significant improvement after direct-acting antiviral agent treatment. Further studies are needed to evaluate the role of elastography at diagnosis and follow-up in children.

Metformin as adjuvant treatment in hepatitis C virus infections and associated complications.

Hepatitis C virus is an important global cause of hepatitis and subsequently cirrhosis and hepatocellular carcinoma. These infections may also cause extrahepatic manifestations, including insulin resistance and type 2 diabetes mellitus. These two complications can potentially reduce sustained virologic responses (SVR) in some drug regimens for this infection. Metformin has important biochemical effects that can limit viral replication in cellular cultures and can improve the response to antiviral drug therapy based on ribavirin and interferon. Clinical studies comparing treatment regimens with interferon, ribavirin, metformin with these regimens without metformin have demonstrated that metformin increases viral clearance, establishes higher rates of SVRs, and increases insulin sensitivity. Metformin also reduces the frequency of hepatocellular carcinoma in patients who have had SVRs. Larger treatment trials are needed to determine metformin's short-term and long-term treatment effects in patients with diabetes using newer antiviral drugs. In particular, if metformin reduces the frequency of cirrhosis and hepatocellular carcinoma, this would significantly reduce the morbidity and mortality associated with this infection.

Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Impact of Public Policy and COVID-19 Pandemic on Hepatitis C Testing and Treatment in France, 2014-2021.

Given the World Health Organization's target to eliminate the hepatitis C virus (HCV) by 2030, we assessed the impact of French public policies and the COVID-19 pandemic on HCV testing and initiation of direct-antiviral agents (DAAs). Using the French National Health Data System, we identified individuals living in metropolitan France with at least one reimbursement for an anti-HCV test and those with a first delivery of DAAs between 1 January 2014 and 31 December 2021. During this period, the annual number of people tested increased each year between 3.3 (in 2015) and 9.3% (in 2021), except in 2020, with a drop of 8.3%, particularly marked in April (-55.0% compared to February 2020). A return to pre-pandemic testing levels was observed in 2021. The quarterly number of patients initiating DAAs presented an upward trend from Q1-2014 until mid-2017, with greater increases in Q1-2015, and Q1- and Q2-2017, concomitant with DAA access policies and availability of new therapies. Then, quarterly numbers decreased. A 65.5% drop occurred in April compared to February 2020. The declining DAA initiations since mid-2017, despite new measures improving access and screening efforts, could be due to the shrinking pool of patients requiring treatment and a need to increase awareness among undiagnosed infected people. Further action is needed to eliminate HCV in France.

A comparative study of different antiviral treatment protocols in HCV related cryoglobulinemic vasculitis.

The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.

Direct-Acting Antiviral Therapy for Patients with Chronic Hepatitis C Infection and Decompensated Cirrhosis.

Patients with chronic hepatitis C virus (HCV) infection and decompensated cirrhosis are an important population for antiviral therapy yet under-represented in clinical trials. HCV direct-acting antiviral (DAA) therapies, unlike interferon-containing regimens, can be safely utilized in decompensated patients. Per guidelines from the American Association for the Study of Liver Diseases (AASLD), therapy of choice in HCV and decompensated cirrhosis is sofosbuvir, an HCV polymerase inhibitor, combined with a replication complex inhibitor (NS5A inhibitor) with or without ribavirin. Combination therapy with a HCV protease inhibitor and an NS5A inhibitor is effective in this population but is specifically not recommended in AASLD guidelines due to safety concerns. Important risk factors for further decompensation during DAA therapy are serum albumin < 3.5 g/dL, MELD (Model for End-Stage Liver Disease) score > 14, or HCV genotype 3 infection. Although sustained virologic response (SVR) is achieved less often in patients with decompensated vs compensated cirrhosis, in clinical studies response rates are > 80%. Both Child-Turcotte-Pugh Class at baseline and viral genotype can affect these response rates. Achieving SVR lowers risk of mortality, but to a lesser extent than in individuals with compensated cirrhosis. Likewise, treating patients for HCV infection along with successful treatment for hepatocellular carcinoma improves risks of both liver-related and overall mortality. In fewer than one third of cases, treating transplant-eligible, HCV-infected patients pre-transplant enables their delisting from transplant wait lists.