Interferon-free Direct-acting Antivirals Research Articles

Targeted Degradation of HCV Polymerase by GalNAc-Conjugated ApTACs for Pan-Genotypic Antiviral Therapy with High Resistance Barriers.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Although interferon-free direct-acting antivirals have led to significant advancements in the treatment of HCV infection, the high genetic variability of the virus and the emergence of acquired drug resistance pose potential threats to their effectiveness. In this study, we develop a broad-spectrum aptamer-based proteolysis targeting chimera, designated dNS5B, which effectively degrades both pan-genotypic NS5B polymerase and drug-resistant mutants through ubiquitin proteasome system. To achieve hepatocyte-specific uptake, we further develop Gal-dNS5B by coupling the dNS5B with a trivalent N-acetylgalactosamine (tri-GalNAc), a ligand for the liver-specific asialoglycoprotein receptor. Gal-dNS5B exclusively accumulates in hepatocytes and suppresses HCV replication by degrading NS5B. Collectively, our research lays the groundwork for a scalable strategy in the development of antiviral medications aimed at addressing current and future challenges posed by hepatitis viruses and other re-emerging viral pandemics.

Impact of the direct acting antivirals on chronic hepatitis C prevalence on the Swiss organ transplantation list: a retrospective analysis

Aim: In Switzerland, the first access to interferon-free direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment was in 2014. This study aimed to analyze the effects of DAAs on the yearly listed numbers of HCV RNA-positive (RNA+) patients and their mortality on the Swiss organ transplantation waiting list (SOWL). Methods: In this retrospective secondary time series analysis of yearly aggregated data on listed and delisted patients from a subset of HCV RNA+ patients on the SOWL, listed patients were grouped by the requested organ, and delisted patients by reason. Time series were split into two periods of equal length, the phases before and after DAA implementation, and the mean difference was tested using the Mann-Whitney U test. Results: From 2008 to 2019, 328 HCV RNA+ patients were listed on SOWL, 86.6% requesting liver, 11.6% kidney, and 1.8% other organ transplantations. A total of 285 RNA+ patients were delisted from SOWL: 14.7% died, 75.4% had been transplanted, and 9.8% were delisted without surgery. There were significant reductions of patients listed for requesting any organ (– 21.7, P = 0.004), liver (– 18.3, P = 0.004), or kidney (– 3.0, P = 0.031) comparing the periods before and after DAA launch. The mean number of delistings after transplantation (– 11.2, P = 0.010), or death (– 4, P < 0.001) show a significant reduction. Conclusions: With DAAs, the rising trend of HCV RNA+ people waiting for organs was broken, as was the increasing trend of mortality on the SOWL among HCV RNA+ individuals.

The impact of HCV eradication using interferon-free direct acting antivirals on bone-mineral, anemia parameters and peripheral insulin resistance in hepatitis c-infected Egyptian hemodialysis cohort

BackgroundHepatitis C virus (HCV) infection is linked to a higher mortality rate in hemodialysis (HD) patients. We aimed to see if HCV eradication using interferon-free direct acting antivirals (DAAs) can affect bone-mineral and anemia biochemical parameters such as serum calcium (Ca++), phosphorus (PO4+), parathormone (PTH), fibroblast growth factor 23 (FGF23), hemoglobin (HB), and ferritin in HD patients and also peripheral insulin resistance by monitoring serum fasting insulin and HOMA insulin resistance (HOMA-IR).MethodsThree hundred and thirty-four adults on regular HD with positive HCV genotype 4 (191 male and 143 female) were included; 157 of them had seroconversion during HD. All were hepatitis B virus (HBV) negative and received treatment with DAAs. All cases were examined for body mass index (BMI), HB, ferritin level, transferrin saturation (TSAT), Ca++, PO4+, PTH, FGF23, serum albumin, alanine transaminase (ALT), fasting insulin level, and HOMA-IR at the beginning and then were measured after 6 and 12 months from a sustained virological response (SVR).ResultsAfter 6 and 12 months from SVR, there was a significant increase in serum Ca despite no change in oral calcium dose requirement over that period (p = 0001), a significant increase in HB, serum iron (p = 0001), and a significant reduction in serum ferritin, PO4, PTH, and FGF23 (p = 0001). Both fasting insulin level and HOMA-IR were statistically significantly dropped.ConclusionHCV eradication with interferon-free DAAs showed a statistically significant impact on hemodialysis patients regarding hemoglobin, ferritin level, bone-mineral parameters, and improvement in peripheral insulin resistance.

Hepatitis C virus eradication by direct-acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low-density lipoprotein cholesterolemia without an increase in body weight.

Hepatitis C virus (HCV) infection has been reported to cause liver steatosis. Thus, eradicating HCV with direct-acting antivirals (DAAs) is expected to reduce liver steatosis. We aimed to clarify long-term changes in the prevalence of fatty liver and hyper-low-density lipoprotein (LDL) cholesterolemia and their associations in patients who achieve successful HCV eradication using DAAs. This retrospective study included patients with HCV who achieved sustained virologic response after interferon-free DAA and analyzed the changes in the prevalence of fatty liver diagnosed with controlled attenuation parameter (CAP), hyper-LDL cholesterolemia, and their relationships at baseline (n=100) and 24weeks (SVR24, n=100), 96weeks (SVR96, n=100), and 144weeks (SVR144, n=90) after DAA. In 100 participants, the prevalence of fatty liver (19% vs. 32%, p=0.0349) and hyper-LDL cholesterolemia (6% vs. 15%, p=0.0379) significantly increased without changes in body weight at SVR96. Median total cholesterol, low-density lipoprotein cholesterol (LDL-C), and small-dense-LDL (sdLDL) levels and CAP values were significantly greater at SVR24, SVR96, and SVR144 than at baseline. Baseline CAP values and changes in CAP values were significantly negatively correlated at every observation point: r=-0.5305, p<0.0001 at SVR24; r=-0.3617, p=0.0005 at SVR96; and r=-0.4735, p<0.0001 at SVR144. A similar relationship was observed in cholesterol levels. Unlike at baseline, CAP values were significantly positively correlated with LDL-C and sdLDL-C levels at all observation points after DAAs. Direct-acting antivirals may cause an increased prevalence of fatty liver accompanying hyper-LDL cholesterolemia without increased body weight. As post-SVR liver steatosis could cause HCC, careful follow-up may be required.

Impact of the direct acting antivirals on chronic hepatitis C prevalence on the Swiss organ transplantation list: a retrospective analysis

Aim: In Switzerland, the first access to interferon-free direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment was in 2014. This study aimed to analyze the effects of DAAs on the yearly listed numbers of HCV RNA-positive (RNA+) patients and their mortality on the Swiss organ transplantation waiting list (SOWL). Methods: In this retrospective secondary time series analysis of yearly aggregated data on listed and delisted patients from a subset of HCV RNA+ patients on the SOWL, listed patients were grouped by the requested organ, and delisted patients by reason. Time series were split into two periods of equal length, the phases before and after DAA implementation, and the mean difference was tested using the Mann-Whitney U test. Results: From 2008 to 2019, 328 HCV RNA+ patients were listed on SOWL, 86.6% requesting liver, 11.6% kidney, and 1.8% other organ transplantations. A total of 285 RNA+ patients were delisted from SOWL: 14.7% died, 75.4% had been transplanted, and 9.8% were delisted without surgery. There were significant reductions of patients listed for requesting any organ (– 21.7, P = 0.004), liver (– 18.3, P = 0.004), or kidney (– 3.0, P = 0.031) comparing the periods before and after DAA launch. The mean number of delistings after transplantation (– 11.2, P = 0.010), or death (– 4, P &lt; 0.001) show a significant reduction. Conclusions: With DAAs, the rising trend of HCV RNA+ people waiting for organs was broken, as was the increasing trend of mortality on the SOWL among HCV RNA+ individuals.

Risk factors for loss to follow-up after the start of direct-acting antiviral treatment for hepatitis C virus infection.

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection. Additionally, interferon-free DAA treatment has improved liver function and reduced the risk of hepatocellular carcinoma (HCC) following HCV eradication. Previous studies on HCV have focused mainly on the treatment rate and the risk of developing HCC, and less attention has been given to loss to follow-up (LTFU) after DAA treatment. Therefore, the present study aimed to identify the definitive risk factors for LTFU after the start of DAA treatment. Between September 2017 and March 2022, 296 patients receiving glecaprevir and pibrentasvir for HCV infection were enrolled in this study. The incidence of LTFU following DAA treatment and the risk factors contributing to LTFU were identified using the patients' clinical characteristics. In the present study, 75 patients (25.3%) interrupted their follow-up visits. Multivariate logistic analysis revealed a history of injection drug use (hazard ratio [HR], 1.81; P=0.017), treatment duration (8 weeks) (HR, 3.51; P=0.0033), and age <70 years (HR, 1.9; P=0.0422) as independent factors associated with LTFU after the start of DAA treatment. Young patients and those with injection drug use are likely to discontinue their follow-up visits after the start of DAA treatment for HCV infection. Therefore, these patients require strict supervision.

Perceptions of hepatitis C treatment and reinfection risk among HIV-positive men who have sex with men and engage in high risk behaviours for hepatitis C transmission: The CEASE qualitative study.

Globally, treatment uptake for hepatitis C virus (HCV) infection among HIV-HCV coinfected men who have sex with men (MSM) has substantially increased since the advent of interferon-free direct-acting antivirals (DAA). However, HIV-positive MSM who engage in high risk behaviours are at an increased risk of HCV reinfection post-treatment. The aim of this study was to investigate perceptions of HCV diagnosis, treatment and reinfection risk among HCV-HIV coinfected MSM who engage in drug use and/or high risk sexual behavior in Sydney, Australia. Participants were recruited from the Control and Elimination within AuStralia of HEpatitis C from people living with HIV (CEASE) cohort (n=402) who reported engaging in drug use and/or high risk sexual behavior for transmission of HCV infection. Participants were interviewed about their perceptions of HCV diagnosis, treatment, and reinfection risk. Interview data were transcribed, coded, and analyzed thematically. Of 33 participants interviewed (mean age 49 years), many participants were 'shocked' by their HCV diagnosis. Participants who believed they acquired HCV infection through sexual exposure felt it was important that their healthcare practitioner agreed with their perspective to mitigate stigmatizing experiences. Overall, participants expressed high satisfaction with their treatment experience due to long-standing therapeutic relationships with their HIV physician. Many participants expressed knowledge of how to prevent HCV reinfection from injection drug use, yet other than condom usage, most were unsure how to reduce high risk sexual activity with such discussions occurring less frequently with healthcare practitioners. Findings indicate that MSM who engage in drug use and high risk sexual activity would benefit from additional education on reducing reinfection risk through sexual activity and services to reduce substance use, if requested.

Low Risk of Failing Direct-Acting Antivirals in People With Human Immunodeficiency Virus/Hepatitis C Virus From Sub-Saharan Africa or Southeastern Asia: A European Cross-Sectional Study.

Several studies have reported suboptimal efficacy of direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) subtypes endemic to sub-Saharan Africa (SSA) and Southeastern Asia (SEA). The extent of this issue in individuals with human immunodeficiency virus (HIV)/HCV from SSA or SEA residing in Europe is unknown. We retrospectively analyzed data from several prospective European cohorts of people living with HIV. We included individuals with HIV/HCV who originated from SSA or SEA, were treated with interferon-free DAAs, and had an available HCV RNA result ≥12 weeks after the end of treatment. The primary outcome was sustained virological response at least 12 weeks after the end of treatment (SVR12). Of the 3293 individuals with HIV/HCV treated with DAA and with available SVR12 data, 142 were from SSA (n = 64) and SEA (n = 78). SVR12 was achieved by 60 (94% [95% confidence interval {CI}, 86%-98%]) individuals from SSA and 76 (97% [95% CI, 92%-99%]) from SEA. The genotypes of the 6 individuals failing DAA treatment were 2, 3a, 3h, 4a, 4c, and 6j. For 2 of the 4 unsuccessfully treated individuals with available sequence data at treatment failure, NS5A resistance-associated substitutions were present (30R/93S in an individual with genotype 4c and 31M in an individual with genotype 6j). SVR12 rates were high in individuals with HIV/HCV residing in Europe and originating from regions where intrinsically NS5A-resistant HCV strains are endemic. HCV elimination for this population in Europe is unlikely to be hampered by suboptimal DAA efficacy.

Impact of Interferon-Free Direct-Acting Antivirals on the Incidence of Extrahepatic Malignancies in Patients with Chronic Hepatitis C.

The incidence of extrahepatic malignancies (EHMs) after hepatitis C virus (HCV) eradication by interferon (IFN)-based and IFN-free direct-acting antivirals (DAAs) treatment remains unclear. The aim was to evaluate the cumulative incidence of EHMs diagnosed for the first time after the antiviral treatments. We analyzed a total 527 patients with chronic HCV infection and without prior history of any malignancies who achieved sustained virological response by antiviral treatments, including IFN-based (n = 242) or IFN-free DAAs (n = 285). The baseline predictors for EHM occurrence were analyzed using Cox regression analysis. Thirty-two patients were diagnosed with EHMs, 14 in IFN-based and 18 in IFN-free DAAs, respectively. The total duration of follow-up was 1,796 person-years in IFN-based and 823 person-years in IFN-free DAAs. The incidence of EHMs in IFN-based and IFN-free DAAs was 7.8 and 21.9 per 1,000 person-years, respectively. The cumulative incidence of EHMs was significantly higher in IFN-free DAAs than IFN-based (p = 0.002). IFN-free DAAs was a single independent predictor for incidence of EHMs (p = 0.012). As for gender, the incidence of EHMs was significantly higher in IFN-free DAAs only in the female cohort (p = 0.002). After propensity score matching, IFN-free DAAs was a single independent predictor for incidence of EHMs in the female patients (p = 0.045). The incidence of EHMs after HCV eradication is higher in IFN-free DAAs than IFN-based regimens, especially in female patients. We should carefully follow-up not only HCC but also EHMs after IFN-free DAAs regimens.

Real-Life Early Anthropometric, Lipid and Liver Changes after Direct-Acting Antiviral Therapy in PLWHIV with HCV Co-Infection.

Treatment with interferon-free direct-acting antivirals (DAA) has become the gold standard in chronic hepatitis C virus (HCV) infection. Nevertheless, little research about the metabolic impact of achieving sustained virological response (SVR) is available in HCV/HIV co-infected patients. This research aimed to evaluate early anthropometric, lipid and liver parameters changes after achieving SVR 12 weeks after treatment (SVR12). A real-life retrospective descriptive before-after study assessed 128 DAA treatment episodes from 2015 to 2019 in HCV/HIV co-infected patients. Anthropometric parameters (weight, body mass index), lipid profile, genotype (GT) and viral load, liver data (basics laboratory necroinflammatory parameters and transient elastography (TE)) were collected before treatment with DAA (baseline), and when SVR12 was achieved. Significant increases (p < 0.01) were found in the early lipid profile, measured by LDLc (84.6 ± 35.0 vs. 108.6 ± 35.1 mg/dL) and total cholesterol (161.3 ± 41.0 vs. 183.3 ± 41.6 mg/dL). Significant changes (p < 0.05) were found in liver parameters, measured by ALT (58.2 ± 34.0 vs. 22.0 ± 16.0 U/L), bilirubin (0.8 ± 0.6 vs. 0.6 ± 0.5 mg/dL), albumin (4.2 ± 0.4 vs. 4.3 ± 0.3 g/dL) and liver stiffness (LS) (13.7 ± 13.3 vs. 11.8 ± 12.1 kPa). The main conclusions were that the use of DAA has an early negative impact on lipid metabolism. Achieving SVR12 against HCV leads to an early improvement in liver function and LS in HCV/HIV co-infected patients without interference with antiretroviral treatment (ART) and DAA. Short-term close lipid monitoring may be necessary when combining protease inhibitors. HCV-GT-3/HIV co-infected patients might require further close monitoring for residual fibrosis. These findings can be relevant for actual clinical practice.

Relapse of Hepatitis C Virus Cryoglobulinemic Vasculitis After Sustained Viral Response After Interferon-Free Direct-Acting Antivirals.

Direct-acting antiviral agents (DAAs) have modified the management of chronic hepatitis C virus (HCV) infection, including HCV-related cryoglobulinemic vasculitis (CryoVas). However, patients might experience vasculitis relapse, and no reliable predictors of CryoVas relapse after sustained virologic response (SVR) have been established. We aimed to describe HCV-CryoVas relapse rates and factors associated with it. An international multicenter cohort where patients with HCV-CryoVas from Egypt, France, and Italy treated with DAA were analyzed retrospectively. Factors associated with relapse-free survival were evaluated in a multivariate-adjusted model. Of 913 patients, 911 (99.8%) obtained SVR. After 35 months of the median follow-up, 798 patients (87.4%) had sustained remission of vasculitis, while 115 (12.6%) experienced CryoVas relapse. By the time of relapse, skin involvement was present in 100%, renal involvement in 85.2%, and peripheral neuropathy in 81.7%. Relapses were treated with glucocorticoids in 90.9%, associated with plasma exchange, cyclophosphamide, or rituximab in 50%, 37.3%, and 6.4%, respectively. The cumulative incidence of CryoVas relapse was 0.7% (95% CI 0.3-1.4), 12.3% (95% CI 10.2-14.6), and 13.1% (95% CI 11.0-15.5) at 12, 24, and 36 months after DAA treatment, respectively. Independent baseline risk factors associated with CryoVas relapse were male sex, skin ulcers, kidney involvement at baseline, and peripheral neuropathy at the end of DAA treatment. Death occurred in 11 relapsers, mainly due to infections. A substantial proportion of patients with CryoVas experience relapse after DAA-induced SVR. Relapses are moderate-to-severe and affect survival after 24 months, mainly due to infections. Independent risk factors for relapse or death were found.

Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment.

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8ng/ml ≥1year following treatment with DAAs (HR, 9.7; p<.0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.

Long-term hepatic function of patients with compensated cirrhosis following successful direct-acting antiviral treatment for hepatitis C virus infection.

Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4years after the end of treatment, and the progression to decompensation was evaluated. The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4<3.25 (40%) and ALBI grade 1 (70%) reached their plateau in the first year; however, there were significant further improvements in platelet count and α-fetoprotein level after the first year. The annual incidence of decompensation was 1.30 (95% confidence interval 0.83-2.02) per 100 person-years. In multivariable analysis, male sex and modified ALBI grade 2b at baseline were associated with decompensation. In a large real-world cohort of patients with compensated cirrhosis treated with a DAA, remarkable improvement in hepatic function was seen after HCV cure, especially during the first year after the end of treatment. Treatment in the early stage of cirrhosis would be of great benefit for preventing liver deterioration to decompensation.

Risk of Non-Hodgkin's Lymphoma in HCV Patients in the United States Between 2013 and 2020: A Population-Based Study

Hepatitis C virus (HCV) is a significant healthcare problem affecting ~1% of the United States population. Meta-analyses of epidemiological studies reported a strong association between non-Hodgkin's lymphoma (NHL) and HCV. Direct oncogenic properties of HCV proteins and chronic antigenic stimulation are possible etiologies. We explored if NHL's prevalence has changed since older HCV therapy based on interferon that shared antiviral and anti-lymphoma properties was replaced with interferon-free direct-acting antivirals (DAA). We reviewed data from a nationwide database (Explorys, IBM) that aggregates records from 26 health-care-systems. We identified patients with chronic hepatitis C infection between June 2013 and June 2020. The control group was gender, race, and age-matched HCV-negative population. Statistical analysis used the odds ratio (OR) with P value <.001 for significance. There were 940 cases of NHL of 129,970 patients in the HCV group versus 107,480 cases of NHL of 37,961,970 in the control cohort [OR 2.6, 95% confidence interval (CI) 2.4-2.7]. A positive association was present for chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, non-Hodgkin T-cell lymphoma, and primary cutaneous T-cell lymphoma. There were no differences in Mantle cell lymphoma. The increased risk of HCV-associated lymphoma was persistent across genders, Caucasians and African-Americans, and age groups. While the risk of NHL in the HCV-negative population was higher in Caucasians than African-Americans (OR 1.8, 95% CI 1.7-1.8), the risk of HCV-associated NHL was not different. Further prospective studies examining the risk of HCV-associated lymphoma following DAA are warranted.

Outcomes in the Era of Interferon-Free Direct-Acting Antiviral Therapy After Liver Transplantation in Patients with Hepatitis C Virus and Hepatocellular Carcinoma

Background/AimsSeveral studies have shown improved outcome of liver transplant (LT) recipients with hepatitis C virus (HCV) since the widespread clinical use of interferon-free direct-acting antivirals (IFN-free DAAs). However, the association of IFN-free DAA therapy on tumor characteristics and on the outcome of LT in patients with hepatocellular carcinoma (HCC) has not been studied. We aimed to examine pre-transplant HCC characteristics and post-LT outcomes in the IFN-based DAA treatment and IFN-free DAA treatment eras.MethodsUsing the United Network for Organ Sharing/Organ Procurement and Transplantation Network database, we analyzed adults with a diagnosis of HCV and HCC who received LTs from deceased donors from 04/2012 to 12/2017. Cox regression models were used to identify the association between the IFN-based DAA treatment vs IFN-free DAA treatment era and study outcomes (mortality, graft failure, and HCC recurrence at 1 and 3 years).ResultsComplete tumor necrosis was significantly higher in the IFN-free DAA treatment era (22.73% vs 18.22%; P <0.01). No other HCC tumor characteristics differed significantly between the two eras. HCC recurrence rates were similar between the two eras. On multivariate Cox regression analysis, patients who had transplants in the IFN-free DAA treatment era had lower risk of graft failure compared with the IFN-based DAA treatment group (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.25–0.77; P <0.01). Patient mortality was lower in the IFN-free DAA treatment era although the difference was not statistically significant (HR, 0.82; 95% CI, 0.60–1.13; P =0.22).ConclusionLT recipients in the IFN-free DAA treatment era had significantly higher complete tumor necrosis in explants. Other HCC tumor characteristics were similar between the two eras. Post-LT graft failure at 1 and 3 years significantly decreased in the IFN-free DAA treatment era among patients with HCV and HCC, although patient mortality was not statistically different.

Effectiveness and Safety of Interferon-Free Direct-Acting Antiviral Hepatitis C Virus Therapy in HIV/Hepatitis C Virus Coinfected Individuals: Results From a Pan-European Study.

To investigate the effectiveness, safety, and reasons for premature discontinuation of direct-acting antivirals (DAAs) in a diverse population of HIV/hepatitis C virus (HCV) coinfected individuals in Europe. All HIV/HCV coinfected individuals in the EuroSIDA study that started interferon free DAA treatment between January 6, 2014, and January 3, 2018, with ≥12 weeks of follow-up after treatment stop were included in this analysis. Sustained virological response (SVR) was defined as a negative HCV-RNA result ≥12 weeks after stopping treatment (SVR12). Logistic regression was used to explore factors associated with SVR12. 1042 individuals started interferon-free DAA treatment after 1/6/2014 and were included, 862 (82.2%) had a known response to treatment, and 789 [91.5%, 95% confidence interval (CI): 89.7 to 93.4] of which achieved SVR12. There were no differences in SVR12 across regions of Europe (P = 0.84). After adjustment, the odds of achieving SVR12 was lower in individuals that received sofosbuvir/simeprevir ± ribavirin (RBV) [adjusted odds ratio 0.21 (95% CI: 0.08 to 0.53)] or ombitasvir/paritaprevir/dasabuvir ± RBV [adjusted odds ratio 0.46 (95% CI: 0.22 to 1.00)] compared with sofosbuvir/ledipasvir ± RBV. Forty-three (4.6%) individuals had one or more components of their HCV regimen stopped early, most commonly because of toxicity (n = 14); of these 14, 11 were treated with ribavirin. Increased bilirubin was the most common grade 3 or 4 laboratory adverse event (n = 15.3%) and was related to treatment with atazanavir and ribavirin. Our findings from real-world data on HIV/HCV coinfected individuals across Europe show DAA treatment is well tolerated and that high rates of SVR12 can be achieved in all regions of Europe.

Direct-Acting Antiviral Treatment for Hepatitis C Genotypes Uncommon in High-Income Countries: A Dutch Nationwide Cohort Study.

BackgroundThe majority of hepatitis C virus (HCV) infections are found in low- and middle-income countries, which harbor many region-specific HCV subtypes. Nevertheless, direct-acting antiviral (DAA) trials have almost exclusively been conducted in high-income countries, where mainly epidemically spread HCV subtypes are present. Recently, several studies have demonstrated suboptimal DAA efficacy for certain nonepidemic subtypes, which could hamper global HCV elimination. Therefore, we aimed to evaluate DAA efficacy in patients treated for a nonepidemic HCV genotype infection in the Netherlands.MethodsWe performed a nationwide retrospective study including patients treated with interferon-free DAAs for an HCV genotype other than 1a/1b/2a/2b/3a/4a/4d. The genotype was determined by NS5B region phylogenetic analysis. The primary end point was SVR-12. If stored samples were available, NS5A and NS5B sequences were obtained for resistance-associated substitutions (RAS) evaluation.ResultsWe included 160 patients, mainly infected with nonepidemic genotype 2 (41%) and 4 (31%) subtypes. Most patients were from Africa (45%) or South America (24%); 51 (32%) were cirrhotic. SVR-12 was achieved in 92% (140/152) of patients with available SVR-12 data. Only 73% (8/11) genotype 3–infected patients achieved SVR-12, the majority being genotype 3b patients with 63% (5/8) SVR. Regardless of SVR, all genotype 3b patients had 30K and 31M RAS.ConclusionsThe DAA efficacy we observed in most nonepidemic genotypes in the Netherlands seems reassuring. However, the low SVR-12 rate in subtype 3b infections is alarming, especially as it is common in several HCV-endemic countries. Alongside earlier results, our results indicate that a remaining challenge for global HCV elimination is confirming and monitoring DAA efficacy in nonepidemic genotypes.

Population impact of direct-acting antiviral treatment on new presentations of hepatitis C-related decompensated cirrhosis: a national record-linkage study

ObjectivePopulation-based studies demonstrating the clinical impact of interferon-free direct-acting antiviral (DAA) therapies are lacking. We examined the impact of the introduction of DAAs on HCV-related decompensated cirrhosis (DC) through analysis...

Risk of Non-Hodgkin's Lymphoma in HCV Patients in the United States between 2013 and 2020: A Population-Based Study

Introduction Hepatitis C virus (HCV) is a major healthcare problem affecting ~ 1% of the United States population. HCV virus is known to have lymphotropic properties and metanalyses of epidemiological studies reported an association between HCV and non-Hodgkin's lymphoma (NHL) with a relative risk range (1.8 to 10.8). 1-4 Most studies included in these metanalyses were heterogenic with different control groups, and contained a relatively small number of patients that prevented the evaluation of racial differences or the association of HCV with distinct NHL subtypes. We conducted a population-based study to address these deficiencies and to explore if the prevalence of NHL has changed since older therapy of HCV based on interferon that shared both anti-viral and anti-lymphoma properties was replaced with the interferon-free direct-acting antivirals (DAA). Methods We reviewed data from a nationwide commercial database (Explorys, IBM) that aggregates records from 26 health-care-systems and includes 72 million patients. We identified adult patients aged ≥ 40 years with HCV between June 2013 and June 2020. The control population was HCV-negative matched for gender, race; Caucasian, and African-American, and two age groups; 40-64 years and ≥ 65 years. We excluded all patients who developed NHL before the study start date and patients with HIV. The association between NHL and HCV was evaluated using odds ratios (OR) with a 95% confidence interval. The differences were considered significant at a P value of less than 0.001. Results There were 940 cases of NHL among 129970 HCV individuals versus 107480 cases of NHL out of 37961970 persons in the control cohort [OR 2.6, 95% confidence interval (CI) 2.4-2.7]. A positive association was present in chronic lymphocytic leukemia (OR 1.4, 95% CI 1.2-1.6), follicular lymphoma (OR 2.7, 95% CI 2.2-3.4), marginal zone lymphoma (OR 5.2, 95% CI 3.8- 7.1), lymphoplasmacytic lymphoma (OR 2.6, 95% CI 1.8-3.8), diffuse large B-cell lymphoma (OR 4.4, 95% CI 3.4 - 5.6), Burkitt's lymphoma (OR 4.2, 95% CI 2.9-6.0), non-Hodgkin's T-cell lymphoma (OR 2.5, 95% CI 2.1-3.0) and primary cutaneous T-cell lymphoma (OR 2.8, 95% CI 1.9-3.3). There was no difference in Mantle cell lymphoma (see Figure 1, and Table 1). The increased risk of HCV-associated lymphoma was persistent when adjusted for gender, Caucasian and African-American races, and in age groups of 40-64 years and &amp;gt; 65 years (see Table 2). While in the control population, Caucasians had a higher risk of NHL compared to African-Americans (OR 1.8, 95% CI 1.75-1.84), there was no difference in HCV-associated lymphoma (see Tables 3 and 4). Discussion: Our study is the largest of population-based studies evaluating the risk of non-Hodgkin's lymphoma in patients with HCV. The Risk of HCV-associated NHL was higher with an OR of 2.6 compared to older studies in the US published before DAA therapy was available reporting an OR close to 1.5.5,6 The observation of increased risk of chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, and diffuse large B-cell lymphoma was comparable with the prior meta-analysis. 1-4 However, we found an increased risk in Burkitt's lymphoma, non-Hodgkin's T-cell lymphoma and primary cutaneous T-cell lymphoma. Possible pathophysiology of HCV-associated lymphomagenesis is shown in Figure 2. Interestingly, while the risk of NHL lymphoma in HCV-negative Caucasians was higher than African-Americans in keeping with US-based epidemiologic studies.7 A novel finding of our study found was the lack of difference in HCV-associated lymphoma between Caucasians and African-Americans. Reason for possible increased oncogenicity of HCV in African-Americans is unclear. Limitations of the databased based project include inaccuracies and miscoding. Given the nature of the data it was not possible to study differences between patients who received interferon-based therapy versus DAA. In conclusion, despite recent advances in HCV treatment, the risk of NHL among HCV infected patients remains elevated and it was persistent in males and females. In contrast to non-HCV background population where Caucasians had a higher prevalence of NHL, there was no difference between Caucasians and African-Americans. An effort to early detect and treat HCV is needed along with establishing prospective studies to examine the impact of HCV therapy with DAA on NHL risk. Figure Disclosures No relevant conflicts of interest to declare.

Characteristics associated with time-to-treatment initiation for chronic Hepatitis C with new direct acting antivirals.

Interferon-free direct-acting antivirals (DAAs) were introduced in 2013 and have transformed the therapeutic landscape for chronic Hepatitis C (HCV). Although treatment is recommended for almost all persons infected with HCV, clinical and psychosocial factors may affect treatment initiation. We conducted an observational cohort study of Kaiser Permanente Mid-Atlantic States members with prevalent or incident HCV infection identified from November 2013 through May 2016 to identify predictors of DAA initiation. We used Cox regression with time-dependent covariates to compare time to treatment by clinical, demographic and societal factors. Of 2962 patients eligible for DAA therapy, 33% (n = 980) initiated treatment over the study period. The majority of patients (97%) were persistent with therapy and most (95%) tested for sustained virologic response (SVR) achieved cure. We found no effect of race, insurance type or fibrosis stage on treatment initiation. We observed that patients aged 41-60 years (aHR: 2.014, 95% CI: 1.12, 3.60) and 61-80 years (aHR: 2.08, 95% CI: 1.15-3.75) had higher treatment rates compared to younger patients. Incident cases were more likely to be treated than prevalent cases (aHR: 3.05, 95% CI: 2.40-3.89). Patients with a history of substance use disorder (SUD) were less likely (aHR: 0.805, 95% CI: 0.680, 0.953) to be treated. In the first 3 years of DAA availability, one-third of patients with HCV initiated therapy, and almost all were persistent and achieved cure. While curative, DAAs remain highly priced. Triaging for non-clinical reasons or perceptions about patients will stall our ability to eradicate HCV.