Direct-acting Antiviral Therapy For Hepatitis Research Articles

Outcomes of Kidneys Transplanted From Hepatitis C Viremic Donors to Naive Recipients From an Appalachian Rural Kidney Transplant Program.

Before the advent of direct-acting antiviral therapy for hepatitis C virus, a large proportion of kidneys from donors with hepatitis C viremia were discarded. Hepatitis C virus is now amenable to effective treatment with excellent seronegativity rates. In this study, we review the outcomes of hepatitis C viremic kidneys transplanted into hepatitis C-naive recipients. In this retrospective observational study, we examined 6 deceased donor kidneys with hepatitis C viremia that were transplanted into hepatitis C-naive recipients between March 2020 and April 2021 at a single center. Because of health insurance constraints, patients were treated for hepatitis C virus with glecaprevir/pibrentasvir for 8 weeks following seroconversion posttransplant. Primary outcome measured was viral seroconversion; secondary outcomes included graft function, posttransplant complications, and all-cause mortality. On average, patients seroconverted 6 days (range, 4-10 d) after transplant and began treatment 26 days (range, 15-37 d) after seroconversion. An 8-week course of antiviral treatment was successful in preventing acute hepatitis C virus infection in all patients. Posttransplant median creatinine was 1.96 mg/dL (range, 1-4.55 mg/dL), whereas median estimated glomerular filtration rate was 41.33 mL/min/1.73 m2 (range, 17-85 mL/min/1.73 m2). Patient survival rate was 66.7%, and death-censored graft survival rate was 100%. Two patients died from unrelated reasons: 1 from acute respiratory failure secondary to SARS-CoV-2 infection and 1 from posttransplant lymphoproliferative disorder. Two patients developed allograft rejection posttransplant (1 developed antibody mediated rejection, 1 developed borderline T-cell-mediated cellular rejection). Other major complications included neutropenia, fungal rash, SARS-CoV-2 infection, cytomegalovirus, BK virus, and Epstein-Barr virus reactivation. Use of hepatitis C-viremic donor kidneys for transplant is a safe option and has great potential to increase the kidney donor pool, as long as high index of suspicion is maintained for allograft rejection and opportunistic infections.

Immune Responses to Anti-Hepatitis C Virus Antibodies during Pre-Liver Transplantation Direct-Acting Antiviral Therapy in Hepatitis C Virus-Infected Recipients Associated with Post-Liver Transplantation Allograft Injury.

The impact of antibody responses following direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined. In this observational cohort study, we aimed to explore the association between changes in anti-HCV antibody titers following pre-LT DAA therapy and allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR). A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (the DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (the DAA-naïve group). A higher incidence of post-LT BCs was observed in the DAA group (p = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation (p = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation (p < 0.005). In conclusion, we speculate that the upregulation of anti-HCV antibody titers, which might have been induced via the restoration of HCV-specific immune responses through pre-LT DAA therapy, was associated with post-LT allograft injury.

A transient positive association between direct-acting antiviral therapy for hepatitis C infection and drug-related hospitalization among people who inject drugs: Self-controlled case-series analysis of national data.

Direct-acting antiviral (DAA) treatment has an established positive effect on liver outcomes in people with hepatitis C infection; however, there is insufficient evidence regarding its effects on the 'extra-hepatic' outcomes of drug-related hospitalization and mortality (DRM) among people who inject drugs (PWID). We investigated associations between these outcomes and DAA treatment by comparing post-treatment to baseline periods using a within-subjects design to minimize selection bias concerns with cohort or case-control designs. This was a self-controlled case-series study. Scotland, 1 January 2015-30 November 2020. The study population of non-cirrhotic, DAA-treated PWID was identified using a data set linking Scotland's hepatitis C diagnosis, HCV clinical databases, national inpatient/day-case hospital records and the national deaths register. Three principal outcomes (drug overdose admission, non-viral injecting related admission and drug-related mortality) were defined using ICD codes. Self-controlled case-series methodology was used to estimate the relative incidence (RI) of each outcome associated with time on treatment and up to six 90-day exposure risk periods thereafter. A total of 6050 PWID were treated with DAAs in the sampling time-frame. Compared with the baseline period, there was a significantly lowered risk of a drug overdose hospital admission in the second to fifth exposure risk periods only [relative incidence (RI) = 0.86, 95% confidence interval (CI) = 0.80-0.99; 0.89, 95% CI = 0.80-0.99; 0.86, 95% CI = 0.77-0.96; 0.88, 95% CI = 0.78-0.99, respectively]. For non-viral injecting-related admission, there was a reduced risk in the first, third and fourth exposure risk periods (RI = 0.76, 95% CI = 0.64-0.90; 0.75, 95% CI = 0.62-0.90; 0.79, 95% CI = 0.66-0.96, respectively). There was no evidence for reduced DRM risk in any period following treatment end. Among people who inject drugs in Scotland, direct-acting antiviral treatment appears to be associated with a small, non-durable reduction in the risk of drug-related hospital admission, but not drug-related mortality. Direct-acting antiviral therapy, despite high effectiveness against liver disease, does not appear to offer a panacea for reducing other drug-related health harms.

Improved health-related quality of life after hepatitis C viraemic clearance among people who inject drugs may not be durable.

Chronic infection with the hepatitis C virus (HCV) has a detrimental impact on health-related quality of life (QoL). Scale-up of HCV direct-acting antiviral (DAA) therapy among people who inject drugs (PWID) is underway in several countries since the introduction of interferon-free regimens. This study aimed to assess the impact of DAA treatment success on QoL for PWID. Cross-sectional study using two rounds of the Needle Exchange Surveillance Initiative, a national anonymous bio-behavioural survey and a longitudinal study involving PWID who underwent DAA therapy. The setting for the cross-sectional study was Scotland (2017-2018, 2019-2020). The setting for the longitudinal study was the Tayside region of Scotland (2019-2021). In the cross-sectional study PWID were recruited from services providing injecting equipment (n = 4009). In the longitudinal study, participants were PWID on DAA therapy (n = 83). In the cross-sectional study, the association between QoL (measured using the EQ-5D-5L quality of life instrument) and HCV diagnosis and treatment was assessed using multilevel linear regression. In the longitudinal study, QoL was compared at four timepoints using multilevel regression, from treatment commencement until 12 months following commencement. In the cross-sectional study, 41% (n = 1618) were ever chronically HCV infected, of whom 78% (n = 1262) were aware of their status and of whom 64% (n = 704) had undergone DAA therapy. There was no evidence for a marked QoL improvement associated with viral clearance among those treated for HCV (B = 0.03; 95% CI, -0.03 to 0.09). In the longitudinal study, improved QoL was observed at the sustained virologic response test timepoint (B = 0.18; 95% CI, 0.10-0.27), but this was not maintained at 12 months following start of treatment (B = 0.02; 95% CI, -0.05 to 0.10). Successful direct-acting antiviral therapy for hepatitis C infection may not lead to a durable improvement in quality of life among people who inject drugs, although there may be a transient improvement around the time of sustained virologic response. Economic models of the impact of scaling-up treatment may need to include more conservative quality of life benefits over and above reductions in mortality, disease progression and transmission of infection.

Alcohol consumption upon direct-acting antiviral therapy for hepatitis C among persons with human immunodeficiency virus in the United States

BackgroundDirect-acting antivirals (DAA) are highly effective against hepatitis C virus (HCV) infection among persons with human immunodeficiency virus (PWH). However, alcohol use post-DAA treatment poses a continued threat to the liver. Whether the focus on liver health alone during HCV treatment can impact alcohol consumption is unclear. Therefore, we examined the change in alcohol use among HCV-coinfected PWH who received DAA therapy by non-addiction medical providers. MethodsIn our longitudinal clinical cohort study, we identified HCV-coinfected PWH who received interferon-free DAA therapy between January 2014 and June 2019 in the Centers for AIDS Research Network of Integrated Clinical Systems. The Alcohol Use Disorders Identification Test—Consumption (AUDIT-C) was the alcohol screening instrument. We used mixed-effects logistic regression models to estimate the longitudinal change in alcohol use upon DAA therapy. ResultsAmong 738 HCV-coinfected PWH, 339 (46 %) reported any alcohol use at the end of HCV treatment, including 113 (15 %) with high-risk use (i.e., AUDIT-C ≥3 for women, ≥4 for men). Concurrently, 280 (38 %) PWH noted active drug use, and 357 (48 %) were currently smoking. We observed no changes in the odds of any alcohol or high-risk alcohol use over time with DAA therapy. Findings were similar in the PWH subgroup with a history of alcohol use before DAA treatment. ConclusionsFor PWH with HCV, alcohol use did not change following interferon-free DAA treatment by non-addiction medical providers. Thus, clinicians should consider integrating targeted alcohol use interventions into HCV care to motivate reduced alcohol consumption and safeguard future liver health.

Serum IL-1β predicts de novo hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C, not during anti-cancer/immunosuppressive therapy

De novo hepatitis B virus (HBV) reactivation occurs during direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-infected patients with resolved HBV infection. We evaluated the predictive factors, mechanical insight, and differences of cytokine levels during anti-cancer/immunosuppressive and DAA. Eleven, 35, and 19 HCV-infected patients with previous HBV infection with HBV reactivation during DAA treatment, previous HBV infection without HBV reactivation during DAA treatment, and without HBV infection resolution receiving DAA treatment, respectively, were enrolled. Clinical data and baseline cytokine levels were analyzed. Low baseline serum interleukin (IL)-1β levels predicted de novo HBV reactivation during DAA treatment (odds ratio: 47.6, 95% confidence interval: 6.94–333.3). HCV-infected patients with the IL-1β gene single nucleotide polymorphism rs16944 AA allele had significantly higher IL-1β levels; no HCV-infected patient with the IL-1β AA allele experienced HBV reactivation during DAA treatment. Compared to HCV-infected patients with HBV infection resolution, non-HCV infected patients with or without HBV reactivation during anti-cancer/immunosuppressive therapy or bone marrow transplantation had remarkably lower baseline IL-1β levels. Low IL-1β levels were not associated with HBV reactivation. IL-1β levels before DAA for HCV-infected patients with resolved HBV infection could predict HBV reactivation during DAA treatment.

Uptake and factors associated with direct-acting antiviral therapy for hepatitis C and treatment outcomes among Canadian immigrants: A retrospective cohort analysis.

We sought to compare rates and factors associated with direct acting antiviral (DAA) treatment uptake and sustained virological response (SVR) between Canadian-born and foreign-born patients. The study was conducted utilizing a retrospective cohort of hepatitis C virus (HCV)-infected patients assessed at The Ottawa Hospital Viral Hepatitis Clinic between January 2015 and October 2021. Risk factors, income, and clinical characteristics of HCV infection associated with DAA therapy uptake and SVR were compared by immigration status using logistic regression. Of 1,459 HCV-infected patients, 264 (18.1%) were born outside of the country. A median 17 years passed from immigration to first assessment at the clinic. The proportion of patients initiating DAA therapy was similar between groups (65.2% versus 69.5%, p = 0.17). Characteristics associated with DAA therapy uptake included age at first assessment (OR 1.02; 95% CI 1.01 to 1.03) and being cirrhotic (OR 3.19; 95% CI 1.99 to 2.13). Crude SVR rate was higher in immigrants than in Canadian-born patients (91.5% versus 83.7%, p = 0.01). After controlling for other variables, only advancing age was associated with the likelihood of achieving crude SVR (OR 1.04, 95% CI 1.02 to 1.05). We found that DAA therapy uptake and HCV cure rates were high in both groups suggesting equity of opportunity in those referred to our program. The older age at presentation suggests missed opportunities to diagnose and engage immigrants in HCV care. These findings emphasize the importance of early large-scale screening and engagement in care for HCV infection of immigrant populations to prevent future complications.

Qualitative analysis of the barriers and facilitators influencing uptake of direct-acting antiviral therapy for hepatitis C in a primary healthcare environment.

Historical interferon and ribavirin therapies for hepatitis C virus have been replaced by modern treatments with improved efficacy and tolerability. Despite the availability of direct-acting antiviral therapy, evidence demonstrates poor uptake in Australia. Presently, the barriers and facilitators influencing uptake of direct-acting antiviral therapy are not fully understood, especially in a primary healthcare environment. Our study aimed to discover methods of improving uptake of treatment in the community. We conducted 15 semi-structured, face-to-face interviews in a metropolitan, primary healthcare clinic in Australia. Interviews were recorded, transcribed and subsequently analysed using thematic content analysis. We identified patient-related and healthcare system-related barriers and facilitators to commencing treatment. This included established themes from current literature, and novel themes unique to direct-acting antiviral therapy and primary care. Overall, our study reinforces the importance of public health campaigns to promote community awareness and emphasises the concomitant role of mental health in fostering treatment uptake. Informed by our findings, we suggest further research on an integrated model of care, focused on the domains of disease awareness, patient engagement and treatment adherence. Hence, a community-oriented approach, driven by primary healthcare, ultimately underpins a successful public strategy to improve outcomes for patients affected by hepatitis C.

Development of Focal segmental glomerulosclerosis 4- years following direct-acting antiviral therapy for hepatitis C virus infection: Case report

Development of Focal segmental glomerulosclerosis 4- years following direct-acting antiviral therapy for hepatitis C virus infection: Case report

Cost-effectiveness and system-wide impact of using Hepatitis C-viremic donors for heart transplant

The advent of direct-acting antiviral therapy for Hepatitis C (HCV) has made using HCV-viremic donors a viable strategy to address the donor shortage in heart transplantation. We employed a large-scale simulation to evaluate the impact and cost-effectiveness of using HCV-viremic donors for heart transplant. We simulated detailed histories from time of listing until death for the real-world cohort of all adults listed for heart transplant in the United States from July 2014 to June 2019 (n=19,346). This population was imputed using historical data and captures "real-world" heterogeneity in geographic and clinical characteristics. We estimated the impact of an intervention in which all candidates accept HCV+ potential donors (n=472) on transplant volume, waitlist outcomes, and lifetime costs and quality-adjusted life years (QALYs). The intervention produced 232 more transplants, 132 fewer delistings due to deterioration, and 50 fewer waitlist deaths within this 5-year cohort and reduced wait times by 3% to 11% (varying by priority status). The intervention was cost-effective, adding an average of 0.08 QALYs per patient at a cost of $124 million ($81,892 per QALY). DAA therapy and HCV care combined account for 11% this cost, with the remainder due to higher costs of transplant procedures and routine post-transplant care. The impact on transplant volume varied by blood type and region and was correlated with donor-to-candidate ratio (ρ=0.71). Transplanting HCV+ donor hearts is likely to be cost-effective and improve waitlist outcomes, particularly in regions and subgroups experiencing high donor scarcity.

Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome

Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.

COST-EFFECTIVENESS AND SYSTEM-WIDE IMPACT OF USING HEPATITIS C-VIREMIC DONORS FOR HEART TRANSPLANT

Background The advent of direct-acting antiviral therapy for Hepatitis C (HCV) has made using HCV-viremic donors a viable strategy to address the donor shortage in heart transplantation . We employed a large-scale simulation to evaluate the impact and cost-effectiveness of using HCV-viremic donors for heart transplant . Methods We simulated detailed histories from time of listing until death for the real-world cohort of all adults listed for heart transplant in the United States from July 2014 to June 2019 (n = 19,346). This population was imputed using historical data and captures “real-world” heterogeneity in geographic and clinical characteristics. We estimated the impact of an intervention in which all candidates accept HCV+ potential donors (n = 472) on transplant volume, waitlist outcomes, and lifetime costs and quality-adjusted life years (QALYs). Results The intervention produced 232 more transplants, 132 fewer delistings due to deterioration, and 50 fewer waitlist deaths within this 5-year cohort and reduced wait times by 3% to 11% (varying by priority status). The intervention was cost-effective, adding an average of 0.08 QALYs per patient at a cost of $124 million ($81,892 per QALY). DAA therapy and HCV care combined account for 11% this cost, with the remainder due to higher costs of transplant procedures and routine post-transplant care. The impact on transplant volume varied by blood type and region and was correlated with donor-to-candidate ratio (ρ = 0.71). Conclusions Transplanting HCV+ donor hearts is likely to be cost-effective and improve waitlist outcomes, particularly in regions and subgroups experiencing high donor scarcity.

Baseline elevated serum angiopoietin-2 predicts long-term non-regression of liver fibrosis after direct-acting antiviral therapy for hepatitis C

We previously revealed that Angiopoietin-2 (Ang2) predicts non-regression of liver fibrosis based on liver stiffness measurement (LSM) at 24 weeks after anti-hepatitis C virus (HCV) treatment. In this study, we extended the observational period to 96 weeks to investigate the factors associated with non-regression after treatment with direct-acting-antivirals (DAAs). Patients treated with DAAs who underwent transient elastography at baseline and 24 and 96 weeks after DAA therapy were included. Baseline and post-treatment serum Ang2 levels were measured. Liver fibrosis stages were defined based on LSM. Multivariate regression was used to evaluate factors associated with non-regression of liver fibrosis between various time points. In total, 110 patients were included. Of these, 11% showed non-regression of LSM-based fibrosis stage at 96 weeks after DAA therapy. In multivariate analysis, advanced liver fibrosis stage and high baseline Ang2 levels were significantly associated with non-regression at 96 weeks. In patients with advanced liver fibrosis (F3/4), baseline Ang2 levels were associated with non-regression of liver fibrosis stage. Between SVR24 and SVR96, post-treatment Ang2 levels and controlled attenuation parameter values at SVR24 were significantly associated with non-regression of liver fibrosis stage in patients with F3/4. Thus, serum Ang2 levels are an important target for monitoring and therapy.

Applying a diffusion of innovations framework to the scale-up of direct-acting antiviral therapies for hepatitis C virus infection: Identified challenges for widespread implementation

Background and AimsInterferon-free, direct-acting antivirals (DAAs) for hepatitis C virus (HCV) offer much promise to achieve World Health Organization targets by 2030. However, impediments at the practitioner and health-system level will continue to obstruct the scale-up of DAAs worldwide unless identified and acted upon. Applying a diffusion of innovations framework, the aim of this study was to identify structural factors impacting practitioner experiences of managing HCV treatment. MethodsIn-depth, semi-structured, telephone interviews took place between September 2018 and April 2019 to investigate barriers and facilitators for engaging in HCV management and DAA therapy amongst general practitioners (GPs) who prescribe opioid agonist therapy and drug and alcohol specialists in Australia. Interviews were transcribed verbatim, de-identified, and coded, and data were analysed with iterative categorisation and thematic analysis using Everett Rogers's diffusion of innovation framework. Resultsamongst 30 participants (12 GPs, 18 drug and alcohol specialists), several structural factors were reported to impede practitioner efforts to deliver optimal HCV care. Two primary themes were explored: contextual factors for the diffusion of DAA therapies, including attempts by participants to shift clinic culture and respond to siloed health structures, and adopter factors. Some participants chose to ‘rock the boat’ by circumventing clinic protocol and HCV guidelines to treat more clients, effectively shifting adopter categories to become greater advocates in HCV care. Also, while a role for GPs as the ‘new adopters’ in HCV management was discussed, many participants expressed uncertainty as to how much GPs should become involved in the diffusion of DAA therapies more widely. ConclusionsReducing the global burden of HCV infection will not be possible without the widespread delivery of HCV treatment amongst practitioners. Practitioners and health workers require leadership and resources from health authorities so that the individual and population-level benefits of DAA therapy are realised.

Reduced Alcohol Use Is Sustained in Patients Provided Alcohol-Related Counseling During Direct-Acting Antiviral Therapy for Hepatitis C.

Patients with chronic hepatitis C and risky/harmful alcohol use experience poor outcomes. Granular data evaluating whether alcohol counseling during hepatitis C treatment impacts longitudinal alcohol consumption are lacking. To evaluate whether provider-delivered counseling in the context of direct-acting antiviral hepatitis C treatment associates with decreased longitudinal alcohol consumption. We performed secondary data analysis from the Hep ART study including adults with hepatitis C who underwent provider-delivered counseling during direct-acting antiviral treatment between October 2014 and September 2017. Demographics and disease characteristics were summarized. Alcohol consumption, abstinence, and heavy drinking were evaluated in periods before, during, and after direct-acting antiviral treatment. Multivariate regression analyses were performed to evaluate the association of alcohol consumption with each 12-week time period for all patients and a subsample with cirrhosis. One hundred twenty-three patients were included; 41 had cirrhosis. Most patients were male (74.0%) and Black (58.5%). Alcohol consumption improved during direct-acting antiviral treatment and was notably sustained (< 12weeks before treatment 32.5g/day; during treatment 20.0g/day; and 12-24weeks after treatment 23.7g/day). Multivariable analyses showed significantly improved alcohol consumption metrics during and after antiviral treatment compared to < 12weeks before treatment (during treatment 13.04g/day less, p = 0.0001; > 24weeks after treatment 15.29g/day less, p = 0.0001). The subsample with cirrhosis showed similar results (during treatment 13.21g/day less, p = 0.0001; > 24weeks after treatment 7.69g/day less, p = 0.0001). Patients with chronic HCV and risky/harmful alcohol use given provider-delivered alcohol-related counseling during HCV treatment sustain decreased alcohol consumption patterns during and after treatment.

UNREALIZED POTENTIAL UTILIZATION OF HCV+ DECEASED-DONOR KIDNEYS AND LIVERS

Introduction: In the era of new, direct-acting antiviral therapy for hepatitis C virus (HCV), HCV+ deceased-donor organs can be transplanted into HCV- recipients with excellent results. Utilization of HCV+ kidneys has increased in recent years but discard rates remain elevated. We estimated the number of additional deceased donor transplants that would occur if HCV+ kidneys and livers offered for transplant were utilized at the same rate as comparable HCV- organs. Methods: Using national registry data from the United States (SRTR) on 189,667 donor kidneys and 89,077 livers 2015-2018, we separately modeled risk of discard in HCV- kidneys and livers based on donor characteristics. We applied these models to the HCV+ donor population to obtain potential HCV+ kidney/liver utilization (i.e. if these organs had been HCV-), and subtracted this from actual utilization to estimate the potential capacity for additional transplants. Results: Discard was substantially higher for HCV+ kidneys (46.3% vs 18.3%) and livers (15.7% vs 10.2%), but declined over time (from 52.6% in 2005 to 33.8% in 2018 for kidney, 26.1% to 7.7% for liver). However, the number of available donors increased dramatically over time. If HCV+ organs were utilized at the same rate as comparable HCV- organs, there would be an additional 229 kidney transplants and 30 liver transplants per year (Figure 1). This has fallen from 36 in 2005 to 11 in 2018 for liver, but increased substantially from 168 to 353 for kidney (Figure 2). Conclusions: Despite decreased discard rates of HCV+ kidneys over time, broader utilization of HCV+ donor kidneys for HCV- recipients has the potential to substantially reduce the organ shortage.Fig. 1.Fig. 2. NIH K01DK101677 (Massie).

Association of Direct-Acting Antiviral Therapy for Hepatitis C With After-Treatment Costs Among Medicare Beneficiaries

Direct-acting antiviral (DAA) therapy for hepatitis C is highly effective but expensive. Evidence is scarce on whether DAA therapy reduces downstream medical costs. To examine the association of DAA therapy with posttreatment medical costs among Medicare beneficiaries. This retrospective cohort study obtained data from various Medicare claims files for 2013 to 2017. The study population comprised patients with a hepatitis C diagnosis in 2014 who were enrolled in fee-for-service Medicare and Part D. Multivariate regression models were used to compare changes in medical costs over a 30-month posttreatment follow-up period between patients who used DAA therapy (treatment group) and a propensity score-matched cohort of patients who did not use DAA (control group). The model was estimated separately for patients with and those without cirrhosis. Data were analyzed between September 1, 2019, and March 31, 2020. Completion of DAA therapy. Two outcomes were established: hepatitis C or liver disease-related costs and total medical costs. Costs were measured by Medicare-allowed payments, which included Medicare reimbursements, patient responsibilities, and third-party payments. A propensity score-matched cohort of 15 198 patients (9038 men [59.5%]; mean [SD] age, 60.2 [10.8] years) was analyzed. During the first 6 months after DAA therapy, hepatitis C or liver disease-related costs decreased by $2498 (95% CI, -$3356 to -$1640) in patients with cirrhosis and by $486 (95% CI, -$603 to -$369) in patients without cirrhosis compared with control or untreated patients. Cumulative reductions in hepatitis C or liver disease-related costs during 30 months after DAA treatment were $15 808 (95% CI, -$22 530 to -$9085) in patients with cirrhosis and $5372 (95% CI, -$6384 to -$4360) in patients without cirrhosis. Among those who used DAA therapy compared with control patients, total medical costs decreased by $2905 (95% CI, -$4832 to -$979) in patients with cirrhosis and by $1287 (95% CI, -$2393 to -$283) in patients without cirrhosis during the first 6 months after DAA therapy. No statistically significant association was found between DAA therapy and total medical cost reductions after 12 months of follow-up. Cumulative reductions in total costs during 30 months after DAA therapy were $7074 (95% CI, -$18 448 to $4298) in patients with cirrhosis and $7497 (95% CI, -$14 287 to -$709) in patients without cirrhosis. This study reported that DAA therapy appeared to be associated with a decrease in hepatitis C or liver disease-related costs for 30 months after treatment and with reduction in total medical costs for only 12 months after treatment in patients with or without cirrhosis. Longer-term follow-up studies with diverse outcomes are necessary to assess the value of DAA therapy.

Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis.

Laursen TL, Sandahl TD, Kazankov K, Eriksen PL, Kristensen LH, Holmboe CH, Laursen AL, Vilstrup H, Grønbæk H. Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 319: G151-G156, 2020. First published June 29, 2020; doi:10.1152/ajpgi.00128.2020.-Effects of direct-acting antiviral (DAA) treatment of chronic hepatitis C (CHC) cirrhosis on metabolic liver function are unknown but important for prognosis. Ureagenesis is an essential metabolic liver function involved in whole body nitrogen homeostasis. We aimed to investigate the ureagenesis capacity before and immediately after DAA therapy and relate the findings to hepatic inflammation and structural changes. In an observational before-and-after intervention study, the ureagenesis capacity was quantified by functional hepatic nitrogen clearance (FHNC) in 9 CHC patients with cirrhosis and 10 healthy volunteers. Hepatic inflammation was evaluated by alanine aminotransferase (ALT) and the macrophage activation markers sCD163 and sMR. Structural changes were estimated as liver stiffness and by portal hypertension as the hepatic venous pressure gradient (HVPG). Before treatment, the FHNC in the patients was half of the controls [16.4 L/h (8.2-24.5) vs. 33.4 (29.2-37.6), P = 0.0004]; after successful DAA treatment, it normalized [28.4 (15.9-40.9), P = 0.008 vs. baseline]. DAA treatment normalized ALT (P < 0.0001) and decreased the elevated sCD163 from 5.6 mg/L (3.5-7.7) to 3.4 (2-0-4.8) (P < 0.001) and sMR from 0.35 mg/L (0.21-0.49) to 0.31 (0.17-0.45) (P < 0.01). Liver stiffness fell by 30% (P < 0.05) but remained over the cirrhosis threshold. HVPG was not affected (P = 0.59). DAA treatment restored the severely reduced ureagenesis capacity, along with amelioration of hepatic inflammation but without normalization of other cirrhosis characteristics. Our findings indicate that the anti-inflammatory effect of virus eradication independent of hepatic structural effects rapidly improves metabolic dysfunction. We suggest this effect to be an important early onset part of the expected clinical DAA treatment benefit.NEW & NOTEWORTHY Antiviral treatment of chronic hepatitis C restores the liver's reduced capacity to produce urea along with an improvement in liver inflammation without immediate effects on structural liver changes. The effect is suggested to be an important early onset part of the expected clinical treatment benefit.

Standard Versus Extended Duration Direct-Acting Antiviral Therapy in Hepatitis C Patients With Slow Response to Treatment.

Response-guided hepatitis C therapy was standard with interferon-based regimens but is not used for direct-acting antivirals (DAAs). Week 4 viral kinetics may predict sustained virological response (SVR) with DAAs, but it is unclear whether extending therapy in slow responders affects outcomes. The primary objective was to compare SVR rates between traditional and extended duration groups. Secondary objectives were to compare SVR rates among subgroups and to determine factors associated with SVR. This institutional review board-approved, retrospective, single-center study identified patients with chronic hepatitis C virus (HCV) infection with detectable week 4 HCV RNA who were treated with DAAs. Patients were excluded for early discontinuation, treatment regimen not recommended first-line, or missing HCV RNA labs. Patients were stratified into traditional and extended duration groups. The primary end point was SVR. Secondary end points included factors associated with SVR and rationale for extension of therapy duration. A total of 363 patients were included; 58 (16%) received extended therapy. Patients were primarily genotype 1a (70%) and treatment naïve (80%). More than half had advanced fibrosis or cirrhosis. SVR12 rates were 100% in the extended duration group and 96.7% in the traditional duration group (P = 0.37). There were no associations with SVR and prespecified patient-specific factors. Sample size was limited. Based on these findings, a recommendation for extension of therapy cannot be made for patients with detectable HCV RNA at week 4 of treatment at this time. Cost analyses may help guide recommendations to re-treat rare failures versus extend therapy in all slow responders.

Elbasvir and grazoprevir for hepatitis C virus genotype 1 infection in people with recent injecting drug use (DARLO-C): An open-label, single-arm, phase 4, multicentre trial.

Background and AimsDirect‐acting antiviral therapy for hepatitis C virus (HCV) is effective, but few prospective studies among people with ongoing injecting drug use exist. This study evaluated the efficacy of elbasvir/grazoprevir in people with HCV genotype 1/4 (G1/4) infection and recent injecting drug use. An exploratory aim evaluated the feasibility of fingerstick point‐of‐care HCV RNA testing prior to and following treatment.MethodsDARLO‐C (http://clinicaltrials.gov: NCT02940691) is an open‐label phase 4 trial. Participants were recruited between May 2017 and March 2018 from two drug treatment clinics, two hospital clinics, and one community clinic in Australia. Inclusion criteria included recent injection drug use (previous 6 months) and HCV G1/4 infection. Exclusion criteria included prior HCV treatment and decompensated liver disease. Participants received elbasvir/grazoprevir once‐daily for 12 weeks. The primary endpoint was undetectable HCV RNA 12 weeks post‐treatment (SVR). Fingerstick whole‐blood samples were tested using the Xpert HCV Viral Load Fingerstick (Xpert HCV VL Fingerstick) assay and compared to the Aptima HCV Quant Dx Assay on plasma samples.ResultsOf a planned 150 participants, 32 were enrolled due to slower than anticipated recruitment [median age 46 years, 10 (31%) female, 29 (91%) G1a]. Eighteen (56%) were receiving opioid agonist therapy and 29 (91%) injected in the previous month. Twenty‐six (81%) of 32 completed treatment (lost to follow‐up, n = 5; incarceration, n = 1). There were no virological failures. Twenty‐four (75%, 95% CI 59%‐91%) of 32 achieved SVR. Two participants who completed treatment did not have SVR (loss to follow‐up, n = 1; refused test, n = 1). Among paired samples (n = 36), sensitivity of the Xpert HCV VL Fingerstick assay for HCV RNA detection was 100.0% (95% CI 75.3%‐100.0%) and specificity was 95.7% (95% CI 78.1%‐99.9%).ConclusionElbasvir/grazoprevir is effective among people with HCV G1 with recent injecting drug use. Implementation of point‐of‐care HCV RNA testing was feasible, but the high error rate requires investigation.