Hepatitis C Virus Direct-acting Antivirals Research Articles

Alcohol does not impact chronic hepatitis C treatment outcomes but increases risk for progressive liver disease: Findings from a prospective multicentre Australian study (OPERA-C).

Alcohol use is common in patients with chronic hepatitis C virus (HCV) infection. We examined the impact of alcohol use on direct-acting antiviral (DAA) therapy outcome and the clinical course of liver disease and 2-year survival for patients receiving HCV DAA therapy. Adults (n = 2624) recruited from 26 Australian hospital liver clinics during 2016-2021 were followed up for 2 years. Risky alcohol use was defined by a combination of self-report (≥40 g/day of ethanol), physician-reported history of problematic alcohol use, and anti-craving medication prescription via population-based database linkage. We examined factors associated with advanced liver fibrosis and survival using multivariable logistic and Cox regression. Among 1634 patients (62.3%) with risky alcohol use, 24.6% reported consuming ≥40 g/day of alcohol, 98.3% physician-reported problematic alcohol use; only 4.1% were dispensed naltrexone/acamprosate. One hundred and forty-three patients with cirrhosis reported ≥40 g/day of alcohol, 6 (4.3%) were prescribed naltrexone/acamprosate. Risky alcohol use was associated with advanced fibrosis (adjusted-odds ratio 1.69, 95% confidence interval 1.32-2.17) and patients were over-represented for cirrhosis (45.1% vs. 25.6% in no-risky alcohol use [p < 0.001]) and hepatocellular carcinoma (5.7% vs. 2.5% [p < 0.001]). Sustained viral response (p = 0.319) and 2-year survival (adjusted-hazard ratio 1.98, 95% confidence interval 0.84-4.63) after DAA therapy were not associated with risky alcohol use. Risky alcohol use in HCV patients was prevalent, but did not reduce HCV cure. Treatment for alcohol dependence was low. Risky alcohol use may be under-recognised in liver clinics. Better integration of addiction medicine into liver services and increased resourcing and addiction medicine training opportunities for hepatologists may help address this.

Effect of direct-acting antivirals on the titers of human pegivirus 1 during treatment of chronic hepatitis C patients.

Human pegivirus 1 coinfections are common in hepatitis C virus (HCV) patients, persisting for years. However, little is known about how pegivirus coinfections are affected by treatment with pangenotypic direct-acting antivirals (DAAs) against HCV. We identified human pegivirus by metagenomic analysis of chronic HCV patients undergoing protease, NS5A, and polymerase inhibitor treatment, in some patients with the addition of pegylated interferon, and followed viral kinetics of both viruses to investigate treatment effects. Only during HCV DAA treatment regimens that included the more broad-spectrum drug sofosbuvir could we detect a consistent decline in pegivirus titers that, however, rebounded to pretreatment levels after treatment cessation. The addition of pegylated interferon gave the highest effect with pegivirus titers decreasing to below the assay detection limit, but without clearance. These results reveal the limited effect of frontline HCV drugs on the closest related human virus, but sofosbuvir appeared to have the potential to be repurposed for other viral diseases.

Changes in Use of Hepatitis C Direct-Acting Antivirals After Access Restrictions Were Eased by State Medicaid Programs

Direct-acting antivirals (DAAs) are safe and highly effective for curing hepatitis C virus (HCV) infection, but their high cost led certain state Medicaid programs to impose coverage restrictions. Since 2015, many of these restrictions have been lifted voluntarily in response to advocacy or because of litigation. To estimate how the prescribing of DAAs to Medicaid patients changed after states eased access restrictions. This modified difference-in-differences analysis of 39 state Medicaid programs included Medicaid beneficiaries who were prescribed a DAA from January 1, 2015, to December 31, 2019. DAA coverage restrictions were measured based on a series of cross-sectional assessments performed from 2014 through 2022 by the US National Viral Hepatitis Roundtable and the Center for Health Law and Policy Innovation. Calendar quarter when states eased or eliminated 3 types of DAA coverage restrictions: limiting treatment to patients with severe liver disease, restricting use among patients with active substance use, and requiring prescriptions to be written by or in consultation with specialists. States with none of these restrictions at baseline were excluded. Quarterly number of HCV DAA treatment courses per 100 000 Medicaid beneficiaries. Of 39 states, 7 (18%) eliminated coverage restrictions, 25 (64%) eased restrictions, and 7 (18%) maintained the same restrictions from 2015 to 2019. During this period, the average quarterly use of DAAs increased from 669 to 3601 treatment courses per 100 000 Medicaid beneficiaries. After states eased or eliminated restrictions, the use of DAAs increased by 966 (95% CI, 409-1523) treatment courses per 100 000 Medicaid beneficiaries each quarter compared with states that did not ease or eliminate restrictions. The results of this study suggest that there was greater use of DAAs after states relaxed coverage restrictions related to liver disease severity, sobriety, or prescriber specialty. Further reductions or elimination of these rules may improve access to a highly effective public health intervention for patients with HCV.

A304 EXPLORING HEPATITIS C TREATMENT COST TRENDS OVER A DECADE: A CROSS-SECTIONAL ANALYSIS WITHIN MEDICARE PART D (2012-2021)

Abstract Background Chronic hepatitis C virus (HCV) infection negatively impacts quality and quantity of life. With the onset of direct-acting antivirals (DAAs), cure rates of HCV have increased to over 95%. Despite these advancements, chronic HCV infection continues to pose a substantial health and financial burden and without drug coverage, treatment of HCV with these DAAs is unaffordable. In the United States, Medicare Part D is a voluntary drug coverage plan predominantly for individuals covered by Medicare (typically over 65 years old) which can facilitate access to these DAAs. Aims This study aims to analyze the shifts in HCV treatment and spending in the USA from 2012 to 2021 for Medicare Part D and assess the impact of generic drugs on overall expenditure. Methods A retrospective cross-sectional study was conducted using publicly available Centers for Medicare and Medicaid Services (CMS) Medicare D drug spending data from 2012 to 2021. The total expenditure and utilization of HCV drugs was calculated, and average spending per beneficiary was utilized to estimate potential cost savings if generic DAAs were employed. Results The study revealed a decline in HCV claims and beneficiaries over 65 since 2015 with a peak of 134,752 beneficiaries decreasing to 35,735 in 2021. Accordingly, spending was the highest in 2015 (8.8 billion USD) and subsequently trended downwards to 1.5 billion in 2021. Over the ten-year period, the USA spent a total of 33.1 billion USD on HCV treatment. Harvoni accounted for 53% of the spending, followed by Sovaldi (17%) and Epclusa (14%). Generic drug utilization slowly increased with the introduction of generics in 2019 with 6.4% of beneficiaries treated with generic DAAs in 2019, rising to 15.3% in 2020 and 14.8% in 2021. If all prescriptions of Harvoni and Epclusa were substituted by ledipasvir/sofosbuvir and sofosbuvir/velpatasvir, respectively, there is a potential $2.7 billion cost reduction. This translates to a potential 47.3% reduction in HCV treatment expenditures from 2019 to 2021. Conclusions The decreasing number of beneficiaries for HCV treatment among people over the age of 65 suggests a decreasing HCV prevalence in this age group. This reflects the success of DAA treatment and low reinfection rates. However, the underutilization of generic DAAs despite their lower cost highlights a missed opportunity for substantial savings. This study emphasizes the importance of policy negotiations to ensure optimal resource management, advocating for a shift towards generic drug usage to alleviate the financial burden associated with HCV treatment. Trends in total spending on DAAs for HCV and number of beneficiaries within Medicare Part D from 2012 to 2021. Annual percent changes in expenditure are shown within the data bars. Funding Agencies None

CD4+ T-cell recovery in HIV/hepatitis C co-infected patients following successful hepatitis C treatment.

Hepatitis C virus (HCV)/HIV co-infection has been identified as a risk for impaired CD4+ T-cell recovery, possibly mediated by HCV-induced liver fibrosis and/or immune activation. As HCV direct-acting antivirals (DAAs) may partially reverse liver fibrosis and immune activation, sustained HCV virological response (SVR) may lead to improved CD4 recovery. We explored the effect of HCV DAA-induced SVR on CD4 recovery among patients living with both HCV and HIV, including those with poor CD4 recovery on antiretroviral therapy (immunological non-responders [INRs]). Subjects aged ≥18 years living with both HIV and HCV who achieved SVR with DAA were included. Pre-DAA CD4 counts were included only after sustained HIV viral suppression and HIV viral suppression was maintained for the duration of the study. Segmented regression of interrupted time series analysis was used to evaluate changes in median CD4 count in the pre-DAA period (-36 months) versus the post-DAA period (+36 months). In total, 156 patients were included. In the full cohort, median CD4 counts increased by 15% (p = 0.002) in the 6-month period following DAA initiation, whereafter CD4 counts decreased by 2.7% per 6-month period (p = 0.004). Among the 13 INRs, there was no immediate effect on median CD4 in the first 6 months after DAA initiation, whereafter there was a sustained CD4 increase (4.1% per 6-month time interval [p = 0.02]). In total, 54% of INRs recorded a post-DAA CD4 count of >350 cells/mm3. Successful DAA therapy induced a modest immediate CD4 immunological reconstitution among this cohort of patients living with both HIV and HCV, although this effect waned with time. By contrast, among INRs, achieving HCV SVR led to slower but sustained CD4 count recovery.

Policies for Expanding Hepatitis C Testing and Treatment in United States Prisons and Jails

Hepatitis C virus (HCV) is highly prevalent in United States prisons and jails. In prisons and jails, rates of infection are ten to twenty times greater than national levels. And, more than thirty percent of all people living with HCV in the United States will spend time in prisons and jails in any given year. Rates are especially high among people who inject drugs (PWID), a population whose members are also likely to move between carceral settings and the community. Thus, addressing HCV among incarcerated populations would have a significant effect on the virus’s transmission both in and out of confinement and is a crucial part of any HCV elimination strategy. Safe and effective HCV treatment is available. Direct-acting antivirals (DAAs) offered in an eight to twelve week course of oral treatment cure HCV in more than ninety percent of cases. Widespread testing and treatment in prisons and widespread testing and treatment or linkage to community care in jails are essential public health approaches. But testing and treatment in confinement lags behind medical guidance and public health recommendations. People incarcerated in prisons and detained in jails are entitled to adequate health care, and the U.S. Constitution prohibits deliberate indifference to their serious medical needs. In recent years, lawsuits filed by people with HCV in carceral facilities across the country have alleged violations of federal law for failure to provide DAA treatment. Although litigation results have been mixed, settlement agreements in states across the country have expanded HCV testing and broadened access to DAA treatment. These settlement agreements reflect a growing understanding that widespread testing and treatment is cost-effective, avoid the harmful health consequences of disease progression, and meaningfully reduce community transmission. This paper recommends model policies for prisons and jails to expand HCV testing and DAA treatment. The policy recommendations draw from relevant settlement agreements and current medical guidelines, supplemented by input from public health experts, medical professionals, and advocates. The paper proceeds as follows: • Part I describes the HCV epidemic in United States prisons and jails, the recent sea change in treatment protocols, and relevant clinical guidance and public health recommendations. • Part II sets out the legal landscape, including governing federal law and judicial decisions interpreting that law in this context, and describes settlement agreements in class action lawsuits addressing DAA access. • Finally, Part III offers model policies for prisons and jails to expand testing and treatment and to support successful outcomes for people with HCV in their custody.

Pretreatment Predictors Associated with Improvement in Hepatitis C Virus Related Decompensated Cirrhosis after Direct-Acting Antiviral Therapy

Background and Aim: The availability of hepatitis C virus (HCV) direct-acting antivirals (DAAs) has led to a paradigm change in the care of HCV related decompensated cirrhosis. Achieving a stained virologic response (SVR) is associated with considerable improvements in both Child-Turcotte- Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores in decompensated cirrhosis. We aimed to evaluate the pretreatment predictors associated with improvement in CTP B cirrhosis after DAAs and evaluate the efficacy and safety of DAAs in these patients.&#x0D; Patients and Methods: A prospective study conducted on 213 decompensated patients (CTP B, 134 received DAAs for 24 weeks and 79 for 12 weeks). Clinical and laboratory data obtained at baseline, during treatment, 12 weeks after end of treatment (EOT), 36 weeks after treatment start, and 24 weeks after SVR.&#x0D; Results: We had 48.4 % and 55.9 % had improved to CTP A at 36 weeks of treatment start and 24 weeks after SVR respectively. A high baseline BE3A score (which includes Body mass index (BMI), Encephalopathy, Ascites, Alanine aminotransferase (ALT) and Albumin) was the significant predictor of attaining CTP A at 36 weeks of treatment start, while high baseline ALT (&gt; 60 IU/L) was the significant predictor of attaining CTP A at 24 weeks after SVR. SVR 12 achieved in 97.3% and DAAs were safe with mild tolerable adverse events.&#x0D; Conclusion: High baseline ALT and BE3A score were the significant predictors of hepatic improvement from CTP B to CTP A after DAAs. HCV DAAs were safe and effective with high SVR rates (97.3%) in decompensated cirrhosis.

Hepatitis C care cascade in a large academic healthcare system, 2012 to 2018.

To determine the hepatitis C virus (HCV) care cascade among persons who were born during 1945 to 1965 and received outpatient care on or after January 2014 at a large academic healthcare system. Deidentified electronic health record data in an existing research database were analyzed for this study. Laboratory test results for HCV antibody and HCV ribonucleic acid (RNA) indicated seropositivity and confirmatory testing. HCV genotyping was used as a proxy for linkage to care. A direct-acting antiviral (DAA) prescription indicated treatment initiation, an undetectable HCV RNA at least 20 weeks after initiation of antiviral treatment indicated a sustained virologic response. Of the 121,807 patients in the 1945 to 1965 birth cohort who received outpatient care between January 1, 2014 and June 30, 2017, 3399 (3%) patients were screened for HCV; 540 (16%) were seropositive. Among the seropositive, 442 (82%) had detectable HCV RNA, 68 (13%) had undetectable HCV RNA, and 30 (6%) lacked HCV RNA testing. Of the 442 viremic patients, 237 (54%) were linked to care, 65 (15%) initiated DAA treatment, and 32 (7%) achieved sustained virologic response. While only 3% were screened for HCV, the seroprevalence was high in the screened sample. Despite the established safety and efficacy of DAAs, only 15% initiated treatment during the study period. To achieve HCV elimination, improved HCV screening and linkage to HCV care and DAA treatment are needed.

Treating Hepatitis C Prior to Total Hip Arthroplasty is Cost-effective: A Markov Analysis

BackgroundPatients infected with the hepatitis C virus (HCV) have high complication rates following total hip arthroplasty (THA). Advances in HCV therapy now enable clinicians to eradicate the disease; however, its cost-effectiveness from an orthopaedic perspective remains to be demonstrated. We sought to conduct a cost-effectiveness analysis comparing no therapy to direct-acting antiviral (DAA) therapy prior to THA among HCV-positive patients. MethodsA Markov model was utilized to evaluate the cost-effectiveness of treating HCV with DAA prior to THA. The model was powered with event probabilities, mortality, cost, and quality-adjusted life year (QALY) values for patients with and without HCV that were obtained from the published literature. This included treatment costs, successes of HCV eradication, incidences of superficial or periprosthetic joint infection (PJI), probabilities of utilizing various PJI treatment modalities, PJI treatment success/failures, and mortality rates. The incremental cost-effectiveness ratio was compared to a willingness-to-pay threshold of $50,000/QALY. ResultsOur Markov model indicates that in comparison to no therapy, DAA prior to THA is cost-effective for HCV-positive patients. THA in the setting of no therapy and DAA added 8.06 and 14.39 QALYs at a mean cost of $28,800 and $115,800. The incremental cost-effectiveness ratio associated with HCV DAA in comparison to no therapy was $13,800/QALY, below the willingness-to-pay threshold of $50,000/QALY. ConclusionHepatitis C treatment with DAA prior to THA is cost-effective at all current drug list prices. Given these findings, strong consideration should be given to treating patients for HCV prior to elective THA. Level of EvidenceCost-effectiveness Analysis; Level III.

Patient-Reported Outcomes During and After Hepatitis C Virus Direct-Acting Antiviral Treatment Among People Who Inject Drugs

ObjectivesPeople who inject drugs (PWID) are at a high risk of hepatitis C virus (HCV) infection. HCV cure is associated with improved patient-reported outcomes (PROs), but there are little data among PWID. This study aimed to assess the change in PROs during and after HCV direct-acting antiviral (DAA) treatment. MethodsThis analysis used data from 2 clinical trials of DAA treatment in PWID. PROs assessed included health-related quality of life, social functioning, psychological distress, housing, and employment. Generalized estimating equations and group-based trajectory modeling were used to assess changes in PROs over time. ResultsNo significant changes in the 3-level version of EQ-5D scores, EQ visual analogue scale scores, social functioning, psychological distress, and housing were observed over the 108-week study period. There was a significant increase in the proportion of participants employed (18% [95% confidence interval (CI) 12%-23%] at baseline to 28% [95% CI 19%-36%] at the end of the study). Participants were more likely to be employed at 24 weeks and 108 weeks after commencing treatment. Having stable housing increased the odds of being employed (odds ratio 1.70; 95% CI 1.00-2.90). The group-based trajectory modeling demonstrated that most outcomes remained stable during and after DAA treatment. ConclusionsAlthough no significant improvement was identified in health-related quality of life after HCV DAA treatment, there was a modest but significant increase in employment during study follow-up. The study findings support the need for multifaceted models of HCV care for PWID addressing a range of issues beyond HCV treatment to improve quality of life.

A Vermont Statewide Educational Intervention to Improve Access to Hepatitis C Virus Treatment in a Rural State.

Improved knowledge of hepatitis C virus (HCV) screening, linkage to care, and treatment is needed among nonspecialist medical professionals to combat the HCV epidemic. The authors sought to implement and analyze the impact of an HCV curriculum for primary care professionals (PCPs) across the state of Vermont, USA. This investigation was a retrospective analysis of uptake of a Vermont HCV educational curriculum and its impact on HCV direct-acting antiviral (DAA) prescribing rates within the state before and after the study period. The curriculum was delivered online and in-person over 2 years from 2019 to 2020. The primary outcome was health care professional performance on a pre- and post-curriculum short-term knowledge assessment exam. The secondary outcome was assessing the number of unique healthcare professionals within a single payor database prescribing DAA treatment for HCV in Vermont before and after the study intervention, from January 1, 2017 until December 1, 2021. There were 31 unique respondents on the pre- and post-intervention examinations, which represented 9% of known participants. Respondents included physicians (n = 15), nurse practitioners (n = 8), and nurses (n = 8). Pre- and post-intervention knowledge scores increased significantly across all provider groups, from 3.2 (SD 0.6) to 4.5 (SD 0.4) 1 to 5 scale (P = .01). The total number of unique HCV DAA therapy prescribers decreased over the study period, from 17 in 2017 to 9 in 2021. A Vermont statewide HCV curriculum for PCPs was successful at increasing short-term HCV-related knowledge. However, this did not obviously translate to an increase in new professionals treating HCV.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.

BackgroundElevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here.MethodsIn a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants.ResultsBefore therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy.ConclusionDuring chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA.

Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment.

BackgroundFor patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up.MethodsIn Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either less than the lower limit of quantification (LLOQ, 20 IU/mL) to equal to or more than LLOQ or equal to or more than LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2× upper limit of normal. Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis.ResultsAll patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12, whereas clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and hepatitis B surface antigen (HBsAg) levels were associated with HBV virologic reactivation and baseline ALT and HBV DNA, and HBsAg levels were associated with HBV clinical reactivation.ConclusionAmong HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy.Clinical Trials RegistrationNCT02613871.

Crushing and Splitting Direct-Acting Antivirals for Hepatitis C Virus Treatment: A Case Series and Literature Review.

Limited data exist regarding the use of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) in patients who are unable to swallow tablets. This case series describes HCV treatment in patients requiring tablet manipulation, providing evidence for safety and effectiveness of HCV DAA tablet manipulation.

Glucose and Lipid Profile Changes in Hepatitis C Patients After Direct Acting Antivirals Therapy

Background: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is associated with development of insulin resistance and therefore type 2 Diabetes mellitus (T2DM), it is also associated with hepatic steatosis and hypocholesterolemia. The treatment by Direct Acting Antivirals (DAAs) leads to sustained virological response (SVR) in almost all infected patients and decreases liver-related as well as all-cause mortality in these patients. The evidence for the effect of DAAs therapy on T2DM is quite conflicting. Some studies agreed with the glucometabolic amelioration induced by the Sustained Virological Response (SVR) but other studies disagreed with this hypothesis. The aim of the work was to evaluate glucose and Lipid Profile changes in hepatitis C patients at 12 weeks post treatment (SVR12) by Direct Acting Antivirals Therapy.&#x0D; Methods: This prospective study was carried out on 80 chronic HCV infected patients who are treatment naïve and subjected to HCV DAAs treatment (Daclatasvir + Sofosbuvir for 12 weeks +/- Ribavirin or any DAA available) with 100% SVR rate at 12 weeks with no relapse. All patients are subjected to assessment of Fasting blood glucose, HbA1C and assessment of Lipid profile; Total cholesterol, Triglycerides, HDL, LDL at baseline (pretreatment) and at end of treatment then they are followed up at SVR12.&#x0D; Results: Average HbA1C, fasting blood glucose has significantly decreased in group A diabetic patients from baseline to end of treatment and to SVR12, Average Total Cholesterol, LDL has significantly increased in group A and B from baseline to end of treatment and to SVR12 respectively. Average Triglycerides has significantly decreased from baseline to end of treatment in group A and B and to SVR12 in group A only. Average HDL has significantly increased only in group B non-diabetics from baseline to end of treatment and to SVR12.&#x0D; Conclusions: Successful clearance of HCV viremia (SVR12) with DAAs treatment has been associated with significant Improvement or decrease of HbA1c and Fasting plasma glucose levels in diabetic chronic HCV infected patients, and has been associated with Rise in the Lipid profile; Total Cholesterol, LDL, HDL (non-diabetics only) while it decreases Triglycerides in both diabetic and non-diabetic chronic HCV infected patients.

Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies

Drug repurposing is an important approach to the assignment of already approved drugs for new indications. This technique bypasses some steps in the traditional drug approval system, which saves time and lives in the case of pandemics. Direct acting antivirals (DAAs) have repeatedly repurposed from treating one virus to another. In this study, 16 FDA-approved hepatitis C virus (HCV) DAA drugs were studied to explore their activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human and viral targets. Among the 16 HCV DAA drugs, telaprevir has shown the best in silico evidence to work on both indirect human targets (cathepsin L [CTSL] and human angiotensin-converting enzyme 2 [hACE2] receptor) and direct viral targets (main protease [Mpro]). Moreover, the docked poses of telaprevir inside both hACE2 and Mpro were subjected to additional molecular dynamics simulations monitored by calculating the binding free energy using MM-GBSA. In vitro analysis of telaprevir showed inhibition of SARS-CoV-2 replication in cell culture (IC50 = 11.552 μM, CC50 = 60.865 μM, and selectivity index = 5.27). Accordingly, based on the in silico studies and supported by the presented in vitro analysis, we suggest that telaprevir may be considered for therapeutic development against SARS-CoV-2.

Prevalence of drug-drug interactions with pangenotypic direct-acting antivirals for hepatitis C and real-world care management in the United States: a retrospective observational study.

BACKGROUND: Direct-acting antiviral (DAA) regimens for hepatitis C virus (HCV) have varying potentials for drug-drug interactions (DDIs). OBJECTIVES: To (1) identify prevalence of potential DDI with glecaprevir-pibrentasvir (GLE-PIB) and sofosbuvir-velpatasvir (SOF-VEL) and (2) describe health care provider actions in response to pharmacist recommendations based on potential interactions with GLE-PIB or SOF-VEL, using 2 complementary data sources. METHODS: Possible interacting drugs were identified among adult patients in a United States electronic medical record database covering 21 health care organizations and 26 million patients in 2018. DDIs were categorized as potential weak interaction (Level 1), potential interaction (Level 2), or contraindicated (Level 3). Real-world recommendations and resultant actions regarding DDIs with GLE-PIB and SOF-VEL were obtained from a specialty pharmacy database. Categorical variable comparisons were done via chi-square analysis with subsequent z-tests of column proportions. RESULTS: DDI prevalence was higher for patients prescribed GLE-PIB (317/769 [41%]) compared with those prescribed SOF-VEL (170/633 [27%]), and the prevalence of a Level 3 (contraindicated) interaction was higher with GLE-PIB than SOF-VEL (61/769 [8%] vs 2/633 [< 1%]). Across all DDI levels, analgesics (139/317 [44%]), proton-pump inhibitors (129/317 [41%]), and lipid-lowering agents (59/317 [19%]) were the top drug classes for the GLE-PIB group with potential for DDI. For SOF-VEL prescribed patients, the top drug classes were proton-pump inhibitors (83/170 [49%]), histamine-2 blockers (42/170[25%]), and lipid-lowering agents (42/170 [25%]). In real-world care management, the overall prevalence of pharmacist recommendations regarding DDIs was significantly lower for SOF-VEL (28/419 [7%]) relative to GLE-PIB (151/1,216 [12%]). Recommended guidance from pharmacists was not followed for 39% (69/179) of patients, 36% (54/151) for GLE-PIB, and 54% (15/28) for SOF-VEL. CONCLUSIONS: The potential for DDIs with pangenotypic HCV DAAs is frequent and may be more frequent with GLE-PIB than SOF-VEL. Physician responses to pharmacist alerts regarding potential interaction can be highly variable, even in cases of contraindication. DISCLOSURES: Funding for this study was provided by Gilead Sciences, Inc. Trio Health Analytics received funding from Gilead Sciences, Inc., to conduct research for this study. Tsai consults for and has received grants and honoraria from Gilead, AbbVie, Merck, and Bristol Myers Squibb; he has also received lecture fees from Gilead and AbbVie. Curry consults for Trio Health Analytics and Gilead and has also consulted for and received grants from Mallinckrodt. Flamm consults for and has received lecture fees from Gilead and AbbVie; he has also received grants from Gilead and AbbVie. Milligan and Wick are employed by Trio Health Analytics and have received research support from Gilead, Merck, and AbbVie. Younossi has received grants from Gilead, Intercept, Bristol Myers Squibb, GlaxoSmithKline, and Novo Nordisk. Afdhal is a paid consultant/advisory board member for Gilead, Echosens, Ligand, Shionogi, and Trio Health; owns stock in Spring-Bank and Allurion and has stock options in SpringBank; receives royalty income from UpToDate; and is on the board of directors for the nonprofit Liver Institute for Education and Research. Data from this study were presented at the American Association for the Study of Liver Disease (AASLD) Liver Meeting 2019; November 8-12, 2019; Boston, MA, and the European Association for Study of the Liver (EASL) International Liver Congress 2020; August 27-29, 2020; virtual.

Access to direct-acting antivirals for hepatitis C-negative transplant recipients receiving organs from hepatitis C-viremic donors.

A barrier to using organs from hepatitis C virus (HCV)-viremic donors is the high cost of direct-acting antivirals (DAAs) and concerns about access for recipients after transplantation. The purpose of this study was to evaluate access, cost, and timing for HCV DAAs following transplantation. This was a single-center, retrospective study of HCV-negative adult transplant recipients from June 2017 to December 2019 who received grafts from HCV-viremic and/or HCV-seropositive individuals and became HCV viremic after transplantation. Between June 2017 and December 2019, there were 60 HCV-negative transplant recipients who became viremic after receiving grafts from HCV-viremic or HCV-seropositive donors. Thirty-eight patients met the inclusion criteria (n = 25 with liver transplants, n = 6 with lung transplants, n = 4 with simultaneous liver and kidney transplants, and n = 3 with kidney transplants). Of these patients, 23 had commercial insurance, 13 had Medicare, and 2 had Medicaid. All patients ultimately received insurance coverage for treatment; however, 36 (95%) required prior authorization and 9 (24%) required appeals to obtain insurance coverage. The median time from DAA prescription to insurance approval was 6 days. The median time from transplantation to start of treatment was 29 days (range, 0-84 days). Patients with Medicaid insurance had a significantly longer time to insurance approval (31.5 vs 6 days, P = 0.007). The average out-of-pocket cost to patients was less than $10 a month after patient assistance. All patients who completed treatment and 12-week follow-up after treatment achieved a sustained virologic response (n = 36). In this study, all HCV-negative recipients who developed HCV following transplantation had access to DAA therapy, with the majority starting treatment in the first month after transplantation.

Hepatitis C treatment outcomes among patients treated in co-located primary care and addiction treatment settings

BackgroundPersons with substance use disorders face major barriers to hepatitis C virus (HCV) treatment. Co-location of addiction and HCV treatment is appealing, yet there are limited data on outcomes using this model. This study evaluated HCV outcomes of patients treated with direct-acting antivirals (DAAs) by primary care providers in two sites of co-located addiction/HCV care. MethodsThe study conducted a retrospective chart review for all patients receiving DAA treatment from 2016 to 2018 at 1) a hospital-based primary care clinic with an office-based buprenorphine program, and 2) a primary care clinic within an opioid treatment program (i.e. methadone clinic). The study classified patients into 3 groups according to treatment status: buprenorphine maintenance, methadone maintenance, or neither. Descriptive analyses compared patient demographics, clinical characteristics, adherence to monitoring and treatment, and the primary outcome of sustained virologic response at 12 weeks (SVR12), defined as an undetectable HCV viral load at least 12 weeks after completing treatment. ResultsThis study included 50 patients who initiated DAA treatment. The majority of patients were unemployed (74.0%), did not smoke tobacco (54.0%), and had psychiatric comorbidities (80.0%). Many also experienced homelessness during treatment (22.0%) and experienced previous incarceration (36.0%). Only a few had recently injected drugs (4.0%). Seven of 7 (100%) patients were treated with buprenorphine, 21 of 24 (87.5%) patients were treated with methadone, and 17 of 19 (89.5%) patients receiving no opioid addiction treatment fully completed HCV DAA treatment. When including patients with missing SVR12 data with the cohort that did not achieve cure, we observe that 44 of 50 patients (88.0%) achieved SVR12. Excluding patients missing SVR12 data, we observed that 44 of 46 patients (95.7%) achieved SVR12. ConclusionPersons with substance use disorders treated with DAAs in co-located primary care and addiction treatment settings can achieve high rates of cure despite significant comorbidities and barriers. DAA treatment should be expanded to co-located HCV and addiction settings.

Naïve CD4+ T Cell Lymphopenia and Apoptosis in Chronic Hepatitis C Virus Infection Is Driven by the CD31+ Subset and Is Partially Normalized in Direct-Acting Antiviral Treated Persons.

BackgroundThe mechanisms underlying naïve CD4+ lymphopenia during chronic Hepatitis C Virus (HCV) infection are unclear. Whether direct-acting antiviral (DAA) therapy restores peripheral naïve CD4+ T cell numbers and function is unknown.MethodsWe enumerated frequencies and counts of peripheral naïve CD4+, CD4+CD31+ and CD4+CD31- T cells by flow cytometry in a cross sectional analysis comparing chronic HCV infected (n=34), DAA-treated(n=29), and age-range matched controls (n=25), as well as in a longitudinal cohort of HCV DAA treated persons (n=16). The cross-sectional cohort was stratified by cirrhosis state. Cell apoptosis/survival (AnnexinV+7AAD+/BCL-2 labeling) and cell cycle entry (Ki67 expression) of CD31+ and CD31- naïve CD4+ T cells was analyzed directly ex vivo and following 3 and 5 days of in vitro culture with media, interleukin (IL) -7 or CD3/CD28 activator.ResultsIn the cross-sectional cohort, naïve CD4+ proportions were lower in chronic HCV infected persons compared to controls and DAA-treated persons, an effect in part attributed to cirrhosis. Age was associated with naïve cell counts and proportions in HCV infected and treated persons as well. Naïve CD4+ cell proportions negatively correlated with plasma levels of soluble CD14 following therapy in DAA-treated persons. Naïve CD4+ cells from HCV infected persons exhibited greater direct ex vivo apoptosis and cell-cycling compared to cells from DAA-treated persons and controls, and this was localized to the CD4+CD31+ subset. On the other hand, no remarkable differences in expression of BCL-2 or IL-7 Receptor (CD127) at baseline or following in vitro media or IL7 containing culture were observed. In the longitudinal cohort, naïve CD4+CD31+/CD31- ratio tended to increase 24 weeks after DAA therapy initiation.ConclusionsActivation and apoptosis of peripheral naïve CD4+CD31+ T cells appear to contribute to naïve CD4+ lymphopenia in chronic HCV infection, and this defect is partially reversible with HCV DAA therapy. Age and cirrhosis -associated naïve CD4+ lymphopenia is present both before and after HCV DAA therapy. These findings have implications for restoration of host immune function after DAA therapy.