Hepatitis C Viral Kinetics in the Era of Direct Acting Antiviral Agents and IL28B.
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ABSTRACT:
SUBMITTER: Dahari H
PROVIDER: S-EPMC3237049 | biostudies-literature | 2011 Jul
REPOSITORIES: biostudies-literature
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Hepatitis C Viral Kinetics in the Era of Direct Acting Antiviral Agents and IL28B.
Dahari Harel H Guedj Jeremie J Perelson Alan S AS Layden Thomas J TJ
Current hepatitis reports 20110701 3
In the last decade hepatitis C virus (HCV) kinetics has become an important clinical tool for the optimization of therapy with (pegylated)-interferon-α (IFN) and ribavirin (RBV). Mathematical models have generated important insights into HCV pathogenesis, HCV- host dynamics, and IFN and RBV's modes of action. Clinical trials with direct acting agents (DAAs) against various steps of the HCV life cycle have revealed new viral kinetic patterns that have not been observed with IFN±RBV. Very recently ...[more]
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Project description:The new era of Hepatitis C management is marked by newly available tests for IL28B polymorphisms, US Food and Drug Administration (FDA) approval of the first direct acting antivirals (DAA; boceprevir and telaprevir), monitoring of drug-related mutations and emerging data on new classes of DAAs and second wave and second generation protease inhibitors. With the previous standard of care (pegylated interferon-alpha and ribavirin), baseline predictors were regularly used to determine treatment candidacy, and recently, IL28B genetic polymorphisms have been identified as the strongest baseline predictors of treatment response. Yet the role of IL28B genotype testing and other baseline predictors is less clear in the setting of DAAs. We will review the current literature assessing the role of IL28B genetic variation in the setting of DAAs and discuss the potential indication for IL28B genotype testing in treatment decision-making in this new therapeutic era.
| S-EPMC3955390 | biostudies-literature
Project description:BackgroundDirect-acting anti-virals (DAA) are safe, effective treatment of hepatitis C virus (HCV). Suboptimal linkage to specialists and access to DAAs are the leading barriers to treatment; however, data are limited.AimTo determine predictors of follow-up, receipt of DAAs, and reasons for the lack thereof.MethodsWe used clinical data from retrospective cohort of HCV-infected patients with previously established HCV care in the US Department of Veterans Affairs to examine predictors of follow-up in HCV clinics and DAA treatment (during 12/1/2013-4/30/2015). We then conducted a structured review of medical charts of HCV patients to determine reasons for lack of follow-up and treatment.ResultsWe identified 84 221 veterans who were previously seen in HCV clinics during the pre-DAA era. Of these, 47 165 (56.0%) followed-up in HCV specialty clinics, 13 532 (28.7%) of whom received DAAs. Older age, prior treatment, presence of cirrhosis or HCC, HIV/HBV co-infection and psychiatric illness were predictors of follow-up. Alcohol/drug abuse and medical co-morbidity were predictors of lack of treatment. Of the 905 prospectively recruited patients, 56.2% patients had a specialist visit and 28% received DAAs. Common reasons for lack of follow-up were relocation (n = 148, 37.4%) and missed/cancelled appointments (n = 63, 15.9%). Reasons for lack of treatment included waiting for newer therapy (n = 99, 38.8%), co-morbidities (n = 66, 25.9%) and alcohol/drug abuse (n = 63, 24.7%).ConclusionsHalf of patients with established HCV care were followed-up in the DAA era and only 29% received DAAs. Targeted efforts focusing on patient and system-levels may improve the reach of treatment with the new DAAs.
| S-EPMC5800315 | biostudies-literature
Project description:BackgroundHepatitis C virus (HCV) remains under-treated in the United States and treatment by nonspecialist providers can expand access. We compare HCV treatment provision and treatment completion between nonspecialist and specialist providers.MethodsThis retrospective study used claims data from the Healthcare Cost Institute from 2013 to 2017. We identified providers who prescribed HCV therapy between 2013 and 2017, and patients enrolled in private insurance or Medicare Advantage who had pharmacy claims for HCV treatment. We measured HCV treatment completion, determined based on prescription fills for the minimum expected duration of the antiviral regimen. Using propensity score-weighted regression, we compared the likelihood of early treatment discontinuation by the type of treating provider.ResultsThe number of providers prescribing HCV treatment peaked in 2015 and then declined. The majority were gastroenterologists, although the proportion of general medicine providers increased to 17% by 2017. Among the 23,463 patients analyzed, 1008 (4%) discontinued before the expected minimum duration. In the propensity score-weighted analysis, patients treated by general medicine physicians had similar odds of treatment discontinuation compared with those treated by gastroenterologists [odds ratio (OR)=1.00, 95% confidence interval (CI): 0.99-1.01, P=0.45]. Results were similar when comparing gastroenterologists to nonphysician providers (OR=1.00, 95% CI: 0.99-1.01, P=0.53) and infectious diseases specialists (OR=1.00, 95% CI: 0.99-1.01, P=0.71).ConclusionsHCV treatment providers remain primarily gastroenterologists, even in the current simplified treatment era. Patients receiving treatment from general medicine or nonphysician providers had a similar likelihood of treatment completion, suggesting that removing barriers to the scale-up of treatment by nonspecialists may help close treatment gaps for hepatitis C.
| S-EPMC8384709 | biostudies-literature
Project description:ImportanceRecent reports based on the US Food and Drug Administration's voluntary Adverse Events Reporting System raised questions about the safety of direct-acting antivirals (DAAs) for treatment of the hepatitis C virus (HCV).ObjectiveTo assess the rates of adverse events in patients with HCV infection exposed to DAAs compared with those not exposed.Design, setting, and participantsA retrospective cohort study calculated unadjusted adverse event rates for exposed vs unexposed time, using claims and clinical data from 3 health systems between January 1, 2012, and December 31, 2017. Of 82 419 eligible adults, a total of 33 808 who met eligibility criteria (age, 18-88 years; HCV quantitative result or genotype from 2012 or later; continuously enrolled; naive to DAA treatment at baseline) were included. Marginal structural modeling methods were used to adjust time-to-event analyses for characteristics that are associated with both outcomes and probability of treatment.Interventions or exposuresExposure to DAAs compared with no DAA exposure.Main outcomes and measuresDeath, multiple organ failure, liver cancer, hepatic decompensation, acute-on-chronic liver event, acute myocardial infarction, ischemic or hemorrhagic stroke, arrhythmia, acute kidney failure, nonliver cancer, hepatitis B reactivation, hospitalizations, and emergency department visits.ResultsOf the 33 808 patients who met all inclusion criteria, 20 899 (61.8%) were men; mean (SD) age was 57.2 (10.6) years. In unadjusted analyses, DAA exposure was associated with significantly lower rates of death (10.7 vs 33.7 events per 1000 person-years; rate ratio [RR], 0.32, 95% CI, 0.25-0.40). Seven other unadjusted adverse clinical events ratios were below 70% and statistically significant favoring the DAA group: multiple organ failure (RR, 0.56; 95% CI, 0.44-0.72), liver cancer (RR, 0.62; 95% CI, 0.48-0.80), hepatic decompensation (RR, 0.62; 95% CI, 0.52-0.73), acute-on-chronic liver event (RR, 0.68; 95% CI, 0.56-0.84), acute myocardial infarction (RR, 0.64; 95% CI, 0.42-0.97), ischemic stroke (RR, 0.63; 95% CI, 0.42-0.95), and hemorrhagic stroke (RR, 0.47; 95% CI, 0.25-0.89); none favored the non-DAA group. In the marginal structural modeling-adjusted analysis, DAA exposure was associated with statistically significant lower odds of adverse events than non-DAA exposure for death (adjusted odds ratio [aOR], 0.42; 95% CI, 0.30-0.59), multiple organ failure (aOR, 0.67; 95% CI, 0.49-0.90), hepatic decompensation (aOR, 0.61; 95% CI, 0.49-0.76), acute-on-chronic liver event (aOR, 0.71; 95% CI, 0.56-0.91), and arrhythmia (aOR, 0.47; 95% CI, 0.25-0.88).Conclusions and relevanceDirect-acting antiviral exposure may not be associated with higher rates of any serious adverse events, including those related to liver, kidney, and cardiovascular systems. Safety concerns based on previous reports did not appear to be supported in this study with more comprehensive data and rigorous statistical methods.
| S-EPMC6563580 | biostudies-literature
Project description:The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus (HCV). In the liver transplant (LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better response rates achieved with boceprevir-based and telaprevir-based triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.
| S-EPMC4381175 | biostudies-literature
Project description:BackgroundMedical students play important frontline roles in the prevention, early detection, and treatment of hepatitis C. This study investigated knowledge and attitudes toward hepatitis C among 5th- and 6th-year medical students and possible associated factors.MethodsA cross-sectional survey was conducted among 2000 students from eight medical universities using a self-administered structured questionnaire.ResultsThe mean knowledge and attitude scores for hepatitis C were 20.1 ± 4.0 (out of 26) and 10.6 ± 2.9 (out of 20), respectively. Approximately, three-quarters (74.4%) of the participants had a good knowledge score, but only a small proportion (3.1%) obtained a good attitude score. Although the participants had fairly high knowledge about the causes, consequences, and transmission routes of hepatitis C, there were important gaps in their knowledge about hepatitis C screening and treatment. In multivariate analysis, female students, 5th-year students, and students from the central provinces had significantly higher knowledge and attitude scores. There was a low positive correlation between knowledge and attitude scores.ConclusionThis study points out the need to update the medical training curriculum to improve the knowledge and attitude of students about hepatitis C infection.
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Project description:Hepatitis C virus (HCV) RNA loads serve as predictors of treatment response during interferon-based therapy. We evaluated the predictive ability of HCV RNA levels at end of treatment (EOT) for sustained virologic response (SVR12) during interferon-sparing direct-acting antiviral therapies.HCV genotype 1-infected, treatment-naive patients were treated with sofosbuvir and ribavirin for 24 weeks (n = 55), sofosbuvir and ledipasvir for 12 weeks (n = 20), sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (n = 20), or sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (n = 19). Measurements of HCV RNA were performed using the Roche COBAS TaqMan HCV test and the Abbott RealTime HCV assay. Positive predictive value (PPV) and negative predictive value (NPV) of HCV RNA less than the lower limit of quantification (<LLOQ) at EOT for SVR12 were calculated.All 55 patients treated with sofosbuvir and ribavirin had HCV RNA <LLOQ at EOT by the Roche and Abbott assays, but only 38 achieved SVR12 (PPV, 69%). Among patients treated with sofosbuvir and ledipasvir with or without GS-9669 or GS-9451, 100% (59/59) had HCV RNA <LLOQ by the Roche assay and 1 relapsed (PPV, 98%). By the Abbott assay, 90% (53/59) had HCV RNA <LLOQ, of whom 1 patient relapsed (PPV, 98%). Notably, 6 patients with HCV RNA ?LLOQ at EOT (range, 14-64 IU/mL) achieved SVR12 (NPV, 0%). Quantifiable HCV RNA (range, 15-57 IU/mL) was measured 2 weeks posttreatment in 4 individuals, and 4 weeks posttreatment in 1 patient (14 IU/mL).Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at EOT do not preclude treatment success.
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Project description:ImportanceFor patients awaiting heart transplant, hepatitis C-positive donors offer an opportunity to expand the donor pool, shorten wait times, and decrease wait-list mortality. While early reported outcomes among few heart transplant recipients have been promising, knowledge of 1-year outcomes in larger cohorts of patients is critical to shared decision-making with patients about this option.ObjectiveTo better define the association of hepatitis C-positive donors with heart transplant volumes, wait-list duration, the transmission and cure of donor-derived hepatitis C, and morbidity and mortality at 1 year.Design, setting, and participantsThis was a prospective, single-center observational study of 80 adult (age 18 years or older) patients who underwent heart transplant using hearts from hepatitis C-positive donors between September 2016 and April 2019 at a large academic medical center. Among donors, who were considered hepatitis C-positive if results from hepatitis C antibody and/or nucleic acid testing were positive, 70 had viremia and 10 were seropositive but did not have viremia. Follow-up was available through May 15, 2019. Comparisons were drawn with patients who underwent transplant with hearts from hepatitis C-negative donors during the same period.ExposuresIn addition to standard posttransplant management, transplant recipients who developed donor-derived hepatitis C infection were treated with direct-acting antivirals.Main outcomes and measuresThe main outcomes included wait-list duration and 1-year survival in all patients, and for those who developed donor-derived hepatitis C, the response to direct-acting antiviral treatment.ResultsOf 80 patients, 57 (71.3%) were men, 55 (68.7%) were white, and 17 (26.3%) were black; the median age at transplant was 54.5 years (interquartile range, 46-62 years). Following consent to accept hearts from hepatitis C-exposed donors, the median days to heart transplant was 4 (interquartile range, 1-18). No recipients of donors with negative nucleic acid testing results (10 [12.5%]) developed donor-derived hepatitis C. Of 70 patients who were recipients of donors with positive nucleic acid testing results, 67 (95.7%) developed donor-derived hepatitis C over a median follow-up of 301 days (interquartile range, 142-617). Treatment with direct-acting antivirals was well tolerated and yielded sustained virologic responses in all treated patients. Within the cohort with infection, 1-year patient survival was 90.4%, which was not significantly different compared with the cohort without infection or with patients who received transplants from hepatitis C-negative donors during the same period.Conclusions and relevanceIn the era of direct-acting antivirals, hepatitis C-positive donors are a viable option to expand the donor pool, potentially reducing wait-list duration and mortality. In heart transplant recipients with donor-derived hepatitis C, infection is well-tolerated and curable, and 1-year survival is equivalent to that in recipients of hepatitis C-negative donors.
| S-EPMC6990812 | biostudies-literature
Project description:The face of hepatitis C virus (HCV) therapy is changing dramatically. Direct-acting antiviral agents (DAAs) specifically targeting HCV proteins have been developed and entered clinical practice in 2011. However, despite high sustained viral response (SVR) rates of more than 90%, a fraction of patients do not eliminate the virus and in these cases treatment failure has been associated with the selection of drug resistance mutations (RAMs). RAMs may be prevalent prior to the start of treatment, or can be selected under therapy, and furthermore they can persist after cessation of treatment. Additionally, certain DAAs have been approved only for distinct HCV genotypes and may even have subtype specificity. Thus, sequence analysis before start of therapy is instrumental for managing DAA-based treatment strategies. We have created the interpretation system geno2pheno[HCV] (g2p[HCV]) to analyse HCV sequence data with respect to viral subtype and to predict drug resistance. Extensive reviewing and weighting of literature related to HCV drug resistance was performed to create a comprehensive list of drug resistance rules for inhibitors of the HCV protease in non-structural protein 3 (NS3-protease: Boceprevir, Paritaprevir, Simeprevir, Asunaprevir, Grazoprevir and Telaprevir), the NS5A replicase factor (Daclatasvir, Ledipasvir, Elbasvir and Ombitasvir), and the NS5B RNA-dependent RNA polymerase (Dasabuvir and Sofosbuvir). Upon submission of up to eight sequences, g2p[HCV] aligns the input sequences, identifies the genomic region(s), predicts the HCV geno- and subtypes, and generates for each DAA a drug resistance prediction report. g2p[HCV] offers easy-to-use and fast subtype and resistance analysis of HCV sequences, is continuously updated and freely accessible under http://hcv.geno2pheno.org/index.php. The system was partially validated with respect to the NS3-protease inhibitors Boceprevir, Telaprevir and Simeprevir by using data generated with recombinant, phenotypic cell culture assays obtained from patients' virus variants.
| S-EPMC4873220 | biostudies-literature
Project description:Around 71 million people are chronically infected with HCV worldwide. HCV antiviral drug development has been remarkable. The availability of pangenotypic direct-acting antivirals with excellent efficacy and good tolerability profiles offer a unique opportunity to achieve HCV elimination worldwide. IFN-free DAA combinations can now cure HCV in more than 95% of patients with HCV infection after 8-12 weeks of treatment. Programmes to eliminate HCV must include increased screening (risk-based and universal), linkage to care, as well as increased access to treatment worldwide. In this paper, we will review the available data on recently approved direct-acting antiviral agents, with sustained virological response that reaches almost 100%.
| S-EPMC7713514 | biostudies-literature