Antiviral treatment of hepatitis C.
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ABSTRACT:
SUBMITTER: Feeney ER
PROVIDER: S-EPMC6880951 | biostudies-literature | 2014 Jul
REPOSITORIES: biostudies-literature
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Antiviral treatment of hepatitis C.
Feeney Eoin R ER Chung Raymond T RT
BMJ (Clinical research ed.) 20140707
Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and t ...[more]
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Project description:<p>Reprinted from http://www.haltctrial.org/</p> <p><b>Purpose</b></p> <p>The <b>H</b>epatitis C <b>A</b>ntiviral <b>L</b>ong-term <b>T</b>reatment against <b>C</b>irrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment.</p> <p><b>Study Hypotheses</b></p> <p> <ol> <li>In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis.</li> <li>In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma.</li> </ol> </p> <p><b>Study Design</b></p> <p>1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys®, Hoffmann-La Roche) 180 µg/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48.</p> <p>662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 µg/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment.</p> <p>Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients.</p> <p>A total 1050 patients were randomized.</p> <p>Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed.</p> <p><u>Quarterly (every 3 months)</u></p> <p> <ul> <li>Interval history of complications, adverse events</li> <li>Current medications</li> <li>Brief physical examination</li> <li>Laboratory tests: liver panel, CBC, INR, AFP</li> <li>Child-Pugh Score</li> <li>Stored serum</li> </ul> </p> <p><u>Annual</u></p> <p> <ul> <li>Complete physical examination</li> <li>Ultrasound of liver</li> </ul> </p> <p><u>1.5 years (M24 visit, middle of study)</u></p> <p> <ul> <li>Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients)</li> </ul> </p> <p><u>3.5 years (M48, end of study)</u></p> <p> <ul> <li>Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients)</li> <li>Endoscopy: evaluate esophageal varices and portal hypertension</li> </ul> </p> <p><u>After Month 48</u></p> <p> <ul> <li>Observation only (no treatment) to determine clinical outcomes</li> <li>Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored</li> <li>Serum</li> <li>Ultrasound of liver every 6 months</li> </ul> </p> <p><b>Outcome Variables</b></p> <p>Primary outcome variables to be assessed in the two groups of patients include: <ul> <li>Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more)</li> <li>Development of hepatic decompensation, as shown by:</li> <ul> <li>Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher</li> <li>Variceal hemorrhage</li> <li>Ascites</li> <li>Spontaneous bacterial peritonitis</li> <li>Hepatic encephalopathy</li> <li>Development of hepatocellular carcinoma</li> <li>Death</li> </ul> </ul> Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma. </p>
| phs000430.v1.p1 | EGA
Project description:Approximately one half of patients who undergo antiviral therapy for chronic hepatitis C virus (HCV) genotype 1 infection do not respond to treatment. African Americans (AAs) are less responsive to treatment than Caucasian Americans (CAs), but the reasons for this disparity are largely unknown. Recent studies suggest that serum lipids may be associated with treatment response. The aims of this study were to evaluate baseline and changes in serum lipids during therapy, determine whether serum lipids are associated with virological response, and assess whether these measures explain the racial difference in efficacy. The study participants were from Virahep-C, a prospective study of treatment-naïve patients with genotype 1 HCV infection who received peginterferon (PEG-IN) alfa-2a plus ribavirin therapy for up to 48 weeks. Fasting serum lipids were analyzed at baseline and during and after therapy in 160 AAs and 170 CAs. A relative risk (RR) model was employed to evaluate characteristics associated with sustained virological response (SVR). Antiviral therapy was associated with changes in serum lipids during and after antiviral therapy, with the changes differing by race and the amount of PEG-IFN taken. Baseline lipid measures independently associated with higher rates of SVR were lower triglyceride and higher low-density lipoprotein cholesterol, with an interaction between high-density lipoprotein cholesterol (HDLc) and gender. Lipid measures did not contribute significantly to an explanation of the racial difference in SVR.Serum lipids are associated with SVR, although these paramaters did not explain the racial difference in treatment response. The results of this study are compatible with proposed biological mechanisms of HCV entry, replication, and secretion, and may underscore new potential therapeutic targets for HCV eradication.
| S-EPMC2938827 | biostudies-literature
Project description:Hepatitis C virus (HCV) infection is the leading cause of chronic liver-related diseases, including cirrhosis, liver failure, and hepatocellular carcinoma. Currently, no effective vaccine is available for HCV infection. Polyethylene glycol interferon-α (PegIFN-α) in combination with ribavirin (RBV) is the standard of care (SOC) for chronic hepatitis C. However, the efficacy of PegIFN-α and RBV combination therapy is less than 50% for genotype 1 HCV, which is the dominant virus in humans. In addition, IFN and RBV have several severe side effects. Therefore, strategies to improve sustained virological response (SVR) rates have been an important focus for clinical physicians. The serine protease inhibitors telaprevir and boceprevir were approved by the United States Food and Drug Administration in 2011. The addition of HCV protease inhibitors to the SOC has significantly improved the efficacy of treatments for HCV infection. Several direct-acting antiviral drugs currently in late-stage clinical trials, both with and without peg-IFN and RBV, have several advantages over the previous SOC, including higher specificity and efficacy, fewer side effects, and the ability to be administered orally, and might be optimal regimens in the future. Factors affecting the efficacy of anti-HCV treatments based on IFN-α include the HCV genotype, baseline viral load, virological response during treatment, host IL28B gene polymorphisms and hepatic steatosis. However, determining the effect of the above factors on DAA therapy is necessary. In this review, we summarize the development of anti-HCV agents and assess the main factors affecting the efficacy of antiviral treatments.
| S-EPMC3870549 | 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:The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B virus (HBV) surface antigen (HBsAg) and HBV DNA from blood, is on eliminating or silencing the intranuclear template for HBV replication, covalently closed circular DNA (cccDNA). However, HBsAg also derives from HBV DNA integrated into the host genome (iDNA). Little is known about the contribution of iDNA to circulating HBsAg with current therapeutics. We applied a multiplex droplet digital PCR assay to demonstrate that iDNA is responsible for maintaining HBsAg quantities in some individuals. Using paired bulk liver tissue from 16 HIV/HBV-coinfected persons on nucleos(t)ide analog (NUC) therapy, we demonstrate that people with larger HBsAg declines between biopsies derive HBsAg from cccDNA, whereas people with stable HBsAg levels derive predominantly from iDNA. We applied our assay to individual hepatocytes in paired tissues from 3 people and demonstrated that the individual with significant HBsAg decline had a commensurate loss of infected cells with transcriptionally active cccDNA, while individuals without HBsAg decline had stable or increasing numbers of cells producing HBsAg from iDNA. We demonstrate that while NUC therapy may be effective at controlling cccDNA replication and transcription, innovative treatments are required to address iDNA transcription that sustains HBsAg production.
| S-EPMC9473722 | biostudies-literature
Project description:BACKGROUND:Antiviral treatment for chronic hepatitis B is costly, which presents challenges for universal drug coverage for the estimated 480 000 people with the disease in Canada. We appraised criteria for reimbursement of chronic hepatitis B antivirals by public drug plans in Canada. METHODS:In this descriptive study, we reviewed the reimbursement criteria for lamivudine, adefovir, tenofovir, entecavir, telbivudine, pegylated or standard interferon, and emtricitabine-tenofovir in the 10 provinces and the Yukon Territory as well as 3 federal programs: Correctional Services Canada, Veterans' Affairs and the Non-Insured Health Benefits Program. We extracted data from publicly available formularies. The primary outcomes extracted were prescriber details, reimbursement regulations and published list price. RESULTS:All public drug insurance plans limit access to antiviral treatment in patients with chronic hepatitis B based on viral characteristics, fibrosis stage and/or specialist approval. Lamivudine use is restricted only in British Columbia and Ontario. Six plans (43%) cover entecavir or tenofovir with no restriction, and 8 plans (57%) cover these agents if patients have advanced fibrosis/cirrhosis. Nine plans (64%) provide coverage of interferon, although 4 of these programs reimburse only nonpegylated interferon, which is not currently recommended for chronic hepatitis B treatment. INTERPRETATION:We found substantial variability among jurisdictions in reimbursement criteria for the treatment of chronic hepatitis B in Canada. The findings can inform health policy and support the development and adoption of a national chronic hepatitis B strategy to ensure equitable and timely access to treatment no matter where patients reside in Canada.
| S-EPMC6440881 | biostudies-other
Project description:BackgroundHighly effective direct antiviral agents (DAAs) for hepatitis C virus (HCV) were introduced recently. Their utilisation has been limited by high cost and low access to care.AimTo describe the effect of DAAs on HCV treatment and cure rates in the United States Veterans Affairs (VA) national healthcare system.MethodsWe identified all HCV antiviral treatment regimens initiated from 1 January 1999 to 31 December 2015 (n = 105 369) in the VA national healthcare system, and determined if they resulted in sustained virological response (SVR).ResultsHCV antiviral treatment rates were low (1981-6679 treatments/year) in the interferon era (1999-2010). The introduction of simeprevir and sofosbuvir in 2013 and ledipasvir/sofosbuvir and paritaprevir/ombitasvir/ritonavir/dasabuvir in 2014 were followed by increases in annual treatment rates to 9180 in 2014 and 31 028 in 2015. The number of patients achieving SVR was 1313 in 2010, the last year of the interferon era, and increased 5.6-fold to 7377 in 2014 and 21-fold to 28 084 in 2015. The proportion of treated patients who achieved SVR increased from 19.2% in 1999 and 36.0% in 2010 to 90.5% in 2015. Within 2015, monthly treatment rates ranged from 727 in July to 6868 in September correlating with the availability of funds for DAAs.ConclusionsDAAs resulted in a 21-fold increase in the number of patients achieving HCV cure. Treatment rates in 2015 were limited primarily by the availability of funds. Further increases in funding and cost reductions of DAAs in 2016 suggest that the VA could cure the majority of HCV-infected Veterans in VA care within the next few years.
| S-EPMC5849458 | 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
Project description:UnlabelledHepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events.ConclusionSVR12 rates for sofosbuvir-based DAA regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.
| S-EPMC4718772 | biostudies-literature
Project description:End stage liver disease due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT) worldwide. Regretfully, infection of the graft by HCV occurs almost universally after LT, causing chronic hepatitis and early progression to cirrhosis in a significant proportion of recipients. Moreover, graft and patient survival are significantly worse in patients undergoing LT for HCV-related cirrhosis than in those transplanted for other indications. Therefore, many LT centers consider antiviral treatment with interferon and ribavirin the mainstay of managing recurrent HCV disease in LT recipients. The optimal time to start treatment is unclear. In most instances, treatment is initiated when histological evidence of disease recurrence, either at protocol or on-demand liver biopsies, is observed after LT. However, antiviral treatment initiated before LT is a potential option for some patients for two reasons: first, clearing or suppressing HCV before LT may reduce or eliminate the risk of recurrent hepatitis C in the transplanted liver and thereby improve survival; second, clearing HCV in cirrhotic patient may halt disease progression and avoid the need for transplantation. In this article, the results obtained by pre-transplant antiviral regimens administered to HCV-positive cirrhotic patients awaiting LT are discussed.
| S-EPMC2500252 | biostudies-literature