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Treatment progress and expansion in Japan: From interferon to direct-acting antiviral

ABSTRACT: Summary Hepatitis C virus (HCV) was first discovered in 1989, and patients infected with HCV were initially treated with interferon (IFN) monotherapy. In the 2000s, pegylated IFN combined with ribavirin was the mainstay of therapy for infected patients, but the sustained virologic response (SVR) rate was less than 50% for patients with HCV genotype 1. To further improve the therapeutic effect, direct-acting antiviral (DAA) was developed, and combination therapy with DAA and IFN has been available since 2011. In addition, IFN-free DAA therapy became available in 2014, and SVR was achieved in more than 95% of patients with chronic hepatitis and compensated cirrhosis. Thus, in just 30 years since the discovery of HCV, we aim to eliminate HCV in almost all patients. However, there are remaining issues to be addressed. Many of the patients who achieved SVR with DAA therapy had advanced liver fibrosis, and it is necessary to verify to what extent DAA therapy improves their prognosis in terms of liver function, hepatocellular carcinoma occurrence, and mortality. Resistance-associated substitutions can cause failure of DAA therapy, and the search for an effective therapy for high-level resistant viruses such as P32 deletion is particularly important. DAA therapy was approved for use in patients with decompensated cirrhosis in Japan in 2019, which is an unmet need so far. It is also important to verify the efficacy and safety in real-world settings. The World Health Organization aims to eliminate HCV by 2030, and Japan must tackle its remaining issues to achieve this goal.

SUBMITTER: Tahata Y

PROVIDER: S-EPMC8562094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world's population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.

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.

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Treatment progress and expansion in Japan: From interferon to direct-acting antiviral

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