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Expert Critique

FROM THE ASCO Reading Room

Olanma Okoji, MD Gastroenterologist Capital Digestive Care

This article aims to delineate and update HCV guidelines as continued research yields better more effective regimens -- all with the goal of cure and decreased mortality and morbidity from hepatitis C-associated end-stage liver disease. The new regimens are pan-genotypic, meant to treat patients who have failed prior treatments as well as shorten the duration of treatment in both cirrhotic and non-cirrhotic patients. There is clear direction in which regimens can be used safely in patients with kidney dysfunction as well as kidney transplant recipients. The guidelines also include direction for treatment in pregnant women and children, with the current recommendation for pregnant women being to treat before pregnancy or after pregnancy. The article highlights that in the ever rapidly changing world of hepatitis C, the guidelines are meant to serve as an online reference document that can be updated as new data becomes available -- in essence also improving and increasing access to care and practitioners who can readily access knowledge in managing their patients.

Full Critique

Widely used were updated in September to reflect the latest drug approvals and recent research in the field.

The guidelines, developed by the (AASLD) and the (IDSA), were developed by a panel of experts based on a comprehensive review of relevant research.

"The HCV Guidance's goal is to respond to emerging issues that affect patients and their care in an ever-changing environment," panel co-chair Arthur Kim, MD, of Harvard Medical School in Boston, told 番茄社区.

Given the speed at which hepatitis C treatment research has been evolving in recent years, the guidelines are not periodically revised and published, but rather are a "living document" online that can be rapidly updated as new data become available.

The latest revision includes the addition of two recently approved direct-acting antiviral (DAA) coformulations. Both are pangenotypic, or active against all six major HCV genotypes.

Mavyret, approved on August 3, is a coformulation containing the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir. It is indicated for treatment-naive patients with HCV genotypes 1 through 6 and for people previously treated with specific prior regimens.

Vosevi, approved on July 18, is a single-tablet regimen containing the HCV NS5B polymerase inhibitor sofosbuvir (marketed separately as Sovaldi), the NS5A inhibitor velpatasvir (currently combined with sofosbuvir in the Epclusa coformulation), and the NS3/4A protease inhibitor voxilaprevir. It is indicated for the retreatment of patients who were not previously cured with specific prior DAA regimens.

"The introduction of these regimens will help to simplify the approach to the management of HCV of all genotypes, and in many instances allow the shortening of treatment to 8 weeks," panel co-chair Raymond Chung, MD, chief of Hepatology at Massachusetts General Hospital, told 番茄社区.

The updated guidelines list glecaprevir/pibrentasvir as a recommended regimen for first-line treatment of patients with all HCV genotypes, using a treatment duration of 8 weeks for those without cirrhosis and 12 weeks for those with cirrhosis.

Previously treated patients with genotypes 1, 2, 4, 5, or 6 who previously used interferon-based therapy can follow the glecaprevir/pibrentasvir recommendations for treatment-naive individuals. Genotype 1 patients previously treated with a NS3 protease inhibitor or sofosbuvir should use glecaprevir/pibrentasvir for 12 weeks regardless of cirrhosis status.

This regimen is not recommended for genotype 1 patients who previously used an NS5A inhibitor or for treatment-experienced genotype 3 patients, even if they have only used interferon/ribavirin. The product label says these groups may extend glecaprevir/pibrentasvir treatment to 16 weeks, and the guidelines include this as an alternative option.

"Until recently, the AASLD guidelines [for genotype 3] included resistance-associated substitution testing for patients with cirrhosis and use of ribavirin for those with Y93H," Steven Flamm, MD, of Northwestern Feinberg School of Medicine in Chicago, explained in a presentation at the 2017 Liver Meeting. Neither resistance testing nor ribavirin coadministration are needed with glecaprevir/pibrentasvir, he said.

Sofosbuvir/velpatasvir/voxilaprevir is recommended for retreatment of people with HCV genotypes 1, 3, 4, 5, or 6, with or without liver cirrhosis, who previously used DAA regimens including NS5A inhibitors, and for genotype 1 patients who previously used sofosbuvir.

Other new additions to the guidelines include a primer on HCV drug resistance and recommendations for treating hepatitis C in pregnant women, children, and people who have undergone kidney transplantation.

"To assist the treater with a deeper understanding of how and when to use resistance testing, we have introduced a new primer for clinicians," Chung said "The updated Guidance also offers an improved user interface that permits easy access to patient-specific recommendations, which is easily adaptable for use on smartphones and tablets as well."

The recommended regimens for kidney transplant recipients are glecaprevir/pibrentasvir or sofosbuvir/ledipasvir (Harvoni), both for 12 weeks.

For pregnant women, the guidelines panel recommends HCV antibody testing for those with known or suspected risk factors, but not universal screening. Due to the lack of safety and efficacy data, hepatitis C treatment during pregnancy is not recommended, and women should consider antiviral therapy before becoming pregnant, if possible. Mother-to-child HCV transmission during pregnancy occurs at a rate of 5% to 15%, but there currently are no known interventions to prevent it.

Hepatitis C is uncommon in children, but it can cause rapid liver disease progression in some cases. Sofosbuvir/ledipasvir was recently approved for children and adolescents age 12 and older.

The panel recommends a 12-week course of sofosbuvir/ledipasvir for previously untreated genotype 1 children with or without cirrhosis and for treatment-experienced children without cirrhosis, extending to 24 weeks for previously treated children with cirrhosis. Those with genotypes 4, 5, or 6 should be treated for 12 weeks regardless of cirrhosis status or prior treatment history. Sofosbuvir plus ribavirin remains the only recommended regimen for children with genotypes 2 or 3.

The guidelines state that treatment of children ages 3 to 11 should be deferred until interferon-free DAA regimens become available for this age group.

"Recent reports indicate that the uptick of HCV among young adults has led to higher prevalence among women of child-bearing age, which in turn has led to renewed concerns about transmission to newborns," Kim said. "The new sections on pediatrics and pregnancy are meant to provide guidance, even as more data emerge."