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EASL 2015: Sofosbuvir/ Ledipasvir Cures More Than 90% of People with Hepatitis C Genotypes 4 and 5

An interferon-free regimen of sofosbuvir and ledipasvir (Harvoni) produced sustained virological response rates of 93% for people with HCV genotype 4 and 95% for those with genotype 5, according to a French study presented at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last month in Vienna.

The advent of direct-acting antiviral agents (DAAs) that can be used in interferon-free combinations has revolutionized treatment for people with hepatitis C virus (HCV) genotypes 1 and 2. Better treatment options are still needed for HCV genotype 3, while limited information is available about treatment for genotypes 4, 5 and 6.

HCV genotype 1 is the most common type worldwide, including in the U.S. and Europe. Genotype 2 is a minority variant everywhere. Genotype 3 is common in some European countries, Russia, and South Asia. Genotypes 4, 5, and 6 are less widely distributed and are mainly found in countries that are poorer or have less medical research infrastructure. Genotype 4 is prevalent in the Middle East and parts of Africa (accounting for most cases in Egypt), genotype 5 is mostly found in South Africa, and genotype 6 is mostly seen in China and Southeast Asia.

Armand Abergel from Université d'Auvergne and colleagues evaluated the safety and efficacy of sofosbuvir/ledipasvir for chronic hepatitis C patients with genotypes 4 or 5. Estimates suggest that these genotypes together account for about 14% of all hepatitis C infections worldwide, he noted (about 1% for genotype 5, the rest genotype 4).

Sofosbuvir/ledipasvir produces cure rates above 90% for people with HCV genotype 1, but ledipasvir is not very active against genotype 3; sofosbuvir plus ribavirin alone is highly effective for genotype 2. Laboratory studies have shown that both sofosbuvir (a nucleotide NS5B polymerase inhibitor) and ledipasvir (an NS5A inhibitor) are active against genotypes 4 and 5 in vitro. Genotype 4 has been studied along with genotype 1 in several clinical trials, but has usually accounted for only a small number of patients.

This Phase 2 study enrolled 44 participants with genotype 4 and 41 patients with genotype 5 at 5 sites in France. In the genotype 4 group about two-thirds were men and the mean age was 51 years. In the genotype 5 group about half were men and the mean age was older at 63 years. In both groups half were treatment-experienced, nearly one-quarter had liver cirrhosis, and most had high baseline HCV viral load. All genotype 5 patients had subtype 5a. A majority of genotype 4 patients had subtype 4a, but several other subtypes were represented (4b, 4d, 4f, 4m, 4o, and 4r).

All participants in this open-label study received sofosbuvir/ledipasvir in a once-daily fixed-dose coformulation (90/400 mg) for 12 weeks.

Results

• 93% of genotype 4 patients and 95% of genotype 5 patients achieved sustained virological response (SVR12) after 12 weeks of therapy plus 12 weeks of post-treatment follow-up.
• In the genotype 4 group, 96% of treatment-naive and 91% of treatment experienced patients achieved SVR12, while there was no difference according to prior treatment status in the genotype 5 group (both 95%).
• 91% of non-cirrhotic and 100% of cirrhotic genotype 4 patients, and 97% of non-cirrhotic and 98% of cirrhotic genotype 5 patients, were cured.
• All 5 treatment failures (3 with genotype 4 and 2 with genotype 5) were due to relapse after completing therapy; 2 of the 3 patients with subtype 4r relapsed.
• Presence of NS5A resistance-associated variants (RAVs) at baseline did not affect SVR12 rates (there were no pre-existing NS5B RAVs).
• 2 relapsers had evidence of emergent NS5B resistance mutations.
• Sofosbuvir/ledipasvir was generally safe and well-tolerated, with no notable side-effects not seen in previous genotype 1 studies.
• The most common adverse events were fatigue/weakness (46%) and headache (26%).
• Most side effects were mild or moderate and there were no grade 3/4 laboratory abnormalities.
• 1 patient experienced a serious adverse event (worsening depression, not considered drug-related) but there were no discontinuations due to adverse events.

"[Sofosbuvir/ledipasvir] for 12 weeks represents a safe and effective all-oral treatment for patients with genotype 4 and genotype 5 HCV," the researchers concluded.

In the U.S. Harvoni is approved only for HCV genotype 1. The latest AASLD hepatitis C treatment guidelines recommend sofosbuvir/ledipasvir, paritaprevir/ritonavir/ombitasvir (Viekirax; part of the Viekira Pak regimen in the U.S.) with ribavirin, or sofosbuvir with ribavirin alone for genotype 4, but only sofosbuvir plus pegylated interferon/ribavirin is recommended for genotype 5.

New EASL hepatitis C guidelines released at the Liver Congress recommend sofosbuvir/ledipasvir for genotypes 4 and 5. Sofosbuvir plus simeprevir (Olysio) and paritaprevir/ritonavir/ombitasvir are also recommended for genotype 4, while sofosbuvir plus daclatasvir (Daklinza, not yet approved in the U.S.) is an option for all genotypes.

5/12/15

Reference

A Abergel, V Loustaud-Ratti, S Metivier, et al. Ledipasvir/sofosbuvir treatment results in high
 SVR rates in patients with chronic genotype 4 and 5 HCV infection. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O056.

Other Source

Gilead Sciences. Gilead Announces Results From Studies Evaluating Sofosbuvir-Based Regimens in Chronic Hepatitis C Patients With Genotypes 2-5. Press release. April 25, 2015.