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Sofosbuvir/ledipasvir cures more than 90% of people with hepatitis C genotypes 4 and 5

Liz Highleyman
20 May 2015

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, Austria.

The advent of direct-acting antiviral agents (DAAs) that can be used in interferon-free combinations has revolutionised 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 Europe and the US. Genotype 2 is a minority variant everywhere. Genotype 3 is common in the UK, 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 of Université d'Auvergne in France and colleagues evaluated the safety and efficacy of sofosbuvir/ledipasvir in people with chronic hepatitis C genotypes 4 or 5. Estimates suggest that these two genotypes together account for about 14% of all hepatitis C infections worldwide, he noted.

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 five 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 (90/400mg) for 12 weeks.

After 12 weeks of therapy plus 12 weeks of post-treatment follow-up, 93% of genotype 4 patients and 95% of genotype 5 patients achieved sustained virological response (SVR12), or continued undetectable HCV RNA.

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%). Ninety-one per cent of people without cirrhosis and 100% of people with cirrhosis with genotype 4, and 97% of people without cirrhosis and 98% of people with cirrhosis and genotype 5, were cured.

All five treatment failures (three genotype 4 and two genotype 5) were due to relapse after completing therapy. Abergel noted that two of the three 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). Two relapsers had evidence of new 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. One person 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.

New EASL hepatitis C treatment guidelines released at the conference recommend sofosbuvir/ledipasvir for genotypes 4 and 5. Sofosbuvir plus simeprevir (Olysio) and paritaprevir/ritonavir/ombitasvir (Viekirax) are also recommended for genotype 4, while sofosbuvir plus daclatasvir (Daklinza) is an option for all genotypes. In the US, Harvoni is approved only for genotype 1. The latest AASLD guidelines recommend sofosbuvir/ledipasvir, paritaprevir/ritonavir/ombitasvir with ribavirin, or sofosbuvir with ribavirin alone for genotype 4, but only sofosbuvir plus pegylated interferon/ribavirin is recommended for genotype 5.


Abergel A et al. Ledipasvir/sofosbuvir treatment results in high
 SVR rates in patients with chronic genotype 4 and 5 HCV infection. EASL 50th International Liver Congress, Vienna, abstract O056, 2015.