Gilead triple combination cures easy-to-treat hepatitis C patients in 6 weeks, but 4 weeks is not enough

A six-week regimen of sofosbuvir (Sovaldi) plus two experimental direct-acting antivirals being developed by Gilead Sciences cured more than 90% of previously untreated people with genotype 1 hepatitis C virus and no liver cirrhosis, according to a poster presentation at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last month in Vienna, Austria. A four-week regimen was not effective for any group, however, and six weeks appears inadequate for harder-to-treat patients. Other studies showed that the new drugs, GS-5816 (velpatasvir) and GS-9857, are also active against other HCV genotypes.

Now that interferon-free direct-acting antiviral (DAA) regimens taken for 12 weeks can cure most people with HCV genotype 1, researchers are working to develop new drugs that work against multiple HCV genotypes (known as 'pan-genotypic') and that can produce sustained viral suppression with a shorter duration of treatment, which would be more convenient for patients and could potentially lower costs.

Edward Gane of Auckland Clinical Studies in New Zealand and colleagues tested a three-drug regimen consisting of Gilead's nucleotide HCV NS5B polymerase inhibitor sofosbuvir, the pan-genotypic NS5A inhibitor GS-5816 and the pan-genotypic NS3/4A HCV protease inhibitor GS-9857 taken for four or six weeks. Combining drugs that attack HCV at three different steps of its lifecycle may enable shorter treatment, the researchers hypothesised.

Glossary

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

treatment-naïve

A person who has never taken treatment for a condition.

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

naïve

In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

In preclinical and early clinical research presented in posters at the International Liver Congress (abstracts P0861, P0899, P0901), GS-9857 demonstrated potent antiviral activity against HCV genotypes 1-6, an improved resistance profile compared to older HCV protease inhibitors, and good pharmacokinetics and oral bioavailability. Further along in the pipeline, a coformulation of sofosbuvir and GS-5816 has shown promising efficacy in patients with all HCV genotypes and is now being evaluated in the phase 3 ASTRAL trials.

This open-label phase 2 study enrolled 75 participants with HCV genotype 1, stratified according to prior treatment experience and presence or absence of liver cirrhosis. A majority were men, 79% had harder to treat HCV subtype 1a and 68% had unfavourable IL28B gene variants.

Previously untreated participants without cirrhosis were randomly assigned to receive sofosbuvir/GS-5816 plus GS-9857 for four or six weeks. Treatment-naive patients with cirrhosis, and treatment-experienced patients (including 17% with cirrhosis) who were not previously cured with interferon-free regimens containing at least two DAAs, all received the triple regimen for 6 weeks.

Looking first at the 6-week regimen, 93% of treatment-naive participants without cirrhosis achieved sustained virological response, or continued undetectable HCV RNA at 12 weeks after completing therapy (SVR12).

The SVR12 rate was 87% for treatment-naive patients with cirrhosis, but fell to 67% for treatment-experienced participants. Within the treatment-experienced group, cure rates were 68% for people without cirrhosis and 60% for people with cirrhosis, but the latter subgroup included only five people.

The four-week treatment duration did not perform as well. Among the 15 treatment-naive people without cirrhosis assigned to this regimen, the SVR12 rate was only 27%.

In all cases, failure to achieve SVR12 was due to relapse after the end of treatment. Recent mathematical modelling research has suggested that four weeks of therapy does not lower viral load enough to achieve sustained response even when combining three classes of direct-acting antivirals.

Younger age and lower HCV viral load at baseline were the only factors that predicted SVR12 in a univariate analysis of the treatment-experienced patients. A pharmacokinetic substudy found that GS-5816 and GS-9857 drugs levels in the body were similar in people who did and did not achieve sustained response.

The cure rate was somewhat higher for people who did not have pre-existing HCV NS3 or NS5A resistance-associated variants (RAVs) at baseline, compared to people who had these mutations (approximately 60% vs 40%); only one person had evidence of NS5B resistance. RAVs were rarely observed at the time of relapse and no one showed resistance to multiple DAA classes.

Treatment with the triple regimen was generally safe and well-tolerated. All study participants completed treatment. There were no serious adverse events or drug discontinuations for this reason. The most common side-effects were nausea (25%), headache (24%) and fatigue (16%). Four people (5%) experienced transient, asymptomatic lipase elevations.

Treatment with sofosbuvir/GS-5816 plus GS-9857 for six weeks "was highly effective in treatment-naive genotype 1 patients without cirrhosis," but "shortening treatment duration to 4 weeks was associated with a higher relapse rate," the researchers concluded. Treatment-experienced patients and those with cirrhosis "may benefit from treatment for [longer than] 6 weeks."

Ongoing phase 2 studies are now testing sofosbuvir/GS-5816 plus GS-9857 for treatment durations of six, eight and twelve weeks in treatment-naive and treatment-experienced people with and without cirrhosis, with HCV genotypes 1 through 6 – including hardest-to-treat genotype 3.

References

Gane EJ et al. Safety and efficacy of short-duration treatment
with GS-9857 combined with sofosbuvir/GS-5816 in treatment-naive and DAA-experienced genotype 1 patients with and without cirrhosis. EASL 50th International Liver Congress, Vienna, abstract LP03, 2015.

Kirby B et al. Evaluation of the pan-genotypic HCV NS3/4A protease inhibitor GS-9857 in healthy volunteers. EASL 50th International Liver Congress, Vienna, abstract P0861, 2015.

Taylor JG et al. Preclinical profile of the pan-genotypic HCV NS3/4A protease inhibitor GS-9857. EASL 50th International Liver Congress, Vienna, abstract P0899, 2015.

Rodriguez-Torres M et al. The pan-genotypic NS3/4A protease inhibitor GS-9857 demonstrates potent antiviral activity in patients infected with HCV genotype 1, 2, 3 or 4 in a 
3-day monotherapy study
. EASL 50th International Liver Congress, Vienna, abstract P0901, 2015.