Hep C quad regimens quashed, but some components go forward

A pair of four-drug interferon-based hepatitis C regimens worked well, but further study has been halted after a few patients experienced serious adverse events, according to a set of presentations last week at the 48th International Liver Congress (EASL 2013) in Amsterdam. While this type of quad regimen has little if any future, some of the component drugs remain promising.

The first direct-acting antiviral agents (DAAs) for chronic hepatitis C were approved in 2011, changing the treatment paradigm. While the future of therapy for most people with hepatitis C is likely to be all-oral regimens, the first two DAAs were approved for use with, and most current candidates were first tested with, pegylated interferon and ribavirin.

The pace of drug development for hepatitis C has been so rapid that some approaches have become obsolete even before they finish clinical trials. Such is the case for two quadruple regimens tested by Gilead Sciences containing dual DAAs in combination with pegylated interferon and ribavirin. Results from three studies were presented at the International Liver Congress.

• Alexander Thompson from St Vincent's Hospital in Melbourne reported results from an evaluation of the HCV NS3 protease inhibitor GS-9451 (200mg once-daily) plus the NS5A inhibitor ledipasvir (formerly GS-5885; 30mg once-daily) plus pegylated interferon and ribavirin for six or 12 weeks in 244 treatment-naive people who had hepatitis C genotype 1 with the favourable IL28B 'CC' gene pattern and no liver cirrhosis. While a quadruple regimen is quite intensive for this easy-to-treat patient population, treatment lasting less than two months would be a breakthrough.

• Gregory Everson from the University of Colorado presented findings from a study looking at the same regimen for 24 or 48 weeks in 163 treatment-experienced, non-cirrhotic, genotype 1 patients.

• Andrew Muir from Duke University reported results from a study of GS-9451 (200mg once-daily) plus the non-nucleoside HCV polymerase inhibitor tegobuvir (formerly GS-9190; 30mg twice-daily) with pegylated interferon/ribavirin for 16 or 24 weeks in 239 treatment-naive, non-cirrhotic, genotype 1 patients.

Overall, both regimens worked quite well.

GS-9451/ledipasvir/pegylated interferon/ribavirin for 6 or 12 weeks produced 12-week post-treatment sustained virological response (SVR12) rates of 79% and 98%, respectively, among early responders who were eligible for duration randomisation. There was no significant difference in response between people with HCV subtypes 1a and 1b. These findings, Thompson said, show that shortened treatment is feasible for patients with favourable response predictors.

The same regimen produced an overall SVR12 rate of 70% for treatment-experienced patients, rising to 87% for those who achieved extended rapid virological response and were eligible for the shorter treatment duration. Here, IL28B 'CC' and HCV subtype 1b both predicted better response.

GS-9451/tegobuvir/pegylated interferon/ribavirin also worked well, though full analysis was not possible because the four-drug regimen was halted prematurely. The reported SVR12 rate for the quad regimen was 79%, but this rose to 97% among people who completed 16 or 24 weeks on the combination Again, people with IL28B 'CC' or subtype 1b saw better response rates.

Both regimens were generally safe and well tolerated, with mostly the usual side-effects associated with interferon and ribavirin. However, Gilead, in consultation with the US Food and Drug Administration, halted testing of both quadruple regimens after three patients developed aplastic anaemia or pancytopenia, a condition that results in deficiencies of red blood cells, white blood cells, and platelets.

It is not clear which, if any, of the experimental drugs – alone or in combination – caused this serious adverse event, but Gilead elected to stop ongoing studies of dual DAAs in interferon-based regimens. This appears to be a reasonable decision: even if safety concerns are resolved, such intensive regimens are not likely to be popular given the development of simpler combinations – including some interferon-free – with similar or better efficacy and tolerability.

Gilead has discontinued all development of tegobuvir. Dr Muir told aidsmap that GS-9451 is still being tested (as part of a non-quad regimen) in at least one ongoing clinical trial, and it remains listed in the development portfolio on the company's website.

Ledipasvir continues to look very promising as a component of interferon-free therapy. According to a report at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2013), a three-drug oral regimen of ledipasvir, the nucleotide HCV polymerase inhibitor sofosbuvir (formerly GS-7997) and ribavirin cured 100% of both treatment-naive patients and prior non-responders. Gilead is now testing a coformulation containing ledipasvir plus sofosbuvir.