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A combination of three drugs that act directly to block hepatitis C (HCV) replication successfully cured most patients who had previously failed therapy with such agents, researchers reported.

In two phase III trials, the investigational combination of sofosbuvir, velpatasvir, and voxilaprevir cleared the virus in 96% and 98% of patients, regardless of whether they had compensated cirrhosis or not, according to Marc Bourlière, MD, of Hôpital Saint-Joseph in Marseille, France, and colleagues.

Adverse events associated with the combination were mild and similar to those seen among patients getting a placebo or the approved combination of sofosbuvir and velpatasvir (Epclusa), Bourlière and colleagues .

While retreatment options are available for patients with chronic HCV who have failed previous treatment with an interferon-containing regimen, there is no approved treatment for those whose treatment with direct-acting antiviral agents (DAAs) was unsuccessful.

Although the DAA regimens are highly effective, with cure rates in many cases of more than 95%, the sheer number of people with chronic HCV -- estimated to be some 150 million around the world -- means that a substantial number will fail therapy and need retreatment.

To help fill the gap, Bourlière and colleagues tested the three-drug combination in two trials -- dubbed POLARIS-1 and POLARIS-4 -- whose central difference was that patients in POLARIS-1 had failed therapy with an NS5A inhibitor, while those in POLARIS-4 had unsuccessful treatment with DAAs attacking other viral targets.

In POLARIS-1, patients with HCV genotype 1 were randomly assigned to 12 weeks of the three-drug combination, co-formulated in a single pill, or a matching placebo, while those with other genotypes were all assigned to the triple-drug pill.

All told, there were 263 patients getting active treatment and 152 on placebo.

In POLARIS-4, 314 patients with genotypes 1, 2, and 3 were randomly assigned to 12 weeks of either the three-drug combination or sofosbuvir/velpatasvir. As well, 19 patients with genotype 4 were assigned to the triple-drug arm.

All three drugs attack different targets in the HCV replication process: Sofosbuvir is a nucleotide analogue NS5B polymerase inhibitor, velpatasvir blocks NS5A, and voxilaprevir inhibits the NS3–NS4A protease.

To be eligible for the trials, patients had to have had virologic failure after at least four weeks of their previous therapy; those who had dropped out because of adverse events or who had been non-adherent were not enrolled.

The primary endpoint of the trials was the proportion of patients who had a sustained virologic response, which the investigators defined as a serum HCV RNA level lower than 15 IU per milliliter 12 weeks after the end of treatment -- the so-called SVR₁₂.

The statistical analysis was designed to test for the superiority of the SVR₁₂ rate among patients receiving the triple drug combination or sofosbuvir/velpatasvir over a performance goal of 85%. In POLARIS-4, the investigators did not plan or perform a comparison of the two combinations.

In POLARIS-1, the investigators reported:

• The overall SVR₁₂ rate in the 263 patients who got the active treatment was 96%, significantly better than the pre-specified performance goal of 85%.
• SVR₁₂ rates were 96% among patients with genotype 1a infection and 100% among those with genotypes 1b, 2, and 6. As well, 95% of those with genotype 3 and 91% of those with genotype 4 HCV reached SVR₁₂. The single patient with genotype 5 also achievedSVR₁₂.
• None of the 152 placebo patients reached SVR₁₂.

Importantly, patients with cirrhosis did almost as well as those without: 93% versus 99% overall.

In the POLARIS-4 trial, 98% of patients getting the triple-drug pill reached SVR₁₂, which was significantly better than the pre-specified 85% benchmark. Some 90% of those getting sofosbuvir/velpatasvir reached SVR₁₂, but that was not significantly better than the benchmark.

In the triple-drug arm, cirrhosis made no difference to response, with a response rate of 98% in each group, but in the other arm, 94% of non-cirrhotics taking sofosbuvir/velpatasvir reached SVR₁₂, compared with 86% of patients with cirrhosis.

In both trials, pre-existing resistance-association mutations in HCV appeared to have little effect.

Among POLARIS-1 patients with available genetic sequence data who took the triple-drug combination, 83% had such mutations and 97% reached SVR₁₂, compared with 98% of the remaining patients.

In POLARIS-4, 49% of patients began with viral substitutions associated with resistance, but 100% of those treated with sofosbuvir/velpatasvir/voxilaprevir reachedSVR₁₂, compared with 99% among those without baseline mutations.

Bourlière and colleagues reported that adverse events among the triple-drug patients were "generally similar" to what was seen among placebo patients in POLARIS-1 and sofosbuvir/velpatasvir patients in POLARIS-4.

But more triple-drug patients than placebo patients in POLARIS-1 had headache and in both trials more sofosbuvir/velpatasvir/voxilaprevir patients had mild-to-moderate nausea and diarrhea -- known effects of some NS3–NS4A protease inhibitors.

The investigators cautioned that there were only small numbers of patients with some of the less common HCV genotypes, so that the results might not apply broadly. As well, some patients had unsuccessful therapy with DAA regimens that are not commercially available.

And the result can't be applied to people co-infected with hepatitis B or HIV and those with decompensated cirrhosis, who were excluded from the studies.

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