Difficult-to-treat hepatitis C patients with liver cirrhosis who were not cured with a prior course of first-generation HCV protease inhibitors had a sustained response rate of 96-97% when re-treated with sofosbuvir/ledipasvir with ribavirin for 12 weeks or without ribavirin for 24 weeks, researchers reported at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting last month in Boston, United States. Sofosbuvir/ledipasvir also worked well for people previously treated with other sofosbuvir-containing regimens.
The advent of interferon-free therapy combining direct-acting antiviral agents that target different steps of the hepatitis C virus (HCV) lifecycle has brought about a revolution in treatment. But the best approach for hard-to-treat patients – including people who did not respond to previous treatment and those with extensive liver damage – remains to be determined.
Prior protease inhibitor failure
Marc Bourlière of Hôpital Saint Joseph in Marseilles, France, reported findings from a French study of Gilead Sciences' nucleotide HCV polymerase inhibitor sofosbuvir and NS5A inhibitor ledipasvir given as a once-daily fixed-dose co-formulation, recently approved and marketed as Harvoni in Europe and the US.
Participants were randomly assigned to take either sofosbuvir/ledipasvir plus a ribavirin-like placebo for 24 weeks, or else placebo alone for 12 weeks followed by sofosbuvir/ledipasvir plus ribavirin for 12 weeks. This enabled patients treated for either 12 or 24 weeks to finish therapy and follow-up at the same time, and allowed a direct comparison of adverse events between sofosbuvir/ledipasvir and placebo. The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12), which is considered a cure.
The study included 155 participants with HCV genotype 1 who did not achieve SVR after sequential treatment with pegylated interferon/ribavirin followed by pegylated interferon/ribavirin plus an HCV protease inhibitor (PI).
Three-quarters of participants were men, most were white and the mean age was 56 years. A majority had harder-to-treat HCV subtype 1a and more than 90% had unfavourable IL28B gene variants. Compensated cirrhosis was an entry criterion, but one-quarter had stomach or oesophagus varices (distended veins), a sign of decompensation. The mean MELD score was 7, indicating a low mortality risk, but some patients had biomarker levels showing serious liver function impairment.
With regard to prior treatment, 59% had previously used telaprevir (Incivo or Incivek), 37% had used boceprevir (Victrelis) and one each had tried simeprevir (Olysio) and faldaprevir (discontinued). Nearly three-quarters had NS3/4A protease resistance-associated viral variants at baseline and 16% had NS5A resistance variants. Participants were stratified according to whether they had ever achieved undetectable HCV viral load during previous treatment (relapsers, viral breakthroughs and partial responders) or not (null responders).
SVR12 rates were 96% for people taking sofosbuvir/ledipasvir plus ribavirin for 12 weeks and 97% for those taking sofosbuvir/ledipasvir alone for 24 weeks.
All treatment failures were due to relapses, with three in the 12-week arm and two in the 24-week arm. All relapsers were men with unfavourable IL28B variants, two of whom had HCV subtype 1a while three had subtype 1b. Four were prior null responders while the fifth had a prior breakthrough during treatment.
SVR12 rates were similar for people with or without NS3/4A protease resistance-associated variants at baseline (96 vs 97%, respectively). However, the cure rate was a bit lower for people with NS5A resistance-associated variants at baseline (92 vs 98%, respectively).
Albumin levels increased and ALT and bilirubin levels decreased following treatment – all signs of improvement – but INR (a measure of blood clotting ability) remained stable.
Sofosbuvir/ledipasvir was generally safe and well-tolerated. Of the 155 participants, 154 completed treatment and follow-up. The remaining patient discontinued treatment early due to an adverse event while taking only placebo. Just one person experienced a serious adverse event considered to be treatment-related (anaemia).
The most common side-effects were weakness, headache, itching, insomnia, nausea and fatigue, mostly mild or moderate in severity. Only headache and fatigue occurred more often in the sofosbuvir/ledipasvir arm compared with placebo. Four people taking sofosbuvir/ledipasvir plus ribavirin and one taking sofosbuvir/ledipasvir alone developed moderate or severe anaemia.
"Twelve weeks of [sofosbuvir/ledipasvir] with ribavirin results in high SVR rates among treatment-experienced patients with cirrhosis who have failed a prior PI-based regimen," the researchers concluded. SVR12 rates were similar after 12 weeks of sofosbuvir/ledipasvir with ribavirin compared with 24 weeks of sofosbuvir/ledipasvir alone.
Bourlière explained that there was no 12-week treatment arm without ribavirin because the aim of the study was to obtain the maximum possible sustained response rates, and when the study was designed researchers did not think the shorter duration without ribavirin would be sufficient.
In terms of cost, adding ribavirin for 12 weeks would be substantially less expensive than doubling the duration of sofosbuvir/ledipasvir to 24 weeks without ribavirin.
Prior sofosbuvir failure
In a related study, David Wyles of the University of California at San Diego and colleagues looked at outcomes among people treated with sofosbuvir/ledipasvir plus ribavirin for 12 weeks after an unsuccessful attempt using sofosbuvir as the sole direct-acting antiviral.
This study included 51 people with genotype 1 hepatitis C. About 60% were men, most were white and the mean age was 54 years. Nearly 60% had HCV 1a, more than 90% had unfavourable IL28B variants and 29% had cirrhosis. Half had previously used sofosbuvir with pegylated interferon/ribavirin, 41% with ribavirin alone and 10% with placebo in prior clinical trials.
At 12 weeks post-treatment, the SVR12 rate was 98%. The single patient who relapsed was found to have been enrolled in error with genotype 3 (ledipasvir is primarily active against genotype 1, so is not indicated for this genotype).
Again, sofosbuvir/ledipasvir plus ribavirin was generally safe and well tolerated. Just two people experienced serious adverse events and one person discontinued for this reason. The most common side-effects were fatigue, headache, diarrhoea, rash, insomnia and nausea. There were five cases (10%) of moderate anaemia.
"These data support the [sofosbuvir/ledipasvir plus ribavirin] treatment regimen as an option for genotype 1 patients who have failed prior sofosbuvir + pegylated interferon/ribavirin or sofosbuvir + ribavirin regimens," the investigators concluded.
Bourlière M et al. Ledipasvir/sofosbuvir fixed dose combination is safe and efficacious in cirrhotic patients who have previously failed protease-inhibitor based triple therapy. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract LB-6, 2014.
Wyles D et al. Retreatment of patients who failed prior sofosbuvir-based regimens with all oral fixed-dose combination ledipasvir/sofosbuvir plus ribavirin for 12 weeks. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract 235, 2014.