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Marc Bourlière from Hôpital Saint Joseph in Marseilles 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 coformulation, recently approved and marketed as Harvoni in the U.S. and Europe.

Participants were randomly assigned to either take 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 adverse events comparison between sofosbuvir/ledipasvir and placebo. The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12), which is considered a cure.

This study included 155 patients 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.

Three-quarters of participants were men, most were white, and the mean age was 56 years. A majority (63%) had harder-to-treat HCV subtype 1a and more than 90% had unfavorable IL28B gene variants. Compensated cirrhosis was an entry criterion, but one-quarter had stomach or esophagus 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 (Incivek), 37% had used boceprevir (Victrelis), and 1 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).

Results

• 96% of people taking sofosbuvir/ledipasvir plus ribavirin for 12 weeks and 97% of those taking sofosbuvir/ledipasvir alone for 24 weeks achieved SVR12.
• All treatment failures were due to relapse, with 3 in the 12-week arm and 2 in the 24-week arm:

o   All relapsers were men with unfavorable IL28B variants;

o   2 had HCV subtype 1a, while 3 had subtype 1b;

o   4 were prior null responders, while the 5th had a prior breakthrough on treatment.

• SVR12 rates were similar for patients with or without NS3/4A protease resistance-associated variants at baseline (96% vs 97% respectively).
• The SVR12 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 decreased following treatment, but INR -- a measure of blood clotting ability -- remained stable.
• Sofosbuvir/ledipasvir was generally safe and well-tolerated.
• 154 of the 155 patients completed treatment and follow-up; 1 person discontinued early due to an adverse event while taking placebo only.
• Adverse events were common overall, but only 1 person experienced a serious adverse event considered to be treatment-related (anemia).
• The most common side effects were weakness, headache, pruritus (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.
• 4 people taking sofosbuvir/ledipasvir plus ribavirin and 1 taking sofosbuvir/ledipasvir alone developed moderate or severe anemia.

"12 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 get 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

In a related study, David Wyles from the University of California at San Diego and colleagues looked at outcomes among patients 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 genotype 1 hepatitis C patients. About 60% were men, most were white, and the mean age was 54 years. 59% had HCV 1a, more than 90% had unfavorable 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 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 2 people experienced serious adverse events and 1 discontinued for this reason. The most common side effects were fatigue, headache, diarrhea, rash, insomnia, and nausea; there were 5 cases (10%) of moderate anemia.

"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.

12/9/14

References

M. Bourlière, J-P Bronowicki, V de Ledinghen, 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, November 7-12, 2014. Abstract LB-6.

DL Wyles, PJ Pockros, JC Yang 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, November 7-12, 2014. Abstract 235.