ATLANTA – Adding ledipasvir to sofosbuvir and ribavirin produced sustained virological responses 12 weeks after therapy in 100% of treatment-naive and prior nonresponder patients with chronic hepatitis C genotype 1 in the ELECTRON trial.
"Certainly adding a second direct-acting antiviral agent, ledipasvir, increases the efficacy of sofosbuvir plus ribavirin," Dr. Edward Gane said at the Conference on Retroviruses and Opportunistic Infections.
Three-quarters of the roughly 170 million people infected with hepatitis C virus (HCV) worldwide have genotype 1, the most difficult strain to treat.
Current treatment includes triple therapy with a protease inhibitor plus peginterferon and ribavirin for 24-48 weeks, but PI-based therapy is limited by complex dosing regimens, the potential for resistance, and lower responses in prior nonresponders, explained Dr. Gane of Auckland Clinical Studies in New Zealand.
The investigators hypothesized that combining two direct-acting antivirals with a different mechanism would enhance response.
At last year’s CROI meeting, Dr. Gane reported that treatment with the nucleotide NS5B inhibitor sofosbuvir (formerly known as GS-7977) and ribavirin alone led to early viral load suppression, but relapses within 4 weeks of stopping treatment resulted in 12-week posttreatment sustained virological response (SVR12) rates of 84% among treatment-naive patients and only 10% among previous interferon-based therapy null responders.
In the current arm of the trial, the NS5A inhibitor ledipasvir (formerly known as GS-5885) was added to sofosbuvir and weight-based ribavirin, all for 12 weeks, in 25 noncirrhotic treatment-naive and 9 null responders, defined by less than a 2-log reduction in HCV RNA after 12 weeks of peginterferon and ribavirin.
The majority of treatment-naive and null responders were genotype 1a (80% and 89%) and had high baseline HCV RNA loads (mean 5.9 log10 IU/mL and 6.9 log10 IU/mL). The more favorable IL28B genotype CC genotype was present in 36% of treatment-naive patients, but in no null responders. The patients median age was 48; 94% were white.
Early on–treatment viral suppression was very rapid, with all treatment-naive patients and all but one prior null responder having an undetectable viral load at week 4, Dr. Gane said. This patient’s load was on the threshold at week 4 and became undetectable by week 5, resulting in SVR12 rates of 100% in both groups.
No viral breakthroughs were observed, and all patients achieved an end-of-treatment response.
Unlike the earlier arm of the trial, however, both groups maintained undetectable HCV viral loads at 4 and 12 weeks after therapy, he said.
The triple combination was well tolerated and safe. Three serious adverse events occurred, but none were treatment related. One patient had to stop therapy at week 8 due to the event, but subsequently achieved SVR24. The most common adverse events were anemia (20%), depression (8%), and headache (4%), and all were in treatment-naive patients.
Grade 3 laboratory abnormalities occurred in 52% of the treatment-naive and 22% of null responders. No grade 4 abnormalities were seen, Dr. Gane said.
Ledipasvir and sofosbuvir have been combined into a single fixed-dose tablet and is being evaluated in phase III studies in patients with cirrhosis and to determine whether there is a need for ribavirin, he said. Additional studies are also underway to explore shorter durations of therapy.
ELECTRON was sponsored by Gilead Sciences. Dr. Gane reported ties with Gilead, Janssen-Cilag, Novartis, Pharmasset, Roche and Vertex.
