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EASL 2014: Sofosbuvir + Ledipasvir Is Safe and Effective for Relapsers and Hard-to-Treat Hep C Patients


A coformulation of sofosbuvir and ledipasvir successfully treated a variety of difficult-to-treat patient populations including people with hepatitis C virus (HCV) genotype 3, patients with decompensated cirrhosis, and people who were not cured with previous sofosbuvir-containing therapy, according to a series of studies presented at the 49thEASL International Liver Congress (EASL 2014) this week in London.

Edward Gane from Auckland Clinical Studies in New Zealand presented results from ELECTRON-2, an analysis of the safety and efficacy of a once-daily fixed-dose combination pill containing the recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi) plus the NS5A inhibitor ledipasvir (400/90 mg) in 3 challenging populations.

Data from the Phase 3 ION trials of the sofosbuvir/ledipasvir coformulation will be presented later at the Liver Congress.

HCV Genotype 3

One cohort consisted of 51 previously untreated participants with HCV genotype 3. Genotypes 2 and 3 were once classified together as "easy-to-treat," but it is now known that genotype 3 does not respond as well to direct-acting antivirals.

Just over half of the participants were women, most were white, and the mean age was approximately 45 years. About half had the favorable IL28B CC genetic variant and about 15% had liver cirrhosis. They were randomized to receive the sofosbuvir/ledipasvir coformulation either alone or with ribavirin for 12 weeks.

Among people taking sofosbuvir/ledipasvir alone, 64% achieved sustained virological response after 12 weeks of post-treatment follow-up (SVR12), while 8 relapsed. Among those taking sofosbuvir/ledipasvir plus ribavirin, however, the SVR12 rate was 100%.

Treatment was generally safe and well-tolerated. There were 4 serious adverse events and 1 early discontinuation for this reason in the sofosbuvir/ledipasvir arm, but none in the group that also took ribavirin. However, 3 people (12%) taking ribavirin developed moderate anemia (hemoglobin <10 g/dL), which was not seen in the ribavirin-sparing arm.

Decompensated Cirrhosis

The second cohort included 20 HCV genotype 1 patients with decompensated cirrhosis (Child-Pugh-Turcotte "B" classification). Most were white men and the mean age was 56 years. Most (90%) had harder-to-treat HCV subtype 1a and about one-third had the IL28B CC variant. About one-third had hepatic encephalopathy (cognitive impairment) and 20% had ascites (abdominal fluid accumulation).

Everyone in this group received the sofosbuvir/ledipasvir coformulation for 12 weeks. They did not use ribavirin, which is often poorly tolerated by patients with advanced liver disease.

There were 13 patients (65%) who achieved SVR12, while 7 relapsed. Regarding tolerability, 2 people experienced serious adverse events, 3 had grade 3-4 laboratory abnormalities, and there was 1 case of moderate anemia.

While the sustained response rate for this cohort was modest compared to rates seen in other groups who also included ribavirin, Gane noted that people with decompensated liver disease "currently have no treatment options."

Prior Sofosbuvir

The final cohort included 19 genotype 1 patients who relapsed after prior treatment with sofosbuvir-containing regimens in the ELECTRON-1 study. Everyone in this cohort was retreated with open-label sofosbuvir/ledipasvir plus ribavirin for 12 weeks.

Two-thirds of participants were men, most were white, and the mean age was 55 years. Most (89%) had HCV subtype 1a, 21% had the IL28B CC variant, and none had cirrhosis. About half had previously taken sofosbuvir plus ribavirin for 12 weeks, 8 had taken sofosbuvir/ledipasvir plus ribavirin for only 6 weeks, and 1 had used sofosbuvir/ledipasvir plus the investigational non-nucleoside polymerase inhibitor GS-9669. All previously relapsed after achieving undetectable HCV viral load during treatment.

All participants in this cohort achieved SVR12. There were no serious adverse events or early discontinuations for this reason, but 3 people (16%) developed moderate anemia.

Retreatment for Genotype 1

Anu Osinusi of the U.S. National Institute of Allergy and Infectious Diseases reported findings from a study evaluating sofosbuvir/ledipasvir for people with HCV genotype 1 who relapsed after prior treatment with sofosbuvir/ribavirin.

This analysis looked at the 17 participants (out of 55) who relapsed treatment with sofosbuvir/ribavirin for 24 weeks in the NIAID SPARE study. Of these, 14 agreed to undergo retreatment with sofosbuvir/ledipasvir for 12 weeks in the SYNERGY study.

More than 90% were African-American men, with a median age of 60 years. A majority (57%) had HCV subtype 1a, only 14% had the favorable IL28B CC variant, and half had advanced fibrosis or cirrhosis (stage F3-F4). An average of 57 weeks elapsed between the 2 courses of treatment.

All 14 patients reached undetectable HCV RNA by week 4 of treatment and maintained viral suppression through the end of post-treatment follow-up, for an SVR12 rate of 100%. This included 1 person with a S282T mutation detected after prior relapse.

Treatment was well-tolerated with no serious adverse events or discontinuations for this reason. There was no significant change in hemoglobin level, unlike the drop seen earlier on sofosbuvir/ribavirin.

"These results suggest that patients who fail sofosbuvir/ribavirin therapy can be successfully retreated with sofosbuvir/ledipasvir for 12 weeks," the researchers concluded.

Retreatment for Genotype 2/3

Rafael Esteban of Vall d’Hebron Hospital in Barcelona and colleagues looked people with HCV genotype 2 or 3 who relapsed after receiving sofosbuvir plus ribavirin for 12 weeks in prior pivotal trials. This study aimed to determine if retreating these patients with sofosbuvir/ribavirin for a longer duration or adding pegylated interferon would improve cure rates.

As previously reported, 97% of treatment-naive participants with genotype 2 in the FISSION trial achieved SVR12, but this fell to 56% among genotype 3 patients. In the POSITRON trial, which looked at people ineligible or unwilling to take interferon, 93% of genotype 2 patients and 61% of genotype 3 patients achieved SVR12. Among treatment-experienced people in the FUSION trial, SVR12 rates were 86% and 30%, respectively.

This open-label study offered participants the option of using sofosbuvir/ribavirin alone for 24 weeks or sofosbuvir/ribavirin plus pegylated interferon for 12 weeks, based on interferon eligibility and patient and investigator preference.

A total of 107 participants enrolled in the study. About 80% were men, most were white, and the mean age was 53 years. Almost all (93%) had HCV genotype 3, given that most genotype 2 patients had previously been cured. About 35% had cirrhosis and a similar proportion had the favorable IL28B CC variant.

SVR12 data were available for 26 patients who opted for extended duration sofosbuvir/ribavirin and 40 who chose to add interferon (the rest are still undergoing treatment or follow-up).

All participants in both treatment groups had undetectable HCV viral load at week 4 and at the end of treatment. However, there were several post-treatment relapses, resulting in SVR12 rates of 63% in the 24-week sofosbuvir/ribavirin arm and 92% in the 12-week triple therapy arm.

Triple therapy worked well for patients with or without cirrhosis (SVR12 rates of 88% and 93%, respectively). However, extended sofosbuvir/ribavirin alone cured fewer than half (47%) of cirrhotic patients, compared with 74% of non-cirrhotics.

Again, treatment was generally well-tolerated; 4 people in the extended sofosbuvir/ribavirin arm and 1 in the triple therapy arm experienced serious adverse events, though there were no early discontinuations for this reason.

"The 12-week regimen containing interferon had higher overall rates of SVR and was more effective in patients with cirrhosis," the researchers concluded. "The 24-week interferon-free regimen was safe and well tolerated and offers a retreatment option for those ineligible to receive interferon."

As the other studies showed, however, dual therapy with sofosbuvir and ledipasvir may be a more effective, convenient, and better-tolerated retreatment option.



EJ Gane, RH Hyland, D An, et al. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and genotype-1 patients with prior sofosbuvir treatment experience. 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O6.

A Osinusi, M Marti, K Townsend, et al (NIAID Hepatitis C SYNERGY Team). Retreatment of relapsers to sofosbuvir/ribavirin with sofosbuvir/ledipasvir: complete and rapid virologic suppression by week 4.
49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O11.

R Esteban, L Nyberg, J Lalezari, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy.49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O8.