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Reuters Health Information: Sofosbuvir-ledipasvir effective for relapsed HCV-1

Sofosbuvir-ledipasvir effective for relapsed HCV-1

Last Updated: 2014-11-03

By Will Boggs MD

NEW YORK (Reuters Health) - The combination of sofosbuvir and ledipasvir is effective for treating chronic hepatitis C virus (HCV) genotype 1 infection that relapses after sofosbuvir plus ribavirin therapy, according to results from a phase 2 study.

"We were surprised because we had several patients with cirrhosis and one with S282T mutation, which confers complete resistance to sofosbuvir in vitro," Dr. Anita Kohli from National Institutes of Health, Bethesda, Maryland told Reuters Health by email. "All of these patients, who had risk factors for relapse, achieved sustained virologic response 12 weeks after completion of treatment (SVR12)."

In an earlier study, 17 of 54 patients treated with sofosbuvir plus ribavirin for 24 weeks had relapse after treatment.

Dr. Kohli and colleagues investigated the safety and efficacy of 12 weeks of treatment with sofosbuvir plus ledipasvir in 14 patients with HCV genotype 1 infection who relapsed after receiving sofosbuvir plus ribavirin.

Thirteen of these 14 patients had wild-type virus at the time of relapse after sofosbuvir plus ribavirin treatment, according to the November 4th Annals of Internal Medicine report.

All 14 patients treated with sofosbuvir plus ledipasvir had HCV RNA levels below the lower limit of quantification by four weeks, and this response was maintained through the end of treatment and through 12 weeks after the completion of treatment.

In contrast to the decreases in hemoglobin levels seen during sofosbuvir plus ribavirin treatment, there were no significant changes in hemoglobin levels during the treatment with sofosbuvir plus ledipasvir.

Renal function did not change significantly during treatment, and there were no serious adverse events or laboratory abnormalities.

Common adverse events included myalgia and hypophosphatemia, and most adverse events were mild.

"The low incidence of adverse events, low pill burden, shorter treatment duration, and high efficacy demonstrated in this group and other populations make this drug combination attractive in a real-world setting," the researchers say.

"This could be the standard of care for patients who have failed sofosbuvir and ribavirin," Dr. Kohli said. "The duration between initial treatment failure after sofosbuvir and ribavirin and retreatment with sofosbuvir and ledipasvir was over one year. We do not know if patients would have responded in a similar fashion had they been retreated sooner."

She added, "Resistance to HCV drugs is an evolving story and seems quite different than with HIV. It will continue to evolve with the introduction of new drugs and drug classes."

"The small sample size and only 1 patient with NS5B S282T mutation after sofosbuvir plus ribavirin therapy may also partially contribute to the high SVR rate of the study, because the SVR rate may become lower when large sample size of patients and large number of patients with NS5B S282T mutation were included," Dr. Zhengwen Liu from First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Shaanxi, China told Reuters Health by email.

"When the results, both the efficacy and the safety, will be supported by future trials with large sample size of patients, this treatment of sofosbuvir and ledipasvir would become one of the standard of care for patients with HCV genotype 1 who relapse with other treatment," concluded Dr. Liu, who has studied the use of sofosbuvir-based treatment for chronic HCV infection.

Dr. Eric M. Yoshida from University of British Columbia and Vancouver General Hospital in British Columbia, Canada has also published research on the treatment of chronic HCV infection. He told Reuters Health by email, "This preliminary study provides evidence that these patients can be re-treated successfully. It is also noteworthy that these patients were drawn from a previous study that had features of a 'difficult to treat' population where the SVR rates were markedly worse than in Gilead's phase 3 clinical trials. Therefore, this was truly a 'real world' patient population, which makes the outcome of this paper all the more encouraging."

"Even though this study had only 14 patients, the outstanding and dramatic response rates, with no significant adverse effects, suggest that patients who relapse to sofosbuvir DAA (direct antiviral agent) monotherapy and who cannot wait for 'better studies' or alternative drugs, should be treated until there is clinical evidence to the contrary," Dr. Yoshida said. "The population I am thinking about are those with established cirrhosis who would otherwise be looking at future liver transplant (and we know how difficult it is to get a transplant given the disparity between available donor organs and the need for liver transplantation)."

"When one has a patient in a desperate situation," he said, "and there is a non-toxic, potentially effective therapy available, it is not appropriate to be academically dogmatic about how robust the published literature is or is not."


Ann Intern Med 2014;161:634-638.



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