Real-world studies show 8-week sofosbuvir/ledipasvir course just as effective as 12-week course for genotype 1 patients without cirrhosis

An 8-week course of treatment with sofosbuvir/ledipasvir is just as effective as a 12-week course of treatment in people without cirrhosis, including those with HIV/hepatitis C virus (HCV) co-infection, and could significantly reduce the cost of treatment if it was prescribed more widely, several large real-life cohort studies presented at last month’s 2016 AASLD Liver Meeting in Boston show.

The US Food and Drug Administration (FDA) recommends that an 8-week course of treatment with sofosbuvir/ledipasvir can be considered for previously untreated people with genotype 1 infection who do not have cirrhosis or a pre-treatment HCV viral load above 6 million IU/ml. This recommendation was based on post-hoc analysis of the phase III ION-3 trial but has not been confirmed in real-world clinical practice.

Furthermore, some liver specialists are sceptical about the effectiveness of an 8-week course of sofosbuvir/ledipasvir in people with HIV/HCV co-infection who do not have cirrhosis. Two phase III studies, PHOTON-1 and 2, tested a 12-week course of treatment in people with co-infection, confirming a high level of efficacy of the combination in people with co-infection. The ION-3 study of an 8-week course of treatment excluded people with co-infection, leading to an absence of evidence on the question. Cohort data have also been lacking, with the exception of data from the German GECCO multicentre cohort, which showed a very high cure rate (98.5%) in a small cohort.

Three studies presented at The Liver Meeting provided reassuring evidence on the use of an 8-week treatment course in real-life, in people with high viral load and in people with co-infection.

The largest study was designed to determine the effectiveness of an 8-week regimen in people who met the FDA criteria, and to identify predictors of relapse.

The analysis pooled data from four cohorts: Burman’s Pharmacy (n = 307), Kaiser Permanente Southern California (n = 203), the Institute for Interdisciplinary Medicine (Hamburg) (n = 126) and HCV Trio (n = 232). The HCV Trio network includes academic and community-based clinics throughout the United States.

The analysis excluded anyone treated with ribavirin and those lacking recent fibrosis staging information, as well as those treated post-transplantation. The analysis identified 868 people who received an 8-week course of sofosbuvir/ledipasvir, of which 798 people met the FDA eligibility criteria. Sixty-one individuals were excluded from the per-protocol analysis on the grounds that they had baseline viral loads above 6 million IU/ml.

The cohort was evenly comprised of men and women, 62.7% white, 25% African-American and 10% Hispanic. Approximately two-thirds of people had genotype 1a infection and the vast majority had less advanced fibrosis (F0-F2) (82.7%).

The per-protocol analysis showed that 98.5% of people treated according to FDA guidance achieved sustained virological response (SVR12). Sub-group analysis showed that at least 95% of people achieved SVR12 in all sub-groups, and logistic regression analysis found no variables associated with relapse.

All 61 individuals with baseline viral load above 6 million IU/ml achieved SVR12.

A separate systematic review by the same group identified six additional studies reporting comparative outcomes in people treated with sofosbuvir/ledipasvir for 8 or 12 weeks. The pooled population comprised 5637 people and per-protocol SVR12 rates were 95.8% in those treated for 8 weeks and 97.2% in those treated for 12 weeks, a non-significant difference. There was no significant difference in the risk of viral relapse.

An analysis of the Deutsches Hepatitis-C Register also found that people treated for 8 weeks enjoy comparable outcomes to those of people treated for 12 weeks. The Deutsches Hepatitis-C Register is a prospective register of hepatitis C treatment outcomes in people treated with direct-acting antivirals.

Of 8090 people who started treatment between 1 February 2014 and 30 June 2016, 2543 people with genotype 1 infection had completed an 8 or 12-week course of sofosbuvir/ledipasvir treatment according to protocol and had SVR follow up data. A total of 976 people received an 8-week regimen and 1509 people received a 12-week regimen. Those who received the 12-week regimen were an average of four years older and had higher liver stiffness measurements, but because this analysis excluded people who received ribavirin, the proportion of the 12-week group who had cirrhosis was low (12%). Of the 12-week group, 58.7% had previous treatment experience.

The analysis showed that 98% of each group achieved SVR12.

The cohort included 278 people with HIV/HCV co-infection: 9.3% of the 8-week group and 12.4% of the 12-week group. Ninety-six per cent of the 8-week co-infected group and 98% of the 12-week co-infected group achieved SVR12.

Regression analysis showed that cirrhosis was the only risk factor for viral relapse in those who received an 8-week course of treatment (2.4% of the 8-week group had cirrhosis). Viral load above 6 million IU/ml did not predict viral relapse, nor did previous treatment experience. The investigators concluded that a large proportion of the cohort was over-treated with a 12-week course of sofosbuvir/ledipasvir.

An open-label phase IIIb study in Russia and Estonia also found no substantial difference in outcome between previously untreated people with HIV/HCV co-infection or monoinfection treated with sofosbuvir/ledipasvir for 12 weeks.

The study population comprised 67 people with monoinfection and 59 people with co-infection, all with genotype 1 infection. Study participants had high viral load (a mean of 5.9 million IU.ml in the monoinfection group and 6.1 million in the co-infection group).

All participants (100%) in the monoinfection arm and 57 of 59 people (97%) in the co-infection arm achieved SVR12. Both cases of virologic failure occurred in people with genotype 1a infection.