Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study

Abstract

Summary Background To shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. Methods In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. The primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Findings Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). No patients experienced any serious adverse events. Interpretation In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings. Funding Center for AIDS Research, National Institutes of Health, US Department of Energy, National Center for Research Resources and the Office of Research Infrastructure Programs, Cheng Si-Yuan (China-International) Hepatitis Research Foundation, and Humanity and Health Medical Group.

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

“…A proof-of-concept clinical trial of triple-DAA treatment (10) also showed that SOF&DCV&SMV can achieve a high SVR rate, while reducing the treatment period from 12 wk to only 3 wk using a response-guided protocol. Our analysis clearly supports a clinical advantage for triple-DAA-based IFN-free treatments as discussed elsewhere (8,10,(20)(21)(22).…”

“…Additional drugs have just been approved, and others will eventually be approved for adding new combination choices (7). Anti-HCV treatment with triple-DAA regimens has also been in clinical trials (8)(9)(10).…”

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

“…Whereas PR required 24–48 weeks of therapy and cured about 50% of chronic HCV patients treated, DAA combinations elicit nearly 100% cure with 12 weeks or less of therapy 2. Significant efforts are ongoing now to reduce the duration of treatment with DAAs without compromising treatment outcomes 3, 4. Indeed, treatments as short as 3 weeks have been shown to succeed in select populations 4.…”

A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics

“…It could also be used to explore age-based models that include further aspects of intracellular HCV life cycle such as translation positive-strand HCV RNA and the synthesis of positive and negative-strand HCV RNA [58]. Finally, since the current age-based HCV multiscale model is a successful milestone but still fails to predict cure in some DAA-treated patients [59][60][61], further model modification will be needed [38,39] and future developments would necessitate some updates in the numerical method. While such models become quickly overwhelming to solve analytically, an extension of the presented method is straightforward.…”