Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens

Abstract

Background & aims: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies.

Methods: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression.

Results: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively.

Conclusions: SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders.

Trial registration: ClinicalTrials.gov NCT01492504.

Keywords: chronic hepatitis C virus; daclatasvir; hepatocellular carcinoma; long-term follow-up; sustained virologic response.

Figure 1

Durability of parent study SVR12. Median (range) follow‐up from parent study follow‐up Week 12: overall, 111 (11‐246) wk; DCV+SOF±RBV recipients, 44 (11‐178) wk; DCV+ASV recipients, 114 (12‐239) wk; DCV+ASV+BCV±RBV, 63 (12‐167) wk; DCV+ASV+pegIFNα/RBV, 113 (25‐225) wk; DCV+pegIFNα/RBV, 163 (12‐246) wk. ^aOne responder, treated for genotype‐1a infection, was re‐infected with genotype‐3a during this study; ^bResponder treated for genotype‐1b infection with NS5A‐Y93H at baseline relapsed at week 24 with emergent NS5A‐L31M; ^cResponder treated for genotype‐1b infection with NS5A‐L31V and ‐Y93H at baseline relapsed at week 24 with no emergent substitutions; ^dResponder treated for genotype‐1b infection relapsed on Day 1 (76 wk after parent study EOT) with emergent NS5A‐L31V and ‐Y93H

Figure 2

Kaplan‐Meier‐estimated cumulative HCC rate since parent study EOT

Figure 3

Treatment and response duration in patients with new HCC

Figure 4

Replacement of emergent NS5A and NS3 substitutions with wild‐type sequences since parent study EOT among non‐responders. Time to replacement of emergent NS5A substitutions among patients infected with (A) genotype‐1a, or (B) genotype‐1b; time to replacement of emergent NS3 substitutions among patients infected with (C) genotype‐1a, or (D) genotype‐1b. ^aOne DCV+pegIFNα/RBV recipient infected with genotype‐1b is excluded due to replacement of their emergent NS5A substitution beyond the study's observational window