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

Abstract

Background & AimsDaclatasvir 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.MethodsPatients 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.ResultsBetween 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.ConclusionsSVR12 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.

Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness 2 years after treatment with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in the AMBER, real‐world experience study

“…Similar rates were noticed in several smaller, one‐centre studies following treatment with Peg‐IFN+RBV . Addition of DAA to interferon‐based therapy did not exclude the risk of relapse, as it was shown in patients after triple therapy containing either boceprevir or daclatasvir . However according to the most recent study by Zoulim et al all 200 patients who achieved SVR after interferon containing triple therapy with simeprevir maintained SVR until the last available visit with median follow‐up time of 35.8 months.…”

“…As long‐term post‐treatment follow‐up of virologic response durability was usually not considered as an endpoint in clinical trials, there are currently limited data supporting durability of virologic response after therapy with interferon‐free regimens. According to recently published by Reddy et al results from a long‐term follow‐up after daclatasvir based therapies, HCV relapse occurred in 3 among 610 (0.5%) patients treated with daclatasvir combined with asunaprevir which is a relatively weak protease inhibitor. In contrast, there were no relapses among 232 patients treated with a more potent regimen of daclatasvir and sofosbuvir.…”

“…No relapses were also observed in another study carried out by Kozbial et al in 551 patients treated with different but potent DAA combinations. Unfortunately, the range of follow‐up in these 2 studies varied between 11 and 239 or 13 and 155 weeks respectively, so at least in some individuals risk of relapse after a monitored period cannot be excluded due to short observation periods . In recently presented data from 1393 patients who achieved SVR in clinical trials with sofosbuvir‐containing regimens, relapse occurred in one patient only.…”

“…Additionally, 2 large cohort studies showed that DAA‐induced SVR was even associated with significant reduction in the risk of HCC occurrence . According to data published by Reddy et al, the majority of new HCC cases may develop in the second and third year of post‐treatment observation. Patients included in our study did not develop de novo HCC within the first year of the follow‐up period, and the annual rate of incidence was similar to that observed in the natural history of HCV‐related liver cirrhosis.…”

Damned if you do, damned if you don't: The evolving story of de novo and recurrent hepatocellular carcinoma amongst those treated with direct‐acting antivirals for hepatitis C virus

“…We acknowledge that the data describing the increased risk of incident HCC are all from intermediate and smaller sized studies. Multiple larger studies published in the abstract form containing thousands of patients did not seem to identify increased risk of incident HCC post DAA while full publications are yet to be available in the literature …”