NS5A substitutions affect early HCV treatment failures, retreatment

SAN FRANCISCO — NS5A resistance-associated substitutions at several positions, including Y93, may hold information about DAA treatment response, according to data presented at The Liver Meeting 2018.

Masayuki Kurosaki , MD, of the Department of Gastroenterology and Hepatology at Musashino Red Cross Hospital, Tokyo, Japan, suggested that in addition to suboptimal results to the first-generation DAA combination of Daklinza (daclatasvir/DCV, Bristol-Myers Squibb) and Sunvepra (asunaprevir/ASV, Bristol-Myers Squibb), early data showed that the Y93 RAS was associated with lower treatment response.

“The aim of this study was to evaluate the prevalence and specific pattern of NS5A RAS in patients who failed prior DCV/ASV,” Kurosaki said. “Also, to evaluate the impact of RAS on the efficacy of retreatment by Harvoni [sofosbuvir/ledipasvir, Gilead].”

The nationwide study included 876 patients who failed daclatasvir/asunaprevir therapy and 1,068 who were DAA-naive. Additionally, 257 patients were retreated with ledipasvir/sofosbuvir. Patients from 83 regional centers in Japan were included.

The researchers assessed NS5A RASs in positions 28, 30, 31, 32, 54, 58, 92, and 93, according to Kurosaki. “The prevalence of NS5A RASs at positions 24, 28, 30, 31, 32, and 93 was significantly high in DCV/ASV failed patients compared to DAA naive patients,” Kurosaki said.

Looking closer, a RAS at the L31 position occurred in 75.2% of patients who failed daclatasvir/asunaprevir therapy but just 4.4% of those in the treatment-naive group. Similarly, 75.6% of treatment failures had a Y93 RAS, compared with 19.9% rate of that RAS in the naive group. Significant differences also were seen in R30 and P32.

Thinking about the association between these RASs and the efficacy of retreatment with ledipasvir/sofosbuvir, Kurosaki pointed out that at the end of treatment, all 257 patients had responded, but the overall SVR12 rate was just 64%. “This was due to a high rate of relapse,” he said.

Kurosaki then reported that SVR decreased in patients having NS5A RASs at positions 31, 32, 92, and 93. “These positions may be key to NS5A RASs,” he said.

The researchers assessed the impact of multiple deletions at these key positions. Among patients who failed daclatasvir/asunaprevir therapy, retreatment with ledipasvir/sofosbuvir yielded a 92% SVR12 rate for patients with no NS5A RASs. However, SVR12 rates were 67% for patients with one NS5A RAS at one of the four key positions, 52% for those with two, and 0% for those with RASs at three of those key positions.

More granular analysis showed that in this retreatment cohort, the A92 deletion yielded an SVR12 rate of just 33.3%. For patients with two of the key variants, the combination of L31 and L32 was associated with the lowest retreatment response, at 20%.

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Multivariable analysis findings showed that in addition to female sex (OR = 2.42; P = .013), absence of resistance variants was associated with the best response to retreatment with ledipasvir/sofosbuvir (OR = 6.83; P = .021).

“This nationwide study revealed highly complex nature of NS5A RASs after treatment failure by DCV and ASV,” Kurosaki concluded. “In addition to signature L31 or Y93 RAS, P32 deletion and A92K was identified as the key RASs to impact the efficacy of retreatment.

The efficacy of retreatment with LDV/SOF was limited in patients having multiple key NS5A RASs.” – by Rob Volansky

Reference:

Kurosaki M, et al. Abstract 200. Presented at: The Liver Meeting 2018; Nov. 9-13, 2018; San Francisco.

Disclosure: Kurosaki reports no relevant financial disclosures.