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GLE/PIB + SOF Effective After
Failure of Prior DAAs, Including GLE/PIB
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EASL International Liver Congress 2022, London, June 22-26, 2022
Mark Mascolini
Glecaprevir/pibrentasvir (GLE/PIB) plus sofosbuvir (SOF) for 16 weeks proved highly effective in providing sustained virologic response (SVR) after failure of previous direct-acting antivirals (DAAs), including GLE/PIB [1]. Researchers who conducted this small open-label study throughout New Zealand stressed that most causes of DAA failure are nonvirologic and that some people with HCV require "wrap-around support" to succeed with therapy.
University of Auckland researchers noted that virologic failure rates lie below 5% with first-generation genotype-1-specific regimens such as LDV/SOF, GZR/EDR, and paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD). But NS5A resistance-associated substitutions (RASs) that arise during treatment with NS5A inhibitor-containing combinations persist for a long time and determine the need for retreatment, which, they proposed, requires three DAA classes-a polymerase inhibitor, a protease inhibitor, and an NS5A inhibitor.
In a previous study of 28 people in whom GLE/PIB failed, retreating with GLE/PIB plus SOF and ribavirin for 16 weeks yielded an overall SVR12* of 96%, including 88% with genotype (GT) 1 HCV, 100% with GT 3, and 100% with GT 6 [2]. The New Zealand team added that both AASLD and EASL guidelines recommend GLE/PIB + SOF with or without ribavirin (RBV) for 12 weeks as one rescue option after NS5A inhibitor regimen failure. They noted that DAA rescue options are limited in New Zealand: GLI/PIB is funded by the government without restriction, but SOF and SOF/VEL/VOX are not.
To test the effectiveness of GLE/PIB + SOF after DAA failure, they are running an open-label trial of that combination for 16 weeks with primary endpoints of SVR12 in an intention-to-treat (ITT) analysis and in a per-protocol analysis. Clinicians monitor participants at least every 4 weeks for adherence and adverse events. Study inclusion criteria included NS5A inhibitor-based experience, confirmed treatment failure demonstrated by a detectable viral load 12 weeks after treatment ended with no history suggesting reinfection, and confirmed NS5A resistance. The trial excluded people with decompensated cirrhosis (Child Pugh class C) or hepatocellular carcinoma, as well as pregnant or breastfeeding women.
Of the 66 study participants, 50 (76%) were men, 63% were European in heritage, 28% Maori (New Zealand natives), 7% Southeast Asian or Chinese, and 2% Indian. While 24 people (36%) had cirrhosis, 8 used opioid substitution with methadone, and 9 were still injecting. Age averaged 56 years. All but 2 people had a confirmed NS5A RAS, and sequencing failed in those 2.
Most people, 55%, had HCV GT 1A, 38% had GT 3, 3% GT 2, 2% GT 4, and 2% GT 1B. A small majority, 54%, had treatment failure with GLE/PIB and 38% with PrOD, while SOF/VEL, SOF/LDV, and other DAAs accounted for the remaining failures. The most frequent NS5A RASs were Y93H in 48%, Q30K/H in 33%, A30K in 25%, and M28T/F/V in 17%. Among people with prior failure of GLE/PIB, the most frequent NS5A RASs were Y93H in 72%, A30K in 39%, and Q30K/H in 25%. Thirty-six people had 1 NS5A RAS, 26 had 2 NS5A RASs, and 2 had 3 NS5A RASs.
Among people who began rescue therapy with GLE/PIB + SOF, 5 stopped within 4 weeks, 8 were on treatment at the time of this report, 55 completed treatment, 52 completed treatment at least 12 weeks ago, and 51 of those 52 had an HCV RNA result. Of those 51, 50 tested negative for HCV RNA to yield an intention-to-treat SVR12 of 93% and a per-protocol SVR12 of 98%.
Serious adverse events were 1 overdose death and 1 resected hepatocellular carcinoma. Three people, all active drug injectors, had nonvirologic failure (1 overdose and 2 losses to follow-up). The single confirmed virologic failure involved a 53-year-old woman with HCV GT 1a, without cirrhosis, previously treated with PrOD + RBV. After 16 weeks of GLE/PIB + SOF + RBV, the only detectable RAS was M28V.
The investigators concluded that GLE/PIB + SOF for 16 weeks constitutes a highly effective and safe rescue regimen after failure of previous DAAs, including GLE/PIB. They asked whether 12 weeks of those three DAAs would be as effective. And they observed that most DAA failures today are not virologic but instead involve nonadherence to treatment or loss to follow-up, which must be addressed by "wrap-around support for patients with complex psychosocial issues."
*SVR 12 weeks after treatment ends.
EASL: Glecaprevir/pibrentasvir & sofosbuvir for 16 weeks without ribavirin is safe and highly effective retreatment for patients who have failed an NS5A inhibitor containing antiviral regimen - (06/27/22)
References
1. Gane EJ, Faire B, Helmy S, et al. Glecaprevir/pibrentasvir and sofosbuvir for 16 weeks without ribavirin is safe and highly effective retreatment for patients who have failed an NS5A inhibitor containing antiviral regimen. EASL International Liver Congress 2022, London, June 22-26, 2022. Abstract OS004.
2. ClinicalTrials.gov. Efficacy and Safety of glecaprevir (ABT-493)/pibrentasvir (ABT 530) (GLE/PIB) in combination With sofosbuvir and ribavirin in participants with hepatitis C virus who did not respond to treatment in a previous AbbVie clinical study (MAGELLAN-3). ClinicalTrials.gov identifier NCT02939989. https://clinicaltrials.gov/ct2/show/NCT02939989
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