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Model Predicts Higher SVR With 24- vs 12-Week
Daclatasvir/Sofosbuvir for HCV-3 Cirrhotics
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16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
Extending daclatasvir/sofosbuvir therapy from 12 to 24 weeks (without ribavirin) may improve sustained virologic response (SVR) rates in HCV genotype 3 (HCV-3) patients with cirrhosis, according to predictions with viral kinetic modeling [1].
HCV-3 infection poses a high risk of progression to liver cancer and liver decompensation. Regimens for HCV-3 usually require 24 weeks of direct-acting antivirals plus ribavirin. ALLY-3 tested 12 weeks of daclatasvir/sofosbuvir without ribavirin in 101 treatment-naive HCV-3 patients and 51 patients with treatment experience [2,3]. One quarter of the experienced group and 19% of the naive group had cirrhosis. SVR12 reached 90% in the naive group and 86% among pretreated patients. But SVR12 proved substantially lower in people with versus without cirrhosis (63% versus 96%).
Bristol-Myers Squibb (BMS) researchers hypothesized that longer daclatasvir/sofosbuvir therapy may improve response in HCV-3-infected people with cirrhosis. To predict SVR24 with daclatasvir/sofosbuvir continued for another 12 weeks, they developed a population viral kinetic (PVK) model. The two-strain model created a competition between a drug-susceptible HCV strain and a drug-resistant strain. The BMS team defined the drug-resistant strain as the most-resistant variant according to population-based HCV RNA sequencing for each of 152 people treated in ALLY-3. The PVK model included replication capacity of each participant's resistant strain and each person's cirrhosis status. The investigators fitted the PVK model to 1608 HCV RNA plasma levels from ALLY-3. Stochastic simulation evaluated SVR12 and SVR24 in HCV-3 cirrhotic and noncirrhotic trial participants treated for 12 or 24 weeks with daclatasvir/sofosbuvir.
The model predicted a 59% SVR12 for people with cirrhosis, close to the 63% observed in the trial. This result indicated good simulation by the model. In ALLY-3 participants without cirrhosis, the model predicted no benefit from stretching daclatasvir/sofosbuvir therapy from 12 to 24 weeks. Simulated SVR12 and SVR24 both stood at 93% in noncirrhotics treated for 12 weeks, while simulated SVR12 and SVR24 both stood at 99% in noncirrhotics treated for 24 weeks.
In contrast, continuing daclatasvir/sofosbuvir for 24 weeks pushed simulated SVR12 and SVR24 of 59% and 57% for cirrhotics treated for 12 weeks to 89% and 89% for cirrhotics treated for 24 weeks. That predicted SVR24 with 24 weeks of treatment nearly mirrors the actual overall 90% SVR12 recorded among treatment-naive patients in the trial.
The BMS team proposed that this modeling analysis "supports 24 weeks of daclatasvir/sofosbuvir without ribavirin for HCV GT-3 cirrhotic patients, a population with high unmet medical need."
References
1. Tafoya E, Lu Y, Luo M, et al. Population viral kinetic modeling: SVR prediction in HCV GT-3 cirrhotic patients with 24 weeks of daclatasvir + sofosbuvir administration. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 3.
2. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61:1127-1135. http://onlinelibrary.wiley.com/doi/10.1002/hep.27726/full
3. ClinicalTrials.gov. Phase III daclatasvir and sofosbuvir for genotype 3 chronic HCV (ALLY 3). ClinicalTrials.gov identifier NCT02032901. https://clinicaltrials.gov/ct2/show/NCT02032901
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