Direct-acting Antiviral Combo Effective Against Treatment-resistant Hepatitis C

A triple drug regimen effectively cured patients with hepatitis C virus (HCV) after they had failed to respond to a combination of 2 oral direct-acting antivirals (DAA), according to a report of 2 international trials.

Lead author David L Wyles (pictured), MD, Chief of Infectious Diseases Denver Health, Medical Center, University of Colorado, and colleagues set out to treat HCV patients he characterized as “one of the most difficult-to-treat populations studied thus far with new DAA regimens.”

 The patients had previously failed treatment with an oral DAA combination that included an NS5A inhibitor. The 2 trials feature patient groups with genotype 1 (GT1) in one, and GT1, 2, or 3 in the other, respectively. 

The second patient group had failed to respond to an initial DAA combination present multiple characteristics that portend subsequent treatment failure, including presence of resistance associated substitution (RAS) viral mutations.

The populations with poorer response to DAA therapies — particularly likely with GT1 and 3 — are also more likely to have cirrhosis and prior interferon failure.

Wyles and colleagues noted there are so few subsequent treatment options that current guidelines recommend deferral of treatment in those without an urgent indication for re-treatment until better options emerge.

"Effective treatment options for people who have failed the current generation of all-oral DAA regimens will require a combination of drugs of sufficient potency to overcome multiple negative predictors, while simultaneously presenting a high barrier to resistance to overcome baseline RASs (potentially multi-class) and prevent emergence of new RASs," the researchers wrote.

Those treatment options appear closer at hand with the results from  the 2 Phase II trials. Each trial employed a once-daily triple-drug regimen under evaluation as a fixed-dose oral combination for HCV. The combination included an NS3/4A protease inhibitor (grazoprevir 100mg); a "next generation" pan-genotypic NS5A inhibitor (ruzasvir 60mg); and an NS5B polymerase nucleotide inhibitor (uprifosbuvir 450mg).

The C-SURGE trial involved 93 patients with GT1 infections unresponsive to a commercially available DAA treatment who were randomized to receive either 16 weeks of the triple drug regimen with additional ribavirin (RBV, 800-1400mg/day) (n=49), or 24 weeks of the regimen without RBV (44). Part C of the trial identified 24 patients with GT1 (n=2), GT2 (14) or GT3 (8) that was resistant to an experimental short course of DAA, and provided them with 16 weeks of the triple regimen and RBV.

"No patients in the C-CREST had cirrhosis, a factor which complicates re-treatment and decreases response," Wyles said.  "Patients in the C-SURGE study represent the most difficult to re-treat population and this population is more representative of the small percentage of patients who fail our currently available HCV treatments."

The treatment was described as generally well tolerated, with more drug-related adverse events occurring, as expected, in those receiving RBV.  The researchers also noted that while over 40% of patients in the C-SURGE trial had cirrhosis, the adverse event profiles were generally similar in chirrhotic and noncirrhotic patients, and there were no instances of hepatic decompensation.

Wyles and colleagues reported that 1 patient in each trial discontinued the study medication before completion, but all completing patients across genotypes 1, 2, and 3 achieved the primary efficacy goal of sustained virologic response (SVR), an essentially undetectable level at end of treatment (HCV RNA <15 IU/ml).

The successful elimination of HCV in patients who had not previously responded to treatment was accomplished with or without RBV, with either the 12 or 24 week regimens, and despite patients presenting with RSAs at baseline.

"The lack of virologic failures is impressive, particularly in the very difficult to treat C-SURGE study population," Wyles said. "However, further studies are needed to determine if shorter durations and the omission of RBV from the treatment regimen maintain this high cure rate."

The report of the 2 trials, "Grazoprevir, Ruzasvir, and Uprifosbuvir for HCV After NS5A Treatment Failure,"  was published online in the journal Hepatology last month.

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