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SYNERGY: Two 6-week DAA combinations yield encouraging results
BOSTON — Twelve-week sustained virologic response was reported in two cohorts of patients treated for 6 weeks with direct-acting antiviral combination therapy, according to findings presented here at the 2014 Conference on Retroviruses and Opportunistic Infections.
The aim of the study was to evaluate the safety and efficacy of three combinations of direct acting antiviral (DAA) agents in a cohort of 60 treatment-naïve, mono-infected patients with HCV genotype 1, according to Anita Kohli, MD, of the Critical Care Medicine Department at the NIH.
The treatment regimens in the phase 2 study included sofosbuvir 400 mg/ledipasvir 90 mg (Gilead) once a day for 12 weeks in a fixed dose combination; the fixed-dose combination plus a 500-mg daily dose of NS5B inhibitor GS-9669 (Gilead) for 6 weeks; or the fixed-dose combination plus 80 mg daily of the HCV protease inhibitor GS-9451 (Gilead) for 6 weeks.
Clinicians performed serial measurements of safety parameters. This included virologic parameters such as HCV RNA as assessed by the Roche Taqman PCR and Abbott assay, along with deep sequencing of baseline mutations and intrahepatic and peripheral host correlates as assessed by flow cytometry.
The study population was 88% African American, 72% men and 70% genotype 1a. Seventy percent had HCV viral load greater than 800,000 IU/L, and 82% had an IL28B non-CC haplotype.
The researchers reported similar baseline demographics across the three treatment arms. Stage 3 or higher liver fibrosis was reported in 35% of patients in the fixed dose-only arm and in 25% of those in both the fixed-dose plus NS5B arm and the fixed dose-plus protease inhibitor arm. There were no patients with cirrhosis in either the NS5B arm or the protease inhibitor arm.
The researchers defined the end-of-treatment response as HCV RNA <LLOQ. Using an HCV assay with a lower limit of quantification of 12 IU/mL, this endpoint was reached by 100% of patients in the fixed-dose arm, 75% in the NS5B arm and 95% of those in the protease inhibitor arm.
When an assay with a lower limit of quantification of less than 43 IU/mL was used, 100% of those in all treatment arms were suppressed by the end of the trial.
Sustained virologic response at 12 weeks was reported in 100% of the fixed-dose patients, 90% of those in the NS5B group and 95% of the protease inhibitor group.
Viral relapse occurred in one patient in the NS5B group. One patient each from the fixed dose only and protease inhibitor arms missed their 12-week sustained virologic response visit.
No grade 4 adverse events or drug discontinuations were reported.
“In this inner city patient population, the addition of a third antiviral agent allowed successful eradication of HCV in 6 weeks,” the researchers concluded, adding that the cohort represents a group that has historically been difficult to treat. “This study presents a new paradigm of combination therapy to reduce HCV treatment duration, which may be vital in the treatment and eradication of HCV globally.”
Kohli said during a press conference that the study was designed to evaluate simple oral therapies in combination for a short duration.
“The idea was to replace ribavirin with a DAA, because previous data showed that ribavirin with combination therapy did not produce good results in 6 weeks,” she said. “We learned a few things from this study. One is that we can treat patients with a short duration of therapy.”
Kohli noted that previous studies have investigated 8 or 12 weeks of therapy, but not 6 weeks.
“Another thing we can take away from this study is that the regimens are very simple,” Kohli said. “They involved one, two or three pills per day.”
African American patients have traditionally been difficult to treat due to frequency of genotype 1a disease and a high viral load, according to Kohli. She suggested that the current regimens may represent a trend toward an easier cure.
“Finally, we should be looking at this short duration of therapy on a global scale,” she said. “We need to be looking at HCV treatments for 180 million people.”
Kohli said the results are very promising and are being investigated: “We are actually pursuing a shorter duration of therapy based on these results.”
For more information:
Kohli A. Abstract #27LB. Presented at: The 2014 CROI. March 3-6, 2014. Boston.
Disclosure: Kohli reports no disclosures.