Source - Correspondence Lancet
Original Text
Anna Alisi a, Claudia Della Corte a, Donatella Comparcola a, Maria Rita Sartorelli a, Valerio Nobili a
We read with great interest the Article by Stanislas Pol and colleagues1 on the use of daclatasvir in previously untreated adult patients with chronic hepatitis C genotype 1 infection.
Daclatasvir belongs to a class of new directly acting antivirals that inhibit non-structural protein NS5A, inhibiting hepatitis C virus RNA replication. Daclatasvir has inhibitory activity against hepatitis C virus, with broad genotypic coverage and a pharmacokinetic profile that supports once-daily dosing.2, 3
Emerging drug-resistant hepatitis C virus variants have been reported previously in patients given daclatasvir in phase 1 monotherapy studies.3 However, as Pol and colleagues showed,1 an appropriate dose of daclatasvir, combined with peginterferon alfa-2a and ribavirin, suppresses resistant virus variants, and results in a more rapid and earlier decrease in plasma hepatitis C virus RNA than does dual peginterferon alfa-2a and ribavirin treatment. This randomised, multicentre, double-blind, placebo-controlled phase 2a trial showed that patients given daclatasvir, mainly at a 10 mg or 60 mg dose, had a better extended rapid virological response at both 4 and 12 weeks of treatment, and a better sustained virological response at 24 months, than did those in the group given peginterferon alfa-2a plus ribavirin. Moreover, the investigators reported no differences in side-effects between the two treatment groups.
Although the treatment of children with chronic hepatitis C is controversial, daclatasvir's good tolerability and the favourable effects of its combination with peginterferon alfa-2a plus ribavirin (triple therapy) encourage clinical trials in children, as suggested by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).4 Because no data exist for the toxicology of daclatasvir in children, a phase 1 clinical trial should be a prerequisite for a phase 2 trial; however, Pol and colleagues’ results support the possibility of a randomised, multicentre, blinded, placebo-controlled, dose-escalation phase 1—2 clinical trial being started. 48 children (age range 6—17 years) with chronic hepatitis C genotype 1 infection and with the eligibility criteria recommended by NASPGHAN4 could be included in the trial. The patients should then be randomly assigned (1:1:1:1) into four groups, including 3 mg, 10 mg, and 30 mg doses of oral daclatasvir once daily, and a placebo. The recommended length of therapy is at least 48 months, and all 48 patients should receive once-weekly injections of 60 μg/m2 peginterferon alfa-2a and 15 mg/kg per day of oral ribavirin.5 As primary endpoints, this phase 1 or 2 clinical trial should include both the identification of side-effects associated with increasing doses and the effectiveness of daclatasvir that was measured by assessment of virological response during follow-up.
We declare that we have no conflicts of interest.
References
1 . Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomized, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis 2012; 12: 671-677. Summary | Full Text | PDF(205KB) | CrossRef | PubMed
3 . Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465: 96-100. CrossRef | PubMed
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