PROPEL: a randomized trial of mericitabine plus peginterferon alpha-2a/ribavirin therapy in treatment-naïve HCV genotype 1/4 patients.
Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment-naïve HCV genotype 1 or 4 patients were randomized to double-blind treatment with oral mericitabine at a dosage of 500 mg twice-daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha-2a (Peg-IFNα-2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A-C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A-E) continued Peg-IFNα-2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow-up; SVR-24). VR rates were higher in arms A-D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non-CC IL28B genotypes. However, the overall SVR-24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response-guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine-resistance mutations (S282T) were observed during mericitabine therapy.


CONCLUSIONS
Treatment with mericitabine plus Peg-IFNα-2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN-free and IFN-containing trials of mericitabine of longer treatment duration are ongoing.
Medizinische Hochschule, Hannover, Germany.
Heiner
H
Wedemeyer
Donald
D
Jensen
Robert
R
Herring
Peter
P
Ferenci
Mang-Ming
MM
Ma
Stefan
S
Zeuzem
Maribel
M
Rodriguez-Torres
Natalie
N
Bzowej
Paul
P
Pockros
John
J
Vierling
David
D
Ipe
Marie Lou
ML
Munson
Ya-Chi
YC
Chen
Isabel
I
Najera
James
J
Thommes
D000293:Adolescent; D000328:Adult; D000368:Aged; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult; D000095022:Interferon Lambda
D003841:Deoxycytidine; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a