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- Hepatitis C virus
- genotype 3
- sustained virological response
- Debio 025
- cyclophilin inhibitor
- hepatitis C
We read with interest the paper by Himmelsbach and colleagues discussing the role of sorafenib in blocking hepatitis C virus (HCV) replication in vitro.1 Further studies are required to delineate the potential antiviral efficacy either in combination with the standard of care (Peg-IFN and ribavirin) or as monotherapy. Currently, a number of new antiviral drugs are being investigated in order to improve sustained virological response (SVR) rates and/or reduce treatment duration in chronic hepatitis C (CHC). However, to date none of the new small molecule drugs appear effective against genotype 3 such that at the present time patients with genotype 3 infection have no other options.
Debio 025 is a selective cyclophilin inhibitor that has previously demonstrated antiviral activity against the hepatitis C virus both in vitro and in vivo.2 3 Results of a phase Ib study indicate that Debio 025 has an important additive anti-HCV effect when coadministered with Peg-interferon (IFN)α-2a to treatment-naive patients with CHC.4 Debio 025 binds strongly to Cyclophilin B (CypB), which is a host cell protein thought to confer a replication advantage to HCV. Debio 025 inhibits CypB and thereby may interfere with the action of the viral RNA polymerase and hence viral replication.5 6
We present a case of a patient with HCV genotype 3 infection who received Debio 025 monotherapy for 29 days and subsequently achieved a SVR. A 33-year-old woman, originally from Pakistan, was diagnosed with elevated liver enzymes (aspartate aminotransferase (AST) 44U/L, alanine aminotransferase (ALT) 72U/L) and was found to be infected with HCV (genotype 3a). Treatment was delayed until 2007, at which time the HCV RNA viral load was 8.38×103 IU/ml. A percutaneous liver biopsy revealed grade 1 activity and stage 1 fibrosis. This patient was enrolled in an international, multicentre, phase II study of treatment-naive patients with CHC and randomised to treatment with Debio 025 1000 mg twice daily for 7 days then 1000 mg daily in June 2007 for a total duration of 29 days.7 The liver enzymes returned to normal with treatment (AST 17 U/L and ALT 17 U/L on day 29). The HCV RNA was undetectable on day 8 of treatment (Quantitative Roche HCV RNA Assay with detection limit 15 IU/ml, Roche Molecular Diagnostics, Pleasanton, California, USA). The patient had to return to Pakistan and preferred to delay the standard of care with Peg-IFN-α2a 180ug subcutaneous weekly and ribavirin 800 mg daily for 24 weeks that was offered after completion of 1 month of Debio 025 treatment. Upon return to Canada in April 2008, serum HCV RNA remained undetectable and she has remained negative at 24 months post treatment.
This patient with genotype 3a HCV infection cleared HCV RNA in 29 days with Debio 025 monotherapy and achieved a SVR. In a phase II trial in patients with hepatitis C mono infection, data revealed that there was a significant difference in viral load reduction between the HCV genotypes (p<0.001).7 In patients with genotypes 2 and 3, the maximum mean HCV RNA reduction was –5.91±1.11 log10 IU/ml in the Peg-IFN with Debio 025 600 mg/day arm and −5.89±0.43 log10 IU/ml in the Peg-IFN with Debio 025 1000 mg/day at day 29. Two-third of the patients (four out of six) had undetectable HCV RNA on day 29 in the Debio 025 monotherapy compared to 83% (five out of six) in the Peg-IFN with Debio 025 1000 mg/day group.
Cyclophilin inhibitors may have a higher barrier to resistance than other molecules currently in development as it interacts directly with the host rather than the virus. This may prevent the selection of resistant strains and lower the risk of HCV RNA breakthrough with short-term antiviral therapy. No viral breakthrough was observed in the phase IIa trial.7
There has been a focus on using a combination of drugs with different mechanisms of action to maximise antiviral activity in order to enhance viral suppression and control the emergence of resistance. However, Debio 025 is a novel cyclophilin B inhibitor, which has been shown to have the potential as monotherapy to achieve a rapid virological response in patients with CHC. We have shown that in a patient with genotype 3 and low viral load, treatment with Debio 025 monotherapy was sufficient to induce sustained viral clearance.
Linked articles 212068.
Funding The project from which this case is taken was funded by Debio Pharm and their approval has been obtained for this case report (Dr. R. Crabbe). Dr. Jenny Heathcote has commercial associations with the following: Hoffmann LaRoche, Schering-Plough, Axcan-Pharma, Gilead Sciences, GlaxoSmithKline, Human Genome Sciences, Novartis, Idenix, Vertex, Bristol Myers Squibb, Pharmasset, Debiopharm, Boerhinger Ingleheim and Tibotec.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Toronto Western Hospital.
Provenance and peer review Not commissioned; not externally peer reviewed.
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