Journal of Clinical Virology - "Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir"

Lovingly pinched from the great NATAP.com - coverage of a study appearing in the 'Journal of Virology' looking at long-term resistance in patients who experienced viral break-through or relapse in the early phase trials of Telaprevir and Boceprevir.  The authors follow 28 patients (14 each for Telaprevir and Boceprevir resistance) a median of 4.2 years post-therapy.  Resistant variants of varying levels were discovered in 2/14 subjects exposed to Telaprevir and 4/14 exposed to Boceprevir. Surprisingly, the dominant quasispecies uncovered during sequencing done at end-of-treatment didn't always match the quasispecies sequencing done at follow-up - whether this was due to the highly replicative nature of the HCV virus, re-infection or some other phenomena, I'm not sure.  


HCV resistance doesn't get a lot of press time, but it's really a critically important issue - most importantly because no one understands it all that well. The jury is still out on re-treatment (and who'd want to do THAT again??).  Sequential therapy with custom-tailored regimens that lack cross-resistance looks to be the logical answer to treatment failures on first generation treatments like Telaprevir and Boceprevir. It looks like we'll have a broad array of potent compounds within differing classes with differing resistance profiles to choose from in the long run, which is fantastic news. In the short-term, it's an issue however.  The patients currently waiting for effective 2nd-line sequential therapy, unless they are enrolled in a clinical trial, may have to wait awhile until other options come to the market. 


There aren't any easy answers until researchers really understand HCV resistance and all it's implications. The best treatment options, in my very humble opinion, would be treatments that don't run the risk of resistance.  Virtually ignored by the press and investors alike was pegylated interferon lambda which garnered impressive results without running the risk of viral resistance. Another contender with a decidedly lower opportunity for resistance are cycophilin inhibitors, which have been regulated as the ugly step-sister of Direct Acting Antivirals drug classes.  It might be time to take a longer, more holistic view on HCV resistance and take a second look at compounds that have the potential to cure patients with less chance of incurring resistance issues that might become more complicated as time goes on. 

Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir

 Journal of Clinical Virology 52 (2011) 321- 327

Simone Sussera , Johannes Vermehrena , Nicole Forestiera , Martin Walter Welkera , Natalia Grigorianb, Caterina Fuller a, Dany Pernera, Stefan Zeuzema, Christoph Sarrazina, a Klinikum der Goethe Universitαt, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
b Universitαtsklinikum Homburg, Klinik fur Innere Medizin 2, Kirrberger Str., Homburg/Saar, Germany

Abstract


Background

Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance.

Objectives

Potential persistence of resistance mutations during long-term follow-up should be analyzed.

Study design

Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment.

Results

After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients. For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4-9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1-10%) while in one patient additionally a combined variant (T54S + R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up.

Conclusions

In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.