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.

More information on the impact of genotype 1a and 1b on resistance and response to Boceprevir...

(More info on the impact of genotype 1a vs 1b in regards to Boceprevir response and resistance from Liz Highwayman published in AIDSMAP.com. Merck researchers gathered data gathered from SPRINT-2 (Tx naive) and RESPOND-2 (prior non-responders) trials.and compared frequencies of boceprevir resistance-associated variants (mutations) among people with HCV genotype 1a and 1b. The researchers found that resistance-associated variants were more common among people with genotype 1a, consistent with the higher likelihood of treatment failure. It appears that it takes only a single mutation for wild-type HCV genotype 1a to become resistant to boceprevir, whereas two mutations are required for genotype 1b, giving a "biological rationale" for differences in response rates. )


Boceprevir response and resistance differs according to HCV genotype 1 subtype


Hepatitis C treatment
Liz Highleyman
Content provided by hivandhepatitis.com
Published: 28 July 2011

People with hepatitis C virus (HCV) genotype 1b respond better to boceprevir and are less likely to develop drug resistance than those with genotype 1a, according to study findings reported last week at the International AIDS Society Conference (IAS 2011) in Rome.

The advent of direct-acting antiviral agents has led to a paradigm shift in treatment for chronic hepatitis C. The first two drugs out of the pipeline – the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek) – are used with pegylated interferon plus ribavirin standard therapy, but all-oral combinations are currently under study. As with HIV treatment, using these new agents in suboptimal regimens can lead to resistance.

Boceprevir, which was approved by the European Commission last week, improved sustained virological response or cure rates when taken with pegylated interferon/ribavirin in the pivotal Phase 3 SPRINT-2 and RESPOND-2 trials. SPRINT-2 included 1097 previously untreated patients with HCV genotype 1 and RESPOND-2 included 403 people who did not respond or relapsed after a prior attempt at standard therapy.

It is well known that HCV genotype 1 is the most difficult to treat, but these trials also revealed differences between subtypes within this genotype. Genotype 1a is predominant in Northern Europe and North America, whilst genotype 1b is more common in Southern and Eastern Europe and Japan.

Daria Hazuda from Merck and colleagues compared frequencies of boceprevir resistance-associated variants (mutations) among people with HCV genotype 1a and 1b in SPRINT-2 and RESPOND-2.

These studies, conducted mainly in Western Europe and the US, enroled HCV mono-infected patients with compensated liver disease. Individuals co-infected with HIV or hepatitis B were excluded. A majority of patients in both studies were men; SPRINT-2 included 14% people of African descent, a group that responds poorly to interferon-based therapy.

In both trials participants received a four-week "lead-in" of pegylated interferon plus ribavirin before adding either boceprevir or placebo. Some participants continued treatment for the standard duration of 48 weeks, whilst others used response-guided therapy based on early HCV viral load reduction.

Hazuda's team collected plasma samples at baseline and again near the time of virological failure if patients did not achieve sustained virological response. The NS3/4a region of the HCV genome was sequenced and major resistance-associated variants were identified.

Among treatment-naive participants in SPRINT-2, sustained response rates were slightly but consistently higher for people with HCV genotype 1b. In the 48-week triple therapy group, rates were 73% for genotype 1b vs 62% for 1b, compared to 41% and 35%, respectively, using standard therapy alone. A similar pattern was observed in RESPOND-2, with sustained response rates of 71% for genotype 1b and 64% for 1a with triple therapy, compared to 18% and 24%, respectively, with pegylated interferon/ribavirin alone.

The researchers found that resistance-associated variants were more common among people with genotype 1a, consistent with the higher likelihood of treatment failure.

In SPRINT-2, 19% of all genotype 1a patients had these mutations compared to 10% of people with genotype 1b. In RESPOND-2 the corresponding rates were 16% and 11%, respectively. Looking only at people who did not achieve sustained response in SPRINT-2, 58% of genotype 1a patients and 48% of genotype 1b patients developed resistance mutations. In RESPOND-2, the rates were 48% and 41%, respectively.

The V36M and R155K resistance-associated variants were detected more often in people with HCV genotype 1a, whilst T54A/S, A156S, and V170A were predominant in patients with genotype 1b.

Hazuda explained that for certain positions in the genome it takes only a single mutation for wild-type HCV genotype 1a to become resistant to boceprevir, whereas two mutations are required for genotype 1b, giving a "biological rationale" for differences in response rates.

She further noted that people with poor response during the interferon lead-in phase defined as less than a 1 log drop in HCV RNA by week 4 of treatment were more likely to develop resistance mutations than those with good early response (69% vs 31%, respectively).

Jurgen Rockstroh comments HCV/HIV coinfection in the era of Direct Acting Antivirals...

Jurgen K. Rockstroh M.D., Professor of Medicine University of Bonn, Germany, gives us a synopsis of what the new DAAs for Hepatitis C will mean for patients with HIV/HCV coinfection. I highly recommend a full read through, Dr. Rockstroh walks through the latest efficacy, resistance and drug -drug interaction data on Boceprevir and Telaprevir as well as current epidemiological patterns in the disease state . We'll need SVR data from both drugs to make a full assessment, but from the interim 12 week data, it appears Telaprevir is very effective at reducing HCV viral load in the coinfected patient, although there are some serious drug-drug interactions to look out for as well as a higher incidence of adverse events. Read the entire article here