TOPIC:

Price passed this on to me:

www.ncbi.nlm.nih.gov/pubmed/26213689

Two Distinct Hepatitis C Virus Genotype 1a Clades Have Different Geographical Distribution and Association With Natural Resistance to NS3 Protease Inhibitors.

Background. Hepatitis C virus (HCV) genotype 1 is the most prevalent worldwide. Subtype 1a, compared with 1b, shows lower response rates and higher propensity to select for drug resistance to NS3 and selected NS5A and nonnucleoside NS5B inhibitors. Two distinct clades of subtype 1a have been described.

Methods. Using Bayesian methodology, we performed a time-scaled phylogeny reconstruction of clade separation and characterized the geographic distribution, phylodynamics, and association with natural resistance variants of NS3 sequences from 362 patients carrying subtype 1a HCV.

Results. All sequences segregated in 2 clearly distinct clades. Clade I showed an earlier origin from the common ancestor compared with clade II. Clade I virus was more prevalent in non-European countries, represented mostly by United States, compared with European (75.7% vs 49.3%; P < .001). The prevalence of the natural NS3 variant Q80K, associated with resistance to the macrocyclic protease inhibitor simeprevir, was detected in 51.6% of clade I and 0% of clade II (P < .001); clade I showed a lower genetic barrier for Q80K, whereas no sign of selective pressure at any protease inhibitor resistance-associated codon was detected.

Conclusions. Hepatitis C virus subtype 1a clades have a clearly different distribution in Europe and the United States, and the natural resistance mutation Q80K is exclusively associated with clade I.

Now this is not my comment but sums it up....

Well I’ll be damned. I’d always put the difference in SVR rates between Europe and the US down to either age or weight differences.

I think I get that.......

How extremely interesting and at the same time unsurprising.
So, GT1a has 2 clades and clade 1 is harder to treat and harks from non-European countries such as USA etc, do I have that right?

and So the Q80K resistance is just towards Simeprevir? or all associated meds ?

Hi LG,

Genotype 1a is more common in the US than in Europe where 1b is more prevalent.
For those with genotype 1a, clade 1 is more common in the US at roughly 1/2 of cases vs 1/4 of cases in Europe.
So yes, 1a clade 1 is represented in a greater proportion of patients in the US than in Europe.

Q80k is a naturally occurring form of resistance to Simeprevir. In other words, it is present before the use of Simeprevir rather than being caused by it. It is present in clade 1 in 50% of cases but 'never' in clade 2.
But importantly for us it appears to be resistant to Simeprevir mostly when used with Peg/Riba.

"In particular, Q80K does not seem to influence the activity of simeprevir when combined with sofosbuvir." (P16 of full article)

So the study has picked up clear differences in the two clades that probably skewed SVR rates when Sim/Peg/Riba was used but probably wouldn't effect retreatment with Sim/Sof and a NS5a inhibitor.

As they point out on page 18 there may be other differences too but these will require further study:

"Whether these different clades influence the response to other DAA-inhibiting HCV at different steps of its life cycle deserves further investigations." (P18)

Thanks Gaj,

"Whether these different clades influence the response to other DAA-inhibiting HCV at different steps of its life cycle deserves further investigations." (P18)

Yes !