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TOPIC: Geographic differences between GT 1a

Geographic differences between GT 1a 2 years 5 days ago #17702

  • DrJames
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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.
YMMV
Last Edit: 2 years 5 days ago by DrJames.
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Geographic differences between GT 1a 2 years 5 days ago #17704

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I think I get that.......
Genotype 1a
Diagnosed in 2004, had HCV for all my adult life. Until 2016!!!!
Harvoni treatment, started 19 March 2016
4 week results Bilirubin 12 down from 14 pre treatment,
Gamma 25 down from 52, ALT 19 down from 63, AST 19 down from 47,
VL <15 down from a lazy 6 million or so

EOT Results
Bilirubin 10, GGT 18, ALT 19, AST 21, VL UND

12 Weeks post EOT
Bilirubin 11, GGT 16, ALT 22, AST 20, VL UND
Cured baby
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Geographic differences between GT 1a 2 years 5 days ago #17705

  • LondonGirl
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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 ?
GT1a Dec14 F2/8.7 VL 900000-2.5M
Jan16 Hepcivir-L MonkMed/Redemption
Baseline: VL 913575 Alt 76 Platelets low
Wk2 VL1157 Alt 23
DET Wk 8 VL 32 Alt19 'In the slow lane'
June16 Fibro 5.7 F0/1 LIF 1.5
Wk 11 VL<12 Alt 13 Det/Unq
Extending tx 12 wks Mylan Sofo/Dac MonkMed
Wk 14 VL <12 Det/Unq
Wk 16 VL UNDETECTED
Wk 22 + 4 Wks Sunprevir FixHepC
Wk 24 UNDETECTED Alt 13
Wk 12 post tx SVR12 Wk 26 SVR24
Thank-you Tim, Dr Debasis @ MonkMed & Dr Freeman @ Fix HepC
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Geographic differences between GT 1a 2 years 5 days ago #17725

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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)
G3a since '78 - Dx '12 - F4 (2xHCC)
24wk Tx - PEG/Riba/Dac 2013 relapsed
24wk Tx - Generic Sof/Dac/Riba 2015/16 relapsed
16wk Tx - 12/01/17 -> 03/05/17 NS3/NS5a + Generic Sof
SVR7 - 22/06/17 UND
SRV12 - 27/07/17 UND
SVR24 - 26/10/17 UND
:cheer: :cheer: :cheer:
Last Edit: 2 years 5 days ago by Gaj.
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Geographic differences between GT 1a 2 years 4 days ago #17751

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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 !
GT1a Dec14 F2/8.7 VL 900000-2.5M
Jan16 Hepcivir-L MonkMed/Redemption
Baseline: VL 913575 Alt 76 Platelets low
Wk2 VL1157 Alt 23
DET Wk 8 VL 32 Alt19 'In the slow lane'
June16 Fibro 5.7 F0/1 LIF 1.5
Wk 11 VL<12 Alt 13 Det/Unq
Extending tx 12 wks Mylan Sofo/Dac MonkMed
Wk 14 VL <12 Det/Unq
Wk 16 VL UNDETECTED
Wk 22 + 4 Wks Sunprevir FixHepC
Wk 24 UNDETECTED Alt 13
Wk 12 post tx SVR12 Wk 26 SVR24
Thank-you Tim, Dr Debasis @ MonkMed & Dr Freeman @ Fix HepC
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