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Post Info TOPIC: About RAV's
Tig


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RE: About RAV's
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Hoodie, 

You‘re correct, RAV = Resistance Associated Variant. You will slso see it referred to as an RAS, which is Resitance Associate Substitution. They mean the same thing. 

Here‘s a discussion we had on the topic. There is a lot of information here on the forum if you search RAV and RAS. There can be variants at many locations on the DNA

RAV/RAS 

HCV Inhibitors  (Dated and technical, but informative)



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Tig

68yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 9+ years!

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Hoodietree


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Canuck, Sorry if I missed it in your post but what are RAVs?

Many thanks in advance, hoodie

Edited to add: oh it must be resistance variants or Resistance to Anti Virals yeah? I feel really bad for people who have RAVs. Will pray for them.



-- Edited by Hoodietree on Sunday 18th of November 2018 10:41:31 AM

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Canuck


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Another article/data presentation about NS5A RAV's (coming out of the current Liver Meeting going on). Interesting (to me). I don't pretend to understand all of this nor the wideness of the ramifications, but it's interesting all the same, noting it IS "Japan" data-heavy, and that it is also drug-heavy limited to the combo Daclatasvir/Asunaprevir (DCV/ASV) - a NS5A and a NS3/4 respectively, as well as being Harvoni retreatment drug-heavy info - about those who failed Asun/Dacla treatment in Japan, and, their further outcomes when they they (and their acquired RAV's) were subsequently re-treated with Harvoni (a NS5A and NS5B combo) - all of this info (on their NS5A RAV's and outcomes) just reinforces prior data on the negative importance of anyone owning Y93, L31 (and other) RAV's.

Nice, the tidbit at the end, that aside from it being a good thing to be a women (if you want to hedge your bets), that generally, it also pays (duh) not to have any RAV's the first place when being re-treated with Ledi. wink 

 

MEETING NEWS - (from the current Liver Meeting going on right now)

NS5A substitutions affect early HCV treatment failures, retreatment

 
 
November 12, 2018

SAN FRANCISCO - NS5A resistance-associated substitutions at several positions, including Y93, may hold information about DAA treatment response, according to data presented at The Liver Meeting 2018.

Masayuki Kurosaki , MD, of the Department of Gastroenterology and Hepatology at Musashino Red Cross Hospital, Tokyo, Japan, suggested that in addition to suboptimal results to the first-generation DAA combination of Daklinza (daclatasvir/DCV, Bristol-Myers Squibb) and Sunvepra (asunaprevir/ASV, Bristol-Myers Squibb), early data showed that the Y93 RAS was associated with lower treatment response.

?The aim of this study was to evaluate the prevalence and specific pattern of NS5A RAS in patients who failed prior DCV/ASV,? Kurosaki said. ?Also, to evaluate the impact of RAS on the efficacy of retreatment by Harvoni [sofosbuvir/ledipasvir, Gilead].?

The nationwide study included 876 patients who failed daclatasvir/asunaprevir therapy and 1,068 who were DAA-naive. Additionally, 257 patients were retreated with ledipasvir/sofosbuvir. Patients from 83 regional centers in Japan were included.

The researchers assessed NS5A RASs in positions 28, 30, 31, 32, 54, 58, 92, and 93, according to Kurosaki. ?The prevalence of NS5A RASs at positions 24, 28, 30, 31, 32, and 93 was significantly high in DCV/ASV failed patients compared to DAA naive patients,? Kurosaki said.

Looking closer, a RAS at the L31 position occurred in 75.2% of patients who failed daclatasvir/asunaprevir therapy but just 4.4% of those in the treatment-naive group. Similarly, 75.6% of treatment failures had a Y93 RAS, compared with 19.9% rate of that RAS in the naive group. Significant differences also were seen in R30 and P32.

Thinking about the association between these RASs and the efficacy of retreatment with ledipasvir/sofosbuvir, Kurosaki pointed out that at the end of treatment, all 257 patients had responded, but the overall SVR12 rate was just 64%. ?This was due to a high rate of relapse,? he said.

Kurosaki then reported that SVR decreased in patients having NS5A RASs at positions 31, 32, 92, and 93. ?These positions may be key to NS5A RASs,? he said.

The researchers assessed the impact of multiple deletions at these key positions. Among patients who failed daclatasvir/asunaprevir therapy, retreatment with ledipasvir/sofosbuvir yielded a 92% SVR12 rate for patients with no NS5A RASs. However, SVR12 rates were 67% for patients with one NS5A RAS at one of the four key positions, 52% for those with two, and 0% for those with RASs at three of those key positions.

More granular analysis showed that in this retreatment cohort, the A92 deletion yielded an SVR12 rate of just 33.3%. For patients with two of the key variants, the combination of L31 and L32 was associated with the lowest retreatment response, at 20%.

Multivariable analysis findings showed that in addition to female sex (OR = 2.42; P = .013), absence of resistance variants was associated with the best response to retreatment with ledipasvir/sofosbuvir (OR = 6.83; P = .021).

?This nationwide study revealed highly complex nature of NS5A RASs after treatment failure by DCV and ASV,? Kurosaki concluded. ?In addition to signature L31 or Y93 RAS, P32 deletion and A92K was identified as the key RASs to impact the efficacy of retreatment. 

The efficacy of retreatment with LDV/SOF was limited in patients having multiple key NS5A RASs.? - by Rob Volansky

 

Reference:

Kurosaki M, et al. Abstract 200. Presented at: The Liver Meeting 2018; Nov. 9-13, 2018; San Francisco.



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HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

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Tig


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Interesting to see it laid out in that fashion. They should make these things easier to understand! I guess they weren't considering us when they developed the data presentation. We'll have a talk with them about that! In the meantime, I'll be putting cold towels on my head to keep things from overheating, whew!

Thanks for the information. When I was on treatment, I was considered fortunate to have access to a single NS3 - Boceprevir, but it did the trick. With the new NS 5a/b combos, along with the new NS3/4a's, it's no wonder we're seeing such high rates of success. These triples are hard for HCV to argue with! The breakthroughs are coming fast, but I have to wonder how many more they'll come up with. Lets keep our fingers crossed on that!



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Tig

68yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 9+ years!

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Canuck


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About RAV's - (not very layman-friendly info)

Roughly from 2016, so, not very current, so of course, little mention of newer drugs that have just come to the fore or are coming to the fore, such as Glilead's Epclusa/Vosevi, Abb Vie's Maviret, Jansen products and Merck's newer combos - various good combos/doublets and triplets, most of these companies now offering new NS5A's, NS5B's and new 3/4A's. (Many of the newer 5A and 5B drugs will not be mentioned here in these reviews, nor will newer 3/4A's like Vox, Grazo and Glec). Basically, all the newest drugs that are working so well for folks with RAV's. But - you can still glean other small important things from these stats - incorrect genotyping is possible, how common (baseline) treatment-naive RAVs can be, the importance of how many fold the resistance is, common tactics that have been used in the past to ensure the greatest success, and in general how successful treatment has become nowadays, despite coming to first treatment with undefined RAV's, or when coming to re-treatment with known RAV's.

Country heavy data - Japan - for first one.

http://congress-ph.ru/common/htdocs/upload/fm/gepatology/2016/prez/2-5-3-e.pdf

Country heavy data - Italy - for second one.

http://regist2.virology-education.com/2016/14EU/25_Cento.pdf

 

 

 



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)
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