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Post Info TOPIC: Understanding Sovaldi
Tig


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Understanding Sovaldi
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Hi,

I don't want to take this thread off the original topic, so I'd like to ask you to repost it identically to your thread '4 weeks into treatment' (On Treatment). I would but can't move an individual post. Thanks.

There are some great improvements in these numbers though!

[Edit: Corrected typo.]



-- Edited by wmlj1960 on Sunday 10th of January 2016 10:20:46 PM

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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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I am hoping to be able to attach blood analysis photo of samples taken last June, November and 01/07/16, rour weeks after beginning treatment with sov/dak/ riba.

Some of the highs have dropped significantly but I was hoping that someone might be able to explain them in a bit more depth than that!

biggrin

[Post merged to 4 weeks into treatment]



-- Edited by wmlj1960 on Sunday 10th of January 2016 10:26:43 PM

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Contracted Hep C 1969. Genome Type 2, treatment naive. Began 12 week RIBA/sof/Dac on 12/11/15. Cirrhosis. VL before treatment 4m. Treatment extended another 12 weeks without Riba. No virus detected at 9 weeks.



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Great explanation on how Sof works, Malcom, even if I had to read it a few times. Haha! Quite interested in the cardio sx aspect in this comment too considering what I'm experiencing right now on Sof/Dac combo. I'm not taking anything else except for some fish oil which I've cut right back to one capsule. I'm fit, surf all the time, though I have just stopped because of these weird arrhythmia episodes when my heart rate is up now. The ocean isn't exactly the best place to be if something did happen and they do feel a bit scary at the time. I'm even getting a few a rest now too and this is starting to get to me. Insomnia may not be helping but there is definitely something going on. Stress test, CT a month ago was all normal. I do remember experiencing an uneven beat for a brief moment once in a blue moon prior to tx but nothing I was concerned about. Maybe I have some mild underlying factor going on. I had severe palpitations and anxiety in the first 6-7 weeks of tx, especially at the start, but no real arrhythmia episodes until week 8. Off to the cardio again Wednesday.

Bill



-- Edited by billym on Sunday 15th of November 2015 06:43:51 AM

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55 yrs M Geno 3a Sof/Dac 24 weeks started 6-10-15 F3 ALT 126 VL 14'000'000


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I hope so. It just feels like many doctors are just not interested in the feedback, but, for whether it worked or not. I have constant rashes still and have become almost over sensitive to things. I never had allergies before treatment and now I even have hives that keep appearing on my arms and sometimes on my legs and back. I am 6 months post treatment and I am starting to feel like it will never end.



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Type 2b, 3485370 IU/mL VL, sovaldi/ribavirin-12weeks, treatment end 11/15/14 SVR-UD, SVR-5-UD,SVR-14 & 32-UD. (64 yr old with hepc since 1970s)

Tig


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Hi Tess,

The reason is because there is little real world information, aside from the trials. Now that there has been some actual post trial use of the drug, we'll start to see more references to the various adverse and side effects from it. I'm sure it will all be analyzed and organized by associations like the AASLD and EASL first. Hopefully that will be distributed by the time the next latest greatest treatment comes along! We didn't see any advances other than Peg and Ribavirin for decades, so it's actually moving pretty fast now. Let's keep our fingers crossed for some actual SFX free treatment soon!



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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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Even after all this time I still find there is almost NO real world information when it comes to sovaldi. No matter how I research all I come up with is the trial data and/or patient blogs and forums. During treatment I found that my heart raced at times feeling like it was out of step and my blood pressure was all over the place. During treatment I called the specialty pharm to report the heart racing etc and found out they were not required to report any feed back because I was also taking ribavirin and treatments with it had no requirements for some time.



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Type 2b, 3485370 IU/mL VL, sovaldi/ribavirin-12weeks, treatment end 11/15/14 SVR-UD, SVR-5-UD,SVR-14 & 32-UD. (64 yr old with hepc since 1970s)



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Thanks Malcolm, very comprehensive explanation. Glad you help simplify the details.



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Dx. 2005-liver bx.:stg 2/gr 1. at that time-GT 1a multiple transfusions in 1981. Started Sovaldi and Olysio 1/16/14 (No prior treatments)Q80K present. UND week 4,8 and at EOT. UND at wk 4EOT, Und at wk 8EOT SVR 12!!!..SVR 24 :-)



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Hi all,

I've been on an ACE inhibitor (Lisinopril-5 mg.) for the last three years, including my time on Sovaldi. I also have a resting heart rate in the 50s which I assume is related to running and cardio exercise. I don't recall any arrhythmia while on Sovaldi, but perhaps someone like me would be in that group that would need closer monitoring.

I guess my time for alarm has passed, at least in regards to Sovaldi and cardio toxicity.

There may be more unknowns regarding Sovaldi as the treatment population expands and more time has elapsed post EOT. At this point, one year after EOT for me, I haven't seen anything that would question my decision to take Sovaldi and its resultant success in beating Hep C.

Good stuff Malcolm. Glad we have you to stay on top of it! Enjoy the Heritage today!



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Geno 1b, compensated cirrhotic, 54 yo, prior null responder.Pre tx VL approx 595,000,tx with Sovaldi/Olysio (no Riba)started1/8/14. VL 40 @ 2 weeks, UND @ 4 weeks. Still UND @ EOT + 1 year.

Gator Man SVR12, Dragon 0, Final Score.



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Hi Mark,

Yeah, it's interesting, but no cause for alarm as yet. Such an early black- box warning is the first hiccup of Sovaldi's amazing journey.

Amiodarone is tricky- it's hard to find the correct maintenance dose and it has many side-effects and drug interactions.

As for other heart meds, at least the docs will be on the lookout.

Dose reductions of Sovaldi are not suggested at this stage. I was on an ACE inhibitor throughout my treatment as well.

Just a heads-up. Cheers.



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Geno 1b, IL28B CT, x3 prior relapser, ex-cirrhotic, 74 yo, did 48 weeks with Victrelis/Peg./Riba. VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30 and 48 weeks. EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR! Still Undet. at EOT +4 years

Malcolm



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Interesting stuff Malcom does that mean patients on such medication could have their sovadi reduced over time during treatment and still retain effectiveness

I was on carvadilol during my trial we were given ECGs regularly so I guess they will soon have more info.



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60 yo male cirrhotic fibroscan 23 base VL 105000 G2 alt250 ast 200 bil high started trial nov. 6 week results alt 32 ast 30 VL blinded other tests normal range



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Hi all,

A 'Sticky' should be revisited from time to time and brought up to date.

Sovaldi has been in the news lately, with the death of one patient and 3 others requiring pacemakers due to a combination of Sovaldi and amiodarone. I've just caught up with my Hepatology Journals, and some things are worth mentioning.

Amiodarone (also known as Aratac and Pacerone) is used for heart arrhythmias (irregular heartbeats). The new warnings suggest Sovaldi +/- other antivirals, should not be used in patients taking amiodarone.

Amiodarone has a very long half-life of 2 months or more. It is fairly quickly absorbed from the gut when taken orally, but it can take many weeks to reach steady-state blood levels. It cerainly has many side-effects, including bradycardia (slow heartbeat). Why should Sovaldi have this dramatic effect, usually within 24-48 hours?

Sorry, to explain this, we have to look at how Sovaldi is metabolised. In large part, Sovaldi is broken down by the P-GP (P-glycoprotein transporter) system. Don't worry about this, but amiodarone is a potent P-GP inhibitor. Was the death due to high levels of Sovaldi? We already have a case where another NS-5B nucleoside inhibitor was stopped in Phase 2 Trials due to cardiac toxicity and a patient death. That was BMS-986094.

So, can Sovaldi be toxic at high blood levels?

Many other heart and blood pressure drugs inhibit the P-GP system. Captopril (ACE inhibitor used for hypertension), Verapamil (calcium channel blocker also used for hypertension), Ritonavir ( in Viekira Pak), carvedilol and diltiazem to name just a few. Perhaps any patients taking any heart or blood pressure meds should have a cardiac assessment and close monitoring when starting Sovaldi (or Harvoni or whatever combo).

It may just be a coincidence, but it raises a few questions. Sovaldi looked great in the Clinical Trials, but now we're in the real world and huge numbers of patients are being treated. These drugs are still new.



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Geno 1b, IL28B CT, x3 prior relapser, ex-cirrhotic, 74 yo, did 48 weeks with Victrelis/Peg./Riba. VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30 and 48 weeks. EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR! Still Undet. at EOT +4 years

Malcolm



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Malcolm-Great post..thank you!



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Geno Type A1- VL 16.2m - F1-F2 Moderate Fibrosis - Started treatment 4/16/13 Sofosbuvir/Ledipasvir 6 months - UND week 4 (5/14/13) - EOT 10/1/13 - 12wk blood draw 12/20/13 UND - 24wk/final blood draw March 2014



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Malcolm,

Your clear explanations have helped me so much in understanding these new drugs. I know this sounds deeply hippy dippy but I have found visualisation to be very effective - if you know your enemy you can defeat it. Now I know how it is formed I can bust it!Nx



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These questions have been bugging me for some time. Thank you for this explanation Malcolm.



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42 yrs old: geno 1b, 23mil VL, ALT/AST 269/94 as of Apr '14. Got HCV when I was 16. Relapsed from Peg/Riba twice, last time in '08. Completed Sol/Oly on 9/2/14, UND as of 10/7/14



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Moderated

Please, if you are going to make factual statements provide links to reputable sources.

Sol vs Ol My observations are men do better with O than S, woman are the opposite. If you read in the inner depths of the O insert it mentions that woman should not take oral contraceptives or hormones while taking the drug- S 's insert says nothing about hormones. That led me to believe that woman of childbearing age might do better with S, as it must be inherently different than O because of the female hormone issue. I then read the insert to my oral contraceptive package where there was a statement about HIV and HCV treatments about how this drug /Essentially female hormones might change the effectiveness of protease inhibitors or ( or with) non nucleoside reverse transcriptase inhibitors. It was nothing more than that, but it was enough for me to know that it's not the oral contraceptive that is really the culprit - it's regular old estrogen and progesterone. Now I was certain that O was not for me, and S must have some way of working in the body without disturbing the metabolism of hormones in the liver. I have seen relapsed O female patients and relapsed S male patients but not the reverse. All the men on S were miserable, all the women on O were sick as hell. As mentioned before I saw a and experienced myself reverse, where women tolerated S best and men O best. Just an FYI



-- Edited by hrsetrdr on Saturday 19th of July 2014 04:09:06 PM

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Great information. I stopped in for a visit and this site just amazes me still.

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"Ah but I was so much older then, I'm younger than that now." Bob Dylan



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I treated in 2002 with peg n rib but wasn't compliant and my mothers insurance dropped me I was 18 and didn't understand. Retreated in 2013 with Vic peg n rib. 28 weeks. Relapsed now I am 29 and am 2 weeks into solvadi peg n rib. So far minimal sides I feel good. Just am scared of the disappointment of relapsing again -_-



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Genotype 1a

1/18/13 - VL 1.5mil triple therapy with boceprevir

2/3/14 - relapsed. 1.7ml

6/28/14 - started solvadi interferon and ribavirin for 12 weeks

7/28/14 - week 4 undetected dosage reduction of rib and peg

11/2/14 und 4 weeks post eot

g



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Great stuff here. I achieved undetected at 4 weeks and at eot on solv/rib/inter as you know.. Are you hearing any relapse stories jere



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John non-responder

Undetected at week 2 on solvaldi/rib/interferon: stayed through week 12 but virus came back as soon as I stopped. on Harvoni and ribravirin 24 weeks undetected after two. 8/2/15 12 week EOT UNDETECTED! SVR

1991-2015 RIP



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Hi Kit,

After initial infection with the HCV, the immune system produces antibodies, but these may take 2-3 months to appear. Even patients who spontaneously clear the virus will continue to have antibodies.

After SVR, antibodies remain, probably forever. There is some evidence that the titre of antibody may reduce over time.

The virus has a core of a single strand of RNA, surrounded by a protective shell of protein and enclosed in a fatty capsule. To replicate, the virus must enter a cell ( usually a liver cell)- this is a complex process but eventually the capsule and shell are gone, and the HepC RNA is incorporated into the host cell. Then it can replicate. After replication, the virions receive a shell and capsule from the host cell before being released back into the bloodstream.

So, you never have free viral RNA in the blood. It is only contained in the virus.

As I've said before, a tiny amount of virus will remain after SVR. It cannot be Detected by normal PCR tests. It will be replicating in liver, blood monocytes or some other tissue. The immune system has learned how to cope with this. If the immune system fails for some reason, then we may have a relapse. Fortunately this is very rare. Hope this explains your question.



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Geno 1b, IL28B CT, x3 prior relapser, ex-cirrhotic, 74 yo, did 48 weeks with Victrelis/Peg./Riba. VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30 and 48 weeks. EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR! Still Undet. at EOT +4 years

Malcolm



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Thank you mallani.

There are more questions appear. If Sovaldi demolishing most of all RNA within therapy, where from then RNA coming after, it is said that parts of RNA are still marked even after 8 years after therapy? And why anti-bodies still exist? So, if there some RNA left marked in blood, why it is not replicating?



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wow, that is some heavy duty information there, thanks

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62 yearoldfemale 1a, f1-2, had virus 40 years STARTED HARVONI for 8 weeks 11/19/14, relapsed one month after tx ended in 1/15. Fibrosis level was only .5 after fibroscan 12/15. Began treatment with Mavyret on January 20, 2018 for 16 weeks! Ending May 12.



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Hi Mallani, SoI'm thinking youmean the NS3/4 protease inhibitors should be forgottenif sovaldi/olysio failure due to possible mutaions from theOlysio?

But what I was wondering about was the viability of using Sovaldi, a NS5bfor retreatment with the NS5A analogueLedipasvir that is currently in the Ion 3 trial. My hepatologist said that Sovaldi has a high resistance barrier and low incidence of cross resistance and should be able to be usedagain toretreat if necessary alongwitha differentDAA (ie NS5a, not another NS3/4proteas inhib).

Thanks again for the informative post. Could you possiblytell me which month Journal of Hepatology the article is in, Feb or March? Thanks so much, Maddie.



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Dx. 2005-liver bx.:stg 2/gr 1. at that time-GT 1a multiple transfusions in 1981. Started Sovaldi and Olysio 1/16/14 (No prior treatments)Q80K present. UND week 4,8 and at EOT. UND at wk 4EOT, Und at wk 8EOT SVR 12!!!..SVR 24 :-)



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Hi Gator Man,

I've done a post on RAV's. Hopefully, no members will relapse on the Sovaldi/Olysio combo. If they do, time to forget the antiprotease and wait for a NS-5A inhibitor. Cheers.



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Geno 1b, IL28B CT, x3 prior relapser, ex-cirrhotic, 74 yo, did 48 weeks with Victrelis/Peg./Riba. VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30 and 48 weeks. EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR! Still Undet. at EOT +4 years

Malcolm



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Hiya and Welcome, Shannon! It would help greatly if you could introduce yourself in the "New Members" section of the forum. More members will be likely to cross your path that way. ;) If you wish, you could include in your signature any other details such as genotype, stage of liver disease, viral load, treatment history etc.

You are not a lone soldier. There are plenty of 1a's having failed treatment. Current guidelines for non-interferon based therapies can be found here: http://www.hcvguidelines.org/sites/default/files/full_report.pdf

Clicking on item #26 in the table of contents will take you to an Initial Treatment Box, which will give you an idea of what is available for the various genotypes using the newly approved meds. There is an alternative 24 week option for geno 1 that does not include Olysio, should that continue to be a problem for you. Also, there is new stuff on the way...

http://hepatitiscnewdrugs.blogspot.com/2014/02/gilead-files-for-us-approvalledipasvirs.html

This is all physician-dependent, of course. Talk to your doc about it. You do have options.

Best of luck to you,

wayne



-- Edited by OldenSlow on Thursday 27th of February 2014 07:17:32 PM

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66 y/o male - Geno 1b - F4 cirrhotic dx 2001 - 16 wk treatment w/ Sovaldi/Olysio/Riba - Und @ EOT+24 SVR



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Hi Birdysmom, I actually had no hand in the approval process. My hepatologist, his nurse and specialty pharmacy all worked on it for me. I actually didn't even know that they had requested approval from my insurance until after it was approved! My doc felt I needed to treat now since the stage 2 bx result was 9 years ago. He seems pretty convinced that I can retreat with sovaldiif necessary. Hope he's right if it comes to that.



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Dx. 2005-liver bx.:stg 2/gr 1. at that time-GT 1a multiple transfusions in 1981. Started Sovaldi and Olysio 1/16/14 (No prior treatments)Q80K present. UND week 4,8 and at EOT. UND at wk 4EOT, Und at wk 8EOT SVR 12!!!..SVR 24 :-)



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maddie wrote:

... He said Sovaldi retreatment should not be a problem because of the high resistanceit has against the virus as long as given with another DAA. I just hope that I never have to test that issue.


Thanks Mallani for a concise explanation of how Sovaldi blocks HCV replication. So the risk of viral resistance with re-treatment is dependent solely on the protease inhibitor that is used conjointly with Sovaldi? This has been a concern for several of us who had (have) the possibility of losing insurance coverage for Olysio mid-tx.



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Geno 1b, compensated cirrhotic, 54 yo, prior null responder.Pre tx VL approx 595,000,tx with Sovaldi/Olysio (no Riba)started1/8/14. VL 40 @ 2 weeks, UND @ 4 weeks. Still UND @ EOT + 1 year.

Gator Man SVR12, Dragon 0, Final Score.



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Maddie,

How did you get the two drugs approved. Looks like you are similar to me?



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Birdysmom will beat this HEP C!


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confuse Hi everyone. Brand new to the group. Is there anyone out there with Genotype 1a that is not treatment Naive? I feel like a lone soldier. did 48 weeks of Interferon, Ribavarin and Victrelis and failed in the last week. Now waiting on appeal to see if insurance will take both Sovaldi and Olysio. They approved Sovaldi but are denied the Olysio. I cannot go through anymore Riba Interferon. It nearly killed me.



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Birdysmom will beat this HEP C!


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maddie wrote:

... I just hope that I never have to test that issue.


Ditto ;) I was going to pose the same question to my doc, who I see tomorrow. Thanks for the reminder!



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66 y/o male - Geno 1b - F4 cirrhotic dx 2001 - 16 wk treatment w/ Sovaldi/Olysio/Riba - Und @ EOT+24 SVR



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Very interesting, Mallani. Now I wonder if Sovaldi will work with ledipasvir to clear the virus and reach svr if God forbid a relapse occurs after treatmentwith Sovaldi and Olysio. I did ask this question of my hepatologist since I have q80k polymorphism.He said Sovaldi retreatment should not be a problem because of the high resistanceit has against the virus as long as given with another DAA. I just hope that I never have to test that issue.

Thanks for the great article.



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Dx. 2005-liver bx.:stg 2/gr 1. at that time-GT 1a multiple transfusions in 1981. Started Sovaldi and Olysio 1/16/14 (No prior treatments)Q80K present. UND week 4,8 and at EOT. UND at wk 4EOT, Und at wk 8EOT SVR 12!!!..SVR 24 :-)



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@Lisa, the young chemist guy (Jeremy Clark) who created this remarkable molecule (PSI-7977) is without a job for quite a while and pretty much ruined professionally, while his ex-boss is some 400mil $ richer from transaction (Pharmasset<Gilead). He tried to fight in the court for his rights, but lawyers team from Mr.Schinazi (his ex boss) destroyed him easily "noresidence jurisdiction" (http://www.gpo.gov/fdsys/pkg/USCOURTS-alnd-5_10-cv-01487/pdf/USCOURTS-alnd-5_10-cv-01487-0.pdf)...

i really do wish this man gets some credit, but then again i bet there are many similar stories like his :(







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GT 3 dg. 08-2012 / FibroScan: 5 kPa F1 / FibroTest: F0-1 A1 / SoC TX: PegInt 120mcg+Riba 1000mg UND from w8 relapse EOT+4w
01-2016 Sof+Dac+Riba UND from w8, SVR24!




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This is a great post, thanks Malcolm, and you`ve explained it very clearly.

I`m making it a `Sticky` post so it doesn`t get lost, this is such useful information!



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Jill

(68 yo, lives in UK)

Was Gen 3a,

24wks Peg/Riba, Sep 2010 - Mch 2011

UND @ Wk.4, UND @ EOT,

SVR Nov 2011 --> Still UND @ EOT + 4 yrs.



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Thanks for that, it seems that this drug with other combo's will be a winner. I wish the guy that created it would be awarded and recognised for a prize, he will save the life of millions!



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Genotype: 3b

VL.�over 15, 000 000

Failed TX 2014: Interferon/Riba.

Cured using Sof/Dak combination.

I can eat cake again! <3



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NEWS FLASH >>>>>>> SOFOSBUVIR PIERCES HCV ARMOR>>>>>A FATAL BLOW HAS BEEN DEALT>>>>>>>WE HAVE A WAY TO KILL THIS MONSTER

THANKS MALLANI, I GET IT NOW!! RC



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M-61 (3 Treatments)( SOF-RIBA 2014)(SOF-RIBA-PEG 2016)(HCC 2016) (LIVER TRANSPLANT 8-2017)(VOSEVI-RIBA 2017) On my way to SVR. SVR-12.3-13-18

HR


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Great post as always.. Still haven't gotten a concrete answer why I relapsed other than "I probably became resistant to Ledipasvir" Still trying to find out the definite answer but information isn't all that easy to come by.



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ION-3 Trial- Sofosbuvir/Ledipasvir 12 weeks.. UND 4 weeks, relapsed 12 week EOT.

3-4 on Ischank scale

Retreat ION-3 Trial- Sofosbuvir /Ledipasvir 24 weeks

GT-1 (1-31-14) Week 1 VL 62 -Week 4,8,12,16,20 UND EOT 7-18-14



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Definitely sticky-worthy. Thanks, Malcolm!



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66 y/o male - Geno 1b - F4 cirrhotic dx 2001 - 16 wk treatment w/ Sovaldi/Olysio/Riba - Und @ EOT+24 SVR



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cheers Malcolm, great and easy to undestand explanation :)



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GT 3 dg. 08-2012 / FibroScan: 5 kPa F1 / FibroTest: F0-1 A1 / SoC TX: PegInt 120mcg+Riba 1000mg UND from w8 relapse EOT+4w
01-2016 Sof+Dac+Riba UND from w8, SVR24!


Tig


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Thank you for the excellent explanation! I would like to recommend this be made a Sticky.

Tig

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Tig

61 yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 1-4 years!

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Hi all,

I haven't done a technical post for a while, and for some this may be of interest. I have been fascinated by Sovaldi (or PSI-7977, then GS-7977) for the last 2 years . Initial claims about it's action (subsequently often repeated by Gilead Sciences) made me question why it could not be used as monotherapy, and why the SVR rate was not 100% across all Genotypes. An article in the latest 'Hepatology' has explained the mode of action in more detail, together with reasons why some patients relapse. Sorry I can't give a link, as it's subscription only.

To understand, we need to revisit basic HCV structure. The HCV has a core of genetic material (RNA) surrounded by a protective sheath of protein, enclosed in a fatty capsule. The RNA is a single strand protein complex with NTR (Non-Translated Regions) at each end. The 5'NTR at one end, is the most highly conserved part of the virus, and from this, the 'target' used in PCR VL testing is obtained. The 'core' consists of an NTR at each end, with the central portion made up of a Structural and a Non-Structural (NS) element. These are made up of ~3,000 amino acids, and each has been named. We are only interested in the NS element. This is divided into 6 complex proteins. We may recognise the names- NS-2, NS-3, NS-4 A & B, NS-5 A & B. For Sovaldi we are only interested in the NS-5B complex.

NS-5B is the HCV RNA polymerase, responsible for the assembly of virions (inert viruses) from the structures cleaved by the proteases. It is shaped like a R hand, with finger, thumb and palm regions. The active site ( which is blocked by Sovaldi) is enclosed in the centre of the structure, and is highly conserved. This site is remarkably constant in all Genotypes, and was said to be present in all viral mutations. This is why Sovaldi was said to have a pan-genotype action, and be active against all known RAV's to other DAA's. This is why I had trouble understanding why Sovaldi could not be used as monotherapy. It seemed to good to be true.

So why can Sovaldi patients relapse or fail treatment? A very small percentage stop treatment due to side effects. The Prescribing Information has listed various drugs that interfere with Sovaldi absorption and/or action. Other drugs may be added in time. Resistant mutations are the obvious answer. Up to recently, the only resistant mutation discovered was called S282T. Gilead steadfastly said this was only found in one patient who relapsed. This mutation is a change in the 282 protein, and evidently the variant with the S,T variation, interferes with action of the Sovaldi tri-phosphate. It rapidly mutates back to S282S which is not a problem. It has been shown that this S282T mutation can only occur in Genotypes 1b, 2a & b, and 3a. So, if you don't have those Genotypes, you would assume you were safe. Now, new RAV's have been found. M289L in Geno 2a, L159F in Geno 1a, 2b and C316N in Geno 1b. These are said to 'interfere' with the action of Sovaldi and lessen it's effectiveness. Post-transplant patients treated with Sovaldi developed a RAV called V321A but only those with Geno 3a. So it seems that Sovaldi has a very high barrier to resistance, but resistant mutations can indeed develop. This is why the second antiviral is required as backup. Although Ribavirin is a good antiviral, we still don't know exactly how it works, and it has side effects. The addition of another new DAA will give the best results, so Olysio has been given it's chance. When Ledispavir or Daclatasvir are approved, this will be the combo of choice, and we should be approaching the 100% SVR goal..Thanks for listening!



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Geno 1b, IL28B CT, x3 prior relapser, ex-cirrhotic, 74 yo, did 48 weeks with Victrelis/Peg./Riba. VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30 and 48 weeks. EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR! Still Undet. at EOT +4 years

Malcolm

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