emo How long to wait before retreatment

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5 years 11 months ago #19522

Hello dr. Freeman,

Thank you for this information.
Shall the same thinking apply for a person that reaches SVR12, but afterwards is again diagnosed with HCV?

Regards,
RHF


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5 years 10 months ago #20304

not heard of someone getting SVR 12 and then relapsing, please enlighten me if this has happened


Treatment naive
F 3/4
Genotype 1 a & b
V/L 17 MILLION
Started Harvoni 11th Dec 2015 for 12 weeks
4 weeks VL UND
6 WEEKS ALT 32, AST 34
EOT 03/03 2016 ! UND
ALT 34, AST 26
04.04.2016 SVR 4
26.05.2016 SVR 12
16.08.2016 SVR 24
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5 years 10 months ago #20305

not heard of someone getting SVR 12 and then relapsing, please enlighten me if this has happened

There is one patient here who got SVR12 and relapsed.

fixhepc.com/forum/viral-load-and-svr/120...-detected-again.html

It is really rare, under 5%, to relapse between SVR4 and SVR12.

It is extremely rare, under 1%, to relapse from SVR12 to SVR24

But sadly it is possible.

Mathematically it looks like this:

For the about the first 2 weeks post treatment you still have adequate levels of drug in your system to suppress most virus.

By 4 weeks you have been on your own for a good 2 weeks so any residual virus, below the level of detection, starts to multiply and usually we can find it by SVR4 - liver functions also get bad almost as quickly as they got good.

Later relapses probably represent relatively more unfit mutants. Mutation carries a price - slower replication. The wild type virus dominates in people because it is the best reproducer, so it out competes the mutants.

The growth curve is exponential, 2 4 8 16 32 64 per unit time so if we start from a really low load it takes time to get to a high enough level to measure.

Which brings us to the "how long to wait question" - being out competed does not necessarily mean disappear. Just because we can't measure it does not mean it's not there. Relapse after UND is proof that our tests are not sensitive enough.

With HIV resistance relates to rate of viral duplication. Provided we get rapid suppression there is very little capacity for mutation. Existing RAV mutations can persist, but new ones have limited opportunity to be created.


YMMV
Last Edit: 5 years 10 months ago by DrJames.
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5 years 10 months ago #20310

Dr Freeman, I have been wondering about the potential for patients who do not achieve SVR to stay on current generation DAAs until newer more effective regimens come along.

If HIV meds can keep the ravages of that virus at bay for HIV patients, would a similar approach for HCV patients be an option?


Failed Interferon 96', G1a, VL = 9 - 5.5 Million, F3/A3, AST 111, ALT 190, Generic DAA treatment Sof/Led (Mylan - India MYHEP LVIR) - 8 June, 2016
2 Week Results 20 June, 2016 AST 19, ALT 32
4 Week Results 06 July, 2016 AST 22, ALT 30, VL = 35
6 Week Results 20, July 2016 VL only = HCV RNA Detected, Non-Quantifiable <15
8 Week Results 04 August 2016, Labs, LFTs Normal, VL = UND
12 Week Results 31 August, 2016 LFTs Normal, VL = UND
EOT + 4 Weeks, LFTs Normal, VL = UND, "SVR4"
SVR12, 21 Nov 2016. CURED!!!
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5 years 10 months ago #20313

Yes Doc I saw that but none with genotype 1 A or B. I have not seen that on any site.


Treatment naive
F 3/4
Genotype 1 a & b
V/L 17 MILLION
Started Harvoni 11th Dec 2015 for 12 weeks
4 weeks VL UND
6 WEEKS ALT 32, AST 34
EOT 03/03 2016 ! UND
ALT 34, AST 26
04.04.2016 SVR 4
26.05.2016 SVR 12
16.08.2016 SVR 24
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5 years 10 months ago #20327

James-Freeman-facebook wrote:

not heard of someone getting SVR 12 and then relapsing, please enlighten me if this has happened

There is one patient here who got SVR12 and relapsed.

fixhepc.com/forum/viral-load-and-svr/120...-detected-again.html

It is really rare, under 5%, to relapse between SVR4 and SVR12.

It is extremely rare, under 1%, to relapse from SVR12 to SVR24

But sadly it is possible.

Mathematically it looks like this:

For the about the first 2 weeks post treatment you still have adequate levels of drug in your system to suppress most virus.

By 4 weeks you have been on your own for a good 2 weeks so any residual virus, below the level of detection, starts to multiply and usually we can find it by SVR4 - liver functions also get bad almost as quickly as they got good.

Later relapses probably represent relatively more unfit mutants. Mutation carries a price - slower replication. The wild type virus dominates in people because it is the best reproducer, so it out competes the mutants.

The growth curve is exponential, 2 4 8 16 32 64 per unit time so if we start from a really low load it takes time to get to a high enough level to measure.

Which brings us to the "how long to wait question" - being out competed does not necessarily mean disappear. Just because we can't measure it does not mean it's not there. Relapse after UND is proof that our tests are not sensitive enough.

With HIV resistance relates to rate of viral duplication. Provided we get rapid suppression there is very little capacity for mutation. Existing RAV mutations can persist, but new ones have limited opportunity to be created.

I think Jean Marc probably didn't do SVR12 VL test.

He only tested for SVR24 VL test after EOT and found that he relapsed.

Quite sad for him.

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5 years 10 months ago #20328

fitz wrote:

Dr Freeman, I have been wondering about the potential for patients who do not achieve SVR to stay on current generation DAAs until newer more effective regimens come along.

If HIV meds can keep the ravages of that virus at bay for HIV patients, would a similar approach for HCV patients be an option?

Good question!

But would there be resistance e.g. worst case is sofosbuvir resistance at position S282T, then it will definitely affect future treatments as sofosbuvir is still the backbone for HCV treatment/retreatment

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5 years 10 months ago #20331

Dr Freeman, I have been wondering about the potential for patients who do not achieve SVR to stay on current generation DAAs until newer more effective regimens come along.

It is certainly possible. With Hep B and HIV - where long term treatment is normal we do see resistance emerge in some patients.

Entecavir monotherapy (one drug only) seems to work happily for years, unlike lamivudine where resistance happens faster.

Lesson 1 - better drugs work better for longer

Lesson 2 - montherapy requires only a mono mutation and then we have a "Houston I think we have a problem" RAV (Resistance Associated Variant)

With HIV monotherapy saw more rapid development of resistance. This almost certainly relates to the fact that HIV is based on single stranded RNA, which is genetically unstable, but HBV is based on double stranded DNA which is inherently much more genetically stable.

Lesson 3 - with RNA viruses mutations happen faster, so monotherapy is a relatively bad idea

With HIV the appearance of resistance is less rapid if we get really good viral supression ie if it ain't duplicating, it ain't mutating (actually I expect the weaker mutants probably get a free ride piggy back off the more fit virus because a virus, during duplication, is really just a sea of chemical floating around in proximity, so has no way to tell if (say) this NS5B came from Arthur or Martha)

Lesson 4 - in patients who rapidly become UND there is very little opportunity for mutations and breakthrough

With drugs like tenofovir (at least in the current TDF form) there are long term issues (bones and kidneys) and for drugs in general there are virtually none with no unwanted side effects. Sofosbuvir has not been used long term in people so we really don't know what the long term impacts might be.

Lesson 5 - as soon as you depart markedly from the trials you are into the area of human experimentation with you as the participant.

Viekira pac is the combination of an NS3/4A, NS5A and weaker than Sofosbuvir NS5B and needs both a booster (that inhibits metabolism of one bit) and Ribavirin to work in GT1a, but even though it might be viewed as 4 weaker drugs mixed into a chemical soup, the overall results are as good as Harvoni.

HAART (Highly Active Anti Retroviral Therapy) for HIV uses combinations of 3 or 4 drugs and the evidence is that doing this is capable of supressing HIV more or less indefinitely.

Lesson 6 - 1+1 might equal 2 but 1+1+1 > 3 and the experience with HIV is that 3-4 drugs is better than 2 so you probably don't just want to do Sofosbuvir+Daclatasvir (which is the rational economy option), but should also be looking at either an NS3/4 or something experimental like chlorcyclizine to get a 3rd agent working for you

DAAs only get out of Phase 2 at the end of 2011, so there has only be 4 years or scale use, and really it's more like 3.

Lesson 7 - if you can wait for retreatment it's not a bad option. There will always be better drugs around the corner and other people can be the guinea pigs. If you can't wait - F4, psychological then I would be chasing 3D (3 drug treatment) or failing that Sof+Vel which is the best 2D regimen available now. Zepatier + Sof, V-pac + Sof look good if you can get the branded stuff on insurance and then add Sof generic, but I would still be going for cure.

And as a last thought, I do know of a couple of patients doing long term DAAs because they were so sick when they started they don't want to risk stopping. So wait if that's reasonable, go hard on retreatment if it's not, buy yes you can go long term.


YMMV
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5 years 10 months ago #20334

Hi Dr James,

What causes the mutants?

Are they caused by interferon treatment, or is it just what happens?

I thought that HCV mutated quickly anyway,and that's what made it so hard to treat.

Regarding as-yet-unknown long term effects of Sofosvubir, well, I have a reasonable idea of what would have happened to me if I hadn't had it. Shortened life expectancy (accelerated ageing) was the absolute best case scenario. Right now my quality of life is so much better than it was, so DAA treatment is a no brainer.


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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5 years 10 months ago #20338

beaches said: "I thought that HCV mutated quickly anyway,and that's what made it so hard to treat."

Yes. Here is a good read on mutants and resistance that Dr James wrote last year.

fixhepc.com/forum/resistance/164-resista...ms.html?limitstart=0

To answer Enkel's question at the end, Sofosbuvir has a high barrier to resistance. It can happen but is uncommon.


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: 5 years 10 months ago by Gaj.
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5 years 10 months ago #20339

Very interesting thread!

Tweakmax you wrote : " But would there be resistance e.g. worst case is sofosbuvir resistance at position S282T, then it will definitely affect future treatments as sofosbuvir is still the backbone for HCV treatment/retreatment
" .

Does it mean that longer treatments with sofosbuvir may cause the Hep C virus to become resistant to it? What comes to mind is when treating G1b - no cirrhosis - tx naive - low VL it would be the ideal to treat it with 8 weeks instead of 12 weeks following Gilead's guidelines. Because if there is a relapse - and 5 % will relapse anyway no matter how well patients follow any specific tx (it is a matter of statistics) there is smaller chance to become resistant to sofosbuvir on a 8 week tx than on a 12 week tx. Right?


Blood transfusion in 1992 - Diagnosed in 2007
Tx naive -G1b - F1
VL 2.270.000
ALT 40
Start tx June 4th/2016 with DAAs - Sof/Led from India
Bloods on two weeks of tx (June 18th)
AST 17 - ALT 10 - GGT 19
Virus UND
Bloods on six weeks of tx (July 16th)
AST 17 - ALT 8 - GGT 12
Virus UND
EOT on August 8th (did 9 weeks and 3 days)

SVR 4 Virus UND (September 7th)
AST 13 - ALT 5

SVR 14 Virus UND (November 12th)
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5 years 10 months ago #20340

Meg wrote:

Very interesting thread!

Tweakmax you wrote : " But would there be resistance e.g. worst case is sofosbuvir resistance at position S282T, then it will definitely affect future treatments as sofosbuvir is still the backbone for HCV treatment/retreatment
" .

Does it mean that longer treatments with sofosbuvir may cause the Hep C virus to become resistant to it? What comes to mind is when treating G1b - no cirrhosis - tx naive - low VL it would be the ideal to treat it with 8 weeks instead of 12 weeks following Gilead's guidelines. Because if there is a relapse - and 5 % will relapse anyway no matter how well patients follow any specific tx (it is a matter of statistics) there is smaller chance to become resistant to sofosbuvir on a 8 week tx than on a 12 week tx. Right?

Must ask the doc haha

What I know is, those on a 8 week tx, if relapsed, have a good chance of curing if do the tx longer the second round!

If I were u, I will just do the normal 12 weeks. 8 weeks is too risky really. But it is your personal choice ;)

Last Edit: 5 years 10 months ago by tweakmax.
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5 years 10 months ago #20362

Hi Meg,

I'm not an expert but I suspect the answer to your question is basically no and the main reason for shorter treatment is economic (see the second half of post#797 of this link fixhepc.com/forum/resistance/164-resista...tml?limitstart=0#797 ) plus a small desire to reduce length of exposure which is a worthy aim with any drug as long as the Tx is effective.

We need to remember that we can't be completely certain before treatment how much fibrosis and other liver damage is present in a patient. Also viral load levels are based on how much RNA can be detected in serum, they do not reflect how many hepatocytes are infected. So when Gilead say that 8 weeks harvoni Tx is suitable for low fibrosis, low viral load 1b patients they are really saying "on average to achieve an acceptable SVR rate".

Also the 95% SVR rate you talk about for 8 weeks harvoni Tx will actually increase to something like 99% if 1b patients are given 12 weeks Tx.

We know that failing treatment is often an indicator of some form of resistance, that is why we repeat Tx with a longer, stronger dose or different drug the next time. So presumably the shorter 8 week Tx results in increased risk of resistance developing compared with longer treatment for the maybe 4% or so extra patients who fail on shorter Tx.

As far as Sofosbuvir S282T resistance goes, it is extremely rare both at baseline and in those who develop viral failure per below quote and is not very good at replicating if it does occur.

In another recent pooled analysis of phase 2 and 3 studies where sofosbuvir based regimen was administered, no S282T variant was detected at baseline. Emergence of this variant was infrequent (1%) in subjects who had virlogical failure. S282T levels declined on average by four fold within two weeks of follow up period confirming low replication fitness of this variant [61].

www.ncbi.nlm.nih.gov/pmc/articles/PMC4690891/

So in most cases any resistance that develops in those who don't reach SVR during standard Tx will be to something other than Sofosbuvir and that takes us back to Dr James post at the top of the thread. :)


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: 5 years 10 months ago by Gaj.
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5 years 10 months ago #20363

Hi Gaj thank you so much for explaining how Sofosbuvir S282T resistance goes and how rare it is to become resistant to Sofosbuvir. Phew! I had no idea. Also have been biased all along by "the desire to reduce length of exposure which is a worthy aim with any drug as long as the Tx is effective" . I have missed this other very important piece of information too that "the 95% SVR rate we talk about for 8 weeks harvoni Tx will actually increase to something like 99% if 1b patients are given 12 weeks Tx." ! This is fantastic! :ohmy: As far as I had understood so far it was just about 1% increase. Lastly I had no idea either that a 8 week tx could in fact increase the risk of resistance comparing to a longer tx. Live and learn everyday!
Thanks again Gaj. #flower


Blood transfusion in 1992 - Diagnosed in 2007
Tx naive -G1b - F1
VL 2.270.000
ALT 40
Start tx June 4th/2016 with DAAs - Sof/Led from India
Bloods on two weeks of tx (June 18th)
AST 17 - ALT 10 - GGT 19
Virus UND
Bloods on six weeks of tx (July 16th)
AST 17 - ALT 8 - GGT 12
Virus UND
EOT on August 8th (did 9 weeks and 3 days)

SVR 4 Virus UND (September 7th)
AST 13 - ALT 5

SVR 14 Virus UND (November 12th)
Last Edit: 5 years 10 months ago by Meg.
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5 years 10 months ago #20366

Hi Meg,

After your comment about the percentages I went back and did some research as previously I took your comment of 95% for 8 weeks and compared that to the overall 12 week results for F0-1 1b's of 99% per the combined ION trials. Anyway, I found this report where comparing like for like in the ION 3 trial the difference was actually 2.3%. So not a huge difference but significant if you are one of those patients. A closer look shows ION 3 naive for just 1b as equal at 98% for both lengths. Personally I think I would be more comfortable with 12 weeks but maybe have a chat with Dr James?

(Note: in the ION-3 study of Harvoni—treatment of naïve patients treated for 8 or 12 weeks with Harvoni who had an HCV RNA (viral load) of less than 6 million IU/mL—the difference in cure rate was -2.3%)

hcvadvocate.org/hepatitis/factsheets_pdf/GT1_Harvoni.pdf

And the eight week treatment doesn't actually increase the risk of resistance as such. However doing 12 weeks Tx means there will be a better chance of SVR and if you SVR then you can't develop resistance.


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: 5 years 10 months ago by Gaj.
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