emo Prof Gane's remarks: implications for relapse

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6 years 4 months ago #10474

In his interview broadcast on NZ Radio Prof Gane referred to a possible risk of some generic ledipasvir emanating from China and Bangladesh not being effective against the hep c virus. There is another thread specifically devoted to the potential application of this to Twinvir – a Bangladeshi generic used by many members of this forum, including me.

(Link to radio broadcast: www.radionz.co.nz/national/programmes/ni...tis-c-buyers%27-club )

In elaborating this point Prof Gane makes another observation which may have potential implications for relapse and so be worthy of a separate thread. Prof Gane points out that the common combination to treat hep c comprises what he calls a “nuke” and what he calls an “NS5A”. The “NS5A” he is most concerned about is ledipasvir, basically because it is so difficult to make – requiring, he says, very sophisticated factories.

Two implications for responding to relapse may arise from Prof Gane's comments. The first implication applies generally to all DAA (direct-acting antiviral) treatment relapses. The second is specific to those relapses which may arise if Prof Gane's concerns about defective ledipasvir turn out to be well-founded and some people relapse as a result.

Taking first the implication of general application: Prof Gane argues that even if a generic does contain defective or substandard ledipasvir this will not be come apparent until after the course of treatment is ended. It will not be revealed by viral load tests during treatment because, he says, even where the NS5A is not working the “nuke” alone will be sufficient to suppress the virus to below the detectable limit as long as treatment continues, but not after. Only when treatment is finished will the defectiveness of the NS5A drug be revealed by allowing the virus to spring back.

What is the “nuke”? Well, by a process of exclusion, as it is not ledipasvir, and although Prof Gane does not expressly say so, he must mean sofosbuvir. If so, am I right in interpreting Prof Gane as saying that sofosbuvir taken alone, although not sufficient to achieve a cure, is capable, while treatment continues, but not beyond, of suppressing the virus to below detectable limits?

If this is true, could this be of potential help to those who are unlucky enough to relapse after DAA treatment? At the moment, I believe I am right in saying, there's some uncertainty as to how to treat DAA relapsers, mainly because it is assumed that relapsers will have developed at least some resistance to an NS5A inhibitor, whether that be ledipasvir or daclatasvir. As a consequence simply repeating the same course of treatment won't be an option.

So would an option for a relapser be to go on permanent, lifelong sofosbuvir in the same way that, for example, Type 1 diabetics take lifelong insulin, or HIV patients take lifelong viral suppression medication? It wouldn't provide a cure; but it would suppress the virus and thereby prevent any further damage to the liver, reducing the risk of going on to develop liver failure or HCC, as well as relieving the symptoms of hep c. There would be a continuing financial cost of buying the sofosbuvir but uncombined sofosbuvir is now one of the cheaper generic DAAs – a bottle of 28 can be obtained for US$275 and, if the Indian licensed generic manufacturers actually start to compete against one another, this price may fall further in the future. Many might regard that as a price worth paying to avoid liver failure or HCC.

What is more, in practice, it may not even have to be lifelong. A new generation of DAAs may eventually become available - perhaps as soon as in 3 to 4 years time. It may then only be necessary for a relapser to take sofobuvir as viral suppression until such time as a new treatment – or more precisely a generic version of the new treatment - becomes available

The second implication of Prof Gane's remarks is specific to those people who have taken generics with defective ledipasvir, and who relapse as a result. If the ledipasvir in their generic medicine was not in the right form to be effective against the virus would this mean that it also would not be effective to give rise to resistance? If so, there would be no NS5A inhibitor resistance and hence no obstacle to simply doing another course of genuine sofosbuvir/ledipasvir obtained from a more reliable source. But if the defective ledipasvir, while not effective enough to cure, is effective enough to give rise to resistance then the unfortunate patients will truly have had the worst of both worlds – no chance of a cure but developing NS5A resistance and so closing the option of re-treatment with authentic versions of the same drugs.

I would most welcome any comments on either of the above questions. I am genuinely worried.


Male Geno 1a F3-4 Tx Naive
Contracted early 1970s Diagnosed 2012
Started 12 wks TWINVIR (Sof/Led) on 15 Nov 2015
Pre-treatment VL 1.8 million
UND at 8 Dec 2015; UND at 12 Jan 2016
Ended 12 wks TWINVIR on 6 Feb 2016
9 Feb 2016 EOT VL test <15 PCR Negative
UND at 3 May 2016 SVR12

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6 years 4 months ago #10478

Phew Thurl, a lot of interesting points you make there, I don't know what to say , except try to
'keep positive' !

These meds can play with our minds, along with all the stress we've endured over time.
I think there's another discussion re this somewhere else and the genuine consensus was that Prof Gane was asking a legitimate question rather than stating a fact?


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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6 years 4 months ago #10481

Can we have a medical reply please ? Just for people's peace of mind? Not me but some may be bewildered
Many people here are using or have used Chinese sof/led
I'm concerned about people being alarmed unnecessarily and think that a doctor can assist anyone who reads this and is now terrified that their tx is of compromised quality (not likely!)
As I have had a gastro here chuck a hissy over Chinese vs Indian myself but I just dust that off with a quick paper trail and know that all FixHC meds are lab tested I do think that this requires a medical answer
Ganes comments seem to keep popping up and causing some alarm
I wouldn't want anyone to be freaking out whilst on tx or waiting for their SVR
Big love to all
Ariel


Gen 1a
Peg/inf/riba 2012(!) stop @ Wk 43 potassium low +issues (rlps week 4 post tx, VL120,000) scnds eg. adenomas.
pre sof/led VL 240,000 Fibsc F0
Day 25 <30
Day 32 UND
Week 10 UND
EOT UND ALT11AST17GGT19
SVR4 UND ALT10 AST16 GGT13
SVR8 UND ALT <9 AST16 GGT15
SVR12 UND ALT14 AST19 GGT12 Bili 5
EOT +18 ALT13 AST20 GGT9 Bili 5
EOT +21 ALT11AST15
Cured SVR12
Dysplasia Adenomas RemvdAug '16
SVR24 UND ALT11AST16
ColonoscopyClear Nov17
LumpectomyClear ‘18
LithotripsyCytoscopyBiopsy 4/18
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6 years 4 months ago #10490

Well,
We will begin to see if Mesochem is capable of producing high quality ledipasvir in a couple of months, won't we. What would you expect someone with his background to say? 'Making the DAAs is like making beer at home...."? No, he is a brilliant man, but a "company man". I wonder how many shares of Gilead he owns?
Edward J. Gane has received grants and done research for Gilead, served on the advisory boards of AbbVie, Boehringer Ingelheim, Gilead, Janssen, Novartis, Roche, Tibotec; has been a speaker for Gilead, Novartis, Roche, Tibotec; has patents with Gilead.
M


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forums.delphiforums.com/generichcvtx

G 1a F-1
Started tx 10/23/15 (Meso sof & led) ALT 48 AST 28 v/l 1.6 mil
11/17/15 4 wk lab ALT 17 AST 16 <15
11/18/15 Started Harvoni
12/16/15 8 wk lab ALT: 15 AST: 13 V/l UND
1/14/16 Fin. Tx
7/07/16 UND SVR 24
Last Edit: 6 years 4 months ago by mgalbrai.
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6 years 4 months ago #10491

Potential conflict of interest: "Prof. Gane advises and is on the speakers' bureau for Gilead and Novartis. He advises Merck, Idenix, and Achillion and is on the speakers' bureau for Janssen".

onlinelibrary.wiley.com/doi/10.1002/hep.27366/abstract

#JustSaying ;)


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
Last Edit: 6 years 4 months ago by LondonGirl. Reason: typo
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6 years 4 months ago #10492

Thankyou to Mike and LG
YES this scare mongering is most unsettling for tx-ers
Add to this division in attitudes and even random slaps on the knuckles at some of us in Oz who have just taken our lives into our own hands, already been burnt, already waited and read enough to get moving and become our own Messiah
Now the promised land is up in the holy of holy's here it's become even more factioned

And here is a song


Gen 1a
Peg/inf/riba 2012(!) stop @ Wk 43 potassium low +issues (rlps week 4 post tx, VL120,000) scnds eg. adenomas.
pre sof/led VL 240,000 Fibsc F0
Day 25 <30
Day 32 UND
Week 10 UND
EOT UND ALT11AST17GGT19
SVR4 UND ALT10 AST16 GGT13
SVR8 UND ALT <9 AST16 GGT15
SVR12 UND ALT14 AST19 GGT12 Bili 5
EOT +18 ALT13 AST20 GGT9 Bili 5
EOT +21 ALT11AST15
Cured SVR12
Dysplasia Adenomas RemvdAug '16
SVR24 UND ALT11AST16
ColonoscopyClear Nov17
LumpectomyClear ‘18
LithotripsyCytoscopyBiopsy 4/18
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6 years 4 months ago #10493

Thanks Thurl. Very interesting topic and scary at the same time.

Might be a 4 weeks of Indian generic at the end of tx can bring some reassurance. I'm 10 weeks tomorrow on Twinvir. Don't really want to add 4 weeks extra, but if that adds extra security then need to take it.

Panic time :(


Gen 1b, F1-F2. Naive.
Started Twinvir tx on 2 nd of December 2015 for 12 weeks.
Starting VL 400000, Alt 49/AST 44
1 week VL 29, ALT 44/AST 30.
4 weeks VL 12, ALT 33, Platelets 145, all other tests normal.
7 weeks VL Detected, ALT 28, all other normal
8 weeks UND, 12 week UND, 24 week SVR UND

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6 years 4 months ago #10496

Gane a brilliant scientist, but I don't think Dr. Freeman would be endorsing substandard ledipasvir, especially after testing it so thoroughly. Just because he said it is difficult to make, doesn't mean a Gilead licensed factory is the only one that can produce it properly. A lot of very, very complicated products can be successfully reverse engineered or manufactured if you you have the formula, expertise and equipment.
The Chinese are very, very good at that.
M


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forums.delphiforums.com/generichcvtx

G 1a F-1
Started tx 10/23/15 (Meso sof & led) ALT 48 AST 28 v/l 1.6 mil
11/17/15 4 wk lab ALT 17 AST 16 <15
11/18/15 Started Harvoni
12/16/15 8 wk lab ALT: 15 AST: 13 V/l UND
1/14/16 Fin. Tx
7/07/16 UND SVR 24
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6 years 4 months ago #10497

Jeez, instead of just speaking about possible complications, couldn't he just get some and test it? Like they did successfully here? I don't know why he isn't demonstrating some scientific evidence along with his "worries"...


HCV 35 yrs G1a F3 Tx naive
started Lesovir-C 15/12/2015
pre tx: VL 5,250,000 ALT 374 AST 208
FIBROSCORE 10.4

4 weeks tx ALT 29/ AST 33. VL < 12 UI/mL
8 weeks tx ALT 29/ AST 34. VL UND
4 weeks after tx UND. SVR4. ALT 24/AST 18
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6 years 4 months ago #10499

Bullshits from Gane,

If Ledipasvir wouldn't be absorbed we couldn't have RVR for one week in Twinvir.

Dr Gane may be right for other sources in china but not for twinvir and mesochem.


Male, Fibro F1. Geno 1b. ALT 67 before treatment Viral load 5 million. My huge viral load replicates in my nervous system as I suffer anxiety.
Started Twinvir 12/12/15.
Two weeks
ALT 17 at 2 weeks
Viral Load UND at 2 weeks
ALT 13.5 at 7 weeks EOT
ALT 10.5 at 15 weeks EOT
ALT 13 at 27 weeks EOT, VL UND, Cured
Last Edit: 6 years 4 months ago by Enkel.
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6 years 4 months ago #10500

The patients I have heard of that have failed most of them never got past 12 up too
week 12. Simply put they never made it to Undetected.

I don't know I buy the theory Sob alone is enough to get us all UD before EOT I think we would have seen
far higher fail rates before EOT so far we have not we have seen UD from week 2/4/6/8/10

Lastly, the one person I know who failed on Gilead Harvoni also never made it past 12 throughout the
12 weeks his Geno type also mutated post treatment. This individual is now on a new Combo and is UD from
week 2 is now UD at week 12 they expect him to succeed.

There is hope for the small percentage who fail.


Sob/Dac from Oct 29 2015
Geno 1b
Fiberscan 9.9 Pre treatment
Fiberscan 7.4 week 10
VL 1.3 million pre treatment
Week 2.5 VL 96
Week 5.5 VL 17
Week 10 VL UD
SVR 3 UD
SVR 16 UD
Cured:
All liver functions in normal ranges.
Last Edit: 6 years 4 months ago by Sirchinenge.
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6 years 4 months ago #10501

How can Sof reduce the virus so much in a short period of time?

I don't think it is possible.


Gen 1b, F1-F2. Naive.
Started Twinvir tx on 2 nd of December 2015 for 12 weeks.
Starting VL 400000, Alt 49/AST 44
1 week VL 29, ALT 44/AST 30.
4 weeks VL 12, ALT 33, Platelets 145, all other tests normal.
7 weeks VL Detected, ALT 28, all other normal
8 weeks UND, 12 week UND, 24 week SVR UND

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6 years 4 months ago #10506

S,

I dont think his geno mutated but he may have had two geno types (double infections)


Sof alone can not make someone UND within one week. His log kill is -4.5. Thats why Dr Freeman have tested RVR one week in order to be sure that both APIs are in paly.


Male, Fibro F1. Geno 1b. ALT 67 before treatment Viral load 5 million. My huge viral load replicates in my nervous system as I suffer anxiety.
Started Twinvir 12/12/15.
Two weeks
ALT 17 at 2 weeks
Viral Load UND at 2 weeks
ALT 13.5 at 7 weeks EOT
ALT 10.5 at 15 weeks EOT
ALT 13 at 27 weeks EOT, VL UND, Cured

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6 years 4 months ago #10507

Again, you must follow the money. Who is losing money because of Chinese APIs? Gilead Sciences. You can be sure Gilead has gotten its greedy hands on some Mesochem ledipasivir and tested it. It probably tested just fine or we would be seeing published results all over the web about the inferior Chinese knock off of its miracle cure.
No, it must have tested perfectly. The next best thing: Get someone who is close to "ground zero",(Australia), who maybe needed another big grant, who had some credentials, whose done a lot of work for them in the past/present, to make some off-handed remarks about product quality.
Like Dr. Freeman said: "Play the ball, not the man".
We know what kind of ball Gilead plays with.
M


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forums.delphiforums.com/generichcvtx

G 1a F-1
Started tx 10/23/15 (Meso sof & led) ALT 48 AST 28 v/l 1.6 mil
11/17/15 4 wk lab ALT 17 AST 16 <15
11/18/15 Started Harvoni
12/16/15 8 wk lab ALT: 15 AST: 13 V/l UND
1/14/16 Fin. Tx
7/07/16 UND SVR 24
Last Edit: 6 years 4 months ago by mgalbrai.
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6 years 4 months ago #10509

Blimey. Enkel, I know the man in question he was Geno type 4 Pre treatment
and post treatment he was Geno Type 3 his consultant same as mine explained it too me.

Geno type mutation is not unheard of!

Anyways back on topic:)

I honestly don't think anyone should get concerned about this I think we will all be fine.


Sob/Dac from Oct 29 2015
Geno 1b
Fiberscan 9.9 Pre treatment
Fiberscan 7.4 week 10
VL 1.3 million pre treatment
Week 2.5 VL 96
Week 5.5 VL 17
Week 10 VL UD
SVR 3 UD
SVR 16 UD
Cured:
All liver functions in normal ranges.
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