TOPIC: Highly detailed article on DAA resistance

freepdfhosting.com/b3d39c5e48.pdf

That's very complex for a bear of little brain like me

Thanks for posting Doc. Will download and read with interest!

Thanks again Dr Freeman for another in depth article. I'll have to read that one in the morning when my brain is firing on all cylinders!

I've been reading so far 1/3rd from this interesting, yet challenging material. (Doctors use a complicated language , no ofense dr. F)

It is like talking about a microuniverse (well in fact it is like this) with different rules and some science fiction stuff... A Star Wars, with rebels and clones.... I look forward to read the rest of the material and see who in the end will have "the force".

Cheers,
RHF

Thanks Dr Freeman, wow that is a lot of info to attempt to digest. Could be a problem for the likes of me with a particularly unscientific mind but will try to go through it all slowly. It is like a foreign language of its own! Just gleaning a little of it I hope it will further assist the specialist to pin point the correct treatment for each individual but it does look unbelievably complex!!!!!! Guess there is always more and more to learn about this tiny yet vicious virus!

Just finished reading the article .

I've reached the point to have a better understanding about why some patients do relapse and what these Resistant Variants are.
From the perspective "risk of developing Resistant Variants", I would say it is quite tricky to treat HCV for 8 weeks only (as Gilead is doing for non-experienced patients). I would not "play" with the duration of the treatment just for saving some money. Since the generic drugs are much much cheaper, it seems to be a non-sense to treat for a shorter duration just to save some dollars.

Also interesting to see that NS5A inhibitor-resistant viruses may persist for years, potentially impairing the results of re-treatment.... This should be deeper thought and discussed with the doctor in case of a relapse, as just buying the same medicines for another course of treatment for "12/24 weeks" might not be enough.

......

I read this whilst resting after colonoscopy last week and I so had plenty of hours to read it a couple of times.

All I can say from my heart is that I am damned lucky to have responded to the Sof/led straight up and that the old tx didn't stuff that up as well as some other parts of my little world.

Also appreciate the posts which included graphs on generic data in another recent thread. I do like stats and data and research, weirdly! Doesn't necessarily fit my profile as a trained classical musician. Mind you we did stats at uni!

Thankyou Dr. for this link.
To those who are still finding avenues with the new meds and combos I am thinking of you all and wish all a positive outcome in treatment
A

My personal view is that the thinking on resistance is wooly.

HCV is a quasi-species meaning that it mutates pretty rapidly. Each replication cycle brings the a possibility of roughly 1:10,000 of creating a mutant. Once this is created it exists. If it can't reproduce it dies. If it can, and it is resistant then it will take it's place in the population according to its fitness. If it is very fit we may be able to see and measure it (fit means makes lots of kids fast), but if it is less fit we won't be able to see and measure it.

THE FACT THAT WE CAN'T SEE ENOUGH TO MEASURE DOES NOT MEAN ITS NOT THERE!

The key point is the the CREATION of resistance requires replication, so it happens BEFORE treatment starts unless we don't get good viral suppression and replication continues.

When we treat we kill of the easy to kill virus and suppress almost all replication. With no replication there is no opportunity for a mutation to form.

Virus that already existed, that is resistant will not be killed efficiently, although it's growth will not be helped by the drugs. Nevertheless it will survive and when we remove the drugs it grows back. Now we can see it and measure it, but it was not created by treatment. It existed before we started.

In HIV we know that resistance occurs in the context of ongoing replication.

www.ncbi.nlm.nih.gov/pubmed/19048205

HIV is an unstable RNA virus like HCV so the lessons there apply here. And the lesson for retreatment should be hit the virus as hard as possible to suppress replication (ie add Riba and or a 3rd DAA) so that an already partly resistant virus can not add more resistance mutations to the same strand of RNA.

Anyway those are my thoughts. I expect conventional wisdom to catch up in due course. As you can see from the abstract above this idea is known, it just does not seem to get talked about much in HCV circles.

The reason for waiting to retreat is, to me, not to wait for RAVs to fall to levels we can't measure. They will still be there, probably forever. It is to wait for access to more powerful drugs, or preferably extra agents

The advantage of a 3rd agent

RAVs deliver a 10x 100x or even 1000x resistance to drugs. What this means is that the EC50 (Effective Concentration to kill 50%) of a better drug needs to be 10x + to make a real difference. Let's look at GT3 EC50:




We can see for example that Velpatasvir needs 20 pM to get to EC50 and Daclatasvir needs 530 pM so VEL is 26.5x more potent than Dac. However this is in a test tube. 75% of VEL is excreted unchanged in faeces so it is possible it's not absorbed (the literature speculates on this). That might well reduce the 26.5x to more like 7x. Anyway if you look at the potencies you can see that even for the best in class ABT-530 (that you can't get) it is at best 250x better than DCV. This is good, but still leaves the 1000x resistance variants as problem children.

Ok, now consider a 3rd good drug.

If the probability of creating 1 resistant variant is 1:1000 (it's lower than this but let's use this) the probability of getting 2 resistance variants in the same bit of RNA is 1:1000 x 1:1000 which is 1:1,000,000. Now if we add a 3rd agent the virus now needs to have 3 resistance sites in the same strand of RNA and the chances of getting that are 1:1000 x 1:1000 x 1:1000 or 1 in a billion. Notice that the extra drug adds what you might call 1000 units of power, whereas even the best most potent new drug add 250x

Conclusion: 3 drugs beats 2 drugs.

Validation: In HIV we start with 1 drug: AZT and it works but resistance is rapid. Then we get ddI and ddC

www.ncbi.nlm.nih.gov/pubmed/19048205

And we find that 2 drugs beats 1 drug. And nowadays with lots of agents HAART (Highly Active Antiretroviral Therapy) with 3 or even 4 agents is the standard of care.

HCV is an RNA based virus like HIV. Yes it does not have a reverse transcriptase but the core genome is RNA so lessons from HIV are broadly applicable.

Validation2: Viekira-pak is a very effective existing poly target treatment, and as the QUARTZ-1 trial shows adding Sofosbuvir to it makes it outstanding. C-SWIFT is adding SOF to Zepatier's NS3/4A + NS5A combination.

www.aidsmap.com/Treatment-intensificatio...atment/page/3014995/

Thanks Doc!
I am not a medical person and lots of this information just does my head in,but I think understand the big picture.
Please correct me if I am wrong, but in my case say if I test positive again (and the chance of re-infection is pretty damn tiny), there should be enough drugs to treat (i.e. destroy without mercy) the mutants that were not destroyed in the first place.
Thanks

James-Freeman-facebook wrote:
Hello dr. Freeman,

thank you for this answer.
Indeed, thinking on resistance might be wooly, however the "(too much) thinking on these resistants" does exist in my case.
During my IFN+RBV treatment my body could not clear the virus in the first 3 months of treatment (was able to clear it within the first 6 months of treatment). This makes me think that I was having perhaps some of these "resistant" viruses ..... Yet now with the SOF+LED treatment, my body was able to clear the virus in less than 4 weeks. So hopefully these "resistant" viruses were killed too.
At this stage however the thinking (at least my thinking) is easily slipping from the science behind the drugs to the fear of "what if ... one resistant virus managed to survive?", which is a different perspective . Well, 1 month + 1 week left till I will know the answer .

Cheers,
RHF

James-Freeman-facebook wrote:
Thanks dr. Freeman for more info!
I have a question, please. What does nM respectively pM unit of measure stands for? M is mol of substance, chemistry?
However, Ledipasvir versus Daclatasvir ... I was very lucky to be cured with Ledipasvir.

It's great that there are already solutions for those who have not succeeded yet, Velpatasvir and Viekira-pak.
But the results for ABT-493 and ABT-530 are even more spectacular.

www.ncbi.nlm.nih.gov/pubmed/27456384

Good luck, good health and only UND to everyone!

Hi isaing4,

I believe the units of measure are nano-Mol and pico-Mol.

But note that chart is only for genotype 3a which is why Ledipasvir looks so bad in comparison and that is why it isn't used for 3a. Ledipasvir would look much better on charts for 1a or 1b and works fine there as you've proved.

Hi Gaj,

You are right, chart for GT3 where Ledipasvir is x1000 less effective compared with Daclatasvir!

Tiny quantity of active substance
1 Mol = 1 M = 6.02 x 10²³ molecules

and in the chart are nM = 10^-9 or pM = 10^-12

Thanks for the explanation!