TOPIC: Slides From AASLD 2015

Here are the Clinical Care Options Official Conference Coverage: Clinical Impact of New Data From AASLD 2015.

As someone with a background in physics and mathematics,I look at many of these results as representing nothing
but a confusing statistical absurdity.
2 examples of many
The Ally 3+ results. of sof dac +/- riba
It would appear that if you have f3 fibrosis there is no advantage in extending treatment from 12 to 16 wks.
If you have cirrhosis there is a 2% dissadvantage in extending tx to 16 wks.
That is until you look at the numbers involved which are so small as to represent a statistical joke.
How can they call this a scientific study?
When you look at the European GT3 study of sof dac +/- riba
for the child pugh class A cirrhotics it is positively harmful (-15%) in adding riba to the tx.
These are just 2 examples of many I can see in these results.
The cohort numbers are to small to offer any useful and meaningful help.
How can any physician offer a tx regime,based on anything but personal evidence based guesswork on results like these?

Hi miko3,

What we should keep in mind with these slides is that they are intended to provide GIs and heptologists at the conference with the latest available trials results rather than being a means to decide treatment options.

The correct place to be looking for treatment advice is the EASL or IDSP recommendations as linked in the"Getting Treated" section on this site. Those contain a consolidated view of the best recommendations by genotype, liver condition, prior Tx experience taken from a larger database of trials and will have factored in more data recorded during the trial that we are not aware of in the slides. Things such as maybe the cirrhosis patients in one arm of a particular trial turned out to be more forgetful (or headstrong) making them less compliant to the dosage timing causing a biasing of results. Even then you will see that there is a scaling of the recommendations such as Grade A, Class 11 as to how much confidence should be placed in the recommendation.

As to the sample sizes of the dataset, I agree it is not ideal but there are a number of factors that can cause this such as:
- willingness to participate in a trial with a "new" medication
- availability of genotype groupings e.g. Gt2 is relatively easy to treat so less Tx experienced Gt2s around.
- availability of researchers and monitoring staff
- cost of trial (yes I know, but given limited dollars do you trial 1 or 2 new DAAs with thousands or multiple DAAs with 10s or 100s)

As a former trial participant I am very much aware of the massive amounts of data collected during these trials, both physical and psychological. I seemed to be constantly filling in forms, daily forms, weekly forms, monthly forms. What time did I take the tablets? the injections? (within 5 mins), What side effects today? How did I feel physically today? Emotionally? For the week? For the month? All cross referenced with further control questions. Blood tests, physical exams. That was for the 6 months of the trial then continued at a reduced pace as follow up for 18 mths. It exhausted me, goodness knows how the researchers felt! And at the end of the day that trial didn't prove up the Tx under test so went nowhere*. Oh, and I didn't end up clearing.
*But gradually all that data comes together in the EASL/IDSP recommendations.


I liked your recent post about real world reporting of results of treatment and hopefully someone is actually doing that diligently other than in the Doc's Redemption trials.

PS looking at your sig your treatment is going well too!

Gaj
I think this guys opening statement says it all.Its still" have a good guess ,and take your chances science.
In my own case the IDSP recommendations are as confusing and different as the EASL Guidlines.

Hi miko3,

I also like hard data and definitive answers so I can't really disagree with you. But as Nezam says, it is a rapidly changing field and the guidelines also need to take into account a number of different variables, so yes, it is a (hopefully) educated guess.
But this isn't all that atypical of a lot of medicine. How often do we hear of new advances that change the face of treatment whether through technology advances or just a better understanding of the human body and/or mind......and then look back and wonder at what we did previously?

I think Yoda sums it up well so when I was given the opportunity......To treat, I chose!

As did you.

Gaj
I will recount my own visit to a Specialist before I began tx\
I had not met him before.He was very friendly and polite.
Naturally the first thing I asked him was if he had anything against Generics.
He replied forcefully that he was all in favor of anything that could lead to a cure,he didn't care what it was.
I had carried in a sheaf of summaries of trials and recommendations collected over months with everything pertaining to me highlighted.
He looked at the pile with a smile.I could see what he was thinking."another smartarse" “what do you want to do",he said ”
I was a little taken aback,but gave him what I thought IMHO were my options.
“Right” he said “which one do you want to go for.
I Replied a little stunned.”This is not my field of expertise,I'm just a dumb layman on this subject,I was rather hoping for an expert opinion.”
He turned the open palms of his hand upwards and said,”All your options are good,take your pick”
Now this guy has quite a reputation,both as a Gastro and the field of Virology.He looks after many HIV patients.He had just come back from the Vienna conference,where the previously posted Video was recorded.
He went on to say that we are getting some stunning results from the new DAA's,but everything is made difficult by costs and the reluctance of drug companies to cooperate on combinations, and we just don't really know the optimal treatments.

The rest of the conversation reverted to mutual mountain bike riding experiences,but I left with the feeling I might just as well seek out a Voodoo Priestess to slaughter a chicken and examine the entrails.

I am aware that this conversation probably detracts from Doc Freemans originall posting so if a moderator want s to move it.okay.

In the words of Yoda...

Well, I'm not sure this discussion detracts from Dr James' post as I suspect he posted so we are aware of the latest information available to the experts while understanding that none of it is definitive at the moment. So we are just fleshing that out a bit here. But yeah if anyone wants to move it to a seperate area I'm comfortable with that.

Let me paint your meeting with your specialist in a slightly different light:

A new patient has just walked into the specialists consulting room and asked him his attitude to generics. The doctor has responded that he is fully supportive of anything that can restore his patient's health.
Said patient has a large pile of paperwork with him which the doctor notes and then smiles as he thinks "ah, here's a patient who is taking charge of their own health and has researched rather than expecting me to just cough up the answers". Respecting that autonomy but wanting to make sure that he doesn't have a voodoo follower on his hands, he has asked the patient what they think are their best options. The patient's responses have reassured him that there are no chicken entrails involved.

Now, at this point he could have leant across the desk, God like, and stabbed his finger down onto any one of the options and said "This Is The One You Need!" <cue suitable flashes of lightning and crashing of thunder>
But instead he respected your intelligence and was honest with you......the options you had chosen were all good ones which would be just as likely to work as each other and he wasn't going to try to pretend to you that there was enough evidence to favour one significantly over another.
I do suspect that if you had been less sure about generics, uninformed about your choices or just plain off track then his approach would have been different.

Though I understand why you could be uncomfortable with the outcome of the meeting based on the age old instilled beliefs we have that the medical profession must have all the answers.

Which goes to show how long that post took me to put together. Much more succinct response from the Doc and he didn't need an hour to write it.

Did I read part of that presentation correctly, i.e, that they were looking at the possibility of some of the virons (?terminology) developing a resistance to the new DAA's and therefore if these things developed a resistance, that the doctors would need to be careful which DAA's to re-treat with in order to overcome the newly developed resistance? (that's was one of my layman's fears that some holdouts would develop a resistance, hole up somewhere, and then burst out again with reinforcements)

Which brings me to one other dumb question: As I understand it the DAA's stop the viruses from replicating/reproducing, but I didn't think the DAA's KILLED off the ones already there, If that's correct, then what happens to the one's already there? Do they just die of old age and get flushed out, or do they eventually succumb to the body's own defenses and therefore the population goes to zero due to loss of the ability to repopulate themselves?

I read the answer to that somewhere, but don't remember where ...

Answer is they don't live very long and have to keep replicating ... don't remember the time frames though. If they can't replicate they die out.

What I think I'm seeing in these trials goes along with what the nurse at the Hobart clinic said when Chester and I were quizzing her ... our questions were basically along the line of "If it comes back just hit it again?" Just up the dosage?" etc. and she said yes, you'd basically just need to hit it harder for longer.

In the trials they are also throwing more types of meds at it, but it sure looks to me like time length is the main thing to eventually get it all in the tough cases.

To answer 2b's first question in laymans terms. Yes, one of the traits of the HCV virus is that as it replicates it creates lots mutations some of which are different enough in structure that the DAA can no longer lock on to the receptor parts on the virus that it would normally use to block replication. So you then have DAA resistant virions in you which sounds bad; the good news here is that like most mutations they tend to be weak in some way and that particularly applies to their ability to reproduce or in this case replicate. So they tend to die out naturally or your immune and garbage disposal systems cleans them up. The problem occurs when a mutation occurs that is resistant to a DAA and can replicate reasonably well. Then because Hep c replicates so fast you soon end up with an infection with some immunity to the DAA and also other DAAs that work on the same receptor. This immunity will apply to whichever receptor that particular DAA works on so to re-treat you need to preferably use a DAA that works on other receptors if available for the genotype or hit it longer and harder and/or add riba or all of the above. It isn't a huge problem but is the cause of some of those few percent who are non responders or relapsers.

Hope that makes sense.

The second answer is.....too bloody long! Or, I have no idea so hope someone else has an answer.

"If it comes back just hit it again?" Just up the dosage?" etc. and she said yes, you'd basically just need to hit it harder for longer"

Thats only an option for a very select group of people.If a health service is paying,forget it.Even with generics it would be pushing the financial limits for a lot of people.
With a 24 wk tx length is there any evidence of the efficacy of changing regimes at the 12 or 16 wk mark?It is probably something that the drug companies would resist trialling for commercial reasons.