TOPIC:

Here is a report about Gilead's new Sofosbuvir + Valpatasvir combination.

www.jwatch.org/fw110863/2015/11/16/new-o...000101242515&jspc=EM

Now first it really just sounds like they are catching up to Sof+Dac but the bit I found interesting was this:

In a companion study, nearly 270 patients with HCV genotypes 1–6 (excluding 5) and decompensated cirrhosis were randomized to receive sofosbuvir-velpatasvir for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The rates of sustained virologic response at 12 weeks' post-treatment were 83%, 94%, and 86%, respectively. Rates of serious adverse events ranged from 16% to 19%.

Now 270 is not that large a number - only 90 in each arm and at that n the error is +/- 10% but the results for 12 weeks with Riba in the context of decompensated cirrhosis bear thinking about. That's a > 10% difference and 83% is like a 1 in 6 chance of failure, whereas 94% is a 1 in 17 chance of failure (or 11 more chances of success per failure).

If your doctor suggests Riba think really carefully if you want to run the risk of doing without it.

Maybe we should be adding 60 days of Ribovarin then Doc ?

Maybe add riba to the last two weeks of treatment? Will that help?

Dear Dr Freeman,I was once married to a doctor,I have a brother who is a doctor,and several others that are close relatives that are medicos..None know I have this virus.One thing I learnt from them all was that if you have a serious illness always get a second and even a third opinion,so I hope in posting the following i am merely trying to add to the pool of knowledge and not challenging you in any way.
The folllowing is an email I sent some time ago to Prof Graham Foster,who you may remember is the author of the much posted you tube video. on Ribavirin.

"Dear Professor Foster,
I am writing on behalf of a number of patients here in Australia who have all watched your excellent you- tube video "which DAA's need to add Ribavirin."
And carefully taken note of your advice.

As f3/f4,f4 cirrhotic  Hep C patients.
We acceot a regime of 24wks of sofosbuvir and Daclatasvir or sofosbuvir ledispovir is necessary.
It has also suggested adding 12 wks of Ribavirin as being sufficient,and efficacious for max effect..

The question that concerns us is this,and we would like your opinion as an expert on Ribovirin
1. Is 12 wks of Ribavirin along with the 24 wks of the other DAA's  sufficient for maximum effect.
   In other words does 24wks of Ribavirin have any added benefit over 12wks if the other DAA's are continued for 24wks?

2. It has been suggested to us that it would be more efficacious to take the 12wks of Ribavirin in the last 12wks of treatment,rather than the first 12wks.
   Is there any scientific basis for this?
Since the range of possible options is up to us to decide we urgently seek a second expert opinion.

I apologise for intruding on your time,as I am sure you are extremely busy.
But your expert opinion would be very much appreciated."


To my complete surprise I received a gracious reply.

"Thank you for asking for my opinion
We don't really understand how ribavirin works and we don't really know the best way to use the drug so it is hard to give an evidence based answer.
My own personal approach is to recommend that for treatment regimes where ribavirin is needed (and for many Genotype 1 infections it is probably not needed with the new DAAs) the best thing to do is to take full dose ribavirin for the full course of therapy. This may be overkill and may (will!) cause a few more side effects but treatment failure is devastating and reduces future treatment options so I think most patients prefer to struggle through rather than have to go through a second course of therapy. 
If the side effects really are dreadful then stopping ribavirin early is clearly necessary and it does not seem to have major effects on response.
I hope this is helpful and am sorry to be so indecisive.
You will appreciate that I am writing in general terms with a personal opinion and you should discuss treatment choices with your doctor as the need and tolerability of ribavirin is very personal and differs from person to person
Good luck with your treatment
BW
Graham "

We don't really understand how ribavirin works and we don't really know the best way to use the drug so it is hard to give an evidence based answer.

...

If the side effects really are dreadful then stopping ribavirin early is clearly necessary and it does not seem to have major effects on response.

So we know Riba has a log kill of 0.5 ie it will kill 2 out of 3 viruses. That's good. if viruses were terrorists we would not be unhappy with that.

Riba is a 3rd DAA, and although it is weak we know from HIV 1 < 2 < 3 < 4 DAAs

What I found interesting with these studies is that the end point or SVR12 was defined as :

In that study, 99% of patients were cured, where a cure was defined (as in all the studies) as a serum HCV RNA level of less than 15 IU per ml measured 12 weeks after the end of therapy -- the so-called SVR12.

www.medpagetoday.com/MeetingCoverage/AAS...11-18&eun=g696864d0r

So not zero detection but less than 15IU per ml.
Have I misunderstood as my understanding is it shouldnt have any detection as SVR12 or 24:
"The changing role of SVR12 in clinical trials of HCV drugs
So is the above inconsistent with this?

"In clinical trials of therapy for hepatitis C virus (HCV) infection, the standard to assess the effectiveness of treatment has been the decline of HCV RNA (viral load) during therapy such that it becomes very low followed by undetectable viral load for 24 consecutive weeks after therapy has ended. Such a response in the 24 weeks after the cessation of therapy is called a sustained virologic response, written as SVR24."

Does seem illogical Ann, but I think its just that the test cannot quantify a specific level <15 IU/ml (at least from my reading if it) And why you have follow-up testing. Just found this on the Mayo site

A result of "<15 IU/mL (<1.18 log IU/mL)" indicates that HCV RNA is detected, but the HCV RNA level present cannot be quantified accurately below this lower limit of quantification of this assay. When clinically indicated, follow-up testing with this assay is recommended in 1 to 2 months. To assess response-guided therapy eligibility, an "Undetected" result is required, and a result of "<15 IU/mL mL (<1.18 log IU/mL)" should not be considered equivalent to an "Undetected" result.



A quantitative result expressed in IU/mL and log IU/mL indicates the degree of active HCV viral replication in the patient. Monitoring HCV RNA levels over time is important to assess disease progression and/or monitoring a patient's response to anti-HCV therapy.

www.mayomedicallaboratories.com/test-cat...d+Interpretive/83142

Hi Zhuk thanks for that.
The point I am trying to make is that the end point in the study was to have HCV RNA detected by less than 15... So that is not a cure is it? The following is lifted straight from the NEJM article where it appeard:

Study End Points
The primary efficacy end point was the rate of sustained virologic response (defined as HCV RNA <15 IU per milliliter) at 12 weeks after the end of treatment in all patients who underwent randomization and received at least one dose of a study drug. Secondary efficacy end points included the change from baseline in the CPT and MELD scores at 12 weeks after the end of treatment.

They then go on to state all these percentages of cure when the above Study End pt does not say that. It says still detected but under countable limits.
Is this skewed research or am I missing something?

Hi Ann,

I'll try to answer this to the best of my knowledge based on laymans understanding of what I have been told. (Anyone else please jump in and correct me if I got it wrong).

The PCR/RNA test used to determine viral load doesn't actually count the number of virions present in your blood but rather the levels of viral genetic material (RNA) present. This allows a calculation of approx levels of viral load which could be say 2 million or UND or < 15.

1. Obviously 2 million is fairly high and would indicate active virions replicating, otherwise your body's garbage system would be reducing the load.

2. UND means that the test was unable to detect RNA but it doesn't actually mean that no viral RNA is present anywhere in your body. However it does tend to indicate that the virus is probably eradicated and is certainly not actively replicating at the moment.

3. < 15 means that some RNA was detected but your load is below the tolerance accuracy of the equipment.

But the thing to remember here is that the measure is RNA rather than viruses. So if you reach SVR12 at UND or < 15 then while some RNA is still being detected, there is no evidence of viral replication during the 12 weeks since treatment as the expectation would be that this virus replicates quite quickly. This would tend to indicate that the viruses have been "defeated" or "killed" even though some of it's genetic materials are still present in your body (sort of similar to the way that scientists can find DNA from wooly mammoths even though they have been extinct for millennium) and so you are considered "cured" for the purposes of the trial.

The point to make here is that the only way to fully determine if someone has truly been "cured" is to follow them and test them for the rest of their natural life which is no use for the trial as we need results within our lifetime. But the good news is that the odds say that if SVR12 or better SVR24 have been achieved then the chance of relapse is extremely low to almost non existent.

www.ncbi.nlm.nih.gov/pmc/articles/PMC3897323/

Historically, Phase II and Phase III clinical trials of hepatitis C virus (HCV) treatments have defined sustained virological response (SVR) as an undetectable HCV RNA 24 weeks after end of treatment (SVR24).

Using < 15 is cheating although I have heard privately that some patients stay detectable but < 15 for a long time, so they still have some trace of virus but it is so mutated it can barely duplicate.

< 15 means detected but too low to count.

On treatment, early on before we get to undetectable, I can imagine some residual RNA from destroyed virus being present but post treatment UND aka undetectable is the definition of success.

Thanks for clarification and correction Dr James.

So UND at 24 weeks would be a much more logical end point in this research. I therefore reiterate that the above research has fudged or fuzzy outcome numbers.

tweakmax wrote: Maybe add riba to the last two weeks of treatment? Will that help?

Anyone have any thoughts on this

I've just found out I am geno 3a when I thought I was a G1
I am 3 weeks into Sof/ Dac and committed to 24 weeks (unconfirmed F3)
I'm now considering a hit of Riba in the final 2-4 weeks
(I have used Riba 12 years ago, but a doctor said that I should have no resistance)

Hi Bloot,

See below link. Post three where Dr James seems to be saying that you need a minimum of 60 days with Riba for full effect.

fixhepc.com/forum/questions-and-answers/...-or-not-to-riba.html

I know my specialist wants me on it for as long as possible because my liver is definitely work hardened.

G

Thanks Gaj
That's a bummer
I've got about 9 weeks (-4 weeks for delivery) to make a decision
I'll see how my results go an play it by ear

Just looked at the new pricing
My next course of sof/ dac is down so i can get a course of riba and still be under what it cost previously
Then I can make the decision at week 12 to finish out the 24 including the riba