Relapse rates for Interferon vs Harvoni

[dragonslayer]

I dont know if anyone can answer this here, but something struck me as curious this morning..  Why is it that, given an Undetected status at End Of Treament for both Interferon based regimens and for Harvoni, the Interferon relapse rate is so much higher than the Harvoni relapse rate?   After all, the virus is done being attacked at that point, and time goes by, and the relapse rate for the former grows by many multiples compared to the Harvoni rate.  By 12 wks post treatment, the heretofore Undetected Interferon patients stand a much greater chance of showing relapse than the Harvoni patients.   Why, after the virus has been cleared in both instances, would this be the case?

[charly8]

Because the virus is not clear, just undetected.  And there is a big difference. 

1. You can be undetected and virus free

2. You can also be undetected but have small amounts of virus that then replicate once treatment is done. i.e. relapse

3. And in the direct virals case, it appears, (as you have shoen) one can be detected at EOT and but the virus dies before it can replicate.

I don't think 3. would happen with the interferon based meds.  Reason is the way interferon works:

a. By attaching to healthy cells to help defend against invading viruses.
b. By helping the immune system to stop the virus from multiplying.
c. By assisting the body in ridding itself of infected cells while preventing healthy cells from being infected.

Where as the direct virals attack the mechanism for virus multiplication directly. 

So if you are detected with interferon at EOT you will relapse 100% of the time.

Why is the relapse rate for Harvoni so much less than Interferon when you are undetected at EOT?  The Harvoni is much more efficient and quicker than interferon at ridding the virus.  So it is much much more likely to get rid of the remaining bits that are there even though you are undetected.

[dragonslayer]

Thanks for responding, Charly.  So if I understand this, just because your lab result reads Undetected doesnt mean the virus is gone... And just because your lab result reads Detected doesnt mean it isnt!  And Undetected means something different for Interferon based treatments and DAA treatments.  No wonder so many are confused!  But I think you helped clarify.. Thanks again.

[charly8]

Lets think of a thought experiment with a few reasonable assumptions:

1. You draw blood and get a initial VL count of 6 million per ml of blood. (log 6.78)
 
2. You have roughly 4000 ml of blood in you body.  Total VL in blood = 2,400,000,000 (log 10.38)

3. Your blood is just the amount of VL that has leaked from your liver.  Your liver is much much higher concentration of virus.  Probably 1000 times the amount in you blood.  Total VL in you body = 2,400,000,000,000 (log 12.38)

4. You take your first blood test at 4 weeks and your VL is undetected <25 with LLOD at 25.  Therefore you could have 24 /ml and you would be undetected.   But you could have up to 24 u/ml X 4000 (ml / body) X 1000 (liver/body concentration) = 96 million VL still in you body!!! Even though you rejoice and say you are undetected. 

5.  So you need an additional time to get rid of all that extra virus in your body that the test cant determine is there.  There is no way of knowing if by the end of treatment if you have gotten rid of all the virus.  Since Harvoni is more effective its log reduction of viral load kill is quicker than Interferon, more likely you will get to zero.  The other issue is resistance that can come up that makes it more complicated but as far as viral dynamics the above is correct.

When I was on my interferon based tx.  I was not responding to Pegasis, but responded to Peg-interferon as slow responder and went undetected at 24 weeks.  I therefore graphed my VL reduction rate from the Peg-interferon on a log scale to determine the amount of time I would need to be on the interferon to reduce the virus according to the numbers I provided above.  All this was presented to my doc at the time, and he agreed with all the assumptions, and gave me a 80% chance of success.    That is why I went 72 weeks of peginterferon/Rib.  But unfortunately I relapsed.

[dragonslayer]

Thanks for the explanation.  Well done.  Apparently, Undetected when reported during or at End of Harvoni treatment is significantly more meaningful than Undetected reported after Interferon treatment...  And at or after 4 wks post treatment, its more meaningful still because if the Undetected that was reported while on treatment was not detecting millions of healthy virions that still existed, by 4 wks post treatment, they'd be replicating and would present with a positive viral load.   

[atomic dog]

Regarding the "detected" status, my pharmacist says that its now being observed that those low detected levels (I'm <20Iu/ml since week 3 on Harvoni) may be "noise" picked up because the tests are so sensitive. I'm not entirely clear what that means but she says it's the reason you can be detected at EOT and remain clear at SVR12. Sounds good to me.

[charly8]

What do you mean by noise? 

[Lynn K]

I would not know what is was like to be undetected on interferon and Ribavirin my viral load increased while I was on treatment with those drugs.

I am pretty much the worst case scenario of a null responder there is

[atomic dog]

What do you mean by noise?

I'll ask for clarification. I took it to mean that the VL tests are so sensitive that they in effect give a false positive at these very low levels. Think about it: we're going from millions of viral units to 20 or less.

[Bituman]

What do you mean by noise?

"Noise" in any kind of testing most often refers to the repeatability or reproduceability of the test.  Repeatability of a test is the ability of a lab tech to get the same result on the same sample tested multiple times.  Reproduceability is the ability of lab techs in different labs to get the same result when testing the same sample.  Collectively, these are called testing precision or "noise."  Most test methods have precision statements that are published as part of the method itself.  In the VL example, if a lab tech ran multiple HCV RNA tests on the same sample, he/she would probably not get the same answer every time.  If they ran it 5 times they might get for example, 27, 38, 16, 21, and 40.  This variation in test results is the noise of the test.  Depending on the known precision of the test, these might all be considered the same number. Most tests are replicated with the results averaged to report a single result.  Tests with better precision require less replication.  I have no clue as to the precision of the HCV RNA test, and likewise have no clue about required replication, if any.  But it is a statistical fact of life that all tests suffer, to a greater or lesser extent, from noise. 

Yes, I manage several labs involved in R and D and quality control testing.  We call this type of stuff the "fog" of the test and we deal with it every day.  My IM doc loves going over lab results with me...NOT. 

BOB

[dragonslayer]

Bob... best discussion of lab test variability Ive seen yet! Thanks much for the explanation.

[Sam1224]

You can even take a digital indicator that has resolution out to 5 or 6 decimal places and measure the same object and get different readings out at the 5th and 6th decimal place. Most engineers will consider this noise and ignore it.
Plus, isn't it correct that some of what is being measured is "debris" that cannot replicate but may be detectable?

[Bituman]

Thanks Paul, test precision is a way of life for me. 

You are right Sam.  Fancy electronic equipment and digital indicators often provide false accuracy.  What discourages me is when some technical folks believe that stuff.  But you're right, most engineers don't get taken in.  Do you remember many years ago the controversy over cold fusion?  That was classic case of people getting carried away with false testing accuracy.  An old friend of mine was a researcher at University of Texas.  Unlike some others, he could not reproduce the phenomenon and claimed it was measurement error.  He was under a lot of academic pressure to buy in to the concept of colf fusion.  But he stuck with his opinion and ultimately saved himself, his department, and the University the embarassment of back tracking.  Fun times...

Bob

[spitzbar]

With respect to the viral load calculations provided at the above post for an imaginary HCV patient, the following is offered:

Step 2
Should be:

(6 * 10^6) x (4*10^3) = 24,000,000,000 (9 zeroes) --> Log 10.3802

Step 2
Currently shown:

(6*10^6) x (4*10^2) = 2,400,000,000 (8 zeroes) --> Log 10.3802 (should be Log 9.3802)

Step 3
Should be:

Total VL:  24,000,000,000 x 1000 = 24,000,000,000,000 (12 zeroes) --> Log 13.3802

Step 3
Currently shown:

Total VL: 2,400,000,000,000 (11 zeroes) (log 12.38)


Remarks: patient VL and complete viral count higher than listed initial estimates

[Bituman]

Remarks: patient VL and complete viral count higher than listed initial estimates

What's a few orders of magnitude among friends?   .  Interesting point that Charly was trying to make. 

Bob

[nadewitt]

I took ribavirin plus interferon and was a null responder. Then I took Incivik, ribavirin & interferon was undetected at week 4 and at week 13. I finished all of the Incivik pills but had to discontinue the additional 12 weeks more with just the ribavirin & interferon because of blood issues. Then I relapsed. I just finished 24 weeks of Harvoni and had my after 3 month blood test. I am undetected but since I have been here before and Incivik worked in a similar way to Harvoni it is hard for me to trust that this is really over. I saw a post on another site of someone who relapse 5 months after treatment who was undetected at EOT. Does anyone have any information that could help me?
Nancy

[Lynn K]

Hi nadewitt

Harvoni and Incevik don't actually have the same mechanism of action

http://healthncare.info/sovaldi-vs-harvoni-vs-olysio-vs-incivek-for-hcv-treatment/

Mechanism of action of incivek:

The drug is categorized as a protease inhibitor because it interferes with the nonstructural proteins 3 and 4A and these impair the synthesis of the proteins that are essential for the survival of the virus.

Mechanism of action of harvoni:

Ledipasvir inhibits viral replication by inhibiting the nonstructural protein 5A while sofosbuvir precipitates premature RNA chain termination by targeting the function of nonstructural protein 5B.

Basically they effect different proteins of the hep c virus. Incevik interferes with the survival of the virus while Harvoni prevents replication of the virus

[nadewitt]

Thanks Lynn. I feel more confident now that I am cured.

[MaryC]

Okay...so I have another question about VL results.  I've noticed that others are given results as an 'undetected' value instead of 'neg' which was given to me by both my Hepatologist (after my 4 week labs) and my specialty pharmacist (after my 8 week labs).  I have not yet seen my Hepatologist since starting my meds, so have not personally seen the results.  Mychart (the patient portal for my provider's electronic medical record) won't release the actual test result since it is considered a 'life altering' result.  When I messaged my Hepatologist he indicated the result was:  HCV PCR: NEG.  I understand that neg is equivalent to undetected, but wonder why it is reported as neg vs undetected (which actually seems more accurate)?
Mary

[Lynn K]

Got me different labs may use different terminology I guess?

I get my results through MyChart also the lab is Lab Corp my results say "not detected"

But semantics aside SVR 12 not detected, undetected, or negative means cured that is what we are all looking to see

Good luck

[nadewitt]

Okay...so I have another question about VL results.  I've noticed that others are given results as an 'undetected' value instead of 'neg' which was given to me by both my Hepatologist (after my 4 week labs) and my specialty pharmacist (after my 8 week labs).  I have not yet seen my Hepatologist since starting my meds, so have not personally seen the results.  Mychart (the patient portal for my provider's electronic medical record) won't release the actual test result since it is considered a 'life altering' result.  When I messaged my Hepatologist he indicated the result was:  HCV PCR: NEG.  I understand that neg is equivalent to undetected, but wonder why it is reported as neg vs undetected (which actually seems more accurate)?
Mary


It is my understanding that a result of negative or positive is giving for a qualitative HCV test and a detected or undetected is given for a quantitative HCV test. I think the Red cross starts out with the qualitative test and if they get a positive result, they then give the blood sample a quantitative test. I am not an expert so I may be wrong but that is how I understand it when I read their testing information on their web site.

[Lynn K]

 My understanding is the Red Cross only does a anti-body test they do not test for the virus that is why when we are cured of Hep c we will still test positive for the antibodies  even though we no longer have the virus so we will not be able to donate blood

[nadewitt]

Thanks for helping me understand that.

[MaryC]

Got me different labs may use different terminology I guess?

I get my results through MyChart also the lab is Lab Corp my results say "not detected"

But semantics aside SVR 12 not detected, undetected, or negative means cured that is what we are all looking to see

Good luck

Thanks for the response.  Whether 'undetected' or 'negative', I am just very happy to see the slaying of the HCV dragon.
Mary