Can one of the Mods please explain about UND, SVR and Relapse?

[BattleTheBeast]

I think with what's going on with our member,  many new members are a bit confused on how this Hep C virus thing works so I wondered if there is an article or something that can help them understand how the virus hides,and UND, SVR and Relapse?

Thanks!

[anniemybaby]

Great question thanks mel

[Lynn K]

Hi Mel
Do you mean to define the terms?

UND test result means it is below the labs ability to test for the virus but does not necessarily mean all virus particles are totally gone. That is why even though your results may say UND at 4 weeks your treatment needs to continue for the recommended duration as in my case 20 more weeks after the 4 week UND result.

SVR sustained viral response meaning that after a given period of time 4 weeks, 12 weeks, 24 weeks, etc you continue to have a sustained response to treatment in that the virus has not returned. So SVR4 means that after 4 weeks post treatment the HCV RNA by PCR is still UND. SVR 4 does nor guarantee you are safe but is a very good sign that treatment has worked. SVR12 is considered by many to be cured but some medical professionals prefer to go with the old gold standard from the interferon days of 24 weeks to feel confident to declare a cure.

Relapse simply means that unfortunately the virus particles that were below the level of detectability by testing survived and have repopulated  and you again have a detectable result with a viral load so you relapsed after treatment.

As to why some relapse well that is the million dollar question the researchers are trying to answer.

I did try to find a link or 2 but most I found were very high level discussions.

This is one of the somewhat simpler ones but still a bit over my head from The New England Journal of Medicine letter to the editor

With regard to the article by Sulkowski et al. (Jan. 16 issue)1: a sustained virologic response that is defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after the end of interferon-based therapy corresponds to a definitive cure of HCV in 99.1% of cases.2 A sustained virologic response that is defined as undetectable HCV RNA 12 weeks after treatment has a concordance of 99.0% with a sustained virologic response 24 weeks after treatment and hence is clinically equally relevant.3

It is well known that after a sustained virologic response, residual HCV RNA persists in mononuclear cells, lymphocytes, and macrophages.4,5 The definitions of a sustained virologic response at 12 weeks and at 24 weeks after treatment have been tested only in interferon-based regimens that are associated with long-term immunomodulation in treated patients, so that once suppressed, the virus remains so in the years to come, even without the drug. Data are lacking on the long-term relevance of these end points in patients who received interferon-free regimens that inhibit the virus by interfering with its life cycle without altering the immune responses (which could be helpful once the patient is no longer receiving the drugs). Similarly, the concept of a sustained virologic response is not applicable in patients with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infection, to whom oral drugs (that only inhibit viral replication) are administered on a long-term and usually lifelong basis.

Harpal S. Dhaliwal, M.D., D.M.
Ram V. Nampoothiri, M.B., B.S.
Postgraduate Institute of Medical Education and Research, Chandigarh, India



The authors reply: Dhaliwal and Nampoothiri suggest that the durability of sustained virologic responses may differ after treatment with interferon and interferon-free regimens. However, clinical data on multiple regimens suggest that virologic relapse is rare 12 weeks or more after treatment, regardless of interferon use.1

The authors propose that interferon-free regimens may be associated with a greater risk of late relapse because of a lack of interferon-induced immune restoration. Although immune restoration after interferon-free therapy remains uncertain, some HCV-specific immunosuppressive effects are related to viral replication and reverse with effective virologic suppression.2 Moreover, the notion that viable HCV persists in peripheral-blood cells is controversial; indeed, evidence suggests that after a sustained virologic response, occult HCV RNA detected in mononuclear cells, unlike HIV and HBV, generally comprises viral fragments that cannot replicate.3,4 This conclusion is supported by the finding that immunosuppression in patients after a sustained virologic response has not led to “reactivation.”

Thus, although the durability of a sustained virologic response with interferon-free regimens remains to be shown, available clinical and virologic evidence raises little cause for concern. We agree that long-term observation of patients who have a sustained virologic response after interferon-free therapy is needed; such studies are ongoing.

Mark S. Sulkowski, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD

[anniemybaby]

Thanks Lynn great article but I'm still alittle confused how does the virus be undetectable n then become detectable does it hide?

[anniemybaby]

I did alittle research n found that woman whom are menopausal and people that are obese are more likely to relapse

[Lynn K]

OK

Think about looking with your eyes at a group something so small that you can hardly see them. Then some of them leave and you cant see them anymore so you get a magnifying glass and can again just barely see them and count them again. Then still more leave and you again can't see them so you get a microscope and can again count them. Finally so many have left you can't see them any more even with a microscope and that is the best test you have. So as far as you can tell there are none there so you report your result a undetected because you cannot detect their presence as there are so few remaining.

It is not that they are hiding there are just so few we cannot tell it they are there or not so the result is not detected, not non existent because they just cannot tell until they wait for a time and see if the virus colony is able to replicate again to detectable levels.

The laboratory doesn't use microscopes I am just using that as an example so you can visualize the concept.

And yes I have seen the post menopause and BMI being factors as well as cirrhosis but the question is why are they factors?

[BattleTheBeast]

Thanks Lynn,

sorry for the delayed response. I finally fell asleep for a couple of hours! Yeah me

Mel

[Lynn K]

Glad you got a nap Mel saw you have been not feeling well. Did what I wrote help clarify at all?

[BattleTheBeast]

I think it did, it's more for others that are new to Hep C and seeing the word relapse and not really understanding how someone can go from Undetected and then 4 or 8 weeks later relapse. Hopefully others will search the forum and see this and it will be helpful

Thanks!

Mel

[anniemybaby]

Thank you so much Lynn n mel

[Islandgirl]

Thanks everyone, I am so glad to have this clarified - and it will make it easier to explain how this works now that I have a better understanding.  Hope more people find your posts - we needed this!  Hugs. ....Islandgirl

[dragonslayer]

Man, there is some good information in this thread! Lynn K and others, thanks much for scoping out these articles.

[dragonslayer]

Hi Lynn,

>>SVR sustained viral response meaning that after a given period of time 4 weeks, 12 weeks, 24 weeks, etc you continue to have a sustained response to treatment in that the virus has not returned. So SVR4 means that after 4 weeks post treatment the HCV RNA by PCR is still UND. SVR 4 does nor guarantee you are safe but is a very good sign that treatment has worked. SVR12 is considered by many to be cured but some medical professionals prefer to go with the old gold standard from the interferon days of 24 weeks to feel confident to declare a cure.<<

This whole question of what is SVR has been bandied about  as though UND is the only measure of SVR...  Apache raised the following point in another thread, and I thought it was important enough to reiterate it here.  According to Gilead, for Harvoni,  UND is NOT the measure of SVR... They are using a LLOQ of 25 and are defining SVR as a quant rna number of less than 25, not UND.   This is from their prescribing document describing how SVR was defined in the trials:

"14.1 Overview of Clinical Trials

The efficacy of HARVONI was evaluated in three Phase 3 trials of 1518 subjects with
genotype 1 chronic hepatitis C (CHC) with compensated liver disease:
 Study ION-3: noncirrhotic treatment-naïve subjects [see Clinical Studies (14.2)],
 Study ION-1: cirrhotic and noncirrhotic treatment-naïve subjects [see Clinical
Studies (14.2)], and
 Study ION-2: cirrhotic and noncirrhotic subjects who failed prior therapy with an
interferon-based regimen, including regimens containing an HCV protease
inhibitor [see Clinical Studies (14.3)].
All three Phase 3 trials evaluated efficacy of HARVONI (one fixed-dose tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir administered once daily) with or without ribavirin. Treatment duration was fixed in each trial. Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint and was defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the posttreatment period after achieving HCV RNA less than LLOQ at end of treatment."

I think this distinction is a very important one for those who are testing at levels near the LLOQ used by Gilead.  Unless Im reading this wrong,  apparently, UND is not the only measure of success.

[Lynn K]

Yes I saw that I the other thread I dont know how I would personally feel spending time as less than 25 vs UND. The test my doctor is using the HCV RNA by PCR  I believe is a different test and from my understanding less sensitive. Also we are in a real world setting not a clinical trial.

Anyway good additional input and food for thought but well above my knowledge to interprete the full ramifications of this information.

In the long run I just  want to get rid of hep c because if I don't I will likely die because of it. So whatever one calls it I need hep c to leave my liver in peace.

[dragonslayer]

I agree, Lynn.. Given my drothers, no doubt Id like to be UND too.. But even UND, as mentioned in that other thread has an LLOD (Lower Level of Detection) which is not zero .. I get the sense that this is a game of relative values rather than absolutes, and understanding this helps to understand both the data, and how our results jibe with that data.. I know that for anyone reading the Gilead trial results, we dont want our individual results to stick out like a sore thumb when matched against the trials...  I just think it lends a lot of perspective and context when we understand how the trial  results we are comparing ourselves to work.

[Lynn K]

Quite true and a good point especially as lay persons trying to sort through unfamiliar technical medical jargon is another challenge we have along with our illness. As most of us know results reported by different labs using different methods just further adds to the confusion. For example for my lab results from Lab Corp there is no option for less than 25 on the HCV RNA by PCR quantitative in the notes explaining the report copied below:

The quantitative range of the assay is 15 IU/mL to 100 million IU/mL
using COBAS(R) TaqMan(R) HCV test, v 2.0. The limit of detection (LOD)
and lower limit of quantification (LLOQ) for this assay is 15 IU/mL.
Results less than the quantitative range of the assay will be reported
as "HCV RNA detected, less than 15 IU/mL".

I will just stay happy with a less sensitive reporting HCV not detected vs the test used in the clinical trial that seems more sensitive.

Perhaps Lab Corp processes their test differently dunno above my pay grade.

It is always good to remember different lab tests for the same thing will be reported differently.

[dragonslayer]

>>But definitely if I was being tested with the COBAS TaqMan HCV test and getting less than 25 I probably would be more than a bit concerned. <<

Lynn, did you mean 'more'?

[Lynn K]

Actually I deleted that I thought my test had a different name maybe my lab just processes it differently as by report says nothing about 25 being a criteria just  a number, or less than 15, or not detected those seem to be the only options for reporting by the process lab corp uses. Like I said above my pay grade to sort out all these nuances.