Will VX-950 and other Protease Inhibitors stop viral replication in our livers?

[miked]

The following was recently published that HCV patients who attain SVR through standard tx (INF + RBV) still have viral replication in their livers even though their bloodstream is virus free.

"Chronic hepatitis C patients who achieve a sustained virological response (SVR) to interferon-based therapy - continued undetectable HCV RNA 6 months after the completion of treatment - are widely considered to be "cured."
However, according to a report in the November 15, 2006, issue of Clinical Infectious Diseases, the hepatitis C virus (HCV) may continue to replicate in the livers of such individuals.

-Positive-strand HCV RNA was found in 19 of 20 liver biopsy specimens (95%).

-Negative-strand HCV RNA was found in 15 of the 19 samples (79%) that had positive-strand HCV RNA.

-Liver necro-inflammation was still present in the post-treatment liver biopsy specimens of 15 patients, and fibrosis was present in 7.

-Liver damage improved in all but 2 patients.

HCV persisted and replicated in the livers and peripheral blood mononuclear cells of most sustained responders," the authors concluded. "Thus, these patients did not experience HCV infection clearance, despite apparent clinical disease resolution."

Are any of the clinical trials for VX-950 or other PI trying to evaluate if the PI kills the bug, even in our livers?  Because the PI interrupts viral relpication this sounds like it should be true.

If it is true does this mean that all who have attained SVR through SOC will have to re-treat with VX-950 or other PI?

I'm curious to see if this is a goal of PIs.

[jmjm530]

Nick,

I posted to you in "Miked's" thread above. All the best luck with a  successful treatment outcome. Please come back and post your viral load results as you get them.

Be well,

-- Jim

[nick m]

Jim and all
Baseline hcv rna 8670000 at 1st screening visit. 14900000 Iu/ml at 2nd screening visit 1 week later (6th and 13th dec '06). Previous PCR from 16th Feb 2006 HCV RNA 2,621,490 IU/ml. ALT 157 AST 122 pre- treatment. 11th Jan, DAY 8 of treatment, ALT 56 AST 52. Frustratingly, but as expected, I've no access to the viral loads till the 12 weeks is up but i'll keep asking about this. All my trial cohort intact. I'm fine, just tired. I was obviously in denial re my biopsies when i said they'd stayed the same. The CT liver triple phase i had a couple of months ago gave a perhaps unwarranted reassurance compared to the trial biopsy from 7th december '06.

CT -
"No focal abnormalities are present in the liver. the liver has a smooth edge and enhances homogenously. The portal vein is patent. The spleen size is normal. There are no varices and no ascites. The pancreas, adrenals and both kidneys appear normal. 2 small calcified granulomata are present in the right lower lobe. the left lung base is clear.
Conclusion - No evidence of an HCC. No features of cirrhosis."

Biopsy -
"Sections show liver in which there is mild - moderate portal tract inflammation including occasional ill formed liver lymphoid aggregates. Focally moderate interface hepatitis is present, and there is focally moderate parenchymal inflammatory activity. Portal tracts show fibrous expansion, and there are occasional portal links. Mild steatosis is present. There is no cholestasis, siderosis, or alpha-1-antritrypsin material.
Comment - Moderate chronic hepatitis, and moderate fibrosis with features in keeping with HCV infection. The degree of inflammation and fibrosis is more than was seen previously in 02S5199 and 97S13793" - ie 1997 and 2002.
It dispells any residual phantasies i may have had concerning enjoying a symbiotic harmony with the virus into a hale and hearty old age - possibly with the assistance of the odd glass of milkthistle and some acupuncture. I'm so grateful i got this opportunity for tx. I have to say i've felt better physically and emotionally since i started the treatment than i've felt for a long time. maybe i was more aware of my condition than i thought. I feel really excited about the whole business like my brains starting to work again. Walking up the hill to the hospital through gale-force winds listening to Mahler's 2nd ( the aptly named 'resurrection symphony') on the mp3 was a wild joy today. hope.   Nick m

[mremeet]

Thanks HR, I can tell you've probably been asked these same questions ad nauseum - sorry for the redundancy. I guess we'll have to keep an eye on the ongoing battle between the persistence advocates and the eradication supporters. Sure would like to know that it's gone for good if we manage to get our SVR's.  Not that it worries me that much, but I've struggled with CFS for years and I'm suspicious an ongoing "occult" infection (and it's associated constant low level immune response) could prevent it from clearing up after EOT and achieving SVR. I'd like to be fully and truly free and clear in every way if possible, like I was when I was 17 years old before coming down with this crud. But we got what we got, I suppose.

Thanks again...

[mremeet]

I don't know if you've been following this whole low level viral persistence thing vs eradication/cure issue raised by various researchers in the past year or so (starting with Castillo et al). I imagine you have, and I know you're an expert on the various testing methods. What do you think of this whole situation? Do you have confidence in Castillo's findings? It's discussed in the referenced link below "HCV Persistence: Cure Is Still A Four Letter Word":

http://www.hivandhepatitis.com/hep_c/news/2005/010305_b.html

The viral persistence crew claim viral remnants were identified in long term SVR liver tissue samples using "...highly sensitive reverse transcription-polymerase chain reaction (RT-PCR)-nucleic acid hybridization assays..." and "...highly sensitive RT-PCR and in situ hybridization..." Are these methods reliable? My doctor mentioned to me that these test methods were under suspicion by many within the medical community, and that these finding are being contested (as evidenced by RTS's reference in this thread). My doctor mentioned something about the possibility of contamination in their sampling/handling methods, which might account for their (apparent) positive HCV findings. What do you think about this whole shebang? And is the TMA test referenced in the link provided by RTS in this thread (which found no viral remnants) comparable in sensitivity to the more specialized tests mentioned above (as used by Castillo et al)?

Thanks in advance...

[Hepatitis Researcher]

The above study by Marcellin obviously seems to contradict the findings of Castillo. Unfortunately, one needs to know the fine details on how they prepared the samples, particularily from the liver tissue and the PBMC to judge if the reported sensitivity of 5- 10 copies was indeed attained. When working at these sensitivities, there easily can be a loss of the RNA during the sample preparation step, since you have to prepare the RNA by lysis and remove the proteins from the sample. Removal of the proteins often pulls out the RNA with it, so the amplification does not yield a realistic picture. And the WHO standard is a serum standard, not tissue.
Again what matters most is the apparant stability of the SVR as a biological phenomenon, so leftover virus is either very unfit or well controlled.

[Hepatitis Researcher]

Unfortunately I cannot give you the date, but yes we have discussed ( I have commented on) exactly these questions re reliability of Castillos etc in a few earlier threads. I gave the reasons after studying the papers method, why their results are to be trusted and cannot be dismissed as contaminations. Basically they had very good controls. Also this is an excellent Spanisch Institute focusing on nothing but advanced hepatitis research.

I dont know how to prevent this, but these threads do go into a black hole, since there is just so much in between. One would need to grab any relevant info and place it into a well organized file.

[mremeet]

Actually I slightly misspoke in my earlier post when saying "My doctor mentioned to me that these test methods were under suspicion by many within the medical community." He didn't really say "the method" was in doubt as in the test itself, but if I understood him properly it was a suspicion that the researchers themselves had not handled/managed/manipulated the samples and/or test properly, perhaps leading to cross contamination. Anyway, that's my rough understanding, just thought I'd clarify.

[mremeet]

Thanks for the response, and you're right the search function here is in desperate need of attention/upgrade. I figured you would have addressed this topic, guess I missed it somewhere along the way. Suffice to say you've indicated you feel that Castillo's claims are valid. And considering you're in a uniquely qualified position to judge, unfortunately it's disheartening to hear that. Although it doesn't diminish my enthusiasm and confidence in the outlook of SVR's, it's still a bummer to think the thing hangs on in some way - possibly eroding our well being in one subtle manner or another.

Not to beat a dead horse, but what do you think of the TMA test referenced above in RTS's post? They appear to be attempting to refute the findings of Castillo et al. And it appears at least partially if this report was specifically for that purpose. Do you think it musters a challenge, especially considering the apparent differences between the cited TMA test and highly sensitive RT-PCR methods referenced by Castillo?

[jmjm530]

What still hasn't been shown to me is -- assuming for a minute that persistent virus exists and replicates -- is why then with the exception of perhaps one or two rare cases, does it not break through the tissue/lymphatic wall and become detectible in serum? Or perhaps does this so-called persistent virus only mimic replication in a harmless way as might be argued by the benefits of SVR including improved histology.

[APKhaos]

Jim said, "Eventually, they should get together, but didn't they say the same with VHS and Betamax?"

ROTFL. Thanks Jim, I needed that.

[jmjm530]

Mre: It'll be interesting to see how this report is received and responded to by the viral persistence originators. But is the TMA assay they reference using for liver tissue testing as sensitive as the test used by the originators of the low level viral persistence theory? I thought they were using a very special and extremely sensitive test, that's not commonly used for normal patient screening, and is far more sensitive than what's currently used in a (non-research based) clinical setting? Anyone know if that's right?
-------------
Our posts crossed or I would have more directly addressed your question. But yes, you've hit it on the nail. Two different types of tests/procedures -- one (TMA) widely accepted in the clinical community, and the other (used in the persistent virus studies) not so widely accepted and in fact disputed by some. Eventually, they should get together, but didn't they say the same with VHS and Betamax?

-- Jim

[returntosender]

Here is an SVR study from the 2006 AASLD conference which I didnt see mentioned here but it is quite optimistic in terms of the durability of SVR and it seems to cast some doubt on these other smaller studies that show such high numbers of viral remnants in SVR patients:

http://www.hcvadvocate.org/news/reports/AASLD_2006/Abstracts/Monday%20Posters_HCV%20Therapy_%20Pre-clinical.htm#preclin_927

"LB9. Sustained Virologic Response Is Associated with Eradication of Hepatitis C Virus and Fibrosis Regression in Patients Treated for Chronic Hepatitis C. S. Maylin; M. Martinot -Peignoux; N. Boyer; M. Ripault; D. Cazals-Hatem; N.
Giuily; C. Castelnau; C. F

[jmjm530]

The study posted, I believe uses conventional TMA tests. Some of the other studies that showed persistent virus used newer tests that are questionable according to some well-respected clinicians. Eventually, hopefully, these two groups will come to some kind of consensus soon. The "no-late relapse" statement is *extremely* encouraging and argues against the so-called persistent virus breaking through from other compartments into serum in any but rare cases. I'd like to see how they arrived at the risk for HCC figures because this seems to contradict other studies and what I've heard. That said, one of my doctors has suggested periodic HCC testing for life while others here have reported otherwise.

Be well,

-- Jim

[APKhaos]

That's an impressive abstract, RTS. Am I right in thinking that these results suggest that the occult and residual viral load so often raised as a bogey here and elsewhere is, in fact, a myth?

[mremeet]

Thank you so much for posting this RTS. Finally an optimistic yin to the low level viral persistence yang. That's a real ray of hope to think we might actually truly eradicate this thing if we SVR. It'll be interesting to see how this report is received and responded to by the viral persistence originators. But is the TMA assay they reference using for liver tissue testing as sensitive as the test used by the originators of the low level viral persistence theory? I thought they were using a very special and extremely sensitive test, that's not commonly used for normal patient screening, and is far more sensitive than what's currently used in a (non-research based) clinical setting? Anyone know if that's right? The TMA mentioned sounds like the same test that's commonly used to determine HCV+/- status prior to EOT. And this test only goes down to ~5 IU/ml or so...if so, again, I thought the tests used in the low level persistence research were much more sensitive than this. Can anyone clarify this?

[nick m]

yeah you've got it. if i clear they stop. if i don't they continue with pegasys and copegus for 48 weeks if necessary - though this latter is not part of the study. Up to now no side effects other than the well-documented ones associated with interferon. will keep posting. nick m

[nick m]

This may be a slightly frustrating posting as i've never really got my head around the viral load other than in vague adjectives; ie 2 years ago when i re-engaged with hepc services here in england (i'd disengaged about 2003/4 after being refused treatment - 'cause assymptomatic and little liver damage) i was told by the nurse it was "high". Again, minimal liver damage 1 to 2 i've been told. genotype 1b probably contracted 1970's. 3 biopsies - 1998, 2003,2006 little discernable progression. However ALT shot up to 187 (52 when first diagnosed in 1994)2 years ago so i re-engaged. The trial is randomised over the 300 participants in europe (9 here in London)so i had no idea before the first day what group i was in (4th jan). My ALT was 96 and AST 70 on the 8th jan (4th day of treatment). When i go back on thursday 18th jan i'll try and get precise figures re load etc and post 'em.
nick m

[jmjm530]

I assume they will be doing viral load tests quite frequently, especially in your group. Should you not have a very rapid viral response, do they still stop at week 12, or will they now add riba or extend/expand treatment in some other manner? I ask this because the operating theory in these shorter treatments seems to be that SVR follows RVR -- and conversly without RVR than perhaps a longer regimen may be required.

-- Jim

[jmjm530]

Thanks for posting Nick's site! It is bookmarked and I will follow Nick's progress. A quick glance shows Nick indeed is in Europe so that accounts for the "no riba". Quick question Nick -- were you able to pick "Group D", or were you just randomly placed into it.

-- Jim

[pln]

Yes, That is what Nick is saying, I have been watching his site and wishing for success. http://nickaround.blogspot.com/

[jmjm530]

Hi Nick,

I wonder if you could clarify your post a little. Are you saying that you're treating with 12 weeks of VX-950 and Pegasys, but no ribavirin?  And then nothing after that? My understanding was that they were only doing no-riba arms in Europe. Maybe you're in Europe?

In any event, please let us  know what your viral load numbers are both during and post treatment as you get them. They will be viewed with EXTREME interest here and elsewhere as you definitely are do the minimal path. Can I ask you to share some stats such as: age, genotype (I assume it's 1), pre-tx viral load and stage liver damage.

All the best with treatment!

-- Jim

[nick m]

Thanks for the clarification re viral re-emergence and the significance (or more likely insignificance)of residual viral replication in the liver. I'm 12 days in on vx950 and interferon (group D, 12 weeks - no ribo, no follow-up combination and no chinese herbs or vitamins while i treat - thats the deal i signed up for and i'm sticking to it). I obviously have a vested interest in the 12 weeks being successful. And, logically, from the evidence so far, significant though sparse, there's no reason why this shouldn't work as the new stand-alone treatment paradigm. Whatever the outcome, the relief at finally getting a chance at meaningful treatment is extremely empowering. but thanks again for the sober perspective
nick m

[GrandOak]

It's my understanding that both classes of new meds being investigated (ie. Protease and Polymerase) act in much the same why as nygirl indicated of aiding Riba in blocking viral replication.

Our HR member can probably better address this from a more professional background, but as I understand it the primary difference is that with Riba, it is not very well understood how it blocks; whereas with the drugs in the pipeline the method of blocking replication is known (Protease or Polymerase) but it's uncertain whether viral mutation will occur to circumvent those inhibitors.

It is also my understanding that the original virus which invades the body often times is vastly different from the one which remains as the infection because it reacts to our immune system attacks by mutating to the point that our system does not recognize it as an invader and stops attacking it.  But, it seems that IFN/Riba work to attack it and prevent replication in such a manner that the virus does not understand and thus does not mutate to develop an immunity to these drugs which is what allows them to be effective to some degree in treating against this infection.

Since Protease and Polymerase enzymes are fundamental in RNA and DNA replication, I would venture a guess that they will stop replication in our livers.  The real questions is for how long and to what degree.  As these meds seem to only be augmentation meds during the initial phases of tx, whether they remain in strength long enough to continue preventing replication so that viral cells do not remain in the liver during the rest of tx does not seem clear from any studies I've seen.

If I am not mistaken the studies which find that the virus can remain and replicate in the liver whilst being undetectable in our bloodstreams is fairly new and was initiated to better understand the percentage of relapses occurring after patients remained UND through tx and 6 month post-tx period.

[jmjm530]

Miked: Are any of the clinical trials for VX-950 or other PI trying to evaluate if the PI kills the bug, even in our livers? Because the PI interrupts viral relpication this sounds like it should be true.

If it is true does this mean that all who have attained SVR through SOC will have to re-treat with VX-950 or other PI?


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Nothing that I've read or heard suggests that the purpose of VX-950, or another other protease inhibitor, is anything other than to offer a safer/less toxic/shorter/more effective alternative to SOC with the sole aim of achieving SVR. SVR being defined as no virus detectible in serum six months post treatment. As to whether, indeed other "bonuses" might occur from newer treatments -- that is something I am sure will be investigated in the future.

As to a hypothetical as to whether those who have achieved  SVR through SOC would have to re-treat with a PI -- assuming a PI kills the so-called persistent virus -- first, I think they would have to demonstrate that persistent virus is doing any harm, something which to date hasn't been shown. Taking the hypothetical further and assuming that the persistent virus is doing some harm -- then the re-treatment decision would be the same as it is with SOC. In other words the rewards of killing off persistent virus would have to be weighed against the risks of whatever PI conconction would kill it off. Personally, if this hypothetical concoction had any interferon in it -- or anything else that might cause me trouble, especially my skin -- I think I would pass.

Right now, SVR concurs me a durable non-detectible response, what appears to be already a regression of liver damage, much less of a chance of HCC, and a normal lifespan. My doctor called this a "cure" and it certainly meets the definition. Until the persistent virus is both definitevly proven to exist AND CAUSE HARM, then there is nothing more to cure.

All the best,

-- Jim