SVR update and random thoughts....

Approaching two years SVR and in many ways feeling healthier and stronger than in past years , I do notice a tendency to develop skeletal problems on a regular basis.  Sometimes it is the middle back, and ribs, sometimes the lower back, and right now it is my neck.  Since so many on the forum seem to also experience similar skeletal pain and what seems to be disc related problems, I have to wonder if it all is not related to our years of HCV?  My biggest concern, is that maybe the HCV remains in the spinal column, even after SVR, and periodically flares up, causing our skeletal aches and pains.  Of course it could also be due to all the interferon we used, or due to a long-standing autoimmune response triggered long ago by the HCV, and now 'locked-in' long term.  Sort of a 'reactive' arthritis.  I still tend to lean toward the first theory.

I still have regular periods of fatigue and low motivation, followed by periods of high energy.  Sort of a waxing and waning of physical and mental state.  The pattern seems to persist.

I notice lately in articles, on medical websites, and even in HCV activist advertising, that the word cure is rarely being used anymore....it had a short shelf life it seems!  Now we are again seeing terms like, the virus remains at undetectable levels, the virus is no longer active in the body, or the virus has gone into remission.  I liked it better when everybody was using the 'cure' word, even if it was premature and presumptious.....it sure felt more reassuring!  

Best wishes to all!

DoubleDose

[nanniegea]

Congrats on your 2 years svr. Good to hear that some have beat this. I know what you mean about the aches and pains, they seem to never fully go away. I think it is something that will remain because after all, they really don't know all there is to know about this virus. I have been in pain for years and now that I know what I'm dealing with I tend to blame it on the hep. Good luck in your future endevours.

[mikesimon]

It's nice to hear from you and learn that you're doing well. I too have aches and pains but attribute mine to age and a hard life. I'm clear 13 months and were it not for a bad motorcycle wreck I'd being feeling great. But, I'm mending nicely I think. Stay well. Mike

[doll face]

DD, Good to see you. Congratulations on the 2 year mark.

I agree. I would like to hear the word CURE more often too, but at the same time wonder also if the virus is just hiding somewhere waiting patiently to attack again. I find myself doubting all the time that it is completely gone. Still have aches and pains, and all the meds caused me so many physical problems,hypothyroidism, bone loss,CTS to mention a few, that I can only imagine what is still going on inside my body. I just wish that we could know once and for all,beyond any doubt that it is gone.

[cuteus]

two years already!!!sure is hiding long term if that is the case!

My orthopaedist and neurologist both did not seem too concerned about the aches and pains, said it was normal  degeneration for people my age. That did not sit right, I rather think hcv is still doing its thing and I am not aging.

[landfill]

I'm SVR at 2 years post tx too.  I still have days with gloomy feelings that I think are a hangover from tx.  It comes at random then it's gone.  I continued the ADs for a year or so EOT but now I just ignore it because I know that it's temporary.

My wife is 54, HCV negative, and she has disk degeneration.  Her ortho says that it's exceedingly common.  He says that the percentage of the population with such changes equals age.  That is, among 30 year olds, 30% have arthritic spinal changes.  He says that it always happens at both the top and bottom of the spine, not at just one end.  Those are the vertebrae that move.  The ones in the middle are rigid.  So whatever's going on in your back may be unrelated to HCV.

I can't tell you why but I don't care much whether it's really eradicated or not.  After reading about viruses for years and talking to the hepc dr I see that we live in a sea of viruses.  Healthy people have harmless viruses that the immune system fights with for a lifetime without causing disease.  There are supposed to be a hundred known cold viruses, some of which are believed to persist.

What matters about HCV is that it stops hurting your liver when you're SVR.  I know that when there are enough long term SVRs to study, there may be effects that we dont know about today but I'm going to get sick from all sorts of other things, too.  So what?  We did what we could now.

Best wishes.

[cuteus]

I am with you on that train of thought.

[jmjm530]

Cuteus said previously: "My orthopaedist and neurologist both did not seem too concerned about the aches and pains, said it was normal degeneration for people my age. That did not sit right, I rather think hcv is still doing its thing and I am not aging."

LOL. For the archives. LOL

DD,

The symptons you describe sound a lot like the normal aging process. My friends and relatives all complain about these things all the time  and none of them have ever had Hep C.

As far as "cure" goes, frankly I find it counter-productive to dwell on that. What we have now (SVR) is our cure.

Maybe tomorrow will bring something else. Or maybe tomorrow they will discover we really are "cured". Right now, I'm in treatment and nothing would make me happier than to achieve SVR to halt and hopefully reverse my liver damage. Anything beyond that is gravy on gravy.

Congratulations on your SVR! Enjoy it!

-- Jim

[honey1616]

DD,,,,If you are in your 40's,50s,,,,it is aging,,,all natural age process which we hate to do.  Now if you are in 30's,,,I would say,,,maybe your theory flies.  Do you get alot of exercise?  That also comes into play as we get older,,,we sit more and then when we do the least bit strenous activity,,,we are aching next day or pulled something.  I know alot do believe that SVR means its still lurking but I would like to see proof and there isn't enough studies to back up.

[carpedi]

Wow! 2 years of SVR! That's wonderful! I would be sooooo happy if I could achieve even 1 PCR with undetectable virus. I'm only on dose #6 this week and go for my first PCR on Friday. The biggest relief for me would be knowing that my kids, grandkids, and husband (and others, of course) are safe from me and I would take any residual symptoms either virus or tx can throw at me in exchange for that assurance. I live in terror that somehow, no matter how careful I am, I will inflict this on someone else. Double, from where I sit, you are one of the luckiest people in the whole world! To me, SVR for 2 years spells CURE. Good luck and enjoy every minute of it!

[scruffy]

Congrats on the approaching two my CURED svr friend. frank

[cigaso]

Thanks for your follow up. It is helping us know what might be expected after tx.

[DoubleDose]

Thanks for all the follow up response!  Good comments, and I tend to agree with all of you as well, even if it sounds contradictory at times.  I am THRILLED at achieving SVR (whatever it turns out to represent), because I also know that the aggressive attack on my liver has been stopped, and that I will probably continue to recover in any number of ways.  I can certainly deal with the aches and pains, knowing that the virus is no longer detectable.  I count my blessings every day.

If it turns out that the 'persistent HCV' research has some validity, AND if it also proves to cause any of our ongoing symptoms, then I am also sure that a medical response to that issue will be in the works soon enough.  Luckily, for now, the SVR outcome seems to prove durable for almost all who achieve it, and it also seems to stop liver damage in it's tracks.  Any other ongoing problems caused by residual virus (if it exists) are a small price to pay for saving our lives...literally.

I also think the massive doses of interferon do cause some long term problems that will (hopefully) clear out after five years or so of continued healthy living and recovery from the virus.

I am an optomist at heart, but also a realist, so I am hopeful for the best down the road, BUT if it turns out we have more work to do, in order to fully recover, then...bring it on!

I do have faith in modern medicine, and that they will find all the answers that we seek.  We have come a long way with the help of medical research, and the latest medications.

'50%-plus' SVR rates for Type 1's seemed impossible just a few years ago!!!!

DoubleDose

[DoubleDose]

Thanks for the information and discussion regarding viral persistence.  I have read the above commentary in past months, and because of the researchers' guarded comments, and their outright concerns about cellular and humoral immunity possibly persisting after SVR, I remain somewhat edgy about the etiology of some of our post-tx complaints and symptoms.  Aging yes, in many instances, natural reactions to the interferon...sure, I agree...but overall, there seems to be a large group of patients who after achieving SVR continue to experience abnormal fatigue, depression, and arthralgias on a long term basis.  My doctor stated that about half of SVR's feel much better after therapy, and the other half continue to experience lots of fatigue, weakness, depression, and other symptoms, on a chronic basis.  Maybe even sub-clinical amounts of replicating HCV could cause a general autoimmune reaction long term, after SVR in many patients...possibly waxing and waning according to internal/external stressors and events.  

The researchers have certainly caused the doctors treating HCV to retreat on language, and expectations.  I think there is still much more info. and research to come.  Let's hope it's more good than bad!

Thanks for your quality responses, and detailed information.  Knowledge is the key to success.

DoubleDose

[willing]

BTW, I don't know if this was already posted but here's another recent discussion on on radkowski's Jan. paper.
-----
Radkowski M, Gallegos-Oroczo JF, Jablonska J, Colby TV, Walewska-Zielecka B, Kubicka J, Wilkinson J, Adair D, Rakela J, Laskus T (Department of Medicine, Mayo Clinic Scottsdale, Scottsdale, Arizona; Institute of Infectious Diseases, Medical Academy, Warsaw, Poland; and National Institute of Hygiene, Warsaw, Poland). Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C (Hepatology 2005;41:106–114).

Seventeen patients with chronic hepatitis C, who had been successfully treated with interferon/ribavirin with a sustained virological response (SVR) after 6 months of follow-up, were restudied an average of 75 months after the end of therapy, and then a further 2–3 times every 3–6 months, for up to 9 years after treatment. Serum and peripheral blood mononuclear cells were collected and lymphocyte and macrophage cultures were established on each occasion. In 11 patients, frozen liver tissue samples were available from follow-up biopsies performed an average of 64 months after therapy. The presence of HCV RNA was determined by a sensitive, reverse transcriptase polymerase chain reaction (RT-PCR), and concentration of positive and negative strands were determined by a novel quantitative real-time RT-PCR. Only 2 patients remained consistently negative in all samples tested. HCV RNA was detected in macrophages of 11 patients and in lymphocytes in 7 patients. Viral sequences were detected in 3 of 11 livers and in the serum of 4 patients. Viral replicative forms were found in lymphocytes from 2 patients and in macrophages from 4 patients. In conclusion, from this limited study, it appears that small quantities of HCV RNA can persist in the liver, macrophages, or lymphocytes for up to 9 years after successful treatment.

Comment
Over 15 years ago, it was shown that patients with HBV infection who had successfully seroconverted from hepatitis B surface antigen (HBsAg) to antibody (HBsAb) or patients with chronic liver disease who had only hepatitis B core antibody (HBcAb) (Hepatology 1995;22:25–29) or had no serum markers of HBV infection, could still have HBV DNA present in their serum or liver (N Engl J Med 1985;312:270–276).This phenomenon was called occult HBV infection, using the word “occult” to mean hidden. That is, the very low levels of HBV DNA present were “hidden” from all but the most sensitive of tests. Thus, about 33% of patients with HBsAg-negative, HBsAb-positive chronic liver disease were shown to have detectable circulating HBV DNA using polymerase chain reaction (PCR) methodology (Hepatology 1991;13:1044–1051), and 50% were shown to have HBV in their livers (J Hepatol 2001;34:447–454). As yet, there is no clear evidence that such patients develop progressive liver disease (Hepatology 2001;34:204–206). So what is the significance of occult HBV infection? More than 25 years ago, it was shown that patients receiving HBsAg-negative, HBcAb-positive blood were still at risk of developing post-transfusional hepatitis B (N Engl J Med 1978;298:1379–1383). Also HBsAg-negative, HBsAb-positive patients undergoing cancer chemotherapy could develop reactivation of HBsAg-associated severe, life-threatening hepatitis (Ann Intern Med 1982;96:447–449). Therefore, the presence of occult HBV infection was undoubtedly clinically significant in certain situations (Hepatology 2001;34:194–203). For example, in a recent report from China, 37% of chronic HBV patients who had seroconverted and cleared HBsAg, and serum HBV DNA, by a mean of 49 years of age, had low titers of intrahepatic HBV DNA, mainly in the form of cccDNA, in the presence of near normal liver histology (Hepatology 2004;39:1694–1701). However, such patients were still at risk of developing hepatocellular carcinoma, although significantly less than patients who have already developed cirrhosis.

Most publications indicate that occult HBV infection is caused by very low viral replication rates (Hepatology 2001;34:194–203). This would explain why patients who seroconverted to HBsAg negativity have persistence of HBV DNA in the liver (Proc Natl Acad Sci 1981;78:3906–3910, Hepatology 2003;37:1172–1179), and the persistence of HBV DNA for up to 30 years after a self-limited attack of acute hepatitis (J Hepatol 2000;33:992–997). It has also become clear that exogenous factors may suppress the replication of HBV DNA, such as renal dialysis and co-infection with HCV. For example, HBV DNA was found in the serum (J Hepatol 2003;38:506–510) and livers of 20%–30% of HCV-positive chronic dialysis patients (N Engl J Med 1999;341:22–26). However, there seemed to be no significant biochemical or hepatic histological differences between HCV patients with or without occult HBV infection. More recent studies from Europe have shown that about 25%–30% of HCV patients have occult HBV infections involving the liver, but this does not seem to be associated with any effect on HCV viral titers, liver biochemistry, liver histology, or response to antiviral therapy (J Clin Virol 2004;29:160–166, J Viral Hepat 2004;11:358–365).

Current antiviral therapy of HCV infection with peginterferon and ribavirin can be successful in over 50% of patients (N Engl J Med 2002;347:975–982). Success is defined as a sustained virological response (SVR), that is, elimination of HCV RNA from the blood, for at least 6 months after therapy (Hepatology 2002;36:S114–S120). Serum HCV RNA negativity is defined as undetectability using assays with a sensitivity of at least 100 viral copies/mL. The question remains as to whether this result represents sterilization of the serum, or very low persistent viral replication? It also begs the question as to whether it also represents HCV sterilization of the liver. Certainly the liver histology improves with successful treatment (J Hepatol 1999;30:783–787) and may even normalize. In one study 8 years ago, HCV DNA was undetectable in the liver in all 27 patients studied 1–5 years after achieving SVR with treatment (Ann Intern Med 1997;127:875–881). In contrast, other studies published around that time, with similar numbers of patients, showed that from 4% to 14% of HCV patients achieving SVR did not clear hepatic HCV RNA a year or more following treatment (Gastroenterology 1993;104:1472–1477, Ann Intern Med 1995;122:586–591, J Med Virol 1998;55:7–11). More recently in a much larger cohort of 400 patients who achieved SVR following treatment, 98% had no detectable hepatic HCV DNA (Hepatology 2002;35:688–693). Nevertheless, HCV RNA was still detected in the liver in 7, or 2%, of patients. Five of the 7 patients were followed up, and in 2 patients there was a reappearance of serum HCV RNA after 12 months.

HCV is not strictly a hepatotrophic virus because HCV has also been shown to replicate in peripheral blood mononuclear cells (PBMCs) (Blood 1998;91:3841–3849, J Virol 1998;72:1640–1646). Therefore, in a recent study of 16 HCV patients undergoing SVR (5 spontaneously, 11 following therapy), the examination of expression of the HCV genome in the sera, PBMCs, and monocyte-derived dendritic cells up to 5 years after resolution of infection, was of considerable interest (J Virol 2004;78:5867–5874). HCV RNA was sought using a highly sensitive reverse transcription RT-PCR nucleic acid hybridization assay (NAH), and by real-time RT-PCR to detect HCV RNA-positive strands. PBMCs, after culture with a T-cell proliferation-stimulating mitogen, were examined for replicative HCV RNA-negative strands. The investigators found that HCV RNA was carried in either the sera or PBMCs of all 16 patients. Thus, the authors concluded that after both spontaneous “clearance” of HCV and therapeutic SVR, HCV RNA does persist at very low levels in the serum, and in an intermediate replicative form in PBMCs. However, the clinical significance of this observation was unclear, especially in liver transplantation in which immunosuppressive therapy may facilitate extrahepatic HCV replication (Transplantation 1998;66:664–666). The present study confirmed these previous observations with some additional findings. First, HCV RNA, in very low titers, can persist for up to 9 years after successful therapy, and the presence of identical genotypes means that it is persistence of the original infection and not reinfection. Secondly, even with the most sensitive of techniques, the presence of very low titers of HCV RNA may be missed on a single testing and only revealed with serial testing, 2 or 3 months apart. As a result, only a small minority of patients, 2 of 17, remained persistently negative in all analyzed compartments, at all times. Finally, the replicative patterns in the hepatic and extrahepatic sites may differ.

Clinically, what are we to make of these 2 studies? The fact that previous studies using less sensitive techniques failed to detect very low titers of HCV RNA, that were likely present in the majority of their patients following SVR, does not minimize the fact that these patients remain in remission with persistent improvement in their liver histology for years. Clearly, persistence of very low titers of HCV RNA will not herald an epidemic of relapsing chronic HCV hepatitis, although reappearance of positive serum HCV RNA can occur (Hepatology 2002;35:688–693). The question of the role of very low titers of HCV RNA in the pathogenesis of HCC is unknown, but we do know that HCC is very uncommon in patients with mildly abnormal, nonfibrotic, or noncirrhotic histology. The role of very low titers of HCV in transmission of HCV via, for example, blood transfusion, is unknown, but should be investigated, especially in potential donors with indeterminate assays for anti-HCV (Lancet 2005;365:276–277). The role of occult HCV as a factor in the development of hepatocellular carcinoma especially in cirrhotic HCV patients achieving SVR needs to be investigated (Ann Intern Med 2005;142:105–114). However, one new area of considerable interest is the recent observation in 100 patients with long-standing elevation of their liver enzymes of unknown cause (J Infect Dis 2004;189:7–14). The sera in all patients were negative for both anti-HCV and HCV RNA. In 57 patients, HCV RNA was detectable in the liver. In 48 of these 57 patients, HCV RNA of negative polarity was found, indicating replicative potential, and in 40 patients, viral RNA was found in their PBMCs. Patients with occult HCV were more likely to have steatosis, necroinflammatory activity, and fibrosis.

In conclusion, occult HCV infection must now be accepted as much an entity as occult HBV infection, and we should no longer loosely refer to prolonged SVR as a cure (Hepatology 2005;41:23–25), especially because this term is still being used today (Ann Intern Med 2005;142:105–114, Hepatology 2005;41:275–279). As clinicians, we may need to revise our clinical attitude to the outcome of SVR following successful treatment of HCV with more careful follow up, and we must be aware of the possibility of occult HCV infection in patients with liver disease of unknown cause.

[MajNeni]

Hello!
I also think that two years (gearing up for tx, doing tx for two short times plus the 48 weeker that led to SVR) aged me at least 5 years.  Before tx I still felt quite young, but now I just can't convince myself; when I look into the mirror, it's like one of my aunts looking back.  MN

[willing]

cuteus - so glad to hear you're not ageing (aging). Me too - except my kids keeps telling me otherwise.

dd: I've started taking bets on my upcoming pcr, still 5 months off. My plan was to wait 2 years and see if I could predict the outcome without the benefit of testing (if it worked I should feel better, right?). Most of the time I feel pretty darn good, so I'm betting it worked, but there are days..it's made me realize this little experiment of mine is flawed by the fact that I've been getting older all along. In fact, I think the ageing (aging) is either picking up speed or I aged about 5 years during that year of tx. Anyway, I'm glad to hear you're doing well.

As for persistence, I'm in the CURED camp. The unchallenged durability of SVR makes it pretty clear our bodies (finally!) learned to keep any residual virus in check. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15838801&query_hl=51">Radkowski's</a> evidence is pretty good - no refutations yet - so I'm pretty sure there's a lot of SVRs out there with residual virus. But so what? Whatever' left is not triggering further damage to the liver.

The great train of life easily picks up hitch-hikers. Look at the massive amount of junk DNA we carry around. The presence of a few stow-aways on board doesn't bother me particularly until someone proves they're doing harm (and remember it wasn't the virus that was directly responsible for the inflammation in your liver, but the immune response's incompetent attempt to get rid of it).

[carpedi]

Ok, after reading the above posts, I guess the real answer to this would be that no one knows for sure yet, but what would be anyone's best guess as to whether, if the virus remains undetectable in the blood, it is still possible to infect someone else by means of a blood exchange?

[willing]

Maj : mirrors lie, don't trust them

carpedi: that seems VERY unlikely. if the quantity of virus in serum is so low as to be undetectableto by a PCR test the chances of a  stray virion getting from your blood into someone else's have to be pretty far out there. The occult HCV studies are reporting residual viral particles *within* cells of different tissue types, the amount of free virus left in serum has got to be miniscule and the likelihood of infection is correlated with the degree of exposure, for example, most of the multi-genotype studies, focus on IDUs (<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15484265&query_hl=15">see</a>).
.
However, as shown by Radkowski's latest paper, it's a good thing SVRs can't give blood ( he focused on subjects with active antibody, undetectable PCRs and normal enzymes). I believe blood banks scan for antibody rather than virus simply because the test is cheaper, but it now looks like this was a good strategy.

dd: I don't think there will be  major progress on such subtle   interactions any time soon. However, it makes for an interesting mystery! Here's a couple of recent papers <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15858018&query_hl=10">Roque-Alfonso</a> and <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15994809&query_hl=2">Zehender</a>,  that indicate  the virus variants that take up residence in the PBMCS have different genetic adaptations. The Zehender paper seems to suggest, the PBMC-resident virus is under little pressure to adapt to any immune system attack.

[friole]

Am I understanding all the techo-bable correctly -- If you give blood and you have hep b antibodies, and no hep b antigens, and you are hep c positive, you can transfer BOTH active hep b and c?
WOW!  I would have thought if you transferred someone the b antibodies, you would be transering the agent to fight the hep b.
Kathy

[willing]

sorry, but I don't think I quite understand the question. If you have HCV antibodies the blood bank won't take your blood and I assume the same is true for HVB. Also, by passing blood you can infect someone with virus but you can't pass on  your immunity - their immune system has to learn to make its own antibodies. BTW did you ever get an infection score on your biopsy?

[willing]

Coming up negative for the surface antigen means you had/have very little HVB, if any. Since about 70% of hbv infections are resolved spontaneously, there's a good chance that, even if you did pass on some virus, your recipent(s) learned to make antibodies, as you did.

If it's any comfort,I'm guilty of the same...

[friole]

" So what is the significance of occult HBV infection? More than 25 years ago, it was shown that patients receiving HBsAg-negative, HBcAb-positive blood were still at risk of developing post-transfusional hepatitis B "

This is the statement from the paper that I am referring to.

[friole]

No, I don't know what an infection score is -- or do you mean the grade.  Yes the pathologist scored it Grade 1 Stage 1.
I am asking about the hep b because when the doc ran that test, I tested positive for the antibodies and negative for the antigens. I didn't know I had ever had it but apparently I did.  As I have stated in past posts, for several years after I had a blood transfusion in 1977 I was a blood donor.  So I am asking if I not only could have infected people with hep c but also hep b. I feel awful.
Kathy