Hi Malcom:

I am a geno type 1b, my mistake. So, should I be asking my doctor to do this blood test to figure out the interferon sensitivity.

He didn't mention it to me. I am so overwhelmed with all the information out there. He told me since my liver damage is in stage

1, then I should wait for all oral treatment. But, I think I am gonna start next year since I have lichen planus because of HEP C.

Thanks Malcom.

Hi Nancy,  I can't explain why the Incivek treatment regime is so different- it is certainly much simpler.  If you are TT at IL28B you are less likely to be interferon sensitive.

In your post of June 13 th, you said you were Geno 1b. Why do you now say you are Geno B?

Malcom,

I don't mean to be stupid, so if I have the TT gene then I might not respond well to interferon. I am kind of lost...

You had 4 weeks of interferon, and ribiviran (spelling), before you took victrellis?  Why incivek regimen different?

I am thinking about treatment for next year, and need to know. The doctors don't really explain well. They think we

are all as smart as you. By the way I am a geno type B and I am originally from the middle east don't know how in the world I got HEP C, and a geno type B???

Hi Nancy, no, it's the other way round. The TT's have only a 30% chance of being Interferon sensitive, compared to 45% of the CT's. I am CT, but because I had a 4 week leadin with Interferon and Ribavirin ( before starting Victrelis), I was able to measure my Interferon Sensitivity directly. As my Viral Load dropped by over 2 logs, I knew I was Interferon Sensitive, and had a better chance of SVR. This is a more accurate way of doing it, rather than relying on a gene! Unfortunately, patients on Incivek do not get this chance, as they do not have a leadin ( I don't understand why!).

Malcom:

Thank you so much for explaining. My last question so, if you are a TT then that means you will respond better to interferon, than if you are a CT right?

Thanks again.

Hi Nancy, I'm a retired Radiologist. My special area was upper abdomen imaging. I've studied HCV for over 20 years, ever since I was diagnosed. So I know a lot of stuff, but I am not an Hepatologist and I am not qualified to give Rx advice ( except to myself!).

SVR is as good as we get to a cure. It means there is a 99.9% chance that we won't get a relapse. There may actually be some residual circulating virus, but our immune system is able to deal with it. In remission is not a term I'd use, as it implies greater probability of relapse.

There is a gene called Interleukin 28B. This may exist in 3 forms- CC, CT or TT. These forms are called alleles, and are part of our genetic makeup. It has been shown that this gene determines likelihood of Interferon Sensitivity. ~65% of people with the CC allele are Inter. Sen. compared with ~45% of the CT's, and ~30% of the TT's. This is a specialised blood test which is only done in large Labs.

Chronic HCV goes though cycles of acute inflammation, which are completely haphazard. This is why the Viral Load can fluctuate wildly. The VL is also completely independent of the amount of liver damage. Cheers.

Thanks Malcome, That explains why I get another one in 4 weeks.  Very expensive injection if you have no insurance and no copay help from the drug co.   $7000. for 1 injection.  More than gold.    

Malcom: 

Are you a doctor?  You know so much. Thanks for sharing your knowledge. So, if you achieve SVR it doesn't really mean that

you are cured. It means that the virus is in remission, Right?? Also, what is CT or TT allele, I have not started treament. I know

that my viral loads goes up every time I have to use any prescription drugs that supresses my immune system. It is so unstable.

It is kind of scary. I have gone from 300,000 to 99,000 then to 979,000 and now to 500,000. I was on steroid cream for 2 weeks.

Hi Cathy, Neulasta is similar to Neupogen. It is pegulated so it has a long action. It works by stimulating the white cell factors to produce more neutrophils. Cheers.

recieving nuelasta injection today for low WBC.  Any info you can offer on this.

Thanks for filling in some of those gaps I was missing. 

Interesting information Malcom. My hemoglobin finally came back over 10 for the first time in a long time. Before treatment it was at 14, and it was under 8 at it's low point.

Vern, I recommend the American Landrace, well known for the quality of it's heart valves! They are highly resistant to HCV.

The virus may enter extrahepatic cells, such as heart, muscle, brain etc. It may cause an inflammatory reaction, which may be the reason for some of our extrahepatic symptoms. Researchers cannot agree that the virus can relicate in such cells, and re-enter the blood stream.

Malcolm, since you bring up Vyrass not hiding in muscle, brain or kidney cells etc. I developed a murmur two years ago and a cardiologist speculated that the virus might be adding to some aortic stenosis, by irritating the valve tissue and contributing to the valves stiffening. So, I thought Id buy a piglet and start raising it for valve replacements.

 Any ideas on this? Is there any type or breed that you like or recommend?

Hi Judy, If Peg. is not used, there will need to be an alternative for the mutations. Abbott's new regime is QUADRUPLE therapy- the virus is blocked at a protease and polymerase site, together with the 'nerve centre' site, plus Riba. This looks exciting. It will be a race between Abbott and Gilead for the 1st non-Inter. ****tail. Steff posts good updates on the trials. Cheers.

Malcolm, I found this; thank you for pointing me over!  This is EXACTLY the info I've been looking for, for a long time, now.  It explains So much.  I really appreciate this; thanks!

I had no idea it resides in our monocytes, as well!  My monos are lower now than they have been throughout tx.  So even the interferon-free tx of future will be triple therapy, or at the least 2 chemical drugs.

Of patients who are Undetected at end of treatment, 10-30% will suffer rebound (relapse) and fail to achieve SVR. If we exclude outside re-infection, the virus can only reappear from 3 sites-  from residual virus in the liver, blood or extrahepatic tissues.

In patients with severe fibrosis or cirrhosis, it is easy to imagine rests of virus remaining in underperfused regenerative nodules. These hepatocytes are hypoxic and may not receive adequate drug exposure due to the reduced hepatic artery and portal vein perfusion. The HCV has very efficient methods of entering these hypoxic hepatocytes. When treatment ceases, any virus in these nodules can go beserk. I am convinced this is the reason for the lower SVR's in F3-4 and F4's. This is not of significance in the F0-F3's.

There is still no agreement on whether HCV can enter extrahepatic tissues and replicate. The viral structure is designed to enter hepatocytes, not muscle, brain or kidney cells etc. I am inclined to dismiss this as a reason for relapse.

This leaves us with rebound, caused by residual virus in the blood. I include a blood cell called a monocyte. HCV has been found in monocytes, and this may be a source of residual virus. Our Undetecteds mean that the PCR test cannot find any virus. There is almost certainly some, and this virus will be a RAV.  VL <10 i.u/ml TND, equates to Undetected, but suppose we have 2 i.u. present- that's 6 viral particles/ml or 6,000/litre of blood. If we have 5l. of blood, we have 30,000 circulating viruses. For some of us, that will lead to rapid replication and within a few weeks, we are back to a VL of 1 million. Those of us who achieve SVR can cope with these residual viruses. Perhaps our immune response has been 'fine-tuned' by treatment. Or perhaps, those who achieve SVR do not have any residual virus at EOT.

Since June 2011, Researchers can identify individual RAV's. Blood examined from relapsers shows the same RAV's (2 in Geno1a, 3 in Geno1b) irrespective of whether the patient was treated with Inciv. or Vict. These RAV's gradually disappear, and the 'in-the-wild' type re-emerges as the dominant  strain. This is obviously the most effective form of the virus.

RAV's will be associated with all the DAA's, including GS7977. All will need mop-up drugs. If Peg. is not used, Riba. and 1 or 2 other DAA's will need to be given. As with antibiotics, we must be very careful to limit RAV's.

Malcolm. Thanks. This is the most detailed explanation I've heard and makes the most sense. I look forward to your next post on this.

By the way, thanks for becoming a Moderator.

My apartment has 15 steps up,,all i can say is whewww...Can only do about 4 steps and have to rest. I am on reduced peg (135). Might have to get riba reduced.

Hi Vern, antiprotease resistant mutations are probably the reason for most treatment failures (for patients on PI Rx). In the literature they are called RAV's (Resistance-Associated Variants). Explaining them is a bit complex, so bear with me.

The HCV exists as a family or quasispecies of viruses with similar, but slightly different structure. The dominant viral structure is called the 'in-the-wild' virus. It is an RNA virus, so has no template for replication- only DNA can encode information. When the HCV replicates, it makes mistakes resulting in virions with similar but slightly different structure. These 'mistakes' may only happen every 10,000 replications, but as there may be up to a trillion replications a day in an average patient, the numbers and variety of these 'mistakes' (mutations) rapidly builds up. Many of these mutations lack certain structural elements, so cannot enter cells or replicate. They just die. Of the other mutations, about a dozen have been identified and named (eg V36M) and these mutations can damage hepatocytes and replicate.

The antiproteases were developed to block an enzyme, the NS3 protease, which is part of the viral structure. This enzyme splits compounds in the hepatocyte cytoplasm allowing the virus to replicate. When we take Incivek or Victrelis, the enzyme is blocked and the virus cannot replicate. End of story? Wrong- the PI only blocks the original 'in-the-wild' virus. The mutations do not have this enzyme at this particular site, so the mutations now take over. If we took Incivek by itself, all the 'in-the-wild' virus would be gone from the blood in a short time. However the VL will rapidly rise again as the mutations take over. The mutations will continue the cycle of liver damage, so we're back to square 1. This is why the PI's cannot be taken as monotherapy. Enter our old friends, Interferon and Ribavirin. They do not distinuish between mutation or 'in-the wild'- they kill them all! Their action is complex but involves host response, blocking cell entry and blocking replication. This is why Interferon sensitivity is so important- unfortunately some patients have poor sensitivity. They will be the non-responders to previous Rx, and the ones who do not get Undetecteds. Often, they have the CT or TT allele at IL28B.

So, in a perfect world, triple therapy should work in Interferon sensitive patients and we should all get SVR's. We don't- I'll do another post about this, as I've developed a headache!

Hi all, most of my symtoms are related to Rx induced anaemia. With the haemolysis of Riba, the bone marrow depression of Peg and both from the PI, it's no surprise that we get anaemic. The reduction of Hb should be at least 3gms/cc, and the aim is to get down to ~10 . Below that, many Hepatologists will start Procrit.(or similar), or reduce Riba. The old rule of 80/80 still applies- i.e. to be on 80% of the optimal dose of Riba and Peg for 80% of the Rx time. I know we have forum members that have been on lower doses, so there are obvious exceptions.The 80/80 rule is particularly important in the first 12 weeks of Rx.

Having Hb levels of ~10 will cause fatigue, and this will affect people differently. However it's a good indication that we are being 'nicely poisoned'. Adequate levels of Peg and Riba are essential to mop up drug-resistant mutations ( to the PI's). The PI's are useless on their own. So, as you puff and pant up the stairs, remember that your low Hb is helping you towards SVR. Cheers.

Malcolm

Adequate levels of Peg and Riba are essential to mop up drug-resistant mutations ( to the PI's). The PI's are useless on their own.

Could you or others say more about this and PI's

Vern