Hep C Discussion Forum

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:

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.

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.    

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.

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

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.

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.

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.

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.