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220090 tn?1379170787

HCV, HIV, HBV and the effectiveness of PIs

I just went to Mt Sinai for my post 2 week physical and blood draw.  I asked the doctors a lot of questions about these viruses and the effectiveness of PIs in treating them.  There has been a lot of confusion on these boards in some recent threads and I include myself among the confused.

So, from the horses mouth:

HCV and HIV are RNA retroviruses.
HBV is a DNA virus.
However, HBV and HIV only reproduce within cells.  HIV uses the DNA of the host cell to reproduce.
HCV reproduces free in the bloodstream and not within a cell.

This makes HCV much easier to treat with PIs since the virus is exposed during reproduction and the other two are hidden.  This is the reason it is possible to cure HCV with a PI, but HIV and HBV are not curable with PIs.

The current PIs attack the Ns3 protease within the RNA and since they are very selective, the can't inhibit reproduction of all mutations of the virus; thus, SOC is required along with the PI.  The newer PIs in early stages, attack a broader range and the polymerase inhibitors take an entirely different approach.  All the Capo Grandes I spoke with think that in the next few years a cure will be available that no longer requires SOC - thank God!!

Eric
38 Responses
137025 tn?1217768341
I'll second that..thank the gods for me too!!!   I'm still trying to process the idea that the PI's may be available to me at my next try at tx in 2009, so the thought of a complete  cure with no interferon seems almost presumptive.  But I'll keep taking the good news as it comes along.  Take care.

Willow
388154 tn?1306365291
It sounds good indeed, its just that i´m starting to get so freeking tierd of this soc shiit so it tempest me to jump of the soc wagon (have 36 weeks left)but when I think about that you been on the wagon 8 times it make my heart bleed so I sincerely hope you made it this time.
Best of luck to  you.

ps I´ve already gone to far to jump.
220090 tn?1379170787
comeagain: Stick with it one day at a time.  You will make it!  It certainly is a test though!

Willow:  These are exciting times for us.  I know full well how difficult it is for you being stage 3 and having things move so slowly!
Take care,
Eric
220090 tn?1379170787
The newer PIs in early stages, attack a broader range
--------------------------------------------------------------------------------------------------------
I meant to say the second generation PIs in early stage development.
Avatar universal
I beg to differ with some of what you wrote, namely:

HCV is NOT a retrovirus.

HCV reproduces in the hepatocytes of the liver.  It is not exposed during reproduction.  Many companies are now working on delivery systems to overcome that problem and carry their antiviral drug into the hepatocytes.  

Well, that's my understanding anyway.

I'd certainly welcome a cure that does not involve SOC and there do seem to be some in the early stages of development right now.  But even if the perfect cure were found today it is still likely to take at least 5 years to go through trials and get FDA approval.  

dointime  
148588 tn?1465782409
Thank you for taking the time to consult over this with your docs. I appreciate any new knowledge - this board is a great resouce.
220090 tn?1379170787
I suggest you give a presentation to the research scientists at Mt Sinai.  They might be enlightened by your explanation.

I did my best to try and find out more about this by talking to experts in the field.  Perhaps they are wrong, I have no way of knowing.  What is your source of information?


Eric
220090 tn?1379170787
You are most welcome.  It was your comments that prompted me to ask the docs.
Avatar universal
What are PIs?
220090 tn?1379170787
Sorry for the abbreviation - stands for Protease Inhibitors.  A class of designer drugs that attack a specific virus at specific points in the RNA structure and inhibit an enzyme that is required for replication.

I am sure someone will disagree with me on that, so keep reading for clarification or confusion as the case may be. :)
Avatar universal
the "retro" in retrovirus comes from reverse trascriptase, an enzyme that reverse the normal (dna->rna)direction of transcription into rna->dna .
See for example
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/R/Retroviruses.html

I believe  correct statements are
HCV and HIV are RNA viruses (carry their genome as RNA)

HVB is a DNA virus
(see eg http://www.microbiologybytes.com/virology/HBV.html_

HIV is a retrovirus (generates a DNA intermediate), HCV however is not: DNA never plays a part in the HCV lifecycle

Also, *all* viruses can repoduce only in living cells (that's what makes them a virus), Viruses travel light, only enough baggage to get into a cell and co-opt the cellular machinery to their own reproductive ends; they can't reproduce on their own.  Perhaps the Drs were referring to reproduction in PBMCs, a type of blood cell.

But these are all just details, thanks for checking.
220090 tn?1379170787
None of us are trained research scientists here especially me.  I am as persistent as a bulldog though and I pester everyone that I think does know something about HCV.

I think that posters on this board should keep an open mind and try to verify their beliefs before they post strong statements.  I am as guilty as anyone of making blanket statements about biochemistry when if fact I am fairly ignorant about this whole field.

Just now I did a google search and found at least 50 sites that claim HCV is a retrovirus, so I think I was given good data.  Might be more than 100 sites :).
Avatar universal
yes.. citations are a good thing..perhaps someone can find a better one, but this one from the "viral hepatitis prevention board" covers the basics:
http://www.vhpb.org/files/html/Meetings_and_publications/VHPB_Meetings/geneva2002/S2AP1%20Grob.pdf

on the page titled "Genetic Organization of HCV" is a layout of the HCV genome. Note how the polyprotein produced by the ribosome is chopped up to yield the various viral proteins, including NS3 (targeted by vx and bc) and NS5B (targeted by R1626). Note that there is no reverse transcriptase - a necessary component of any retrovirus.

On the page titled "HCV life-cycle" is a basic schematic of what HCV does to make copies of itself. NS3 is needed at step 4, NS5B at step 5 so whenever either of these gets blocked no progeny virions are produced.

What's meant by "blocking" can perhaps be best understood by looking at a picture of the actual protease with a bound inhibitor - here's a recent example:
http://www.rcsb.org/pdb/explore.do?structureId=2GVF

You can click on the "JMol" link to get a better picture. The large, blob of spaghetti is a part of the viral protein, the small molecule is a stand-in for the the drug.
220090 tn?1379170787
Thanks for the clarification.  What do you make of all the papers on the Net that refer to HCV as a retrovirus?

I have no training in this field at all, my background is in computer science.  There is so much disagreement here on basic issues, that I tried to get the information from the research people at the hospital.  Perhaps I misunderstood them, but they seemed clear that both HBV and HIV reproduce very differently from HCV and that HCV was exposed to the PI during reproduction. They were also clear the HIV and HBV are hidden from the PI during most/all of the cycle.  Could the HCV  virus leave the host cell after it takes what it needs?

Are you a biochemist?

Thanks again for the clarification.
Avatar universal
Willing -  thanks for weighing in here.  I do think it is important to try and maintain accuracy about the basic facts of HCV.  

Andiamo - here is a graphic description of the lifecycle of the HCV virus, showing in pictures the invasion of the hepatocyte and subsequent mechanism of replication.
    
Your wrote "I suggest you give a presentation to the research scientists at Mt Sinai.  They might be enlightened by your explanation."
I would be happy for you to take this along to the researchers at Mt Sinai, although I doubt that they would not already know these facts.

http://hopkins-gi.org/multimedia/database/intro_293_VC-04.swf

dointime
Avatar universal
dointime - nice movie - much clearer than the diagram.

andiamo: the main point of your post is very interesting. I've been so bogged down with hcv I haven't really taken the time to read much about hbv/hiv and their response to designed drugs. It seems encouraging that experts anticipate greater success with targeting PIs at hcv than at the other two viruses. (both nastier than hcv). And no, I'm not a biochemist - actually a computing-to-bio retread - the two are starting to look more alike every day.
220090 tn?1379170787
I thank you for your clarification of the virus definitions.

I know next to nothing about biochemistry.  In this post, I repeated what one of the research people told me without verifying it.  I won't do that again, as I have no idea what she meant.  I do know what she said and that is what I repeated.

All of them said that HBV and HIV reproduced in a different way than HCV even though HIV was an RNA virus, HBV a DNA virus and HCV an RNA virus.  One of them definitely said that HBV and HIV were embedded within the host cells and hidden from the PIs.  While HCV was exposed in the blood stream.

Perhaps I read in that they were embedded during reproduction and HCV was not and she meant during a different part of the life cycle.

In any case, I apologize if I came across as testy.  I am feeling worse two weeks post treatment than I did during treatment.  I will probably stop posting until I feel better and get some sleep.

232778 tn?1217450711
It is important to realize though that PI's are not the only promising lines of research at the moment. In addition to research on a vaccine, there seem to be new "discoveries" every other day in updates, as to potential lines that are promising. If a PI come's along, that eliminates the need for other drugs, that will be great. But, it is a bet that PI's will be first, and no more than that. The "lucky" thing for us is that a lot of people have Hep C, so there is money for big Pharma and small Pharma in exploring it. If we had instead had a rare disease, it is not so prommising, sadly.
Avatar universal
yes, lots of new stuff on the horizon : RNAi, ribozymes, peptides like the one Mike posted about recently, but... trouble is, the distance to the horizon isn't likely to get much shorter. For example, there was nothing particularly revolutionary about VX: inhibitors of serine proteases have been the poster story for rational drug design and Vertex got to build on much previous work, including BILN-2061. However, lab development was finished by 2003 or thereabout and the currently recruiting  PhaseIII trial won't complete until March 2010, with FDA approval hopefully shortly thereafter. That stretch of time isn't likely to get shorter - and I'm not sure it should considering the number of recent candidates, including biln-2061 and hcv-796 , that have been discontinued because of adverse effects.

So unless you're willing to wait 10 years or more, it looks like the near-future tx landscape will consist of an ns3 inhibitor (vx or bc), an ns5b inhibitor (r1626),  soc and ntz/alinia (drugs like ntz that already have fda approval and get redirected are a great short cut).

With VX in 2010, reasonable guesses are bc by 2012 and R1626 by 2014 - or 6 more years - and then there's the question of how to combine them. From what's available now my nomination for an ideal tx, would be:

week -4 : start ntz/alinia
week -1 : start weight-based rbv
week 0 : start soc
week 4 : add vx or bc (soc lead-in should work for either)
week 20: add r1626
week 24: stop vx/bc and drop ifn (but not rbv) to half dose
week 44: end r1626
week 48: end soc and ntz, eot

this gives 4 weeks where any resisting virions have to be cross-resistant to both types of inhibitors - a tough act to pull off. The one week rbv pre-dosing may or may not make a difference and could be replaced by beng careful about evenly distributing rbv pills through the day at start.
R1626 seems slightly more sluggish about killing off virus but resistance mutations are near non-existent, thus the 2nd 6 months, at half dose-ifn should be ample time to eliminate residual infected cells. I'd be curious to hear any thoughts about other combo strategies... now if I could just beg/borrow/steal the pills before 2012..
Avatar universal
I've been thinking along much the same lines as you regarding my tx options and the timeline.  I agree that in about 5years+ we will be looking at one protease and one polymerase inhibitor + SOC/alinia.  That is unless one of the vaccines comes up trumps.  There's also Locteron as the interferon which would be bi-weekly and not give so much injection site inflammation.  

As I have aready had VX950 and don't fancy the rash again, I would like the protease to be either vx500 or itmn-191, both currently in phase 1 development.  For the polymerase my choice would be Pharmasset's R7128 because of it's lack of sides and because there's no resistance to it been found.  It is also in phase 1 development.

Your ideal tx is very interesting and gives me food for thought.  I am a subscriber to the 'put the virus down hard and fast at the front of tx' school of thought.  This may be because my 2 failed tx's were because of breakthrough so I need to nail the b****** before it can get up again.  I would do:

week -4 : start alinia
week -2 : start high-dose rbv    
week 0 : start inf + protease inh. + polymerase inh, drop riba to weight-based +200mg
week 8 - 12 stop the protease during this time depending on sides.
week 24: reduce riba and inf only if necessary because of sides
week 40: stop all, eot
I would stop at week 40 assuming RVR as that would be 36 weeks after UND.  It would also cut down on exposure to inf and riba.  

I guess that everyone's ideal tx would be different depending on how their virus behaved during their previous tx's.  I got to UND with no problem but the virus just got up again and that was the end of that.  For others, a slow and steady war of attrition may be the best approach.

Great topic you raised!  I'd like to hear other's thoughts on combo strategies too.

dointime    

  
Avatar universal
skin problems, primarily ifn-fueled escalation of otherwise dormant psoriasis, were a problem with me as well, which is why I think I'd rather risk the boceprevir nausea than the telaprevir rash. I'm curious why you would wait for itmn-191 and r7128 when boceprevir and r1626 are already in phase II, seem quite tolerable, and have given very encouraging data.

The options in  mixing this cocktail seem  open-ended, and it seems  unlikely one size will fit all, the strength of one's ifn response probably being the main determinant. Unfortunately, the mechanisms of breakthrough and relapse are still mostly unknown, so planning the best path is still mostly speculation. My main reason for not wanting to use all the ammo up front is that it's pretty clear from relapse that a relatively small number of immune-undetected but infected cells can remain for a long time (consider the benefits observed in extended soc). Eliminating these seems to require more than soc, and r1626, with half-dose ifn seems an ideal candidate. How early on was your breakthrough?
Avatar universal
There seems to be a question about boceprevir results.  Maybe we will get clear results from EASLD at the end of the month.  If they were comparable to VX950 for speedy VL knockdown then I'd go with boceprevir.  

I'm not too keen on the neutropenia associated with R1626.  I would need to see how the trials go using only a half dose of interferon.  R7128 has so far not reported neutropenia, still it's early days for both those drugs.  If I thought I could get through 40 weeks of R1626 and not have to use neupogen (yet another drug and another injection) then I'd go for R1626.  

I guess the bottom line is that when my liver calls time I'll have to grab whatever is available and do the best I can with it.  

I agree that the ifn response is probably the main determinant of the tx strategy.  That said, most strategies probably should have a predosing phase, a killing phase and a mop-up phase.  

The mop-up phase is the easiest to design.  That phase is a war of attrition with the last few virions and, as you say, can last a long time.  So drugs which don't develop resistance, like alinia, are most useful.  Actually I am not sure about the resistance profile of R1626, another reason why I preferred R7128, which has not so far produced resistant mutations.    

The killing phase will be the most individual I think.  A lot will depend on how tolerable it will be to take both the protease inh. and the polymerase inh. at the same time.  If it can be tolerated I don't see any advantage in holding off with R1626 till week 20.  Why would you not just take it for all 48 weeks?  I am depending on the virus not being able to mutate round both these drugs at the same time, so I would want to maximize the time that I took both together.  The protease inh kills very quickly then develops resistance, so the timing of that strike could be important.  Even after resistance has set in it still has the function of preventing the virus reverting back to wild-type, so there's one less place for the virus to hide and that is good because it is more likely to make fatal mistakes while mutating.  My hope would be that the killing phase would kill every last one of the virions, making the mop-up phase purely for insurance.    

I was UND at day 15 with VX950 and ifn (no riba) then had confirmed breakthrough by day 28.  I then started SOC, was UND at week 6 and had another breakthrough around week 16.  I think that if I had had the triple therapy all at once from the start it might have worked.  From this, I believe that using all the active agents at once is more effective that using them serially within a tx.    

Anyway, I know that I can go UND quickly, but that I have a job on my hands to hit the virus very hard and fast before it can get up again - and without killing myself in the process!  

Did you do a previous tx?  If so, what happened?

dointime                        
Avatar universal
I know what you mean about when it's time it's time. My mental image of re-tx planning is a bit like being on an airplane that's on fire and is losing altidude over shark-infested waters, but is approaching the coast: jump too soon and you're lunch but wait too late and you're toast. The EASL presentations are already online though I think the press embargo may limit publicity - there's a discussion of the results in that "Good news from Vertex" thread andiamo started 3/31.

My overall impression of BC's phase II (Sprint 1) relative to the VX Prove I and II results was comparable - particularly w12 stats with the 4 week soc lead in. Also the results on lack of resistance mutations to R1626 and w4rvr-eot correlation (84%!) are  very encouraging. At this stage, my plan is to jump whenever both are available, and it looks like r1626 is the longest wait, particularly if vx gets early approval for re-tx patients on the basis of  prove III results (Schering will probably not be able to do the same because their phase II results on tx-experienced are such a mess). I doubt we'll see much data on tolerabillity of multi-drug tx until after approval so I'm assuming it'll be my turn to be the lab rat on that one. Re. using the ns3 pi for the whole time, it'll be interesting to see whether the vx and bc 44-48 results differ from the 24 but my hunch is the NS3s PIs are so effective in eliminating all but resistant mutations that the extra time won't make a big difference - you're just extending the rash/nausea misery.  It sounds like in your case resistant strains were quickly selected and then only partially eliminated by the addition of soc so starting with both ns3 and ns5b pis up front may be the better strategy - though there's also the question of how much your ifn response would be strengthened by the ntz.  I had no breakthrough as far as I know (std 48 week tx but with a slightly ominous inflection point in the vl curve around w8) so am more concerned about end-game reduction.

One issue you'll probably want to investigate is cross resistance of vx,bc and itmn. There are a few papers on this and  I haven't looked at the question  in any detail but it may well be that the selection effect of the first tx may rule out both vx and bc in a re-tx since they are so similar.
Avatar universal
I'm confused by your posts. I thought the beauty of Vertex and other PIs, etc was that it was so potent it would LOWER the time needed for treatment. It seems that both your treatments with multiple PIs, and alinia the SOC still lasts 40+ weeks. Are you basically talking about Genotype1's who have either relapsed or never responded or are you talking about all 1s. I assume for 2s and 3s the time of treatment would be much lower, possibly only 12 weeks.  Could you explain the long SOC with the PIs

Thanks,
Barry
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