Hepatitis C Virus: Warehousing in the Age of Protease Inhibitors

Posted by Jeff Berk, BOLT International

In follow up to the questioner regarding what BOLT’s Infectious Disease Thought Leader panel thinks about warehousing hepatitis C patients vs. treating them today, we asked that very question a couple months back.  So once we get past today’s cactus flower, I’m going to share their sentiment.  So today’s spiny beast is an ariocarpus fissuratus.  This guy is about six inches across and about 50 years old.  And in response to the questioner who asked why I start most blogs with a cactus flower…  I’ll run out of blogs before i run out of cactus flowers in my garden.  So it’s a way to stall you just a little bit.  Besides, they’re COOL (says me).


Okay, enough stalling.  So let’s talk about warehousing:

  • The patients who are going to receive protease inhibitors will be those who are genotype-I stage-3 or stage-4 (advanced liver disease) getting primary treatment and those who are being re-treated after some response to interferon + ribavirin.  These are not null responders, but rather the group includes patients who may have had an inadequate response because they were dropped from therapy due to side effects or some other reason.  There are going to be some more complicated patients who will not be warehoused; for instance, patients more clinically obvious cirrhosis who may be looking at a liver transplant down the line, or African Americans who are at higher risk.


“How you look at a patient and decide whether or not you will actually write a prescription for one of these new protease inhibitors? Will be any difference in the patient demographic, etc? Well, the fact that the efficacy is so much better if people have pharmacy benefit plans that will pay for the drugs, I think I will use both drugs and I will use them virtually exclusively in the primary treatment and in the retreatment.  If someone comes to me starting out with a low hemoglobin I might try telaprevir first.  If someone comes to me and is being retreated and they had terrible rash from ribavirin with their first round of treatment I would use boceprevir (Merck).  So there are just some of those little things that probably affect decisions in maybe 10 or 15 percent of patients.  Otherwise, I think everybody that is going to get treated or retreated is going to be using triple therapy by the protocols that were presented a couple of weeks ago”.


“First of all, there are some genotype-I patients who I have encouraged to wait over the last year or two so they are going to get treated.  Secondly, there are going to be patients who were deemed treatment failures previously.  Now often they are not really treatment failures.  They were inadequately treated and then they got a side effect so therapy was discontinued.  But they are truly not treatment failures.  They are just inadequately treated.  And thirdly, there are going to be some more complicated patients, for instance, patients more clinically obvious cirrhosis who may be looking at a liver transplant down the line.  They are going to be candidates for therapy also.  Again, some genotype-I patients treatment-naïve that we have encouraged to wait.  Secondly, people who are treated previously and didn’t respond or treatment was inappropriately stopped, and then thirdly the more complicated patients.  But I am comfortable doing that because we have got the infrastructure here to undertake the management of a lot of patients.  I again I think it is going to be very difficult for the average general gastroenterologist to undertake treating a lot of these patients”.


“Clearly there are a few people who we feel won’t be able to wait; people with more advanced stage diseases and you see them go slowly downhill and we have been trying to get them ready for treatment but approval is not going to come in time for them.  So those patients we are carrying on and moving forward to treat but patients who we are encouraging to wait it is a joint decision with them.  They are more than happy actually where if my chance of increasing my response rates go from 40 to 60 odd percent I am all for it.  African American patients are obviously a main group of patients as well.  If they have got minimal or moderate stage disease their response may go from 20 up to 40 percent or maybe higher they are all for that as well”.


“I think my decision will be based on the age of patients and the my sense of the level of compliance.  For many patients taking a lot of medications it could interact with the P450 cytochrome metabolism.  For these patients I probably will try to avoid using new drugs but mainly due to compliance issues”.



  • Stage-1 and Stage-2 treatment naive and null responders to interferon and ribavirin should continue to be warehoused when protease inhibitors are approved for HCV.  No patients should be given HCV monotherapy with a protease inhibitor, and null responders would in effect be receiving protease monotherapy.  This is highly likely to lead to resistance to protease inhibitors, which will be a direct treatment failure, and also limit the potential use of a protease inhibitor cocktail once polymerase inhibitors, NS4B, NS5A and other classes of antivirals come on line over the next few years.


“The warehousing aspect comes from the fact that as best we understand the natural history of hepatitis C is obviously different in different people but the disease progression is what we are trying to prevent.  It has a long natural history and the absence of obvious respects like HIV or alcohol, etc.  The people you are considering treating you have some evidence that after 10, 20, 30 years of the disease this is what you are dealing with like a stage 1 or stage 2 even.  We know there are newer drugs coming around the market which will increase your efficacy rates.  And we are certainly doing the same in terms of the warehousing that we are encouraging people who are eligible treatment with the current standard of care to say, look, six months from now your disease progression is not going to be significantly different from now.   We would wait and encourage people to wait to take part either in a direct acting antiviral study or wait for FDA approval so we can treat once these medications are available.  How are your patients responding to that? Pretty favorably actually because they are all on web chats and have friends and colleagues and family and other people they are in social contact with who have taken interferon and are like I don’t want to do that.  Everyone is hesitant towards treatment”.


“Who is going to be the patient eligible for treatment with monotherapy for these? For monotherapy it should be no one.  So we know if you put someone on telaprevir (Vertex) or boceprevir but there is good data that shows within days you can drop your viral load rate quickly but also within days you get resistant virus.  We definitely cannot use either of these as a monotherapy.  Now we can use it by adding on to standard of care so interferon, ribavirin and protease inhibitor.  The problem there is related to that in that if you have a patient who truly is a null-responder to standard of care then you are effectively giving them something akin to like functional monotherapy when you give them a protease inhibitor.  The problem is we don’t know apriority who is a true null responder to standard of care.  And that is the rub here because if the patient who is a null responder to standard of care and they are getting boceprevir it is almost like you are giving them monotherapy and they are at much higher risk of developing resistance and not only then that means they could fail this therapy but that could really mess them up for potential future therapy, which presumably will rely on one of these compounds as a component.  And so then if they had high level resistance to this then that is going to make them ineligible for future things as well that rely on this.  And again, that would apply to anything that is coming out first.  But unfortunately since many people have been warehousing their patients waiting for better stuff to give them I think it is going to be really important to resist the temptation to just throw everybody on this as soon as it comes out because they are just going to get into huge problems with resistance and it is really going to be the proper selection of patients to identify who has the best shot of benefiting from this as opposed to getting messed up from this.  I think there is actually a liability issue from the physician’s standpoint and even the companies, because I don’t think there is enough marketing, their education and then adequately conveying the risks to patients and when a patient comes back and says he doc now I am resistant, not only to this but this is going to mess me up for the future why didn’t you tell me about this and why did you put me on this.  So I think that has to be a critical part of the process, of course the physician has to be educated enough but to educate the patient that there is a significant risk here and we can’t tell for sure who is going to respond to this and who isn’t and the risk of not responding is also making you maybe less likely to respond in the future”.


“I think anybody who is a potential candidate for therapy is going to be encouraged to get treated over the next few years.  That is going to include a lot of treatment-naïve patients in addition to patients who were unsuccessfully treated in the past for a variety of reasons.  Can you comment on that term “warehousing”? Is that term warehousing a term that your community uses regularly? Absolutely.  And like any cadre term it is now completely overused.  But I think there are a lot of patients waiting in the wings for these new drugs to be licensed as are their doctors”.


“These major new drug; it is appropriate to treat many of the patients who have been waiting until now”.



  • Patients with an adequate liver (fibrosis measured by biopsy) who have a contraindication to interferon due to psychiatric or cardiac reasons should continue to be warehoused.


“I think patients who have an absolute contraindication to an interferon-based regimen.  They have got major psychiatric problems.  They have unstable cardiac disease or whatever.  So they are not going to be probably treated the first go around.  And it is going to be tricky because treatment is clearly going to be better.  But on the other hand if we are seriously concerned about somebody’s inability to tolerate an interferon-based regimen is it appropriate to wait three to five years?  I think for a lot of patients the answer will be maybe.  We will do what we have been doing with some of the other patients in the system.  That is to do a liver biopsy and figure out how severe their liver disease is and make a judgment call about whether they should continue to hold out for something better that is not interferon based”.





  • Savvy patients who do not have advanced liver disease, who are progressing slowly will get a recommendation to hold off from protease inhibitor monotherapy (note: really this is a PI + interferon + ribavirin).  These patients will continue to be warehoused until the PI can be combined with a polymerase inhibitor or other new class.


“It depends on where they are with their disease.  If their liver disease is advanced so far or the patient can’t think of not going another day without being treated then fine, but you do the best you can with what you have got.  But if they are a savvy person or their disease isn’t so rapidly progressed or not rapidly progressing and they could hang out another year or two the good news is there is a lot of good stuff coming down the pipeline.  I do tell my patients and I look them in the eye and I tell them I do believe we will have things that will benefit you in your life time and I can’t say that for many diseases in medicine.  I really do think this is an encouraging area going forward.  It is just that unfortunately not everything is being developed at the same time or approved at the same time.  A lot of great drugs that worked well in the lab have failed in the clinic to date so we have got a big grave yard of products that have failed.  But eventually I think a couple will make it through and that will make therapy much more successful even having one additional direct acting antiviral to add on so you have two that you add on to standard of care and that is going to, I think, really help a lot”.

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