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Table of Contents

• Case Study
• Questions & Answers
• Post-Test

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Hello and thank you for joining us this morning. What I'm going to talk about today is a case of an individual with HIV infection and liver disease. Now as you'll see, this is a complicated case, but is, indeed, a true case from my clinical practice really highlighting some of the challenges that liver disease, particularly viral hepatitis B and C, present with HIV disease. One other feature before we get into the case itself. What I'd like to is use the feature that allows us to have interactive polling, so at various times in this case I'll stop and send out to you via the web a polling question, which you can then answer and we'll use that as a basis for a response. We'd like to have this be an interactive session.

Case Study

Click slide to enlarge

So with that backdrop, let me begin by telling you about my patient. This is a 47-year-old man who was referred to me for evaluation of an elevated serum ALT level. In looking through his medical records and speaking to him, it's clear he had been HIV-infected since the late 1990s and had presented with a low CD4 cell count, although there was no clear history of opportunistic infections and he was doing well on highly active antiretroviral therapy. Now in the panel of lab tests that he brought to me, he was receiving zidovudine, 3TC, and efavirenz, and his HIV RNA was >50 copies/mL. CD4 count was quite stable in the 600 range.

Now what was interesting about his records, he was actually referred to me for evaluation of chronic hepatitis C infection. He, indeed, did have a positive antibody with late remote injection drug use, but he was also hepatitis B surface antigen positive. So in meeting him, it became fairly clear that he had liver disease that was medically important. His exam revealed hepatosplenomegaly. His laboratory tests, revealed a total bilirubin of 1.5, and remember he was not on atazanavir or indinavir, so this represents likely a liver source. His prothrombin time/international normalized ratio (PT/INR) was 1.6. His albumin was 3.2, creatinine was 0.9. We also found he did have active hepatitis C infection with a hepatitis C viral load of 6.5 million IU/mL and he was infected with genotype 1, subtype A. In addition, he had evidence of a reactive hepatitis B surface antigen. Now his E antigen was negative and his E antibody was positive.

Now I'm going to go to the first polling question in a minute here, but I did want to pause to mention that in terms of evaluating liver disease, some of the key basic laboratory tests are actually shown here. The platelet count could be an important predictor of liver disease stage and in this context, knowing that he has thrombocytopenia in the face of the undetectable HIV RNA, that's a potential trigger of liver disease. The total bilirubin, PT/INR and serum creatinine, along with the patient age, are all components of what is called the MELD score (the model for end-stage liver disease) developed by the Mayo Clinic and now used to allocate livers for transplantation. It is a prognostic marker and in essence, by putting these laboratory data into an equation, which you can access online through the UNOS (United Network for Organ Sharing) website (http://www.unos.org/resources/meldPeldCalculator.asp), you can calculate how high the MELD score is. Like many things, the higher it is, the worse the prognosis. So in this case, these lab tests are important in that the key component is PT/INR. That's not often obtained when caring for HIV-infected patients.

I'm going to attempt to send you a polling question. The polling question asks what additional tests would you like to have in the care of this patient at this time? Now remember he is hep C infected with viremia. He is hep B surface antigen positive.

1. Hep B DNA test.
2. HIV genotype.
3. CT scan of the abdomen.
4. Liver biopsy.
5. Both DNA test and a CT scan.

Let me tell you what I'm thinking with respect to these questions and what I can tell you in terms of showing the results. We've had just a couple of people vote.

The testing or the correct results, as I would envision them on this slide, is that you would want to do a hepatitis B DNA test. Why hep B DNA? We know this individual is hep B surface antigen negative. We know he's E antigen negative, but many patients with chronic hep B are, indeed, antigen negative due to the presence of what's called a pre-core or core antigen. And in this context, we cannot rule out the possibility that he is chronically infected with hepatitis B and need to do a DNA test to assess this. So I would go as far as to say any HIV positive patient with a hep B surface antigen positivity ought to have a hep B DNA test performed. The other thing that I would have picked is a CT scan, so that would actually be the one in three category and why I'd want a CT scan, as I alluded to in my discussion, there are some markers of bad liver disease. You've got a low platelet count, an elevated bilirubin, and my hunch is, based on his physical exam as well as his preliminary laboratory tests, that he may have cirrhosis. Now the CT scan could very well show us the results of cirrhosis and thereby eliminate the need for biopsy. With that said, I don't think a biopsy is an incorrect answer here and I often like to get a biopsy, particularly in the context of having both hep B and C, to try to determine which one is actually the active pathogen. So let me try to close this and then move on to continue our case.

The answer there, again, was both a hep B DNA and a CT scan, but I don't think a liver biopsy is wrong. In fact, I would have liked that in this patient.

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Here are the results. You asked for a hep B DNA and a CT scan and a hep B DNA was undetectable, <22 IU/mL-no evidence of active replication. The CT scan, as I predicted, shows a cirrhotic liver without a liver mass. Now the important thing here is he needs to be screened for hepatocellular carcinoma. All cirrhotic patients, whether it be due to hepatitis B or hep C, need to be screened for liver cancer.

How do we do that? There is a serum AFP and I know if you're like me, you learned that in school the serum AFP is the best way to screen. Well it turns out that the enthusiasm with serum AFP has really dwindled with recent evaluations and actually the most recent guidelines for screening for hepatoma from the liver society suggests that imaging studies should be the primary driver, so a CT scan, ultrasound, at least once a year in a cirrhotic patient. The reason for this is that the AFP is both insensitive, meaning it misses tumors, and it's not specific. It's elevated without showing any tumor on scan, so it's false-positive and false-negative.

He does have an enlarged spleen but no ascites and no varices are noted. His Child Pugh score, shown there, which is based on the presence or absence of ascites, the presence or absence of encephalopathy, PT, and albumin, and total bilirubin is 7, so that's slightly elevated. He's got Child's B cirrhosis, which is a little bit more advanced that we'd like. His MELD score is 13 and I mentioned this earlier in that this is the test that's used to allocate liver organs. Now if a person without liver disease were to have a MELD score calculated, it would be quite low, at around 6, perhaps 7, depending on their age. So this is not a high MELD score. Most people actually get liver transplants in the 20's, but this is elevated at a time I start to think about is this person really engaging in liver failure, and I need to be very concerned about.

Let's try another interactive question.

What do you recommend next in the management of this patient? His CT scan shows cirrhosis, his hep B DNA is negative, and his hep C is certainly positive. He's got a viral load of 6.5 million and genotype 1a.

1. Start peg interferon/ribavirin.
2. Stop zidovudine, add tenofovir.
3. Liver biopsy.
4. Refer for liver transplant evaluation
5. Both 2 and 4

We've got at least some people wanting to start taking interferon and ribavirin, we've got some who want the liver biopsy, and then some who want to do both stop zidovudine, add tenofovir, and also refer for a transplant.

Someone asked if HIV-infected patients are transplanted only through clinical trials. That really varies by center, but I would say that the vast majority of liver transplants in the United States are being done through an NIH-funded protocol. That doesn't mean that is considered wrong to transplant a person who is not in a clinical trial, but that's certainly not the way it is being done routinely in the United States. Increasingly there are options for transplant and we're hoping to get more and more people transplanted, although as we can talk about, there are some really very important issues that we have to deal with, both with respect to the transplant itself and organ allocation, but also with respect to recurrence of infection.

Let's go back to the case. You make the recommendation to switch to tenofovir. I certainly in my practice would have stopped zidovudine and switched to tenofovir. Now why would I do that? For two reasons. One is that this patient is only on lamivudine for his hepatitis B and I don't like to treat patients with hep B with just one drug. Now one could argue that it is working, but one could also argue that we don't know what his status is. So I would actually remove the zidovudine and switch to tenofovir, hence giving him two drugs for hepatitis B, both tenofovir and lamivudine.

The other reason to remove AZT is that I may at some point, plan to treat him with peg interferon and ribavirin. In the context of peg interferon and ribavirin, AZT increases the risk of anemia. We published a study showing that the risks of anemia and the need for EPO is probably two to three times higher if AZT is on board. So I like to stop AZT when I'm thinking about peg interferon and ribavirin.

I would not treat him with peg interferon and ribavirin at this juncture because his liver is just a little too sick. In the APRICOT trial, people with Child B scores, that is 7 or greater, had an increased risk of death with treated with peg interferon and ribavirin. I would attempt to manage him conservatively and hope that he gets better. I would also refer him for transplant. We have a very active transplant program here, so I'm spoiled in that capacity, but I like to refer HIV-infected patients for transplant when their MELD scores are somewhere >12, but not too high, because it gives an opportunity for evaluation. So I would have picked 2 and 4, which is transplant and tenofovir.

Prior to making the switch, he presented to an outside hospital with both confusion and an elevated liver enzyme test. A CT scan of his head was negative. So this is an individual coming in with an HIV infection, liver disease, and confusion. He is on AZT, 3TC, and efavirenz and has not yet made that switch that we had wanted.

What is the most likely cause of this patient's confusion? Now you're an ER physician and a patient walks in with a CD4 count of around 600, on HAART, with a negative viral load, and he's got liver disease and he's receiving efavirenz. The choices are:

1. Efavirenz
2. Illicit drug use
3. Hepatic encephalopathy
4. Cryptococcal meningitis
5. Depression

He has just been told he's got a bad liver, so perhaps depression is a possibility. Let me show you what we've got so far and I'll send these [polling] results out to you.

What we see here is there's at least 25% voting for efavirenz. There is no question that efavirenz can cause mental status changes. I would not suspect this number one on my list because he has been on efavirenz for some time. I would point out there is at least one study that shows efavirenz levels are … elevating say a liver disease. It's possible that although he is on a stable efavirenz regimen, his levels are now higher because his liver is getting sick.

What about illicit drug use? Well I'll just say that it was not illicit drug use in this patient, but it certainly could be and I think you can't be suspicious enough in this context and must always consider illicit drug use.

No one voted for cryptococcal meningitis and no one voted for depression. I think it's unlikely he'd have an OI with a CD4 count of 600. He certainly could be depressed, but I wouldn't think that would present with confusion.

So the majority here, I think, got the question right, which is hepatic encephalopathy. There are many ways in which a liver can fail, but in general, people have either liver dysfunction in which there is coagulopathy, hyperbilirubinemia. People can also in this context of liver failure, have encephalopathy where they're not clearing toxins from the blood. They could have portal hypertension or have bleeding varices and they could have tumors. So in this case, encephalopathy is going to be high on the list.

So let's get back to the case. He was admitted to an outside hospital and he stopped his antiretroviral therapy. The concern was that this [confusion] could be because of the efavirenz so all the HIV drugs were stopped. An LP [lumbar puncture] was not done because of low platelet counts. He was covered with broad spectrum antimicrobials (vancomycin, ceftriaxone, fluconazole), and they did, indeed, add lactulose for encephalopathy.

On hospital day five, things took a turn for the worse. His serum ALT increased from around 200 to 865, AST went to 1,056, total bilirubin went to 5.6, his INR went up to 2.5. He is now coagulopathic and he's got ascites. So this is a patient who is admitted with confusion. We think it was probably hepatic encephalopathy, and now he's got evidence of liver injury and liver dysfunction, both with an elevated bilirubin, coagulopathy, as well as ascites.

So we'll try another polling question here, asking what is the most likely cause of his liver problems?

1. Fluconazole hepatoxicity
2. Hepatitis C flare
3. Hep B flare
4. Portal vein thrombosis
5. Acetaminophen toxicity

Acetaminophen was administered in the hospital.

There is no question that fluconazole hepatoxicity could be one of the issues. We need to be careful when treating patients with liver disease with hepatoxic medications. That could include antiretroviral therapy, but it could also include drugs like fluconazole. One of the issues here is, did he really need fluconazole? Well probably not. Fungal infection was low on the list and that could very well have caused toxicity.

What about hep C flare? That's certainly possible, but it's not necessarily what I would predict to be the leading cause.

Portal vein thrombosis? That's always a possibility and should be checked for with a CT or ultrasound imaging.

Acetaminophen? Obviously you need to be careful with Tylenol in the context of liver disease and that includes when a patient is admitted to the hospital, avoiding p.r.n. orders.

And finally hep B flare. The correct answer turns out be a hep B flare.

The hepatitis B, in this case, turns out that was it was being held down by the 3TC. 3TC, when it was removed by the admitting physician, actually led to a resurgence of his hepatitis B. He's worked up in the hospital for this problem and now his hepatitis B DNA is no longer low. It's not <22, it's 2.36 million IU/mL. His hep C RNA is 5.6 million. His MELD score is now 23, up from 13, because now he's got the elevated bilirubin and the INR. The ultrasound shows no portal vein thrombosis, but there is ascites, and his HIV is really gone bad very quickly. His HIV RNA is 89,000 copies/mL, and his CD4 count is 97. So things have gotten worse really quite rapidly; more rapidly than we would have liked.

So let's see about what we do next in this case. How would you manage this person who's now got acute on top of chronic liver failure?

1. Peg interferon/ribavirin to treat the hepatitis C
2. Consult with the transplant team
3. Start efavirenz, tenofovir, and FTC, essentially putting him back on the same regimen which was an efavirenz-based regimen
4. Start lopinavir /ritonavir + tenofovir and FTC

Let me just switch over to the other version where you can see some of the results thus far and what we've got now is a decision to consult with the transplant team, which I think is obviously a very good decision. This is a person whose liver is in a lot of trouble and if things don't get better quickly, he is going to die of his liver disease. So consult of the transplant team is definitely a good option.

Now what about peg interferon/ribavirin, choice number one? I would personally not think peg interferon/ribavirin was a good choice here. The reason being that it will actually make the situation worse. It will cause more problems and not make them better.

Let's look at the choices between efavirenz + tenofovir and FTC and lopinavir/ritonavir + tenofovir and FTC. What's good about these two regimens? What's good about it is that the tenofovir and FTC will treat his hep B. We believe his hep B was treated by 3TC and FTC will provide that coverage, as will tenofovir. So that provides the necessary backbone. Now what about the choice between efavirenz or NNRTI-based regimen and lopinavir /ritonavir? That's an interesting choice. I think a concern one might pose here is could he have developed efavirenz resistance, because remember, it was stopped quickly and has a long PK tail and there might very well be resistance. Now of course, the other concern with lopinavir/ritonavir is potential toxicity. So we really need to balance these things.

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So as you see here on the next slide, I would actually recommend an HIV genotype in this context and sure enough, he's actually got a K103 mutation, and he is now resistant to efavirenz. So after discussion with the transplant team, the decision was made to get him back on HIV treatment, because his CD4 count is too low for transplant. Current transplant protocols require that you have a CD4 cell count at least above 100 and controlled HIV, so that really is no good.

The recommendation is for PI-based HAART. Now what would you choose here? Well if he's got no resistance mutations, one could choose from across a number of different medications. In clinical trials, nelfinavir actually has one of the better liver toxicity profiles. Atazanavir also has a good liver toxicity profile, but he has an elevated bilirubin and this may or may not be a good choice. And the third option of lopinavir/ritonavir could also be considered. So I don't know if there's a right PI choice here, but one thing is clear; he needs to get back on HIV treatment, as well as hep B treatment.

In this case, his PI-based HAART plus tenofovir and FTC actually make his liver better. You can see after 12 weeks of therapy, he is clinically better with no ascites. His HIV RNA is also suppressed to <50 copies/mL. His CD4 count has nudged up to 100. His MELD score is down to 15 and that's because his bilirubin has improved and his hep B DNA has gone down to 236 IU/mL, so he is certainly getting better on this regimen.

Let's do another management type question and see what we want to do next for this individual. So here are the options. What would you do next? Here's a guy who is getting better. His HIV is suppressed. His MELD score is down to 15. His hep B DNA level is 236,000 IU/mL. Would you start peg interferon/ribavirin? Add entecavir for hepatitis B treatment? Add adefovir for hepatitis B treatment? Or proceed with listing for transplant?

There are a couple of things to consider. The first is whether his liver healthy is enough at this juncture for peg interferon/ribavirin. And unfortunately, I would probably say that the answer is no, that his liver is not quite healthy enough for peg interferon/ribavirin.

What about adding entecavir? Well this certainly could be considered. I think that there's no reason not to add entecavir at this point. It might add additional coverage for his hepatitis B and since his hepatitis B is causing severe problems, we would want to consider that. Keep in mind that entecavir is active against HIV, but we could use it here because he is fully suppressed. I would not use entecavir if he was not fully suppressed.

What about adding adefovir? Well, think of adefovir as similar to tenofovir with respect to hepatitis B, except tenofovir is better. Very recently there was a clinical trial with HIV negative persons with chronic hep B in which the adefovir was compared to tenofovir and, again, this is not HIV patients, but this is patients with just hep B. And tenofovir, as one might expect from our experience in HIV, was a vastly superior medication for suppression of replication, so I don't see any role for adding adefovir.

The majority of respondents, two-thirds, want to list for transplantation. And I think this remains a good idea. I would not be overly encouraged by his improvement, but would rather say that he is still at increased risk for progressing to liver failure and transplantation is a good idea here. So to summarize, I think adding entecavir is a reasonable option, but listing for transplant is also important, because we simply don't know how much recovery he will get.

Let's move on. So after an extensive and prolonged course with a lot of ups and downs, he actually underwent orthotopic liver transplantation. At the time of transplant, he was looking really quite good. His hepatitis B DNA level was <22 copies/mL, his HIV RNA was <50 copies/mL, and his CD4 count was 205, so from an HIV standpoint, he is now doing well again. From a hepatitis B standpoint, he is fully suppressed, and his hepatitis viral load at the time of transplant is 5.3 million IU/mL. Keep in mind, through the course of this entire medical care, we've not been able to touch his hepatitis C with treatment. We've been unable to use peg interferon/ribavirin because of concerns about the toxicity of peg interferon and ribavirin in this context. So he gets transplanted.

My next question is which of the following is the greatest threat to this individual following liver transplant? What do we need to worry about?

1. AIDS-related OIs. He is now on immunosuppressive therapy plus transplant liver plus HIV. Is he at risk for OIs and is that a big threat to him?
2. Drug/drug interactions. He is on lopinavir and ritonavir and it is well recognized that many of the HIV drugs can interact with immunosuppressive agents.
3. Recurrent hepatitis B. Now keep in mind that he went into transplant with his hepatitis B fairly well controlled, but is that certainly a possibility?
4. Hepatitis C. Keep in mind that the liver that was cirrhotic was taken out and a new liver was put in, but most livers are infected with hepatitis C following transplant.
5
5. Rejection of the donor liver.

Let's take a look at what folks have said. Well, interesting comments, and let me make a few comments here and certainly if you all have questions or want to make contributions, send them in via the web-based Q&A system and certainly we can open up the phone lines a little bit later and talk, as well.

It turns out so far in the experience of treatment that AIDS-related OIs have not been a major problem with transplant. In part, that's because HAART is effective and in part because we can use medications like Bactrim and other medications to prevent infection.

Drug/drug interactions are unquestionably very important, but clinical pharmacologists, as well as transplant teams, have figured out how to dose medications and measure levels. There have been some very remarkable cases in the past where the transplant patient actually stopped taking their HIV drugs and then, because the ritonavir was no longer boosting, in these cases, cyclosporine, they actually had a rejection.

I'm not particularly concerned about recurrent hep B and part of the reason is that I think that a tenofovir, FTC, and entecavir regimen is really quite potent and I think that's going to control his infection. In addition, the standard post-transplant protocol is to give people immunoglobulin, that HBIG or hepatitis B immunoglobulin to prevent infection in the donor liver. So we have the ability, both with the medications and immunoglobulin to protect that new liver.

Recurrent hepatitis C. This actually turns out to be one of the biggest threats. Hepatitis C returns post-transplant in nearly 100% of individuals and there have been a number of hepatitis C-infected patients with HIV who have experienced a very severe disease, so I would certainly list recurrent hepatitis C infection as a major concern in this individual. As we'll discuss, this can occur very rapidly with progressive fibrosis.

What about rejection of the donor liver. I think one of the remarkable things that has been seen, particularly with respect to kidney transplant, is that rejection happens at the same frequency. One might think that because the HIV weakens the immune system, you'd see less rejection of donor livers or donor kidneys, but that's actually not true. We still see rejection, although it is manageable and not likely to be a major cause of morbidity in this context.

Let's move on. It's now six months after his transplant and he begins to experience lower extremity edema and his ALT is quite high at 256. His total bilirubin is 1.7. His hepatitis C viral load is 8.3 million IU/mL. We finally got that liver biopsy. This is important in this context because his liver is flaring with an ALT of 256 and we really don't know if it is rejection or what the cause is. And it turns out that there is no evidence of rejection on biopsy, but there is severe hepatic inflammation with evidence of bridging fibrosis. What this means is that his hepatitis C has come roaring back and within six months he's progressed. One could argue that that's a very rapid period of time, but certainly I would tell you that this is something we've seen in practice. Although we prefer that things don't progress this quickly, we certainly do see it in some people.

So now his hepatitis C has moved up to problem number one. Let's do another question-what would you do next? He's progressing pretty rapidly. He's now got a bilirubin of 1.7. So here are the choices.

1. List for second liver transplant.
2. Change his HIV drugs to raltegravir/tenofovir/FTC, stopping lopinavir/ritonavir.
3. Stop prednisone.
4. Start peg interferon/ribavirin.
5. Both 3 and 4.

I would actually agree with the votes here; 100% have selected both 3 and 4. Prednisone is particularly problematic in the context of hepatitis C. Any time I'm treating a patient with hepatitis C, I would prefer they get off prednisone. We've seen this time and time again where responses are muted when we use prednisone. So that's a good idea to remove that. I don't see much value in removing lopinavir/ritonavir because the biopsy showed hep C and we don't yet understand the hepatic profile of raltegravir, the integrase inhibitor, although we'll certainly learn about it. Listing for a second liver transplant? Well, the news here is that there is no option for a second liver transplant in this case. HIV patients are not considered for redo transplants. And peg interferon/ribavirin? I would agree with the option selected here. It is time to treat his hep C. I've said it hasn't been time before this, but now it is.

Let's move back to the case. Well, he switched to a prednisone-sparing regimen. Peg interferon and ribavirin is started. His ribavirin is dosed at 600 mg. One of the real big problems post-transplant is that ribavirin is very difficult to tolerate. Ribavirin is renally excreted and in the transplant setting, there is renal insufficiency, so ribavirin is dosed low. I would suggest that in your practice, if you're going to dose ribavirin, if the kidneys are dysfunctional, I would suggest dosing a little bit lower on the ribavirin, as we've done here.

So after four weeks of therapy, he's having a bit of trouble. His hemoglobin is now 6.7 grams/dL so down from a normal hemoglobin of around 14, to 6. That's a big drop in hemoglobin due to interferon-related bone marrow suppression and ribavirin-related hemolysis. The second problem is his white blood cells are not enjoying peg interferon. ANC is down to 420 and his hepatitis C viral load, after four weeks of therapy, is still 3.5 million IU/mL. That's a drop from 8.3 million, so on one hand it's down about 5 million IU/mL; on the other hand, it's still pretty high at 3.5 million and has barely dropped a half a log. So let's think about what to do next.

So I've given you a couple more options here. We now have a patient who has completed four weeks of therapy and by any measure, he is very challenged with this. He is anemic, he is neutropenic, and his viral load is not responding well. Let's look at the choices that here.

1. List for second liver transplant
2. Add EPO
3. Add filgrastim (Neupogen)
4. Stop peg interferon/ribavirin
5. Stop ribavirin and continue peg interferon as a maintenance dose

We've got 25% voting for EPO, 25% voting for stopping both peg interferon and ribavirin, and about half saying stop ribavirin and continue the peg as maintenance. I think certainly that if one was to continue therapy this patient would need a blood transfusion, he would need EPO, and probably Neupogen (or filgrastim) to get through this.

The question that I've got in this case is should we continue therapy? And there was a very interesting paper that was a subanalysis of the large RIBAVIC trial and what this analysis, and it was published by an author named Payan in the journal, Gut [Payan. Gut 2007;56:1111-1116]. They attempted to ask, can we predict failure after four weeks of therapy with peg interferon ribavirin? And what they showed is that if an HIV/hepatitis C-positive patient treated with peg interferon/ribavirin had a hep C viral load >500,000 after four weeks of therapy, the probability of response was zero. So the suggestion is that, although we're used to looking at week 12, that we can tell this patient that the odds of response are minimal.

What about this last choice, stop ribavirin and continue peg? Well I can't say for sure it wouldn't help him, but I can tell you that two large studies, one in HIV-negative patients called HALT-C and another in HIV-positive patients called SLAM-C, done by the ACTG, both indicate that low-dose peg interferon is not associated with liver benefit. It's possible that it may help a subgroup like this, post-transplant. I can tell you that there are certainly doctors that would give this individual maintenance therapy, but certainly there's no studies to support it.

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Let's wrap up the case and this is the last slide. He is now two years post-transplant. We did, indeed, stop the peg interferon/ribavirin. This is a tough therapy to take. He was having a lot of anemia with it and it wasn't working. He now has fully established cirrhosis of his new liver. He remains relatively stable. He's got mild ascites, controlled with spironolactone and furosemide. He is on nadolol to prevent primary bleeding from varices and he's also on trimethoprim-sulfamethoxazole for a spontaneous bacterial peritonitis prophylaxis. And it's important to note that Bactrim, in this case, is a good option for preventing SBP. HIV disease remains undetectable. Hep B remains undetectable.

So what's the really problem here? The real problem here is that we don't have hepatitis C drugs that work, particularly in the context of liver dysfunction. It's remarkable that you can take a patient with a Child B score that's quite high and treat them for hepatitis B and they get better. So we don't have hep C drugs yet. It is also important to recognize that there are drugs like hepatitis C polymerase inhibitors and hepatitis C protease inhibitors in the clinical trials today. Indeed, hepatitis C protease inhibitors are anticipated to move to phase III trials in 2008, perhaps to FDA approval in 2009.

But there are several issues to consider. One issue is that so far in clinical trials, hepatitis C protease inhibitors must be used with peg interferon/ribavirin. The problem is when they're used without a secondary backbone, resistance occurs. And it looks like that resistance is really quite common when you give a hep C person an inhibitor without peg interferon/ribavirin. So we're not getting away from peg interferon and ribavirin. That's the bad news. The good news is that 24 weeks of therapy with the hepatitis C protease inhibitor telaprivir plus peg interferon plus ribavirin in HIV-negative patients was associated with a 65% eradication rate, which was a 25% improvement over standard therapy for 48 weeks, so we are making progress. That said, there's a lot of work to do.

I'm going to stop there. I'm going to ask that the operator open up the lines for questions and I'm happy to discuss any issues or concerns that came up with this case. I'm also happy to talk about other issues not related to this particular case at all.

Questions & Answers

The question is about a patient who is clinically depressed with bipolar disorder and was prescribed Risperdal. The question is, is it recommended to wait until a patient is more balanced to get interferon? I think the answer is definitely yes. I think one of the striking observations from our treatment experience thus far is that you can treat patients with stable psychiatric disease. The key word is stable. We have found in our clinical practice, within the Johns Hopkins Moore Clinic, the HIV clinic, that patients who are in psychiatry care and the psychiatrist tells me that they're stable, go ahead and treat, do really quite well. The patients that don't do well are the ones that are not in psychiatric care. They're the ones that tend to get in trouble with interferon-based treatment. So my recommendation is always to stabilize the psychiatric disease before moving on with interferon. But once they're stable, it's okay to treat.

So let me go on to answer another question. After successfully treating hepatitis C, how long does one have to wait before having a child? There are two issues here. The first issue is the peg interferon and ribavirin. Ribavirin is teratogenic and the recommendations are very strict. Men and women are asked not to reproduce for a period of six months following interferon and ribavirin treatment and the rationale for that time period is based on ribavirin having a long intracellular half life and in theory, it takes at least three months for all the ribavirin to be out and the concern for a man is that ribavirin might be transmitted via seminal fluid to a woman and potentially contaminate the embryo. That's a theory. It has not been proven. There is very little evidence of this and, indeed, when one looks at the pregnancy registry, it is not really clear what the risk is for a man. So to be ultraconservative, the recommendation for a man is to wait six months off peg interferon and ribavirin. That's probably the best advice.

There's a question about should a patient with hepatitis B core antibody positivity be vaccinated? And this is a bit of a vexing question. These are patients who are hep B surface antigen negative, hep B DNA negative, hep B/E antigen negative and all they have - the only marker of hep B they have - is hep B core IgG. The question is, whether this is a true positive, meaning that they were once infected with hepatitis B and now have natural immunity or is it a false-positive, meaning they were never infected and have no immunity? And the way this has been studied is to give people who have isolated core-positivity hep B vaccinations. And if they have a rapid and vigorous response to hep B vaccine, that suggest they have a memory of the virus and you're seeing a natural immunity. If they have a slow or muted response to vaccine, then it's probably not natural immunity. And when people look at this in studies, it's often times a false-positive. So I think the more conservative thing to do in these patients-and this is my practice-is if I have a patient with an isolated core antibody positive, I would go ahead and vaccinate them. The rationale is first, it may be a false negative and they may be susceptible to hep B. Secondly, there is no harm in giving vaccine other than the cost of the vaccine itself, it won't hurt the patient, so I tend to vaccinate.

There is a question about transplant in rural areas and what I would suggest is that if you're looking for where your patient could be transplanted, there is a website for the HIV transplant protocol and I believe that website is HIVtransplant.com and they have a listing of where the active sites are in the US. I think that is an important place to look and certainly is a way that you can track down what's going on in your region.

What percentage of infected patients are cured after current treatment? The cure rates are not anywhere near 100%, but they certainly can cure some patients. It's about 30% for genotype 1 and about 60% for genotype 2 and 3.

We'll do just one last question. . If you can't get a biopsy, what should you do? It's an important question. I would typically do an imaging study and an HCV FibroSURE^TM test. This is a noninvasive marker that is available through LabCorp. It is commercially available only at that lab and it includes five blood tests that are put together to yield an estimated liver score. It's not perfect, but in a patient who won't get a biopsy, for example a hemophiliac, it's a good test.

So with that last question, I'd like to thank you for your attention and your participation in today's call.