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Treating Hepatitis C: A Clinician's Perspective
An Interview with Jerry Powell, MD

by Bob Roehr

July 1998

Jerry Powell, 48, has the demeanor of a modern-day Marcus Welby, MD: tall and imposing without being authoritarian; willing to listen to patients, yet with an underlying faith that doctor often knows best; and a '90s edge of cynicism that makes it seem all the more real. He jokes of the "illegitimacy" of his birth. His parents were married, but his father was an intern at a time when hospital rules prohibited marriage. So the relationship was a secret.

His education was at Stanford, with medical school training at the University of Washington, house staff training at the University of Chicago, then back to Washington to specialize in hematology and join the teaching staff. He was recruited to the Hoffmann-La Roche Research Institute and spent three years in Basel, Switzerland.

"But I like students almost as much as I like patients," he says. Interest in teaching led him back to the United States in 1989. He was attracted to the intellectual ferment of the San Francisco Bay area and thinks that future historians will view the age of Silicon Valley "as a golden time in western civilization comparable to the Age of Pericles" in ancient Greece.

The University of California, Davis, was a perfect fit. Among the many hats he wears are those of Professor of Hematology, Director of the Hemophilia Treatment Center, and researcher in gene therapy for hemophilia and oncology. He jokes that "half my lab cannot talk to the other half when we have our meetings."


Journal: What is your caseload?

Powell: We are the second-largest hemophilia treatment center in California. I follow about 240 patients -- that includes about 90 hepatitis C patients and 40 HIV patients.

Journal: How many of your patients with HIV are coinfected with HCV?

Powell: Thirty-seven of the 40 -- over 90 percent.

Journal: Why has there been this recent burst of attention around HCV?

Powell: Two reasons. First, HCV was somewhat of a hidden epidemic. There wasn't a lot of non-A and non-B hepatitis prior to the late 1960s. Then there was a blossoming of transfusion use. If you look at blood banks, the number of units transfused just took off logarithmically in the 1960s and 1970s. So it was the right social conditions, and the right environmental conditions with the use of transfusions, and a relatively new virus coming into the population.

Then add to that the slow progression of the disease. You do not get liver failure for 18 to 20 years. Suddenly it becomes apparent in the 1990s. But then our focus was on HIV. And everyone thought that if you have HIV you are going to die anyway, so why bother with a chronic virus like hepatitis C? Then protease inhibitors came along and gave hope to people with HIV and many of them could look forward to a more productive life. Then the cases of liver failure became more apparent and more important.

The hepatitis C virus was identified in 1989, and we had our first antibody test in 1991. So eventually all these factors started to merge. Finally, in 1997 the hemophilia community needed to find a way to finance the funding for centers for comprehensive care. With HIV dwindling away, the hemophilia community went after hepatitis C with a vengeance and sent that message to the CDC. Once people started saying, "Oh gosh, there are 4 million people with hepatitis C," and "Oh yeah, 60 percent of them are going to get liver failure," it became a self-fulfilling interest.

Journal: Describe to me the process you go through with a new patient.

Powell: I try to screen my patients as aggressively as possible. If I think a patient was ever exposed to HCV, which means having a blood transfusion as far back as 1950, or I think that they ever had blood-to-blood contact of any kind -- sexual, needles, whatever -- even though they may deny it, I will screen them for HCV.

Step one is the antibody test. There are some false positives but very few false negatives. Essentially zero false negatives now that we have a third-generation hepatitis C antibody test. If the antibody test is negative, that is a stop. If it is positive, then I need to know their liver function tests over the last three years.

Journal: How accurate is the antibody test on patients coinfected with HIV?

Powell: It misses some. In that case we need to look for the virus as well. So if they have HIV, I do the viral load test for hepatitis C. And it has to be PCR. The branch DNA is not sensitive enough, but I think that test eventually will be worked out.

If they are hepatitis C antibody positive, and their liver function tests are normal, the current teaching is, do not go on, regardless of the viral RNA. But if the patients have an interest in being more aggressive, we try to treat them.

That is why I am so interested in this AmFAR study. These guys are smart. They realize that it makes a lot more sense to treat the virus than it does to treat liver dysfunction.

Journal: Have you had any direct experience in clearing HCV?

Powell: I have had some. I think it is because of the comprehensive care team that we have for hemophilia. If we start patients on interferon, we push them much further than most gastroenterologists are willing to go in terms of side effects. We call them twice a week, try to talk them out of any depression rather than simply stop the drug, etc. So I have never yet actually stopped a hemophilia patient's interferon. Whereas if you read the studies, close to 10 to 15 percent have to stop.

Journal: As I recall, you do not think that the FDA-approved regimen [3 million units, three times a week] works well.

Powell: I think the regimen is crazy. The dosing should be according to the way the virus replicates. It is clear that the virus replicates one to two times in 24 hours. So if it is replicating, and the interferon is gone after six hours, you are looking at a day and a half with no interferon. You then have to assume that the biological effects last longer than the five to six hour half-life of interferon in vivo. Well, that has not been shown.

They did an interferon dosing study in Japan with 1, 3, 5, 10, 15 million units, and they actually hit some patients with 20 millions units. There is a steep rise in effect from 3 to 5, and the shoulder end of the plateau is from 5 to 7. There is no significant advantage to 10. And that is daily dosing, not three times a week. I suspect that current and future studies will demonstrate that higher doses and daily therapy will produce more sustained responses with fewer relapses in the years after therapy is stopped.

Journal: Is interferon dosing related to body weight?

Powell: These studies tend not to include markedly obese or wasted patients. But you really would like to see the data with a per/kilogram or a per/meter-squared, like cancer drugs. I would never give the same dose of a cancer drug to everyone. And some side effects of interferon correlate with body weight. However, the studies still need to be completed to demonstrate that these questions are significant clinically. The other part about the dosing is the timing. Here at UC Davis, what we are doing informally, and also beginning as a randomized trial, is starting people on 5 million units, going up to 10 to 15 million if they tolerate it. Then, as soon as the virus clears, so we have undetectable virus, going back to 5 million units three times a week.

Journal: Are you doing this with HIV-coinfected patients?

Powell: No, not yet.

Journal: How manageable are the side effects of interferon?

Powell: Side effects can be difficult. A side effect may only effect one percent of the population, but if you are one of the one percent, then it can be serious.

Depression is the worst side effect of interferon. You have a patient call you at 6 AM and you are pretty groggy but trying to wake up. You hear the words, "I dreamed of the angel of death last night," and you wake up quickly. You call their wife or have the police go visit them and bring them in, all of that kind of stuff. It is pretty scary. Mostly because you are dealing with a patient who has a chronic disease. They will not die of liver failure for several years, maybe longer. Then all of a sudden you have given them a side effect where they might go out and commit suicide.

Some doctors have difficulties in dealing with these problems. I like to treat depression aggressively, but it does require a team that follows these patients closely.

Journal: What about some of the less life-threatening side effects?

Powell: The major one is the low platelet count-thrombocytopenia. That's the one that has scared people with HIV. Because HIV itself causes thrombocytopenia, and ZDV also causes thrombocytopenia, and all of the other drugs can mess up the system, a patient may get associated thrombocytopenias. And then you are going to give them interferon on top of that. It is pretty scary.

We in hematology/oncology deal with platelet counts of 10,000-20,000/mm³ without batting an eye; a gastroenterologist sees a count of 90,000/mm³ and goes berserk. There is a huge range in there.

That is one reason why I often continue interferon when another physician may stop treatment. A gastroenterologist will stop at 70,000-80,000/mm³. Schering-Plough's interferon protocols require a patient's platelet count to be over 100,000/mm³; treatment has to stop when it gets below 70,000/mm³.

With the AmFAR study we can start much lower (60,000/mm³), and we do not have to stop right away. I am glad that Schering agreed to that protocol, because if you do a study with 200 patients, and you stop the drug in 50 of them, you are not going to learn that much. Plus, if you do see a benefit, you cannot treat that many people. The thrombocytopenia is reversible after stopping the interferon. And often, lower doses of interferon can be used effectively after the platelet counts recover.

The other complication is a low white blood cell count. This one is a little harder to put together. Patients' absolute neutrophil counts will drop quite low with interferon. I have not seen a good study anywhere that says it is safe to go very low, but since in oncology we allow the neutrophils to go to 500/mm³, that is basically how I interpret the counts before getting too concerned.

Because white blood cell counts are in the expertise of hematologists, I'll have a gastroenterologist call me and say, "Oh my God, the white blood cell count is down to 500 absolute neutrophils," I'll say, "That's okay, keep going. When it gets to 300, stop." So far we have not had any major infections.

The AmFAR study may change that. The assumption here is that if you have HIV, with cell-mediated immunity and T-cell depression, and you drop your neutrophil count because of the interferon, you are a little bit in double jeopardy. I do not know yet how dangerous that situation might be. And I hope we do not find out.

Journal: What are the side effects of ribavirin?

Powell: They are primarily related to the hemolysis, some of which is pretty significant. It can drop the hemoglobin quite severely. I don't think there is enough knowledge about the combination of interferon and ribavirin as initial therapy to say clearly that it is not detrimental.

Journal: Does that apply to the higher doses of interferon as well?

Powell: Yes. That's why I would wait. I know that with the interferon, if you clear the virus by week three you have an 80 percent chance of sustained remission. That is why I would probably hold off. I have just seen too many studies that promised combinations were wonderful. Then when you tested them you ended up with bad side effects that you did not predict, including occasionally worse treatment for the original disease.

Journal: What percentage of people on the higher dosage clears it by week three?

Powell: Up to 50 percent in some early studies have achieved sustained remission. The problem with that statement today for the dosing of 5 million units daily is that, like everything else in clinical research, your initial enthusiasm does not always pan out. And so when I say that the sustained remission rate looks like 50 percent, it may drop to 40 percent when larger and more complete studies are finished.

What I like about ribavirin is that the initial data with the lower-dose interferon go from 18 percent to 30 percent sustained remission, essentially doubling it. If you can take the 40 percent sustained remission with high doses of interferon and the ribavirin doubles that, you are talking 70 to 80 percent. This needs to be proven of course, but it is very interesting.

How long to use ribavirin is open, as is whether it can be used to lower the dose of interferon after, say, week ten or twelve.

Journal: Do you treat the HIV/HCV-coinfected patient differently?

Powell: I don't treat the coinfected differently in terms of dosing. However, I have our team call them more often, up to four times a week instead of two. And we have them come in for blood tests more often.

Journal: How often?

Powell: Once a week rather than once a month. I tend to think pretty strongly that tender loving care talks a lot of side effects away.

Journal: Are there any special challenges or concerns in caring for the HIV/HCV-coinfected?

Powell: There are some theoretical concerns. For example, if the patient is already anemic from the ZDV and already debilitated, then the hemolysis of the ribavirin is a little bit scary -- but not a big deal. Transfusions are always there. If you follow them frequently with blood tests, you will pick it up in the first two or three weeks. It is not life-threatening. It would only be life-threatening if the patient and family or partners do not call, or we do not check blood tests frequently.

Journal: Hepatitis C trials have excluded the HIV-coinfected. The only real data that we have from the studies may not be applicable to these patients. Why have these trials excluded the coinfected?

Powell: Two reasons. One, the people who have been funding the trials do not want to be involved in the publicity that is often involved in AIDS trials. The AIDS community often generates publicity both positive and negative around these trials. I seriously think that has scared a number of companies away.

The more important reason is that, if you are focused on getting FDA approval, you want the population to be as healthy as possible. Why take a risk by including people who are HIV-positive? I think both obstacles are understandable from the sponsor's perception. So it's up to us to convince them otherwise.

Journal: Do you use liver biopsies before you start interferon?

Powell: I require it. The reason is that we have no way of knowing what is going on in the liver except through tissue samples. Interferon therapy is strenuous for 6, 12, 18 months, with the feeling that they have the flu in a good half of the patients. If the doctor and the patient do not know what is going on, where they are starting from -- that is a long time to sustain a strong positive attitude.

It is critical to get the biopsy to know if it is early cirrhosis, minimal scarring, or chronic active or chronic persistent hepatitis. I do not require a biopsy after finishing treatment but I encourage it for the same reason. This is a big deal; in a sense, interferon therapy is like going to war. You want to know if you have actually won; you want to have the data in hand.

For the hemophilia population, there was one death in a patient who got a liver biopsy about 20 years ago in France, and that kind of poisoned the community. It took a lot of discussion to get past that. Now with factor replacement, liver biopsies in patients with hemophilia are as safe as in patients without hemophilia.

Journal: Do you then use the biopsy results as an exclusionary factor for therapy?

Powell: Yes. I won't treat cirrhosis, which is a clear histologic, pathologic diagnosis. Scarring or cirrhosis is irreversible. However, there are some data coming out of Japan that if you do treat people with cirrhosis you can prevent the development of liver cancer, even though you do not change anything about the course of the cirrhosis. That would be interesting, but further study is needed.

In people who are hepatitis C positive, with or without interferon, if the biopsy shows there is any scarring at all, I then put them on an ultrasound scan every six months looking for liver cancer. That goes until who knows when. The feeling is that if you clear the virus, then you stop the ongoing damage. But we do not yet have the answer that if you clear the virus and stop the ongoing damage that they never get cancer.

Journal: Is fear of pain a factor in patient resistance to a biopsy?

Powell: Yes it is. I lay a lot of that to the doctor. I asked them not to talk to their patients about pain with a liver biopsy. Have them give me a call and we will discuss it, because it is too important. Unless you have had major surgery, people do not relate to pain; they do not know how to grade it from 1 to 10.

Patients never believe their doctor when he tells them that something won't hurt. A doctor probably told them when they got shots as a kid that the shot wouldn't hurt. But it hurt like hell. You really have to put a lot of effort into explaining to people that a liver biopsy will hurt like crazy. There is blood there. And blood inside of the peritoneal cavity is extraordinarily irritating.

We can treat the pain and it will go away quickly. By the next day you are going to feel a little bit of side ache. The day after that you may feel like singing. A week later you can do whatever you want, unless you are a football player. So I think that it is important to minimize the pain. And so far, I have never had patients come back and tell me that I misled them.

Journal: Are there ways to minimize the initial pain?

Powell: No, unless you started to do general anesthesia. It is too important to completely kill the sensation of pain because the liver biopsy is a blind biopsy -- you need to have them feel some sensation so that they can tell you where you are going, so you do not make a big mistake. That is for percutaneous liver biopsies.

More and more people around the country are starting to do a transjugular route. You can numb the pain a whole lot better. Once you are in the liver, with the catheter down the jugular vein, you can pop in and get the biopsy and come back out. And there are essentially no side effects afterwards.

Journal: Is that the type of biopsy that should be used if you have the option?

Powell: I think so. The main reason for it is that if there is a bleeding complication, the bleeding goes back into the bloodstream as opposed to the peritoneal cavity, where it hurts like crazy. I have actually sent a patient to San Francisco to do that because he was so reluctant. He kept saying, I cannot stand pain, and I knew that he was a little bit of a wimp. So I sent him to San Francisco and they did it. Everything worked out okay. The patient always comes first.

Journal: Have any of your hepatitis C patients had liver transplants?

Powell: Yes. When many patients with hepatitis C go for a liver transplant, it is because they have a low platelet count and they have anemia. As soon as the enlarged spleen is removed, the bad liver taken out, and the good liver put in, all of those things disappear. One of our patients went in with a platelet count of 20,000/mm³, and the day after surgery the platelet count was 240,000/mm³. There was no treatment -- it was simply taking out the spleen and replacing the liver.

Journal: Remove the problem and the body resets.

Powell: Right. But circulating monocytes will reinfect the new liver. The nice thing is that it is a very slow disease. So you can still justify doing a liver transplant, getting 15 to 20 more years. And you can then try therapy to actually clear the virus after transplant.

Journal: Is there any medical reason why people who are HIV/HCV-coinfected should not have liver transplants?

Powell: The reasons are more psychological. The liver transplant community remembers that there were four highly publicized transplant cases at the University of Pittsburgh in the early 1980s where they were trying to cure hemophilia with liver transplants and didn't know that the patients had HIV. The patients all died horrible deaths within two weeks.

Because of the immunosuppressants used for the liver transplant, the HIV just blew up and wiped them out as an overwhelming viral infection. They didn't know it was HIV at the time, so they described an unknown but an apparently overwhelming viral infection. Years later, after tests were developed, they went back and looked at those frozen tissue samples; they were all HIV-positive.

UCLA, UCSF, Pittsburgh, Mt. Sinai -- are all looking to be the first to do an HIV/hepatitis C liver transplant. We are talking about relatively special candidates because they have to be young and healthy, have no other medial problems, have a good psychosocial attitude, etc. Otherwise, the doctors are not even going to try.

Journal: What is the cutoff age?

Powell: Generally they are going to argue less than 40. They will do liver transplants in less than 65. But if you are going to ask this question, you do not want them to be 59. So, less than 40, HIV positive, on a tolerable triple-drug regimen so that their virus is undetectable for three months to a year, a CD4+ count of 200/mm³ minimum, hepatitis C that has already caused their liver to fall apart. And then the challenge will be to get them high enough on the liver transplant list that they are a class I liver transplant candidate so that they do not take the liver from someone else who might benefit from it. It is really a pretty complicated and daunting clinical experiment but very interesting. I hope someone does it soon.

So you need to have somebody who is a cowboy, basically someone as healthy as John Wayne (before he had cancer) but who also has HIV and HCV. I do not know what outcome I would predict. If you stop triple-drug regimens, HIV comes back very quickly. The concern is, if you are immunosuppressed, will the triple-drug regimen be strong enough to keep the HIV under control. Nobody really knows.

Journal: What do you tell your HCV patients when they ask you about whether they can continue sexual relations and other forms of intimacy?

Powell: When they ask me if they can have sexual relations or even kiss their partners and avoid universal precautions, I know I am supposed to say, "Always use universal precautions," but I think it is also legitimate to say, "I don't know the answer for hepatitis C."

I can show studies where in chimpanzees hepatitis C was transmitted by saliva. But it was a lot of saliva, and it was most likely through a mouth sore. So it was not blood to blood, but it was very close.

I can point to Japanese studies where they have followed monogamous couples for 30 years. And you would think that if one partner had hepatitis C and it were sexually transmitted, that it would have been transmitted after 30 years, yet the incidence was less than 10 percent. That is not much different from the background rate, so you cannot really say that they did not get some other common exposure.

Some of my patients will say, "Okay, I'll use universal precautions and I will not kiss my partner." And I'll tell them that as long as they are happy, and our social worker is happy with the way the situation is at home, I will leave it. For everyone else it is universal precautions, especially if we are dealing with HIV.

Journal: How do you convince some of your colleagues who are not familiar with advancements in treating HIV and HCV to properly care for their patients?

Powell: I tell them to send me their patients. This is the silver lining of the black cloud of managed care. They have to be efficient. It costs them time if they are into something that they do not feel completely confident with. So I just tell them, send me the patient, I will see him once or twice and send him back. The key is to explain to them that I am not going to steal the patient. Most physicians are very cooperative and thankful. And after a couple of patients like that, they have heard back from their patients that everything is okay and start getting comfortable with recommending liver biopsies, interferon, and treatment.

I think the biggest negative in the gastroenterology community is the experts that they use at their meetings. They are saying that a 15 percent sustained response is dismal. I argue from the oncologist's viewpoint and ask them, "If I told you that I could cure 15 percent of your metastatic colon cancer, would you send me your patients?" And they say, "Of course I would."

Then we talk about HIV, which they often have little experience with. But the media tells them that HIV is incurable. I ask them, "How many patients would come beat down your door if you had a cure effective for only 15 percent of patients with HIV?" The final argument is, I ask them how rich they would be if they could cure HIV. Generally there is a little bit of laughter and chuckling, and they understand.

Another obstacle to the aggressive treatment of hepatitis C with interferon, is a published study that the death rate for patients who got hepatitis C from transfusions is no different whether they were treated or not treated. If you look carefully at the numbers, these were elderly patients who were transfused. The number who got hepatitis C and were followed for 30 years is tiny.

Journal: Because they were already in their 70s when they were exposed?

Powell: Exactly. Most people who contract HIV are young. Our hemophilia, HIV, hepatitis C population is young. My patients have a 60-year life expectancy ahead of them and a disease that in 20 years will result in up to 80 percent of them with cirrhosis, liver transplant, liver complications. It becomes a no-brainer to treat it. But for a while there in the 1980s it was pretty hard to convince somebody to treat hepatitis C.

But we always believe that the patient comes first.


Bob Roehr is a medical writer based in Washington, D.C. E-mail: bobroehr@aol.com



©1998, Medical Publications Corporation




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