February 4, 2008
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There's nothing like hearing the results of studies directly from those who actually conducted the research. It is these women and men who are transforming HIV treatment and care. In this interview, you'll meet one of these impressive HIV researchers and read an explanation of the study he is presenting at CROI 2008. Accompanying me on this interview is Dr. Gerald Pierone, an HIV clinician/researcher and the founder and executive director of the AIDS Research and Treatment Center of the Treasure Coast in Fort Pierce, Florida.
Daniel Fierer, M.D.
I'm Daniel Fierer. I'm an infectious diseases physician at the Mt. Sinai School of Medicine in Manhattan. My presentation is describing accelerated liver fibrosis in the outbreak of acute hepatitis C in HIV-infected men,1 which had not been previously described. These were otherwise pretty healthy men who had well controlled HIV infection, many of whom were having unprotected sex with other HIV-infected men, and presented to their primary providers with classic acute hepatitis C: a new increase in liver enzymes, and new antibody to hepatitis C. They were referred, then, to me, where we performed liver biopsy early in the course after onset of their hepatitis, and nine of 11 had stage 2 out of 4 fibrosis.
That is an unprecedented finding. In other studies of acute hepatitis C in people who don't have HIV infection, it was rare to find any fibrosis at all. In an Egyptian study of over 80 patients with acute hepatitis C, biopsied early, none had any fibrosis (all with stage 0 fibrosis). And a much smaller group in Italy of nine people who had been infected by an unfortunate contamination when they were in a clinical trial, only four had stage 1 fibrosis, the other five had no fibrosis.
Click to enlarge|
For additional slides from this study, click here.
Daniel Fierer et al. CROI 2008; abstract 1050. Reprinted with permission.
And so, our findings were completely unexpected. In the recent European outbreaks of acute hepatitis C in HIV-infected men, systematic liver biopsies were not performed. I'm presenting here biopsy results from our first 11 patients: nine of them had stage 2 fibrosis; one of them had stage 1 fibrosis; and one had a different flavor of liver disease, but that is not necessarily characteristic of hepatitis C. Overall, significant fibrosis early in the course of hepatitis C infection in fairly healthy people who didn't have any other reason to have underlying liver disease.
Gerald Pierone: So, what do you think?
Daniel Fierer: I think that underlying immunosuppression in general is a set-up for aggressive liver disease after acute hepatitis C infection. And the course of liver disease with underlying HIV infection appears to be particularly aggressive.
If you have underlying immunosuppression of some sort, schistosomiasis, for example, in Egypt causes an accelerated course of fibrosis after acute hepatitis C, four times faster than in patients without schistosomiasis. Another example is people who have had liver transplants due to hepatitis C receive immunosuppressive drugs; in some cases, biopsies show a little over stage 1 fibrosis in a year.
In contrast, our patients had stage 2 fibrosis in as little time as three weeks, up to a little over a year. People say, "Hmm accelerated fibrosis in HIV," and think, "Oh, we know that." But this is actually a different disease process.
Gerald Pierone: How do you know? There are emerging reports of patients with long-term exposure to HIV medications having fibrosis based on drugs. How do you know you're just not picking up this person, if you pulled him off the street without hep C and biopsied him, wouldn't have stage 2 disease?
Daniel Fierer: It's a good question, one that our reviewers have asked us as well. The short answer is that we have one patient who has never received antiretrovirals and so his fibrosis, which is indistinguishable from the eight others with stage 2 fibrosis, could not have been caused by antiretrovirals. In addition, we have one patient who had less than a year of antiretrovirals, and a number who had less than 5 years of antiretrovirals, and no D-drugs, which are considered the ones responsible for liver damage. So while some of our patients had antiretrovirals for 14 or 16 years, and did receive D-drugs as I said, most had shorter-term treatment, from less than a year, three years, five years... And those studies evaluating liver disease from antiretrovirals, they are very few and far between. We have looked in the literature for all of them that suggested fibrosis in people who took antiretrovirals. There are few reports of biopsies from only a very small number of people who had ALT elevation, and they didn't see, from what we can tell, what would be considered to be hepatitis C-like fibrosis -- although we haven't seen those biopsies ourselves.
Gerald Pierone: Along those lines, do many of your patients have much in the way of steatohepatitis in conjunction with...?
Daniel Fierer: A really good question. There is some fat, but not of the kind usually seen with antiretrovirals or non-alcoholic steatohepatitis, it is characteristic of hepatitis C.
One of our patients might have had something related to NASH; he was the one who was infected only less than a year, and was on very few and short duration antiretrovirals. So we don't know quite what was going on with him to explain his liver disease but it was unlikely to have been due to his antiretrovirals. Overall, I'm hoping to get a follow up liver biopsy on some of these people after treatment to see if this fibrosis has reversed at all.
But I think we can state very confidently that this is not the antiretrovirals that have caused the fibrosis that we observed.
Bonnie Goldman: I wanted to back up and talk about the infections. Because I think this is the first time in the United States where MSM has been described to have HCV transmitted to them. Because the other descriptions were in Europe. Is that correct?
Daniel Fierer: Well, I have to give credit to Annie Luetkemeyer and her colleagues at UCSF, who described a retrospective study of, as I remember, nine patients in JAIDS in 2006. And they remarked that going back to the chart and talking to the patients, that some clearly were not injection drug users, and the authors believed that there may have been sexual transmission of hepatitis C.
I am now collecting a prospective cohort, very much like the European experience, so we hope to be able to come to a more detailed understanding of the risk factors for transmission.
Bonnie Goldman: And this is in New York? Right. And could you talk about their exposures?
Daniel Fierer: Yeah, absolutely. We have a very detailed questionnaire that's derived from Mark Dantas from London. I asked my patients to help me modify it to be relevant to New York -- for example, which Web sites they're visiting. And our results have been fairly similar to what was reported in England, and also in Holland, who had the most detailed questionnaire studies. Most of the men in our study had unprotected anal intercourse, and also a fair number of activities that would be considered high risk for some trauma, and not many had risk factors of injection or other percutaneous exposures.
Having said that, of the 11 here who had liver biopsies -- a few of them, due to, I think, a fairly mature crystal meth epidemic, have been slamming.
Bonnie Goldman: Can you describe what slamming is?
Click to enlarge|
For additional slides from this study, click here.
Daniel Fierer et al. CROI 2008; abstract 1050. Reprinted with permission.
Oh, I'm sorry. Injecting crystal meth, in particular. Some long-time crystal meth users One person was pretty sure that he had shared his works with somebody else. The others have really said they've been very careful to not do it but, being that high, just simply couldn't remember it. So it's the minority of the group, but it's more, percentage-wise, than was reported in Europe. And I think that may represent different patterns of crystal meth use in New York compared to Europe. M patients are certainly telling me that they have seen quite a number of people who inject meth in the clubs. In addition, there are people who are going in and injecting people, as a service. So there is a fair amount of injection drug use around, anecdotally.
And I think that brings up a very significant concern, that this hepatitis C outbreak could really explode if injection drug use becomes popular in MSM, because hepatitis C is much more infectious through blood route. This could be ther route to introduce in a big way hepatitis C into this group of men in whom hepatitis C was relatively uncommon, I think, relative to other populations. Which I think is one of the reasons why sexual transmission in MSM was relatively rare in the past. But I think we may be reaching, and I hesitate to use the word "threshold" in its technical epidemiology sense, but in a more informal way: a threshold prevalence of hepatitis C at which point this outbreak may amplify significantly.
Bonnie Goldman: I see some of the exposures might have been straws. Could you talk about that, also from a prevention point of view? People don't realize that using a straw might be dangerous.
Daniel Fierer: Epidemiologic evidence has suggested that sharing of straws is a risk factor for having hepatitis C infection. In at least one study, hepatitic C virus has been isolated from straws that have been used for snorting cocaine, but in a minority of cases. We list any possible exposures, so straws are on the list as a possibility in those who reported using them. In reality, the men in our study who shared straws had had unprotected sex with many men as well and so we don't know that it was a straw that transmitted the virus. I think the medical community is quite skeptical in this country about hepatitis C being sexually transmitted, possibly because we haven't had the reports in this country of outbreaks of hepatitis C until the UCSF report and ours.
Other researchers have asked me, "How do you know transmission wasn't from injecting drugs or sharing straws? Here's the most conservative look. This patient told me that he shared a straw a couple of times. That's the sum total of the percutaneous exposure.
So straw sharing certainly has been considered to be a risk factor for hepatitis C infection, especially with cocaine use. And I don't see why crystal meth would actually be different -- it's a pretty abrasive substance.
Gerald Pierone: You mentioned before that you're going to be treating these, or you've treated these, patients. Any of them: did you follow them to see what percentage would actually clear the virus on their own? So my question is, perhaps could we be seeing a phenomenon where some of these patients might clear virus on their own, and also clear fibrosis on their own, as in a treated patient?
Daniel Fierer: But I think it's a very important point about patients clearing virus on their own, that is, their own immune system clears the virus. It's something I'm very interested in
Backing up for a second. The definition that's in the books of what acute hepatitis C is: It was simply defined as the first six months of infection, starting from the time of infection. Well, in our patients we can't really identify the time of infection, too many possible exposures. It is more clear in the case of a transfusiontransmitting hepatitis C. But we really can't know that in our patients. Back to the definition of acute hepatitis C, I think the 6-month time period wasextrapolated from the hepatitis B experience after the discovery of hepatitis C.
With hepatitis B, 95% of people clear it, and they do it very quickly, within six months. Hepatitis C is totally different than that, it's controversial how long it takes people to clear. If you look at different cohorts, they give very different answers. Some publishedthat everybody who's going to clear clears in three months. But in an Australian cohort, for up to two years a significant number of people were still clearing.
So, based on that experience, and tempered with the consideration that underlying HIV infection may change things, I have been really individualizing the evaluation by watching patients very closely for the characteristics of acute HCV infection, which include fluctuations in viral load and LFTs.
So, back to the question: Absolutely. I give people a chance to clear, and at least 12 weeks. But sometimes up to 24 weeks from their first ALT elevation -- which, technically speaking, would be longer than six months after infection because it takes a couple of months or so for the first ALT elevation. But there are patients who have wide viral load fluctuations. We want to give those people a chance. Because I think that immunologically they do much better. If they clear on their own, it's much better. Not to mention, not having to get six months of interferon and ribavirin.
Gerald Pierone: So, did any of these 11 clear?
Daniel Fierer: I wait at least six months of an undetectable viral load to consider the patient to have cleared. We have three people who appear to have cleared by that definition. I have really just started recruiting this cohort, only about a year and a half ago, plus or minus when our first couple of patients came in. And so I haven't had time as much as the European cohorts have had to observe them. But, yes. We have somewhere around 15 percent who spontaneously cleared right now. Others, we've started treatment. We have had really excellent success so far. Nobody whom we've initiated treatment on has failed yet, knock on wood. But we're talking about seven or so people right now who have made it far enough to really assess to end of treatment. So, as I said: I have about 25 patients who we've seen. But considering the observation period and the length of treatment and then the six months afterwards to determine SVR, I don't have long-term data on many. But we are optimistic that, despite this observation of stage 2 fibrosis, they are behaving as acute hepatitic C, and that we continue to have a very high rate of treatment success.
Gerald Pierone: Had you done any FIB-4 or FibroSures or anything to try to link to this, or no?
Daniel Fierer: I've looked, done a couple of the calculations.. But it is too early in the liver disease. I think most people acknowledge that stage 2, while being very significant if you have it within a month or two of your HCV infection, is not far enough advanced to see on the non-invasive tests. So it's really silent without a biopsy.
Gerald Pierone: Why not?
Daniel Fierer: Well, I think the non-invasive tests are pretty much acknowledged to only pick up things at about stage 3 and stage 4. They are pretty good at identifying cirrhosis and stage 3 fibrosis.
Gerald Pierone: But when you look at the receiver operating curves, though, they seem to perform well.
Daniel Fierer: They perform well, but not at stage 2. They just can't predict the earlier stages. And we're interested in FibroScan, and are trying to obtaining a FibroScan device. We've been working on the funding for that. We're interested to see that. But to get the sensitivity to detect stage 2 fibrosis, the specificity isn't good. The Spaniards have a lot of experience with FibroScan and report that finding at this meeting, although I have not seen their actual data on that. But we'd be very interested to be able to find the fibrosis in other, non-invasive, ways.
I'm really interested in trying to understand what is driving the fibrosis. And the liver biopsy is really, unfortunately, the only way we're going to be able to identify other contributing elements. Our pathologists have been looking very carefully for such things. This report is focused on the periportal fibrosis, but we are investigating other elements that may give us clues as to what other inflammatory processes may be going on. It would be nice to have non-invasive markers to be able to follow people over time to see how they will do, of course. But in order to really discover the pathogenesis, we do need the liver tissue.
Gerald Pierone: That would be ideal. If you do FibroSures, FibroScans, link it with your biopsy. And then, once you get a little bit of a database, then maybe you could sort things out.
Daniel Fierer: Right. And we plan to do that. But unfortunately, from fairly large experience of people with chronic hepatitis C, we don't expect to have useful results from that. Because at least in people with chronic hepatitis C, stage 2 is really flying below the radar of these non-invasive tests. But that would be very helpful to have one that worked for us, no question.
Bonnie Goldman: I have a final question about the HCV transmission. I notice that most of the men are older. What's your feeling about that? I don't know if that's duplicated in the other reports? There's not a man in his twenties. So the average age is probably 42, or something. So that's kind of striking. And what do you make of that?
Daniel Fierer: There are a couple of observations in there that I find distressing, as well. Some of these men in their forties have had HIV infection for some time. Some, however, were very recently HIV infected. This man whose liver biopsy is shown on the poster had only become HIV infected one year prior to his acute hepatitis C infection. Another patient had been diagnosed with HIV infection only 11 months prior.
As matter of fact, I have a number of patients who are still enrolled in an acute HIV cohort study. So not only were they newly HIV-infected, but they were involved in a clinical trial and weretherefore, very aware of risk factors.
It is particularly distressing that men in their forties who have lived through the HIV epidemic and watched their friends die...only now to become, and then hepatitis C-infected. And it's certainly much worse for their liver, getting hepatitis C at 40.
Gerald Pierone: Do you think methamphetamine may have played a role at all in fibrosis? Early literature on methamphetamine effects on the liver?
Daniel Fierer: Methamphetamine, in large doses, can cause fulminant hepatic failure. It's been reported a couple of times. However, many drugs cause fulminant hepatic failure. And there's nothing reported that I have found -- and I've really looked, including the human and animal toxicology literature -- that showed that long-time lower level exposure as seen in typical recreational use can cause periportal fibrosis.
Actually, there's a little more evidence for marijuana being a problem, interestingly enough, than methamphetamine. So that is something we're starting to look into.
So, I don't think the drug use is what is causing the fibrosis that we have seen. In fact, I'm going to state definitively that it's not. The best evidence for that is that many of these men never used drugs at all. Our first few patients enrolled were all pretty big drug users. But subsequently we enrolled a number who didn't use any drugs. And I think they're pretty clear about their drug use and dont minimize. They are really straightforward about their sexual risks and other things in the clinic visits and on the questionnaire. Other investigators have asked "How do you know? They're just not telling you." There's a long history of docs not believing patients about sex and drug use, probably for good reason. And I think that, well, if it were one person, I could say, OK, maybe one person is telling me a story. But I've had enough people who, when I talk to them, have been very frank about other parts of their lives and sex lives, that I believe that they are not trying to avoid telling me that they use crystal, when they don't use anything. So I'm pretty confident about that.
Bonnie Goldman: Thank you very much. It's really interesting.
Daniel Fierer: You're welcome. I hope this information gets out into the MSM community, especially to those who are having unprotected sex who dont think they are at risk for getting hepatitis C. The patients in my study, pretty much to the man, when they first come to see me have said, "I'm not a heroin addict. How did I get this?" Everyone needs to know that hepatitis C isnt just an infection of people who share needles. And given our finding of the nearly immediate occurrence of fibrosis, the risk of not being diagnosed and then not getting treated could be very high.
Bonnie Goldman: Many clinicians do not have it on their radar of something to test.
Daniel Fierer: That's right. We have some very smart and aware docs in New York, but it hasnt been on may peoples radar, unless theyve seen a case. I'm trying to be a part of that education piece, and encourage people to at least screen ALT every three months, and hep C antibody every year. Annual hepatitic C testing is not formally recommended for MSM, and that recommendation should be changed.
In summary, hepatitis C can be transmitted sexually in MSM, although we don't know the exact mechanisms. We therefore need to change how we think about hepatitis C transmission, and educate the MSM community and educate docs to be on the lookout for it, both with routine testing and after any sexually transmitted infection (including testing in follow up, because it may take months after infection for antibody to be made). Finally, our study shows the possibility of significant risks for missing the diagnosis, with rapid onset of significant fibrosis in HIV-infected men who develop acute hepatitis C infection. The good news is that the prospects of clearing the infection with treatment are excellent, and we hope this clearance will allow reversal of some of the liver damage already incurred. Early treatment is much more effective than treatment during the later, chronic phase of hepatitis C, so the benefits of making the diagnosis early are that much greater.
Bonnie Goldman: Thank you.
This transcript has been edited for clarity. Additional follow-up information was obtained from the interviewee after the interview concluded.
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