The Body Covers: The 15th Conference on Retroviruses and Opportunistic Infections
Immune Reconstitution May Trigger Hepatic Flares in HIV/Hepatitis B Coinfected Patients Starting HAART
An Interview With Megan Crane
February 5, 2008
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 she 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.
My name is Megan Crane. I'm from Monash University in Melbourne, Australia. What we were actually looking at was the phenomenon of flares in HIV/HBV coinfected patients shortly after they begin the HAART treatment.1 So, what happened in our study: We had 36 patients in Thailand that were on a HAART regimen. And within 12 weeks of starting the HAART, actually 8 of the 36 patients, so about 25%, suffered an hepatic flare, which we defined as a higher-than-normal ALT, basically.
We hypothesized that this was basically an immune reconstitution syndrome. So the CD4 cells come back because of the HAART. You get a renewed response to your underlying infections, which, in this case, is the HBV. So, basically just looking at markers of immune activation in the patient plasma, and we're looking at some markers of NK cell activation in the PBMCs [peripheral blood mononuclear cells].
What we found, basically, was that ... Well, this is just summarizing the clinical data, basically. The flare cases had the ALT flare in 8 weeks, and they had higher viral loads from baseline up to week 10. From our lab data, we found in the controls -- which are the ones that didn't flare -- the levels of CXCL10, which is a T-cell activation marker, and a marker of activated natural killer cells. That actually fell over the 12 weeks. And in our cases, the ones that flared, that level of CXCL10 was maintained.
Soluble CD30 is another marker of T-cell activation. That actually peaked in our flare cases at week 8, which is mirroring what happened with ALT. Levels of soluble CD26, which is produced in response to interferon gamma production, actually: we didn't find any difference between the case and control groups, but they both actually increased over the 12-week period.
Correlations: We found that CXCL10 and soluble CD30, as well as IL-18 and MCP-1, actually correlated with high LT. In terms of our NK cells, what we were actually looking for was trying to emulate what we saw in -- or what another group saw in -- HBV monoinfection, where activated NK cells were important in the flares that occur, just acute flares in HBV. So they found increased levels of trial attrition, which is just an apoptosis inducing factor on the NK cells in the liver and the periphery of those patients. We didn't find that in our coinfected patients. So I think there's something different going on in the monoinfection and the coinfection setting.
And then, basically, this is the first study to look at immune reconstitution to these in HIV/HBV coinfected patients.
Bonnie Goldman: This has never been described before?
Megan Crane: Well, it has been, in the clinic; it's been described. So, it's been seen. But no one actually has looked at the immune mechanisms that are involved. So this is the first kind of feeling out, testing out, what's going on. So we're quite happy that we've found some interesting things going on with the soluble CD30.
Bonnie Goldman: What are your next steps in this?
Megan Crane: This was a pilot study, basically. We're going to get a bigger cohort. We'll follow on looking at these kinds of immune activation markers. We'll expand it, look at a lot more things, because we'll have a lot more cells. And basically we also wanted to include the seroconversion aspect of it. So these flares that occur in this IRD [immune restoration disease] setting can actually be beneficial to the patient, in that they will actually end up clearing the virus. So we're hoping to sort of try and correlate in our own the immune events that lead to viral clearance, or the immune events that ... In one case, we actually had one patient die from a very severe flare. So maybe those immune events are different in those two situations.
Gerald Pierone: Were there any clinical factors that you can look back on that would separate the patients that had a flare, versus those that did not?
Megan Crane: Yes. There is the higher baseline ALT, which is pretty well described in this, to predict a flare in the setting. And the higher HBV viral loads are also another picture -- and low CD4 count. If you have a very low CD4 count to begin with, you're going to have a greater sort of rebound in your CD4 cells, and possibly a greater immune response to your underlying infection.
Gerald Pierone: So maybe one of the messages for clinicians would be, if you have a coinfected patient with high viral load, low CD4 count, higher LFTs to begin with; be careful of that patient whenever you find an acute flare up.
Megan Crane: I'm not a clinician, but from what I know, it's very poor sort of guidelines as to what to do with these patients and what to look out for, and how do you treat them. So there's a little debate at the moment about whether to treat the HBV first before you start your HAART regimen, or to, like we say, just sort of almost let them have the flare, but monitor it very closely, so you don't get a situation where someone dies. But let them have the flare, because that could lead to actually viral clearances. It could be a beneficial effect.
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