The Body Covers: The 15th Conference on Retroviruses and Opportunistic Infections
Viral Clade May Impact HIV Disease Progression Rate Among Treatment-Naive Patients, Canadian Study Suggests
An Interview With Marina Klein, M.D., M.Sc., and Marina Keller, M.D.
February 4, 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 two of these impressive HIV researchers and read an explanation of the study they are presenting at CROI 2008. Accompanying me on this interview is Gerald Pierone, M.D., an HIV clinician/researcher and the founder and executive director of the AIDS Research and Treatment Center of the Treasure Coast in Fort Pierce, Fla.
Marina Klein: I'm Marina Klein from McGill University Health Center, Montreal Chest [Institute], and this is Marina Keller, an infectious disease fellow who did this project with me.
Basically, we were interested in looking at the role of viral subtype in determining disease progression. That was measured by changes in CD4+ cell count over time and progression to an AIDS-defining illness in antiretroviral-naive patients.1
We're kind of in a unique situation in Montreal, where the study was based, in that we have three populations we can study. Most of the previous studies that have attempted to address this question might be confounded by socioeconomic factors -- recent immigrants and refugees coming from countries where nutritional problems may be present or comorbidities may be present.
What we have in Montreal are two immigrant populations: one from Haiti, which is largely infected with subtype B; and one from Africa, which is infected with non-B subtypes. Then we have the Canadian population, which also has subtype B. We can try to make comparisons between these groups, try to isolate the effect of the viral clade. The Africans and Haitians are much more similar in terms of their demographic characteristics, whereas the Canadians and the Haitians are much more similar in terms of their viral characteristics.
Bonnie Goldman: When you say Canadians, do you mean of English origin or French origin?
Marina Klein: In Quebec, the majority are French Canadians, though we do have patients that have come from various provinces and may have even immigrated from the United States or Europe. By and large, these are French Canadians.
We broke the patients down into those three groups, according to the country in which they acquired their infection, and then compared the slope -- or the decrease in CD4+ cell count -- over time. What we observed was that patients who are infected with clade B viruses -- that's the Canadians and the Haitians -- had very similar reductions in CD4+ cell count over time: on average, about 1% per year. Whereas the Africans, who are infected with non-subtype B, had a much lower decline in CD4+ cell count.
We then looked at the incidence of new AIDS-defining illnesses in each of these three populations and showed that the same thing kind of held true: The African patients seemed to progress more slowly to AIDS-defining illnesses. In conclusion, we felt that viral clade may be an important determinant of clinical outcomes in antiretroviral-naive patients.
Bonnie Goldman: Do you know if this has ever been studied before?
Marina Klein: Currently, we're writing up the manuscript, and it's clear that there are other places in which this has been studied. Marina, maybe you want to talk about that a bit?
Marina Keller: Sure. I can say there are quite a few studies. Several studies on African patients -- endemic African patients -- had a lot of methodologic flaws, problems with patients lost to follow up, so it's hard to interpret the results.2,3 There are a few studies that have been done in Western centers: one notably in Sweden,4 one in London5 and one in Michigan in the U.S.6 All three compared local patients with HIV to African immigrants. What was very interesting about those three groups is that the Swedes and the Brits found that their Africans fared just the same as their local HIV-infected patients, whereas in the American cohort, Africans fared worse than Americans. The overall interpretation of this is that it was a difference in terms of access to medical care and universal health care.
In our study, we emphasize the fact that all these patients have the same exact access to health care. They have extremely subsidized medications, so usually the cost of medication isn't a limitation to their therapy. We add that added interest of the Haitian population to the African refugee versus the local HIV patient to try to further tease out socioeconomic differences versus the biology of the actual viral clade.
Bonnie Goldman: Were these patients on treatment?
Marina Keller: This is before treatment; these are treatment-naive patients.
Gerald Pierone: Are you planning follow-up studies to look at response to therapy? You talk about access to health care and response, but really, that should have nothing to do with the natural history before starting therapy.
Marina Keller: Some of them developed AIDS-defining illnesses even before they started therapy for HIV. Those medications [to treat AIDS-defining illnesses] as well, any medications they would need during their therapy -- even before they started ARVs [antiretrovirals] -- would be highly subsidized.
Marina Klein: Health care itself is universal. Doctor's visits, et cetera.
Gerald Pierone: Was there a certain level at which the patients were started on therapy? Were they guideline-based?
Marina Klein: This is a clinic-based cohort, so it's basically at the discretion of the treating provider. By and large, we follow the general recommendations of the guidelines. Most individuals will be considered for therapy when their CD4+ cell count falls below 350 cells, but our average start of HAART in our clinic is somewhere just above 200 cells; 230, I think, is usually the median time for starting HAART. We did do an analysis of time to start HAART -- [the amount of time that passed between] initial visit [and HAART initiation]. It was a slight amount longer in the Africans than the other groups, but it wasn't statistically significant.
Gerald Pierone: I also noticed from your baseline data that the Africans had lower CD4+ counts. Was that controlled for? I don't know how you could control for that.
Marina Klein: This was an issue we had concerns about, because we know that the norms for lymphocyte counts differ in African populations versus Caucasian populations. So we looked both at changes in absolute CD4+ count as well as [CD4 percentage]. That's why the data that we're presenting was really in the CD4 percent, to try and account for those differences at baseline. We generally observed a similar trend in absolute CD4+ count, in terms of the differences in slope; but it's quite a lot clearer when we look at CD4 percent.
Bonnie Goldman: Could this all be due to racial characteristics rather than clade? An effect of black race?
Marina Klein: It could be, but that was the reason for having the Haitian group, who are all black. They're closer in ethnic proximity to the Africans than the Caucasians would be. Obviously, they've been in the Caribbean for many, many generations, so there may be differences in terms of the regions from which they came in Africa.
The numbers that we have in this particular cohort don't really support detailed analysis between the non-B types, but there's probably differences within the different subtypes of non-B. It looks like a certain subtype is actually driving most of this: It's probably subtype A -- and A and mixtures -- rather than subtype C, but we have to further that analysis. I think the general conclusion is that clade can't be ignored and might actually be an important contributor. But we have more work to do before we can determine whether that's all non-B or just a certain [non-B] subtype.
Gerald Pierone: If you look to the literature for non-B clade natural history, are there differences out there that you can comment on?
Marina Keller: Those are the few trials I mentioned, that are coming out of Uganda and Kenya. They're very early-on trials, there are problems with the methods, and a large number of patients were lost to follow up -- for a large percentage of patients, they weren't able to perform a genotype. There's one abstract that just came out at this conference, coming out of the Rakai collaborative group. It shows data that, with better methodologic parameters, there's a difference between the different clades.7 But that work is really in its infancy. They're really [still] teasing that out.
Gerald Pierone: There was some recent media attention over clade C regarding more rapid progression.
Marina Klein: I think it may be more rapid progression, with respect to other non-B subtypes. But what we saw preliminarily mirrors more what we saw with the B subtype. This is kind of interesting in that there's tremendous diversity in the viral strains that are present in Africa, largely because that's probably the origin of the pandemic. There may be certain, older strains that maybe are more adapted with their hosts than newer strains, evolutionarily. But that's just total hypothesis generation. [laughs]
Marina Keller: The abstract that they're presenting at this conference -- Rakai, that I mentioned -- shows that clade D does a lot worse. Which is what a few other abstracts have mentioned in the past. Clade still needs to be sorted out.
Marina Klein: I think there's a lot of work that still needs to be done. But it's clearly important.
This transcript has been lightly edited for clarity.
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