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The Body Covers: The 16th Conference on Retroviruses and Opportunistic Infections

5% or More of Perinatally HIV-Infected Adolescents May Be Long-Term Nonprogressors, U.S. Study Suggests
An Interview With Rohan Hazra, M.D.

By Bonnie Goldman

February 10, 2009

There's nothing like hearing the results of studies directly from those who actually conducted the research. In this interview, you'll meet one of these impressive HIV researchers and read his explanation of a study he presented at CROI 2009.

I'm Rohan Hazra. I work at the Pediatric, Adolescent and Maternal AIDS Branch of the National Institute of Child Health and Human Development, which is one of the institutes that make up the [U.S.] National Institutes of Health.

We have a project called PHACS, the Pediatric HIV/AIDS Cohort Study, which aims to enroll 450 HIV-infected children between the ages of 7 and 16. All of these children acquired HIV from their mother; they were perinatally infected. We're looking at long-term outcomes in these children related to cognitive function, cardiac function, liver disease, kidney disease and bone health.

Rohan Hazra, M.D.
Rohan Hazra, M.D.
We have a number of posters in this meeting addressing some of those issues. This particular work actually grew out of the work that's presented in the next poster,1 which looks at trends in treatment and how they have changed over time, as new drugs have been developed (some of which end up being approved for children while some aren't). As we were doing that analysis, we realized that 5% of the children in the PHACS project were not on any antiretrovirals when they enrolled on the study. So we thought it would be interesting to see: Is there something about those children that would be interesting to report?2

Descriptive Summary of ART Stoppers
George Siberry et al. CROI 2009; abstract 900. Reprinted with permission. Click here to view the full presentation.
As I mentioned, it's 5% of the cohort. At the time that we did the data analysis, that was 12 children. When we looked at their criteria, we realized that some of them may actually need to be on treatment, but for whatever reason, were not. We wanted to look more closely at those that did not, at this point, meet criteria for treatment. So we defined those criteria accordingly: They needed to have been off antiretrovirals for six months or more, have a good CD4 count and have no clinical progression of disease.

Then we put together a fair amount of information on them, which showed a number of things. We are enrolling children ages 7 to 16, so the median age of this group was 14 and a half. About half were female. Half were black. Most of them did not have extensive clinical disease: One third of them had what we call CDC [U.S. Centers for Disease Control and Prevention] Category B or C disease. All of them had been treated in the past with HAART [highly active antiretroviral therapy], but while on this protocol, for whatever reasons, were not on antiretrovirals. They'd had a total of close to nine years of treatment, and now had been off for four to five years.

Despite being off treatment, they basically have maintained a relatively good CD4 count: Most of them have a CD4 count in the 500s to 600s. They have positive viral loads, but they are low to moderate.

What we're trying to do is say that these children do exist. Hopefully, this should prompt investigators to think about designing very careful clinical trials to see whether our adolescent patients, especially during their teenage years when they have a lot of problems with adherence to medication, can safely discontinue treatment for a short period of time -- for a couple of years while they are growing and developing, and dealing with a lot of other stresses in their lives -- with the idea that, at least based on what we know now, they are ultimately going to need lifelong antiretroviral treatment.

This study does not answer that. This is purely a description of what we're seeing in this cohort. But we hope that it will prompt some discussion and carefully designed clinical studies to look at this as an option for some children, as they age into teenage years and adulthood.

Is the issue that, since the recommendation is to treat all children, we can't tell who is a nonprogressor? Because there is no test right now that can predict whether a child's immune system can handle HIV by itself, and yet you think that the children you've isolated in this study are nonprogressors.

Correct. There's been a lot of work presented at this conference on the genetic markers that are potentially associated with being able to control HIV and maintain a CD4 count. We don't have any of that information on this group. But I think that a very good point to make is that we would have the ability to do it, because the study is designed to be able to look at those kinds of things. We would potentially be able to look at something like that.

Could it be that these children are not nonprogressors, but that something happened as a result of starting treatment so early in their HIV disease that enabled them to later not have to take treatment?

I doubt that, because the time at which they started ARVs [antiretrovirals] and their median duration of treatment are very similar to the rest of the group, which has continued on treatment.

To the point that you made: In this country, and increasingly around the world, when a baby or young child is diagnosed, almost all of them end up on treatment. I think in the United States, we've been quite aggressive with that. Almost all diagnosed infants and young children in this country used to go on treatment. Something we should probably make sure of, because I think it's a good question, is that it's not that there was something different about the trajectory of treatment in these children. From what I can remember, they did not differ from the rest of the group that had to continue on treatment.

What are some of the reasons that these children discontinued treatment?

Table 2: Reasons Reported for ART Discontinuation</div>
George Siberry et al. CROI 2009; abstract 900. Reprinted with permission. Click here to view the full presentation.
For this study, we actually had to go back and ask the sites for this information. They then went back to their medical records to try to piece this out. It turned out, for most of these children, that the person looking after them really felt that they didn't need antiretrovirals. I think there was a hint, even while they were on treatment -- they didn't seem to be having illnesses the way the other children were. They were able to very easily get their CD4 counts up and keep their viral loads down. Whatever that hint was, the major reason for why they were not on treatment was the sense of the caregiver, the clinician, that they didn't seem to need antiretroviral treatment.

This is, I believe, the first time this has ever been described.

It's interesting; it's one of the reasons we wanted to do it. It's something that all of us, as clinicians, have recognized. In fact, about half of the people who have come by the poster today have said, "Oh, we have these kids, as well, in our practices." But you're exactly right: There's not been extensive description of it. That's what we were trying to do, in a small way.

I do want to say that this phenomenon is potentially much, much more common in the developing world, because of the fact that the only HIV-infected children that would survive into adolescence without treatment were kids that were long-term nonprogressors. If they didn't have treatment beforehand, unfortunately most HIV-infected children would die. Those children who are long-term nonprogressors that do survive then make up a much larger percentage of the adolescent HIV-infected population.

I think it's something that we as clinicians have recognized, but it's just not been something that we have been able to systematically describe. This project has given us that opportunity.

What percentage of children are thought to be nonprogressors? Is it known? Do we know from the developing world?

I don't think we know. [In the United States], would we say 5%? I have to say, as a clinician, and from talking to some of the other clinicians, that seems about right. Some folks say they have maybe 10%. But what we're always missing is the denominator. Here, we have probably a better sense because at least it's from a whole cohort. But there may be some bias as to who actually is enrolled into this study: Either these children are overrepresented in this study because they are doing well, or they are underrepresented because the kids that are not on treatment are, in fact, not seeking care regularly, and therefore they don't show up at the sites to actually be eligible. I don't think we know, but I think most of us would say it's somewhere in the 5% to 10% range.

What are your next steps?

The big thing about this project is really trying to identify overall how these youth are surviving -- and, I would like to hope, thriving, despite their HIV and their transition into the late teen years and young adulthood. That's the larger project.

I think with this particular project, you've raised some of the issues. I think we need to tease out a little bit more what are the factors about these nine youths that have allowed them to do well despite not receiving HIV treatment. I think we should consider some of the genetic questions that you have asked.

I think we should have a lot of discussion, but again, I would stress this is not something to try at home. I think that we would want to just think about: Is there a carefully designed clinical trial that we could do to see if we can do this in a systematic fashion? Because I think these are real issues for youth, in terms of medication, fatigue, adherence. Usually it's in these years that responsibility for medication administration switches from the parent to the child, as well. Plus, there are just a lot of issues going on in adolescence. I think being able to have the option of considering treatment cessation temporarily for these youths would be a very good one, within the clinical armamentarium.

Thank you very much.

This transcript has been edited for clarity.


References

  1. Van Dyke R, Patel K, Read J, et al, and the Pediatric HIV/AIDS Cohort Study. ART among children with perinatally acquired HIV infection: temporal changes in ART and virologic and immunologic outcomes in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 901.
    View poster: Download PDF
  2. Siberry G, Patel K, Burchett S, et al, and the Pediatric HIV/AIDS Cohort Study. Discontinuation of ART among children with perinatally acquired HIV infection. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 900.
    View poster: Download PowerPoint




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