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TheBody.com covers the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009)
  
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Can a Trofile Assay Be Used to Predict HIV Disease Progression?

An Interview With Matthew Goetz, M.D.

September 20, 2009

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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 her explanation of a study she presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009).

Hi. I'm Dr. Matthew Goetz. I'm the lead author on this poster which looks at the relationship between dual/mixed tropism (as defined by the application of ES Trofile assay by Monogram), and disease progression in a treatment cohort of HIV-infected individuals.1

Matthew Goetz, M.D.

Matthew Goetz, M.D.

This is a follow-up analysis of work that we presented a few years ago in Sydney, and published recently in JAIDS,2 wherein we demonstrated that people who had evidence of X4-using virus by the standard Trofile assay had a greater rate of disease progression.

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If we walk through this, this is a cohort from the long-term monitoring group of patients that were prospectively followed by the CPCRA [Terry Beirn Community Programs for Clinical Research on AIDS]. These were treatment-naive individuals who had a median follow-up of approximately 48 weeks.

The eligibility for inclusion into this study required that people be, just as I say, treatment naive; give a written, informed consent; have a baseline CD4 cell count greater than 450 cells; a baseline viral load of greater than 1,000; and a successful prior performance of their original Trofile assay.

The primary analyses that we looked at were exploring the impact of identifying samples of CXCR4 use near the limits of detection, as defined by the Trofile assay, as well as those people having unambiguous use of CXCR4 and disease progression.

When we looked at disease progression, our definition was a composite outcome, wherein we looked at the initiation of antiretroviral therapy, a decrease in the CD4 cell count to less than 350, or death, as being the outcome. The outcomes are really driven by the initiation of antiretroviral therapy and decrease in CD4 cell counts. There were few deaths in the group.

Overall, we originally had 314 samples which were assessed by the Trofile assay, our original work. We were able to successively perform the enhanced Trofile assay in 310 of these individuals.

That's the newer assay that's more sensitive.

Precisely right. So, in the original assay ... I'm going to try to work through the flow of patients. We had 314 results, as I said. For four of these individuals, we weren't able to perform the ES assay.

Of the 282 individuals who had R5 coreceptor tropism in the original assay, 254 were shown to have R5 coreceptor tropism; 18 were shown to have dual/mixed coreceptor tropism, where the level of X4 virus was near the limit of detection; and six of those individuals were shown to have dual/mixed coreceptor tropism which, I'll say, was unambiguous.

Of the 32 individuals who had dual/mixed coreceptor tropism by the original assay, two of them were found to have low levels of dual/mixed coreceptor tropism by the enhanced assay, and 30 of them were shown to have unambiguous dual/mixed receptor tropism. So we're left with 254 individuals with R5 virus, 20 individuals with dual/mixed coreceptor tropism near the lower limits of detection, and 36 individuals who were above the limits of detection.

In our primary analysis, we lumped together those 20 individuals who had dual/mixed tropism near the limits of detection with the 254 people with R5 virus. When we look at it in this regard, the median CD4 cell count in the group with R5 virus was 636, versus 586 for those people with dual/mixed tropism. The viral loads were 4.05 and 4.35, on a log10 basis.

There was a statistical difference in the viral loads. That's corrected. All analyses I'm going to present are corrected for viral loads.

When we look at the Kaplan-Meiers and the rates of disease progression using the composite outcome I spoke of, we saw that the people who had dual/mixed coreceptor tropism above the limits of detection -- well above the near limit of detection -- it was more rapid, with a p-value of .0234.

When you say more rapid, can you quantify what that means?

Again, more rapid disease progression was a decrease in CD4, reaching the composite outcome of a CD4 cell count less than 350, or the decision by the treating clinician to initiate antiretroviral therapy -- recognizing that, of course, decisions to initiate therapy may be based upon other clinical signs and symptoms in individuals.

I should emphasize that all the laboratory analyses were done after the closure of the study, and that none of the treating clinicians had any access to the coreceptor tropism results. So their decisions were obviously, then, independent of the coreceptor tropism.

If we look at, then, in the multivariate analysis -- again, correcting specifically for the baseline viral load and baseline CD4 cell -- we see that the tropism, the hazard ratio was 1.71, with a p-value of .026.

As expected, of course, a baseline CD4 cell count and baseline viral load were also predictive of rates to disease progression.

We did multiple other analyses, correcting for gender, same sex exposure, injection drug use and such. We found that those really did not influence the model whatsoever.

We also did analyses looking at the individual components of a decrease in the CD4 cell count to less than 350, or initiation of antiretroviral therapy, and showed that those were also statistically significant.

We also looked at reaching a combined endpoint of less than 200, rather than 350 CD4 cells; and that remained statistically significant.

Death, as I say, was a rare event; and we did not see any relationship between coreceptor tropism and death as a separate outcome.

We compared the work with what we found in the original Trofile assay, and essentially, the results are parallel. I won't run through that complete data.

Now, we also did an analysis where we took the 20 individuals who had X4-using virus near the limit of detection, and combined them with those people who had higher amounts of X4 use, and asked whether there was any relationship between X4 tropism and that combined group with disease progression. We did not see any relationship there.

So the suggestion here -- and the other analyses bear this out -- is that those 20 individuals with X4 virus near the lower limits of detection behave -- from a prognostic perspective -- the same way as people who have only detectable R5.

In discussing the implications of this work, the first thing is, I think I pointed out, that with the ES Trofile assay, people who have X4 virus well above the NLOD [near the limit of detection] behave the same way as people who have X4-using virus, defined by the original Trofile assay.

Does the assay need to be refined even some more?

I think that we have to think about how we use the results of the assay. Because what these results suggest -- and, clearly, this would warrant validation in another cohort before we draw comprehensive conclusions -- but what this suggests is that there is an uncoupling between the results of the assay that predict whether a person is likely to respond to a CCR5 antagonist, and results of the assay that have prognostic significance.

Whether this is related to a quantitative difference in the amount of X4-using virus, or a qualitative difference in the genetic determinants of an X4-using virus would require clonal analysis and much more extensive work. But these may be avenues that warrant investigation.

So, I guess, predicting the future: let's say this works out to be true, that we can use this assay. Then could we give this test to someone who is just diagnosed? One good example would be someone who has a high CD4 count, so it's not evident they need treatment immediately. We could look at the results.

It certainly provides an intriguing thought in that regard, and in an era where the NA-ACCORD [North American AIDS Cohort Collaboration on Research and Design] data suggest that, at any CD4 cell count, there may be benefit to using antiretroviral therapy.3 We need to recognize, though, that there is substantial heterogeneity amongst patients.

There are some individuals with CD4 cell counts of 600 who have been off therapy and who remain off therapy for 5, 10, 15 years, with essentially stable CD4 cell counts. Now, whether there is benefit from using this laboratory assay to predict disease progression and, therefore, start therapy, or whether it would be equally effective to simply serially monitor CD4 cell counts, is perhaps an arguable point. But there is certainly some room for considering that this may play a role.

Great. Thank you.


References

  1. Goetz MB, Leduc R, Labriola A, et al. Prediction of HIV disease progression by an enhanced co-receptor tropism assay (CRT). In: Programs and abstracts of the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2009; San Francisco, Calif. Abstract H-1583.
  2. Goetz MB, Leduc R, Kostman JR, et al. Relationship Between HIV Coreceptor Tropism and Disease Progression in Persons With Untreated Chronic HIV Infection. J Acquir Immune Defic Syndr. March 2009;50(3):259-266.
  3. Kitahata MM, Gange SJ, Abraham AG, et al, and the North American AIDS Cohort Collaboration on Research and Design. Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival. N Engl J Med. April 30, 2009;360(18):1815-1826.

  
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This article was provided by TheBodyPRO.com. It is a part of the publication The 49th Interscience Conference on Antimicrobial Agents and Chemotherapy.
 
See Also
Tropism Testing

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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

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