July 9, 2002
When to start highly active antiretroviral therapy (HAART) is one of the most important questions facing HIV-infected persons and clinicians, although now that everybody seems to be reaching very similar conclusions it is starting to lose freshness, and it has become a little bit unexciting to go again to another seminar trying to address the issue.
Today, the Centers for Disease Control and Prevention (CDC) presented a second analysis of their large cohort study trying to address the question of when to start therapy.
Previously the CDC's Adult and Adolescent Spectrum of Disease Project evaluated survival as a function of the CD4+ cell count at the time of initiation of antiretroviral therapy. Late initiation of antiretroviral therapy (at CD4+ lymphocyte count less than 200 cells/mm3) was associated with increased risk of death. This was presented two years ago during the Retrovirus conference (Kaplan et al. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago, Illinois. Abstract 520). In that study the investigators reviewed the charts of 5,110 patients who started two- or three-drug antiretroviral therapy after 1994. Starting treatment with a CD4+ cell count less than 200 cells/mm3 was associated with an increased two-year risk of death when compared with higher CD4+ cell count strata. However, there was no significant increase in mortality for patients who started therapy with CD4+ cell counts greater than 200 cells/mm3, such as those in the 200-249 cells/mm3 or the 250-299 cells/mm3 strata, compared with those with higher CD4+ cell counts.
In the new iteration of this study the followup is obviously much longer, and the authors were able to better dissect the gray area between 200 and 350 CD4+ cell counts, where most, if not all, the action regarding this decision is. They evaluated 2,478 patients and assigned them to different categories based on CD4+ cell count at the time of initiation of antiretroviral therapy. Within each group they further divided them into two categories -- one with a "high viral load" and the other with a "low viral load" (I believe they used a cut off of 55,000 copies/ml to separate these two groups). There was no difference between the group that had a CD4+ between 200 and 350 and a low viral load when compared to patients that started therapy at higher CD4+ cell counts: the relative risk of death was 1.5 (95 percent CI 0.8 to 3.1). However, the patients with high viral load tended to do worse than that reference group with a relative risk of death of 2.4 (95 percent CI 1.3 to 4.6).
The results of this trial add to the rationale of a more conservative approach to the initiation of antiretroviral therapy (as current guidelines do), and delay initiation of therapy until the CD4+ cell count consistently drops below 350 cells. For patients with CD4+ cell counts between 200 and 350 it might be reasonable to wait if the viral load is low. However, for patients with high viral load and a similar CD4+ cell count, it might be reasonable to start antiretroviral therapy.
This study has already been presented twice with only slight variations in conclusion, and it is time to submit it for publication. The authors might run into some difficulty, though, because last winter two large studies were published in JAMA, one from the Swiss cohort and another from the British Columbia Cohort,1-2 addressing a very similar question. The results were similar and consistent with this study.
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