November 19, 1999
There has been a lot of discussion lately about the fact that some patients have divergent viral load and CD4+ count responses. These individuals frequently are experiencing a rebound in their viral load on antiretroviral therapy while maintaining a steady CD4+ count, despite the rise increase in viral replication, the so called viral load -- CD4+ count disconnect. Two reports at this meeting attempt to describe this phenomenon further.
Dehovitz and colleagues described the CD4+ count changes of 249 women who were on antiretroviral therapy consisting of two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor over a one year follow-up period. (Abstract 332) Patients were classified as responders if they had > 1.0 log decline in viral load at the six month and one year follow-up visits; mixed responders if they had a > 1.0 log decline at their first follow-up visit, but a < 0.5 log decline at their second follow-up visit; and non-responders if their viral load was < 0.5 log from baseline at both follow-up visits.
CD4+ count changes did not differ with respect to patients' baseline CD4+ count, ethnicity, history of drug use, age, or education. CD4+ counts increased steadily in the responders category, rising over 150 cells/mm3 from baseline after one year. CD4+ counts increased to a lesser extent in the mixed responders category after six months, and remained at a plateau level over the ensuing six months. CD4+ counts did not change from baseline in the non-responders.
A second group examined the effect of the initial rise in CD4+ counts -- those that occurred from the time of initiation of the current antiretroviral combination until the viral load declined to < 500 copies/mL -- on the subsequent rise in CD4+ counts that occurred after the viral load reached undetectable levels. (Abstract 446) 291 patients at 10 primary care sites in the San Francisco region were enrolled if they achieved a viral load < 500 copies within 120 days of initiating or changing their antiretroviral history. Patients were described as CD4+ count responders if they had a rise in CD4+ counts of > 50 cells/mm3 at the time their viral load first reached undetectable levels. 45% of patients had a CD4+ count response of this magnitude. CD4+ count responders could not be distinguished by race, history of injection drug use, baseline viral load, baseline CD4+ count, or time to an undetectable viral load. However, those individuals with a brisk initial CD4+ count increase continued to have a more rapid increase in CD4+ counts after the viral load reached undetectable levels than the group classified as the CD4+ count non-responders. In those individuals who experienced a viral load rebound, CD4+ counts continued to rise in those individuals without a brisk initial CD4+ cell increase, while CD4+ counts fell after a virologic rebound in those patients with a brisk initial CD4+ cell count rise. The authors conclude that patients with different initial CD4+ count trajectories may have different CD4+ cell responses following a rebound in viral load.
I'm not sure what insights these two studies provide with respect to patient management. The study by Dehovitz et al. shows that women experiencing better virologic control have better CD4+ count responses, a lesson we've learned in studies that have principally included HIV infected men a long time ago. The goal of antiretroviral therapy continues to be to get the viral load to as low a level as possible. This is the best predictor (along with patient adherence) of a durable response to therapy. Deciphering what is responsible for differences among patients in CD4+ count responses following the initiation of antiretroviral therapy and following virologic rebound will give us a better understanding how to preserve immunologic integrity. Until immune based therapies such as IL-2, that can augment CD4+ counts in some patients, become more readily accepted, the only option for preserving CD4+ counts is inhibition of viral replication with antiretroviral therapy.
For those studying the preservation of CD4+ counts that occurs in some patients after viral load rebound, the task ahead is to determine how to incorporate that observation into clinical practice. For patients who have exhausted their antiretroviral therapy options, the answer is simple -- continuing on something has been shown to preserve CD4+ counts compared to stopping therapy. For those patients with other antiretroviral therapy options, the question becomes when to use those options. Is it better to continue a combination until the CD4+ count declines to a certain level before switching, rather than switching early? Most studies suggest that a quick switch is more likely to bring the viral load back to an undetectable levels. Delaying the change more often results in the accumulation of more resistant virus. In those patients with stable CD4+ counts following a rebound in viral load, I think it will be just a matter of time until the counts begin to decline. I vote for the quick switch.