February 6, 2001
When to start treatment remains one of the most controversial issues in HIV therapy. The new edition of the antiretroviral guidelines takes a big turn for a more conservative, rational approach to therapy. The latest recommendations suggest that therapy should be delayed until the CD4 reaches 350, or the viral load is above 35,000 copies/mL or even higher. Based on previous experience (and multiple editions of these guidelines, which keep changing based on not too much new data) I would say that we still do not really know when to start therapy.
This study, from the University of Alabama tried to answer this question looking at their large clinical database. They asked what was the long-term survival of patients based on the CD4 cell count they had when they started antiretroviral therapy. They followed 1,037 patients for about four years. There was no survival difference for patients who had started antiretroviral therapy when their CD4 count was above 200 cells per mm3. Those patients who had started with CD4 cell counts below 200 tended to do worse overtime, but much of this difference happened very early, the slopes of the two survival curves where pretty much the same after the second year. This is telling us that most of the deaths occurred early on, when the immune system of the patient was not doing well.
This study confirms the results of previously presented data by the Julio Montaner group in Durban. They showed that if therapy is started when CD4 is above 200, patients tend to do better, and that, in fact, it did not really matter if you wait until the CD4 cell count is close to that figure. So it seems reasonable to wait to begin treatment until the CD4 count drops to a reasonable low level before embarking on the adventure of antiretroviral therapy and all the toxicities associated with it.
This study also shows how important it is to identify patients with HIV infection early -- to avoid having them show up in doctor's offices when they develop an opportunistic infection, with a very low CD4 count. The probability of a good response to antiretrovirals goes down in a situation like that, so efforts to identify infected individuals early are crucial, as we discussed yesterday.
If eradication is not feasible, and if immune reconstitution occurs in most patients, the question of when to start therapy in order to maximize the long term clinical benefit becomes critical, and the main driving force to make this decision will be avoiding toxicities. I think the idea of "hit early, hit hard" is pretty much dead.
For the future I wonder about the impact of our much more conservative approach to therapy on the enrollment of clinical trials in this country, because many patients will elect to wait before being treated.