When to Start Antiretroviral Therapy

Antiretrovirals perform superbly in combating HIV infection. But when to initiate therapy in asymptomatic, nonpregnant, hepatitis-free, HIV-infected persons is not securely established. Of two completed randomized trials using modern therapy, a Haitian trial demonstrated a benefit to initiating therapy between 200 and 350 CD4 cells/mm3 as compared with less than 200 CD4 cells/mm3 and an international trial demonstrated a benefit to starting at greater than 350 CD4 cells/mm3 as compared with less than 250 CD4 cells/mm3. Many observational cohorts support initiating treatment at less than 350 CD4 cells/mm3. Of these, three large studies supported initiation at less than 350 cells/mm3, less than 450 CD4 cells/mm3, and less than 500 CD4 cells/ mm3, respectively, but only the last supported starting at higher counts. Such studies are not probative, given the problem of confounding. No conventional antiretroviral regimen is free of long-term adverse effects, especially over decades of use. All are expensive and require expensive monitoring. When resources are restricted, initiation of antiretrovirals for persons with high CD4 count diverts treatment from more needy persons. Pathophysiological considerations favor universal treatment because antiretrovirals mitigate systemic inflammation, which aggravates atherosclerosis. There are suggestions that HIV hastens the natural decline of cognitive, renal, and pulmonary function as well as bone mineral loss; the mechanism(s) are uncertain, as is the ability of antiretrovirals to counteract the probable acceleration. The four major guideline panels, although all have issued updates in the past year, are not consistent in recommendations for treatment of HIV-infected persons with counts greater than 350 CD4 cells/mm3.