SURROGATE MARKERS FOR SURVIVAL IN PATIENTS WITH AIDS AND AIDS RELATED COMPLEX TREATED WITH ZIDOVUDINE

Objective - To determine whether early effects of zidovudine treatment on CD4+ lymphocyte count and concentrations of beta-2 microglobulin, neopterin, or HIV p24 antigen or antibody are correlated with survival in patients with AIDS or AIDS related complex. Design - Retrospective study of changes in laboratory markers and survival. Setting - Multicentre trial at university hospital clinics. Subjects - '90 Patients with AIDS or AIDS related complex. Intervention - Patients started zidovudine 200 mg orally every four hours. Fifty six of the patients died a median 17 months after starting zidovudine; the remaining 34 patients were followed up for a median 25.5 months. Main outcome measures - Changes in CD4+ lymphocyte count and serum concentrations of p24 antigen and antibody, beta-2 microglobulin, and neopterin; survival of the patient. Results - The pretreatment characteristics that independently predicted poor survival were determined using a multivariate proportional hazards models: a diagnosis of AIDS (upsilon-AIDS related complex), age over 45 years, and the logarithm of serum neopterin concentration. When these baseline characteristics were controlled for the logarithm of CD4+ lymphocyte count at weeks 8-12 of treatment (p = 0.007) and an increase in serum beta-2 microglobulin concentration at weeks 8-12 (p = 0.05) also independently correlated with survival. In the 38 patients with a better pretreatment prognosis, 24 month survival estimated by the product-limit method was 88% for those with a good response on both surrogate markers during early treatment compared with only 50% for those with a poor response on either marker. In the 38 with a worse pretreatment prognosis, 24 month survival was estimated to be 49% for those with a good response on both surrogate markers compared with only 18% for those with a poor response on either. Conclusion - These data suggest that CD4+ lymphocyte count at 8-12 weeks and, perhaps, change in serum beta-2 microglobulin concentration could be surrogate end points for clinical outcome in trials of antiretroviral drugs for patients with HIV disease.