Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: A meta-analysis

Objective: To evaluate treatment-mediated changes in HIV-1 RNA and CD3 coun t as prognostic markers and surrogate end points for disease progression (A IDS/death). Methods: Data from 13,045 subjects in all 16 randomized trials comparing nucleoside analogue reverse transcriptase inhibitors and having H IV-1 RNA measurements at 24 weeks were obtained. A total of 3146 subjects h ad HIV-1 RNA and CD3 count determinations at 24 weeks after starting treatm ent. Results: At Week 24, the percentage of subjects experiencing an HIV-1 RNA decrease of >1 log(10) copies/ml or a CD4 count increase of >33% was si milar (22% vs 25%). Changes in both markers at Week 24 mere significant ind ependent predictors of AIDS/death: across trials, the average reduction in hazard was 51% per 1 log(10) HIV-1 RNA copies/ml decrease (95% confidence i nterval: 41%, 59%) and 20% per 33% CD4 count increase (17%, 24%). In univar iate analyses, the hazard ratio for AIDS/death in randomized treatment comp arisons was significantly associated with differences between treatments in mean area under the curve of HIV-1 RNA changes to Weeks 8 and 24 (AUCMB) a nd mean CD3 change at Week 24, but, in multivariate analysis, only mean CD4 change was significant. Conclusions: Change in HIV-1 RNA, particularly usi ng AUCMB, and in CD4 count should be measured to aid patient management and evaluation of treatment activity in clinical trials. However, short-term c hanges in these markers are imperfect as surrogate end points for long-term clinical outcome because two randomized treatment comparisons may show sim ilar differences between treatments in marker changes but not similar diffe rences in progression to AIDS/death.