An evaluation of HIV RNA and CD4 cell count as surrogates for clinical outcome

Objectives: To evaluate the role of viral load, as measured by HIV-1 RNA, a nd CD4 cell counts as surrogates for clinical outcome using the data from t he Delta trial. Methods: A total of 1280 participants (40% of the 3207 participants in the Delta trial) with baseline and at least one other serum sample stored at -7 0 degrees C were included in the extended virology study, of whom 411 were allocated to zidovudine (ZDV) alone, 439 to ZDV plus didanosine (ddl) and 4 30 to ZDV plus zalcitabine (ddC). The extent to which changes in HIV or CD4 cell levels up to week 32 can explain the benefit of combination therapy w as investigated by fitting these marker levels in addition to allocated tre atment to Cox proportional hazards models for time to death and to disease progression. Findings: RNA at baseline and changes at weeks 8, 16 and 32 were independen t and highly significant predictors of disease progression or death. The ha zard of progression was increased fourfold (P < 0.0004) for each log(10) hi gher baseline RNA and was reduced by 43% (P = 0.004) and by 38% (P = 0.002) for each log,, reduction at weeks 8 and 16, respectively. Compared with ZD V monotherapy, the progression rate was reduced by 43% (P = 0.0001) by ZDV plus ddl and by 36% (P = 0.001) by ZDV plus ddC. After adjusting for RNA up to week 16, however, there was a highly significant treatment effect favou ring ZDV monotherapy, which was not explained by RNA: the adjusted progress ion rates were 66% higher (P = 0.005) for ZDV plus ddl and 67% higher (P = 0.004) for ZDV plus ddC compared with ZDV alone. In contrast, after adjusti ng for CD4 to week 16 there remained a significant treatment effect favouri ng combination therapy: compared with ZDV monotherapy, the progression rate was reduced by 29% (P < 0.0001) by ZDV plus ddl and 12% (P = 0.1) by ZDV p lus ddC. Adjustment for both RNA and CD4 to week 16 resulted in a relative increase in the hazard of progression (49% (P = 0.04) For ZDV plus ddl and 37% (P = 0.09) for ZDV plus ddC) not explained by the two markers combined. Conclusion: Clinical benefit from combinations of ZDV plus ddl or ZDV plus ddC was underestimated by CD4 cell counts and overestimated by RNA levels a nd by the two markers combined. Neither HIV RNA levels nor CD4 cell counts appear to be complete surrogates for clinical outcome. (C) 1999 Lippincott Williams & Wilkins.