An evaluation of HIV RNA and CD4 cell count as surrogates for clinical outcome. Delta Coordinating Committee and Virology Group.

OBJECTIVES To evaluate the role of viral load, as measured by HIV-1 RNA, and CD4 cell counts as surrogates for clinical outcome using the data from the 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 -70 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 430 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 was investigated by fitting these marker levels in addition to allocated treatment 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 independent and highly significant predictors of disease progression or death. The hazard of progression was increased fourfold (P < 0.0004) for each log10 higher baseline RNA and was reduced by 43% (P = 0.004) and by 38% (P = 0.002) for each log10 reduction at weeks 8 and 16, respectively. Compared with ZDV 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 favouring ZDV monotherapy, which was not explained by RNA: the adjusted progression 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 adjusting for CD4 to week 16 there remained a significant treatment effect favouring 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 plus 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 and by the two markers combined. Neither HIV RNA levels nor CD4 cell counts appear to be complete surrogates for clinical outcome.