CORRESPONDENCE BETWEEN THE EFFECT OF ZIDOVUDINE PLUS LAMIVUDINE ON PLASMA HIV LEVEL CD4 LYMPHOCYTE COUNT AND THE INCIDENCE OF CLINICAL-DISEASE IN INFECTED INDIVIDUALS

Objectives: To investigate whether apparently beneficial changes in pl asma HIV RNA level and CD4 lymphocyte count that are induced by antire troviral therapy are associated with a corresponding clinical benefit. Methods: For 620 patients in two randomized, double-blind trials of l amivudine (3TC) and zidovudine (ZDV) plasma HIV RNA and CD4 lymphocyte count changes were compared in patients randomized to 3TC plus ZDV an d patients randomized to other treatment arms. The effect of therapy o n the HIV RNA level and CD4 count was compared with the effect of ther apy on clinical endpoints over the same rime period. Results: Median b aseline values for all subjects were 42 420 copies/ml for HIV RNA and 277 x 10(6)/l for CD4 count. During the trial a significantly lower HI V RNA level and higher CD4 count was sustained in the ZDV/3TC group co mpared with the other group, with a difference in the median area unde r the curve from baseline per month of follow-up of 0.38 log(10) copie s/ml HIV RNA and 0.18 log(2) x 106/l CD4 cells (P < 0.001 in each case ). For patients who were initially asymptomatic or in CDC stage B, the adjusted relative hazard.(RH) of AIDS for a twofold lower CD4 count w as 3.14 [95% confidence interval (Cl), 1.44-6.831 and for a 10-fold hi gher HIV RNA level was 3.22 (1.20-8.59). The RH of progression to AIDS expected with ZDV/3TC compared with the control treatments, given the observed effects of treatment on CD4 cell counts and HIV RNA levels, is 0.52, whereas the observed value was 0.16 (0.03-0.74). After adjust ment for HIV RNA and CD4 changes over time the observed RH of progress ion to AIDS for ZDV/3TC treatment compared with controls was increased to 0.36 and was no longer significant (95% CI, 0.07-1.85). Conclusion : In this analysis of two trials, the effects of ZDV/3TC in reducing p lasma HIV RNA and raising peripheral blood CD4 counts were associated with concurrent clinical benefits and the effect of treatment on these markers could account for at least part of the clinical benefits of t herapy that were observed.