Objectives:To investigate whether apparently beneficial changes in plasma HIV RNA level and CD4 lymphocyte count that are induced by antiretroviral therapy are associated with a corresponding clinical benefit. Methods:For 620 patients in two randomized, double-blind trials of lamivudine (3TC) and zidovudine (ZDV) plasma HIV RNA and CD4 lymphocyte count changes were compared in patients randomized to 3TC plus ZDV and patients randomized to other treatment arms. The effect of therapy on the HIV RNA level and CD4 count was compared with the effect of therapy on clinical endpoints over the same time period. Results:Median baseline values for all subjects were 42 420 copies/ml for HIV RNA and 277 × 106/l for CD4 count. During the trial a significantly lower HIV RNA level and higher CD4 count was sustained in the ZDV/3TC group compared with the other group, with a difference in the median area under the curve from baseline per month of follow-up of 0.38 log10 copies/ml HIV RNA and 0.18 log2 × 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 was 3.14 [95% confidence interval (CI), 1.44–6.83] and for a 10-fold higher 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 adjustment for HIV RNA and CD4 changes over time the observed RH of progression 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 plasma 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 therapy that were observed.

Objective: To assess the prognostic value of HIV RNA levels for predicting clinical disease independently of the CD4 lymphocyte count in patients on antiretroviral therapy.Design: Cohort of HIV-infected patients from two trials of lamivudine therapy.Patients: For 620 patients randomized in the North American NUCA3001 and NUCA3002 trials of lamivudine, HIV RNA levels were measured (median, seven measures per patient) and CD4 counts were assessed at a central laboratory (median, 13 counts per patient). Patients were in the 1993 Centers for Disease Control and Prevention (CDC) stages A (n = 439), B (n = 135) or C (n = 46) at baseline.Outcome measures: For patients who were in CDC stage A at baseline we considered the ability of HIV RNA levels and CD4 counts to predict the development of CDC stage B or C disease. A Cox proportional hazards model was used. In a second analysis, patients who were AIDS-free at baseline were considered, and the endpoint was AIDS (CDC stage C).Results: Patients' initial CD4 counts ranged (5-95% centiles) from 104 to 529x10(6)/l (median, 274x10(6)/l) and HIV RNA levels from 1 900 to 339 680 copies/ml (median, 44 240 copies/ml). For the first analysis, with CDC stage B or C disease as endpoint, both the most recent HIV RNA level and CD4 count predicted the development of clinical disease [relative hazard (RH) for HIV RNA, 1.96 per 10-fold difference in HIV RNA; 95% confidence interval (CI), 1.41-2.73; P=0.0001; and RH for CD4 count, 1.82 per twofold difference in CD4 count; 95% CI, 1.27-2.56; P=0.0009]. When both HIV RNA and CD4 count were included in a multiple regression model, both markers provided information additional to that given by the other (RH for HIV RNA, 1.75; 95% CI, 1.23-2.50; P=0.002; and RH for CD4 count, 1.40; 95% CI, 0.95-2.07; P=0.09). In the second analysis, with AIDS as endpoint, both HIV RNA level (P=0.02) and CD4 count (P=0.004) were independently associated with clinical progression. These results were essentially unchanged after adjustment for treatment arm (zidovudine/lamivudine versus control arms).Conclusion: The HIV RNA level shows ability to predict the development of clinical disease and may thus be of importance in addition to the CD4 count in patient monitoring.

BACKGROUND:Clinical trials of antiretroviral drugs can take years to complete because the outcomes measured are progression to the acquired immunodeficiency syndrome (AIDS) or death. Trials could be accelerated by the use of end points such as changes in CD4+ lymphocyte counts and plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA and beta 2-microglobulin, but there is uncertainty about whether these surrogate measures are valid predictors of disease progression.METHODS:We analyzed data from the Veterans Affairs Cooperative Study on AIDS, which compared immediate with deferred zidovudine therapy. Patients' plasma levels of HIV-1 RNA and beta 2-microglobulin were measured in stored plasma.RESULTS:Among the 129 patients in the immediate-treatment group, 34 had disease that progressed to AIDS, as compared with 57 of the 141 patients in the deferred-treatment group (P = 0.03). Progression to AIDS correlated strongly with base-line CD4+ lymphocyte counts (P = 0.001) and plasma levels of HIV-1 RNA (P < 0.001), but not with base-line levels of beta 2-microglobulin (P = 0.14). A decrease of at least 75 percent in the plasma level of HIV-1 RNA over the first six months of zidovudine therapy accounted for 59 percent of the benefit of treatment, defined as the absence of progression to AIDS (95 percent confidence interval, 13 to 112 percent). Plasma beta 2-microglobulin levels and CD4+ lymphocyte counts explained less of the effect of treatment. A 75 percent decrease in the plasma HIV-1 RNA level plus a 10 percent increase in the CD4+ lymphocyte count could explain 79 percent of the treatment effect (95 percent confidence interval, 27 to 145 percent).CONCLUSIONS:Treatment-induced changes in the plasma HIV-1 RNA level and the CD4+ lymphocyte count, taken together, are valid predictors of the clinical progression of HIV-related disease and can be used to assess the efficacy of zidovudine and possibly other antiretroviral drugs as well.