MONITORING PLASMA HIV-1 RNA LEVELS IN ADDITION TO CD4(+) LYMPHOCYTE COUNT IMPROVES ASSESSMENT OF ANTIRETROVIRAL THERAPEUTIC RESPONSE

Background: CD4(+) lymphocyte counts and plasma HIV-1 RNA levels predi ct progression of HIV-related disease, but the relative importance of these and other virological factors in defining response to antiretrov iral therapy is not yet clear. Objective: To determine the short-term variability of plasma HIV-1 RNA level during stable therapy; the relat ive importance of pretreatment values and early changes in CD4(+) coun t, HIV-1 RNA levels, and infectious HIV-1 titers in mononuclear cells of peripheral blood and pretreatment syncytium-inducing phenotype of a n HIV-1 isolate for prediction of disease progression and decline in C D4(+) counts during therapy. Design: Data were collected prospectively in a randomized, clinical trial comparing two combination regimens (A CTG [AIDS Clinical Trials Group] Protocol 241) and pooled across treat ments. Setting: 8 AIDS Clinical Trials Units. Patients: 198 adults wit h HIV-1 infection and no more than 350 CD4(+) lymphocytes/mm(3) who ha d received at least 6 months of nucleoside therapy. Interventions: All patients received zidovudine and didanosine; 100 received nevirapine and 98 received placebo. Measurements: CD4(+) lymphocyte counts, plasm a HIV-1 RNA levels, and infectious HIV-1 titers in cells were measured before and 8 and 48 weeks after study treatment. Assay for the syncyt ium-inducing viral phenotype was done at baseline. Progression was def ined as occurrence of opportunistic infection, malignancy, or death du ring the 48 weeks after treatment began. Results: The difference betwe en two measurements of HIV-1 RNA levels at baseline was within +/-0.39 log(10) copies/mL (2.5-fold) for 90% of 167 patients receiving stable therapy. In a multivariate model, risk for disease progression was re duced by 56% (95% CI, 8% to 79% [P = 0.028]) for every 10-fold lower H IV-1 RNA level at baseline, by 52% (CI, 6% increase to 79% reduction [ P = 0.071]) for every 10-fold reduction in HIV-1 RNA level at 8 weeks after treatment initiation, and by 67% (CI, 42% to 81% [P < 0.001]) fo r every 2-fold higher CD4(+) count at baseline. These risk factors and syncytium-inducing viral phenotype at baseline, but not infectious HI V-1 titers in circulating cells, were associated with change in CD4(+) counts over 48 weeks. Conclusions: For an individual patient, a chang e in plasma HIV-1 RNA level of 2.5-fold or more probably indicates a t rue biological change. Monitoring HIV-I RNA levels and CD4(+) lymphocy tes before a change in antiretroviral treatment and monitoring HIV-1 R NA levers shortly thereafter improves prediction of disease progressio n and decline in CD4(+) counts for 1 year compared with monitoring CD4 (+) counts or HIV-1 RNA levels alone. Additional monitoring of infecti ous HIV-1 titers in mononuclear cells of peripheral blood is not usefu l.