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Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection
12 auth. J. Mellors, A. Muñoz, J. Giorgi, J. Margolick, C. Tassoni, Phalguni Gupta, ...
The rate of disease progression among persons infected with human immunodeficiency virus type 1 (HIV-1) varies greatly. Approximately 5% of infected persons [1, 2] develop the acquired immunodeficiency syndrome (AIDS) within 3 years of infection. By…
The rate of disease progression among persons infected with human immunodeficiency virus type 1 (HIV-1) varies greatly. Approximately 5% of infected persons [1, 2] develop the acquired immunodeficiency syndrome (AIDS) within 3 years of infection. By contrast, approximately 12% of infected persons are expected to remain free of AIDS for more than 20 years [1, 3]. The variable course of HIV-1 infection causes uncertainty for the infected person and complicates decisions about when antiretroviral therapy should begin. Many clinical and laboratory measures have been used to assess prognosis in HIV-1 infection [4]. In a previous comparative study of eight cellular and serologic markers [5], the single best predictor of progression to AIDS was the percentage or absolute number of circulating CD4+ lymphocytes. Since that report was published, new methods have been developed to reproducibly quantify plasma viral load, measured as the concentration of HIV-1 RNA [6-8]. Previous studies have shown that the HIV-1 RNA concentration in plasma after acute HIV-1 infection (seroconversion) provides prognostic information that is independent of the CD4+ lymphocyte count [9-12]. In a recent study [13], plasma viral load was found to be a better indicator of prognosis than the CD4+ lymphocyte count; this study, however, had a small cohort and did not assess the value of other predictive markers or combinations of markers. In the present study, we compared the prognostic value of plasma viral load with that of clinical, serologic, and cellular markers in a large cohort of HIV-infected men. We have incorporated the two most predictive markers-plasma viral load and CD4+ lymphocyte count-into a regression tree that is useful for assessing the prognosis of individual patients. Methods Study Sample Between March 1984 and April 1985, the Multicenter AIDS Cohort Study (MACS) enrolled a cohort of 4954 homosexual men who were 18 years of age or older and were free of clinical AIDS (according to the Centers for Disease Control and Prevention 1987 definition). Other details about the recruitment and characteristics of the MACS cohort have been reported elsewhere [14]. Participants in MACS returned for follow-up visits at 6-month intervals. All participants gave written informed consent, and the study was approved by the internal review boards of each clinical center. The baseline visit for the current study was either the third or fourth MACS follow-up visit (these visits occurred 1.0 or 1.5 years after enrollment). These later visits were selected to minimize the inherent variability in collecting and processing blood samples in the start-up phase of cohort studies. The eligible study sample consisted of HIV-1-infected persons who were free of AIDS at the baseline visit for this study and were either seropositive at enrollment into MACS (n = 1813) or had seroconverted before the baseline visit for this study (n = 169). All study participants were required to have a baseline CD4+ lymphocyte count (measured at the third or fourth MACS follow-up visit), to have plasma samples available in the repository for measurement of HIV-1 RNA concentration, and to have had follow-up after the baseline visit for this study. A total of 1639 of 1982 eligible men (83%) met these criteria; HIV-1 RNA concentration was measured in 1604 of these men. Measurement of Plasma HIV-1 RNA Concentrations Heparinized plasma samples were stored at 70C until testing was done. The average interval between collection of blood and freezing of plasma samples is estimated to have been approximately 6 hours, but times were not always recorded. A sensitive branched-DNA (bDNA) assay (Chiron Corp., Emeryville, California) was used to quantify HIV-1 RNA in duplicate 1.0-mL samples. This assay has a lower quantification limit of 500 copies/mL and is linear to concentrations as high as 1.6 106 copies/mL (one copy of HIV-1 RNA is equal to one molecule of HIV-1 RNA). Additional details about the bDNA assay and its performance characteristics are reported elsewhere [15]. The mean coefficient of variation between the 1604 duplicate results was 10.3%. Measurement of T-Lymphocyte Subsets, Serum Levels of 2-Microglobulin, and Serum Levels of Neopterin T-lymphocyte subsets were measured in ficollhypaque purified peripheral blood mononuclear cells (done in the centers in Baltimore and Pittsburgh) or EDTA-anticoagulated whole blood (done in the centers in Chicago and Los Angeles) by staining with fluorescent dye-conjugated monoclonal antibodies that were specific for CD3+, CD4+, and CD8+ lymphocytes (Becton Dickinson, Mountain View, California), as reported previously [16]. Serum levels of 2-microglobulin (Kabi Pharmacia, Uppsala, Sweden) and neopterin (Henning, Berlin, Germany) were measured by using commercial radioimmunoassays in comparison with standards provided by the manufacturers. Study Variables We analyzed plasma HIV-1 RNA concentrations; the number and percentage of CD3+, CD4+, and CD8+ lymphocytes at the baseline visit; and participants' reports of either oral candidiasis (thrush) or fever of no less than 2 weeks' duration. Neopterin and 2-microglobulin levels were measured at the baseline visit; if no baseline levels were available, we used levels obtained during visits that occurred within 1 year before the baseline visit. Two time intervals were used in analyses of disease progression: the time to development of AIDS (according to the 1987 definition from the Centers for Disease Control and Prevention) and the time to AIDS-related death. Censoring strategies have been reported elsewhere [1]. The date of analysis for this study was 1 July 1995. For participants in whom two or more CD4+ lymphocyte counts were available after the baseline visit (1531 of 1604 participants [95%]), we determined the rate of decline of CD4+ lymphocyte counts as an alternate outcome measure. Statistical Analysis To assess the relative prognostic power of each marker, a variant of q-q plots [17] (Splus software: q-q plot function [Statistical Sciences, Inc., Seattle, Washington]) was used to compare the percentile values of each marker in the group that developed AIDS with the percentile values in the group that remained AIDS-free. We calculated the natural logarithms of the ratios of the percentile values because these ratios have no units and will approximate zero if the distribution of the marker values does not differ between groups. We divided the study sample into four groups of approximately the same size according to the baseline HIV-1 RNA concentration (that is, quartiles), with breakpoint values of 3000, 10 000, and 30 000 copies/mL. To separate participants whose HIV-1 RNA concentrations were below the quantification limit of the bDNA assay, we subdivided the first group at 500 copies/mL. This produced five categories (I through V) of HIV-1 RNA concentrations: 500 copies/mL or less; 501 to 3000 copies/mL; 3001 to 10 000 copies/mL; 10 001 to 30 000 copies/mL, and more than 30 000 copies/mL. Kaplan-Meier curves [18] and log-rank tests for the HIV-1 RNA categories were calculated for the entire study sample and for the subgroups that either subsequently received antiretroviral therapy or never received such therapy. We used a proportional hazards model with risk-set stratification [18] to estimate and test the statistical significance of the values of relative risks for AIDS and death among persons in HIV-1 RNA categories I through V (PROC PHREG software, SAS Institute, Cary, North Carolina). Strata were defined by five categories (I through V) of CD4+ lymphocyte count (with breakpoint values at 200, 350, 500, and 750 cells/mm3), two categories of neopterin levels (with a breakpoint value equal to the median of 11.5 nmol/L), and two categories of symptoms (the presence of thrush or fever or the absence of both thrush and fever). The breakpoint CD4+ lymphocyte values of 350, 500, and 750 cells/mm3 correspond to the approximate quartile values. The first quartile was divided into two categories ( 200 and 201 to 350 cells/mm3) because persons who have 200 CD4+ lymphocytes/mm3 have a higher risk for AIDS [19]. To determine the predictive value of combining the baseline HIV-1 RNA concentration with CD4+ lymphocyte counts, we constructed a regression tree using all five categories for both HIV-1 RNA concentrations and CD4+ lymphocyte counts. To define the first five nodes of the tree, we compared the results of two Cox regression analyses using the five categories of the two variables and selected the variable with the highest likelihood ratio statistic. For each of the first five nodes, we then used recursive partitioning [20] to determine which categories of the second variable defined significantly different risks for AIDS (that is, likelihood ratio test of Cox regression for a binary split significant at the 5% level). We summarize the effect of the second variable by providing the P value that corresponded to the likelihood ratio statistic for each group of secondary nodes of the tree. Estimates of the probability of AIDS by 3, 6, and 9 years were derived from Kaplan-Meier curves for each group defined by the terminal nodes of the tree. The percentile method was applied to 500 bootstrap samples in order to provide 95% CIs for the estimates [21]. Funding Source The MACS investigators analyzed and interpreted all data; analysis was not influenced by the funding source (National Institute of Allergy and Infectious Diseases) or the manufacturer of the bDNA assay (Chiron Corp.). Results Study Sample and Comparison of Prognostic Markers Of the 1604 study participants, 998 had developed AIDS and 855 had died of AIDS by 1 July 1995. Median follow-up of AIDS-free participants was 9.6 years. Table 1 provides descriptive statistics for the prognostic markers at baseline. Comparison of the natural logarithms of the ratios of the quartile values in the AIDS group and AIDS-free group for each prognostic marker
Published in
Annals of Internal Medicine
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239
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11 | 1997 |
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