IMMUNOLOGICAL MARKER PATHS FOR SEROCONVERSION - SINGLE DETERMINATIONSOF IMMUNOGLOBULIN-A AND BETA(2)-MICROGLOBULIN ARE NOT ADEQUATE TO ESTIMATE TIME OF HIV-INFECTION

Objective: To investigate the usefulness of single determinations of s erum immunoglobulin (Ig) A and beta(2)-microglobulin (beta(2)M) levels in estimating the time from HIV seroconversion. Subjects: Five cohort s were represented in the workshop. The Multicohort Analysis Project ( MAP) workshop database comprised 1744 HIV-infected patients with docum ented HIV seroconversion times, 363 of whom had AIDS. Overall, 1430 pa tients had two or more pre-AIDS CD4+ cell counts (13056 counts); 896 p atients had two or more pre-AIDS IgA measurements (6081 observations); but only 2964 beta(2)M measurements were available. Main outcome meas ures: Marker paths for log, IgA and log, beta(2)M and for root CD4+ ce ll count. Dependence on cofactors (age, sex, mode of HIV transmission) and attention to inter-individual variation in seroconversion level a nd annual decline in root CD4+ cell count. Logistic discrimination was performed using cofactor-adjusted paired log, IgA and log(e) beta(2)M to date HIV infections as recent (within 3 years of seroconversion), intermediate, or distant (greater than or equal to 6 years after seroc onversion). Transition intensities between immunologically defined sta tes (using IgA or beta(2)M) and to clinical AIDS. Results: Linear func tional form described the decline in root CD4+ cell count, except for the Italian cohort where a steeper annual loss of root CD4+ cell count occurred in the first year than thereafter. root CD4+ cell count at s eroconversion depended on age and mode of transmission. Annual loss of root CD4+ cell count was less severe in those infected by sexual tran smission. Non-monotone functional form emerged for log, IgA with an in itial decrease in the first year after seroconversion followed by an i ncrease thereafter. Log, IgA levels were higher in older subjects and in those infected by sexual transmission, but lower in women. A quadra tic growth curve described the marker path for log, beta(2)M, which in creased for 5-6 years after seroconversion but declined thereafter. Lo g, beta(2)M Values were significantly higher in older patients and inj ecting drug users, but lower in women. The considerable heterogeneity of marker paths between individuals affected all three markers, but ma rker values appeared to track within an individual. Discrimination bas ed on paired IgA and beta(2)M measurements from single blood samples p erformed poorly in classifying HIV infections as recent, intermediate or distant. High intensities of backward as well as forward transition s between immunologically defined states explained the poor discrimina tion based on single sample per individual. Conclusions: Further study of how serum IgA reflects HIV infection and careful clinical and stat istical assessment of reduced beta(2)M from 5 or 6 years after HIV inf ection are needed. The dependence of marker paths on mode of HIV trans mission suggests that sexual transmission may have implications for HI V disease progression. The feasibility of using serum IgA and beta(2)M , evaluable in single stored blood samples, to estimate time of HIV in fection has been set back by our results.