Immunologic markers of AIDS progression: consistency across five HIV-infected cohorts. Multicohort Analysis Project Workshop. Part I.
OBJECTIVE
To provide background on five HIV-infected cohorts with documented seroconversion times and serum immunoglobulin (Ig) A and beta 2-microglobulin (beta 2M), CD4+ cell count and haemoglobin levels. To give a relative risks (RR) regression summary of the prognostic value of serial CD4+ cell count, IgA, beta 2M and haemoglobin measurements for clinical AIDS, and to examine whether cofactors such as current age, sex and exposure category affect these RR.


METHODS
The Multicohort Analysis Project (MAP) workshop was an international collaboration which brought statisticians, immunologists and clinicians from the five cohorts to work together for 10 days. A predefined restricted database was made available by each cohort for the workshop.


METHODS
The Medical Research Council (MRC) Biostatistics Unit, Cambridge, UK hosted the MAP workshop from 19 to 30 April 1993.


METHODS
MAP workshop database comprised 1744 patients with documented HIV seroconversion times, with 407 women, over 900 injecting drug users (IDU) and over 500 homosexual men; 363 patients had AIDS and there were 308 deaths.


METHODS
Descriptive statistics on survival and progression to clinical AIDS by cohort and exposure category, CD4+ cell count at AIDS diagnosis and pre-AIDS zidovudine therapy. RR summarizing the joint prognostic significance of serial markers and cofactors such as age, sex and exposure category for progression to clinical AIDS.


RESULTS
Slower progression to AIDS for IDU [95% confidence interval (CI), 0.35-0.71] and heterosexuals (95% CI, 0.19-0.98) compared with homosexual men was confirmed after adjusting for current age-group and serial CD4+ cell counts. CD4+ cell counts at AIDS diagnosis were much higher among homosexual men before than after 1988 (median, 150 and 90 x 10(6)/l, respectively). Little zidovudine use was observed among AIDS cases diagnosed before 1988 (2%) but increased use was recorded after 1988 and 1989 (24%) and even greater use after 1990 (59%). Low serial CD4+ cell count, haemoglobin levels and high serum IgA and beta 2M levels were associated with an increased risk of progression to AIDS. CD4+ cell count always provided prognostic information in addition to other markers; IgA and beta 2M (95% CI, 1.23-1.50 and 105-1.51, respectively) were jointly prognostic. beta 2M did not provide significant extra information (95% CI, 0.91-1.47) to the combination of serial CD4+ cell count and IgA, although haemoglobin did (95% CI: 0.74-0.91 for 10 g/l increase in haemoglobin). Interactions between cofactors, particularly exposure category and serial markers, were used to test for modifications in RR. The association between AIDS risk and serial CD4+ cell count was weaker, and with elevated IgA stronger, for homosexual men; RR associated with high beta 2M values were lower for IDU, in whom beta 2M may be elevated for reasons other than HIV disease.


CONCLUSIONS
IgA and beta 2M, which can be measured in small volumes of stored blood, are jointly predictive of progression to AIDS. Results were broadly consistent between cohorts representing different age-groups, seroconversion periods and exposure categories. Some regression effect modifications by exposure category were noted, however, which merit further independent study.
D000328:Adult; D000367:Age Factors; D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis*; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D015897:Comorbidity; D016208:Databases, Factual; D018450:Disease Progression; D004219:District of Columbia / Q000453:epidemiology; D005260:Female; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology* / Q000276:immunology; D006679:HIV Seropositivity; D018451:Homosexuality, Male; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007558:Italy / Q000453:epidemiology; D015993:Life Tables; D008131:London / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009519:New York City / Q000453:epidemiology; D009864:Ontario / Q000453:epidemiology; D011379:Prognosis; D012044:Regression Analysis; D012306:Risk; D012307:Risk Factors; D012606:Scotland / Q000453:epidemiology; D012737:Sex Factors; D012725:Sexual Behavior; D015819:Substance Abuse, Intravenous / Q000453:epidemiology; D016019:Survival Analysis; D013997:Time Factors; D015215:Zidovudine / Q000627:therapeutic use; D001613:beta 2-Microglobulin / Q000032:analysis
D000998:Antiviral Agents; D015415:Biomarkers; D015483:HIV Antibodies; D007070:Immunoglobulin A; D001613:beta 2-Microglobulin; D015215:Zidovudine