THE CAUSAL ROLE FOR GENITAL ULCER DISEASE AS A RISK FACTOR FOR TRANSMISSION OF HUMAN-IMMUNODEFICIENCY-VIRUS - AN APPLICATION OF THE BRADFORD-HILL CRITERIA

Background and Objectives: Genital ulcer disease (GUD) has been report ed to increase the risk for the acquisition of human immunodeficiency virus (HIV). Although many investigators have reported an increased ri sk for HIV infection in persons with concurrent or previous GUD, not a ll studies have been designed to determine whether GUD causes an incre ased risk for HIV infection or acts only as a risk marker for infectio n. The evidence from the literature is discussed, and the criteria for causal inference proposed by Sir Austin Bradford Hill are applied. Go al: To evaluate the strength of the association between GUD and infect ion by HIV. Study Design: Case-control, cross-sectional, and cohort st udies that examined the association between HIV seroconversion and GUD were chosen from the literature. Twenty-seven epidemiologic studies w ere selected for analysis, many of which reported separate analyses of the association between HIV infection and herpes simplex virus infect ion, syphilis, or nonspecified GUD. The studies were analyzed to inves tigate the magnitude of association between GUD and HIV, and the evide nce evaluated using Hill's criteria. Results: Approximately two thirds of the analyses reported a statistically significant association betw een GUD and HIV infection. Fourteen studies reported 29 separate analy ses using a case-control design, 18 of which reported a statistically significant association between GUD (GUD, herpes, and syphilis) and HI V infection, four analyses were of varying significance depending on t he analytical technique used, and seven were nonsignificant. Thirteen studies reported 23 separate longitudinal analyses that used a nested case-control or cohort design: 11 reported a significant association, 11 had nonsignificant findings, and results of one study varied. No st udy reported a statistically significant negative association. When ap plying the literature to Hill's criteria, all nine criteria for causal inference were met, providing additional evidence that genital ulcers are associated with an increased risk for the development of HIV infe ction. Conclusions: The published evidence suggests that GUD increases the risk for HIV acquisition. Few studies, however, have examined car efully the temporal association between preexisting GUD and subsequent HIV acquisition. The analyses that simultaneously controlled for addi tional risks for HIV infection, such as lifetime sex partners or histo ry of injection drug use, report a generally lower risk for HIV associ ated with GUD. It is likely that studies that adequately control for r isk factors will find a lower risk associated with GUD than was report ed in the literature earlier in the HIV epidemic. Future research need s and the problems associated with conducting these types of studies a re discussed.