title: The causal role for genital ulcer disease as a risk factor for transmission of human immunodeficiency virus. An application of the Bradford Hill criteria.
abstract: OBJECTIVE
  Genital ulcer disease (GUD) has been reported to increase the risk for the acquisition of human immunodeficiency virus (HIV). Although many investigators have reported an increased risk for HIV infection in persons with concurrent or previous GUD, not all studies have been designed to determine whether GUD causes an increased risk for HIV infection or acts only as a risk marker for infection. The evidence from the literature is discussed, and the criteria for causal inference proposed by Sir Austin Bradford Hill are applied.
  
  
  OBJECTIVE
  To evaluate the strength of the association between GUD and infection by HIV.
  
  
  METHODS
  Case-control, cross-sectional, and cohort studies that examined the association between HIV seroconversion and GUD were chosen from the literature. Twenty-seven epidemiologic studies were selected for analysis, many of which reported separate analyses of the association between HIV infection and herpes simplex virus infection, syphilis, or nonspecified GUD. The studies were analyzed to investigate the magnitude of association between GUD and HIV, and the evidence evaluated using Hill's criteria.
  
  
  RESULTS
  Approximately two thirds of the analyses reported a statistically significant association between GUD and HIV infection. Fourteen studies reported 29 separate analyses using a case-control design, 18 of which reported a statistically significant association between GUD (GUD, herpes, and syphilis) and HIV infection, four analyses were of varying significance depending on the 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 study reported a statistically significant negative association. When applying 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 infection.
  
  
  CONCLUSIONS
  The published evidence suggests that GUD increases the risk for HIV acquisition. Few studies, however, have examined carefully the temporal association between preexisting GUD and subsequent HIV acquisition. The analyses that simultaneously controlled for additional risks for HIV infection, such as lifetime sex partners or history of injection drug use, report a generally lower risk for HIV associated with GUD. It is likely that studies that adequately control for risk factors will find a lower risk associated with GUD than was reported in the literature earlier in the HIV epidemic. Future research needs and the problems associated with conducting these types of studies are discussed.
authors.affiliation: Epidemiology Department, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 27709, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Dickerson
authors.forename: J
authors.initials: J
authors.lastname: Johnston
authors.forename: T E
authors.initials: TE
authors.lastname: Delea
authors.forename: A
authors.initials: A
authors.lastname: White
authors.forename: E
authors.initials: E
authors.lastname: Andrews
mesh_terms: D016022:Case-Control Studies; D015984:Causality; D002601:Chancre / Q000150:complications*; D002602:Chancroid / Q000150:complications*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000453:epidemiology / Q000382:microbiology* / Q000635:transmission*; D006558:Herpes Genitalis / Q000150:complications*; D006801:Humans; D008297:Male; D012107:Research Design; D013997:Time Factors