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The Causal Role for Genital Ulcer Disease as a Risk Factor for Transmission of Human Immunodeficiency Virus: An Application of the Bradford Hill Criteria

DICKERSON, MARY C. BS*; JOHNSTON, JEFF BA*; DELEA, THOMAS E. MSIA; WHITE, ALICE PhD*; ANDREWS, ELIZABETH PhD*

Original Article

Background and Objectives: 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.

Goal: To evaluate the strength of the association between GUD and infection by HIV.

Study Design: 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.

*From the Epidemiology Department, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina, and †Policy Analysis, Inc., Brookline, Massachusetts

Reprint requests: Mary Dickerson, Epidemiology Department, Glaxo Wellcome, Inc., 3030 Cornwallis Road, Research Triangle Park, NC 27709.

Received for publication October 5, 1995, revised January 11, 1996, and accepted January 17, 1996.

THE EFFECT OF GENITAL ULCER DISEASE (GUD) on the transmission of human immunodeficiency virus (HIV) has been the subject of much debate. Of particular interest is whether the presence of active genital lesions or, more generally, a history of GUD is sufficient to increase the risk for HIV transmission. Numerous studies suggest that coexisting or preexisting sexually transmitted diseases (STD) increase the risk for HIV transmission. One hypothesis proposes that STD increase the transmission of HIV by inducing the proliferation and activation of macrophages and T lymphocytes, which are more susceptible to HIV infection.1,2 An extension of this argument posits that only GUDs significantly increase the transmission of HIV by providing easier access into the bloodstream through the mucosal lesions.3 Other researchers have suggested that all STD may increase susceptibility to HIV by inducing immunosuppression.4

These hypotheses are difficult to test. The ethics and logistics of prospectively following up cohorts with STD have severely limited the number of studies to examine the temporal relationship between active GUD at the time of sexual contact with an HIV-infected partner and subsequent HIV seroconversion.

We researched the epidemiologic literature and reviewed selected articles to weigh the epidemiologic evidence of a relationship between HIV and GUD. A useful mechanism for assessing the body of evidence supporting a causal association between GUD and HIV transmission is to apply to the literature the rules of evidence suggested by Hill in his classic article.5 Although developed for the field of occupational epidemiology, these criteria provide a useful framework for assessing the evidence in a body of literature that includes diverse studies in vastly different populations.

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Methods

Articles were selected from a review of AIDSLINE at the National Library of Medicine (Bethesda, MD) and through an examination of frequently referenced articles from those found in the literature review. AIDSLINE indexes biomedical journals, meeting abstracts, and monographs on HIV and AIDS. The database search covered all HIV- and AIDS-related citations from January 1985 through October 1995.

To identify citations relating specifically to GUDs, the following Medical Subject Headings were used: Syphilis, Herpes simplex, and Chancroid; genital ulcer was used as a text word. These search terms were crossed with the Medical Subject Headings terms Acquired immunodeficiency syndrome or HIV infections to create a list of more than 600 citations to review.

The literature search for GUD covered three diseases: chancroid, herpes simplex virus infection (HSV), and syphilis. Less common GUDs, i.e., lymphogranuloma venereum and granuloma inguinale (donovanosis), were not included in the search because few studies could accrue enough cases to study the association between these less prevalent diseases and HIV acquisition. The search did not include nonulcerative STD for two primary reasons. First, a cutaneous ulcer permits more direct access of pathogens into the body; therefore, it is reasonable to hypothesize that risk estimates for HIV acquisition may be greater among patients with STD with GUDs than among those with nonulcerative STD. Limiting this review to GUDs allows evidence for causation to be sought in persons in whom the greatest effect is expected. Second, because GUDs breach the integument, these diseases provide HIV with a common route by which to enter the body. Restricting the population studied to those with physical ulcers permits a simpler, more consistent application of Hill's criteria, particularly in examining biologic plausibility.

The articles reviewed represent diversity in cultures and transmission direction (i.e., male to male, female to male, male to female), and to include cohort and case-control studies. Case reports and case series were not reviewed. For some articles, review was limited by inadequate or ambiguous description of methods and statistical techniques. Moreover, not all published studies collected sufficient data to control for potential confounders and were not used in this review.

Study designs, patient populations, and transmission routes were compared across the studies, as were the magnitude of the measures of association between genital ulcer disease, HSV, syphilis, and other risk factors thought to be associated with HIV transmission. The evidence was then evaluated using the following criteria proposed by Hill to assess whether sufficient evidence for a causal relationship exits: strength of association, consistency, specificity, temporality, biologic gradient, plausibility, analogy, coherence, and experiment.

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Results

Review of the Studies

Twenty-seven articles were selected for analysis from our literature search.2,3,6–30 Of the 27 articles reviewed, 13 were prospective studies consisting of either a cohort or nested case control design,3,6–17 and 14 were case-control studies.2,18–30 Fourteen studies examined the relationship between HIV and GUD,6,8,9,12–16,18,21,22,25,29,30 12 studies examined the specific relationship between HIV and HSV,2,3,9–11,15,17,19,21–23,27 and 18 studies examined the specific relationship between HIV and syphilis.2,3,7,8,11,12,14,15,17,19,20,22–28 The articles were grouped according to study design and specific STD.

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Genital Ulcer Disease and Human Immunodeficiency Virus

It should be noted that chancroid is the primary GUD in most of the studies reviewed in this section. However, some articles do not specify the type of GUDs observed in their patient populations, and, thus, unspecified GUDs are not assumed to be chancroid. Syphilis incidence, for example, can vary markedly between cities or patient populations. As a result, the mix of diagnoses lumped as GUDs may differ markedly by location or over time. Nonetheless, for the purpose of this review, the entire range of infections classed as GUDs appear to increase the risk for HIV acquisition even when the specific infectious agents cannot be identified.

Prospective Studies (Cohort and Nested Case-Control Studies). Eight prospective studies examined the relationship between GUD and subsequent transmission of HIV (Table 1).6,8,9,12–16 Five of the eight found a statistically significant relationship with measures of effect estimates (relative risk, odds ratios) ranging from 1.8 to 7.7.6,13–16 All these remained significant after logistic regression analysis controlling for potential confounders, such as number of lifetime sex partners, payment for sex, or male circumcision. Kassler et al8 reported a marginal association between GUD and HIV acquisition that varied with the statistical analysis used. The low incidence of GUD in this study limited the power to detect a strong association. Keet et al9 found no significant association, and Laga et al12 found an association between GUD and HIV in a nested case-control study involving transmission from males to female sex workers, but the association was not statistically significant possibly because of lack of statistical power. Although the study by Laga et al12 used serial laboratory assays to detect STD, less rigidly designed studies that rely on self-reporting of symptoms could suffer from misclassification and result in the under-ascertainment of STD; STD are frequently asymptomatic, and the diagnosis can be difficult in women.31 The prevalence of GUD in the cohort studied by Laga et al12 was only 5%, resulting in low statistical power to detect a significant association with HIV transmission. This study may have been biased toward the null by selecting a highly compliant cohort to follow, which may have received faster treatment for STD and been more accepting of risk behavior modification.

TABLE 1

TABLE 1

The study by Keet et al9 involved a group of male homosexuals at especially high risk, so any association between GUD and HIV seroconversion may have been masked by additional risks borne by this population because of an exceedingly large number of lifetime sex partners (seroconverters, 799 ± 45; controls, 866 ± 39).

Case-Control Studies. Six case-control studies evaluated the relationship of GUD to HIV (Table 2).18,21,22,25,29,30 Five of six showed a significant positive association, four of which included multivariate analysis.18,21,25,29,30 In the study in which no association was found,22 male-to-female transmission was examined; this study might be subject to recall bias because all information on the history of GUD and other risk factors were collected only by interview, and no confirmatory clinical evaluations or laboratory tests were used to determine a GUD “case.”

TABLE 2

TABLE 2

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HSV-2 and HIV

Prospective Studies (Cohort and Nested Case-Control Studies). Herpes simplex virus was evaluated specifically as a risk factor for HIV infection in 12 of the 27 articles reviewed. Three of six prospective studies3,9,11 showed a risk for HIV among persons infected with HSV-2 (Table 3). Keet et al4 further analyzed and evaluated men in whom seroconversion to HSV-2 occurred before seroconversion to HIV-1, but they did not find an association between seroconversion to HSV-2 and seroconversion to HIV-1.9 The authors attributed their previous significant finding to sexual behavior. Holmberg et al,3 however, did find a significant association between seroconversion to HSV-2 and seropositivity to HIV-1 in a United States cohort of gay men. The remaining three prospective articles did not find any significant association with HIV.10,15,17 Two of these studies used cohorts of homosexual men.10,17 The study by VanRaden et al17 relied on personal history of HSV-2 without clinical evidence, possibly subjecting the data to misclassification.

TABLE 3

TABLE 3

Case-Control Studies. Four of six case-control studies ascertained the role of STD history and number of life-time sex partners and found an association between HSV-2 and HIV (Table 4),2,19,23,27 although no association of HSV-2 and HIV was found among women in the studies by Hook et al23 or Quinn et al.27 Two other studies showed no association.21,22 It should be noted that the study by Greenblatt et al21 selected only men who had active genital ulcers and were treated at STD clinics. Selecting patients for enrollment based on the presence of active genital ulcers is not an appropriate study design to detect whether preexisting GUD increases the risk for HIV seroconversion. HIV infection that concurs with an existing GUD would not be detectable using antibody-based assays for a mean of 6 to 8 weeks. However, in a logistic regression analysis, Greenblatt et al21 did find that a history of GUD was associated with HIV seropositivity (OR = 2.35), whereas concurrent GUD was not. The study by Hayes et al22 was conducted in women and involved male-to-female transmission. Hayes et al22 used serologic markers of STD exposure; this should have reduced the misclassification of STD in their study. Nonetheless, the prevalence of GUDs was low, possibly because routine health examinations of the prostitutes may have excluded women in whom GUDs developed or may have reduced the duration of GUD exposure through treatment.

TABLE 4

TABLE 4

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Syphilis and Human Immunodeficiency Virus

Prospective Studies (Cohort and Nested Case-Control Studies) Eight studies were conducted to look for an association between syphilis and an increased risk for HIV seropositivity using a prospective design (Table 5).3,7,8,11,12,14,15,17 Darrow et al7 and Kuiken et al11 showed an association between syphilis and HIV (OR = 3.5, OR = 2.3, respectively). Of the six remaining studies in which no significant association was found, two involved male-to-female transmission.12,14 The sample studied by Kassler et al8 lacked the power to detect an association; only 2 of 147 patients were diagnosed with syphilis. Another study comprised a cohort of homosexual males for whom sera had been stored before HIV seroconversion and looked at a history of syphilis concurrent with HIV.3

TABLE 5

TABLE 5

Case-Control Studies. Nine of 10 case-control studies showed a statistically significant association between syphilis and HIV (Table 6A–6B).2,19,20,23–28 Odds ratios ranged from 1.7 to 8.6. In the study by Quinn et al,27 however, the association between syphilis and HIV was found only for men and was not significant for the women studied; in the study by Hook et al,23 the odds ratio dropped to 1.2 and was not significant after adjusting for other risk factors in logistic regression analysis. The case-control study in which syphilis and HIV were not associated22 involved male-to-female transmission.

TABLE 6

TABLE 6

TABLE 6

TABLE 6

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Application of Hill's Criteria

Because direct experimental evidence is unavailable, applying Hill's criteria to the literature reviewed provides a framework for assessing whether the relationship is a causation or an association. The nine criteria were applied to the evidence in the literature we reviewed, and the results are summarized below.

Strength of Association. The strength of the association is the first criterion used by Hill in determining whether an association is causal.5 Most of the literature indicates that both STD and GUDs are associated with an increased risk for the transmission of HIV, even when adjusted for confounders such as sexual behavior, although the effects are less pronounced in male-to-female transmission, possibly because of diagnostic difficulties and asymptomatic disease among women. Compared with men exposed heterosexually, women may have a greater predisposition for heterosexually acquired HIV in the absence of a GUD. This may reduce the differential magnitude of observed risk imparted by a GUD in women. Female-to-female transmission appears to be unreported in the literature.

It is difficult to arrive at a level of effect because of the differences in study methods, populations, and statistical techniques used for analysis, but estimates of the effect from the more stringently controlled studies range .31 from approximately 2.0 to 3.5, with some groups at higher risk (homosexual men) in the 8.0 to 13.0 range.31 These reasonably large odds ratios, especially in the groups at higher risk, support a possible causal relationship.

Torian et al16 showed that the magnitude of HIV sero-prevalence has increased over time among the subset of patients with GUDs, even though the overall HIV sero-prevalence and overall GUD incidence have declined during the same period. In addition, they showed that the association between nonulcerative STD and HIV has decreased over time.

Consistency. An observed association is consistent if it has “been repeatedly observed by different persons, in different places, circumstances and times.”5 The consistency of the association between GUD and HIV infection has been established by a positive result in different populations and in different locations. A statistically significant association between GUD, HSV, or syphilis, is reported in multiple studies. Statistical significance was reported in 11 of the 14 articles that analyzed GUD and HIV,6,8,13–16,18,21,25,29,30 7 of the 12 articles that analyzed HSV and HIV,2,3,9,11,19,23,27 and 11 of the 18 articles that analyzed syphilis and HIV.2,7,11,19,20,23–28 The magnitude of association is similar across studies. No study has reported a statistically significant negative relationship between HIV and GUD, HSV, or syphilis.

Specificity. Specificity addresses the association of a particular factor to a particular disease. For this review, do specifically ulcerative STD increase transmission of HIV, or do other factors, such as nonulcerative STD or behavior, also increase HIV transmission? Numerous other factors have been proposed as associated with an increased risk for HIV acquisition. Some of these factors, such as a large number of lifetime sex partners, also would be expected to be associated with the incidence of GUD. To account for the confounding effect of these factors and to help estimate the specific role of HSV, syphilis, or unspecified GUD in HIV acquisition, some investigators performed multivariate analyses to adjust simultaneously for potential confounders.

Eighteen articles2,3,6,8,11,13–16,20,21,23–25,27–30 reported the use of logistic regression analysis to adjust for multiple confounders in 23 separate analyses. Of these, all 10 logistic analyses of any GUD were significant,6,8,13–16,21,25,29,30 as were all 5 analyses of HSV2,3,11,23 and 5 of 8 analyses of syphilis.2,20,23–25,27,28 The results of 20 analyses indicated a significant association between GUD and HIV infection.2,3,6,8,11,13–16,20,21,23–25,27–30 The three analyses that yielded nonsignificant results from a logistic regression analysis all examined syphilis as the dependent variable.2,23,25 In two of these analyses,23,25 adjusting for confounders eliminated a significant association observed in bivariate analyses of the association of syphilis and HIV seropositivity. These analyses suggest that GUD is a specific risk for HIV infection after adjustment for other confounding factors.

Nonulcerative STD and HIV infection were not specifically addressed in the studies included in our review unless these diseases were analyzed in addition to the GUDs that formed the basis for this review. Wasserheit31 comprehensively reviewed studies of nonulcerative STD. She included in her review only studies that controlled for potential effects of sexual behavior, suggesting that other mechanisms may account for the association between all STD, ulcerative and nonulcerative, and HIV transmission. In her review, she concluded that the body of evidence supports increased risk for HIV transmission associated with both nonulcerative and ulcerative STD. She summarizes that STD may be associated with HIV transmission by recruitment of HIV-susceptible or HIV-infected cells or by the disruption of epithelial barriers in the genital tract. She concluded that the “efficiency with which GUD increases HIV transmission, however, may be due in part to the simultaneous operation of both of these mechanisms.”

Temporality. The temporal relationship of GUD and HIV infection is important because the GUD must proceed or coincide with HIV infection if the GUD is to enhance infectivity. Many case-control and cross-sectional studies examined and found a relationship between history of GUD with current HIV seropositivity; however, this does not show that GUD preceded HIV. To examine this adequately, a study must be conducted to look for the presence of a GUD before conversion. Of the 14 studies we reviewed that examined the relationship of GUD to HIV, five looked specifically at the presence of genital ulcers before HIV seroconversion.8,9,12,13,15 Plummer et al13 and Telzak et al15 found a statistically significant positive relationship. Kassler et al8 reported a nonsignificant association in their matched analysis (OR = 2.7; 95% CI, 0.6 to 11.9) but a strong association in a multiple logistic analysis (OR = 11.3; 95% CI, 1.6 to 80.2). However, the wide confidence interval indicates that the study population was too small or that the incidence of GUD was too low to detect such an association with adequate power. Keet et al9 found no association between preexisting GUD and subsequent risk for HIV seroconversion. The authors, note, however, that, unlike some other cohorts of gay men, this group had a high prevalence of HSV-2 infection before HIV seroconversion, which may have created a “saturation effect.” Laga et al12 found an association that was statistically nonsignificant, possibly because of lack of statistical power.

The presence of the HSV before HIV seroconversion was examined in 6 of 12 articles reviewed that looked specifically at HSV-2.3,9,10,11,15,17 Holmberg et al,3 Kuiken et al,11 and Keet et al9 reported a significant association between HSV-2 before HIV seroconversion. Keet et al9 also looked at HSV-2 seroconversion before HIV seroconversion but found no association. Kingsley et al,10 Telzak et al,15 and VanRaden et al17 did not find an association with HIV, but, as stated previously, two of these studies were conducted in homosexual men, and VanRaden et al17 could been subject to misclassification by relying on personal history of HSV-2 without clinical evidence.

Of the 18 studies reviewed that looked specifically at the association of syphilis and HIV, six examined the temporal relationship of a syphilis diagnosis before HIV seroconversion.7,8,11,12,15,17 Darrow et al7 and Kuiken et al11 showed a significant association. Four studies did not show an association.8,12,15,17

None of the study findings that have been reviewed report whether the outcome preceded the exposure—that is, whether an increased HIV seroconversion rate occurs in those in whom GUDs subsequently develop.

Biologic Gradient. Hill's fifth criterion states that “if the association is one which can reveal a biological gradient, or dose-response curve, then we should look most carefully for such evidence.”5 Plummer et al13 support an association between GUD and the risk for HIV seroconversion by showing a dose-response relationship between the annual frequency of GUD and HIV seroconversion. Their results showed that the mean number of annual ulcer episodes was 1.32 ± 0.55 in women who seroconvert and 0.48 ± 0.21 in women who are seronegative (P < 0.02). The seroconversion rates were approximately 60%, 80%, or 100%, when the annual ulcer rate was <1, 1 to 3, or >3, respectively. Boulos et al19 also support this idea by showing higher odds ratios observed for the association of HSV-2 with HIV (OR = 7.5; 95% CI, 3.4 to 18.5) compared with the association of syphilis with HIV (OR = 3.4; 95% CI, 1.2 to 9.3). This is “consistent with the premise that repeated disruptions of genital mucous membranes in women increases the efficiency of sexual transmission of HIV-1” because persons with HSV-2 have more outbreaks of ulcerative lesions than do those with syphilis.19

Biologic Plausibility. The literature support the hypothesis that STD, and particularly GUDs, facilitate HIV transmission by compromising the physical or immunologic integrity of the genital mucosa. Biologic mechanisms, both for STD and GUDs, have been suggested in an attempt to understand how the transmission of HIV is increased. Several authors speculated that the STD-HIV interaction might be explained by the fact that STD induce macrophage and T-lymphocyte activation. Both cell types have been shown in vitro to be more susceptible to HIV infection than unstimulated cells.1,2 Sexually transmitted diseases also may increase susceptibility to HIV by causing immunosuppression.4 It has been suggested, as well, that the transmission could be caused by the interaction of HIV and STD pathogens.31 Holmes postulates that increased transmission with nonulcerative STD results from the same general mechanisms as the classic GUDs.32 At his presentation at the First National Conference on Human Retroviruses (Washington DC, 1993), he speculated that STD such as gonorrhea, chlamydia, or trichomoniasis, typically considered nonulcerative diseases, enhance the risk for HIV transmission through inflammation of epithelium of the urethra, cervix, or penis. Levine et al33 also studied non-GUD STD enhancement of HIV transmission and theorized that increased susceptibility may be caused by the significant increase in endocervical CD4 lymphocytes.

Biologic mechanisms by which GUDs could facilitate HIV transmission are accepted widely. It has been shown that the integrity of the genital mucosa protects against infections34 and that ulceration breaks the integrity of this mucosa, thus allowing easier access of HIV into the bloodstream.3

Analogy. The association between GUD and increased risk for HIV infection also meets the criterion of analogy. Findings of other studies indicate that STD are associated with an increased risk for infection with human T-lymphotrophic virus type-I (HTLV-I), another retrovirus.35,36 Moreover, nonulcerative STD have been associated with an increased risk for infection with other STD.37

Coherence. For Hill's criterion of coherence, he stressed that “the cause-and-effect interpretation of our data should not seriously conflict with the generally known facts of the natural history and biology of the disease.”5 An association of GUD and HIV infection does not conflict with generally accepted biologic facts of the natural history of HIV infections. A primary route of heterosexual virus transmission is through the membranes of the genital tract.

Experiment. Although the focus of this review comprises observational studies (because it is generally more accepted that experimentation would be unethical in humans), Grosskurth et al38 reported a clinical trial evaluating the impact of treatment of STD, including GUDs, on HIV transmission. This trial showed that improved STD treatment reduced the HIV incidence by approximately 40% (P = 0.007). This study does not appear to be confounded by sexual behavior because no change in reported sexual behavior was observed in either the treated or the untreated groups.

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Discussion and Conclusions

Most of the literature we reviewed provides evidence of a causal relation between HIV infection and GUD, syphilis, HSV, or all three and shows a statistically significant interaction even when adjusted for confounders such as sexual behavior. Applying Hill's criteria to the literature provided additional evidence that genital ulcers are associated with an increased risk for the development of HIV infection.

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The Evidence Needed: Future Studies

Future studies of the association between GUD and HIV infection should be conducted carefully to detect a clear temporal association between previous GUD and subsequent HIV status. Several studies have assessed HIV seroprevalence by looking for coexisting GUD and HIV infections. The resultant measures of association are unlikely to produce accurate estimates because the time to seroconversion for HIV typically exceeds the incubation period for GUDs by several weeks.26 Other potential confounders or effect modifiers, e.g., the number of lifetime sex partners and substance abuse, also should be assessed. Martin et al39 suggest that among a population with a high prevalence of cocaine abuse, GUD “simply could be a marker for additional high-risk sexual behavior.”

Because of the nature of studying STD, few of the studies examining the association between GUD and HIV infection had the option of studying patients across time or obtaining extensive histories and information on other cofactors from patients. In this setting, cohort studies of patients with STD are expensive and impractical. Moreover, few studies are truly population based, and the cross-section of the population represented at STD clinics, for example, is unlikely to reflect the risk profile that exists in the community at large. Such a truly representative, population-based study may not even be possible for most STD because many STD go undiagnosed or unreported by private physicians.40 Genital ulcer disease, particularly primary and latent syphilis and HSV, often go unnoticed by patients. In some instances, HSV or latent syphilis can persist for years before diagnosis. Sexually transmitted diseases also can be self-treated using antibiotics purchased on the street or through other means.41 Studies of STD clinics are particularly problematic in assessing risk in the population because all persons who are infected with HIV—but in whom STD do not develop or who do not seek treatment for STD—serve to increase the measured association between HIV and GUDs among patients at STD clinics.6

Despite these problems in measuring the true risk for HIV infection associated with preexisting GUD, the evidence provided by the published literature strongly supports increased risk. In addition to a literature review, we support the hypothesis that genital ulcers are associated with an increased risk for HIV infection because of our examination of the literature using the criteria for causal inference proposed by Hill.5 These criteria consist of strength of association, consistency, specificity, temporality, biologic gradient, plausibility, analogy, coherence, and experimentation and are considered to provide a widely accepted framework for assessing a causal association when experimental evidence is unavailable.42 All nine of the criteria for causal inference were met, providing additional evidence that genital ulcers are associated with an increased risk for the development of HIV infection.

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