Clinical GUDs together increase susceptibility to HIV, both in women and men, with the effect 1.6 times higher in men. Too few studies exist on any of the single GUDs (i.e., herpes, syphilis, and chancroid) for an examination of the difference between female and male susceptibility or a possible difference between the different GUDs. Although herpes and chancroid constitute most of the lesions in studies of clinical GUDs, few studies of these disorders exist, and almost all of these have used only serology for diagnosis (i.e., current lesions were not examined), except for one study of female chancroid in which culture was used.
Clinically diagnosed NUDs also have an effect in both women and men, with a relative difference between the genders similar to that found for GUDs. However, the effect is approximately 60% of that observed for GUDs. That GUDs have a stronger effect than NUDs also is shown by two studies in which the difference was examined directly. 5,22 When the results from these two studies were combined, the susceptibility to GUDs was shown to be significantly increased over susceptibility to NUDs (RR, 3.7; 95% CI, 1.6–8.7). Very few studies have investigated the effects that any of the specifically diagnosed NUDs have on male susceptibility.
Candidiasis and bacterial vaginosis both are a type of vaginitis and not traditionally considered STDs. 50 The presence of both depends on the microbial ecosystem of the vagina and may be linked to sexual activity. The Candida yeast and the bacteria prominent in bacterial vaginosis both may be transmitted from a male partner, but factors other than successful transmission are necessary, and these may also be sufficient for the establishment of vaginitis. Candidiasis seems to double the female susceptibility to HIV. The two studies on bacterial vaginosis indicate that clinical bacterial vaginosis increases susceptibility to HIV by a factor of 1.4 after adjustment. 33,35 A follow-up assessment of the latter study using the absence of lactobacilli or the presence of abnormal vaginal flora as indicators of bacterial vaginosis gave an effect estimate of 2. 34 This suggests that a vaginal milieu with a high pH and a lack of H2O2 production is favorable for HIV transmission. 51 Because bacterial vaginosis also is linked to an increased prevalence of other STDs, 52 it may be an important factor in HIV transmission.
Two longitudinal studies have investigated the effect of a concurrent STD on the HIV donor (i.e., HIV infectiousness) in discordant partnerships. In a study from Haiti, the unadjusted relative risk was 2.9 (95% CI, 1–9.1) when the donor had a GUD, 0.9 (95% CI, 0.1–6.9) when he or she had genital discharge, and 2.3 (95% CI, 1.1–4.6) when positive syphilis serology existed. 28 These effect estimates all were lower than those found in the HIV recipient with an STD: 6.8 (95% CI, 3–15.7), 2.6 (95% CI, 1.3–5), and 2.9 (95% CI, 1.4–6.2), respectively. These latter estimates possibly suggest a stronger effect of STDs on susceptibility than on infectiousness. The combined effect (i.e., STD in both donor and recipient) was 5.5 (95% CI, 0.8–36.6) for GUDs and 4.5 (95% CI, 1.3–15) for syphilis, indicating that the sum of increased susceptibility and infectiousness was less than additive.
A study from Rakai, Uganda, reported adjusted rate ratios of 1.6 (95% CI, 0.6–4.2) for GUD and 1.5 (95% CI, 0.7–3.3) for any STD in the HIV donor. 39 This was lower than the effect of GUD on susceptibility (RR, 3.1; 95% CI, 2–5) found in the parallel community cohort study, pointing also toward a lower effect on infectiousness than on susceptibility. Another report from the Rakai study found no effects of GUD, dysuria, syphilis, gonorrhea, chlamydia, trichomoniasis, or bacterial vaginosis, and a small but insignificant effect of genital discharge (RR, 1.9; 95% CI, 0.9–3.5). 53 This analysis was adjusted for blood viral load, and some STDs may increase both plasma viral load and genital shedding. Altogether, the data from these longitudinal studies are too limited for drawing firm conclusions.
Infectiousness has been studied indirectly by investigating the effect of STDs on biologic markers of increased transmission. The number of CD4 cells in endocervical specimens was significantly increased in patients with NUDs. 54 Chlamydia infections, gonorrhea, and bacterial vaginosis were associated with detection of cervical interleukin-10, which is an enhancer of macrophage HIV replication. 55 Both of these observations have been regarded as indicators of increased susceptibility, but they also could be markers of increased infectiousness. In women, HIV has been identified in GUDs, 56 whereas in men, it has been detected in chancroid ulcers 57 and herpes lesions. 58 In patients at STD clinics, HIV has been identified in herpes, syphilis, and chancroid ulcers. 59 In the latter study, detection of HIV was associated with a diagnosis of chancroid, a long-lasting ulcer and concurrent NUD. Detection of HIV in urethral specimens also is associated with urethritis and gonococcal infection. 60 Treatment of gonorrhea reduced the rate of HIV detection.
Several studies also have looked at the effect of STDs on seminal HIV. Two case reports showed that treatment of chlamydial urethritis 61 and gonococcal or nongonococcal urethritis 62 reduced seminal HIV. In a study comparing seminal HIV in patients with and those without urethritis, the viral load was approximately eight times higher in the men with urethritis. 63 It was higher in patients with gonorrhea than in those with nongonococcal urethritis, but both groups responded with a reduction after antibiotic treatment. Seminal viral load was reduced threefold after 2 weeks of treatment. On the basis of the reported linear correlation between blood and seminal viral load 64,65 and the 2.45 relative risk of seroconversion for each log increment in blood viral load, 53 the infectiousness caused by urethritis can be estimated as increased 1.5- to 2.2-fold, with the first estimate based on the effect from 2 weeks of treatment, and the second on the difference between the urethritis and control groups. This magnitude of effect accords with estimates from the discordant couple studies. Seminal viral load was increased in symptomatic but not in asymptomatic trichomonas urethritis. 63,66 Asymptomatic urethritis indicated by seminal leukocytosis was, however, associated with HIV seminal shedding. 67–69 Seminal viral load also was increased in patients with nongonococcal urethritis who had concomitant GUD. 70
Early studies found an association between cervical pus or inflammation and detection of cervical HIV. 71,72 A study of 223 pregnant women found a significant association between cervical HIV and cervical pus, but no association with gonorrhea or chlamydia. 73 An association between vaginal HIV and vaginal discharge also was observed, but no effect of trichomoniasis, candidiasis, or bacterial vaginosis. Another large study found that gonorrhea and cervical inflammation, but not chlamydia, were associated with endocervical HIV, whereas vaginal inflammation and candidiasis, but not trichomoniasis or bacterial vaginosis, were related to vaginal HIV shedding. 74 In a study of 604 women, detection of HIV in samples of cervicovaginal lavage was found to be associated with gonorrhea, chlamydia, and cervicovaginal ulcers, but not with trichomoniasis, syphilis, cervical pus, or vaginal discharge. 75 Although bacterial vaginosis was not related to increased HIV shedding in the aforementioned studies, a recently characterized factor that increases HIV replication has been found in cervicovaginal lavage samples. 76–78 This factor has been linked to bacterial vaginosis–associated, flora-like Mycoplasma hominis and Gardenerella vaginalis.79–81 Such a factor may be implicated in both increased infectiousness and susceptibility. On the basis of these qualitative and somewhat conflicting results, a quantitative assessment of the effects that STDs have on the infectiousness of women is not possible.
The hypothesis that concurrent infections may alter the natural history of HIV is difficult to examine because a concurrent disease such as an opportunistic infection may be a marker and not a cause of progression. Considering that viral load is correlated with survival, the hypothesis that other infections alter progression to AIDS was supported by the findings that antigenic stimulation from tetanus toxoid, influenza, pneumococcal, and cholera vaccines transiently increased blood viral load. 82–86 The last of these vaccines was oral, suggesting that even a mucosal antigenic challenge (i.e., similar to some STDs) can induce viremia. Transient alterations in viral load also have been observed in patients with tuberculosis infection, bacterial pneumonia, and a variety of acute infections. 87–89
In general, the evidence for an effect of transient increases in viremia on disease progression is lacking. A recent study found no effects of pertussis vaccination on disease progression in children infected with HIV. 98 Tuberculosis is the most studied intercurrent disease, and a review based on data from observational studies and randomized controlled trials concluded that there is no clear evidence for increased progression of HIV disease caused by intercurrent tuberculosis. 99 A meta-analysis has shown a significant beneficial effect of acyclovir treatment on HIV survival, suggesting that herpes simplex or varicella infections may increase disease progression. 100 However, firm evidence for an effect of intercurrent STDs on HIV progression is lacking, and an effect is not likely.
Relatively few epidemiologic studies have looked specifically at the effects of HIV on STD transmission. However, many of the cross-sectional case–control studies on the effects of STD on HIV transmission are equally relevant for examining the reciprocal relation because the odds ratios are the same if disease and exposure categories are interchanged. This was the main reason for not including cross-sectional studies in the meta-analysis of the effects that STDs have on susceptibility to HIV. The same arguments can be used for not relying on a cross-sectional design in studies of the opposite connection. Nevertheless, some cross-sectional studies are useful because the prevalence of STDs has been observed in different HIV disease stages based on clinical measures or CD4 counts.
The prevalence of chancroid ulcers in female sex workers in Kenya was greatest in women with generalized lymphadenopathy or AIDS who were HIV-positive. 101 A similar study of female sex workers from the Ivory Coast found a significant trend, with increased prevalences of GUDs, trichomoniasis, syphilis and genital warts, but not gonorrhea, in those who had HIV-positivity and decreasing CD4 counts. 102 Likewise, significant trends were found for bacterial vaginosis and abnormal vaginal discharge, but not for candidiasis and trichomoniasis, in women with HIV infection whose partners were male blood donors in Thailand who were HIV-positive. 103
These studies suggest a possible effect of HIV on susceptibility to several STDs, but a more rigorous analysis in longitudinal studies is required. Surprisingly few such studies have been conducted, although the incidence of STDs generally is higher than HIV incidence, which should make such studies easier than longitudinal studies of HIV transmission. Table 3 summarizes the five identified studies, 104–108 indicating that a significant effect of HIV is generally observed. The studies are too few for calculations of reliable estimates for the increased susceptibility. However, the two studies on herpes simplex infections together give a combined effect estimate of 4.4 (95 CI, 3.3–6).
No epidemiologic studies investigating the effects of concurrent HIV and STD infection on the transmission of STDs were identified. Infectiousness evaluated by measuring the presence of bacteria or virus in genital samples has only been explored for herpes. Findings show that HSV-2 shedding can occur in both symptomatic and asymptomatic periods. 109 Such shedding was found to be four times more frequent in genital samples from women infected with HIV than in a control group. 110 Viral shedding was higher in women with lower CD4 counts. At delivery, HSV-2 shedding also is four times as common in pregnant women who are HIV-positive than in those who are HIV-negative. 111 A preliminary study on HSV-2 shedding among women from the Central African Republic found an increased prevalence and quantity of shedding in women who were HIV-positive, as compared with those who were HIV-negative. 112 Another recent study reported increased shedding in women with lowered CD4 counts. 113
In men who engage in sex with men, clinical anogenital HSV-2 shedding (i.e., shedding measured on a day of herpes symptoms) was as frequent in men who were HIV-negative as in men who were HIV-positive. However, subclinical shedding was six times as common in the men who were HIV-positive. 114 Altogether, it seems that concurrent HIV infection increases the asymptomatic shedding of HSV-2. How this will translate into an increased relative infectiousness of herpes is difficult to estimate.
A relatively large literature exists concerning the effects of HIV infection on the natural history of classic STDs and their response to therapy. Most of this literature has limited value because they lack HIV-negative control groups, and few controlled studies were identified. Genital herpes recurrences are more common in men who are HIV-positive than in those who are HIV-negative (0.34 versus 0.23 recurrences per month or a ratio of 1.5). 114 Together with the increased asymptomatic shedding, this results in a markedly increased period of infectiousness. Prevalence of acyclovir-resistant HSV is higher in patients with HIV than in others. 115
A case–control study found that patients with HIV presented more often with secondary syphilis, and that chancres were more common. 116 This finding suggests a prolonged duration of infectiousness, but no prospective studies have confirmed this observation. There has been some debate on the effect of HIV on the serologic tests for syphilis. Nontreponemal tests such as the rapid plasma reagent test and the VDRL test seem to give more false positives in persons who are HIV-positive, whereas treponemal tests may serorevert in patients with HIV infection. 117–119 These altered laboratory tests probably have led to overestimation of treatment failures. A recent randomized controlled trial found few, and not a significantly different number of clinical treatment failures, in patients who were HIV-positive and those who were HIV-negative. 120
It has been reported that HIV infection causes decreased responsiveness to standard antibiotic treatment of chancroid. 121–124 More recent studies have found no effect of HIV serostatus on the number of treatment failures. 125–127 However, patients with HIV presented with ulcers of longer duration, and the time to healing was longer even after controlling for ulcer size. 125 One reason for the reported treatment failures may be increased prevalence of HSV-infected ulcers. 127
Studies examining the effect of HIV on the consequences of NUDs have focused on pelvic inflammatory disease. Although pelvic inflammatory disease seems to be more severe in women with HIV infection, treatment is successful. 128–135 When infected with chlamydia, patients who are HIV-positive have a higher risk for development of pelvic inflammatory disease than those who are HIV negative. 131 The bacterial etiologies of nonendometrial pelvic inflammatory disease (i.e., salpingitis) are similar between women with and those without HIV infection, 133 whereas HIV seems to increase the prevalence of endometritis with an atypical bacterial origin, possibly related to bacterial vaginosis. 134,135
Randomized controlled experimental studies have the strongest epidemiologic study design for establishing a causal relationship and for assessing intervention strategies. A causal effect of STDs on HIV transmission was found in a community intervention trial in Mwanza, Tanzania, 136 and this improved management of STDs was highly cost effective. 137 However, the next community randomized trial conducted in Rakai, Uganda, found no effect on HIV incidence. 138 The discrepancy between these two trials has been explained by differences in the stage of the HIV epidemic: greater effects of continuously improved treatment than of pulsed mass treatment, stronger impact of symptomatic than asymptomatic bacterial STDs, and differences in the prevalence of untreatable viral STDs. 139 A better and more quantitative understanding of the interactions between HIV infection and classic STDs is needed. Although the best indication of an STD effect on HIV transmission was provided by a randomized design, observational studies must be used to quantify the different interactions outlined in this systematic review.
Several problems are intrinsic to any systematic review and meta-analysis of observational studies in this field. In our review we identified three levels of bias. First, in each individual study, the fact that the route of transmission is common to the disease and the exposure of interest makes the quantification of association difficult. Sexual behavior is the common risk factor for contracting both HIV and STDs. Even after controlling for variables measuring number of partners, risk behavior, use of contraceptives, and the like, residual confounding probably will continue to exist because reliable and complete measures are lacking. Although the confidence intervals of our combined estimates are narrow, the underlying differences in study designs and adjustments to control for confounding and bias probably make them unreliable. They therefore represent a spurious precision. 13
Recently, systematic reviews on the impact of two other important potential confounders, female hormonal contraceptives and male circumcision, have been conducted. Two systematic reviews have examined the effects of hormonal contraceptives on HIV transmission. 140,141 Stephenson 140 concluded that the quality of the studies was too poor and the findings too inconsistent for a statistical meta-analysis, whereas Wang et al 141 performed a meta-analysis of more or less the same studies and found a significantly increased risk for HIV infection with use of oral contraceptives.
A meta-analysis of the studies examining the effect of circumcision on HIV transmission concluded, surprisingly, that men with circumcised penises had a small increased risk of HIV infection. 142 However, a reanalysis of the same set of studies with a proper statistical estimation of the overall effect reached the opposite conclusion. 143 Two other recent reviews concluded that there is substantial evidence for a protective effect of circumcision. 144,145 The latter review found evidence for a stronger protective effect of circumcision among high-risk men than among men in the general population. This raises the question whether the identified studies on the STD cofactor effect being conducted mostly in East Africa, and largely among high-risk groups are representative of the general population and other geographic regions. However, the studies, particular the prospective studies, must be conducted among groups in which the risk of infection is high enough to allow for robust estimation of the impact from risk factors.
These somewhat contradictory reviews also illustrate the problems of observational studies in this field. Examining the effects of STDs is still more complicated because STDs, in contrast to the two more constant factors, may be found in both the male and female partners, may be transmitted, and are dynamic entities in their own right. A particular problem is that the STD may be present for only a period of the time during which a person is at risk for HIV infection. This will tend to dilute the effect of the STD. 146 In addition, several of the studies relied on self-reported or serologically defined STDs, thereby suggesting that the STD may not have been present at the time of HIV transmission. Such a timing problem may lead further to underestimation of the effect.
Another problem is that both HIV and the STD may be transmitted at the same time. For example, in the study of Cameron et al, 5 the GUDs identified in male clients of female sex workers probably were caught from the women simultaneously with HIV, thereby suggesting that GUD increases infectiousness and not necessarily susceptibility. This would lead the study to conclude that the STD transmitted to the person at risk of HIV led to an increased susceptibility, whereas the effect may be explained solely by the impact of the STD on the infectiousness of the partner with HIV infection. This is an inherent problem in the reviewed studies.
In addition to the problem of confounding in the individual studies, the problem of misclassification also is evident. Several of the studies we identified relied on clinical diagnosis of the STD and therefore looked at the effects of heterogeneous entities such as GUDs and NUDs. Other studies used self-reported disease as a measurement of the exposure. Both approaches probably led to misclassification of the exposure. Hopefully, this misclassification was nondifferential, thereby leading generally to bias toward the null hypothesis of no association. Nevertheless, for robust studies, an etiologic laboratory diagnosis of the STD should be used. Too few studies have examined the individual STDs for firm conclusions to be drawn concerning the impact on any single STD.
The second level of bias involves reporting only adjusted effects from significant STDs in studies after controlling for confounders such as sexual behavior. Our review discovered that when a study identified an STD associated with a significantly increased risk of HIV infection, the study often reports only an adjusted effect estimate for this one STD and only unadjusted or no effect estimates for the other STDs examined. These unadjusted estimates probably are higher than they should be. As a result, the combined-effect estimates from meta-analyses would be overestimates.
Third, there is evidence of publication bias in our meta-analysis of studies concerning the effect of STDs on susceptibility to HIV. This likely bias is toward the reporting of significant results, which will cause the overall effect estimates to be overestimates. It probably is more difficult to identify potential unpublished work in observational epidemiology than in randomized trials, for which an effort is made to register all planned and ongoing trials. A recent assessment suggested that a publication bias existed in approximately half of a sample comprising systematic reviews of randomized controlled trials, but that it affected only the magnitude and not the quality of the conclusions (i.e., it had little bearing on the difference between an effect or no effect). 147
With all these biases, our estimates for the described interactions are uncertain. More information is needed on all the STDs and their interactions with HIV infection. It is possible on clinical grounds to group different STDs as ulcerative or nonulcerative, and as curable or incurable, although the observed heterogeneity suggests that the impact of different etiologic agents is not uniform. The limited empirical data reviewed are too restricted for detailed categories to be analyzed.
In a broad summary, assuming that confounding and publication biases were eliminated successfully, the studies indicated that GUDs increase male susceptibility approximately fourfold and female susceptibility about threefold, whereas NUDs increase male susceptibility threefold and female susceptibility twofold. There appears to be a twofold increase in the infectiousness of HIV from sources with an STD, although data are very sparse for women with an NUD. The combined effect of the HIV-susceptible and the infectious partner both having an STD, is greater than when one alone has the STD, but appears to be less than additive or multiplicative. This less than additive effect would be expected if the transmission probability became saturated when one of the partners was infected with the STD. Studies concerning the effects of HIV infection on STD transmission and duration were few. However, evidence was found for an impact of HIV on susceptibility to clinical GUDs and HSV, and on the shedding of HSV, although many more studies are required on this direction of the relation between HIV and STDs.
In general, the STDs seem to have a stronger effect on the susceptibility to HIV than on the infectiousness of HIV. This may suggest that interventions should be targeted to people not infected by HIV. However, the relative risks do not guide us to decide the importance of the increased risk on a population level. The population-attributable fraction or risk is a measure that takes the prevalence of the risk factor into account and describes the impact of the risk factor on the incidence of disease. Such a population level impact of the STDs on HIV incidence has been estimated. 16,39 Nonetheless, such a measure is problematic for infections. For instance, the effects on infectiousness may be more significant than the effects on susceptibility. Increased infectiousness will increase the transmission probability in all partnerships of the person infected with HIV and STD, whereas increased susceptibility will have an impact only in the partnerships where the person with STD infection engages in sex with a person who has HIV infection. The impact of STDs increasing HIV infectiousness may therefore be more important for the epidemiology of HIV even if it has a weaker effect, suggesting that treatment of STDs in patients who are HIV-positive should be targeted.
The baseline male-to-female HIV transmission probability is approximately twice the probability of transmission in the opposite direction. The data indicate that the susceptibility of men to HIV infection is more affected by the classic STDs than the susceptibility of women. Therefore, the HIV transmission probability from women to men is similar to the transmission probability from men to women in partnerships wherein the partner who is HIV negative also has an STD. This can have a major impact on the epidemiology of HIV because the likelihood of transmission from women to men may be a limiting factor. The gender differentials must, however, be confirmed by more studies in which an etiologic STD diagnosis is achieved because misclassification, especially that of NUDs in women, may lead to bias toward the null model, and because a gender differential in susceptibility is difficult to explain biologically.
Overall, the evidence points toward important positive bidirectional interactions between HIV infection and other STDs. The classic STDs and HIV infection may therefore reinforce the spread of each other and lead to a synergistic amplification, resulting in increased incidence and prevalence of both the STDs and the HIV infection. The impact of the epidemiologic interactions identified in our systematic review is, however, difficult to estimate in a static framework. Theoretical dynamic models of the combined epidemiology of STDs and HIV may aid such an understanding.
Despite our ability to estimate broadly the impact of STDs on susceptibility to HIV and infectiousness, and despite the large number of studies published, the major conclusion of this review must be that further studies with a more detailed focus are necessary before our understanding of this field is adequate. The meta-analysis on susceptibility to HIV has identified major problems related to reporting bias and problems in analysis of data. This should be kept in mind when new epidemiologic studies are designed and conducted.
First, the studies should allow for frequent STD sampling, thereby permitting its inclusion as a time-dependent covariate in survival analyses. Ideally, the number of sexual contacts with and without the STD should be taken into account when such studies are designed and analyzed because the transient nature of the STDs will dilute the relative risks found in epidemiologic studies, making the true increased risk per sexual contact much higher than the estimated risk. 146 Second, the data should be separated according to direction of heterosexual transmission because male susceptibility seems to increase more than female susceptibility. Third, sex behavior and other possible confounders must be measured in a rigorous way so adjustments can be made for them in the statistical analyses. Fourth, all STDs examined should be included in a multivariate analysis that allows control for confounders to reduce the problem of reporting bias. All this would suggest larger more detailed studies rather than a multiplicity of small often unreported studies. However, should the former prove to be prohibitively expensive, it may be worth establishing a database of studies examining risk factors similar to those internationally coordinated for studies estimating HIV prevalence.
Although our precise knowledge concerning the interaction of STDs and HIV is limited, we believe that STD control programs should be a part of all HIV prevention efforts. This conclusion stems in part from the promising results of the Mwanza project, 136 although they were not repeated in the Rakai trial, 138 and in part from the overall picture generated by this systematic review. Even if in the end it is found that STDs have only a limited impact on HIV transmission, we cannot afford to miss the potentially cost-effective chance of controlling HIV through their treatment. Additionally, STDs are important diseases, which by themselves cause major morbidity and reduced fertility, demanding control.
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