Sexually transmitted infections (STIs) have for many years been recognized as important cofactors in the sexual transmission of human immunodeficiency virus type 1 (HIV-1).1 Numerous cohort studies have demonstrated that HIV-infected individuals with STIs are more susceptible to HIV than individuals without STIs, and other genital tract infections such as bacterial vaginosis and vulvovaginal candidiasis have also been shown to increase the susceptibility to HIV.1–4 In addition, HIV-infected individuals who are coinfected with other STIs appear to be more likely to transmit HIV sexually than HIV-infected individuals who are not coinfected.5,6 An understanding of these associations between genital tract infections and HIV transmission is critical to the formulation of HIV prevention strategies.
A number of factors may explain the association between genital tract infections in HIV-infected individuals and HIV infectiousness. HIV has frequently been detected in genital ulcer specimens collected from HIV-infected individuals.7–10 Independently of their effect on mucosal and epithelial barriers, genital tract infections also increase HIV infectiousness by promoting HIV viral shedding in the genital tract. This may be due to the recruitment of HIV-infected leukocytes to the genital tract in response to local infection, or it may be the result of increased production of inflammatory cytokines, which may stimulate HIV replication.11–14 Herpes simplex virus type 2 (HSV-2) can coinfect HIV-infected CD4+ cells and cause increased HIV replication,15,16 and bacterial vaginosis-associated flora may stimulate HIV replication through a heat-stable HIV-inducing factor.17
This review and meta-analysis examines the effect of genital tract infections on HIV-1 shedding in the genital tract. An earlier meta-analysis showed that the detection of HIV-1 in the genital tract was increased in the presence of gonorrhoea (OR 2.4, 95% CI: 1.8–3.3) and chlamydial infection (OR 1.5, 95% CI: 0.9–2.5).18 Much remains unknown regarding the relative significance of other genital tract infections and the relative effects of asymptomatic and symptomatic infections in promoting HIV shedding. A better knowledge of which genital tract infections increase the risk of HIV transmission could be important in formulating treatment and screening protocols for HIV/AIDS management programs. It would also assist in mathematical modeling of interactions between HIV and other STIs.
The focus of this review is restricted to those genital tract infections that are commonly associated with the genital ulcer disease (GUD), urethral discharge, and vaginal discharge syndromes: syphilis, chancroid, genital herpes (HSV-2), gonorrhoea, chlamydial infection, trichomoniasis, bacterial vaginosis, and vulvovaginal candidiasis. Conditions such as urethritis, cervicitis, and cervical mucopus are also included, even if there are no specific indicators of infection.
Materials and Methods
The PubMed, Embase and AIDSearch databases were searched on January 8, 2007 using the following search terms: (HIV or human immunodeficiency virus) and (shedding or detection or concentration) and (genital or cervicovaginal or cervical or vaginal or urethral or seminal or semen) and (herpes or syphilis or chancroid or chlamydia or gonorrh* or trichomon* or candid* or vaginosis or vaginitis or mucopus or cervicitis or urethritis or inflammation or ulcer*). Reference lists of relevant articles were searched for further studies that might prove relevant, and reference lists of earlier reviews on HIV-1 shedding3,4,18–21 were also searched. All abstracts were independently reviewed by both authors.
Studies were included in the review if they examined the effect of genital tract infections on the presence of HIV-1 shedding, or the concentration of HIV-1 DNA or RNA, in the genital tract of individuals with confirmed HIV-1 infection. Studies were excluded from the review if they dealt exclusively with factors affecting the shedding of HIV-2, if they measured shedding only in genital ulcers (since such studies lack an appropriate control group) or if they dealt only with infections other than those listed previously (e.g., human papillomavirus, cytomegalovirus, and Mycoplasma hominis). Information from the included studies was independently recorded by both authors, and where there were discrepancies in recordings, these were resolved through discussion.
A meta-analysis was performed on those studies that reported the effects of genital tract infections on HIV-1 shedding in terms of an odds ratio (OR), or which presented results in sufficient detail to allow for the calculation of an OR. For each of these studies, the following information was recorded: location of study population, nature of population sampled, date of study, study design, sample size, number of individuals with genital tract infection, method used to diagnose genital tract infection, unadjusted and adjusted ORs (together with 95% confidence interval) representing effect of infection on odds of detecting HIV in genital tract, method used to detect HIV-1 in genital tract and factors controlled for in multivariate analysis. In the cases in which more than one study was published relating to the same sample of individuals, only 1 OR was included per infection considered, that being the result published in a peer-reviewed journal or the result based on the larger sample size. In the cases in which specimens for HIV-1 detection were collected from more than 1 anatomical site, only the results for the site most frequently associated with the relevant infection (the cervix in the case of gonorrhoea and chlamydial infection, and the vagina in the case of trichomoniasis, bacterial vaginosis, and vulvovaginal candidiasis) were included. In the cases in which more than 1 HIV-1 genome detection method was used, only the results for the method that detected HIV-1 DNA were included in the meta-analysis, to avoid double-counting (HIV-1 DNA was chosen because it was the measure to which the most effect estimates related). Sensitivity analyses were performed to examine the effects of including only those studies that detected HIV-1 DNA and only those studies that detected HIV-1 RNA.
For each of the infections and clinical conditions of interest, a meta-analysis was performed on the recorded OR, using a random effects model. Tests for heterogeneity between estimates were performed by conducting χ2 tests on Q statistics,22 and the interstudy variance was estimated from the expectation of the Q statistic.22 The summary OR for n studies was calculated as
;)
where θi is the OR estimated in study i, and wi is the weight given to study i (the inverse of the sum of the interstudy variance and the variance of the ith OR on a natural log scale).22 Wherever possible, results from multivariate analyses were used in place of results from univariate analyses. In each case, tests for publication bias were conducted using the Begg adjusted rank correlation test23 and the Egger regression asymmetry test.24 However, because the number of studies pooled was small in all cases, and because these tests for publication bias have low power when the number of studies pooled is small, the stratified versions of Begg test and Egger test were applied to the combined data for all infections and clinical conditions, treating the different infections and conditions as different strata. Funnel plots were also visually examined for evidence of publication bias.23 STATA 9.2 (StataCorp, College Station, TX, USA) was used to generate all graphs and to perform all statistical analyses.
Several sensitivity analyses were conducted. As it may take some time for HIV shedding to return to normal levels after treatment of genital tract infections,25–27 studies that compare levels of HIV shedding before and soon after treatment may understate the true effect of genital tract infections on HIV shedding. In addition, a number of studies have been based only on patients attending STI clinics. If all genital tract infections affect HIV shedding in the genital tract to some degree, then a comparison of HIV shedding in individuals with one particular infection and that in individuals with other genital tract infections is also likely to understate the true effect of that infection on HIV shedding.28 Sensitivity analyses were therefore performed to examine the effects of excluding those studies that were either based only on STI clinic attenders or based only on comparison of individuals pre- and post-treatment. Male and female data were combined, although sensitivity analyses were performed to examine the effect of excluding men. In the case of candidiasis and HSV-2 shedding, sensitivity analyses were also conducted to assess the effect of excluding studies that did not control for CD4+ count or blood plasma viral load, as candidiasis and HSV-2 reactivation are known to occur more frequently in immunosuppressed individuals,29–32 and an observed association between these infections and HIV shedding in the genital tract could therefore be due to the effect of low CD4+ count or high plasma viral load on genital HIV shedding, independently of any effect of candidiasis or HSV-2. Sensitivity analyses were not performed in cases in which there were fewer than 3 ORs to combine.
Results
A total of 63 studies were identified that compared the shedding of HIV in the presence and absence of genital tract infections. Although the focus of the review was not restricted to publications in English, only English publications were identified. Studies were excluded either because they combined infections when examining effects of genital tract infections on HIV shedding,12,33–37 used unconventional measures of HIV shedding,14,38 repeated observations that were reported elsewhere,39–46 calculated ORs when there were fewer than 4 STI cases,47 or reported only that the effect of genital tract infections on HIV shedding was significant or not significant.48–54 After excluding these studies, 39 remained. Of these, 27 assessed the effect of genital tract infections on the odds of detecting HIV shedding in the genital tract, and 18 assessed the effect of genital tract infections on the concentration of HIV in the genital tract. The results of the former group of studies are summarized in Table 1 and the results of the latter group of studies appear in Table 2. Two of the studies that assessed the effect of genital tract infections on HIV concentrations are not included in Table 2 because they presented only the change in viral load associated with the infections, not the absolute levels of viral load in individuals with the infections.55,56
TABLE 1: Effects of Genital Tract Infections on HIV-1 Detection in the Genital Tract
TABLE 1: (Continued)
TABLE 1: (Continued)
TABLE 2: Effects of Genital Tract Infections on HIV-1 Concentrations in the Genital Tract
TABLE 2: (Continued)
Meta-analysis was performed on the results of the studies summarized in Table 1. The combined ORs appear in Table 3 and the corresponding forest plots are shown in Figure 1. Overall, there was little evidence of publication bias, either by the stratified Begg test (P = 0.60) or by the stratified Egger test (P = 0.14). Funnel plots were also found to be reasonably symmetric in all cases. Except in the case of GUD and HSV shedding, there was no evidence of significant interstudy variation, and results from random and fixed effects models were therefore similar. Excluding studies conducted among individuals attending STI clinics did not alter the combined ORs in any consistent manner.
TABLE 3: Combined Estimates of Effect of Genital Tract Infections on the Odds of Detectable HIV-1 Shedding in the Genital Tract
Fig. 1: Forest plots of effects of genital tract infections on the detection of HIV in the genital tract. Squares represent the results of individual studies, with the size of each square representing the weight given to the relevant study. Diamonds represent the combined odds ratios.
Fig. 1: (Continued)
Candidiasis was the most frequently studied infection, and was found to increase the detection of HIV significantly (OR 1.8, 95% CI: 1.3–2.4). The effect of candidiasis on the shedding of HIV-1 DNA (OR 2.2, 95% CI: 1.6–3.2) was greater than the effect on HIV-1 RNA (OR 1.5, 95% CI: 1.0–2.2), though not significantly so. The method used to diagnose candidiasis did not significantly affect the association; in 4 studies that diagnosed candidiasis on the basis of culture alone the OR was 1.7 (95% CI: 0.8–3.8), in 7 studies that diagnosed candidiasis on the basis of microscopy alone the OR was 1.8 (95% CI: 1.1–2.9) and in 3 that diagnosed candidiasis on the basis of symptoms the OR was 1.6 (95% CI: 1.0–2.5). Excluding studies that did not control for CD4+ count or blood plasma viral load did not reduce the combined OR; in the 4 studies that controlled for CD4+ count or blood plasma viral load, the combined OR was 2.1 (95% CI: 1.0–4.2). Studies that quantified viral load in genital secretions supported these findings, showing changes of between 0.3 and 0.6 log RNA copies associated with candidiasis.80,88,90
Bacterial vaginosis had little effect on the detection of HIV-1 in the genital tract (OR 1.0, 95% CI: 0.7–1.5). The effect differed between the 6 studies that used the Amsel criteria to diagnose bacterial vaginosis (OR 1.5, 95% CI: 0.7–3.2), and the 5 studies that used the Nugent criteria (OR 0.8, 95% CI: 0.5–1.2), though this difference was not statistically significant. Studies that quantified the effect of bacterial vaginosis on HIV concentrations were conflicting, 2 studies finding that bacterial vaginosis increased HIV concentrations80,88 and 2 studies finding that bacterial vaginosis decreased HIV concentrations.55,90 All 4 studies used the Nugent criteria to diagnose bacterial vaginosis.
Trichomoniasis was also found to have little effect on the detection of HIV in the genital tracts of women (OR 0.9, 95% CI: 0.7–1.3). However, in 2 studies that examined the effect of trichomoniasis on HIV-1 RNA concentrations in semen, trichomoniasis was found to increase viral concentrations substantially, especially when symptomatic.85,87 Wang et al.80 also found that the treatment for symptomatic trichomoniasis in women was associated with a 0.6 log reduction in HIV-1 RNA concentrations. Like trichomoniasis and bacterial vaginosis, vaginal discharge was not significantly associated with the detection of HIV, although it approached statistical significance (OR 1.5, 95% CI: 0.9–2.6).
Gonorrhoea and chlamydial infection were both found to increase the detection of HIV significantly (OR 1.8, 95% CI: 1.2–2.7 and OR 1.8, 95% CI: 1.1–3.1 respectively). Studies have shown that the treatment of these infections is associated with significant reductions in HIV-1 RNA concentrations in the semen25,27 and in the cervix,71 though 1 study found that in 8 women treated for gonorrhoea, the median HIV-1 RNA concentration increased by 0.7 log after treatment.90 No studies have examined the effects of chlamydial infection on HIV shedding in men, although 1 case report91 suggests that the effect of chlamydial infection in men could be significant.
Consistent with the effects of gonorrhoea and chlamydial infection, cervical discharge and cervical mucopus were found to increase HIV shedding in the genital tract significantly (OR 1.8, 95% CI: 1.2–2.7). Cervicitis, defined in terms of leukocyte concentrations in cervical secretions, increased HIV shedding to an even greater extent (OR 2.7, 95% CI: 1.4–5.2). Urethritis, defined in terms of leukocyte concentrations in urethral smears, was also associated with increased likelihood of HIV shedding (OR 3.1, 95% CI: 1.1–8.6), although the combined OR was based on only 3 studies, one of which reported an extremely high OR from a small sample.81 Concentrations of HIV in semen are typically 0.7 to 0.9 log copies higher in urethritis cases than in controls, though the change in viral concentrations 2 weeks after treatment of urethritis is usually less than 0.5 log copies.25,27,89
Most studies that examined the effect of HSV-2 on HIV-1 shedding in the genital tract examined the effect of HSV-2 shedding rather than the effect of HSV-2 seropositivity. The presence of HSV-2 shedding in the genital tract was found to have no significant effect on the detection of HIV in the random effects analysis (OR 1.3, 95% CI: 0.7–2.5), but there was significant heterogeneity in effect estimates (P = 0.04), and HSV-2 shedding did significantly affect HIV shedding in the fixed effects analysis (OR 1.5, 95% CI: 1.0–2.1). Two of the studies that found no association between the presence of HSV-2 and HIV-1 shedding found significant positive correlation between HSV-2 concentrations and HIV-1 concentrations in those individuals with detectable shedding.56,70 In another 4 studies that assessed the effect of HSV-2 shedding on the quantity of HIV-1 RNA in genital secretions, a positive association was found.69,82,83,88 Adjusting for CD4+ count or blood plasma viral load did not alter the associations in any consistent manner. Only 1 study examined the effect of HSV-2 seropositivity on HIV-1 shedding. This study found that HIV-1 RNA concentrations in semen were slightly higher in HSV-2 seropositive men than in seronegative men, but HSV-2 seropositivity had no effect on HIV-1 RNA concentrations in women’s cervicovaginal secretions.83
Syphilis, which was serologically defined in all cases, was found to have a weak positive effect on the detection of HIV in the genital tract (OR 1.3, 95% CI: 0.9–1.9). However, 2 studies found that individuals who were initially infected with syphilis experienced an increase in HIV-1 RNA concentrations in their genital tracts after treatment for syphilis.26,90 Only one study examined the effect of chancroid on HIV-1 shedding, and reported no significant effect.68 Despite the weak effects of HSV-2, syphilis, and chancroid on the detection of HIV-1 in the genital tract, the GUD syndrome was found to be positively associated with HIV-1 detection (OR 1.8, 95% CI: 0.8–3.8), though there was significant heterogeneity in effect estimates (P = 0.03). This association became statistically significant after excluding the one study that had been conducted among STI clinic attenders, which may have understated the true effect of GUD due to the inappropriate control group (OR 2.4, 95% CI: 1.2–4.9).
Discussion
This systematic review and meta-analysis suggests that genital tract infections differ substantially in terms of their impact on HIV shedding in the genital tract. There is a clear association between HIV shedding and the concentration of leukocytes in genital secretions. Evidence of this association is the high ORs calculated for urethritis and cervicitis, both of which are defined in terms of the concentration of white blood cells or polymorphonuclear leukocytes. Further evidence is the finding that polymorphonuclear leukocytes or white blood cells counts in the genital tract have a ‘dose-response effect’ on HIV shedding.25,68,72,74 Studies have found that trichomoniasis is associated with lower leukocyte counts in genital secretions than gonorrhoea and chlamydial infection,85,92,93 and bacterial vaginosis has also been shown to have little or no effect on leukocyte counts in cervicovaginal secretions.80,93–95 The absence of any effect of trichomoniasis and bacterial vaginosis on HIV-1 shedding in the genital tract could therefore be explained by the relatively weak inflammatory responses associated with these infections.
Although most studies do not suggest that HSV-2 shedding affects the detection of HIV-1 in the genital tract, a number of studies have suggested that HSV-2 shedding increases the concentration of HIV-1 in the genital tract. Recent randomized controlled trials of HSV-2 suppressive therapy in individuals coinfected with HIV have found that HSV-2 therapy reduces the frequency of HIV-1 detection and the concentration of HIV-1 in the genital tract,96–102 though in some cases these reductions have not been statistically significant. This bodes well for the trials that are currently being conducted to assess the effects of HSV-2 suppressive therapy in HIV-serodiscordant couples, in which the HIV-infected partner is receiving HSV-2 suppressive therapy.103,104
Few studies have assessed the relative significance of symptomatic and asymptomatic infections on HIV shedding in the genital tract. However, to the extent that symptomatic infections are associated with greater leukocyte concentrations than asymptomatic infections, one might expect symptomatic infections to have a more significant effect on HIV-1 shedding. The fact that the detection of HIV-1 shedding in the genital tract is significantly associated with GUD but not with HSV-2 or serological evidence of syphilis suggests that HSV-2 and syphilis could increase HIV-1 shedding when symptomatic, but have relatively little effect when asymptomatic. The effect of syphilis on HIV shedding is therefore probably only significant during the primary syphilis stage, as symptoms and immune activation in the genital tract are rare after the primary stage. This analysis has also shown that although trichomoniasis does not significantly affect the detection of HIV-1 in the genital tracts of women, symptomatic trichomoniasis does have a substantial effect on the concentration of HIV-1 RNA in the genital tracts of both men and women. Wang et al.80 have also shown that the reductions in HIV-1 RNA concentrations after the treatment of candidiasis and bacterial vaginosis are significantly greater in the women with symptoms or signs of infection. If symptomatic infections are indeed more significant than asymptomatic infections in increasing HIV infectiousness, then it is particularly important that HIV-infected individuals be encouraged to seek treatment for STI symptoms promptly, and to abstain from sexual activity until their symptoms have passed.
As noted previously, the associations between HSV-2 shedding, candidiasis and HIV-1 shedding may be confounded by CD4+ count and/or blood plasma viral load. Although we did not find any significant evidence to suggest that univariate associations differed consistently from multivariate associations, after controlling for CD4+ count and blood plasma viral load, we cannot exclude the possibility of confounding. It is also possible that the association between candidiasis and HIV shedding may be confounded by the stage of the menstrual cycle, as some studies suggest that HIV shedding is most intense during the luteal phase and at the time of menstruation,53,55,105 the same period in which candidiasis is believed to be most frequent.106–109 Future epidemiologic studies will need to control for CD4+ count, blood plasma viral load and stage in the menstrual cycle in order to clarify the role of candidiasis and HSV-2 in HIV-1 shedding.
It remains unknown which measures of HIV-1 shedding correlate best with HIV-1 infectiousness. It is unclear whether proviral DNA, cell-associated RNA or cell-free RNA is the principal determinant of HIV-1 infectiousness. In addition, the relative significance of HIV-1 in cervical and vaginal secretions remains unknown, both in the case of female-to-male sexual transmission and in the case of mother-to-child intrapartum transmission. Further studies are required to determine which types of HIV-1 shedding are most strongly correlated with the transmission of HIV-1.
Despite these uncertainties, it is possible to use the results presented here to determine rough estimates of the factor by which HIV infectiousness is increased in the presence of genital tract infections. Chakraborty et al.110 have developed a model of male-to-female transmission, which predicts that if the amount of nonsynctium-inducing HIV-1 RNA per ejaculate increases by a factor of 10, the HIV transmission probability would increase by a factor of 6 (100.778). As an example of how this model can be utilized, one might use the results from the study of Cohen et al.25 (Table 2) to estimate that urethritis increases the male-to-female HIV transmission probability by a factor of
Similar estimates of the cofactor effect could be derived for other genital tract infections. However, these cofactor estimates reflect only the effect of genital tract infections on HIV concentrations in semen, and not the effect of genital tract infections on the epithelial barriers to HIV. The latter effect could be particularly significant in the case of ulcerative STIs, as HIV-1 is frequently detected in ulcer specimens.7–10 A further limitation of this method is that Chakraborty et al. do not report confidence intervals around the estimate of 0.778, and it is therefore not possible to determine the range of uncertainty around the estimated cofactor effect. This method applies only to male-to-female transmission, and similar models are needed to assess the effects of HIV-1 shedding on female-to-male transmission and intrapartum mother-to-child transmission.
For most of the infections considered in this meta-analysis, there is little information relating to HIV shedding in males, and it is therefore not possible to establish whether there are gender differences in the effects of these infections on genital HIV shedding. Such differences might be expected in the case of GUD, for example, because males with GUD are likely to experience shedding of HIV in their external ulcers but HIV shedding would probably not be increased in their urethral or seminal specimens.72 In women experiencing vaginal or cervical ulcers, on the other hand, HIV shedding in ulcers would be picked up in cervicovaginal lavage, and the detection of HIV in cervicovaginal lavage would therefore be increased as a result of cervicovaginal GUD. The significant heterogeneity in the ORs relating HIV detection to GUD (P = 0.03) can be explained by these gender differences, because all of the included ORs for female GUD relate specifically to cervicovaginal ulcers.
This review confirms that genital tract infections increase both the detection and the concentration of HIV-1 shedding in the genital tract, particularly when the infection is associated with recruitment of leukocytes to the genital tract. Although there is still some uncertainty regarding the effect of HIV-1 shedding on HIV infectiousness, there appears to be an association between heterosexual HIV transmission and blood plasma viral load,111–113 even though this a more distal determinant of sexual transmission than the viral load in the genital tract. It would therefore be reasonable to assume that by increasing HIV-1 shedding in the genital tract, genital tract infections increase HIV-1 infectiousness substantially. Providing prompt and effective treatment to HIV-infected individuals experiencing genital symptoms is thus important in limiting the transmission of HIV. Together with the evidence of the effect of genital tract infections on susceptibility to HIV,2 the evidence reviewed here points to the need for improved strategies for preventing and treating genital tract infections, particularly in developing countries with large HIV/AIDS and STI burdens. It is also important that behavior change be promoted to people living with HIV, as primary prevention programs have been shown to be effective in reducing levels of unprotected sex and risk of STI acquisition among HIV-infected individuals.114
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