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).
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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