Trichomonas vaginalis (TV) and bacterial vaginosis (BV) are conditions that occur frequently among women with human immunodeficiency virus (HIV). Trichomoniasis results from a sexually transmitted infection with the organism TV, a single-celled flagellated protozoan parasite.1 Bacterial vaginosis is caused by a disruption in the normal microbiological flora in the vaginal compartment whereby H2O2–producing Lactobacillus sps. are replaced by anaerobic bacteria that raise the pH of the genital tract.2 Among HIV-positive women, the prevalence of TV ranges from 6% to 53%,3–10 the prevalence of BV ranges from 23% to 52%,11,12 and the rate of co-occurrence of TV/BV has been reported to be from 44% to 61%.11,13
Bacterial vaginosis 14–16, TV,17,18 and higher plasma viral load (PVL)19–23 are associated with increased vaginal shedding of HIV-1. The current US treatment guidelines recommend that all persons who test positive for HIV begin a treatment regimen of antiretroviral therapy (ART) to both reduce the risk of disease progression and decrease the risk of HIV transmission.24 However, only 26% of HIV-infected persons seeking care in the United States are virally suppressed25; thus, additional preventive measures are needed. US treatment guidelines recommend testing for BV and TV for women with vaginal discharge. However, most women with TV and BV are asymptomatic.26 In fact, 30% to 85% of women diagnosed as having TV experienced no symptoms of infection,27,28 and approximately half of all individuals with BV are asymptomatic.2 Thus, many HIV+ women are not getting tested for BV and TV, which may lead to increased HIV in their vaginal compartment.
The quantity of virus in the vaginal compartment that is needed for transmission to occur is unknown. In general, although PVL directly correlates with vaginal viral load (VVL), increases in vaginal shedding may occur independent of PVL.29 One serodiscordant couples study found no transmission where the infected person had a PVL of 1500 copies/mL or less.30 Other studies, however, have found that any shedding of HIV-1 RNA in the vaginal compartment has the potential to increase the risk of sexual 30,31 and perinatal transmission.32–34 It is essential, therefore, to understand which treatable conditions influence VVL, so that interventions can be refined. The purpose of this study was to determine if a synergistic relationship exists between the co-occurrence of TV/BV and vaginal shedding of HIV-1 RNA.
MATERIALS AND METHODS
The study sample was taken from 2 cohorts of HIV-positive women. The first cohort, cohort A, consisted of 248 women who were recruited from an HIV outpatient clinic in New Orleans, LA, between June 2002 and January 2005 to participate in a study designed to investigate the influence of treatment of TV on vaginal shedding of HIV.17 The second cohort, cohort B, consisted of 125 HIV-positive, TV-positive women recruited from HIV outpatient clinics in Houston, TX; Jackson, MS; and New Orleans, LA; between May 2006 and July 2009 to participate in a randomized treatment trial that sought to determine whether a 2-g single dose of metronidazole (MTZ) was as effective as a 7-day 500-mg twice-a-day dose for treatment of TV in HIV-positive women.35
To be eligible for either study, women were required to provide consent, be HIV positive, be 18 years or older, and have their positive test result for TV confirmed by InPouch culture technique (InPouch; Biomed Diagnostics, White City, OR).35 Exclusion criteria for both cohorts were as follows: pregnancy, incarceration, alcoholism, taking disulfiram, having received MTZ within the previous 14 days (to avoid persistent TV), or having a medical contraindications to MTZ.
For both studies, clinical, behavioral, and specimen data collection procedures were similar and the same laboratory and laboratory methods were used.17,35 In brief, eligible and consenting women underwent a gynecological examination from their HIV outpatient clinic provider. During the examination, the medical provider collected vaginal and cervical swabs. For the detection of HIV-1 RNA, a cervical specimen was frozen at −20°C and transported to the Louisiana State University Health Sciences Center microbiology laboratory for processing. The sample was analyzed with the Amplicor HIV-1 Monitor ultrasensitive protocol (Indianapolis, IN). This assay is able to detect a lower limit of 50 copies of HIV-1 RNA per milliliter. Vaginal viral loads were reported as copies per milliliter, and undetectable quantities were reported as less than 50 copies/mL. Blood samples were also collected and analyzed by the same protocol and therefore had the same lower limit of detection.
CD4 lymphocyte counts were reported as cells per millimeter cube of blood. Urine specimens were collected to determine the presence of Neisseria gonorrhoeae and Chlamydia trachomatis via the ProbeTec strand displacement DNA amplification method (Becton Dickinson and Company, Sparks, MD). Vaginal specimens were used to screen for TV via InPouch culture (Biomed Diagnostics), BV by Gram Stain testing using Nugent score criteria,36 and vulvovaginal candidiasis by culture. The medical provider also assessed and recorded the amount and color of vaginal discharge. The amount of vaginal discharge was recorded as scant, moderate, or large. The color of vaginal discharge was recorded as abnormal (white/gray, yellow/green) or normal (clear/none).
Participants were also interviewed at baseline via computer-assisted self-interview. The survey consisted of questions regarding sociodemographic information, sexual activity and sexual risk taking behaviors, partner information, alcohol use, and medication adherence. The institutional review board of Tulane University School of Public Health and Tropical Medicine approved this secondary analysis. The parent studies had institutional review board approvals from all participating institutions.
Baseline clinical, behavioral, and demographic characteristics were computed and reported as frequency with percent, mean with SD, or median with range, as appropriate. The outcome of interest was detectable vaginal shedding of HIV-1 RNA. Women who had a VVL of at least 50 copies/mL of HIV-1 RNA were categorized as detectable, and women with a VVL less than 50 copies/mL were categorized as undetectable. Factors associated with a detectable VVL were determined by Student t test, Pearson χ2 test, or Fisher exact test, where appropriate. Associations significant at P ≤ 0.10 were examined through multivariable analysis using backward stepwise logistic regression. Odds ratios and 95% confidence intervals (CIs) were determined. After confirming any independent associations between the presence of TV and vaginal shedding, and BV and vaginal shedding, interactions between TV/BV co-occurrence and vaginal shedding of HIV-1 RNA were assessed using multivariable techniques to examine the direction and magnitude of associations after adjusting for potential confounders. All analyses were conducted using SAS version 9.1 (SAS Institute, Cary, NC).
Characteristics of Participants
From the 2 cohorts of HIV-positive women, data from 373 participants were analyzed. Baseline characteristics by cohort can be found in Table 1. Few demographic, behavioral, and clinical differences were seen between the 2 cohorts. However, women in cohort A were older than cohort B (P < 0.003), and cohort B had a higher percentage of African American women than did cohort A (P < 0.001).
The combined sample was mostly African American (89.0%) with a mean (SD) age of 38.1 (9.3) years. Most women (74.9%) were unemployed, and 22.8% of women had less than a high school education. Behaviorally, women exhibited high risk behaviors: 26.5% reported that they binge drank in the last month; 29.2% reported not using a condom at the latest occurrence of vaginal intercourse; 12.8% reported having 2 or more sexual partners in the last 3 months; and 24.7% of women reported having anal intercourse in the last month.
Vaginal viral load or shedding of HIV-1 RNA was detected (≥50 copies/mL) in 33.2% of women. Approximately one-third of women (28.9%) had suppressed immune function (CD4 <200 cells/mL), and 60.3% had a PVL greater than 500 copies/mL. The median VVL was 187 copies/mL (range, undetectable to 768,837 copies/mL). The median CD4 count was 386 (range, 2–1821 cells/mL), and the median PVL was 2221 (range, undetectable to 847,000 copies/mL). More than half of the women (59.9%) were taking an ART regimen. Among those on ART, most women (83.4%) were classified as adherent as measured by self-report of “taking all ART yesterday as prescribed.” Of those who were currently on ART, 20.6% (n = 46) had detectable VVL with a median of 165 copies/mL (range, undetectable to 768,837 copies/mL). More than half of the women who were not on ART (57.1%; n = 77) had detectable VVL with a median of 371 copies/mL (range, undetectable to 89,300 copies/mL). Of these 46 women, 13.0% (n = 6) had undetectable PVL. These 6 women were on ART and adherent to their current protocol, had undetectable PVL, and had highly variable VVLs. Two women had VVLs less than 500 copies/mL, but the other 4 women had VVLs of 1965, 18,448, 21,006, and 768,837 copies/mL of HIV-1.
Prevalence of sexually transmitted infections varied. Prevalence of N. gonorrhoeae and C. trachomatis were 1.1% and 3.2%, respectively. More than half of the sample (60.1%) was TV positive, 56.7% were diagnosed as having BV, and 43.1% of women had a co-occurrence of TV and BV.
Upon provider examination, 44.5% of women were characterized as having moderate to copious vaginal discharge (compared with scant/none), and 22.0% were characterized as having abnormally colored vaginal discharge (white/gray or yellow/green vs. clear/none). Slightly more than a quarter (25.8%) of women reported experiencing symptoms of vaginal itching and irritation.
Factors Associated With Vaginal Shedding of HIV-1
To determine the factors associated with vaginal shedding of HIV-1 RNA, women who had a detectable VVL (≥50 copies/mL HIV-1 RNA; n = 124) were compared with women whose VVL was undetectable (<50 copies/mL HIV-1 RNA; n = 249; Table 2). In bivariate analysis, women who were shedding vaginally were more likely to be younger (P = 0.001), unemployed (P = 0.046), and to report having 2 or more sexual partners in the last 3 months (P = 0.043). Women who were shedding vaginally were less likely to be taking ART (P = 0.001) and more likely to have a PVL greater than 500 copies/mL (P = 0.001). With regard to sexually transmitted infections, women who had detectable VVL were more likely to have a diagnosis of C. trachomatis (P = 0.024), TV (P = 0.032), BV (P = 0.001), and TV/BV co-occurrence (P = 0.001). They were also more likely to report symptoms of vaginal itching and irritation (P = 0.002).
Synergism Between TV/BV Co-occurrence and Vaginal Shedding of HIV-1
In multivariable backward stepwise logistic regression, the likelihood of shedding HIV-1 RNA was associated with younger age (P = 0.04), not taking an ART regimen (P < 0.001), having a PVL greater than 500 copies/mL (P < 0.001), having a diagnosis of TV (P = 0.001), a diagnosis of BV (P < 0.001), and co-occurrence of TV/BV (P < 0.001).
The strata-specific measures of association for the interaction between TV/BV and vaginal shedding of HIV-1 RNA can be found in Table 3. In the presence of TV, when adjusted for age, ART status, and PVL, the odds of shedding detectable copies of HIV-1 vaginally change at each level of BV. In the presence of TV, when BV is absent, the odds of vaginal shedding are 4.07 (95% CI, 1.77–9.37); however, when BV is present, the odds of vaginal shedding are 18.63 (95% CI, 6.71–51.72). Likewise, in the presence of BV, when TV is absent, the odds of vaginal shedding are 5.65 (95% CI, 2.64–12.10). This indicates that there is a synergistic relationship between TV/BV co-occurrence and vaginal shedding of HIV-1 RNA in this cohort of women.
In this sample of HIV-positive women, there was a clear synergy between TV and BV co-occurrence and the presence of vaginal shedding of HIV-1. This finding underscores the need to promote screening for these conditions among HIV+ women. Moreover, 1 in 5 women who had undetectable PVL had a detectable VVL; thus, reliance solely on ART for the prevention of sexual and perinatal HIV transmission may be misguided.
Reasons for this synergy are likely related to intensified localized inflammation of the genital tract in the presence of coinfection.37–39 Thurman and Doncel40 proposed several mechanisms by which TV and BV may increase shedding in the vaginal compartment and thereby increase the risk of HIV transmission. First, the cervicovaginal mucosa, in response to TV, elicits a proinflammatory response. If this response is too weak, TV continues to proliferate; if the response is too strong, tissue damage may ensue, making the individual more prone to HIV infection. Pregnant women with BV who had co-occurring TV had increased markers of mucosal inflammatory response (interleukin [IL] 1β, IL-8, and vaginal neutrophils) compared with women with BV alone,40,41 and IL-8 has been associated with increased replication of HIV-1.42
Second, the mucosa’s natural defenses such as lactic acid (H2O2) and specific cationic antimicrobial polypeptides have been found to be virucidal to HIV-1 in animal and in vitro studies.43 In the presence of TV and BV, these natural defenses are reduced; thus, innate immunity to HIV-1 in the vaginal compartment decreases. In addition, healthy vaginal flora includes adequate levels of H2O2-producing lactobacilli bacteria, which keep the pH of the vaginal compartment low. One of the hallmarks of BV is a vaginal pH greater than 4.5, which may indicate an absence of these helpful bacteria. Furthermore, lower levels of lactobacilli have found to be associated with increased vaginal shedding of HIV-1 RNA.44
We observed high rates of TV/BV co-occurrence among HIV-positive women cross sectionally at 3 urban HIV treatment centers (43.1%). Although the cohort may only be generalizable to HIV+ women in the South, our sample was demographically similar to HIV+ women in the United States13 and may have external validity. Approximately one-third of the women (33.2%) in this study were shedding detectable levels of HIV-1 RNA, which is consistent with other published studies where the percentages of women infected with HIV who shed HIV-1 RNA vaginally range from 26% to 90%.14,17–23,45–56 In our study, factors associated with vaginal shedding of HIV-1 were consistent with other published studies. Clinical factors that have been found to be associated with an increase in vaginal shedding of HIV-1 are higher PVL19–23, BV,14–16 and sexually transmitted infections such as N. gonorrhoeae,45,57,58C. trachomatis,57,58 and TV.17,18
Co-occurrence of TV/BV among HIV+ women also has an influence on the treatment of TV. There is mounting evidence that single-dose MTZ is not effective among HIV-positive women and the lack of efficacy is influenced by BV. Kissinger et al.35 found that the 2-g single dose of MTZ for the treatment of TV infection in HIV-positive women was less effective than the 7-day twice-daily 500-mg dose, but that this treatment effect was only found among women with BV.59 Balkus et al.13 found similar findings in a cohort of African sex workers. Furthermore, both of these studies found that ART also seemed to interfere with MTZ treatment of TV.13,60 Currently, the Centers for Disease Control and Prevention recommends a 2-g single dose of MTZ for the treatment of TV infection and a 7-day twice-daily 500-mg dose of MTZ for the treatment of BV,2 but these recommendations are likely to change in the next treatment guidelines to favor multidose of MTZ over a single dose.
This study has some limitations. Because our study was cross sectional, some nuances may have been lost. Longitudinal studies have found that vaginal shedding of HIV-1 RNA may vary according to menstrual cycle phase,53,61 and vaginal shedding of HIV-1 RNA can occur intermittently.53,61 Longitudinal studies also suggest that cervical shedding is influenced by variations in hormonal levels and that there is a decline in viral RNA during the follicular phase of the menstrual cycle and a rise in viral RNA during the luteal phase.53,61 Hormone levels of participants were not collected, and this lack of data on a known confounder is a limitation.
Another potential limitation is that VVL is subject to misclassification in the event that the participant had engaged in vaginal sexual intercourse with an HIV-infected partner just before the time in which the VVL swab was collected. In this event, it is possible that the detection assay would quantify partner HIV-1 RNA rather than participant HIV-1 RNA. Although data on the entire sample were not available, in cohort B, 8 (9%) of 88 reported sexual intercourse within 72 hours of specimen collection and only 1 (1%) had a detectable VVL, so this potential source of error was minimal.
Sensitivity issues are also a limitation. The assay is only able to detect levels of RNA of at least 50 copies/mL. If women were shedding at a level that is below the sensitivity of the assay, they would be misclassified. In our study, TV was diagnosed via InPouch culture (Biomed Diagnostics) and BV via Nugent score rather than a nucleic acid amplification test. This could have resulted in missed cases of TV because the clinical sensitivity of the InPouch culture is approximately 79.0% to 86.2% 62 and of BV because Nugent score is only 72% to 96% sensitive.63 Although this potential misclassification could have resulted in underdetection of BV and TV, it would be unlikely to have affected the odds ratios.
Despite these limitations, this study is the first study reported in the literature to examine the synergistic relationship between TV/BV co-occurrence and vaginal shedding of HIV-1 RNA. Health care providers for HIV-positive women should be aware of the high rates of co-occurrence of these 2 conditions among women with HIV. Although either condition alone is sufficient to increase the odds of shedding vaginally, when these conditions co-occur, the odds of vaginal shedding of HIV are potentiated. Also, because only approximately one-quarter of HIV-infected persons are virally suppressed25, it is critical that other preventive measures are done. Furthermore, because so much of TV and BV is asymptomatic, clinicians should consider screening HIV+ women who do not have vaginal discharge for BV and TV.
Co-occurrence of TV and BV was high (41%).
T. vaginalis and BV were independently and synergistically associated with vaginal shedding of HIV-1 RNA.
Detection and treatment of these vaginal conditions may help reduce transmission of HIV.
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