JAIDS Journal of Acquired Immune Deficiency Syndromes:
The Occurrence of Vaginal Infections Among HIV-Infected and High-Risk HIV-Uninfected Women: Longitudinal Findings of the Women's Interagency HIV Study
Watts, D Heather MD*; Springer, Gayle MLA†; Minkoff, Howard MD‡; Hillier, Sharon L PhD§; Jacobson, Lisa ScD†; Moxley, Michael MD‖; Justman, Jessica MD¶; Cejtin, Helen MD#; O'Connell, Casey MD**; Greenblatt, Ruth M MD††
Received for publication March 18, 2006; accepted July 6, 2006.
From the *Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research on Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; †Department of Epidemiology, Johns Hopkins University, Baltimore, MD; ‡Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NY; §Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA; ‖Department of Obstetrics and Gynecology, Georgetown University, Washington, DC; ¶Center for Infectious Disease Epidemiologic Research, Columbia University, New York, NY; #Department of Obstetrics, Gynecology, and Reproductive Sciences, John H. Stroger Hospital of Cook County, Chicago, IL; **Department of Medicine, University of Southern California, Los Angeles, CA; and ††Department of Medicine and Epidemiology, University of California, San Francisco, CA.
The Women's Interagency HIV Study is funded by the National Institute of Allergy and Infectious Diseases, with additional funding from the National Cancer Institute, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Dental and Craniofacial Research, the Agency for Health Care Policy and Research, and the Centers for Disease Control and Prevention (U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632 (NICHD), U01-AI-34993, U01-AI-42590, N01-AI-35161, MO1 RR00079, and NCI R01 CA85178-01).
Reprints: D. Heather Watts, MD, Pediatric, Adolescent, and Maternal AIDS Branch, CRMC/NICHD/NIH, 6100 Executive Boulevard, Room 4B11, Bethesda, MD 20892 (e-mail: firstname.lastname@example.org).
Objectives: To evaluate changes over time in rates of bacterial vaginosis (BV), trichomoniasis (TV), and yeast vaginitis (YV) among HIV-infected and similar HIV-uninfected women.
Methods: Two thousand fifty-six HIV-infected women and 554 HIV-uninfected women were evaluated semiannually from 1994 until March 2003 in a prospective cohort study. BV was diagnosed by Gram stain, TV by wet mount, and YV by symptoms with microscopically visible hyphae or positive culture. Trends were assessed using Poisson models.
Results: At baseline, BV was present in 42.8% and 47.0% of HIV-infected and uninfected women (P = 0.21), TV in 6.1% and 7.8% (P = 0.17), and YV in 10.0% and 3.8% (P < 0.001). Over time, rates of BV and TV decreased significantly in both groups, whereas rates of YV declined only among HIV-infected women. Risk of BV was not associated with HIV status, whereas HIV-infected women had a lower risk of TV. Highly active antiretroviral therapy (HAART) use was associated with decreased risk of all 3 infections.
Conclusions: Declines in BV, TV, and YV represent decreased morbidity for HIV-infected women and, potentially, decreased risk of transmission of HIV, because each has been associated with increased genital detection of HIV.
Vaginal infections, including bacterial vaginosis (BV), trichomoniasis (TV), and yeast vaginitis (YV), are common among HIV-infected women. In 2 large American cohort studies, BV occurred at similar rates at baseline among HIV-infected and HIV-uninfected women but was found to be more persistent among HIV-infected women in one of the studies.1-3 BV and TV have been associated with an increased risk of postoperative infections and pelvic inflammatory disease.4-7 Symptomatic vaginal yeast infections are increased among HIV-infected women with low CD4+ lymphocyte counts in the absence of antifungal prophylaxis.8,9 All these infections have been associated with increased levels of HIV RNA in the genital tract, which may be a marker for increased transmissibility to sexual partners or infants at delivery.10-14 BV and TV have been shown to increase the risk of HIV acquisition among women, underscoring their importance from a public health perspective.15-19 Thus, these vaginal infections directly cause significant morbidity, especially among HIV-infected women, and may contribute to increased risk of sexual and perinatal HIV transmission.
The effect of highly active antiretroviral therapy (HAART) on vaginal infections among HIV-infected women has been evaluated only to a limited extent.3,20,21 Changes in vaginal milieu, such as in immunologic cell populations, cellular activation, and cytokine production, could alter susceptibility or response to infections, influencing their incidence and prevalence. Improved health or decreased perception of risk of HIV transmission could lead to increased rates of unprotected sexual activity and increased rates of TV infection. Improved immune response could reduce the occurrence of YV. Thus, the changes in rates of these common vaginal infections over time are important to evaluate in the context of increasing utilization of HAART. The Women's Interagency HIV Study (WIHS) maintains longitudinal surveillance of a sizable cohort of women who are representative of women with HIV infections in the United States. The objectives of the present study were to assess the point prevalence of vaginal infections over time and to evaluate the effect of HAART on these rates.
A detailed description of the methods of the WIHS has been published.22 Briefly, between October 1994 and November 1995, 2085 HIV-infected women and 567 high-risk HIV-uninfected women were recruited at 6 sites in Bronx/Manhattan and Brooklyn, New York; Washington, District of Columbia; Chicago, Illinois; San Francisco, California; and Southern California or Hawaii. Women were considered to be at risk for HIV infection if they had a history of injection drug use, a history of receipt of blood or blood products, multiple sex partners in the past 6 months, or sex with someone known to be infected with HIV. After informed consent, as approved by the local institutional review board, was obtained, each woman was interviewed regarding her medical, social, and treatment history as well as current symptoms and medications and underwent a physical examination, including pelvic examination. Swabs were used to collect vaginal secretions for preparation of saline wet mounts and smears for subsequent Gram staining. Visits were repeated every 6 months.
Saline preparations of vaginal secretions were examined via 400× magnification microscopy for white blood cells, motile trichomonads, and hyphal forms of yeast. In addition, 10% potassium hydroxide (KOH) was added to the mixture to test for amine odor and for examination for hyphae. Air-dried smears of vaginal secretions were Gram stained and examined at 1000× magnification for bacterial morphotypes, white blood cells, and hyphal forms. Gram stains were read by staff at the Magee-Womens' Hospital, without knowledge of clinical variables. Smears were scored using the Nugent criteria as normal (score of 0-3 indicates predominant lactobacilli morphotypes), intermediate (score of 4-6 indicates decreased lactobacilli and increased other morphotypes), or BV (score of 7-10 indicates markedly decreased or absent lactobacilli morphotypes and increased gram-variable and gram-negative rods).23 Gram stain results were available through March 2001, because funding was not available for evaluation of subsequent slides. Symptoms were not required for the diagnosis of BV or TV. TV was diagnosed when motile trichomonads were present on a vaginal wet mount. YV was diagnosed in the presence of a subject's complaint of increased curd-like discharge or vaginal or perineal itching or irritation as well as a positive wet mount, KOH preparation, or Gram stain for hyphal yeast forms or a vaginal culture positive for yeast. Results for TV and YV were analyzed through March 2003.
Women diagnosed with BV, TV, or YV on clinical examination were offered appropriate therapy by study clinicians or referred to their primary care provider. Because therapy for BV, TV, and YV is usually of short duration, women receiving episodic treatment were not excluded from subsequent analyses. Women reporting use of any antibiotic since the previous visit were coded as having recent antibiotic use for the current visit.
Quantification of HIV RNA in plasma was performed using the isothermal nucleic acid sequence-based amplification (NASBA/Nuclisens) method, with a lower limit of detection of 80 copies/mL (BioMerieux, Inc., Durham, NC),24 with the exception that 9% of specimens were tested with an assay with a lower limit of detection of 4000 copies/mL. Values for undetectable HIV RNA levels were set as the lower limit of detection for the assay used. CD4+ lymphocyte subsets were quantified using standard flow cytometric methods.25 Values for HIV RNA were log10 transformed, and CD4+ cell counts were examined in 100-cell/μL increments.
Antiretroviral therapy at each visit was classified as none, monotherapy, combination therapy if 2 or more agents not meeting the definition of HAART were being used, and HAART. The definition of HAART was guided by the Department of Health and Human Services (DHHS)/Kaiser Panel guidelines.26
Additional time-dependent variables examined included age at visit, current alcohol use, number of male sex partners since the last visit, hormonal contraceptive use, current pregnancy status based on history and a urine pregnancy test, smoking status, and injection drug use during the preceding 6 months. Self-reports of condom use were assessed at each visit as always, sometimes, or never using a condom. At each visit, women were queried regarding whether they had been diagnosed as diabetic since the previous visit and whether they were postmenopausal (ie, no menses for at least 1 year). Once a woman reported one of these events, she was considered to have the finding (diabetes or menopause) at all subsequent visits. Baseline characteristics examined included detection of HPV DNA in cervicovaginal fluids, race/ethnicity, history of injection drug use, self-reported history of Chlamydia species and genital herpes, and lifetime number of male partners.
The prevalence of BV, TV, and YV at each visit was calculated and plotted in HIV-infected and HIV-uninfected women. HIV-uninfected participants who developed serum antibodies to HIV during the study (n = 16) were excluded. Each of the demographic, behavioral, and HIV-related factors listed in Table 1 was assessed by univariate analyses for association with the 3 infections at each visit. These variables have each been associated with 1 or more of the infections in previous studies. Multivariable models were constructed using logistic regression, by first including all covariates that were statistically significant (P < 0.05) in univariate analyses. To obtain final multivariable models, nonsignificant covariates from the full multivariable model were removed, added back 1 at a time, and included if they reached statistical significance. The generalized estimating equation was used to correct for repeated measures over time. For analyses of risk factors for each infection among HIV-infected women, use of antiretroviral therapy, CD4+ lymphocyte count, and HIV RNA levels were assessed in each model. Poisson regression was used to model the frequency rates and to determine the statistical significance of observed trends.
Baseline characteristics of women according to HIV infection status are shown in Table 1. HIV-infected and HIV-uninfected women were similar in race, parity, recent injection drug use, and rate of diabetes. HIV-infected women were slightly older and more likely to report reaching menopause, had more lifetime sexual partners but were less likely to have a current male partner or to use hormonal contraception, more likely to use condoms, less likely to smoke or use alcohol currently, and more often reported past injection drug use. Pregnancy was reported at fewer than 2% of visits.
The baseline prevalence of BV was similar in HIV-infected and HIV-uninfected women, (43% vs. 47%; P = 0.21). At each visit, the prevalence of BV by Gram stain was lower among HIV-infected women than among HIV-uninfected women (Fig. 1A), with the difference being significant at visits 4 (pre-HAART era), 11, and 12. The occurrence of BV declined significantly over time among HIV-infected women (P < 0.0001) and HIV-uninfected women (P = 0.003). Factors found to remain significantly associated with detection of BV on multivariate analysis are listed in Table 2. Of note, HIV serostatus was not independently associated with prevalent BV (adjusted odds ratio [AOR] = 0.92, 95% confidence interval [CI]: 0.79 to 1.07). Nonwhite race was associated with an increased risk, with the highest risk being among African Americans (AOR = 2.69, 95% CI: 2.25 to 3.21). Having 2 or more current male sexual partners, current smoking, moderate or heavy alcohol use, and human papilloma virus (HPV) detection at baseline were also associated with a significantly increased risk of BV detection. Increasing age, hormonal contraception, being postmenopausal, having recent antibiotic use, or diabetes was associated with a lower risk of BV. Risk factors for BV among HIV-infected women were similar to those in the entire group (Table 2), except that hormonal contraceptive use was not associated with a lower risk. In addition, use of antiretroviral therapy and 1 or 2 drugs (AOR = 0.80, 95% CI: 0.70 to 0.92) or HAART (AOR = 0.62, 95% CI: 0.54 to 0.72) was associated with a decreased risk of BV, whereas the risk of BV was associated positively with increasing HIV RNA level (AOR = 1.18 for each 1-log10 increase in HIV RNA, 95% CI: 1.12 to 1.24). CD4+ lymphocyte level was not associated with the detection of BV.
TV was diagnosed by wet mount in 6.1% of HIV-infected and 7.8% (P = 0.17) of HIV-uninfected women at baseline. The prevalence of TV ranged between 2% and 9% over the 19 visits, with rates being slightly higher at each visit in the HIV-uninfected women (Fig. 1B) and the difference reaching statistical significance at visits 4, 10, 12, 13, 15, and 16 (P < 0.05). A statistically significant decrease over time in TV was observed in HIV-infected (P < 0.0001) and HIV-uninfected (P = 0.0003) women. Unlike the case for BV, HIV infection status was associated with TV, with HIV-infected women demonstrating a significantly lower prevalence over time (AOR = 0.65, 95% CI: 0.51 to 0.84). Factors associated with an increased risk of TV included African-American race (AOR = 4.72, 95% CI: 3.19 to 7.00), 1 or more recent male sexual partners (AOR = 1.34 to 1.73), current smoking (AOR = 2.35, 95% CI: 1.89 to 2.93), recent injection drug use (AOR = 2.15, 95% CI: 1.58 to 2.93), moderate or heavy alcohol use (AOR for heavy use = 1.69, 95% CI: 1.27 to 2.24), and detection of HPV DNA at baseline (AOR = 1.37, 95% CI: 1.11 to 1.68) (Table 3). Current hormonal contraceptive use and diabetes were associated with decreased detection of TV. In addition to these factors, among HIV-infected women, HAART use (AOR = 0.58, 95% CI: 0.45 to 0.75) and increased CD4+ lymphocyte count at the prior visit (AOR = 0.94, 95% CI: 0.89 to 0.99 for each 100-cell/μL increase) were associated with a decreased rate of TV. Increasing HIV RNA levels (AOR = 1.11, 95% CI: 0.98 to 1.26) were minimally associated with detection of TV.
The prevalence of symptomatic YV at baseline was 10% among HIV-infected women and 3.8% among HIV-uninfected women (P < 0.0001). At most visits, the diagnosis of YV was more common among HIV-infected women compared with HIV-uninfected women (Fig. 1C); the differences reached statistical significance at visits 1 through 6 and at visits 9 and 10 (P < 0.05). Rates over time were fairly stable in the HIV-uninfected women, whereas the rates declined significantly in the HIV-infected women (P ≤ 0.0001). HIV-infected women were twice as likely to have YV (AOR = 2.17, 95% CI: 1.72 to 2.75; Table 4). Other factors associated with YV included African-American or Hispanic race/ethnicity (AOR = 1.38 to 1.63), detection of genital HPV DNA at the baseline WIHS visit (AOR = 1.19, 95% CI: 1.01 to 1.41), current pregnancy (AOR = 1.55, 95% CI: 1.08 to 2.24), diabetes (AOR = 1.99, 95% CI: 1.58 to 2.51), and recent antibiotic use (AOR = 1.69, 95% CI: 1.31 to 2.20). Increasing age was associated with a decreasing risk of symptomatic infection (AOR = 0.64 to 0.32). Among the HIV-infected women, use of HAART (AOR = 0.82, 95% CI: 0.68 to 0.99) and increasing CD4+ lymphocyte count (AOR = 0.93, 95% CI: 0.89 to 0.98) were associated with a decreased risk of infection, whereas increased HIV RNA level was associated with an increased risk (AOR = 1.18, 95% CI: 1.08 to 1.28).
We have shown a significant decrease in the detection of BV, TV, and YV over nearly 10 years among HIV-infected women in the WIHS and an association between HAART use and reduced rates of all three vaginitides. The decrease over time in these infections represents a significant benefit to the women in terms of decreased symptoms and potential risk of complications, such as postoperative morbidity after obstetric and gynecologic procedures.4-7 In addition, these reductions may represent a significant public health benefit, because the absence of these infections has been associated with decreased levels of HIV in the genital tract, potentially decreasing the risk of sexual and perinatal HIV transmission.10-14
Multiple studies among HIV-infected women have found BV to be a risk factor for detection of HIV RNA or DNA in the vagina, even after adjustment for plasma HIV RNA levels.10-12,27 Unfortunately, in the single study that evaluated the efficacy of treatment of BV on genital HIV levels, no change in levels of genital HIV was found.13 Despite resolution of symptoms, most treatment recipients failed to regain normal lactobacilli in the vagina after treatment, suggesting incomplete resolution of disturbances that may contribute to the increased detection of HIV. Lactobacillus species that produce H2O2 are present in the healthy vagina, and H2O2 has been shown to be virucidal to HIV.28 With BV, H2O2-producing lactobacilli disappear and high levels of Mycoplasma hominis are found.29 In addition, the normally low pH of the vagina inhibits CD4+ lymphocyte activation and decreases the number of HIV target cells, such as lymphocytes and macrophages, in the vagina.30 These positive effects may be lost with the rise in pH associated with BV. A better understanding of the changes in the vaginal ecosystem with BV and methods to repopulate the vagina with H2O2-producing lactobacilli after reduction in anaerobic flora are needed.
Although a decrease in all 3 of the infections studied was seen among HIV-infected women and HAART was associated with this decrease, BV and TV also decreased among the HIV-uninfected women, suggesting a contribution from other factors. Study examinations may have resulted in increased detection and treatment of these infections, and education regarding safer sexual practices provided at study visits may have contributed to decreased acquisition. Women on HAART may also have more medical visits, providing additional opportunities for treatment. Conversely, rates of YV declined significantly only among the HIV-infected women, and risk decreased with increasing CD4+ lymphocyte counts. This finding is consistent with those of other studies that have shown an increased risk of symptomatic vaginal yeast infections as the CD4+ lymphocyte count declines.8,9,31,32
HIV infection was not found to be a risk factor for the Gram stain diagnosis of BV in the WIHS. This finding is consistent with findings at baseline in the WIHS and in the HIV Epidemiology Research Study (HERS).1,2 Several cross-sectional studies and a longitudinal analysis of the HERS found HIV infection to be a risk factor for an increased prevalence of BV, however.33-38 Two prospective studies have found increased acquisition of HIV infection among women with BV at baseline compared with similar women without BV.15,16 Because BV seems to increase the risk of HIV acquisition, higher rates of BV among HIV-infected women would be expected in study observations obtained shortly after incident HIV infection. Because women were excluded from enrollment into the HERS but not into the WIHS if they had a previous AIDS-defining illness,39 the difference in the association of BV with HIV could be related to duration of HIV infection. This difference could be magnified further if women with more advanced HIV infection were seen more often for routine clinical care, which might include assessment and treatment for vaginal infections. This theory is consistent with a previous finding from the WIHS that HIV-infected women on HAART, indicating more advanced disease, had a higher probability of more than 3 primary care visits per 6 months than women not on HAART.40 Other unmeasured confounders that varied between populations could also contribute to the difference in findings.
We found that the risk of TV infection was lower among HIV-infected women compared with HIV-uninfected women, even after adjustment for the number of current male partners and condom use. Previous studies have found no association between TV and HIV status or an increased risk of TV among HIV-infected women, suggesting the possibility of enhanced acquisition of HIV with TV.36,41-44 In the HERS, baseline prevalence and incidence and prevalence of TV over time did not vary with HIV status.41 In contrast, 3 cross-sectional studies from Africa, where the background prevalence of HIV and TV is high, found the risk of TV to be 1.6 to 3.0 times higher among HIV-infected women compared with HIV-uninfected women,36,42,43 and a serologic study from Zimbabwe found that women seropositive for antibodies to TV had an AOR of 2.11 for being infected with HIV.45 A prospective study found that TV was associated with a 2-fold increased risk of HIV seroconversion.17 These populations tended to be younger and may have had more recent HIV infection. As with BV, the association of TV with HIV may vary between populations and with the duration of HIV infection. HAART use and higher CD4+ lymphocyte count were associated with a decreased risk of TV. This effect may be related to better access to health care, with more frequent diagnosis and treatment of TV infection as discussed previously with BV, a more normal vaginal milieu with antiretroviral treatment, less risky sexual behavior, or other factors.
The association of higher TV rates among African-American women has been noted in previous studies.18,37,41,46 As noted previously, TV may increase the risk of acquisition of HIV and may be a factor in the burgeoning rate of HIV infection among African-American women in the United States.47 TV is associated with altered vaginal flora and decreased lactobacilli, as is BV, which may alter the vaginal defenses.38
Although our study includes the largest cohort of HIV-infected women followed over the longest period to date for evaluation of vaginal infections, there are limitations. Gram stain diagnosis remains the “gold standard” for study of BV, but detection of TV by wet mount is less sensitive than culture, polymerase chain reaction testing, or antigen detection and likely detects only approximately half of infections.48 Wet mounts were used consistently throughout the study; thus, trends in diagnosis should not be related to a change in methodology. If HIV infection led to higher levels of TV in the genital tract, wet mounts would be expected to be positive more frequently in HIV-infected women, and we did not find this. Requiring a combination of symptoms and microscopic detection of hyphae should increase the specificity of diagnosis of YV; however, again, sensitivity is likely to be less than with consistent culture testing. Another limitation is lack of consistently collected information on number of visits to the primary health care provider and interval treatment of vaginal infections. Although this lack of data limits our ability to determine completely the reasons for the decrease in vaginal infections over time among HIV-infected women, it does not diminish the importance of this decrease to the women and the potential for transmission of HIV. Despite its limitations, our study does provide directions for more detailed studies of vaginal infections among HIV-infected women.
Vaginal infections are a common and often recurrent problem for HIV-infected women, even in the HAART era, underscoring the need for regular gynecologic assessment. These infections may increase HIV levels in the genital tract and facilitate transmission of HIV to sexual partners and infants. Further research is needed to identify improved strategies for treatment of these infections and recolonization of the genital tract with lactobacilli to ensure a healthy vaginal milieu.
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