THE IMPACT OF THE HIV epidemic in women has been recently recognized. Acquired immunodeficiency syndrome (AIDS) is now the third leading cause of death among women of reproductive age.1 In 1994, 18% of new cases of AIDS occurred in women.2 However, the importance of other sexually transmitted infections(STIs) during the course of HIV disease is not well appreciated.
Studies have demonstrated that STIs producing ulcerative lesions, such as syphilis, chancroid, and genital herpes simplex virus (HSV), are associated with a higher rate of HIV transmission.3 It is believed that the ulcer provides a portal of entry for the HIV virus. In addition, nonulcerative STIs have also been associated with a three- to five-fold increase in the risk of HIV infection.4,5
Several epidemiologic studies have addressed the prevalence of HIV infection in cohorts of homosexual men, intravenous drug users (IDUs), and in patients attending STI and genitourinary medicine clinics.6–10 The prevalence of HIV infection and other STIs has also been described in women with pelvic inflammatory disease.11 However, few studies have focused on the risk of STIs in HIV-infected women. A study that examined the prevalence of genital ulcer disease in a cohort from a women's HIV clinic demonstrated a prevalence of 14% in 307 women followed over a 20-month period.12 Another recently published retrospective study found a 14.7% incidence of STIs (gonorrhea, syphilis, and chlamydia) during a safer sex promotion program in a women's HIV clinic.13 A prospective study from the Netherlands14 found that STIs were common in a group of heterosexual men and women (the majority of whom were not HIV-infected) recruited from a sexually transmitted disease clinic. There are limited published prospective data that can be used to estimate the incidence of these infections in HIV-infected women.
We report data on STIs that were found at baseline and during follow-up in patients enrolled in a clinical trial for HIV, the Women's Fungal Study (CPCRA 010).15 The purpose of the study was to determine the efficacy and safety of weekly fluconazole in the prevention of mucosal candidiasis in HIV-infected women with CD4+ counts ≤ 300 cells/mm3.
Patients were enrolled in the study from 14 centers participating in the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), a NIAID-funded clinical trials network. HIV-infected women were eligible if they were ≥ 13 years of age and had a CD4+ count ≤ 300/mm3 or < 20% of total lymphocyte count. Patients were excluded if they had a past history of Candida esophagitis, were receiving systemic antifungal agents, had a known intolerance to azoles, or were pregnant or lactating. The protocol was approved by the IRB at each site, and informed consent was obtained from all patients.
At baseline, a gynecologic history was obtained, and a pelvic examination including a Pap smear or colposcopy was performed. History or presence on examination of each of the following was assessed: 1) gonorrhea, 2) chlamydia, 3) trichomoniasis, 4) pelvic inflammatory disease (PID), and 5) syphilis. The protocol did not mandate specific diagnostic procedures to confirm each of the STIs. All gynecologic conditions including STIs were diagnosed as per the procedures at each of the collaborating sites. However, all sites had capability to perform wet preps for diagnosis of trichomoniasis, and this was the recommended method according to the protocol. Gonorrhea infections were diagnosed by culture or DNA probe and all sites had access to one of these methods. Syphilis was diagnosed by either history or the presence of a positive screening test (RPR). In addition, as previously described (14), a history of mucosal candidiasis, including vaginal candidiasis, was assessed at baseline.
During follow-up, patients were seen every 3 months. Pelvic examinations, including Pap smears, were recommended, but not required, every 6 months. At each 3-month follow-up visit, new gynecologic conditions diagnosed or treated by a physician since the last visit were recorded. The protocol did not mandate that this was restricted to physicians participating in the study. However, in most cases, the patients were receiving all of their HIV care from the same physicians who were investigators in the study. Also, as previously reported,15 symptoms of candidiasis and vaginal yeast cultures were obtained for documenting the primary endpoints of the randomized trial of fluconazole. This information from 3-month follow-up visits was used to estimate incidence rates for each infection.
The relationship of baseline factors to either a history or presence at baseline of each infection was assessed using multivariate logistic regression analysis. The following baseline factors were jointly studied: age; race, categorized as African-American, Latina, and white/other; HIV risk factors categorized as history of injecting drug use (IDU), sex with an IDU, and other; CD4+ cell count; and prior AIDS-defining condition.
Cumulative incidence of STIs after 1 and 2 years of follow-up was estimated using the lifetable methods appropriate for interval censored data. Baseline predictors of new or recurrent STIs reported at each 3-month visit were studied using a discrete logistic model.16 In these analyses, follow-up is censored at the last 3-month examination attended, and the baseline predictors previously mentioned were considered along with a baseline history of any of the STIs. All analyses were controlled for the center where the patient was enrolled; associations are expressed as odds ratios (ORs) with 2-sided p-values and 95% confidence intervals.
Between May 1992 and January 1994, 323 women were enrolled in the trial. Details about the recruitment and baseline characteristics of the women enrolled have been reported.15 Briefly, the average age was 37 years; 65% were African-American; 20% were Latina; and 15% were white. Forty-five percent reported a history of injection drug use (IDU); and 51% reported having sex with an IDU. The average CD4+ lymphocyte count was 199 cells/mm3, and 25% had a history of an AIDS-defining condition.
All women had a baseline gynecological examination, and 289 (89%) had an interpretable Pap smear or colposcopy at entry. Of these, 68% were normal. The most common STIs based on history and/or examination at baseline were trichomoniasis (42%), gonorrhea(27%), and syphilis (20%); 65% of women had at least one STI (Table 1). Of the 323 women randomized, 31% had two or more STIs by history or examination at baseline. Most conditions identified at baseline were based on patient history; only 10 of 123 women with no history of an STI (8.1%) had one identified upon examination.
Table 2 summarizes the results of a multiple logistic analysis for each STI and for any of the five considered. Younger age was significantly associated with PID and gonorrhea, whereas the association with syphilis was of borderline significance (p = 0.056). Trichomoniasis, gonorrhea, and syphilis were found more often among African-American than white women. The prevalence of syphilis was significantly higher among Latinas than white women.
Seven women did not attend a follow-up examination; they are excluded from the remainder of the analyses. For the remaining 316 women, during the median follow-up of 2.1 years, 25% had a new/recurrent STI (Table 3); trichomoniasis accounted for most cases reported both among women with an STI at baseline and those without. Cumulative incidence after 12 months and 24 months for any STI was 17% and 26%, respectively.
At least one pelvic examination was performed during the first year of follow-up for 76% of women; among women alive at the end of the first year, 64% had at least one pelvic examination during the second year of follow-up. This rate varied among participating centers (range: 53% to 100% in the first year). To assess whether the percentage of women developing new/recurrent STIs differed in centers that more frequently carried out pelvic examinations, the lifetable analysis described above was repeated for the seven centers (93 women) for which more than 80% of women had pelvic examinations in the first year. For these centers, cumulative incidence after 12 months and 24 months for any STI was 18% and 34%, respectively.
A summary of the relationship of baseline predictors for new/recurrent STIs during follow-up is given in Table 4. African-Americans and women reporting sex with an IDU as an HIV risk behavior were at a significantly increased risk of a new/recurrent STI. Younger age was of borderline significance(OR = 1.41, p = 0.07). No association with CD4+ cell count at baseline was found. A history/presence of STIs at baseline was significantly associated with the development of STIs during follow-up (OR = 1.79; p = 0.047). When this analysis was repeated for trichomoniasis, the most common STI, the results were similar.
The data presented here are derived from a study initiated by the CPCRA to assess the efficacy and safety of weekly fluconazole for the prevention of mucosal candidiasis in women. Despite participating in a clinical trial and receiving ongoing care for HIV disease, a substantial number of women in this study developed new STIs during the course of the trial.
A study by Kissinger and colleagues13 found a similar high incidence of new or recurrent STIs in a group of women participating in a safer sex promotion program for HIV-infected women, including new infections in women who reported consistent use of condoms. This latter study found a strong association between previous diagnoses of STIs and new STIs. They also reported a higher risk of developing STIs in younger women and in women with a history of substance use. Our study demonstrated that race, a history of sex with an IDU, and prior diagnosis of STI were significantly associated with increased risk of STIs.
The previously mentioned study from the Netherlands14 found a high incidence of recurrent STIs during follow-up, which occurred despite the subjects' participation in a study of HIV seroconversion where consistent condom use was promoted.
Although our study did not specifically examine condom use or other safer sex practices, it should be appreciated that a variety of social and cultural factors may have influenced these women's decisions about sexual practices and their ability to negotiate condom use with their partners.17 Other studies have found that lack of power in relationships, social and economic dependence on a male partner, and male resistance to condom use all constitute barriers to a woman's ability to take steps to protect herself from sexually transmitted infections.18,19 Female-controlled methods of STI prevention may help some of these women.20
Our study is limited by the small sample size and by the fact that routine screening for STIs was not a required part of the trial. Thus, STI incidence may be underestimated. However, 76% of the study participants had at least one pelvic exam during the first year of follow-up and all participants were questioned at each follow-up visit about symptoms of genital infections. Although the questions were directed at diagnosing candidal infections, they would have led to evaluation for other infections as well. Despite these limitations, our study confirms findings of a high incidence of STIs in a cohort of HIV-infected women and of an association with previous diagnoses of STIs. As noted in the results section, a large number of these infections were due to trichomonas. The high rate of trichomoniasis could be due in part to the fact that a major endpoint of the study was vaginal candidiasis. It is possible that trichomoniasis was diagnosed more often because women with symptoms of vaginitis were evaluated more completely to diagnose candidiasis. Although trichomoniasis is not associated with the same risk of complications as the other STIs, it is usually sexually transmitted and has the same implications as an indicator of unsafe sexual practices.
In conclusion, we found a high rate of new STIs in the women in our study during their participation in a clinical trial. Such participation indicates that these women were closely followed by their clinicians and had multiple contacts with the health care system. This population is similar to many others who receive HIV care in a variety of settings. This finding highlights the importance of integration of clinical care with efforts at careful assessment of sexual risk behavior and providing patients with knowledge and skills to prevent sexually acquired infections.
This study also has implications for the prevention of the spread of HIV infection. This must be a two-pronged approach. The first is a focus on primary prevention among individuals at risk who are not HIV-infected. The second effort must focus on prevention of transmission of HIV from those already infected. The latter group has not received sufficient attention in prevention efforts in the United States and around the world.
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