managing recurrent disease- bacterial vaginosis
Recent studies suggest a possible link between bacterial vaginosis and susceptibility to other infections, including HIV. We'll review that evidence, describe the effects of BV on the vaginal ecosystem, and discuss new ways to manage recurrent disease.
Vaginitis is one of the most common reasons women see their physicians, with more than 10 million new cases reported every year in the United States.1,2 Although bacterial vaginosis (BV) is at least as common as vulvovaginal candidiasis (VVC), the general population has paid more attention to the latter, particularly with the advent of over-the-counter antifungal agents, which now account for an estimated $250 million in annual sales. Despite extensive self-diagnosis and self-treatment for VVC, many women are not well educated about these two infections and may even be unaware of the existence of BV. For example, Ferris and colleagues found that only 3% of women can accurately recognize the classic symptoms of BV and only 11% can identify those of VVC.3
Yet BV remains the most prevalent type of vaginitis in women of childbearing age.4 Reported incidence rates for BV have ranged from 5% in the general population to 64% in patients visiting sexually transmitted disease clinics.4,5 The true incidence of BV is difficult to estimate for various reasons. For one, diagnosis and proper treatment of BV may be delayed or never occur because of lack of awareness. Moreover, the infection takes an asymptomatic course in many women, complicating the diagnosis.4 In addition, there is no ongoing surveillance of vaginal infections in the US.
In the past, many clinicians viewed BV as a nuisance rather than a serious health problem. But we now know that it may be a risk factor for other infections of the female genital tract. Recent research has also revealed a disturbing connection between BV and subsequent infection with HIV. Another concern is the recurrent nature of BV, a problem that has resisted traditional management strategies. But other approaches are now being developed.
Maintaining a healthy vaginal ecosystem might have health implications beyond avoiding odor or vaginal discharge: There is a stronger case now for BV screening and effective treatment. This article is a reconsideration of BV, including a review of new evidence and treatment strategies.
It is commonly believed that STDs such as gonorrhea and syphilis may increase the risk of HIV transmission by causing inflammation or compromising skin integrity.6,7 Traditionally, BV was not considered a risk factor for HIV because it does not disrupt the skin barrier. Current data, however, suggest that BV may indeed increase women's risk of acquiring HIV infection (Table 1).
Cross-sectional studies. Evidence for this first showed up several years ago in a cross-sectional study of 144 commercial sex workers in Thailand, of whom 62 (43%) were HIV-positive.8 In these women, a clinical diagnosis of BV was associated with HIV-positive status (crude odds ratio 2.7; 95% confidence interval 1.3-5.5). This association between BV and HIV infection remained strong after adjustment for age, number of sexual encounters per week, current condom use, and current STD infection.
A second cross-sectional study evaluated 4,718 women in Uganda.9,10 Women with severe BV had a significantly higher frequency of HIV (26.7%), compared with those who had normal vaginal flora (14.2%). Associations between BV and HIV were also observed in studies of pregnant women in Malawi.11 A total of 9,148 women, most of them in the second trimester of pregnancy, agreed to be tested for HIV. Increasing prevalence of HIV significantly correlated with increasing severity of vaginal disturbances. As in other studies, the association between BV and HIV appeared to be independent of sexual activity, concurrent STDs, and level of immunosuppression (CD4 cell status).
Prospective studies. Because these early studies reporting an association between BV and HIV infection were cross-sectional, they did not indicate whether BV occurred before or after HIV seroconversion. A longitudinal follow-up study of pregnant and postpartum women in Malawi was one of the first to assess the temporal relationship between the two diseases.12 HIV- negative women were enrolled and observed during pregnancy and after delivery. Among the 1,196 seronegative women who were observed antenatally, 27 were positive by the time of delivery. Another 97 women seroconverted postnatally. Risk of seroconversion for both periods was significantly correlated with pre-existing BV.
In the most recent prospective study, the association between BV and HIV was evaluated in a population of 657 HIV-seronegative female sex workers, who were screened monthly for STDs, BV, and HIV.13 BV was defined by symptomatic vaginal discharge, pH greater than 4.5, and the presence of clue cells. At the initial visit, lactobacilli were isolated from 26% of the women, hydrogen peroxide (H2O2)-producing lactobacilli were found in only 11%, and BV was diagnosed in 36%. During the follow-up period, 68 women seroconverted for antibodies to HIV. There was a significant association between lactobacillus status and HIV seroconversion. Specifically, risk increased in a stepwise manner: Women with H2O2-producing lactobacilli had the lowest risk for HIV, women with non-H2O2-producing lactobacilli had higher risk, and women without lactobacilli and those with abnormal vaginal flora (that is, BV) were at highest risk. These findings suggest that lactobacillieven strains that are non-H2O2-producingmay exert a protective effect against HIV.
Association between BV and HIV reported in US. Most of the studies evaluating this connection have been conducted in parts of the world where HIV is more common. Even in the US, however, there are some data to suggest that BV increases a woman's susceptibility to HIV infection. Investigators in North Carolina screened 724 women receiving prenatal care.14 Gram's stain analysis was used to determine vaginal flora scores, ranging from normal to BV. As in the other studies, women with BV were more likely to have HIV and this association was independent of age, ethnicity, and sexual activity.
In summary, studies suggest that BV facilitates the acquisition of HIV. The majority of these studies are cross-sectional, so it is difficult to definitively link BV to HIV infection. But the recent prospective studies further support the theory that BV can increase the risk of HIV. Apparently, when lactobacilli levels are compromised and there is an overgrowth of abnormal flora, the vaginal tract becomes vulnerable to infectious pathogens such as HIV. It is possible that lactobacilli or their products somehow protect the vaginal ecosystem from pathogenic attack.
HIV infection in women occurs predominately via heterosexual genital contact. Accordingly, we can expect the vaginal ecosystem to play an important role in determining the efficiency of this transmission.15 Studies identify lactobacilli depletion as a significant pathogenic factor in HIV acquisition.
Lactobacilli are among the predominant organisms in the healthy vaginal microflora and may provide a first line of defense against infection in a number of ways (Figure 1). Certain strains of lactobacilli create a hostile environment for infectious agents by producing H2O2.15 Whether alone or in combination with a halide or peroxidase, H2O2 has been documented to have in vitro viricidal effects on HIV.16 Levels of H2O2 that are toxic to HIV are present in vaginal fluids and interact with self-produced peroxidase and halide to create an environment where HIV cannot survive.
The protective role of H2O2 was confirmed by showing that the antimicrobial properties of lactobacilli are lost in the presence of an enzyme that degrades H2O2.16 Furthermore, when women lack lactobacilli, particularly H2O2-producing strains, they are at greater risk for acquiring vaginal infections, including BV.17-19
In addition to H2O2, lactobacilli produce lactic acid from glucose. This product maintains the acidic pH of the vagina. This effect may be important because studies have shown that HIV is inactivated at acidic pH levels.20 In the absence of lactobacilli, vaginal pH increases, and HIV may then penetrate the vaginal epithelium more easily. Furthermore, acidic environments inhibit activation of T lymphocytes and decrease T-lymphocyte susceptibility to HIV.21 In addition, other organisms in an unbalanced vaginal ecosystem, such as anaerobic gram-negative rods, may produce substances that make the vaginal epithelium more susceptible to HIV.22-24
In short, there are a variety of mechanisms through which the lack of lactobacilli can make a woman more vulnerable to infection. The role of lactobacilli is complex, however, and we need further research to confirm and further explain these mechanisms.
In the US, women are one of the fastest growing segments of the HIV-infected population. From 1991 to 1995, the number of women diagnosed with AIDS in the US increased by 63%, which was the largest increase of any group of persons with this disease.25 The BV/HIV connection, if confirmed, would have significant implications for preventing the spread of HIV among women.
If BV, often considered a simple and common vaginal infection, contributes to a woman's risk of acquiring HIV, maintaining optimal vaginal health becomes more important. Even with today's limited evidence, we should appropriately diagnose and treat all vaginitis. Although BV has traditionally been ignored when the patient is asymptomatic, these recent findings suggest that we should consider routinely screening for and treating BV in all women. By not doing so, we may be neglecting a potentially serious risk.
If we recognize that treating BV is more important than previously thought, we come up against the ongoing challenge of how to treat cases of recurrent BV. The true incidence is not known, but studies of BV treatments suggest that recurrence may be very common. In a recent presentation, recurrence rates of 30% after 3 months, and as high as 80% within 9 months, were reported.26
The cause of recurrence is not clear. One common conjecture is that there is reinfection from a sexual partner. But studies indicate that early recurrences are more likely to be due to relapse rather than reinfection, although antimicrobial resistance does not appear to be a factor.27,28 Relapses may be due to the persistence of abnormal flora after treatment and failure to reestablish protective flora.
A variety of approaches have been suggested for treating recurrent BV, but the optimal management strategy remains undetermined (Table 2). Whereas some proposed approaches have been ineffective or are theoretically without merit, others have enough promise to warrant further evaluation.
Treatment of sexual partner
Suggesting the use of condoms
Longer treatment periods
Prophylactic maintenance therapy
Oral ingestion or vaginal application of yogurt containing Lactobacillus acidophilus
Intravaginal planting of other exogenous lactobacilli
Hydrogen peroxide douches
Intermittent prophylaxis with lactate gel/acid preparation
Although BV can occur in virginal women, it is more frequent in sexually active women.29 For this reason, treatment of sexual partners has been advocated, but this turns out to be ineffective.30-33 If one accepts the hypothesis that BV is caused by a lack of the right types of lactobacilli and the patient's inability to reestablish protective flora after antimicrobial therapy, then it makes sense that treating the partner would be ineffective.
Maintenance therapy has been proposed as a prophylactic management strategy for recurrent BV. In a pilot prospective, controlled trial, women with recurrent BVthat is, a history of more than three documented episodes in the previous yearwere treated for 3 months with twice-weekly administration of 0.75% metronidazole vaginal gel (MVG) or with placebo gel.26 During the 3-month maintenance phase, one of six patients in the MVG group had symptomatic recurrence, versus four of six women in the placebo group (P=0.241, Fisher exact test). The mean time to recurrence was 5.7 months for the MVG group and 2.8 months for the placebo group. During a 6-month off-therapy observation period, only one of 12 patients remained free of symptoms.
From these data, it appears that maintenance regimens might help prevent BV recurrence, but a 3-month regimen is inadequate for long-term resolution of the problem. Oral metronidazole, three times weekly for 3 months, has been used with some success in our practice, but this approach was prone to medication-related adverse events and has not been thoroughly evaluated (unpublished observation).
Alternative regimens have been suggested to prevent BV recurrence. One option is lactobacilli, either ingested orally or implanted directly in the vaginal tract. In one study, women who ingested yogurt containing Lactobacillus acidophilus had fewer episodes of recurrent BV than did women who ate pasteurized yogurt.34 In theory, this could work, but commercial preparations often do not contain H2O2-producing lactobacilli and hence may not have the desired effect.35
Two additional alternative strategies have been discussed as having the potential to reduce BV recurrence. Hydrogen peroxide douches may restore a degree of protection against pathogenic organisms. A total of 30 women with confirmed recurrent BV were enrolled in a study to evaluate the efficacy of a single vaginal washout with 3% H2O2.36 After 3 weeks, symptoms cleared completely in 78% of patients and improved in 13%. The amine test was negative in all women, mixed anaerobes were not reisolated, microscopy did not show clue cells, and vaginal acidity was restored in 96% of the women. However, it is difficult to draw any conclusions from this study, because patients were not followed up after 3 weeks.
Local intermittent application of an acid lactate gel has also been evaluated as a prophylactic strat-egy for recurrent BV.37 Forty-two women with serious cases of recurrent BV were treated with the lactate gel for 7 consecutive days. Afterward, they entered into a double-blind clinical trial, and they were treated prophylactically 3 days a month for 6 months, with either lactate gel or placebo. Of women treated with the lactate gel, 88% improved, compared with 10% of the placebo group. Vaginal lactobacilli flora were restored in 83% of the treated group but in only 16% of the placebo group.
As our understanding of the pathophysiology of BV improves, it has become clear that the local ecological disturbances caused by the condition can have serious ramifications. The new evidence with regard to HIV transmission may add a certain urgency to increasing public awareness of BV and physician awareness of the need for proper diagnosis and treatment. However, BV is not a simple infection with a quick, long-term cure, and future research will need to investigate optimal ways to manage the relatively common problem of recurrence.
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