Emerging challenges in bacterial vaginosis

By Paul Nyirjesy, MD

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.

The BV/HIV connection: an emerging challenge

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).

Table 1
Studies documenting an association between bacterial vaginosis and HIV acquisition

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 lactobacilli—even strains that are non-H₂O₂-producing—may 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.

The protective role of lactobacilli in the vaginal ecosystem

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.

Clinical implications

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.

The challenge of recurrent BV

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.

Table 2
Possible management strategies for recurrent bacterial vaginosis

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 BV—that is, a history of more than three documented episodes in the previous year—were 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.

REFERENCES

1. Sobel JD. Vaginal infections in adult women. Med Clin North Am. 1990;74:1573-1602.

2. Migeon MB, Desnick L, Elmore JG. Office management of vaginal infections. Cortlandt Forum. 1998; 184-192.

3. Ferris DG, Dekle C, Litaker MS. Women's use of over-the-counter antifungal medications for gynecologic symptoms. J Fam Pract. 1996;42:595-600.

4. Thomason JL, Scaglione NJ. Bacterial vaginosis. Contemporary OB/GYN. 1999;44:15-24.

5. Embree J, Caliando JJ, McCormack WM. Nonspecific vaginitis among women attending a sexually transmitted diseases clinic. Sex Transm Dis. 1984;11:81-84.

6. Laga K, Manoka A, Kivuvu K et al. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS. 1993;7:95-102.

7. Hillier S. Synergy between STD's/HIV: how genital infections contribute to the heterosexual HIV epidemic. Presented at: The National Association of Nurse Practitioners in Women's Health, October 1999; New Orleans, La.

8. Cohen CR, Duerr A, Pruithithada N, et al. Bacterial vaginosis and HIV seroprevalence among female commercial sex workers in Chiang Mai, Thailand. AIDS. 1995;9:1093-1097.

9. Sewankambo N, Gray RK, Wawer MJ, et al. HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis. Lancet. 1997;350:546-550.

10. Gray RK, Wawer MJ, Taha T, et al. Depleted vaginal lactobacilli and BV increase HIV acquisition in studies in Uganda and Malawi. Paper presented at: 35th Annual Meeting of the Infectious Diseases Society of America; September 13-16, 1997; San Francisco, Calif.

11. Taha TE, Hoover DR, Dallabetta GA, et al. Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV. AIDS. 1998;12:1699-1706.

12. Taha TE, Gray RH, Kumwenda, NI et al. HIV infection and disturbances of vaginal flora during pregnancy. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:52-59.

13. Martin HL, Richardson BA, Nyange PM, et al. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis. 1999;180:1863-1868.

14. Royce RA, Thorp J, Granados JL, et al. Bacterial vaginosis associated with HIV infection in pregnant women from North Carolina. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:382-386.

15. Hillier SL. The vaginal microbial ecosystem and resistance to HIV. AIDS Res Hum Retroviruses. 1998;14(Suppl 1):S17-S21.

16. Klebanoff SJ, Coombs RW. Viricidal effect of Lactobacillus acidophilus on human deficiency virus type 1: possible role in heterosexual transmission. J Exp Med. 1991;174:289-292.

17. Hillier SL, Krohn MA, Klebanoff SJ, et al. The relationship of hydrogen peroxide-producing lactobacilli to bacterial vaginosis and genital microflora in pregnant women. Obstet Gynecol. 1992;79:369-373.

18. Hillier SL, Krohn MA, Rabe LK, et al. The normal vaginal flora, H₂o₂-producing lactobacilli, and bacterial vaginosis in pregnant women. Clin Infect Dis. 1993; 16(Suppl 4):S273-S281.

19. Hawes SE, Hillier SL, Benedetti J, et al. Hydrogen peroxide-producing lactobacilli and acquisition of vaginal infections. J Infect Dis. 1996;174:1058-1063.

20. Martin LS, McDougal JS, Loskoski SL. Disinfection and inactivation of the human T lymphotropic virus type III/Lymphadenopathy-associated virus. J Infect Dis. 1985;152:400-403.

21. Hill JA, Anderson DJ. Human vaginal leukocytes and the effects of vaginal fluid on lymphocyte and macrophage defense functions. Am J Obstet Gynecol. 1992;166:720-726.

22. Rotstein OD, Pruett TL, Fiegel VD, et al. Succinic acid, a metabolic by-product of Bacteroides species, inhibits polymorphonuclear leukocyte function. Infect Immun. 1985;48:402-408.

23. McGregor JA, French JI, Jones W, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol. 1994;170:1048-1060.

24. Robertson JA, Stemler ME, Stemke GW. Immunoglobulin A protease activity of Ureaplasma urealyticum. J Clin Microbiol. 1984;19:255-258.

25. Newman MD. New developments in HIV care for women. Available at: http://hivinsite.ucsf.edu/medical/iasusa/2098.4736.html . Accessed February 19, 2000.

26. Sobel JD, Leaman D. Suppressive maintenance therapy of recurrent bacterial vaginosis utilizing 0.75% metronidazole vaginal gel. Int J Gynecol Obstet. 1999;67(Suppl 1):S41.

27. Holst E. Reservoir of four organisms associated with bacterial vaginosis suggests lack of sexual transmission. J Clin Microbiol. 1990;28:2035-2039.

28. Sobel JD. Bacterial vaginosis. Br J Clin Pract Suppl. 1990;71:65-69.

29. Bump RC, Buesching WJ III. Bacterial vaginosis in virginal and sexually active adolescent females: evidence against exclusive sexual transmission. Am J Obstet Gynecol. 1998;158:935-939.

30. Mengel MB, Berg AO, Weaver CH, et al. The effectiveness of single-dose metronidazole therapy for patients and their partners with bacterial vaginosis. J Fam Pract. 1989;28:163-171.

31. Moi IL, Erkkola R, Jerve F, et al. Should male consorts of women with bacterial vaginosis be treated? Genitourin Med. 1989;65:263-268.

32. Vejtorp M, Bollerup AC, Vejtorp L, et al. Bacterial vaginosis: a double-blind randomised trial of the effect of treatment of the sexual partner. Br J Obstet Gynaecol. 1988;95:920-926.

33. Colli E, Landoni M, Parazzini F. Treatment of male partners and recurrence of bacterial vaginosis: a randomised trial. Genitourin Med. 1997;73:267-270.

34. Shalev E, Battino S, Weiner E, et al. Ingestion of yogurt containing Lactobacillus acidophilus compared with pasteurized yogurt as prophylaxis for recurrent candidal vaginitis and bacterial vaginosis. Arch Fam Med. 1996;5:593-596.

35. Hughes VL, Hillier SL. Microbiologic characteristics of Lactobacillus products used for colonization of the vagina. Obstet Gynecol. 1990;75:244-248.

36. Winceslaus SJ, Calver G. Recurrent bacterial vaginosis—an old approach to a new problem. Int J STD AIDS. 1996;7:284-287.

37. Andersch B, Lindell D, Dahlen L, et al. Bacterial vaginosis and the effect of intermittent prophylactic treatment with an acid lactate gel. Gynecol Obstet Invest. 1990;30:114-119.

Dr. Nyirjesy is Associate Professor of Obstetrics and Gynecology, Temple University School of Medicine, Philadelphia, Pa.

Dr. Nyirjesy is a member of 3M Pharmaceuticals' advisory board on vaginitis.

Paul Nyirjesy. Emerging challenges in bacterial vaginosis.

Contemporary Ob/Gyn

2000;11:15-28.