Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples

Craig R Cohen, Jairam R Lingappa, Jared M Baeten, Musa O Ngayo, Carol A Spiegel, Ting Hong, Deborah Donnell, Connie Celum, Saidi Kapiga, Sinead Delany, Elizabeth A Bukusi, Craig R Cohen, Jairam R Lingappa, Jared M Baeten, Musa O Ngayo, Carol A Spiegel, Ting Hong, Deborah Donnell, Connie Celum, Saidi Kapiga, Sinead Delany, Elizabeth A Bukusi

Abstract

Background: Bacterial vaginosis (BV), a disruption of the normal vaginal flora, has been associated with a 60% increased risk of HIV-1 acquisition in women and higher concentration of HIV-1 RNA in the genital tract of HIV-1-infected women. However, whether BV, which is present in up to half of African HIV-1-infected women, is associated with an increase in HIV-1 transmission to male partners has not been assessed in previous studies.

Methods and findings: We assessed the association between BV on female-to-male HIV-1 transmission risk in a prospective study of 2,236 HIV-1-seropositive women and their HIV-1 uninfected male partners from seven African countries from a randomized placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus (HSV)-2, and their HIV-1-seronegative partners. Participants were followed for up to 24 months; every three months, vaginal swabs were obtained from female partners for Gram stain and male partners were tested for HIV-1. BV and normal vaginal flora were defined as a Nugent score of 7-10 and 0-3, respectively. To reduce misclassification, HIV-1 sequence analysis of viruses from seroconverters and their partners was performed to determine linkage of HIV-1 transmissions. Overall, 50 incident HIV-1 infections occurred in men in which the HIV-1-infected female partner had an evaluable vaginal Gram stain. HIV-1 incidence in men whose HIV-1-infected female partners had BV was 2.91 versus 0.76 per 100 person-years in men whose female partners had normal vaginal flora (hazard ratio 3.62, 95% CI 1.74-7.52). After controlling for sociodemographic factors, sexual behavior, male circumcision, sexually transmitted infections, pregnancy, and plasma HIV-1 RNA levels in female partners, BV was associated with a greater than 3-fold increased risk of female-to-male HIV-1 transmission (adjusted hazard ratio 3.17, 95% CI 1.37-7.33).

Conclusions: This study identified an association between BV and increased risk of HIV-1 transmission to male partners. Several limitations may affect the generalizability of our results including: all participants underwent couples HIV counseling and testing and enrolled in an HIV-1 prevention trial, and index participants had a baseline CD4 count ≥ 250 cells/mm³ and were HSV-2 seropositive. Given the high prevalence of BV and the association of BV with increased risk of both female HIV-1 acquisition and transmission found in our study, if this association proves to be causal, BV could be responsible for a substantial proportion of new HIV-1 infections in Africa. Normalization of vaginal flora in HIV-1-infected women could mitigate female-to-male HIV-1 transmission.

Trial registration: ClinicalTrials.com NCT00194519.

Conflict of interest statement

The authors have declared that no competing interests exist.

References

    1. (UNAIDS) JUNPoHA. Global report: UNAIDS report on the global AIDS epidemic 2010. New York: UNAIDS; 2010.
    1. Chaisson RE, Keruly JC, Moore RD. Association of initial CD4 cell count and viral load with response to highly active antiretroviral therapy. JAMA. 2000;284:3129.
    1. Graham SM, Holte SE, Peshu NM, Richardson BA, Panteleeff DD. Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 shedding. AIDS. 2007;21:507.
    1. Donnell D, Baeten JM, Kiarie J, Thomas KK, Stevens W. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet. 2010;375:2098.
    1. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:505.
    1. Fredricks DN, Fiedler TL, Marrazzo JM. Molecular identification of bacteria associated with bacterial vaginosis. N Engl J Med. 2005;353:1911.
    1. Mitchell C, Moreira C, Fredricks D, Paul K, Caliendo AM. Detection of fastidious vaginal bacteria in women with HIV infection and bacterial vaginosis. Infect Dis Obstet Gynecol. 2009;2009:236919.
    1. Bukusi EA, Cohen CR, Meier AS, Waiyaki PG, Nguti R. Bacterial vaginosis: risk factors among Kenyan women and their male partners. Sex Transm Dis. 2006;33:367.
    1. Martin HL, Richardson BA, Nyange PM, Lavreys L, Hillier SL. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis. 1999;180:1868.
    1. Sewankambo N, Gray RH, Wawer MJ, Paxton L, McNaim D. HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis. Lancet. 1997;350:550.
    1. Atashili J, Poole C, Ndumbe PM, Adimora AA, Smith JS. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS. 2008;22:1501.
    1. Coleman JS, Hitti J, Bukusi EA, Mwachari C, Muliro A. Infectious correlates of HIV-1 shedding in the female upper and lower genital tracts. AIDS. 2007;21:759.
    1. Sha BE, Zariffard MR, Wang QJ, Chen HY, Bremer J. Female genital-tract HIV load correlates inversely with Lactobacillus species but positively with bacterial vaginosis and Mycoplasma hominis. J Infect Dis. 2005;191:32.
    1. Wang CC, McClelland RS, Reilly M, Overbaugh J, Emery SR. The effect of treatment of vaginal infections on shedding of human immunodeficiency virus type 1. J Infect Dis. 2001;183:1022.
    1. Hashemi FB, Ghassemi M, Faro S, Aroutcheva A, Spear GT. Induction of human immunodeficiency virus type 1 expression by anaerobes associated with bacterial vaginosis. J Infect Dis. 2000;181:1580.
    1. Simoes JA, Hashemi FB, Aroutcheva AA, Heimler I, Spear GT. Human immunodeficiency virus type 1 stimulatory activity by Gardnerella vaginalis: relationship to biotypes and other pathogenic characteristics. J Infect Dis. 2001;184:27.
    1. Clemetson DB, Moss GB, Willerford DM, Hensel M, Emonyi W. Detection of HIV DNA in cervical and vaginal secretions. Prevalence and correlates among women in Nairobi, Kenya. JAMA. 1993;269:2864.
    1. Rebbapragada A, Howe K, Wachihi C, Pettengell C, Sunderji S. Bacterial vaginosis in HIV-infected women induces reversible alterations in the cervical immune environment. J Acquir Immune Defic Syndr. 2008;49:522.
    1. Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010;362:439.
    1. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991;29:301.
    1. Forsum U, Jakobsson T, Larsson PG, Schmidt H, Beverly A. An international study of the interobserver variation between interpretations of vaginal smear criteria of bacterial vaginosis. APMIS. 2002;110:818.
    1. Campbell MS, Mullins JI, Hughes JP, Celum C, Wong KG. Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial. PLoS One. 2011;6:e16986. doi: .
    1. Lingappa JR, Baeten JM, Wald A, Hughes JP, Thomas KK. Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial. Lancet. 2009;375:833.
    1. Sahai H. Statistics in epidemiology: methods, techniques, and applications. In: Sahai H, Khurshid A, editors. Boca Raton (Florida): CRC Press; 1996.
    1. Baeten JM, Kahle E, Lingappa JR, Coombs RW, Delany-Moretlwe S. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Sci Transl Med. 2011;3:77ra29.
    1. Tanton C, Weiss HA, Le Goff J, Changalucha J, Rusizoka M. Correlates of HIV-1 genital shedding in Tanzanian Women. PLoS One. 2011;6:e17480. doi: .
    1. Moreira C, Venkatesh KK, DeLong A, Liu T, Kurpewski J. Effect of treatment of asymptomatic bacterial vaginosis on HIV-1 shedding in the genital tract among women on antiretroviral therapy: a pilot study. Clin Infect Dis. 2009;49:992.
    1. Cohen CR, Plummer FA, Mugo N, Maclean I, Shen C. Increased interleukin-10 in the the endocervical secretions of women with non-ulcerative sexually transmitted diseases: a mechanism for enhanced HIV-1 transmission? AIDS. 1999;13:332.
    1. Bukusi EA, Thomas K, Nguti R, Cohen CR, Weiss N. Topical penile microbicide use by men to prevent recurrent bacterial vaginosis in sex partners: a randomized clinical trial. Sex Transm Dis. 2011;38:489.
    1. Gray RH, Kigozi G, Serwadda D, Makumbi F, Nalugoda F. The effects of male circumcision on female partners' genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda. Am J Obstet Gynecol. 2009;200:e47.
    1. Price LB, Liu CM, Johnson KE, Aziz M, Lau MK. The effects of circumcision on the penis microbiome. PLoS One. 2010;5:e8422. doi: .
    1. Donoval BA, Landay AL, Moses S, Agot K, Ndinya-Achola JO. HIV-1 target cells in foreskins of African men with varying histories of sexually transmitted infections. Am J Clin Pathol. 2006;125:391.
    1. de Jong MA, Geijtenbeek TB. Human immunodeficiency virus-1 acquisition in genital mucosa: Langerhans cells as key-players. J Intern Med. 2009;265:28.
    1. Klebanoff MA, Schwebke JR, Zhang J, Nansel TR, Yu KF. Vulvovaginal symptoms in women with bacterial vaginosis. Obstet Gynecol. 2004;104:272.
    1. Amsel R, Totten PA, Spiegel CA, Chen KC, Eschenbach D. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med. 1983;74:22.
    1. Baeten JM, Strick LB, Lucchetti A, Whittington WL, Sanchez J. Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. J Infect Dis. 2008;198:1808.
    1. Eschenbach DA. History and review of bacterial vaginosis. Am J Obstet Gynecol. 1993;169:445.
    1. Greenblatt RM, Bacchetti P, Barkan S, Augenbraun M, Silver S. Lower genital tract infections among HIV-infected and high-risk uninfected women: findings of the Women's Interagency HIV Study (WIHS). Sex Transm Dis. 1999;26:151.
    1. Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006;193:1486.
    1. Tabrizi SN, Fairley CK, Bradshaw CS, Garland SM. Prevalence of Gardnerella vaginalis and Atopobium vaginae in virginal women. Sex Transm Dis. 2006;33:665.
    1. Verstraelen H, Verhelst R, VaneechoutteTemmerman MM. The epidemiology of bacterial vaginosis in relation to sexual behaviour. BMC Infect Dis. 10:81.
    1. McClelland RS, Richardson BA, Hassan WM, Chohan V, Lavreys L. Improvement of vaginal health for Kenyan women at risk for acquisition of human immunodeficiency virus type 1: results of a randomized trial. J Infect Dis. 2008;197:1368.
    1. Anukam KC, Osazuwa E, Osemene GI, Ehigiagbe F, Bruce AW. Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. Microbes Infect. 2006;8:2776.
    1. Bolton M, van der Straten A, Cohen CR. Probiotics: potential to prevent HIV and sexually transmitted infections in women. Sex Transm Dis. 2008;35:225.
    1. Hemmerling A, Harrison W, Schroeder A, Park J, Korn A. Phase 2a study assessing colonization efficiency, safety, and acceptability of Lactobacillus crispatus CTV-05 in women with bacterial vaginosis. Sex Transm Dis. 2010;37:750.
    1. Swidsinski A, Mendling W, Loening-Baucke V, Ladhoff A, Swidsinski S. Adherent biofilms in bacterial vaginosis. Obstet Gynecol. 2005;106:1023.
    1. Swidsinski A, Mendling W, Loening-Baucke V, Swidsinski S, Dorffel Y. An adherent Gardnerella vaginalis biofilm persists on the vaginal epithelium after standard therapy with oral metronidazole. Am J Obstet Gynecol. 2008;198:96.
    1. Thoma ME, Gray RH, Kiwanuka N, Aluma S, Wang MC. The Short-term Variability of Bacterial Vaginosis Diagnosed by Nugent Gram Stain Criteria Among Sexually Active Women in Rakai, Uganda. Sex Transm Dis. 2011;38:116.
    1. Wawer MJ, Sewankambo NK, Serwadda D, Quinn TC, Paxton LA. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Rakai Project Study Group. Lancet. 1999;353:535.
    1. Hemmerling A, Cohen CR. Probiotics: the potential for a live microbicide to prevent HIV. J Acquir Immune Defic Syndr. 2011;56:101.
    1. MacPhee RA, Hummelen R, Bisanz JE, Miller WL, Reid G. Probiotic strategies for the treatment and prevention of bacterial vaginosis. Expert Opin Pharmacother. 2010;11:2995.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir