McClelland RS, Richardson BA, Hassan WM, Chohan V, Lavreys L, Mandaliya K, et al. 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;197:1361-8.
To test the effectiveness of monthly periodic presumptive oral treatment with 2 g of metronidazole plus 150 mg of fluconazole to reduce the incidence of bacterial vaginosis (BV), vaginal candidiasis, and Trichomonas vaginalis infection and to promote vaginal colonization with Lactobacillus species among sex workers in Mombasa, Kenya at risk for HIV-1 acquisition
A randomized, double-blind, placebo-controlled trial among female sex workers followed monthly as part of an open cohort study of risk factors for HIV-1.(1)
Eligibility criteria included HIV-1-seronegative female sex workers from Mombasa, Kenya, aged 18-45 years, not pregnant nor planning to become pregnant in the next year, and no abnormal vaginal discharge or symptoms of vulvovaginal pruritus. Most worked in bars or nightclubs, supplementing income with sex work. Exclusion criteria included a history of intolerance to either study drug, anticipation of travel outside the Mombasa area, and the inability to abstain from alcohol for 48 hours after each dose of study drug.
Between May 2003 and November 2005, 378 women were screened for the study, 310 were enrolled, 155 in each arm. Fifty percent of the women were block randomized into groups of 10 to the intervention (8 capsules containing 250 mg metronidazole each plus 1 capsule containing 150 mg of fluconazole) and the other 50% to the control arm (8 metronidazole placebo capsules and 1 fluconazole placebo capsule), with participants and investigators blinded to the allocation of treatment. All participants provided written informed consent.
All women were scheduled to return for up to twelve monthly follow-up visits, where they underwent a brief interview, physical examination, collection of genital specimen, HIV-1 serological testing, and urine pregnancy testing and received the study drugs, which were administered orally as directly observed treatment in the clinic. Participants were invited to return to the clinic 1 week after each examination to receive their laboratory results.
At enrollment, and at each follow-up visit, sexually transmitted infections including gonorrhea, microscopic cervicitis, and T. vaginalis were treated according to WHO and Kenya Ministry of Health guidelines. Those reporting abnormal vaginal discharge or vulvovaginal itching were treated syndromically with a single, open-label, 2-g dose of metronidazole plus 200-mg doses of clotrimazole vaginal suppositories nightly for 3 nights. During this treatment, the study drug was withheld.
Participants were considered lost if they were >6 weeks late for a scheduled follow-up visit, and they were censored before 12 months of follow-up if they had HIV-1 seroconversion, became pregnant, or remained in active follow-up at the completion of the trial in December 2006. Participants were considered nonadherent to the study drug when they were >2 weeks late for a scheduled appointment, as the study drug was administered on-site.
The primary outcomes of the trial were the incidence of BV, vaginal candidiasis, and T. vaginalis infection and of cultures positive for any Lactobacillus organisms and for H202-producing Lactobacillus organisms.
Of the 310 women enrolled, 151 women in the intervention and 152 in the placebo returned for at least one follow-up visit and were included in the primary analysis. A median of 12 follow-up visits per subject was recorded in both study arms. Participants in both arms did not differ significantly at baseline with respect to demographic, obstetrical, or behavioural characteristics or laboratory findings. The women's median age was 32 years, and both groups had 8 median years of education. Participants had been involved in sex work for a median of 4 years, and had had one sex act in the past week. Over half (200/310) reported 100% condom use, a third reported using Vaseline as a lubricant, and three-quarters were HSV-2 seropositive. Greater than 40% of women had vaginal infections at baseline.
Using Andersen-Gill proportional hazards models with robust variance estimates to allow for multiple events per woman, the intervention group showed that monthly treatment reduced the number of episodes of BV by nearly half (hazard ratio [HR], 0.55; 95% confidence interval [CI]: 0.49-0.63; P<0.001). Similarly, the intervention arm was more likely to have an increase in the frequency of colonization with Lactobacillus organisms, including those that produce H202 (HR, 1.47; 95% CI: 1.19-1.80; P<0.001). Among women in the intervention arm, there were fewer cases of vaginal candidiasis and trichomoniasis than among the women in the placebo arm; however, these differences were not statistically significant.
Five women in the intervention group and 7 in the placebo group seroconverted to HIV-1 (HR, 0.6; 95% CI: 0.2-2.3; P=0.6). Six women in each study arm acquired gonorrhea (HR, 1.0; 95% CI: 0.6-1.7; P>0.99). Using criteria from the Division of AIDS, National Institute of Allergy and Infectious Diseases, no severe adverse events occurred in either study arm; however, nausea was reported at 36 visits in the intervention arm compared with 21 visits in the placebo arm (HR, 1.7; 95% CI: 1.0-2.9; P=0.5).
The authors concluded that monthly, directly observed therapy with metronidazole plus fluconazole significantly decreased the number of new episodes of BV and increased the frequency of vaginal colonization with Lactobacillus species. Given the association between vaginal health and HIV-1 risk, vaginal health interventions have the potential to provide simple, female-controlled approaches for reducing the risk of HIV-1 acquisition.
According to the Newcastle-Ottawa quality assessment scale, the random selection of female sex workers was comparable in both the intervention and placebo groups. Staff and subjects were blinded to who was taking the intervention drug, and follow-up and outcomes assessment was appropriate. Follow-up was good in both arms (87% treatment, 90% placebo). All analysis was intention to treat. The authors suggest that their study may have been limited by the monthly rather than weekly administration of fluconazole, which was shown previously to be more effective in reducing the recurrence of vulvovaginal candidiasis.(2) Also, the effect of fluconazole may have been counterbalanced by an increased risk of vaginal candidiasis following treatment of BV with metronidazole;(3,4,5) however, yeast cultures were not performed, so this could not be evaluated. The sample size provided adequate power for detecting differences in the rates of BV, vaginal candidiasis, and Lactobacillus colonization; however, the final sample size provided less power for detecting differences in T. vaginalis. The authors suggest that the low incidence of T. vaginalis as an insignificant finding may have been the result of monthly risk reduction counseling, free condoms, and directed treatment for T. vaginalis infection. These findings could be generalizable to other Kenyan female sex workers; however, the effectiveness of monthly preventive treatment could differ with demographic characteristics, such as location, age, and exposure to risk reduction counseling and provision of condoms.
Although strengthening women's health is important on many levels, providing preventive treatment for BV may not alone reduce HIV-1 acquisition. It is known that sexually transmitted infections increase the likelihood of HIV transmission; however, a recent study found suppressing genital herpes with acyclovir does not reduce the risk of HIV acquisition.(6) Likewise, although vaginal infections are common and have been associated with increased risk for HIV-1, further studies with novel approaches are required to justify an effective link between vaginal health interventions and reduction in HIV-1 acquisition. This study was not powered to detect a difference in rates of HIV-1 infection.
Although the authors conclude that addressing vaginal health may provide insight into a new therapeutic approach to reduce the risk of HIV-1 acquisition, this is not yet successfully proven, and the known benefits of other methods, such as condoms, should continue to be promoted foremost.
- Martin HL Jr, Jackson DJ, Mandaliya K, et al. Preparation for AIDS vaccine evaluation in Mombasa, Kenya: establishment of seronegative cohorts of commercial sex workers and trucking company employees. AIDS Res Hum Retroviruses 1994;10(Suppl 2):S235-7.
- Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004;351:876-83.
- Sobel JD, Ferris D, Schwebke J, et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol 2006;194:1283-9.
- Hillier SL, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993;81:963-7.
- Livengood CH 3rd, Soper DE, Sheehan KL, et al. Comparison of once daily and twice-daily dosing of 0.75% metronidazole gel in the treatment of bacterial vaginosis. Sex Transm Dis 1999;26:137-42.
- Celum C, Wald A, Hughes A, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet�2008;371:2109-19.