bacterial vaginosis: a sexually transmitted infection, and benefit of treating men

 A recent article confirmed that bacterial vaginosis is a sexually transmitted infection, and recurrent infections in women can be decreased by treating their male partners (see bacterial vaginosis treat male NEJM2025 in dropbox, or DOI: 10.1056/NEJMoa2405404)

 

Details:

-- open-label, randomized, controlled trial of women in Australia who had bacterial vaginosis and were in a monogamous relationship with a male partner

-- partner-treatment group: women received first-line recommended antimicrobial agents (metronidazole 400 mg tablets twice daily for seven days, or, if contraindicated, intravaginal  2% clindamycin cream for seven nights or intravaginal 0.75% metronidazole cream for five nights), and male partner had oral metronidazole 400 mg and 2% clindamycin cream applied to the penile skin, both twice a d​ay for seven days

-- control group: women received the above treatment, and the partner received no treatment (this was an open-label trial because of concern that a placebo cream might affect the penile microbiota)

 

Baseline characteristics for women:

-- age 30, 55% from the Western Pacific region/25% from Europe/11% from Americas/4% from Southeast Asia

-- Contraception: IUD 30%, always using condoms with regular male partner for vaginal sex 4%

-- median number of previous diagnoses of BV was 3; median number of male sexual partners during lifetime was 15; median number of female sexual partners during lifetime was 0; median duration of sexual relationships with the regular male partner was 14 months; median number times per month reporting vaginal sex with regular male partner was 10

-- clinical findings at enrollment (having BV was required for the study): vaginal pH>4.5 97%, characteristic homogeneous vaginal discharge 96%, fishy odor or positive amine test 94%, presence of clue cells visualized on wet mount 93%, Nugent score of 4 to 6 in 14%, Nugent score of 7 to 10 in 86%

    -- Nugent score: gram stain scoring system for vaginal swabs for large Gram-positive rods (Lactobacillus) score 0-4; small Gram-variable rods ( Gardnerella vaginalis) score 0-4; and curved Gram-variable rods (Mobiluncus) score 0-4.  total score of 0-3 negative for BV; 4-6 indeterminate for BV; 7+ indicative of BV

 

Baseline characteristics for males:

-- 32 years old, 80% uncircumcised, median number of female sexual partners during lifetime was 19

 

-- primary outcome: recurrence of bacterial vaginosis in women within 12 weeks

 

Results:

-- this trial was stopped early after 150 couples had completed the 12-week follow-up because of evident benefit in decreasing recurrent BV in women by treating the males; this reduced the total number of couples to 81 in the partner-treatment group and 83 in the control group

-- in modified intention-to-treat analysis, BV recurrence in women:

    -- partner-treatment group: 24 of 69 women (35%), 1.6 per person-year (1.1-2.4)

        -- recurrence of BV within 12 weeks: mean time 73.9 days

    -- control group: 43 of 68 women (63%), 4.2 per person-year (3.2-5.7)

        -- recurrence of BV within 12 weeks: mean time 54.5 days

-- 63% decrease in the partner-treatment group over 12 weeks: HR 0.37 (0.22-0.61)

-- absolute risk difference of -2.6 recurrences per person-year (-4.0 to -1.2)

note that the divergence of curves begins by four weeks and continues throughout the study

 

-- secondary analyses for imputed data in the intention-to-treat population and per-protocol assessment had essentially the same results

-- subgroup analysis by IUD use or nonuse as well as circumcision status found no difference between the groups, and there was no association between recurrences and contraceptive or sexual practices

 

-- Adherence data: available for all 69 women and 56 of 69 men in the partner-treatment group, and 67 of 68 women in the control group:

    -- female participants: all took at least 70% of their prescribed medication

    -- male participants: 14% reported taking less than 70% of doses, with men missing more doses of topical clindamycin versus oral metronidazole

    -- the lowest recurrence rate of 1.3 per person-year was among partners of men who were 100% adherent to treatment

 

-- adverse events:

    -- women: 59% had nausea, headache, and vaginal itch

    -- men: 57% had nausea, headache, and metallic taste (redness or irritation of penile skin was found in only 4 participants)

 

Commentary:

-- bacterial vaginosis is remarkably common, affecting 30% of women worldwide

-- though there are quite effective therapies for women, including metronidazole and clindamycin, the incidence of recurrence within three months is more than 50%

-- BV can be associated with an array of bad outcomes: obstetric and gynecologic sequelae, including preterm delivery in pregnant women, and postpartum fever; endometritis, post-hysterectomy vaginally cuff cellulitis, post-abortal infection; increased risk for acquisition and transmission of HIV; increased risk for acquisition of other sexually transmitted infections including HSV, gonorrhea, chlamydia, and trichomonas; and perhaps increased persistence of HPV infections in women

-- although prior conceptions of BV suggested that changes in the vaginal pH were associated with increased risk and it was not really a sexually transmitted infection, there have been an array of clinical studies suggesting it is in fact a sexually transmitted infection (STIs):

    -- as with other STI’s, it is associated with new sexual partners and has a similar incubation period.

    -- the risk of recurrent infections in women who have a regular sexual partner is twice that of women who do not have a regular partner

    -- men may harbor the bacterial species associated with BV in their distal urethra and coronal sulcus : https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036298 . and, studies have found that specific penile microbiota are associated with a woman’s risk of BV

        -- however, for women, the altered vaginal microbiota/dysbiosis reveals that there are many different bacterial species that vary in women who have BV, and this lack of a single responsible bacteria has been an impediment in defining BV as an STI (per Koch's postulates)

 

-- this current study found a significant benefit for women against developing recurrent BV infections when male partners were treated simultaneously, and those men who had 100% adherence of the meds had the lowest recurrence rate in women

    -- and, most women in this study were at high risk for recurrent infections since 87% had a history of BV, 80% had an uncircumcised male partner, and nearly 1/3 used in IUD

 

-- One concern with the methodology of the study is that the participants were treated with oral metronidazole:

    -- the oral form is associated with significant changes in the gut microbiome: https://pmc.ncbi.nlm.nih.gov/articles/PMC7517498/

    -- oral metronidazole is associated with many adverse effects, as was found in this study

    -- for women, the historical effectiveness of topical intravaginal metronidazole cream is the same as with pills

    -- so it seems reasonable to study topical metronidazole (or perhaps clindamycin) in women and men as an alternative to the oral metronidazole

  

Limitations:

-- the largest group of patients in the study attended one specific clinic in Australia, and this may not be generalizable to other populations with different risk factors for BV recurrence

-- the actual sample size of the study was small, related to the fact that it was appropriately stopped early because of clear evidence of benefit for the partner-treated model

-- the study also recruited women who had monogamous relationships (though nine couples reported sex with an additional partner), and this finding is not necessarily completely accurate since it was self-reported

    -- the study did not have the design or power to assess the utility of partner treatment in women with BV or the men who had multiple partners

-- this was an open-label study for fear that using a placebo cream might alter the male genital microbiota, though being open-label typically does impart a bias to the study. However the laboratory staff and microscopist assessing the primary outcome were blinded

-- No comment on type or composition of other contraceptives besides IUD and condoms

 

So,

-- impressive study confirming:

    -- the high likelihood that BV is a sexually-transmitted infection

    -- treating male partners is effective in decreasing the usually quite common recurrences of BV in women

-- but, it would be great to have other studies that used purely topical antibiotics in women and men, thereby avoiding the adverse effects of oral metronidazole including on the precious gut microbiota

geoff

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