By Rebecca H. Allen, MD, MPH

Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School, Brown University Women & Infants’ Hospital, Providence, RI

Dr. Allen reports that she receives grant/research support from Bayer, and is a consultant for Bayer, Mylan, and Merck.

SYNOPSIS: In this randomized controlled trial of 228 women, Lactobacillus crispatus CTV-05 (Lactin-V) applied vaginally for 11 weeks reduced the incidence of recurrent bacterial vaginosis from 45% in the placebo arm to 30% in the Lactin-V arm.

SOURCE: Cohen CR, Wierzbicki MR, French AL, et al. Randomized trial of Lactin-V to prevent recurrence of bacterial vaginosis. N Engl J Med 2020;382:1906-1915.

Recurrent bacterial vaginosis (BV) is a problem that affects many women, with an estimated 50% of women developing a recurrence within 12 months of treatment.1 The authors of this study tested the efficacy of a novel product, Lactobacillus crispatus CTV-05 (Lactin-V), in reducing bacterial vaginosis recurrence in this phase 2b clinical trial. This product contains a naturally occurring vaginal strain of L. crispatus in the form of a powder with 2 × 109 colony-forming units (CFU) preserved with inactive ingredients and administered via a vaginal applicator. Previously, the product was tested successfully in a phase 2a clinical trial.2 This was a multicenter, randomized, placebo-controlled, double-blind trial to assess the efficacy of intravaginal Lactin-V in preventing a recurrence of BV among women who had received a diagnosis of BV at a screening visit. Women in the study were 18 to 45 years of age who met three of four Amsel criteria (thin, white, homogeneous discharge, > 20% clue cells on wet prep, vaginal pH of > 4.5, and positive whiff test), and were diagnosed with BV and treated with a five-day course of 0.75% metronidazole gel. A swab also was sent for a Gram stain to determine the Nugent score (0-3, normal; 4-6, intermediate; and 7-10, indicative of BV).

Nonpregnant women whose Nugent score was 4 or greater and who had negative sexually transmitted infection (STI; HIV, syphilis, gonorrhea, chlamydia, and trichomonas) screening were seen within 48 hours of completing the vaginal metronidazole treatment. They were randomized in a 2:1 ratio to receive Lactin-V at 2 × 109 CFU per dose or matching placebo. The schedule consisted of four consecutive doses in week 1, followed by twice-weekly doses for 10 weeks. The patients were seen at four, eight, 12, and 24 weeks after treatment. The primary outcome was the percentage of participants who had recurrent BV, defined by three out of four Amsel criteria or a Nugent score of 4 or more at any follow-up visit up to and including week 12. Secondary outcomes included recurrent BV at 24 weeks and acceptability.

From April 2016 through February 2019, 228 women underwent randomization, 152 to the Lactin-V group and 76 to the placebo group. More than half the sample reported a history of five or more episodes of BV. Adherence to the treatment assigned was 77% in the Lactin-V arm and 74% in the placebo arm. In the intention to treat analysis, BV recurrence by week 12 occurred in 46 participants (30%) in the Lactin-V group and 34 participants (45%) in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.44-0.87). Among those without a known recurrence by week 12, an additional 13 (12%) participants in the Lactin-V group and seven (17%) in the placebo group had a recurrence by week 24 (RR, 0.73; 95% CI, 0.54-0.92). There was no difference between the two groups in terms of adverse events, both local (abnormal vaginal discharge, vaginal odor, genital itching) and systemic (abdominal pain, headache, frequent urination).

COMMENTARY

L. crispatus is a hydrogen peroxide-producing Lactobacillus that keeps the vaginal pH low and prevents other organisms from proliferating.3 Lactobacilli predominate in healthy, normal vaginal flora, accounting for 70% to 90% of the microbiome. When this microbiome becomes disrupted, a biofilm infection, primarily consisting of Gardnerella vaginalis, adhering to the vaginal epithelium can occur. This biofilm promotes the growth of other anaerobic bacteria, leading to the symptoms of BV and malodorous vaginal discharge. The prevalence of BV varies by the population studied, but it can range from 15% to 40%.3

First-line treatment options include 0.75% metronidazole gel applied vaginally for five nights, clindamycin cream 2% applied vaginally for seven nights, or 500 mg of oral metronidazole taken twice a day for seven days. Recurrence rates are high, and the optimal strategy to manage recurrence is unknown. One common regimen to treat recurrence is 0.75% metronidazole gel applied twice weekly for four to six months after induction treatment.4 However, more therapeutic options are needed, and I applaud the authors for taking on this issue. Despite BV’s prevalence, it is not a well-funded disease.

The authors of this study showed a modest reduction in BV recurrence with the use of a novel product, Lactin-V, at 12 weeks and extending through week 24. The use of Lactin-V after treatment with 0.75% metronidazole gel is an attempt to repopulate the vagina with healthy lactobacilli. This makes biologic sense, more so than consuming probiotics orally, and the treatment was well tolerated. Presumably, the authors will continue to study this product in a phase 3 clinical trial and are aiming for U.S. Food and Drug Administration approval. For now, the product is not available commercially.

Nevertheless, besides the burden of BV on the individual patient, the disease is important because it increases the acquisition of other STIs and has been associated with an increased risk of preterm birth, endometritis after delivery or abortion, pelvic inflammatory disease, and infection after hysterectomy.3 Although a 15% difference in recurrence rates is not drastic, women may be willing to use a vaginal product with minimal side effects to attempt to decrease their chance of recurrence. It is possible that different doses or lactobacilli products may have a different effect. It is hoped that exploration in this area will continue.

REFERENCES

  1. Bradshaw CS, Morton AN, Hocking J, et al. 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;193:1478-1486.
  2. Hemmerling A, Harrison W, Schroeder A, et al. Phase 1 dose-ranging safety trial of Lactobacillus crispatus CTV-05 for the prevention of bacterial vaginosis. Sex Transm Dis 2009;36:564-569.
  3. Paavonen J, Brunham RC. Bacterial vaginosis and desquamative inflammatory vaginitis. N Engl J Med 2018;379:2246-2254.
  4. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR Recomm Rep 2015;64:1-137.