In the past, people tended to visit a doctor only when they experienced noticeable symptom or discomfort. This approach led to a limited number of women being diagnosed with aBV. As a result, most studies focused on women with sBV32, and research on aBV was relatively scarce33. However, in recent years, as living standards have improved, an increasing number of women who do not exhibit any symptoms have started seeking medical examinations. This shift has allowed for the detection of many women with aBV who would have otherwise gone undiagnosed. Consequently, there is a growing demand for reliable research findings regarding the management and treatment of aBV. Unlike previous studies12,25,34,35,36,37,38,39,40, we conducted this prospective, large-scale, multicenter, randomized controlled trial involving 716 Chinese women with aBV who were at general risk to compare the efficacy of two therapeutic options, and the result showed that probiotics had a comparable therapeutic cure rate to Metronidazole, but a significantly lower rate of recurrence when compared to Metronidazole (Table 2).
The primary outcome
The first randomized, double-blind, placebo-controlled trial compared the efficacy of metronidazole gel with placebo for the treatment of aBV was published in 2000 by Schwebke32, and the result showed an improvement in efficacy in metronidazole group compared to the placebo group. However, the difference between the two group was not statistically significant. Another study published in 2007 aimed to investigate whether treatment of aBV with intravaginal metronidazole gel could reduce the incidence of sexually transmitted diseases STDs, and the results demonstrated that prophylactic treatment of aBV with metronidazole gel led to a significantly lower incidence of chlamydia cases compared to the observation group38. A placebo-controlled randomized clinical trial investigated the effects of administering edible vitamin D on the cure rate of aBV in women with vitamin D deficiency. And according to the result, the administration of edible vitamin D was found to significantly increase the cure rate of aBV41. Since participants in the above studies were selected from special populations, such as women from STD clinics, or women with vitamin D deficiency, so the results may not be generalizable to general women42.
In our study, volunteers were selected from a general population, and a large sample size, long-term follow-up, and randomized control group were used to provide valuable insights into the management of aBV that can be applicable to a broader range of individuals. Furthermore, standard treatment regimen, not placebo, was used as control group. While the difference in cure rates between the probiotics group and the Metronidazole group may not be statistically significant in our study, it is noteworthy that the probiotics group had higher cumulative cure rates. This suggests that probiotics may have a potential advantage over Metronidazole in terms of effectiveness for treating aBV.
Although the exact causes and mechanisms of BV are not clearly defined, there is a general consensus regarding its diagnostic criteria. It is currently believed that the essence of BV is a syndrome caused by a disruption in vaginal microbiota. This raises the possibility that BV is a result of multiple etiological factors leading to microbial imbalance, and its pathogenesis may also be diverse. As a specific type of BV, aBV may similarly have a range of potential causes and mechanisms. Investigating a syndrome resulting from different causes and pathophysiological mechanisms as a whole may lead to significant heterogeneity in results. This may be an important reason for the insignificance in cure rates between the two groups. Another reason for the insignificance in cure rates may be insufficiency of the sample size.
Different strains or species of Lactobacilluscan have distinct biological functions43, and the therapeutic response to interventions can vary among different populations with a particular disease44. As a result, selection of appropriate patient population who may significantly benefit from probiotics therapy may substantially improve the efficacy of cure rate. Indeed, the approach of selecting specific patient populations for targeted therapies has shown promising effects in various areas of medicine, including cancer treatment. The example about the use of Olaparib (a poly adenosine-diphosphate-ribose polymerase inhibitor, PARP-i) in women with familial and somatic BRCA1/2 mutations and high-grade serous ovarian cancer is a notable one. When women with high-grade serous ovarian cancer and BRCA1/2 mutations were selected as the patient population, Olaparib demonstrated significant improvements in progression-free survival (PFS)45. This means that these patients experienced a longer period without disease progression compared to those who did not receive Olaparib or who did not have the specific BRCA1/2 mutations. This personalized approach can lead to significant improvements in patient outcomes and represents a promising direction for future research and clinical practice.
Consequently, subgroup analyses were conducted based on various factors such as menstruation status (Postmenopausal or not), history of BV/STD, habits of vaginal douching, condom use only, and frequent travel to identify specific populations that may benefit greatly from probiotics in the context of aBV. The results of these subgroup analyses indicated that probiotics had a significant improvement in cure rates for women who used condoms or women who had frequent travel. This suggests that the efficacy of probiotics would be much higher than that of antibiotics if appropriate aBV patients with certain characteristics were properly selected. Further research and larger-scale studies are needed to validate these findings.
The present study also aimed to determine the optimal time point for evaluating the efficacy of a treatment for aBV. Since there is no global consensus on this issue, we analyzed the cure rates at different time points: the 1st week, the 1st two weeks, and the 1st four weeks after completion of treatments. Based on the findings of our study, in the Probiotic group, the cure rate during the 1st two weeks after treatment was significantly higher than that during the 1st week (p = 0.009), however, the difference in the cure rate between the 1st four weeks and the 1st two weeks was not statistically significant (p = 0.575). A similar trend was observed in the Metronidazole group, and there was no statistical significance. Consequently, 2 weeks after completing treatments may be the optimal time point for assessment of efficacy of aBV.
In previous studies, the use of Metronidazole to treat sBV resulted in a cure rate of 80–90% one month after treatment46, However, in the present study, the cure rate for aBV in the Metronidazole group was only 41% one month after completing therapy. The most principal reason for the disparity in cure rates between the two trials might be the difference in study populations. Another possible reason may be that aBV might have a different pathogenesis, response to antibiotic therapy, or complication rates from sBV, and aBV might be a milder form of infection than sBV19,33,47.
The second outcome
Although several treatment regimens have been found to be generally effective in curing bacterial vaginosis (BV), the main challenge in managing this condition has always been the high rate of recurrence48,49,50. As a subtype of BV, there is limited research specifically focused on the recurrence of aBV. In a study by Sobel51, participants with aBV were randomly assigned to receive either metronidazole vaginal gel or a placebo. The results demonstrated that at the end of the third month after completing the therapy, the recurrence rate was 25.5% in the metronidazole group and 59.1% in the placebo group. This indicates a significant difference in recurrence rates between the two groups (relative risk [RR] = 0.43, p = 0.001). It’s worth noting that the participants with aBV in the above research, were enrolled from another clinical trial, and these women, to some extent, represented high risk women.
In our study, participants with general risk were enrolled, and the results showed the recurrence rates in three months after completing therapy were 45.5% in the Metronidazole group and 11.8% in the Probiotics group, which suggested that probiotics, compared to metronidazole, was more effective in preventing recurrences. These findings indicate that local use of metronidazole gel may be more effective than oral metronidazole in preventing recurrences of aBV. To sum up, the recurrence rate of the probiotic group is indeed lower than that of the metronidazole group, regardless of whether the treatment is local (intravaginal) or oral medication, which suggests that probiotics may be more effective in preventing recurrences of aBV compared to metronidazole.
The mechanism of relapse of BV has been extensively studied, and several factors have been identified as potential contributors to BV recurrence. These factors include: failure to recolonize with Lactobacillus species, persistent colonization with BV-associated bacteria, formation and persistence of biofilms, and potential re-exposure to BV-associated bacteria from sexual partners, and reinfection48,49,52,53. Several strategies are currently used to reduce the recurrence of BV. They include use of probiotics (alone or in combination with antibiotics), acidifiers, and biofilm disruptors, and Suppressive therapy and periodic presumptive treatment (PPT)49, extended course of metronidazole treatment54.
However, as a special type of BV, it is currently unclear whether the mechanism of the recurrence of aBV differs from that of BV. This uncertainty arises from the lack of published research specifically investigating the recurrence mechanisms of aBV55. Therefore, it remains to be determined through clinical trials whether the strategies employed to reduce BV recurrence would also be effective in preventing the recurrence of aBV, and further research is needed to shed light on the recurrence mechanisms and evaluate the efficacy of preventive strategies for aBV49,55.
The use of probiotics, which supplement vaginal Lactobacillusinstead of targeting pathogenic bacteria, has emerged as a promising therapeutic approach for infectious diseases. Researches have indicated that probiotics can effectively reduce the recurrence rate of BV25,47,56,57,58,59. In the present study, probiotics were evaluated as a standalone treatment for aBV for the first time, and the results demonstrated that probiotics significantly decreased the cumulative recurrence rate of aBV. This finding highlights the potential of probiotics as a valuable strategy for preventing the recurrence of aBV.
Previous studies have indicated that a history of BV/STD, vaginal douching habits, and frequent travel are highly correlated with the recurrence of BV25,55,60. In light of these findings, subgroup analyses were conducted in the present study to identify potential risk factors that may influence the recurrence rate of aBV and identify populations that may benefit more from specific treatments. Surprisingly, the results showed that there was no significant difference in the recurrence rates of aBV between the Probiotics and Metronidazole treatment groups in the subgroups of individuals with a history of BV/STD, vaginal douching habits, and frequent travel. However, the menstrual status and condom use were found to significantly affect the recurrence rates. This suggests that women who exclusively use condoms may have a lower risk of aBV recurrence. These findings highlight the importance of considering condom use as potential factors in the prevention of aBV recurrence.
Metronidazole, as an antibiotic, functions by eliminating anaerobic bacteria, thereby restoring the balance of vaginal microbiota48. On the other hand, probiotics work through a different mechanism, which involves supplementing the vaginal lactobacillus to restore the microbial balance48. Although the mechanism of action of probiotics and metronidazole seems different, there is no significant difference in cure rates between the two groups. This finding indicated that multiple mechanisms may be involved in the pathogenesis of aBV, and investigation of aBV could be performed from various perspectives.
The present study had several limitations. Firstly, the follow-up time was relatively short. Enrolling an adequate number of women with aBV proved challenging. Asymptomatic BV is a type of vaginal infection that often goes unnoticed by individuals, particularly when no symptoms are present. Consequently, only a small proportion of women with aBV were willing to participate in the study. Requesting a longer follow-up period would have likely resulted in decreased compliance among participants.
Secondly, the effects of the sequential use of Metronidazole and probiotics were not investigated in this study. Since Metronidazole and probiotics work through different mechanisms in treating vaginal flora disorders, some scholars have proposed that combining the two therapies may have a superimposed effect59,61. It would be valuable for future research to explore the effects of sequential use of Metronidazole and probiotics to determine if there are any synergistic benefits when these treatments are used in combination. This could provide valuable insights into the optimal management of vaginal flora disorders.
Thirdly, in a study by Schwebke, treatment and prophylactic use of intravaginal metronidazole gel can result in significantly fewer cases of chlamydia, while the rate of cure and recurrence were not mentioned38. In the present study, cure rate and recurrence rate, rather than the potential harmful outcomes were the endpoint. As the number of cured individuals increases and the number of relapses decreases, is it possible to definitively state that all potentially harmful outcomes from aBV will disappear? This requires designing new research to explore in future studies.
In summary, the study provides evidence supporting the use of a 10-day course of intravaginal probiotic capsules as an effective treatment for aBV in Chinese women, with comparable cure rates to metronidazole and significantly lower recurrence rates. This finding positions probiotics as a promising therapeutic option for the management of aBV.
