4.1. Summary of findings
With regard to astodrimer gel versus placebo for treatment of bacterial vaginosis, we included three studies comprising four independent RCTs with a total of 1165 patients (614 and 551 patients received astodrimer gel and placebo, respectively). Results obtained from this systematic review and meta-analysis are clinically significant and all the included RCTs are of high quality and low risk of bias.
Astodrimer gel was significantly superior to placebo for all pooled efficacy outcomes, including clinical cure rate, Nugent cure rate, patient self-reported absence of vaginal odor/discharge, resolution of Amsel criteria and percentage of patients who received rescue therapy. These efficacy outcomes consistently favored, without heterogeneity, astodrimer gel over placebo at subgroup analyses at 9-12 and 21-30 days. In 2008, a workshop was conducted by bacterial vaginosis experts from United States National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) and Department of Health and Human Services (DHHS).30 The workshop recommended timeframes of 7-10 and 35-40 days (posttreatment commencement) for assessment of ‘early’ and ‘late’ treatment efficacy, respectively. For the included studies in this review, the timeframes 9-12 and 21-30 days are relatively close to the ones recommended by the workshop.30 Nonetheless, long-term follow-up periods are needed to concretely conclude the efficacy of astodrimer gel in sustaining therapeutic cure and preventing relapse.
The pooled clinical cure rate for bacterial vaginosis at 9-12 days of 59% is relatively analogous to an experimental anti-infective drug TOL-463 (50%)31 and standard of care antibiotics, such as metronidazole 1.3% gel (46%)32 and 2-gram secnidazole (58%).33 Interestingly, the pooled clinical cure rate at 21-30 days was reduced by almost half (30%), suggesting that recurrence of bacterial vaginosis took place. However, this proportion is largely equivalent to metronidazole 0.75% gel administered for five days (29%) in patients with bacterial vaginosis.34
Clinically, bacterial vaginosis is characterized by distressing thin white vaginal discharge and fish-like odor.35 Both symptoms negatively impact infected women at multiple levels, including physically, sexually, emotionally and socially.36Thus, the qualitative and speed of resolution of these symptoms are critically important. Chavoustie et al.22 and Waldbaum et al.23 demonstrated that more than half the of patients who received astodrimer 1% gel had resolution of vaginal odor within as early as one day post-initiation of treatment. This finding contrasts satisfactorily when compared to the relatively longer median time to resolution of vaginal odor of two and three days for metronidazole 1.3% and 0.75% gel, respectively.34
Waldbaum et al.23 used three different concentrations of astodrimer gel (0.5%, 1%, and 3%). Interestingly, the mid-dose 1% was associated with the best outcomes, in terms of efficacy and safety. This observation is in agreement with the postulation that treatment of bacterial vaginosis with astodrimer gel rectifies the dysbiotic vaginal environment and reestablishes equilibrium of the normal vaginal microbiota.23 Thus, higher doses of astodrimer gel may negatively exhibit a suppressing impact on normal vaginal bacterial flora, namely lactobacilli. On the other hand, lower doses of astodrimer gel may be not adequate enough to exert an antimicrobial effect. This phenomenon is noted with rifaximin whereby a mid-range dose is associated with the maximum cure proportion in patients with bacterial vaginosis.37 Based on the efficacy and safety of astodrimer 1% gel, one phase III38 and two phase II clinical trials were carried out.22 Due to the small number of included studies, we could not perform meta-regression for the different doses.
With respect to safety profile, astodrimer gel demonstrated equal tolerability to placebo for all pooled safety outcomes, expect for vulvovaginal candidiasis and treatment-related vulvovaginal candidiasis. The pooled proportion of drug-related vulvovaginal candidiasis was only 4.9% (n=31/639) and this proportion compares favorably when contrasted to oral 2-gram secnidazole (13.6%).33 This overall safety of astodrimer gel can be ascribed to its favorable pharmacokinetics, in terms of topical application and decreased systemic absorption20, 21 when compared to conventional antibiotics.