Reviewer’s report
Title: 
Intravaginal lactic acid gel versus oral metronidazole for treating women
with recurrent bacterial vaginosis: the VITA randomised controlled trial
Version: 
0 
Date: 
19 Sep 2022
Reviewer's report:
The VITA study was a randomised controlled open-label pragmatic trial which
aimed to determine if treating women with BV with a lactic acid gel for 7 nights
was superior to oral metronidazole. The authors highlight that in the era of
promoting antimicrobial stewardship and a reluctance by patients to take
antibiotics, we need alternative treatments for BV, a highly refractory infection
with limited treatment options. Patients were randomised to either 7 days of first-
line standard of care treatment with metronidazole (400mg bd) or a lactic acid
gel used for 7 days intravaginally. The primary outcome was self-report of
resolution of symptoms within 2 weeks of diagnosis. Secondary outcomes
included adherence, microbiological resolution of BV within 2 weeks, time to
first recurrence of symptoms, number of recurrences and repeat treatments over
6 months, and side effects. The authors also conducted a sensitivity analysis
which limited the resolution of symptoms data to only women with confirmed
BV by microscopy at enrolment. The trial was stopped due to futility, but the
results are presented based on the 518 randomised participants.
The study found that the proportion of women who self-reported BV symptoms
within 2 weeks of diagnosis was higher for those using the lactic acid gel vs
metronidazole (47% vs 70%). However, in a subset of women who completed
follow up, the proportion of women with BV recurrence within 6 months was
similar between both treatment arms (70-71%). Women treated with
metronidazole reported more side-effects.
The authors have acknowledged many of the limitations of their trial including
the higher than anticipated number of participants who were lost to follow up
and differing lactic acid products used. 
The paper is well-written according to CONSORT guidelines, and the findings
are in line with the aims of the study and methods used. I have provided some
comments for the authors' consideration.
1) The use of the self-report of symptom resolution for the primary outcome was
pragmatic and based on how women present to clinics in the "real-world".
However, it may be problematic because women may confuse their vaginal
discharge and have candida rather than BV following BV therapy (especially if
antibiotics are used). The authors included a microbiological resolution of BV
endpoint at 2 weeks, however the sample size was very limited. Despite the
smaller sample size, there was a slight increase in the participants who reported
symptom resolution (77% vs 70%). The use of self-report as well as the limited
microbiological confirmation analysis may have resulted in an over estimation of
BV recurrence within 6 months generally, but especially in the metronidazole
arm. The absence of clinical examination or further microscopy following
enrolment should be considered as a limitation of the study design. 
2) Please consider using confidence intervals, especially when presenting the
proportion who experienced resolution of symptoms or recurrence of symptoms.
3) Line 48 of the results reports on the time to resolution of symptoms, however
the participants who were included in the analysis was unlear as written in the
text. For example, were those who were LTFU included? Please refer to the table
and expand what uncensored data means in text.
4) Line 270 states that the number of BV treatment courses was similar between
groups. However, it is unclear as to what the treatments that participants used
were. Please consider including additional data.
5) One of the biggest limitations, as acknowledged in line 297 in the Discussion,
was the reduced sample size. Although the authors state that the participants who
provided recurrence data were similar with respect to baseline characteristics to
those who did (lines 256/257 of results), it would be important to acknowledge
that there may be other key differences in the women who were LTFU and those
who were not. Could it be possible that women who were LTFU may have
experienced a higher rate of symptom resolution and therefore be less likely to
respond? This data may have provided a higher confidence estimate around the
two recurrence rates.
6) Could the authors expand on what other factors could underly the high rate of
self-reported recurrence in both treatment arms? In the introduction, the authors
list some of the key mechanisms responsible for the high recurrence rates (i.e.
lines 84-87), however further analysis of these are not included in the study or
discussion. For example, did the two arms differ with respect to ongoing
exposure to a sexual partner? Were any of the women using an IUD, which has
been demonstrated to be associated with recurrence in prior studies? Could the
authors also stratify the data by exposure to a hormonal contraceptive? Studies
have also shown that oestrogen- and progesterone containing contraceptives may
be protective against recurrence.
7) Line 326 states that caution is required interpreting the limited 6-month data.
The authors might also want to include that there was no clinical or
microbiological assessment of BV recurrence at this time point as a limitation.
Further, as noted above, could it be that women were not able to distinguish
between a BV discharge and other vaginal discharges? As the results were not
clinically confirmed, the results should be considered in that context.
8) In Line 330 the authors discuss the use of self-report of resolution of
symptoms (which was also assess microbiologically for a subset) as the primary
outcome to maximise the trial's relevance. The authors also state that
microbiological evidence can be present without symptoms and therefore make
interpretation difficult. However, several studies have shown that women with
microbiological evidence of BV or a vaginal microbiome classified as diverse
can still be affected by adverse obstetric and gynaecologic sequelae. It has been
hypothesised that in some settings vaginal dysbiosis, regardless of symptom
presentation, may be clinically relevant. Again, the lack of microbiological or
clinical confirmation may be expanded on as a limitation of the trial findings,
and the importance of confirmation of symptom resolution may be necessary in
some settings.
9) Clearly, further data regarding the effectiveness of lactic acid gels, and
potentially their use as an adjunct rather than sole therapy for BV are required. In
Line 368 the authors state why the two brands of lactic acid gels used were
equivalent and therefore equally effective. However, this data may be
misleading. In the review that the authors cite, there are several other
characteristics of lactic acid products that are listed that need to be considered
when evaluating lactic acid as a potential therapeutic. For example, the effective
concentration that is released, the isomer or isomer ratio and the osmolality of
the product. More rigorous clinical trials are needed.
10) The authors provide an interpretation of their trial and state that the findings
may help patients and clinicians make informed choices about therapy. The 2019
US Food and Drug Administration guidelines for developing BV treatments
recommends that clinical cure be defined as the absence of 3 Amsel criteria,
specifically resolution of vaginal discharge, a negative whiff test and clue cells
<20% per high-power field on wet mount. In the absence of a
clinical/microbiological assessment, it is important that the interpretation is
tempered and acknowledges that the lack of clinical assessment in the VITA
study may have resulted in an over-or under-estimation of true rates of
recurrence. This is important because although some women may prefer
intravaginal lactic acid therapy, without more data on its effectiveness it may put
women at risk of further downstream obstetric and gynaecologic sequalae.
Additional minor comments
11) Some of the sentences would benefit from being shortened or the use of
more punctuation (e.g. lines 99, 115, 242)
12) Please consider including references in your last introduction paragraph
when describing the expected effects of lactic acid.
13) Please clarify in text that the primary outcome was within 2 weeks of
enrolment/diagnosis.
14) Table 1 - do you have data on IUD use?
15) The arrows in the flow chart need fixing
16) Line 653 appears to have text missing (footnote to flowchart)
17) Table S2 - consider including confidence intervals
18) The value of the censored times in Table S2 is unclear
19) The x axis labels in Figure S1 are incorrectly aligned.
20) Consider including 95% confidence intervals in Figure S2 Kaplan Meier plot
- also the data at 14 days (2 weeks) seems incorrect given that BV recurrence
was 30% in the metronidazole arm but 53% in the lactic acid arm? 
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Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes