Title: Prevalence of depression, syndemic factors and their impact on viral suppression among
female sex workers living with HIV in eThekwini, South Africa
Version: 4 Date: 02 Nov 2022
Reviewer's report:
BMC Women’s Health Review
Thank you for the opportunity to review the manuscript entitled “Prevalence of depression,
syndemic factors and their impact on viral suppression among female sex workers living with
HIV in eThekwini, South Africa”. The authorship team is well-balanced and comprised of
many authors affiliated with South African institutions, the country in which this work was
completed. The manuscript presents an analysis of several syndemic problems among FSW,
including depression, substance use, and violence. The authors demonstrate factors associated
with screening positive for depression, and associations between some syndemic problems and
viral load. The manuscript could provide an interesting contribution to the literature on the
syndemic effects of multiple comorbidities on HIV outcomes among FSW in SA, which is
of public health significance. However, enthusiasm about the manuscript’s contribution was
diminished due to a number of factors presented below. The overarching main issue is that the
analytic approach and conceptualization of syndemic problems is convoluted and several issues
were identified that detract from these analyses.
Major Issues:
1. Overall, given that syndemic factors are the focus of this manuscript, it would be helpful to
expand on the background of the concept of syndemic theory and the research on syndemic
factors among people with HIV. It would also be helpful to move this earlier review of extant
literature earlier in the Introduction to better orient the reader to the overarching theory utilized
in this study. Some of the main papers on syndemic theory (e.g., Singer 1994, Singer 1996) are
missed in this review, and the same paper (though important) is referenced for the discussion
of the major theory in this manuscript. I would encourage the authors to expand upon their
review of syndemic theory, as well as to actually inform the readers what the effects of syndemic
problems are on HIV outcomes. Currently, the authors state that this research exists, but do not
include review of the actual findings of the research.
2. Relatedly, there are issues with the conceptualization of syndemics, as currently framed, in
the manuscript. The authors focus on the SAVA syndemic, but also include depression. The
SAVA syndemic is the examination of two common problems (substance use and violence)
that are syndemic with HIV. When including depression as another syndemic problem, the
question is then raised as to why the SAVA syndemic is used to frame the study rather than just
examining the syndemic effects of depression, substance use, and violence on HIV outcomes
among FSWs with HIV in South Africa. In other words, if the authors are departing from
SAVA, which is a strength of the manuscript (to include depression), why frame their work only
within the SAVA syndemic. Another point within this, is the framing of the SAVA syndemic
as structural problems. Extant literature examining structural syndemic problems has focused
on incarceration, food insecurity, poverty, structural barriers to care, housing instability, etc.—
factors that are not changeable at the individual level per se. It is not clear how substance use
and violence are structural problems. These appear to be individual-level factors in the realm
of psychosocial syndemic problems. This is further highlighted in the lack of mention of any
structural factors in Figure 1, the guiding theoretical framework. Also, stigma is reported on
in the results but not at all discussed in the Introduction. Could stigma be conceptualized as a
psychosocial syndemic factor?
3. Line 121: The stress-diathesis conceptual model is mentioned as the guide for analyses in the
present study. However, no citation is provided for this model in text (only in the figure). And,
importantly, this is the first mention of the model in the manuscript. If this model was used to
guide analyses, readers should be oriented to the model in the Introduction, extant research using
this model in a relevant context should be summarized and presented, and this model should be
discussed in relation to syndemic theory.
4. The decision to use a cut-off 50 copies/mL for unsuppressed/suppressed viral load should
be justified. In much extant literature, 200, 400 or 1,000 are used as cutoffs of unsuppressed.
50 may be utilized as undetectable/detectable viral load, but it depends on the test that is used.
Was it the case that all viral load tests utilized had a cutoff of 50 and this analysis represents
undetectable/detectable viral load, or were these tests sensitive to 20 copies but 50 was used as
a cutoff? If so, why?
5. The decision to examine a ‘joint effect’ of depression (one syndemic problem) with substance
use and violence (two syndemic problems being modeled as one) is confusing. In table 4, the
authors present a multivariate regression model comparing depression alone, SAVA alone, and
depression and SAVA together with no depression and no SAVA as the referent group. Is the
depression and SAVA syndemic variable here (PR=1.15) an interaction term? If this is not
an interaction term, then this method of analysis introduces the problem of multicollinearity.
If this is an interaction term, please clearly label it as such. The inclusion of what appears to
be an interaction effect is a strength of this manuscript (see https://www.thelancet.com/pdfs/
journals/lancet/PIIS0140-6736(17)30403-8.pdf). However, it is statistically problematic to take
an index of 2 problems and interact it with a third problem. Perhaps it would make more analytic
sense to split these into three terms: violence, substance use, depression, and model them that
way. Taking this further, one could also argue that there are in fact 5 syndemic problems here:
depression, sexual violence, physical violence, alcohol use, and illicit substance use. Or 7 if
you include stigma and unstable housing (a structural problem). The decision to just look at
SAVA and depression, when viewed in this way, is therefore somewhat confusing and could be
better justified or revisited. There are two main ways syndemic problems have been analyzed
in the extant literature: additive effects and interaction effects. The analysis at present appears
to do both of these only part of the way. It would be helpful to reconsider the analysis plan
and consider what are the additive effects of these 3 (or 5, or 7) syndemic problems on viral
load? And, what are the interactive effects of depression with substance use and depression with
violence on viral load?
Minor Issues:
-Abstract
1. Line 6: It’s not entirely accurate to state that syndemic theory is merely an aggregation of
multiple risk factors. It would be helpful to define syndemic theory better here.
2. Line 13: Is depression not considered a syndemic factor? Are you only conceptualizing
structural problems as syndemics? This is unclear to the reader in the abstract; please clarify.
3. Line 19: When discussing univariate associations in the beginning of the Abstract’s results,
it would be helpful to indicate that p-values were significant (e.g., (all p’s < .05).
4. Line 24: What is meant by depression in the absence of SAVA syndemic factors? Was this
an analysis among people with only depression and none of the SAVA syndemic factors?
5. Line 25: Authors report aPRs in the abstract without mentioning covariates. It would improve
readability to include mention of the covariates, as space allows.
6. Line 25: The term non-viral suppression is confusing. It appears the authors mean
unsuppressed viral load, which is a more standard and widely accepted term (please address
elsewhere throughout the manuscript as well).
7. Line 35-37: The conclusion within the abstract that training for non-mental health providers
(or perhaps better said as primary care / medical providers) and better referral pathways are
needed to address unmet mental health needs is not well-supported by the evidence in the
abstract. It’s not clear that screening and referrals are the source of the treatment gap here.
Perhaps interventions are needed? The screening and referral pathway raises the question:
referral to what? This should be further discussed or a more direct conclusion should be made
that is supported by these data as presented.
-Introduction
1. Line 68: Resistance to ART can occur at any stage of treatment, not only first-line. It would
likely also be helpful to include background on why resistance is a major concern in LIMCs
(i.e., only a limited number of ART regimens are available in LMICs).
2. Line 73: Please avoid the term vulnerability to HIV as it is potentially stigmatizing. The
NIH Style Guide (https://www.nih.gov/nih-style-guide/person-first-destigmatizing-language)
suggests alternative terms.
3. The topic sentence on lines 73-74 is not very clearly written.
4. Line 91-92: It is confusing to state that the study assesses depression and the syndemic of
depression…
-Method
1. Line 127-153: It would be clearer to the reader to present the measures in separate paragraphs.
As is, this paragraph is extremely dense and difficult to read. In general, why were splits made at
these points (e.g., R1,500 and R3,000, cohabiting vs. not cohabiting vs. single, and the physical
violence cutoffs). These should be better explained and rationalized. Of particular interest, why
is experiencing physical violence 4 times in the past 6 months substantially different than 5
times? Also, no mention is made of the severity of the violence experienced.
2. Line 133:134: If AIDS is not specifically discussed from a clinical perspective, HIV is a
sufficient term. More importantly, how is time since HIV diagnosis a factor that relates to risk
for worse mental health outcomes? And, what are the three categories?
3. Line 140-143: Was a continuous measure of substance use available? I also question the
inclusion of alcohol use and substance use together. The syndemic framework would allow
splitting of both of these into their own distinct syndemic factors.
4. Line 145: handling of missing data was discussed for social support but not for other measures
included.
5. Line 148: Why was sex work modeled as binary and split at 5 years?
6. Line 149-151: How was stigma scored? No information is provided on the response options
and scoring, or the measure from where these items are drawn.
7. Line 167: what specifically is meant by the majority of modules when referring to
missingness?
8. Line 173: It may be helpful to specify the upstream factors referenced here.
9. Line 174-175: It is confusing to state that factors that were significantly associated at the
p<.01 level, as .05 is the generally accepted cutoff. Perhaps reword to say that factors showing
evidence of a statistical trend at p<.01.
10. Line 179: What is meant by jointly assessing the relationships between depression and SAVA
syndemic factors? Was this done via an additive approach or were interaction effects examined,
this is a bit unclear. When reporting research on syndemic problems, it is important to clearly
present how scores on syndemic indicators were calculated. Was it the case that having substance
use (either alcohol or substances) and also having violence (either sexual or physical) was a 1
and having one or none of these was a 0? Another way to examine these data would be to split
alcohol use and substance use and sexual and physical violence and calculate a range 0-4.
-Results
1. Line 223-224: The authors state that the AUDIT-C was missing for 390 participants due to
survey error. This should be discussed in the data analysis plan as well. How was this handled
with respect to missingness?
2. Line 249-250: Substance use and violence are reported as being associated a 13% increase
but the aPR is 1.15, please clarify.
3. Line 253-255: The antagonistic effect is difficult to interpret. Is this an interaction term? If
so, please call it as such. Using the term joint effects here and the term ‘jointly experiencing
depression and SAVA’ is confusing if these are different. If this is indeed an interaction, as
it appears to be given the modification of effect, then it would be helpful to provide a figure
plotting this interaction effect because otherwise it is difficult to interpret this finding.
4. In some adjusted regressions, age is included as a covariate and modeled as age+age2 and in
another as age3. Why were these modeled differently?
-Discussion
1. Line 270: Why compare prevalence of depression among FSW with HIV in this study only
to the total adult population of SA? Would a better comparison be people with HIV in SA?
33% is consistent with extant literature of PWH in SA. I would also suggest not leading off the
Discussion with this review of prevalence of depression. I do not think that is the main finding
of this study, and it would be helpful to the reader to begin by highlighting your main findings.
2. Line 295-297: The statement that the findings support a “dose-response relationship between
the extent of recent physical violence and depression” is not accurate. First, as analyzed here,
because the variable was made into a categorical variable and dummy coded, the significant
finding is that more than 5 recent experiences of violence was associated with higher likelihood
of depression compared to no recent violence. This is not a dose-response relationship, but
states a lot of violence is worse than no violence with respect to depression. It also is somewhat
awkward to use the term dose-response relationship when discussing violence and depression.
3. Line 299: please use person-centered language – FSW with HIV. Also line 301.
4. Line 315-317: why do the authors merely hypothesize that homelessness and stigma attenuate
the findings they expected to see – why not actually examine this question statistically since the
data are available?
5. Line 326-332: in a cross-sectional study, one cannot imply causality or temporality (as you
state on line 342 directly after this paragraph imply temporality). The PHQ-9 assesses the past
2 weeks and from the data presented, it is not clear whether depression precedes these other
factors or vice versa, or whether these data imply that we can prevent depression. A takeaway
that is supported by these data is that these things are associated and when one is identified,
depression should also be screened and treated. The second half of this paragraph makes much
more sense as a focus – get the treatments that work to those who need them most and where
they would have the most impact.
6. Line 342 paragraph on limitation: The massive amount of missing data on the AUDIT ought
to be discussed here.
7. Line 358: it is a little surprising to discuss peer case managers in the Conclusion paragraph
when they were not at all a focus of this analysis.
8. Line 352 paragraph: The Conclusion should be improved. Nowhere in this paragraph does the
term syndemic appear, when that was the main focus of the manuscript. Similarly, the stress-
diathesis model is not mentioned at all. The conclusion should focus on this manuscript rather
than future directions (which could be a separate paragraph in the Discussion more broadly).
-Figures
1. It is unclear how figure 1 incorporates syndemic theory.
2. Why is only depression mentioned as a mental health outcome and not substance use?
Substance use is not included in the figure at all, though seems to be an important syndemic
factor in this manuscript.
-Table A1
1. This table could be shortened significantly though reformatting.