January 30th, 2021
Dear Prof. Joerg Heber, Dr. Endi Lanza Galvão, and respected reviewers,
Thank you for the comments from the editor and reviewers on our manuscript entitled
“The effect of human immunodeficiency virus infection on adverse events during treatment
of drug-resistant tuberculosis: a systematic review and meta-analysis” by Gilbert
Lazarus, Kevin Tjoa, Anthony William Brian Iskandar, Melva Louisa, Evans L. Sagwa,
Nesri Padayatchi, Vivian Soetikno (manuscript ID: PONE-D-20-36024). We really appreciate
the constructive and detailed feedback on our manuscript. We have revised the current
submitted manuscript based on the reviewers’ feedback. Please find the details of
revisions attached within the 'Response to Reviewers' file in the submission system.
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Responses to In-house Editor
1. The Introduction section did not provide sufficient detail about the rationale
for the review in the context of what is already known.
Thank you very much for the feedback. Regarding the critique to provide more details
on the rationale for conducting the systematic review, we have added an additional
explanation illustrating our reasoning on the potential interplay between HIV infection
and drug-resistant tuberculosis (DR-TB) in the development of adverse events (AEs).
"In light of this, studies have also shown that human immunodeficiency virus (HIV)
infection is also prevalent among DR-TB patients particularly in low- and middle-income
countries[1,2]. Several factors including HIV-induced immunosuppression, viral-mediated
toxicity, and the possibilities of additional drug-drug interactions suggest a potential
interplay between these two major infectious diseases in affecting treatment outcomes.[3,4]
This necessitates the importance of comprehending the effect of HIV infection on the
development of AEs during DR-TB treatment to help clinicians anticipate and promptly
treat these patients, hence preventing further deterioration of treatment adherence
and outcomes. As the current evidence remains equivocal[2,5], this systematic review
aims to thoroughly investigate the effect of HIV infection on AE occurrence during
DR-TB treatment." [see page 4 line 64-73]
In short, we presumed that HIV infection, which may induce immunosuppression and toxicity
to the host, may increase the likelihood of developing AEs in the treatment of DR-TB.
Furthermore, as HIV-infected patients receive antiretroviral (ARV) treatments, these
agents may induce drug-drug interactions either with the other ARV drugs or with anti-DR-TB
drugs. Lastly, as the current evidence on the effect of HIV infection on the development
of AEs in DR-TB patients remain equivocal[2,5], we decided to perform a systematic
review to investigate this matter.
References:
1. Singh A, Prasad R, Balasubramanian V, Gupta N. Drug-resistant tuberculosis and
HIV infection: current perspectives. HIV/AIDS (Auckland). 2020;12: 9–31. doi:10.2147/HIV.S193059
2. Schnippel K, Firnhaber C, Berhanu R, Page-Shipp L, Sinanovic E. Adverse drug reactions
during drug-resistant TB treatment in high HIV prevalence settings: A systematic review
and meta-analysis. J Antimicrob Chemother. 2017;72: 1871–1879. doi:10.1093/jac/dkx107
3. Naif HM. Pathogenesis of HIV infection. Infect Dis Rep. 2013;5: 26–30. doi:10.4081/idr.2013.s1.e6
4. Montessori V, Press N, Harris M, Akagi L, Montaner JSG. Adverse effects of antiretroviral
therapy for HIV infection. CMAJ. Canadian Medical Association; 2004. pp. 229–238.
5. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant
tuberculosis. Geneva: World Health Organization; 2014.
2. An explicit statement of the question addressed concerning participants, exposures,
comparisons, outcomes, and study design (PECOS) is required in the main document.
Thank you very much for the feedback. Regarding the critique to provide the PECOS
of our study, we have added the PECOS in our eligibility criteria as below:
"Studies were included in this review if they met the following inclusion criteria:
(1) design, interventional or observational studies including but not limited to cohort,
case-control, and cross-sectional studies; (2) studies enrolling both HIV-infected
and HIV-uninfected DR-TB patients receiving second line anti-TB drugs; and (3) studies
reporting AEs based on HIV seropositivity." [see page 5 line 96-100]
In this regard, the PECOS of our study is: (1) participants, DR-TB patients; (2) exposure,
HIV infection; (3) comparison, no HIV infection; (4) outcome: AE occurrence; and (4)
study design, interventional or observational studies. Furthermore, we have also added
the detailed PICOTS (population, index prognostic factor, comparison prognostic factor,
outcome, timing, and setting) of our study in Supplementary Table S2. We believe that
the PICOTS framework is appropriate for prognostic reviews as the timing and setting
of the prognostic factor studied (i.e. HIV infection) or the outcomes may define the
focus of our review.[1]
Reference:
Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, et al. A guide to systematic
review and meta-analysis of prognostic factor studies. BMJ. 2019;364. doi:10.1136/bmj.k4597
3. The authors did not indicate if a review protocol exists and where it can be accessed.
Thank you very much for the feedback. We have added our protocol to the manuscript,
which was prospectively registered in PROSPERO on 5 July 2020.
"This review was conducted based on the guideline of systematic review of prognostic
factor studies guideline proposed by Riley et al.[1] and was reported according to
the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement[2].
A detailed protocol has been prospectively registered in PROSPERO (CRD42020185029[3]).
Deviations from the protocol are described in Supplementary Table S1." [see page 4-5
line 76-81]
In addition to citing our protocol, we have also specified the protocol in the PRISMA
checklist (see Supplementary Material_PRISMA checklist). Furthermore, we have also
added a supplementary table, listing all deviations made along with the explanations
(see Supplementary Table S1). Following a thorough review, we discovered that interventional
studies were not a criterion for exclusion, thus we decided to include the interventional
study in our systematic review. The details of the revision are illustrated in Figure
1. As there is only one interventional study, we decided to exclude the study from
the quantitative analysis (i.e., meta-analysis) and opted to analyze the study qualitatively.
Details of the study’s characteristics and outcomes can be seen on Supplementary Table
S6 and S9, respectively, while the result of risk of bias assessment of the aforementioned
study are illustrated in Supplementary Figure S1.
4. There is a contradiction in the Methods section: firstly, they reported that "No
language restrictions were applied" and then they stated that a criterion for exclusion
was "articles not in English".
Thank you very much for the feedback. Regarding the critique that there is a contradiction
in the methods section concerning the eligibility criteria, we intended to assess
whether language restrictions may affect our findings. Hence, we did not filter the
search results by language, but rather excluded the potentially eligible non-English
articles discovered during the search.
"Conversely, criteria for exclusion were: (1) non-original research, including qualitative
research, case studies, reports, or case series with <20 patients; (2) irretrievable
full-text articles; or (3) articles not in English." [see page 5-6 line 101-103]
The implementation of this criterion enabled us to assess the language bias arising
from the language limitation, which we deemed negligible considering the large number
of patients pooled in this systematic review and the fact that only three potentially
eligible non-English articles were excluded. Regardless of this, we have acknowledged
this as a limitation in the text as follows.
"Lastly, although language bias may arise from our eligibility criteria, our study
included a relatively large number of patients and only three non-English articles
were excluded, suggesting that any language bias may be negligible." [see page 19
line 356-359]
References:
1. Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, et al. A guide to
systematic review and meta-analysis of prognostic factor studies. BMJ. 2019;364. doi:10.1136/bmj.k4597
2. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting
items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6:
e1000097. doi:10.1371/journal.pmed.1000097
3. Lazarus G, Soetikno V, Iskandar A, Louisa M. The burden of human immunodeficiency
virus infections on adverse events occurrence in the treatment of drug-resistant tuberculosis:
a systematic review and meta-analysis. PROSPERO 2020. CRD42020185029. [cited 2021
Jan 19]. Available: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=185029
5. Authors should be aware that for cross-sectional studies, a commonly reported measure
of effect is the Odds Ratio (OR), but it is common for ORs to be wrongly interpreted
as Risk Ratios. In the present manuscript, the authors use relative risk for cross-sectional
studies. Thus, corrections are required.
Thank you very much for the feedback. We agree with the reviewer that the estimates
of cross-sectional studies should not be interpreted as relative risks (RRs), but
rather as odds ratios (ORs). In this study, there was only one cross-sectional study
(i.e. Sineke et al[1]). Although the study expressed their outcomes with relative
risks (RRs), we deemed that it is more appropriate to calculate the OR rather than
RR, especially considering that the study is a cross-sectional survey. Furthermore,
we obtained the outcome from binary data, thus enabling us to calculate the crude
OR.
However, we discovered that we inadvertently included the study in the analysis of
unadjusted outcomes (i.e. primary outcome in Supplementary Figure S2 and subgroup
analyses in Supplementary Figure S4). Hence, we decided to re-run the analysis with
the exclusion of Sineke et al[1]. In short, no significant differences were found
with the exclusion of Sineke et al[1], including the primary analysis (RR 1.18 [95%
CI: 1.05-1.32]; Supplementary Figure S2) and antiretroviral therapy subgroup (RR 1.21
[95% CI: 1.02-1.43]; Supplementary Figure S4). However, as there were initially only
two studies in the severe immunosuppression subgroup (CD4<50 and ≥50 cells/mm3), the
exclusion of Sineke et al[1] refrained us from performing a meta-analysis. Hence,
we decided to include the estimates in Supplementary Table S9 and qualitatively analyzed
the evidence.
Reference:
1. Sineke T, Evans D, Schnippel K, van Aswegen H, Berhanu R, Musakwa N, et al. The
impact of adverse events on health-related quality of life among patients receiving
treatment for drug-resistant tuberculosis in Johannesburg, South Africa. Health Qual
Life Outcomes 2019;17:94. https://doi.org/10.1186/s12955-019-1155-4.
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Responses to Reviewer 1
1. While HIV is understood to be a risk factor for aggravating some of the adverse
events seen during the MDR-TB treatment, it would have been good if the role of specific
regimen and drug-drug interactions in such patients was discussed. This becomes specifically
relevant in light of evolving recommendations for newer regimen for MDR-TB.
Thank you very much for the feedback. We agree with the reviewer that the role of
specific regimen and drug-drug interaction may provide essential information in determining
which DR-TB treatment regimen to use. However, as we did not intend to analyze patient-level
data, and as the treatment regimens used in each study intertwined with each other,
we were unable to analyze specific drug-drug interaction. In light of this, we discussed
for a way to shed light on possible roles of specific regimen and drug-drug interaction
and managed to perform a subgroup analysis based on DR-TB treatment regimen, dichotomizing
studies into studies utilizing injectable agents (i.e. kanamycin, amikacin, and capreomycin)
and all-oral regimens (i.e. using bedaquiline, pretomanid, and linezolid). We discovered
that injectable-containing DR-TB regimens was associated with a more apparent risk
of developing adverse event (RR 1.11 [95% CI: 1.01-1.21] vs all-oral regimens: RR
1.61 [95% CI: 0.92-2.84]; Table 1), although it is worth noting that further research
are required to confirm our findings as there is currently limited evidence on studies
utilizing all-oral DR-TB regimens. We have also added a discussion recommending the
transition of injectable-containing DR-TB regimens to all-oral treatment regimens.
"In this regard, all-oral treatment regimens become the preferred option for most
DR-TB patients.[1] This is saliently true considering that our findings suggest that
injectable-containing DR-TB regimens may result in a more apparent risk of developing
AE, although further studies are required to confirm these premises. Furthermore,
all-oral DR-TB regimens have shown to be more cost-effective with less logistical
challenges[2,3], thus rendering them more worthwhile to be implemented especially
in resource-limited settings. All in all, these necessitates the widespread implementation
of oral-only regimens as the mainstay of DR-TB treatment." [see page 17 line 309-316]
In addition, we have also shed light on the potential interplay between anti-DR-TB
agents and ARV drugs in the development of treatment-related AE as proven by the increased
risk of developing AE in HIV/DR-TB patients receiving ART (RR 1.21 [95% CI: 1.02-1.43]
vs not on ART: RR 1.24 [95% CI: 0.90-1.69]; Table 1). Although we were unable to investigate
specific drug-drug interaction between these drugs, we have discussed some potential
drugs which have documented interactions.
"In addition, we also observed that HIV/DR-TB patients receiving concomitant ART were
more vulnerable to AEs. Interestingly, we found that the extent of immunosuppression
was not associated with AE occurrence, implying that the observed risk was presumably
driven by drug-drug interactions rather than HIV-mediated immunosuppression. However,
we were unable to explore the suspected drug-drug interactions as patient-level data
were not available. Some anti-DR-TB drugs have been reported to induce adverse interactions
when concomitantly administered with ART, including bedaquiline, delamanid, and moxifloxacin,
which had documented interactions with several protease inhibitors (e.g. lopinavir/ritonavir)
and non-nucleoside reverse transcriptase inhibitors (i.e. efavirenz and rilpivirine)[4],
thus potentially leading to multiple toxicities resulting in deleterious health consequences[5]."
[see page 16 line 290-299]
References:
1. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment 2019. Geneva: World Health Organization; 2019
2. Ionescu AM, Mpobela Agnarson A, Kambili C, Metz L, Kfoury J, Wang S, et al. Bedaquiline-
versus injectable-containing drug-resistant tuberculosis regimens: a cost-effectiveness
analysis. Expert Rev Pharmacoeconomics Outcomes Res 2018;18:677–89. https://doi.org/10.1080/14737167.2018.1507821.
3. Reuter A, Tisile P, Von Delft D, Cox H, Cox V, Ditiu L, et al. The devil we know:
is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc
Lung Dis. 2017;21:1114–26
4. HIV Drug Interactions. Anti-tuberculosis treatment selectors. Univ Liverpool 2019.
hiv-druginteractions.org/prescribing-resources (accessed October 11, 2020).
5. Mukonzo J, Aklillu E, Marconi V, Schinazi RF. Potential drug–drug interactions
between antiretroviral therapy and treatment regimens for multi-drug resistant tuberculosis:
Implications for HIV care of MDR-TB co-infected individuals. Int J Infect Dis 2019;83:98–101.
https://doi.org/10.1016/j.ijid.2019.04.009.
2. Overall 3 AEs are highlighted throughout the narrative – hearing loss, depression
and renal impairment. However, looking at table S9, there are several other adverse
events for which RR was greater than those for these adverse events. There is also
no mention of whether statistical significance of these associations was checked.
Hence, the reason for prioritizing the mention of just 3 adverse events needs to be
clarified.
Thank you very much for the feedback. Regarding the critique to provide reasons for
prioritizing 3 AEs instead of all AEs, we believe that out of all analyses for specific
AEs, only hearing loss, depression, and renal impairment yielded statistically significant
results (i.e. confidence interval [CI] does not cross the reference line). We utilized
CIs instead of p-values for point estimates as p-values may be misleading especially
when only small studies or sample sizes are included in the analysis. This is especially
true considering that p-values are usually interpreted according to a threshold (i.e.
0.05), which is arbitrary and may yield insufficient statistical power in some circumstances,
including in the setting of small meta-analyses[1]. Hence, we believe that CIs may
provide better statistical interpretation than p-values especially in the context
of meta-analyses.
Reference:
Schünemann HJ, Vist GE, Higgins JPT, Santesso N, Deeks JJ, Glasziou P, Akl EA, Guyatt
GH. Chapter 15: Interpreting results and drawing conclusions. In: Higgins JPT, Thomas
J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for
Systematic Reviews of Interventions version 6.1 (updated September 2020). Cochrane,
2020. Available from: www.training.cochrane.org/handbook
3. It may also be worth mentioning here that in Table 1 in the main narrative, where
meta-analysis and sub group analyses for the pooled adjusted effects on the association
between HIV co-infection and adverse events occurrence, is presented the RR for any
AE is more than 1 for HIV+ individuals while RR for serious AE is equivocal for HIV+
and HIV- individuals. However, the three commonly associated AEs, as above, are generally
considered serious AE (specifically hearing loss and renal impairment).
Thank you very much for the feedback. We agree with the reviewer that it is worth
discussing that although our findings indicate that HIV was independently associated
with AE occurrence in DR-TB patients, we also discovered that HIV was not associated
with an increased risk of serious AE. That being said, a majority of AEs encountered
in HIV/DR-TB patients are manageable and not life-threatening, thus further indicating
that antiretroviral treatment should not be deferred in such patients.
"Altogether, although we discovered that HIV co-infection was associated with an increased
risk of developing any AE in DR-TB patients, ART should not be needlessly deferred
in such patients. This is especially true considering that HIV co-infection was not
associated with an increased risk of serious AE occurrence. Rather, we encourage clinicians
to increase pharmacovigilance on HIV/DR-TB co-infected patients, especially in terms
of ototoxicity, nephrotoxicity, and depressive symptoms. Therefore, routine audiological,
laboratory (i.e. renal panel), and mental health assessments on such patients are
strongly recommended." [see page 18 line 331-334]
On the other hand, although hearing loss and renal impairment may be debilitating
and considered severe, we defined serious AE in this study according to the criteria
published by the World Health Organization, including AEs leading to treatment discontinuation,
requiring prolongation or initiation of hospitalization, requiring immediate interventions
to prevent permanent damage, or resulting in significant disabilities, congenital
abnormalities, or death[1]. We have also added the operational definition of serious
AE used in this study in the methods section.
"A serious AE was defined as an AE leading to treatment suspension, withdrawal or
discontinuation, requiring prolonged hospitalization or immediate interventions to
prevent permanent damage, or resulting in significant disabilities, congenital abnormalities,
or death.[1]" [see page 6-7 line 124-127]
References:
World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment 2019. Geneva: World Health Organization; 2019
4. It is also expected that ‘serious AE’ would be a subset of ‘any AE’. However, this
doesn’t appear to be the case in analysis shown in Table 1. This needs to be clarified.
Thank you very much for the feedback. Regarding the query concerning the difference
between ‘Serious AE’ subgroup and ‘Any AE’ subgroup, some studies (i.e. Merid et al[1],
van der Walt et al[2], and Kvasnovsky et al[3]) only reported SAEs rather than any
AEs. Hence, we decided to perform a subgroup analysis based on the reporting criteria
(i.e. any AE vs serious AE only) to investigate whether the pooling of these studies
to the main model introduced heterogeneity or significantly affected the estimate.
From the analysis, we discovered that incorporating the studies reporting only SAEs
did not significantly affect the point estimate, nor did it introduce substantial
heterogeneity (see Table 1).
References:
1. Merid MW, Gezie LD, Kassa GM, Muluneh AG, Akalu TY, Yenit MK. Incidence and predictors
of major adverse drug events among drug-resistant tuberculosis patients on second-line
anti-tuberculosis treatment in Amhara regional state public hospitals; Ethiopia: a
retrospective cohort study. BMC Infect Dis 2019;19:286. https://doi.org/10.1186/s12879-019-3919-1.
2. Van der Walt M, Lancaster J, Odendaal R, Davis JG, Shean K, Farley J. Serious Treatment
Related Adverse Drug Reactions amongst Anti-Retroviral Naïve MDR-TB Patients. PLoS
One 2013;8. https://doi.org/10.1371/journal.pone.0058817.
3. Kvasnovsky CL, Cegielski JP, Erasmus R, Siwisa NO, Thomas K, der Walt ML van. Extensively
Drug-Resistant TB in Eastern Cape, South Africa: High Mortality in HIV-Negative and
HIV-Positive Patients. JAIDS J Acquir Immune Defic Syndr 2011;57:146–52. https://doi.org/10.1097/QAI.0b013e31821190a3.
5. Terms ‘adverse reaction’ and ‘adverse events’ seem to have been used interchangeably
at some places. The former term may be used if causality assessment has been conducted.
Thank you very much for the feedback. We have rechecked the utilization of the term
‘adverse reaction’ and ‘adverse events’ and changed them according to the context.
"This alarming evidence is further aggravated by the fact that DR-TB patients are
more susceptible to drug-related adverse events (AEs) when compared to drug-susceptible
TB patients." [see page 4 line 58-60]
"This meta-analysis revealed that HIV co-infection was independently associated with
AEs in DR-TB patients" [see page 16 line 276-277]
"In conclusion, this meta-analysis adds to the growing body of evidence supporting
the independent association between HIV co-infection and AEs in DR-TB patients." [see
page 19 line 364-365]
6. Line 54 – ‘440,000 new cases and 150,000 deaths each year’. These figures are for
RR/MDR-TB while the sentence starts with only DR-TB. DR-TB is an encompassing term
for other forms/types of resistance as well.
Thank you very much for the feedback. Regarding the critique to clarify the epidemiological
measures of DR-TB, we have revised the figures, breaking down DR-TB into rifampicin-resistant-
and isoniazid-resistant-TB. In addition, we have also updated the data according to
the latest report.
"Drug-resistant tuberculosis (DR-TB), defined as the emergence of resistance pattern
of TB bacilli to one or more anti-TB drugs[1], remains a major global health burden
with approximately 465,000 cases of rifampicin-resistant/multidrug-resistant tuberculosis
(RR/MDR-TB) and 1.4 million cases of isoniazid-resistance TB cases in 2019[2]. Moreover,
about 182,000 deaths from RR/MDR-TB were also reported in the same year.[3]" [see
page 4 line 54-58]
We believe that these numbers represent the prevalence of DR-TB as a whole. This is
saliently true considering that these figures include multidrug-resistant, extensively
drug-resistant, polydrug-resistant, and total drug-resistant TB patients who had resistance
to either rifampicin or isoniazid.
References:
1. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment 2019. Geneva: World Health Organization; 2019
2. Singh A, Prasad R, Balasubramanian V, Gupta N. Drug-resistant tuberculosis and
HIV infection: current perspectives. HIV/AIDS (Auckland) 2020;12:9–31.
3. Institute of Medicine. Facing the reality of drug-resistant tuberculosis in India:
Challenges and potential solutions - Summary of a joint workshop by the Institute
of Medicine, the Indian National Science Academy, and the Indian Council of Medical
Research. Washington (DC): National Academies Press; 2012.
7. Line 93-94 – ‘AEs were defined as any untoward event occurring following the administration
of second-line anti-TB agents’. Please clarify is this also included AEs associated
with ARV administration.
Thank you very much for the feedback. Regarding the query to clarify the definition
of AE, we have clarified that the definition includes both AEs from second-line anti-TB
agents and antiretroviral agents.
"AEs were defined as any untoward event occurring following the administration of
second-line anti-TB and/or antiretroviral (ARV) agents." [see page 5 line 100-101]
8. Table 1: ‘HR’ and ‘OR’ abbrevi-ations in the ‘Outcome’ column need to be elaborated.
Thank you very much for the feedback. We have add-ed the definition of the abbreviation
‘HR’ and ‘OR’ in the footnote of Table 1.
AE, adverse event; CI, confidence interval; ES, ef-fect size; HIV, human immunodeficiency
virus; HR, hazard ratio; MDR-TB, multidrug-resistant tubercu-losis; N, total sample
size; NA, not available; OR, odds ratio; RR, risk ratio; TB, tuberculosis; XDR-TB,
extensively drug-resistant tuberculosis [see the footnote of Table 1 in page 14 line
237-240]
9. As per Table 1, the RR for adverse events seems more pronounced for XDR-TB patients
but this doesn’t find mention in subsequent narrative (line 234).
Thank you very much for the feedback. Regarding the query on the RR for MDR-TB and
XDR-TB, we judged that there was no significant difference between MDR-TB and XDR-TB
from the analysis of the adjusted outcomes. Although the RR for XDR-TB was larger
(vs MDR-TB: 1.61 vs 1.28; see Table 1), the 95% confidence interval (CI) for XDR-TB
was also wider than MDR-TB (0.92-2.84 vs 0.98-1.66; see Table 1), thus suggesting
uncertainties in the point estimate. Furthermore, data on the adverse events for XDR-TB
are lacking since only one study (i.e. Olayanju et al[1]) was included in the subgroup
analysis. Hence, we decided to interpret the findings from unadjusted outcomes, which
showed that the risks were more pronounced in MDR-TB than XDR-TB (RR [95% CI]: 1.22
[1.04-1.42] vs 0.80 [0.51-1.26]). Although the number of studies included in each
subgroup was unbalanced (i.e. MDR-TB vs XDR-TB: 15 vs 4 studies), we believe that
these 4 studies (i.e. Olayanju et al[1], Padayatchi et al[2], Shean et al[3], and
Kvasnovsky et al[4]) may be more representative than the only study in the adjusted
outcomes (i.e. Olayanju et al[1]). Nonetheless, we realized that unadjusted outcomes
are limited by the fact that they are non-independent of potential confounders. Therefore,
we decided to regard this as a limitation of our study.
"This study has several limitations. Although our findings highlighted the unfavorable
effect of HIV co-infection on AE development in patients receiving DR-TB treatments,
some of the pooled estimates were unadjusted for confounders due to study scarcity,
emphasizing caution in the interpretation of our findings." [see page 18-19 line 348-351]
References:
1. Olayanju O, Esmail A, Limberis J, Gina P, Dheda K. Linezolid interruption in patients
with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment
regimen. Int J Infect Dis 2019;85:74–9. https://doi.org/10.1016/j.ijid.2019.04.028.
2. Padayatchi N, Gopal M, Naidoo R, Werner L, Naidoo K, Master I, et al. Clofazimine
in the treatment of extensively drug-resistant tuberculosis with HIV coinfection in
South Africa: A retrospective cohort study. J Antimicrob Chemother 2014;69:3103–7.
https://doi.org/10.1093/jac/dku235.
3. Shean K, Streicher E, Pieterson E, Symons G, van Zyl Smit R, Theron G, et al. Drug-Associated
Adverse Events and Their Relationship with Outcomes in Patients Receiving Treatment
for Extensively Drug-Resistant Tuberculosis in South Africa. PLoS One 2013;8. https://doi.org/10.1371/journal.pone.0063057.
4. Kvasnovsky CL, Cegielski JP, Erasmus R, Siwisa NO, Thomas K, der Walt ML van. Extensively
Drug-Resistant TB in Eastern Cape, South Africa: High Mortality in HIV-Negative and
HIV-Positive Patients. JAIDS J Acquir Immune Defic Syndr 2011;57:146–52. https://doi.org/10.1097/QAI.0b013e31821190a3.
10. In addition to monitoring for AEs, use of injection free regimen could be part
of the recommendations because some of the common and serious AEs are associated with
the injections being used for treatment of RR/MDR-TB
Thank you very much for the feedback. We agree with the reviewer that the use of injection-free
DR-TB regimens should be preferred whenever possible. This is further supported by
our findings where injectable-containing DR-TB regimens were associated with a more
apparent risk than all-oral DR-TB regimens (RR 1.11 [95% CI: 1.01-1.21] vs RR 1.61
[95% CI: 0.92-2.84]; Table 1). Furthermore, injectable DR-TB agents (i.e. amikacin,
kanamycin, and capreomycin) have also been proven to augment the risk of hearing loss
and nephrotoxicity in DR-TB patients, which is also in line with our findings where
aminoglycosides were among the most utilized drugs in the included studies. Lastly,
Lan et al. further corroborated our premises by stating that these injectable agents
were among the drugs with the highest risk of developing adverse events leading to
permanent drug discontinuation.[1] Therefore, we have added a recommendation suggesting
the widespread implementation of all-oral DR-TB regimens as the mainstay of DR-TB
treatments.
"This meta-analysis further indicated that the effect of HIV infection was more prominent
in the increased risk of developing hearing loss and nephrotoxicity. It has been well-established
that some anti-TB drugs, particularly aminoglycosides, are associated with hearing
loss.[2,3] Aminoglycosides were also associated with nephrotoxicity as they were primarily
renally excreted and may cause tubular necrosis.[4,5] This is in line with our findings
where amikacin and kanamycin were among the most utilized drugs in the included studies,
thus further elaborating the observed link. In addition, Lan et al. also stated that
these drugs resulted in the highest incidence of adverse events leading to permanent
drug discontinuation[1], indicating that a safer and better-tolerated regimen is required
to reduce aminoglycoside-related morbidities. In this regard, all-oral treatment regimens
become the preferred option for most DR-TB patients.[6] This is saliently true considering
that our findings suggest that injectable-containing DR-TB regimens may result in
a more apparent risk of developing AE, although further studies are required to confirm
these premises. Furthermore, all-oral DR-TB regimens have shown to be more cost-effective
with less logistical challenges[7,8], thus rendering them more worthwhile to be implemented
especially in resource-limited settings. All in all, these necessitates the widespread
implementation of oral-only regimens as the mainstay of DR-TB treatment." [see page
17 line 300-316]
References:
1. Lan Z, Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, et al. Drug-associated
adverse events in the treatment of multidrug-resistant tuberculosis: an individual
patient data meta-analysis. Lancet Respir Med 2020;8:383–94.
2. Hong H, Budhathoki C, Farley JE. Increased risk of aminoglycoside-induced hearing
loss in MDRTB patients with HIV coinfection. Int J Tuberc Lung Dis 2018;22:667–74.
https://doi.org/10.5588/ijtld.17.0830.
3. Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing
loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J 2012;40:1277–86.
4. Updated guidelines on managing drug interactions in the treatment of HIV-related
tuberculosis. MMWR Morb Mortal Wkly Rep. 2014;63:272.
5. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: Nephrotoxicity. Antimicrob Agents
Chemother 1999;43:1003–12
6. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment 2019. Geneva: World Health Organization; 2019
7. Ionescu AM, Mpobela Agnarson A, Kambili C, Metz L, Kfoury J, Wang S, et al. Bedaquiline-
versus injectable-containing drug-resistant tuberculosis regimens: a cost-effectiveness
analysis. Expert Rev Pharmacoeconomics Outcomes Res 2018;18:677–89
8. Reuter A, Tisile P, Von Delft D, Cox H, Cox V, Ditiu L, et al. The devil we know:
is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc
Lung Dis. 2017;21:1114–26.
---------------------------------------------------------------------------------------------------------------------------------------
Responses to Reviewer 2
1. On the conversion of OR/HR to RR. I am not convinced this method is appropriate
for pooling effect estimates in a meta-analysis. This conversion method may still
introduce bias. A sensitivity analysis where original odds ratios are pooled separately
from risk ratios may be helpful to see if the pooled effects are similar across the
effect measures used. In addition, it would be useful to indicate on any forest plots,
in which they appear, the studies that have had their OR/HR converted.
Thank you very much for the feedback. We agree with the reviewer that the conversion
of OR and HR to RR warrants cautions in interpreting our results, as these conversions
may introduce heterogeneity to the model[1]. We decided to set our common measure
as relative risk (RR) in order to ease the interpretation of our results, as the pooling
of HR, OR, and RR separately may confuse and complicate the interpretation. Furthermore,
to the best of our knowledge, there are no currently known method to convert HR to
OR and vice versa. We have also elaborated in the Supplementary Material pg. 12 that
the conversion of HR to RR may introduce bias ratio of at most 16% for outcome probability
of 0.2-0.8, 45% for outcome probability of 0.1-0.9, and 93% for outcome probability
of 0.05-0.95, which was remarkably lower than interchangeably using HR and RR which
may introduce bias with a factor of 1.80 (80%) for outcome probability of 0.2-0.8,
2.47 (147%) for outcome probability of 0.1-0.9, and 19.00 (1900%) for outcome probability
of 0.05-0.95. We have also added that only one study[2] reported outcome probability
between 0.9-0.95, thus minimizing the risk of potential bias arising from these conversions.
Nonetheless, to anticipate bias and heterogeneity arising from these conversions,
we decided to perform a subgroup analysis based on the original effect measure (i.e.
OR and HR), which analysis showed that the heterogeneity arising from the pooling
of these two converted effect measures was negligible. Although the point estimates
for OR subgroup is substantially higher than those in HR subgroup (RR 1.15 [95% CI:
1.03-1.28] vs RR 1.05 [95% CI: 0.88-1.24]; see Table 1), we believe that this does
not suggest potential bias arising from the conversion method as these numbers reflect
specific study outcomes and are highly affected by other factors (i.e. study design,
population, intervention, etc.)
Reference:
1. Riley RD, Moons KGM, Snell KYIE, Ensor J, Hooft L, Altman DG, et al. A guide to
systematic review and meta-analysis of prognostic factor studies. BMJ. 2019;364:k4597
2. Smith JP, Gandhi NR, Shah NS, Mlisana K, Moodley P, Johnson BA, et al. The Impact
of Concurrent Antiretroviral Therapy and MDR-TB Treatment on Adverse Events. JAIDS
J Acquir Immune Defic Syndr 2020;83:47–55. https://doi.org/10.1097/QAI.0000000000002190.
2. One of the main predictors for AE are the specific drugs used (as mentioned in
the discussion). Some stratification for cohorts that used PZA, Eto, and Km vs. those
who did not (if possible given the data) should be attempted. As individual adjustments
for drug use are not possible, this may help determine whether HIV is independently
associated with AE rather than driven by the drugs used in specific cohorts.
Thank you very much for the feedback. We agree with the reviewer that it is imperative
to investigate whether the effect of HIV on the development of AE in DR-TB patients
was driven by HIV-related immunosuppression or drug-drug interactions. However, as
we did not intend to analyze patient-level data, and as the treatment regimens used
in each study intertwined with each other (e.g., studies not utilizing kanamycin utilized
other aminoglycosides, i.e., amikacin or kanamycin), we were unable to analyze specific
drug-drug interactions. Hence, we discussed for a way to explore the potential interplay
of specific regimens and drug-drug interactions and decided to perform a subgroup
analysis based on DR-TB treatment regimen, dichotomizing studies into studies utilizing
injectable agents (i.e. kanamycin, amikacin, and capreomycin) and all-oral regimens
(i.e. using bedaquiline, pretomanid, and linezolid). We discovered that injectable-containing
DR-TB regimens was associated with a more apparent risk of developing adverse event
(RR 1.11 [95% CI: 1.01-1.21] vs all-oral regimens: RR 1.61 [95% CI: 0.92-2.84]; Table
1), although it is worth noting that further research are required to confirm our
findings as there is currently limited evidence on studies utilizing all-oral DR-TB
regimens. Considering our findings, we have added a discussion favoring over the use
of all-oral treatment regimens.
"In this regard, all-oral treatment regimens become the preferred option for most
DR-TB patients.[1] This is saliently true considering that our findings suggest that
injectable-containing DR-TB regimens may result in a more apparent risk of developing
AE, although further studies are required to confirm these premises. Furthermore,
all-oral DR-TB regimens have shown to be more cost-effective with less logistical
challenges[2,3], thus rendering them more worthwhile to be implemented especially
in resource-limited settings. All in all, these necessitates the widespread implementation
of oral-only regimens as the mainstay of DR-TB treatment." [see page 16 line 290-299]
In addition, our findings also indicated that the effect of HIV was primarily driven
by drug-drug interactions between ARV drugs and anti-DR-TB agents rather than HIV-related
immunosuppression, as proven by subgroup analyses shown on Supplementary Figure S4
(ART vs not on ART: RR 1.21 [95% CI: 1.02-1.43] vs RR 1.24 [95% CI: 0.90-1.69]; CD4≥200
vs <200 cells/mm3: RR 0.94 [95% CI: 0.81-1.08] vs RR 0.96 [95% CI: 0.68-1.37]). In
response to this, we have also added a discussion on the potential specific drug-drug
interactions between ARV and anti-DR-TB drug.
"In addition, we also observed that HIV/DR-TB patients receiving concomitant ART were
more vulnerable to AEs. Interestingly, we found that the extent of immunosuppression
was not associated with AE occurrence, implying that the observed risk was presumably
driven by drug-drug interactions rather than HIV-mediated immunosuppression. However,
we were unable to explore the suspected drug-drug interactions as patient-level data
were not available. Some anti-DR-TB drugs have been reported to induce adverse interactions
when concomitantly administered with ART, including bedaquiline, delamanid, and moxifloxacin,
which had documented interactions with several protease inhibitors (e.g. lopinavir/ritonavir)
and non-nucleoside reverse transcriptase inhibitors (i.e. efavirenz and rilpivirine)[4],
thus potentially leading to multiple toxicities resulting in deleterious health consequences[5]."
[see page 17 line 309-316]
References:
1. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment 2019. Geneva: World Health Organization; 2019
2. Ionescu AM, Mpobela Agnarson A, Kambili C, Metz L, Kfoury J, Wang S, et al. Bedaquiline-
versus injectable-containing drug-resistant tuberculosis regimens: a cost-effectiveness
analysis. Expert Rev Pharmacoeconomics Outcomes Res 2018;18:677–89. https://doi.org/10.1080/14737167.2018.1507821.
3. Reuter A, Tisile P, Von Delft D, Cox H, Cox V, Ditiu L, et al. The devil we know:
is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc
Lung Dis. 2017;21:1114–26
4. HIV Drug Interactions. Anti-tuberculosis treatment selectors. Univ Liverpool 2019.
hiv-druginteractions.org/prescribing-resources (accessed October 11, 2020).
5. Mukonzo J, Aklillu E, Marconi V, Schinazi RF. Potential drug–drug interactions
between antiretroviral therapy and treatment regimens for multi-drug resistant tuberculosis:
Implications for HIV care of MDR-TB co-infected individuals. Int J Infect Dis 2019;83:98–101.
https://doi.org/10.1016/j.ijid.2019.04.009.
6. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment 2019. Geneva: World Health Organization; 2019
7. Ionescu AM, Mpobela Agnarson A, Kambili C, Metz L, Kfoury J, Wang S, et al. Bedaquiline-
versus injectable-containing drug-resistant tuberculosis regimens: a cost-effectiveness
analysis. Expert Rev Pharmacoeconomics Outcomes Res 2018;18:677–89. https://doi.org/10.1080/14737167.2018.1507821.
8. Reuter A, Tisile P, Von Delft D, Cox H, Cox V, Ditiu L, et al. The devil we know:
is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc
Lung Dis. 2017;21:1114–26
9. HIV Drug Interactions. Anti-tuberculosis treatment selectors. Univ Liverpool 2019.
hiv-druginteractions.org/prescribing-resources (accessed October 11, 2020).
10. Mukonzo J, Aklillu E, Marconi V, Schinazi RF. Potential drug–drug interactions
between antiretroviral therapy and treatment regimens for multi-drug resistant tuberculosis:
Implications for HIV care of MDR-TB co-infected individuals. Int J Infect Dis 2019;83:98–101.
https://doi.org/10.1016/j.ijid.2019.04.009.
3. In addition to the use of individual drugs, the use and availability of drugs has
changed over the last two decades, as well as the guideline recommendations for DR-TB
treatment. Combining cohorts from these different eras may not be appropriate as some
assumptions between their comparability may be violated. Was the effect of HIV consistent
between cohorts ending before 2010 and cohorts that began after 2010? Some stratification
of cohort periods may provide some insight into this. If the data does not allow for
these stratification to be made, some discussion regarding treatment periods in addition
to the drugs used should be included.
Thank you very much for the feedback. We agree with the reviewer that the use of individual
drugs may differ between studies. To the best of our knowledge, one substantial revolution
in the treatment of DR-TB during the 2010s occurred in 2012 with the introduction
of bedaquiline, delamanid, pretomanid, and linezolid, thus initiating the era of all-oral
DR-TB treatment.[1] In light of this, we decided to add an additional analysis by
dichotomizing studies based on their treatment regimens (i.e. injectable-containing
regimens vs all-oral regimens). We discovered that injectable-containing DR-TB regimens
were associated with a more apparent risk of developing AE (RR 1.11 [95% CI: 1.01-1.21]
vs all-oral regimens: RR 1.61 [95% CI: 0.92-2.84]; Table 1), although further studies
are required to confirm our findings as the current model was limited due to paucity
of studies utilizing all-oral DR-TB regimens. In summary, only 4 studies utilized
bedaquiline[2-5], and only two of which utilized and reported all-oral DR-TB regimens[2,4].
However, one[2] was excluded from the meta-analysis due to distinct study design (i.e.
interventional study), thus leaving only one study[4] in the all-oral subgroup in
the meta-analysis model. Considering our findings, we decided to add an elaboration
on the use of all-oral DR-TB regimens in the discussion section.
"In this regard, all-oral treatment regimens become the preferred option for most
DR-TB patients.[11] This is saliently true considering that our findings suggest that
injectable-containing DR-TB regimens may result in a more apparent risk of developing
AE, although further studies are required to confirm these premises. Furthermore,
all-oral DR-TB regimens have shown to be more cost-effective with less logistical
challenges[12,13], thus rendering them more worthwhile to be implemented especially
in resource-limited settings. All in all, these necessitates the widespread implementation
of oral-only regimens as the mainstay of DR-TB treatment." [see page 16 line 290-299]
As some studies do not allow the stratification of cohorts ending before 2010 and
after 2010, we were unable to perform a stratification based on the treatment period.
Nonetheless, we believe that the effect of HIV was consistent between studies as our
model yielded negligible heterogeneity (I2=0%; p=0.75; Table 1). We hope that the
additional subgroup analysis by DR-TB treatment regimens may fulfill the concerns
raised by the reviewer.
References:
1. Swindells S. New drugs to treat tuberculosis. F1000 Med Rep. 2012;4: 12. doi:10.3410/M4-12
2. Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Bedaquiline,
pretomanid and linezolid for treatment of extensively drug resistant, intolerant or
non-responsive multidrug resistant pulmonary tuberculosis. N Engl J Med. 2020;382:
893–902. doi:10.1056/nejmoa1901814
3. Sineke T, Evans D, Schnippel K, van Aswegen H, Berhanu R, Musakwa N, et al. The
impact of adverse events on health-related quality of life among patients receiving
treatment for drug-resistant tuberculosis in Johannesburg, South Africa. Health Qual
Life Outcomes. 2019;17: 94. doi:10.1186/s12955-019-1155-4
4. Olayanju O, Esmail A, Limberis J, Gina P, Dheda K. Linezolid interruption in patients
with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment
regimen. Int J Infect Dis. 2019;85: 74–79. doi:10.1016/j.ijid.2019.04.028
5. Hughes J, Reuter A, Chabalala B, Isaakidis P, Cox H, Mohr E. Adverse events among
people on delamanid for rifampicin-resistant tuberculosis in a high HIV prevalence
setting. Int J Tuberc Lung Dis. 2019;23: 1017–1023. doi:10.5588/ijtld.18.0651
6. Hong H, Budhathoki C, Farley JE. Increased risk of aminoglycoside-induced hearing
loss in MDRTB patients with HIV coinfection. Int J Tuberc Lung Dis. 2018;22: 667–674.
doi:10.5588/ijtld.17.0830
7. Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing
loss in patients on treatment for drug-resistant tuberculosis. European Respiratory
Journal. 2012. pp. 1277–1286. doi:10.1183/09031936.00044812
8. Updated Guidelines on Managing Drug Interactions in the Treatment of HIV-Related
Tuberculosis. MMWR Morb Mortal Wkly Rep. 2014;63: 272.
9. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: Nephrotoxicity. Antimicrobial
Agents and Chemotherapy. American Society for Microbiology; 1999. pp. 1003–1012. doi:10.1128/aac.43.5.1003
10. Lan Z, Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, et al. Drug-associated
adverse events in the treatment of multidrug-resistant tuberculosis: an individual
patient data meta-analysis. Lancet Respir Med. 2020;8: 383–394. doi:10.1016/S2213-2600(20)30047-3
11. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment. Geneva: World Health Organization; 2019.
12. Ionescu AM, Mpobela Agnarson A, Kambili C, Metz L, Kfoury J, Wang S, et al. Bedaquiline-
versus injectable-containing drug-resistant tuberculosis regimens: a cost-effectiveness
analysis. Expert Rev Pharmacoeconomics Outcomes Res. 2018;18: 677–689. doi:10.1080/14737167.2018.1507821
13. Reuter A, Tisile P, Von Delft D, Cox H, Cox V, Ditiu L, et al. The devil we know:
Is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc
Lung Dis. 2017;21: 1114–1126. doi:10.5588/ijtld.17.0468
4. Line 267 – this statement regarding what was reported in Lan et al. is not correct.
In fact, what was reported for drug stoppage, if anything, was close to indicating
the opposite (HIV may decrease the odds of having a drug stopped). This statement
should be revised to reflect this.
Thank you very much for the feedback. We agree with the reviewer that we misinterpreted
the statement by Lan et al. We realized that the statement referred to severe adverse
events and not all adverse events, which may be incompatible to the context of our
discussion. Furthermore, based on our findings in the Supplementary Figure S3, we
did not discover any significant association between HIV seropositivity and severe
AE (RR 1.23 [95% CI: 0.81-1.87]), which was in line with the findings by Lan et al.
who stated that HIV status was not associated with AEs leading to drug discontinuation[1].
Hence, we decided to revise the statement as follows:
"This meta-analysis revealed that HIV co-infection was independently associated with
adverse events in DR-TB patients. Although our findings were in contrast with the
findings by Schnippel et al.[2], the study interpreted the association between HIV
infection and drug-related AE using vote counting method based on subjective rules,
thus potentially predisposing such analysis to poor performance validity[3]." [see
page 16 line 276-290]
Reference:
1. Lan Z, Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, et al. Drug-associated
adverse events in the treatment of multidrug-resistant tuberculosis: an individual
patient data meta-analysis. Lancet Respir Med 2020;8:383–94. https://doi.org/10.1016/S2213-2600(20)30047-3.
2. Schnippel K, Firnhaber C, Berhanu R, Page-Shipp L, Sinanovic E. Adverse drug reactions
during drug-resistant TB treatment in high HIV prevalence settings: A systematic review
and meta-analysis. J Antimicrob Chemother 2017;72:1871–9. https://doi.org/10.1093/jac/dkx107.
3. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al., editors. Cochrane
handbook for systematic reviews of interventions version 6.0 (updated July 2019).
6th ed. Cochrane; 2019. https://doi.org/10.1002/9781119536604.
5. Issues of duration of TB drug use and time to adverse event are important for interpretation
of effect estimates.
As mentioned above: Issues of duration of TB drug use and time to adverse event are
important for interpretation of effect estimates, and there should be some mention
of this in the discussion.
Thank you very much for the feedback. We agree with the reviewer that the duration
of DR-TB treatment and the onset of adverse events (AEs) are imperative to take account
upon interpreting our findings. This is particularly important in order to make a
suggestion on the optimal timing of treatment monitoring, thus allowing the early
detection and prompt treatment of such AEs to take place. However, we were unable
to perform such an analysis due to differences in the length and time point of follow-up
between the included studies. Hence, we decided to discuss this matter qualitatively
as shown below.
"Altogether, although we discovered that HIV co-infection was associated with an increased
risk of developing any AE in DR-TB patients, ART should not be needlessly deferred
in such patients. This is especially true considering that HIV co-infection was not
associated with an increased risk of serious AE occurrence. Rather, we encourage clinicians
to increase pharmacovigilance on HIV/DR-TB co-infected patients, especially in terms
of ototoxicity, nephrotoxicity, and depressive symptoms. Therefore, routine audiological,
laboratory (i.e. renal panel), and mental health assessments on such patients are
strongly recommended. These routine assessments should be performed periodically by
taking into account the common onset of each AEs. However, our current data did not
permit such an analysis due to differences in follow-up duration, thus limiting our
ability to explore these factors. According to a study by Zhang et al.[1], most AEs
in patients receiving injectable-containing DR-TB regimens occurred within the first
six months. In contrast, most AEs in all-oral regimens appeared to develop more quickly,
ranging between two weeks to three months[2,3]. Considering this, it is plausible
for such assessments to be performed monthly, thus allowing the early detection and
prompt management of potential AEs.[4] This is particularly important as AEs were
among the most common reasons leading to treatment non-adherence and failure in DR-TB
patients.[5]" [see page 337-347]
In addition, we have also added a recommendation to standardize the reporting standard
of follow-up duration to
investigate the effects of duration of DR-TB treatments and onset of AEs.
Furthermore, we were unable to perform subgroup analysis by duration of follow-up
due to heterogeneity in reporting, suggesting that a standardized reporting of follow-up
duration in future studies are urgently needed. [see page 19 line 354-356]
References:
1. Zhang Y, Wu S, Xia Y, Wang N, Zhou L, Wang J, et al. Adverse events associated
with treatment of multidrug-resistant tuberculosis in China: An ambispective cohort
study. Med Sci Monit. 2017;23: 2348–2356. doi:10.12659/MSM.904682
2. Hughes J, Reuter A, Chabalala B, Isaakidis P, Cox H, Mohr E. Adverse events among
people on delamanid for rifampicin-resistant tuberculosis in a high HIV prevalence
setting. Int J Tuberc Lung Dis. 2019;23: 1017–1023. doi:10.5588/ijtld.18.0651
3. Olayanju O, Esmail A, Limberis J, Gina P, Dheda K. Linezolid interruption in patients
with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment
regimen. Int J Infect Dis. 2019;85: 74–79. doi:10.1016/j.ijid.2019.04.028
4. Mase SR, Chorba T. Treatment of Drug-Resistant Tuberculosis. Clinics in Chest Medicine.
W.B. Saunders; 2019. pp. 775–795. doi:10.1016/j.ccm.2019.08.002
5. Wang Y, Chen H, Huang Z, McNeil EB, Lu X, Chongsuvivatwong V. Drug non-adherence
and reasons among multidrug-resistant tuberculosis patients in Guizhou, China: A cross-sectional
study. Patient Prefer Adherence. 2019;13: 1641–1653. doi:10.2147/PPA.S219920
6. Line 57 – ‘Adverse event’ is first mentioned, but not abbreviated until line 64
Thank you very much for the feedback. We have revised the usage of the initial abbreviation
of adverse event accordingly.
"This alarming evidence is further aggravated by the fact that DR-TB patients are
more susceptible to drug-related adverse events (AEs) when compared to drug-susceptible
TB patients[1], indicating that better understanding on the factors associated with
the development of AEs during DR-TB treatment is urgently needed. This is saliently
important, considering that AEs remain as one of the major predictor of unfavorable
treatment outcomes.[2,3]" [see page 4 line 58-63]
References:
1. Wu S, Zhang Y, Sun F, Chen M, Zhou L, Wang N, et al. Adverse events associated
with the treatment of multidrug-resistant tuberculosis: A systematic review and meta-analysis.
Am J Ther 2016;23:e521--30. https://doi.org/10.1097/01.mjt.0000433951.09030.5a.
2. Shean K, Streicher E, Pieterson E, Symons G, van Zyl Smit R, Theron G, et al. Drug-Associated
Adverse Events and Their Relationship with Outcomes in Patients Receiving Treatment
for Extensively Drug-Resistant Tuberculosis in South Africa. PLoS One 2013;8. https://doi.org/10.1371/journal.pone.0063057.
3. Sineke T, Evans D, Schnippel K, van Aswegen H, Berhanu R, Musakwa N, et al. The
impact of adverse events on health-related quality of life among patients receiving
treatment for drug-resistant tuberculosis in Johannesburg, South Africa. Health Qual
Life Outcomes 2019;17:94. https://doi.org/10.1186/s12955-019-1155-4.
7. Materials/methods – was a protocol registered/published?
Thank you very much for the feedback. We have added our protocol to the text, which
was prospectively registered in PROSPERO on 5 July 2020.
"This review was conducted based on the guideline of systematic review of prognostic
factor studies guideline proposed by Riley et al.[1] and was reported according to
the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement[2].
A detailed protocol has been prospectively registered in PROSPERO (CRD42020185029[3]).
Deviations from the protocol are described in Supplementary Table S1." [see page 4-5
line 76-81]
In addition to citing our protocol, we have also specified the protocol in the PRISMA
checklist (see Supplementary Material_PRISMA checklist). Furthermore, we have also
added a supplementary table, listing all deviations made along with the explanations
(see Supplementary Table S1). Following a thorough review, we discovered that interventional
studies were not a criterion for exclusion, thus we decided to include the interventional
study in our systematic review. The details of the revision are illustrated in Figure
1. As there is only one interventional study, we decided to exclude the study from
the quantitative analysis (i.e., meta-analysis) and opted to analyze the study qualitatively.
Details of the study’s characteristics and outcomes can be seen on Supplementary Table
S6 and S9, respectively, while the result of risk of bias assessment of the aforementioned
study are illustrated in Supplementary Figure S1.
References:
1. Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, et al. A guide to
systematic review and meta-analysis of prognostic factor studies. BMJ. 2019;364. doi:10.1136/bmj.k4597
2. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting
items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6:
e1000097. doi:10.1371/journal.pmed.1000097
3. Lazarus G, Soetikno V, Iskandar A, Louisa M. The burden of human immunodeficiency
virus infections on adverse events occurrence in the treatment of drug-resistant tuberculosis:
a systematic review and meta-analysis. PROSPERO 2020. CRD42020185029. [cited 2021
Jan 19]. Available: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=185029
8. Newcastle-Ottawa scale is not a good tool and for these study designs involving
an intervention (or in general: see Stang et al. 2018 Eur J Epidemiol. “Case study
in major quotation errors: a critical commentary on the Newcastle–Ottawa scale”).
I think the quality assessment should be redone using ROBINS-I tool or similar to
assess bias. Additionally, a sensitivity analysis stratifying on study quality as
done with the NOS grading should be included as well – as selection bias, duration
of treatment, and timing of AE may all affect the point estimates presented in the
included studies.
Thank you very much for the feedback. We agree with the reviewer that Newcastle-Ottawa
Scale (NOS) may be limited due to poor inter-rater reliability.[1] Hence, prior to
quality assessments, we performed an in-depth discussion among the investigators in
order to align our comprehension and perceptions on the signaling questions in hope
that our assessments will be sufficiently objective. Furthermore, most of the included
studies were longitudinal observational studies with only one study each being an
experimental[2] and a cross-sectional study[3], hence we believe that NOS is an appropriate
tool to assess the quality of the respective studies. This is also in line with the
recommendation by Zeng et al.[4] On the other hand, as for the experimental study,
we decided to assess the quality of the study using the ROBINS-I tool as the study
was single-armed and non-randomized. The results of the risk of bias assessment of
the study can be seen in Supplementary Figure 1. The choice of the risk of bias tools
was made prospectively as shown in our PROSPERO protocol (ID: CRD42020185029).[5]
References:
1. Oremus M, Oremus C, Hall GBC, McKinnon MC. Inter-rater and test–retest reliability
of quality assessments by novice student raters using the Jadad and Newcastle–Ottawa
Scales. BMJ Open. 2012;2:e001368
2. Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Bedaquiline,
pretomanid and linezolid for treatment of extensively drug resistant, intolerant or
non-responsive multidrug resistant pulmonary tuberculosis. N Engl J Med. 2020;382:
893–902. doi:10.1056/nejmoa1901814
3. Sineke T, Evans D, Schnippel K, van Aswegen H, Berhanu R, Musakwa N, et al. The
impact of adverse events on health-related quality of life among patients receiving
treatment for drug-resistant tuberculosis in Johannesburg, South Africa. Health Qual
Life Outcomes. 2019;17: 94. doi:10.1186/s12955-019-1155-4
4. Zeng X, Zhang Y, Kwong JSW, Zhang C, Li S, Sun F, et al. The methodological quality
assessment tools for preclinical and clinical studies, systematic review and meta-analysis,
and clinical practice guideline: a systematic review. J Evid Based Med. 2015;8(1):2-10
5. Lazarus G, Soetikno V, Iskandar A, Louisa M. The burden of human immunodeficiency
virus infections on adverse events occurrence in the treatment of drug-resistant tuberculosis:
a systematic review and meta-analysis. PROSPERO 2020. CRD42020185029. [cited 2021
Jan 19]. Available: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=185029
9. Further, was there an a priori adjustment set for which you would considered appropriate
to pool adjusted effect estimates? A mix of estimated effects that may have been adjusted
for different covariates may not be appropriate either (especially if they are being
converted). Some clear mention of this should be included in the methods as well.
Thank you very much for the feedback. We agree with the reviewer that the incorporation
of studies with diverse adjustment sets may be inappropriate as it may complicate
the interpretation of our analysis. Hence, we have defined a minimum adjustment factors
of age and sex as a criterion for studies to be included in the analysis of the adjusted
outcome.
"Both adjusted and unadjusted estimates were pooled in the meta-analysis; however,
adjusted estimates were prioritized for the interpretation of the results[1]. As the
covariates adjusted in each study are highly variable[2], we pre-specified a minimum
adjustment factors of age and sex for study estimates to be included in the analysis."
[see page 7 line 144-147]
Furthermore, as this criterion was not specified in our protocol, we have also added
an explanation to the deviation in Supplementary Table S1.
"We realized that it may be inappropriate to indifferently pool the adjusted outcomes
of each study into a single model as the adjustment factors utilized may substantially
differ, thus subsequently complicating the interpretation of our meta-analysis results[2].
Hence, we decided to set an additional inclusion criterion to the meta-analysis, in
which a study must adjust for at least age and sex to be included in the quantitative
analysis of adjusted outcomes." [see Supplementary Table S1]
References:
1. Dretzke J, Ensor J, Bayliss S, Hodgkinson J, Lordkipanidzé M, Riley RD, et al.
Methodological issues and recommendations for systematic reviews of prognostic studies:
an example from cardiovascular disease. Syst Rev 2014;3:140. https://doi.org/10.1186/2046-4053-3-140.
2. Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, et al. A guide to
systematic review and meta-analysis of prognostic factor studies. BMJ 2019;364. https://doi.org/10.1136/bmj.k4597.
10. Line 85 – “No language restrictions were applied”, but on line 96 an exclusion
criteria is ‘articles not in English’, can you please clarify language restrictions?
Thank you very much for the feedback. Regarding the critique that there is a contradiction
in the methods section concerning the eligibility criteria, we intended to assess
whether language restrictions may affect our findings. Hence, we did not filter the
search results by language, but rather excluded the potentially eligible non-English
articles discovered during the search.
"Conversely, criteria for exclusion were: (1) non-original research, including qualitative
research, case studies, reports, or case series with <20 patients; (2) irretrievable
full-text articles; or (3) articles not in English." [see page 5-6 line 101-103]
The implementation of this criterion enabled us to assess the language bias arising
from the language limitation, which we deemed negligible considering the large number
of patients pooled in this systematic review and the fact that only three potentially
eligible non-English articles were excluded. Regardless of this, we have acknowledged
these as a limitation in the text as follows.
"Lastly, although language bias may arise from our eligibility criteria, our study
included a relatively large number of patients and only three non-English articles
were excluded, suggesting that any language bias may be negligible." [see page 19
line 356-359]
11. Line 120 – I am not sure what is meant, do you mean data was extracted/estimated
from figures if unavailable from text/tables? Some clarification would be helpful.
Thank you very much for the feedback. Regarding the query to clarify the following
statement “In the case of studies reporting the aforementioned outcomes only through
graphical illustrations, the data were digitized with GetData Graph Digitizer ver.
2.26 (www.getdata-graph-digitizer.com).” [page 7 line 127-129], some studies (i.e.
Figure 3 in Brust et al[1] and Figure 1-2 in Schnippel et al[2]) only reported the
outcomes on adverse events through graphical illustrations (i.e. figures). Hence,
in order to maximize the utilization of the available data, we decided to extract
the data points of those figures by using a digitization software (i.e. GetData Graph
Digitizer). To the best of our knowledge, such a practice is encouraged by Cochrane,
especially in cases where the queried authors are unresponsive, and the data are not
available elsewhere.[3]
References:
1. Brust JCM, Shah NS, Mlisana K, Moodley P, Allana S, Campbell A, et al. Improved
Survival and Cure Rates with Concurrent Treatment for Multidrug-Resistant Tuberculosis-Human
Immunodeficiency Virus Coinfection in South Africa. Clin Infect Dis 2018;66:1246–53.
https://doi.org/10.1093/cid/cix1125.
2. Schnippel K, Berhanu RH, Black A, Firnhaber C, Maitisa N, Evans D, et al. Severe
adverse events during second-line tuberculosis treatment in the context of high HIV
Co-infection in South Africa: A retrospective cohort study. BMC Infect Dis 2016;16.
https://doi.org/10.1186/s12879-016-1933-0.
3. Li T, Higgins JPT, Deeks JJ. Chapter 5: Collecting data. In: Higgins JPT, Thomas
J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for
Systematic Reviews of Interventions version 6.1 (updated September 2020). Cochrane,
2020. Available from: www.training.cochrane.org/handbook
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Additional changes
1. We changed the position of the ‘p-values’ in the ‘Outcome’ column in Table 1. The
p-values reflect between-subgroup significance. Hence, we believe that it is more
appropriate for these values to be placed in the same row with the ‘type of subgroup’
name rather than with one of the subgroups.
2. We have also added funding information on the submission system. We discovered
that we had not provided relevant financial disclosure during the initial submission
process, while in fact our project received a grant from the Universitas Indonesia.
Hence, we have added relevant information, stating that:
This project was funded by the PUTI Q1 research grant from the Universitas Indonesia
(grant number: BA-1005/UN2.RST/PPM.00.03.01/2020). The funder had no role in study
design, data collection and analysis, decision to publish, or preparation of the manuscript.
We have also inputted relevant information to the submission system, stating that
the author VS was the recipient of the aforementioned grant.
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We hope you will kindly reconsider our submission and we are looking forward to the
publication of our manuscript. Thank you very much in advance for your kind consideration.
Sincerely yours,
Representing all authors
Gilbert Lazarus
Faculty of Medicine Universitas Indonesia,
Jl. Salemba Raya No. 6, Jakarta 10430, Indonesia,
E-mail: gilbert.lazarus@ui.ac.id
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