Clinical Microbiology and Infection 30 (2024) 189e196

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Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Systematic review

Effectiveness and safety of tuberculosis preventive treatment for

contacts of patients with multidrug-resistant tuberculosis: a
systematic review and meta-analysis
Guozhong Zhou 1, Shiqi Luo 2, Jian He 3, Nan Chen 4, Yu Zhang 4, Shunli Cai 5, Xin Guo 5,
Hongbo Chen 3, Chao Song 6, *
1)
Department of Science and Research, The Affiliated Anning First People's Hospital of Kunming University of Science and Technology, Kunming, Yunnan
Province, China
2)
Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical
College, Beijing, China
3)
Department of Pulmonary and Critical Care Medicine, The Affiliated Anning First People's Hospital of Kunming University of Science and Technology,
Kunming, Yunnan Province, China
4)
Department of Endocrinology, The Affiliated Anning First People's Hospital of Kunming University of Science and Technology, Kunming, Yunnan Province,
China
5)
School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan Province, China
6)
Department of Medical Imaging, The Affiliated Anning First People's Hospital of Kunming University of Science and Technology, Kunming, Yunnan
Province, China

a r t i c l e i n f o a b s t r a c t

Article history:
Background: Contacts of patients with multidrug-resistant tuberculosis (MDR-TB) are at risk of devel-
Received 17 May 2023
oping TB disease. Tuberculosis preventive treatment (TPT) is an intervention that can potentially reduce
Received in revised form
12 September 2023
this risk.
Accepted 16 September 2023 Objectives: To evaluate the effectiveness and safety of TPT for contacts of patients with MDR-TB.
Available online 22 September 2023 Data Sources: EMBASE, PubMed, Web of Science, and the Cochrane Library were searched for eligible
studies on 24 July 2023, without start date restrictions.
Editor: E. Bottieau Study eligibility criteria: We included studies that compared TPT with no treatment in contacts of pa-
tients with MDR-TB and reported outcomes of progression to TB disease.
Keywords: Participants: Contacts of patients with MDR-TB.
Contact Interventions: TPT.
Meta-analysis
Assessment of risk of bias: A modified version of the Newcastle-Ottawa Scale was used.
Multidrug-resistant tuberculosis
Methods of data synthesis: Random-effects meta-analysis was utilized to calculate the relative risk for
Preventive treatment
Risk of progression disease progression to TB in contacts of patients with MDR-TB who received TPT compared to those who
did not. Additionally, completion, adverse effect, and discontinued rates were assessed.
Results: Involving 1105 individuals from 11 studies, the pooled relative risk for disease progression in
contacts receiving TPT versus those without treatment was 0.34 (95% CI: 0.16e0.72). Subgroup analysis
indicated a lower pooled relative risk for regimens based on the drug-resistance profile of the index
patients with TB compared to uniform treatment regimens (0.22 [95% CI: 0.06e0.84] vs. 0.49 [95% CI:
0.17e1.35]), although not statistically significant. The pooled completed rate was 83.8%, adverse effect
rate was 22.9%, and discontinued rate was 6.5%. After excluding the levofloxacin and pyrazinamide
regimen study, the completed rate increased to 88.0%, and adverse effects and discontinued rates
decreased to 8.0% and 4.0%, respectively.
Discussion: TPT reduces TB disease progression risk in contacts of patients with MDR-TB. Tailored TPT
regimens based on drug-resistance profiles may offer additional benefits. Furthermore, efforts to

* Corresponding author. Chao Song, Department of Radiology, The Affiliated Anning First People's Hospital of Kunming University of Science and Technology, Kunming,
Yunnan Province, 650302, China.
E-mail address: [email protected] (C. Song).

https://doi.org/10.1016/j.cmi.2023.09.015
1198-743X/© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
190 G. Zhou et al. / Clinical Microbiology and Infection 30 (2024) 189e196

improve completed rates and manage adverse effects are essential for optimizing effectiveness and
safety. Guozhong Zhou, Clin Microbiol Infect 2024;30:189
© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology
and Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction manually checked for other potentially relevant studies. We fol-

lowed the Preferred Reporting Items for Systematic Reviews and
The WHO global tuberculosis (TB) report for 2021 revealed that Meta-Analyses [13], and the protocol was registered in PROSPERO
10.6 million people were newly diagnosed with TB, including (CRD42022348122).
450 000 new cases of multidrug-resistant tuberculosis (MDR-TB) or The inclusion criteria were as follows: (1) adults and/or children
rifampicin-resistant TB [1]. However, the current treatment regi- in contact with patients with MDR-TB; (2) diagnosis as TB infection
mens for patients with MDR-TB are considerably suboptimal [2]. with interferon-gamma release assay or tuberculin skin test; (3)
Compared to drug-susceptible TB treatments, MDR-TB regimens compared TPT group with untreated group; and (4) reported out-
require longer durations, a higher pill burden, and more toxic comes of progression to TB disease, regardless of drug resistance or
medications [2]. drug susceptibility. Progression to TB disease is defined as the
MDR-TB refers to TB diseases caused by Mycobacterium tuber- occurrence of TB disease in individuals who did not have TB disease
culosis (M. tuberculosis) strains that are resistant to at least both at the start of the follow-up period and developed TB disease 3 or
rifampicin and isoniazid [2]. This resistance can emerge either more months after the initiation of follow-up.
through de novo mutations during tuberculosis treatment or by The exclusion criteria were as follows: (1) evidence of TB disease
transmission from other individuals with infectious MDR-TB dis- within 3 months after baseline testing, (2) follow-up < 1 year, (3)
ease [3]. According to Kendall et al. [3], a significant proportion isoniazid monotherapy, and (4) abstracts, reviews, case reports, and
(54%) of MDR-TB cases is attributed to patients who have never animal studies. Additionally, we excluded studies that solely relied
undergone TB treatment [3]. Moreover, a significant proportion of on registry matches, as they could be considerably influenced by
new MDR-TB cases, even among individuals with a history of patient mobility and loss of follow-up, leading to an inability to
tuberculosis treatment, is predominantly due to MDR-TB trans- accurately identify incident TB cases.
mission [3]. A meta-analysis by Chiang et al. [4], revealed that the Two investigators (GZZ and SQL) thoroughly screened the article
pooled resistance profile concordance between index patients with titles and abstracts obtained from the literature search indepen-
MDR-TB and their household contacts was 54.3%, and pooled dently. Subsequently, the full texts of potentially eligible studies
isoniazid/rifampin concordance was 82.6% [4]. Therefore, the pre- were further evaluated for final inclusion. To ensure accuracy, a
vention of MDR-TB transmission is a focus of MDR-TB control ef- third investigator (CS) cross-checked the extracted data, and any
forts [5]. discrepancies were resolved through consensus.
Four of the available guidelines agree on the need to treat
contacts of patients with MDR-TB [6e9]. However, these recom-
mendations are based on low-level evidence. In 2012, a systematic Data extraction and quality assessment
review was published to evaluate the effectiveness of treatment for
contacts of patients with MDR-TB; however, only two observational Non-English/foreign-language abstracts and articles were
studies were included [10]. In 2017, Marks et al. [11], conducted a accurately translated for full-text review. In a preconceived and
meta-analysis that included six comparative studies and reported a standardized data extraction form, information was collected on
significant estimated 90% reduction in MDR-TB incidence with the first author's name, year of publication, title, journal, study
tuberculosis preventive treatment (TPT). However, it is crucial to country, study design, timing of data collection (prospective or
highlight that only five of these studies were included in the final retrospective), patient demographics, definition of MDR-TB and
meta-analysis [11]. In 2018, as part of a WHO guideline document, a contact, treatment regimen, duration of treatment, follow-up time,
systematic review was conducted with strict inclusion criteria, and the person-years of follow-up, number of contacts, number of pa-
only four studies with contacts of patients with MDR-TB who tients who underwent TPT, number of patients who completed TPT,
completed TPT were included [12]. In 2020, the WHO attempted to number of adverse effects, number of patients who discontinued
update the systematic review, but no new studies were added [7]. treatment because of adverse effects, number of patients who
There have been some recently published studies on the use of progressed to TB disease, and the proportion of TB cases that were
treatment for MDR-TB contacts, which add to the existing literature microbiologically confirmed (i.e., culture, molecular or genotypic
and might provide additional evidence. Therefore, we conducted method). The data extraction process from individual studies was
this systematic review and meta-analysis to assess the effectiveness carried out independently by two investigators (GZZ and SQL). To
and safety of TPT in contacts patients with MDR-TB. ensure accuracy, a third investigator (CS) cross-checked the
extracted data, and any disagreements were resolved through
mutual agreement and consensus.
Methods A modified version of the Newcastle-Ottawa Scale with refer-
ence to previous meta-analyses [14], was used to assess the quality
Search strategy and selection criteria of each study. The modified Newcastle-Ottawa Scale consists of
three parts and nine items: selection (0e4 points), comparability
We searched EMBASE, PubMed, Web of Science, and the (0e2 points), and outcome assessment (0e3 points). Studies with
Cochrane Library for eligible studies on 24 July 2023, without a start Newcastle-Ottawa Scale scores of 1e3, 4e6, and 7e9 were
date or language restrictions. The search terms were “drug-resis- considered as low, intermediate, and high quality, respectively. The
tant tuberculosis”, “contact” and “treatment.” The details are pro- methodological quality of the studies was independently assessed
vided in Table S1. The reference lists of the relevant articles were by two investigators (GZZ and SQL). Additionally, a third
 G. Zhou et al. / Clinical Microbiology and Infection 30 (2024) 189e196 191

investigator (CS) independently reviewed these assessments. In categorized into three levels: high, moderate, and low or very low
cases of any disagreements, a consensus was reached through based on the five Grading of Recommendations Assessment,
discussion and agreement among the investigators. Development and Evaluation system domains [17].

Outcomes Results

We calculated the relative risk for disease progression in con- Of the 1942 potentially eligible studies, 1201 articles were
tacts of patients with MDR-TB who were treated versus those who screened for titles and abstracts after removing duplicates, and 94
were untreated. Additionally, we calculated the completed rate, full-text articles were reviewed. After a full-text review, 11 studies
adverse effect rate, and discontinued rate. The completed rate [18e28] involving 1105 individuals were included in the analysis
represents the proportion of individuals who successfully complete (Fig. 1). The study by Huang et al. [29], was excluded because it
the full course of TPT as prescribed. The discontinued rate refers to evaluated the use of isoniazid monotherapy. The study by Attamna
the proportion of individuals who prematurely stop or discontinue et al. [30], was excluded because it relied solely on registry matches.
TPT due to adverse effects. Out of the 11 studies, five were prospective cohort studies, while
the remaining six were retrospective cohort studies. Among these
Data analysis studies, eight were conducted in areas with a TB burden ranging
from 0 to 100 per 100 000 people, and three studies were con-
Given the heterogeneity of patient populations, settings, de- ducted in areas with a higher TB burden of more than 101 per
signs, quality, and regimens, a random-effects model meta-analysis 100 000 people. For details about the selected studies, please refer
was used to obtain pooled results and their 95% CI. The heteroge- to Table 1 and Table S2.
neity of the included studies was assessed using the I2 statistic, Nine and two studies were scored as moderate and high quality,
where I2 > 50% indicates significant heterogeneity [15]. To assess respectively. The included studies had several limitations. Only five
publication bias, the Egger's test was employed. All p were two- studies clearly defined MDR-TB. None of the studies reported
sided, and statistical significance was defined as p < 0.05. The adjusted OR or RR; therefore, additional factors were not
meta-analysis was conducted using the “meta” package in R sta- controlled. Only one study reported blind assessments or recorded
tistical software version 3.4.3. The Grading of Recommendations the linkages. There were five studies where more than half of the TB
Assessment, Development and Evaluation system was used to rate disease cases were confirmed by microbiology. Details are shown in
the primary outcome [16]. The overall certainty of evidence was Figure S1. A Grading of Recommendations Assessment,

Records identified from database searching Potential studies included in previous meta-analysis
(N =1937) (N = 5)

Removal of duplicates
(N = 741)

Records screened
(N = 1201)

Excluded after screening of title and abstract

(N = 1107)

Full-text articles assessed for eligibility

(N = 94)

83 Excluded after full text screening

45 had no progression results
17 prophylaxis information was not reported
18 abstract, reviews, case reports
1 isoniazid monotherapy
1 followed up less than 1 year
1 relied solely on registry matches

Total studies included in the meta-analysis

(N =11)

Fig. 1. Study selection.

 192 G. Zhou et al. / Clinical Microbiology and Infection 30 (2024) 189e196

Development and Evaluation system summary of findings for the

Stopped
TPT (n)

primary outcomes can be found in Table S3, and the overall cer-
tainty of the evidence was rated as low.

NS

NS

NS
11
d

d
4

3
0

1
1

1
Eleven studies were eligible for the comparison of the rate of
events (n)

disease progression in contacts of patients with MDR-TB who

Adverse

received treatment versus those who did not receive treatment,

and the pooled RR was 0.34 (95% CI: 0.16e0.72, I2 ¼ 0%) (Fig. 2).

NS

NS

NS

NS
26
d

d
4

3
1

6
2
Although the univariate meta-regression results did not show sta-
confirmed events (n)

tistical significance (p > 0.05), there were differences in the pooled

Microbiologically

RR by age group, definition of close contact, treatment regimen,

study design, and quality of the included studies. The pooled RR of
developing TB disease on TPT in the children group was lower than
that in the all-age group (0.27 [95% CI: 0.09e0.76, I2 ¼ 0%] vs. 0.44
[95% CI: 0.10e1.88, I2 ¼ 32%]). In studies with a well-defined defi-
NS
NS

NS
NS

NS
NS

NS
NS

NS
NS
NS
NS
13
0
3

0
2

0
1
2

0
3
nition of close contacts, the pooled RR for developing disease was
All developed

lower than that in studies where close contacts were poorly defined
(0.28 [95% CI: 0.12e0.67, I2 ¼ 0%] vs. 0.60 [95% CI: 0.13e2.69,
events (n)

I2 ¼ 0%]). The pooled RR for developing disease was lower in the

drug-resistant profile-guided regimen group compared to the
13

13
0
0
0
3

0
0
1
0
2
0
0

1
2

2
0
2

0
0
0
0
uniform treatment regimen (0.22 [95% CI: 0.06e0.84, I2 ¼ 18%] vs.
0.49 [95% CI: 0.17e1.35, I2 ¼ 0%]). The risk of developing TB disease
Completed
TPT (n)

on TPT was lower in the prospective cohort than in the retrospec-

tive studies (0.23 [95% CI: 0.05e1.01, I2 ¼ 33%] vs. 0.51 [95% CI:
121

NS
93

52
18

21

41

41

30
d

d
8

0.18e1.45, I2 ¼ 0%]). The pooled RR for developing TB was lower in

Initiated

the high-quality studies than that in the moderate-quality studies

TPT (n)

(0.10 [95% CI: 0.01e0.99, I2 ¼ 54%] vs. 0.52 [95% CI: 0.21e1.32,
104

172
NS
26

58
18

11

24

41

50
d

I2 ¼ 0%]), see Table 2 and Figure S2eS8.

8

Sensitivity analysis of the pooled RR showed that the results were

Participants

stable. The details are presented in Figure S9. Verification was con-
ducted in nine studies reporting completion of TPT information, and
104

145
172

166
(n)

the pooled RR for the disease progression rate in contacts of patients

15
26

50
20
44
11
38
24
10
58
14
45

43
41
64
5

8
4

with MDR-TB who completed treatment versus those who did not
Follow-up

receive treatment was 0.34 (95% CI: 0.14e0.84, I2 ¼ 0%), (Fig. S10).
(month)

Two included studies reported crude ORs. In a study by Bamrah

108
108
NS
NS
24
24
36
36

24
54
54
12
12
25
24
30
30
24

30
30

24
24

et al. [19], 104 patients with TB infection were placed on

fluoroquinolone-based TPT, of which 93 (89%) completed treatment
Male

43.3
43.3

51.2
57.8

51.2
57.8
100

and none developed TB disease, whereas 3 of 15 (20%) contacts who

(%)

NS

NS
NS

NS
NS
NS
NS
40
47

53
47
51
51
50
50

refused treatment developed MDR-TB (OR ¼ 0.02, 95% CI:

0.00e0.39). A study by Schaaf et al. [26], showed that the disease
Age group

Children
Children

Children
Children

Children
Children
Children
Children

Children
Children

Children
Children

Children
Children

developed in 2 (0 confirmed) of 41 children who received tailored

All age
All age

All age
All age

All age
All age
All age
All age

TPT and in 13 (3 confirmed) of 64 children who did not receive

proper TPT (OR ¼ 0.20, 95% CI: 0.04e0.94).
Retrospective cohort
Retrospective cohort

Retrospective cohort
Retrospective cohort
Retrospective cohort
Retrospective cohort
Retrospective cohort
Retrospective cohort

Retrospective cohort
Retrospective cohort

Retrospective cohort
Retrospective cohort

Nine studies were eligible for the calculation of the completed

Prospective cohort
Prospective cohort

Prospective cohort
Prospective cohort

Prospective cohort
Prospective cohort
Prospective cohort
Prospective cohort
Prospective cohort
Prospective cohort

rate, with a pooled completed rate of 83.8% (95% CI: 69.3e94.3%,

I2 ¼ 93%). Seven cohorts were eligible for the calculation of adverse
Study design

effect rate, with a pooled adverse effect rate of 22.9% (95% CI:
3.1e53.7%, I2 ¼ 96%). Nine cohorts were eligible for the calculation
of discontinued rate, with a pooled discontinued rate of 6.5% (95%
CI: 1.9e13.5%, I2 ¼ 77%) (Fig. 3). The sensitivity analysis of pooled
TPT, tuberculosis preventive treatment; NS, not specified.
TPT

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

rates showed that the results were not stable, and heterogeneity
No

No

No

No

No

No

No

No

No

No

No

was mainly attributed to the study by AdlerShohet et al. [18], in

South Africa
South Africa

South Africa
South Africa

which a 9-month regimen of levofloxacin (LVX) and pyrazinamide

Australia
Australia
Australia
Australia

(PZA) was used. After excluding this study, the completed rate
Pakistan
Pakistan
Russia
Russia
Brazil
Brazil
Detailed individual study characteristics

increased to 88.0% (95% CI: 76.0e97.0%), and the adverse effect and
Area

USA
USA
USA
USA

USA
USA
UK
UK

discontinued rates decreased to 8.0% (95% CI: 4.0e14.0%) and 4.0%

(95% CI: 0.2e6.0%), respectively. Details are presented in Figure S11.
Adler-Shohet et al., 2014 [18]
Adler-Shohet et al., 2014 [18]

Garcia-Prats et al., 2014 [22]

Garcia-Prats et al., 2014 [22]

Egger's test was employed to assess publication bias for the

Denholm et al., 2012 [21]
Denholm et al., 2012 [21]

Williams et al., 2013 [28]

Williams et al., 2013 [28]

pooled RR and completed rates, and the results indicated no evi-

Bamrah et al., 2014 [19]
Bamrah et al., 2014 [19]

Gureva et al., 2022 [23]

Gureva et al., 2022 [23]
Kritski et al., 1996 [24]
Kritski et al., 1996 [24]

Schaaf et al., 2002 [26]

Schaaf et al., 2002 [26]
Chang et al., 2021 [20]
Chang et al., 2021 [20]

Malik et al., 2021 [25]

Malik et al., 2021 [25]

Trieu et al., 2015 [27]

Trieu et al., 2015 [27]

dence of publication bias (p ¼ 0.7954).

Discussion

To assess the effectiveness and safety of TPT for contacts of

Study
Table 1

patients with MDR-TB, we collected and analysed data from 11

studies on contacts of patients with MDR-TB who received TPT and
 G. Zhou et al. / Clinical Microbiology and Infection 30 (2024) 189e196 193

Fig. 2. Forest plot of the relative risk for the rate of disease progression in contacts of patients with MDR-TB who were treated versus untreated.

Table 2
The relative risk for the rate of disease progression in contacts of MDR-TB patients who were treated versus untreated

Variable Cohorts Individuals RR (95% CI) I2 (%) pa

All studies 11 557/548 0.34 (0.16e0.72) 0 d

Participants (n)
>100 5 412/433 0.34 (0.10e1.12) 33 1
99 6 145/115 0.36 (0.09e1.45) 0 0.9211
Age group
Children group 6 168/135 0.27 (0.09e0.76) 0 1
All-age group 5 389/413 0.44 (0.10e1.88) 32 0.5054
Definition of close contact
Close contacts were well-defined 6 235/271 0.28 (0.12e0.67) 0 1
Close contacts were poorly defined 5 322/277 0.60 (0.13e2.69) 0 0.3973
Treatment regimen
Drug-resistant profile-guided regimenb 4 174/161 0.22 (0.06e0.84) 18 1
Uniform treatment regimenc 7 383/387 0.49 (0.17e1.35) 0 0.3204
Study design
Prospective cohort 5 425/302 0.23 (0.05e1.01) 33 1
Retrospective cohort 6 132/246 0.51 (0.18e1.45) 0 0.3026
TB burden of study aread
0e100 per 100 000 8 320/431 0.35 (0.13e0.89) 0 1
More than 101 per 100 000 3 237/117 0.34 (0.10e1.15) 0 0.9685
Year of publication
1996e2019 8 309/447 0.32 (0.14e0.74) 0 1
2020e2022 3 248/101 0.45 (0.07e2.70) 0 0.7406
Quality
Moderate 9 412/469 0.52 (0.21e1.32) 0 1
High 2 145/79 0.10 (0.01e0.99) 54 0.1213

FQ, fluoroquinolone; MDR, multidrug-resistant; RR, relative risk; TB, tuberculosis.

a
The p values were obtained through an univariate meta-regression.
b
The drug-resistant profile-guided regimen refers to treatment regimens that are tailored based on the drug-resistance profile of the index patients with TB.
c
Uniform treatment regimen refers to a standard or generic treatment approach that is not personalized based on the drug-resistance profile of the index patients with TB.
d
Data from WHO website (https://www.who.int/teams/global-tuberculosis-programme/tb-reports).

those who did not receive TPT. Using random-effects analysis, we CI was very wide, since only five studies were included in the meta-
found that the MDR-TB incidence reduction was estimated to be analysis. Our study included 11 studies (6 new studies were
66% with TPT. Subgroup analysis revealed that pooled RRs might be included) and found that the pooled RR was 0.34 (95% CI:
influenced by age group, definition of close contact, treatment 0.16e0.72). Our estimated reduction (66% [95% CI: 28e84%]) in
regimen, study design, and the quality of the included studies. MDR-TB incidence was lower than that reported in Marks et al. [11],
Overall, TPT is considered safe, with pooled completion, adverse study, but 95% CI was more precise. Furthermore, our results
effect, and discontinued rates of 83.8%, 22.9%, and 6.5%, respec- revealed that the effectiveness of TPT for contacts of patients with
tively. However, it is essential to emphasize that the safety of TPT MDR-TB was lower than the effectiveness of TPT for contacts of
may be influenced by the specific regimen employed. drug-susceptible patients with TB. In comparison, Martinez et al.'s.
Marks et al. [11], previously assessed the effectiveness of TPT for [31], individual-participant meta-analysis, which included 46
contacts of patients with MDR-TB using a systematic review and studies involving 137 647 children contacts, found that the effec-
meta-analysis, and found that the pooled RR was 0.10 (95% CI: tiveness of TPT was 85% among those with TB infection. Therefore,
0.01e0.91), suggesting that the MDR-TB incidence reduction was there is still room for improvement in the effectiveness of TPT for
estimated as 90% (95% CI: 9e99%) with TPT [11]. However, the 95% contacts of patients with MDR-TB.
194 G. Zhou et al. / Clinical Microbiology and Infection 30 (2024) 189e196

Fig. 3. Forest plot of the completion, adverse, and discontinued rates. A, completed rate; B, adverse rate; and C, discontinued rate.

While the univariate meta-regression results did not reach immune systems, which places them at an elevated risk for TB
statistical significance between subgroups (p > 0.05), they have disease and consequently underscores the greater efficacy of TPT in
unveiled valuable insights. Notably, TPT exhibited a noteworthy this specific subgroup. Similarly, in the analysis involving close
reduction in the likelihood of TB disease development in children contacts with a well-defined definition, TPT demonstrated a note-
group (pooled RR ¼ 0.27 [95% CI: 0.09e0.76]). However, the pro- worthy reduction in the likelihood of TB disease development
tective effect of TPT was inconclusive in group with all-age ranges (pooled RR ¼ 0.28 [95% CI: 0.12e0.67]). However, for close contacts
(pooled RR ¼ 0.44 [95% CI: 0.10e1.88]), due to the inclusion of one without a clear definition, the protective effect of TPT was incon-
within the 95% CI. These findings can be attributed to the height- clusive (pooled RR ¼ 0.60 [95% CI: 0.13e2.69]). This discrepancy can
ened vulnerability of children due to their underdeveloped be attributed to the rigorous inclusion criteria applied to close
 G. Zhou et al. / Clinical Microbiology and Infection 30 (2024) 189e196 195

contacts with a well-defined definition, ensuring the enrolment of (interquartile range: 1.9e30.2%) [7]. Therefore, based on our find-
individuals with higher exposure levels to patients with MDR-TB. ings, TPT can be considered safe for contacts of patients with MDR-
Therefore, our findings underscore the potential for enhanced TB, as it showed a high completed rate and a lower discontinued
protective effects when targeting individuals at elevated risk of rate than the previous study conducted by Marks et al., [11].
MDR-TB infection for TPT. This highlights the importance of Notably, the treatment regimen of LVX and PZA appears to be an
assessing the infection risk of contacts during the implementation essential factor in the adverse effect and discontinued rates. In the
of TPT, taking into consideration factors such as their immune study conducted by Adler-Shohet et al. [18], 26 children were
status, level of exposure, and sputum smear results of the index administered a 9-month regimen of LVX and PZA. Unfortunately, all
case. of the treated children experienced adverse effects during the
A daily LVX-based treatment is the prevailing regimen recom- course of treatment, and as a result, 42% of them had to discontinue
mended for both adults and children, as stated in the available TPT prematurely. After excluding the study by Adler-Shohet et al.
guidelines [5]. Notably, the joint guidelines from the American [18], the completed rate increased to 88.0%, the adverse effect rate
Thoracic Society, the U.S. Centers for Disease Control and Preven- decreased to 8.0%, and the discontinued rate was 4.0% (Figure S11).
tion, the European Respiratory Society, and the Infectious Diseases Similar results have been reported in two case series. Papastavros
Society of America advocate for the use of a daily LVX monotherapy et al., followed 17 contacts of patients with MDR-TB with an LVX
for a duration of 6 to 12 months [6]. Similarly, the WHO guidelines and PZA regimen; all participants experienced adverse effects and
propose a fluoroquinolone-based regimen, with or without a stopped TPT [35]. Horn et al., followed 16 contacts of patients with
companion drug such as ethionamide and/or ethambutol [7]. MDR-TB with an LVX and PZA regimen, 13 participants experienced
However, our subgroup analyses showed that the resistant profile- adverse effects, and all stopped TPT [36]. Therefore, our results
guided regimen of TPT had a significant protective effect against the support the viewpoint of Kherabi et al., that fluoroquinolone and
development of TB disease, whereas the uniform treatment PZA should not be used together in TPT [5].
regimen did not exhibit a statistically significant effect (pooled RR, This study had several limitations. First, since all included
0.22 [95% CI: 0.06e0.84] vs. 0.49 [95% CI: 0.17e1.35]). Our findings studies used a cohort design, nonrandom distribution of partici-
lend strong support to the viewpoint put forth by Chiang et al. [4], pants may have led to bias. Second, all included studies were
emphasizing the importance of providing contacts of drug- conducted on small sample sizes. Small sample studies are prone to
resistant patients with TB with treatment regimens based on the bias in the long-term follow-up study. Third, no studies reported
drug-resistance profile of the index patients with TB. This approach person-years of follow-up. As a result, pooled RR as a measure of
assumes that both the TB infection in the contact and TB disease in effect may only partially account for the variation in follow-up time
the index cases are caused by the same drug-resistant among the included studies, potentially introducing bias when
M. tuberculosis strain [4]. comparing the emergence of MDR-TB disease. Fourth, none of the
Subgroup analyses also revealed that the protective effect studies included in the analysis reported the adjusted relative risk,
against the development of TB disease was statistically significant indicating that it was impossible to control for potential con-
in high-quality studies, while the effect was inconclusive in studies founding factors in the results. Fifth, the lack of consistent reporting
with moderate quality (pooled RR, 0.10 [95% CI: 0.01e0.99] vs. 0.52 of contacts and TB infection definition may lead to bias.
[95% CI: 0.21e1.32]). Similarly, the protective effect against the
development of TB disease was significant in prospective studies, Conclusions
but it remained inconclusive in retrospective studies (pooled RR,
0.23 [95% CI: 0.05e1.01] vs. 0.51 [95% CI: 0.18e1.45]). Our findings TPT for contacts of patients with MDR-TB is associated with a
suggest that study quality and study design may be an important reduced risk of TB disease progression, and the regimen based on
factor influencing the pooled results. In our meta-analysis, all the drug-resistance profile of the index patient may offer additional
included studies were cohort studies. The nonrandom distribution benefits. Efforts to improve treatment completion and manage
of the treatment and non-treatment groups may have affected the adverse effects are essential to maximize the effectiveness and
outcomes. In recent years, 2 randomized prospective trials of LVX safety of TPT for this high-risk population. Further research and
for contacts of patients with MDR-TB are on-going [32,33], the implementation of tailored TPT strategies are warranted to opti-
primary endpoint is the incidence of TB disease among patients mize TB prevention among contacts of patients with MDR-TB.
receiving LVX treatment versus patients receiving placebo treat-
ment. One trial has completed enrolment, treatment, and follow- Author contributions
up, so the results will be released soon [32].
Toxicity and adverse effects must be carefully considered in the GZZ, HBC, and CS initiated the project and were responsible for
TPT of contacts of patients with MDR-TB. Marks et al. [11], reported protocol design. GZZ and SQL performed the literature review,
a completed rate of TPT among contacts of patients with MDR-TB as collected the data, assessed the quality of the studies, and analysed
68% (95% CI: 64e71%). However, our meta-analysis yielded a higher the data. JH, NC, YZ, SLC and XG interpreted the data. GZZ and CS
completed rate of 83.8% (95% CI: 69.3e94.3%), which is similar to wrote the initial draft of the manuscript. All authors were respon-
the completed rate observed among contacts of drug-susceptible sible for critical revision of the manuscript and provided important
tuberculosis. Interestingly, in 2019, across 80 reporting countries, intellectual content. All authors have approved the final version of
the median completed rate percentage among people starting TPT the manuscript for publication.
was 86% [34]. Regarding adverse effects, our meta-analysis found
an adverse effect rate of TPT as 22.9% (95% CI: 3.1e53.7%), with most Transparency declaration
events being mild, such as gastrointestinal symptoms, abdominal
pain, and elevated liver enzymes. Furthermore, the rate of treat- The authors declare no conflicts of interest. This systematic re-
ment discontinuation due to adverse effects was assessed at 6.5% view was supported by the Talent Project of Kunming Health Sci-
(95% CI: 1.9e13.5%), which was significantly lower than that re- ence and Technology (Grant no. 2022-SW [Leading Talents]-001)
ported in Marks et al.’s study (19% [95% CI: 16e22%]). However, our and the Special Project “Spring City Plan” Famous Doctor (Grant no.
finding was more consistent with the systematic review conducted C202012016). It is important to note that the funding source played
for the WHO guideline, which reported a discontinued rate of 5.1% no role in the study's design and conduct, data collection,
196 G. Zhou et al. / Clinical Microbiology and Infection 30 (2024) 189e196

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