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Drug resistance patterns and dynamics of tuberculosis in Zhejiang Province, China: Results from five periodic longitudinal surveys

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  • Zhejiang Provincial Center for Disease Control and Prevention

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Background As one of the high multi-drug resistance tuberculosis countries, it is critical for China to understand patterns of drug resistance to better formulate effective treatment regimens. Methods The anti-TB Drug resistance surveillance has been conducted in Zheijang Province in years 1999, 2004, 2008, 2013, and 2018 respectively. We compared the prevalence of DR-TB from the latest survey with that of the previous four surveys in terms of all four first-line anti-TB drugs. We also examined the prevalence of rifampin-resistant TB (RR-TB) between the last two surveys and routine surveillance data. Results Among 996 patients surveyed in 2018, the prevalence of RR-TB in new and previously treated TB cases was 2.5 and 4.3%, respectively. The prevalence of RR-TB among previously treated cases was much higher than for new cases in the four surveys from 1999 to 2013, while there was no significant difference between these groups in the 2018 survey. The percentage of TB cases resistant to fluoroquinolones in new patients was 3.8%. The prevalence of non-tuberculous mycobacteria increased over time; the prevalence of RR-TB among new cases slowly decreased. The prevalence of RR-TB in both new and previously treated TB cases from the latest two surveys was consistent with routine surveillance data. Conclusions This consistency between routine surveillance and periodic surveys for TB cases implies that with universal testing in Zhejiang Province, data from routine surveillance could be used instead of periodic surveys to improve access to timely and appropriate treatment for DR-TB. Levels of resistance were lower than whole-country and global estimates, further indicating the value of universal drug susceptibility testing.
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TYPE Original Research
PUBLISHED 29 November 2022
DOI 10.3389/fpubh.2022.1047659
OPEN ACCESS
EDITED BY
Ying Zhang,
Zhejiang University, China
REVIEWED BY
Bhavesh Modi,
All India Institute of Medical
Sciences, India
Prakasini Satapathy,
Post Graduate Institute of Medical
Education and Research
(PGIMER), India
*CORRESPONDENCE
Songhua Chen
shchen@cdc.zj.cn
Xiaomeng Wang
xmwang@cdc.zj.cn
Yanlin Zhao
zhaoyl@chinacdc.cn
These authors have contributed
equally to this work
SPECIALTY SECTION
This article was submitted to
Infectious Diseases: Epidemiology and
Prevention,
a section of the journal
Frontiers in Public Health
RECEIVED 18 September 2022
ACCEPTED 15 November 2022
PUBLISHED 29 November 2022
CITATION
Zhou L, Wu B, Huang F, Liu Z, Wang F,
Zhang M, Chen B, Chen S, Wang X and
Zhao Y (2022) Drug resistance patterns
and dynamics of tuberculosis in
Zhejiang Province, China: Results from
five periodic longitudinal surveys.
Front. Public Health 10:1047659.
doi: 10.3389/fpubh.2022.1047659
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©2022 Zhou, Wu, Huang, Liu, Wang,
Zhang, Chen, Chen, Wang and Zhao.
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not comply with these terms.
Drug resistance patterns and
dynamics of tuberculosis in
Zhejiang Province, China:
Results from five periodic
longitudinal surveys
Lin Zhou1†, Beibei Wu1†, Fei Huang2† , Zhengwei Liu1,
Fei Wang1, Mingwu Zhang1, Bin Chen1, Songhua Chen1*,
Xiaomeng Wang1*and Yanlin Zhao2*
1Provincial Center for TB control and prevention, Zhejiang Provincial Center for Disease Control and
Prevention, Hangzhou, China, 2National Center for TB control and prevention, Chinese Center for
Disease Control and Prevention, Beijing, China
Background: As one of the high multi-drug resistance tuberculosis countries,
it is critical for China to understand patterns of drug resistance to better
formulate eective treatment regimens.
Methods: The anti-TB Drug resistance surveillance has been conducted in
Zheijang Province in years 1999, 2004, 2008, 2013, and 2018 respectively.
We compared the prevalence of DR-TB from the latest survey with that of
the previous four surveys in terms of all four first-line anti-TB drugs. We also
examined the prevalence of rifampin-resistant TB (RR-TB) between the last two
surveys and routine surveillance data.
Results: Among 996 patients surveyed in 2018, the prevalence of RR-TB in new
and previously treated TB cases was 2.5 and 4.3%, respectively. The prevalence
of RR-TB among previously treated cases was much higher than for new
cases in the four surveys from 1999 to 2013, while there was no significant
dierence between these groups in the 2018 survey. The percentage of TB
cases resistant to fluoroquinolones in new patients was 3.8%. The prevalence
of non-tuberculous mycobacteria increased over time; the prevalence of RR-
TB among new cases slowly decreased. The prevalence of RR-TB in both new
and previously treated TB cases from the latest two surveys was consistent with
routine surveillance data.
Conclusions: This consistency between routine surveillance and periodic
surveys for TB cases implies that with universal testing in Zhejiang Province,
data from routine surveillance could be used instead of periodic surveys
to improve access to timely and appropriate treatment for DR-TB. Levels
of resistance were lower than whole-country and global estimates, further
indicating the value of universal drug susceptibility testing.
KEYWORDS
tuberculosis, China, survey, drug, resistance
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Introduction
Antimicrobial resistance has become the paramount health
peril for public health systems worldwide over the last
two decades (1). Mycobacterium tuberculosis, for which drug
resistance first emerged in the 1940s (2), merits being one of the
highest priority pathogens, as drug-resistant tuberculosis (DR-
TB) accounts for 29% of deaths attributable to antimicrobial
resistance. Since the initiation in 1994 of a global project
to monitor the development of DR-TB (3), 169 countries
(87% of the 194 World Health Organization [WHO] Member
States) have reported data on drug resistance; collectively, these
countries have more than 99% of the world’s population and
tuberculosis (TB) cases (4). Routine testing of all patients with
TB is widely recognized as the most appropriate surveillance
approach for monitoring trends in drug resistance and detecting
outbreaks and hotspot regions (5). More and more countries
are transferring from a reliance on periodic surveys to the
establishment of continuous surveillance systems based on
routine drug susceptibility testing. With the expansion of rapid
molecular tools, including whole genome sequencing, universal
testing has the possibility of becoming a reality even in resource-
limited countries (6,7).
WHO has listed China as a high burden country for
TB, TB and HIV co-infection, and multidrug-resistant TB
(MDR-TB) during the period 2016–2020 (8). Yet the treatment
landscape for TB has changed dramatically in recent years.
In particular, the China government has strengthened and
expanded implementation of rapid molecular techniques for
DR-TB diagnosis in the last 5 years (9,10). This improvement,
coupled with the introduction of new anti-TB drugs, offers a
critical opportunity to understand drug resistance in China and
better formulate effective treatment regimens. Several provinces
have recently reported their epidemiological status of DR-TB
(1113); however, they did not use the latest definition of
extensively drug-resistant tuberculosis (XDR-TB) from 2021 but
rather the former definition formulated by WHO in 2006 (14).
Moreover, they did not compare the results of periodic surveys
with routine surveillance.
To address the above issues, our study analyzed
drug-resistance patterns within the TB epidemic in
Zhejiang Province—the first province in China to launch
sentinel surveillance and conduct drug resistance surveys
following initiation of the WHO/International Union
Against Tuberculosis and Lung Disease global anti-TB
drug resistance surveillance project in 1994. Zhejiang
Province was also the first province in China to conduct
periodic surveys for DR-TB since WHO integrated
the country into its surveillance network for DR-TB
in 1999.
To our best knowledge, our study is the first to address
the different prevalence patterns of RR-TB among new and
previously treated TB cases over the past two decades in a well-
developed province with a cascade of drug resistance surveys.
With the implementation and improvement of DR-TB control
and prevention in Zhejiang Province, the routine surveillance
should be able to reflect the real epidemic of DR-TB. Our
findings, using the latest definition of DR-TB from WHO, could
provide insights for the province to estimate anti-TB drug
procurement as well as improve interventions for TB control
and prevention.
Methods
Study design and participants
We undertook a longitudinal analysis of data from the 1999,
2004, 2008, 2013, and 2018 anti-TB drug resistance surveys in
Zhejiang Province, which is in the southeast of China with a total
population of 57 million. In accordance with WHO protocol,
each of the five surveys was a cross-sectional survey conducted
with the same method in the same 30 counties randomly
sampled from the 90 counties in Zhejiang Province, which could
reflect the appropriate and representative population (13,15).
For the 2018 survey, the sample size of new TB cases was 30,
according to probability-proportional-to-size sampling. Patients
who were newly diagnosed as sputum smear-positive since
January 1, 2018, were eligible for inclusion and patients with
the history of DR-TB were excluded. All eligible patients were
enrolled sequentially until 30 new patients were enrolled in each
site. All the enrollment was completed before the end of 2018.
The survey obtained ethics approval from Zhejiang Provincial
Center for Disease Control and Prevention (CDC) and written
informed consent from patients.
Procedures
Trained physicians at the sites gave all eligible TB patients
involved in this study a questionnaire on their treatment
history. Patients under 14 years of age or with intellectual
disabilities were interviewed together with their guardians. The
questionnaire was then double-checked by another trained
physician. In the event of inconsistences, the local county
CDC reconfirmed the questionnaire responses by interviewing
patients again, visiting TB patients’ family members, and
inquiring of their medical record. All questionnaire confirmed
by local county CDC will be submitted to the provincial CDC
every week, and the provincial CDC will randomly selected
the questionnaires for rechecking again before entering into an
electronic database in parallel.
Each presumptive TB case were asked to provide three
sputum samples for sputum smear microscopy, and the morning
and evening samples were collected in their home and the
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TABLE 1 TB case distribution by five surveys in Zhejiang Province, 1999–2008.
Year Total sample
size
Mycobacterium tuberculosis NTM
(%)
Others
(%)
New cases
(%)
Previously
treated cases (%)
Subtotal
(%)
1999 1,013 807 (84.6) 147 (15.4) 954 (97.4) 25 (2.6) 34 (3.4)
2004 1,066 846 (84.3) 158 (15.7) 1,004 (97.1) 30 (2.9) 32 (3.0)
2008 1,077 842 (89.8) 96 (10.2) 938 (96.4) 35 (3.6) 104 (9.7)
2013 1,010 842 (90.0) 94 (10.0) 936 (94.8) 51 (5.2) 23 (2.3)
2018 996 768 (91.8) 69 (8.2) 837 (91.2) 81 (8.8) 78 (7.8)
NTM, non-tuberculous mycobacteria; Others, specimens were not recovered successfully.
TABLE 2 Drug resistance patterns of eight anti-TB drugs in Zhejiang Province, 2018.
Resistance patterns New TB cases (N=768) Previously treated TB cases (N=69)
No. % (95 CI) No. % (95 CI)
Susceptible to nine anti-TB drugs 568 74.0 (70.9–77.1) 46 66.7 (55.5–77.8)
Susceptible to four first-line drugs 621 80.9 (78.1–83.6) 52 75.4 (65.2–85.5)
Susceptible to rifampin 749 97.5 (96.4–98.6) 66 95.7 (90.8–100)
Susceptible to isoniazid 699 91.0 (89.0–93.0) 61 88.4 (80.9–96.0)
Resistant to isoniazid (Hr-TB) 50 6.5 (4.8–8.3) 5 7.2 (1.1–13.4)
Resistant to fluoroquinolones 29 3.8 (2.4–5.1) 3 4.3 (0.0–9.2)
Resistant to rifampin (RR-TB) 19 2.5 (1.4–3.6) 3 4.3 (0-9.2)
Susceptible to isoniazid 3 0.4 (0–0.8) 1 1.4 (0–4.3)
Resistant to isoniazid (MDR-TB) 16 2.1 (1.1–3.1) 2 2.9 (0–6.9)
Susceptible to all other drugs 3 0.4 (0–0.8) 1 1.4 (0–4.3)
Resistant to fluoroquinolones (pre-XDR) 6 0.8 (0.2–1.4) 0 -
Resistant to cycloserine 4 0.5 (0–1) 0 -
Resistant to ethambutol 13 1.7 (0.8–2.6) 1 1.4 (0–4.3)
Resistant to aminoglycosides 3 0.4 (0–0.8) 0 -
Resistant to prothionamide 2 0.3 (0–0.6) 0 -
Resistant to p-aminosalicylic acid 4 0.5 (0–1) 0 -
CI, confidence interval.
spot samples was collected in the hospital. Two samples were
cultured by solid Löwenstein-Jensen media in each site as well.
Drug susceptibility testing was performed at provincial TB
reference laboratory using the proportion method, and results
were compared with results for standard strain. The quality
of provincial reference laboratories is ensured and evaluated
annually by the national reference laboratory of the China CDC.
Statistical analysis
Cochran-Armitage trend test was used for categorical data,
and the risk factors associated with DR-TB were examined by a
multivariate logistic regression model. All statistical tests were
two-tailed, and the p-value <0.05 was considered significant. All
tests were done by Base R (version 3.6.3).
Results
Patients
A total of 996 cases were enrolled in the survey in 2018;
of these, 78 cultures (7.8%) were not recovered successfully.
Of the 918 cases with a positive mycobacterial culture, 81
(8.8%) were nontuberculous mycobacteria (NTM), the left
837 (91.2%) acquired drug susceptibility testing (DST) results.
Among these with DST, 768 were new cases, and 69 were
previously treated cases (Table 1). The percentage of new
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TABLE 3 Characteristics of rifampin-resistant TB by multivariate
analysis in Zhejiang Province, 2018.
Factors Estimate Standard
error
p-value Odds ratio
(95% CI)
Intercept 2.7594 0.6515 <0.0001
Gender
Male ref ref ref ref
Female 0.1243 0.4973 0.8026 1.1 (0.4–3.0)
Age group
<25 years ref ref ref ref
25–44 years 0.7658 0.3534 0.0502 0.4 (0.1–1.8)
45–64 years 0.4071 0.4596 0.3063 1.4 (0.2–8.2)
65 years 0.1294 0.4620 0.7793 1.0 (0.2–5.8)
Address
Local ref ref ref ref
Migrant 0.2137 0.5066 0.6732 0.8 (0.3–2.2)
Diabetes
No ref ref ref ref
Yes 0.4358 0.6708 0.4220 0.6 (0.2–2.4)
Treatment
history
No ref ref ref ref
Yes 0.7631 0.5848 0.1919 0.5 (0.1–1.5)
Household
contacts
No ref ref ref ref
Yes 1.3681 0.6002 0.0226 3.9 (1.2–12.7)
Hepatitis B
No ref ref ref ref
Yes 1.0849 0.8191 0.1854 0.3 (0.1–1.7)
ref, reference category in dummy coding.
cases increased significantly, from 84.6% in 1999 to 91.8%
in 2018 (p<0.0001), and the percentage of NTM increased
significantly as well, from 2.6% in 1999 to 8.8% in 2018 (p
<0.0001).
Drug-resistant tuberculosis in 2018
In the latest survey, 74.0, 80.9, and 97.5% of new TB cases
were susceptible to all nine anti-TB drugs, all four first-line
drugs, and rifampin, respectively, while 66.7, 75.4, and 95.7%
of previously treated TB cases were susceptible to all nine anti-
TB drugs, all four first-line drugs, and rifampin, respectively.
Overall, 2.5% of new cases and 4.3% of previously treated
cases were rifampin-resistant TB (RR-TB), of which 81.8%
were multidrug-resistant TB (MDR-TB—i.e., resistant to both
rifampin and isoniazid) (Table 2).
Among the new cases with susceptibility to rifampin, 3.8%
were resistant to fluoroquinolones, higher than the 2.5% of new
cases with resistance to rifampin (p<0.0001). Among the
patients with MDR-TB, 18.8% (3/16) of new cases and 50.0%
(1/2) of previously treated cases were susceptible to all the other
five anti-TB drugs, 37.5% (6/16) of new cases had additional
resistance to fluoroquinolones (so-called pre-XDR), and 81.3%
(13/16) of new cases were resistant to ethambutol.
Factors linked to drug-resistant
tuberculosis
Multivariate analysis showed that all factors but living with
TB cases from the family had no association with RR-TB.
Patients with TB who lived with any TB cases from the family
had about a four-fold higher chance of acquiring RR-TB than
those who did not live with TB cases from the family (Table 3).
Epidemic trends of drug-resistant
tuberculosis
The prevalence of susceptibility to all four first-line anti-TB
drugs was much higher for new TB cases than for previously
treated cases in the first four drug-resistance surveys (p<
0.0001), while there was no significant difference between the
two groups in the latest survey in 2018 (p=0.2705). The
prevalence of both new and previously treated cases susceptible
to all four first-line anti-TB drugs has steadily increased since the
third survey, in 2008 (Figure 1).
The prevalence of isoniazid-resistant TB (Hr-TB) with new
cases of TB was lower than for previously treated cases in the
first survey in 1999 (p=0.0404), but there were no significant
differences in the latest four surveys (p>0.05). The prevalence
of Hr-TB with new cases of TB had no significant difference
among the five surveys (p=0.1140), as did the prevalence of
Hr-TB with previously treated cases (p=0.9762) (Figure 2).
The prevalence of RR-TB with previously treated cases was
much higher than for new cases in the first four surveys (p<
0.0001), while there was no significant difference between these
groups in the latest survey in 2018 (p=0.2705). In general, the
prevalence of RR-TB among both new and previously treated
cases showed a downward trend (Figure 3).
Drug susceptibility testing was not conducted for
fluoroquinolones in the first three surveys, thus data on
the prevalence of fluoroquinolone-resistant TB are not available
for those years. In terms of the latest two surveys, there was no
significant difference in the prevalence of pre-XDR-TB among
new cases, but there was a sharp decrease in the prevalence of
pre-XDR-TB among previously treated cases (Figure 4).
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FIGURE 1
Prevalence of TB cases susceptible to all four first-line anti-TB
drugs: breakdown by treatment history in five periodic surveys.
FIGURE 2
Prevalence of isoniazid-resistant TB: breakdown by treatment
history in five periodic surveys.
FIGURE 3
Prevalence of rifampin-resistant TB: breakdown by treatment
history in five periodic surveys.
Comparison with routine surveillance
data
The prevalence of rifampin resistance among new cases in
2013 and 2018 from the routine surveillance system was 3.7%
(95% CI, 3.1–4.4) and 2.6% (95% CI, 2.4–2.9), respectively,
and had no significant difference compared with the surveys
conducted those years (p=0.3786 and 0.7992, respectively).
According to routine surveillance data, after a drop in 2012,
the prevalence of RR-TB increased slightly through 2013 before
peaking in 2015, decreasing through 2018, and reaching its
lowest point in 2019 (Figure 5).
The prevalence of rifampin resistance among previously
treated cases in 2013 and 2018 as per the routine surveillance
system was 31.1% (95% CI, 27.2–35.1) and 9.2% (95% CI,
8.0–10.5), respectively, and had significant difference between
them (p=0.0005). The prevalence of rifampin resistance
among previously treated cases in the survey of 2013 and 2018
was 24.5% (95% CI, 15.8–33.2) and 4.3% (95% CI, 0.0–9.2),
respectively, and had no significant difference compared with
the routine surveillance system those years (p=0.1944 and
0.1646, respectively). In general, the prevalence of RR-TB has
declined since 2011 (Figure 6).
Discussion
Drug resistance in new cases normally implies a
transmission control problem, whereas in previously treated
cases it reflects on the treatment process, either poor compliance
or irrational regimens. Accordingly, the slowly decreasing
prevalence of RR-TB among new cases in Zhejiang Province
suggests that primary resistance is being driven by ongoing
transmission with few changes, while the sharp drop in
prevalence of RR-TB among previously treated cases indicates
high treatment adherence and good treatment outcomes over
the past 5 years. The findings reflect the importance of infection
control and treatment adherence, which should be delivered by
both the physicians to TB patients and CDCs to social mass.
RR-TB is the most important indicator of MDR-TB and has
implications for treatment regimens. The latest drug-resistance
survey in Zhejiang Province presents a much lower prevalence of
RR-TB (2.5% in new cases and 4.3% in previously treated cases)
than the average prevalence in China (7.1% in new cases and
21.0% in previously treated cases) as well as globally (3.4% in
new cases and 18.0% in previously treated cases) in 2018 (16).
Several possible reasons could contribute to this. First, non-
compliance with the chemotherapy regimen and misuse or
misadministration of anti-TB drugs often leads to emergence
of drug-resistant strains (17), but with the transition of the
China TB service system, Zhejiang Province has been able to
guarantee affordable, qualified TB clinical care for accurate
diagnosis, rational treatment regimen, and adequate treatment
course since 2011 (18). This has led to the sharp decline in the
prevalence of acquired DR-TB. Second, with support from the
Global Fund to Fight AIDS, Tuberculosis and Malaria during
2008–2012, followed by China central government funding since
2013, Zhejiang Province scaled up drug-susceptibility testing
across the whole province. The directive for all DR-TB suspects
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FIGURE 4
Prevalence of pre-extensively drug-resistant TB: breakdown by
treatment history in five periodic surveys.
FIGURE 5
Comparison of prevalence of rifampin-resistant TB among new
cases in periodic surveys and routine surveillance.
to get drug-susceptibility testing led to the detection of most
RR-/MDR-TB cases and a reduction in transmission.
According to several previous studies, the estimated
proportion of MDR-TB resulting from transmission accounts
for the majority of cases and varies substantially with different
countries’ notification data, ranging from 48 to 99% (1922).
The national survey of DR-TB in China in 2008 indicated that
primary transmission accounted for 80% of MDR-TB cases
(23). Another study in China further suggested that recent
transmission of MDR-TB strains helped drive the MDR-TB
epidemic in Shanghai City, which is adjacent to Zhejiang
Province (24). The current universal drug-susceptibility testing
coverage for all TB patients and the low prevalence of
RR-TB in Zhejiang highlights the importance of shortening
the diagnosis delay and strengthening hospitalization of RR-
TB cases until sputum conversion to negative. Preventive
treatment of MDR-TB close contacts with TB infections is
also currently recommended (25). Both of these measures can
decrease transmission.
The prevalence of susceptibility to all four first-line
anti-TB drugs among both new and previously treated TB
cases increased since the third survey, which was consistent
FIGURE 6
Comparison of prevalence of rifampin-resistant TB among
previously treated cases in periodic surveys and routine
surveillance.
with the declining prevalence of RR-TB. Although only the
last two surveys had drug-susceptibility testing results for
fluoroquinolones, the prevalence of pre-XDR-TB among new
and previously treated TB cases followed the same pattern as that
of RR-TB with the same reasons mentioned above. However,
the higher percentage resistant to fluoroquinolones in new TB
cases than resistant to rifampin was likely due to the wide use
of fluoroquinolones for antibiotic therapy in China. Hr-TB is
the most common form of DR-TB worldwide (26); however, the
prevalence of Hr-TB in Zhejiang Province varied from 4.7 to
7.8% in new cases and from 7.2 to 9.6% in previously treated
cases, which remained stable, with no significant difference in
prevalence between new and previously treated TB cases in the
latest four surveys, suggesting that previous TB combination
therapy is unlikely to contribute to the prevalence. With the
rollout of molecular tests, Hr-TB is likely to be more commonly
diagnosed in the coming years (27).
The latest survey observed that living with TB cases
from the family was the only risk factor linked to DR-
TB (odds ratio =3.9, 95% CI 1.2–12.7). This was different
from the first four surveys, where previous treatment was
the strongest predictor for MDR-TB (odds ratio =10.9,
95% CI 9.4–12.7) (13). As the first four surveys showed
a higher prevalence of RR-TB in previously treated TB
cases than that in new TB cases, previous TB treatment
was not surprisingly a predictor for MDR-TB, a trend
reflected in previous studies (28). Accordingly, stopping
the transmission of RR-TB strains should be prioritized in
the future.
Our analysis also indicates that NTM prevalence is
increasing over time, which is valuable information for clinicians
using molecular identification methods for suspicious MDR-
TB. Other studies have also suggested an increase in the
prevalence rates of NTM over the last four decades (29).
Previous studies indicated that Bacille Calmette-Guérin (BCG)
vaccination confers cross-protection against NTM, thus in
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countries without a nationwide BCG immunization program,
a rise in NTM cases is expected (3033). However, BCG
is compulsory for all newborns in China since 1978, and
BCG coverage in Zhejiang Province in 2017 was more than
90% (34). This clearly indicates that the increased trend
of NTM is happening despite BCG coverage. Additional
studies have shown that the incidence and prevalence of
pulmonary NTM is associated with a range of underlying health
conditions, such as immunosuppression, age, sex, previous
history of lung disease, and increased incidence of chronic
lung disease (35,36). This correlation needs to be further
studied as it relates to the increasing trend of NTM in
Zhejiang Province.
This study had a number of limitations. First, the
survey was not designed to estimate the resistance to
new anti-TB drugs; namely, bedaquiline and linezolid.
Therefore, the study could not present a full picture of the
drug-resistance epidemic in Zhejiang Province. Second,
the study was designed as a cluster sample survey with a
probability-proportional-to-size sampling, meaning that
not all TB patients in the sites in 2018 were recruited;
however, the survey was designed to be representative of
the entire TB patient population in Zhejiang Province.
Third, the method used for the drug-resistance surveys was
conventional phenotypic testing rather than a molecular-based
method, which has inherent limitations and is less reliable for
second-line drugs.
Continuous antimicrobial resistance surveillance is an
essential part of national containment strategies (37). The
last result of our study was the remarkable consistency
between routine surveillance data and periodic drug-resistance
surveys for both new and previously treated TB cases, which
suggests that Zhejiang Province, a setting with universal
access to drug susceptibility testing, could use data from
routine surveillance instead of periodic surveys to improve
access to timely and appropriate treatment and care for DR-
TB. Finally, as the shorter, all-oral, bedaquiline-containing
MDR-TB regimen is likely to increase in the coming years
(38,39), drug susceptibility testing for fluoroquinolones
should be added to the routine surveillance network in
Zhejiang Province while continuing to monitor for rifampicin
resistance. In the future, molecular technologies, including high-
throughput sequencing-based technologies, should be scaled up
to replace conventional phenotypic testing in drug resistance
surveillance (40).
Data availability statement
The raw data supporting the conclusions of this article will
be made available by the authors, without undue reservation.
Ethics statement
The studies involving human participants were reviewed and
approved by Ethics Committees of Zhejiang Provincial Center
for Disease Control and Prevention. Written informed consent
to participate in this study was provided by the participants’ legal
guardian/next of kin.
Author contributions
SC, XW, and YZ conceived of the presented idea. ZL, FW,
MZ, and BC carried out the study and collected data. FH wrote
the manuscript with support from LZ and BW. All authors
contributed to the article and approved the submitted version.
Funding
This study was supported by China CDC-Tuberculosis
Control and Prevention Project (228711).
Acknowledgments
The authors thank all the people at peripheral TB
units of Zhejiang Province for their efforts in terms of
case enrollments, questionnaires, follow-ups and laboratory
performance throughout the surveys. Special thanks go to
the National Center for TB Control and Prevention of China
CDC, which, despite the high workload, managed to give an
uncountable number of hours for this study to be completed.
We gratefully acknowledge the contribution from the health
authorities at the district and prefectural level for facilitating the
execution of the study.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
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