RESEARCH ARTICLE

Impact of Multidrug Resistance on

Tuberculosis Recurrence and Long-Term
Outcome in China
Yanni Sun1* , David Harley1, Hassan Vally2, Adrian Sleigh1

1 National Centre for Epidemiology and Population Health, Research School of Population Health, ANU
College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia,
2 School of Public Health & Human Biosciences, La Trobe University, Melbourne, Victoria, Australia
a1111111111
* sunyanni72@hotmail.com
a1111111111
a1111111111
a1111111111
a1111111111 Abstract
Little is known about the impact of drug resistance on recurrence in TB. We conducted a
cohort study to measure the impact of multi-drug resistance (MDR) on TB recurrence over
nine years in Henan Province China. We reviewed medical records and conducted field inter-
OPEN ACCESS
views of 100 MDR and 150 non-MDR TB patients who were treated between 2001 and 2002.
Citation: Sun Y, Harley D, Vally H, Sleigh A (2017)
We compared long-term recurrence rates, risk factors, and outcomes in 2010 for 234 individu-
Impact of Multidrug Resistance on Tuberculosis
Recurrence and Long-Term Outcome in China. als who could be followed up. About one third (29.5%, 69/234) suffered recurrence after com-
PLoS ONE 12(1): e0168865. doi:10.1371/journal. pletion of treatment. The overall recurrence rate was 35/1,000 patient-years (PY), with a much
pone.0168865 higher rate (65/1,000 PY) among MDR-TB patients. MDR (HR: 2.75; CI: 1.58–4.79) and
Editor: Lei Gao, Chinese Academy of Medical patient annual household income less than 10,000 Yuan (HR: 2.05; CI 1.11–3.80) were asso-
Sciences and Peking Union Medical College, ciated with recurrence. The mean time for recurrence among MDR-TB patients was 5.7 years,
CHINA
compared to 7.2 years among non-MDR-TB patients. Among the recurrence group members,
Received: June 30, 2016 61.3% died, and 18.8% had failed treatments. We believe that the high TB recurrence rate
Accepted: December 7, 2016 after 9 years suggests that a high cure rate cannot accurately predict long-term outcome. We
Published: January 24, 2017 recommend that TB surveillance and control should be strengthened with a focus on MDR-TB
and directly observed treatment, to reduce TB recurrence and transmission of MDR-TB.
Copyright: © 2017 Sun et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Introduction
Data Availability Statement: We obtained baseline Poor adherence to treatment is a well-known risk factor for tuberculosis (TB) recurrence.
data from a third party that we cannot make
publicly available without the third party’s approval.
While there are few published data on recurrence rates, it is considered probable that drug
The data is owned by Dr Wang Guojie, resistance increases risk of recurrence [1–3].
Tuberculosis Control and Prevention Institute, Multidrug resistance (MDR), defined by resistance to both isoniazid (H) and rifampicin
Henan Provincial CDC. Address: East Nongye (R), is a major barrier to TB control [4]. Patients with MDR-TB have poor treatment outcomes
Road, Zhengdong Xinqu, Zhengzhou, Henan compared with patients with drug-sensitive TB [5–8]. Research on the contribution of
Province, China. For those interested readers/
MDR-TB to TB recurrence provides evidence for targeting control efforts and more efficient
researchers, please contact Sun Yanni via
sunyanni72@hotmail.com or Dr Wang Guojie at
use of health resources in high TB burden countries, like China.
rbtwgj@hotmail.com to request data that could be Recurrence occurs in 3.0 to 36.0% of TB cases [1–4, 9, 10]. The average relapse rate among
provided. Hereby, all authors confirm that for those notified TB patients in China in 2014 was 3.0%, but the rate among MDR-TB patients was not

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 1 / 11

 MDR-TB and TB Recurrence

interested readers who want to access to the data, reported [11]. China has the second highest national burden of MDR-TB (54,000) after India
they can send a data request email with the in 2014 [11]. Given the high burden and the low treatment cure rate for MDR-TB (48.0%), the
purpose and information request to the contact
adequacy of case management for MDR-TB requires investigation [2, 12] to aid TB control in
persons. Data will be provided as the same way to
the authors of the paper. China. The impact of MDR-TB on recurrence has not been investigated in China.
We conducted a retrospective cohort study in Henan Province, China to measure the long-
Funding: The Funding for the study was partially
term outcomes among patients who completed treatment under directly-observed treatment
provided by the Centre for Epidemiology and
Population Health, Australian National University, short-course (DOTS), with a particular focus on recurrence in MDR-TB. We reported mortal-
as the PhD study project for Yanni Sun, a PhD ity elsewhere [8]. Here we report causes of recurrence, particularly multidrug resistance, over
candidate at the Centre. Yanni Sun also paid in part nine years in Henan Province China.
for the study as the internal budget was
insufficient. The funders had no role in study
Methods
design, data collection and analysis, decision to
publish, or preparation of the manuscript. Study setting
Competing Interests: The authors have declared Henan Province is in the middle of China and had a population of 99.1 million people in 2010
that no competing interests exist. [13]. Although the incidence of TB in Henan (71.1 per 100,000 in 2010) is close to the China
national average, the absolute number of notified TB cases in 2010 (68,042) was the second
highest among all provinces [13]. DOTS, as recommended by the World Health Organization
(WHO), was implemented progressively in Henan Province starting in 1996, and the reported
coverage by county reached 100% in 2005.

Study population and methods

Our study sample was drawn from a 2001 representative drug resistance survey (DRS) sup-
ported by the World Health Organization (WHO) in Henan Province. We chose Henan
because it had the second highest number of TB and MDR-TB cases and had conducted high
quality DRS in 2001. A total of 1,854 newly-registered HIV-negative, sputum smear-positive
cases from 30 of 159 counties and districts, who had been treated for TB between July 2001
and June 2002, were selected at random from the DRS and resurveyed. The survey’s methods,
findings for initial treatment outcomes, and 1,487 cases with culture results and complete
medical records are reported elsewhere [14]. Among these 1,487 cases, there were 192 MDR-
TB patients and 1,295 non-MDR-TB patients. One thousand two hundred and sixty of the
1,487 cases completed their treatment and were eligible for inclusion in the follow-up study.
Among these, 112 were culture-proven MDR-TB patients and 1,148 were non-MDR-TB
patients [14].
The follow-up study was powered to detect a 2-fold ratio in risk of recurrence over nine
years between the MDR and the non-MDR groups, using a 2-sided significance level of 0.05
and a power of 0.8, and assuming a 40% recurrence in the MDR-TB group. The predicted
recurrence rate in MDR-TB was based on literature and expert opinion of local experts at the
TB Control Institute (TBCI) [9, 15–17]. Non-MDR patients were oversampled in a 2:1 ratio to
increase precision. The minimum required sample sizes were 133 non-MDR patients and 67
MDR patients; the samples were increased proportionately to 150 and 100 patients, respec-
tively, to account for loss to follow up.
Cases were selected at random from the baseline dataset. Patients surveyed in 2001 were
listed, and a unique number was allocated to each individual in the dataset. A random number
table was then generated using a Microsoft™ Excel spreadsheet. Next, a starting point in the
random number table was chosen and was read for selecting cases for MDR-TB group. A cor-
responding number in the dataset led to a case being selected as part of the study sample. This
process was repeated until 100 cases had been selected for the MDR-TB group from 17 coun-
ties and the non-MDR-TB cases were then randomly selected from the same seventeen coun-
ties by repeating the process until 150 cases had been chosen (Fig 1).

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 2 / 11

 MDR-TB and TB Recurrence

Fig 1. Selection of the study population in 2010 (reprinted, originally printed @BMC Public Health
2015 [8]).
doi:10.1371/journal.pone.0168865.g001

Before starting the fieldwork, a management team (2 RAs from TBCI and the first author)
and an interview teams (doctors or nurses at selected county CDCs) were formed. The two
RAs had been working on TB at TBCI for many years and were very familiar with local TB
Control Departments (TBCDs) and staff who could facilitate the investigation. Discussion on
the research content, survey methods and requirements was undertaken with them. An addi-
tional 30 skilled staff at county TBCDs were recruited as interviewers. They included 24 doc-
tors and six nurses working at county TBCDs. All had majored in medicine, public health and
nursing and had participated in one or more nationwide TB surveys.
The first author held a one-day training workshop in Zhengzhou for interviewers from
study counties. The first author and the two RAs provided telephone training for those unable
to attend.
Trained interviewers went to selected patients’ households on the sample list in each village.
The village doctors and leaders helped interviewers to locate the interviewees in the surveyed
village. The sites of interviews were usually respondents’ homes, but occasionally were in yards
where they were working or at clinics. Adult family members were allowed to attend the inter-
views to provide supplementary information. If patients were not available for interview, other
adult family members (partners, parents or siblings), or their grown-up offspring were inter-
viewed. Each interview lasted half to one hour.
The first author and the two RAs extracted data on demographics, treatment history, drug
susceptibility test (DST) results, and treatment outcomes from the DRS. All information was
verified against patients’ medical records. Discrepancies found, such as age, diagnosis year and
residential address, were resolved with information obtained from county or district TB dis-
pensaries and phone calls to patients and family members. We conducted interviews from

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 3 / 11

 MDR-TB and TB Recurrence

Fig 2. Geographical location of counties surveyed in Henan Province, 2001 & 2010.
doi:10.1371/journal.pone.0168865.g002

January to May 2010. Sputum status was obtained from laboratory and medical records in
county or district anti-TB departments. If a patient had been reported to have died after com-
pletion of treatment in 2002, his or her medical-file information, including date and cause of
death, was abstracted. If a patient could not be interviewed because they had died, moved out
of the home, or were absent from the home when the interview was attempted, we interviewed
family members, neighbours, village doctors, and other village leaders to collect the required
information. The respondents included 129 (55.0%) patients and 105 (45.0%) family members
and village doctors.
We were unable to contact 14 of the 100 MDR-TB patients, and we excluded 2 of the 150
non-MDR-TB patients due to poor data quality. The final dataset included 86 MDR-TB and
148 non-MDR-TB patients from 17 counties (Fig 2).

Treatment regimens and outcomes

Treatment regimens followed the Chinese National Tuberculosis Control program (NTP)
treatment guidelines [18], as recommended by WHO [19]. Treatment of new smear-positive
patients consisted of 2 months of H, R, pyrazinamide (Z), and ethambutol (E) followed by 4
months of H and R three times weekly. Patients who had previously received at least one
month of TB treatment (i.e. retreatment patients) received 2 months of H, R, Z, S and E, fol-
lowed by 6 months of H, R, and E three times weekly. Doctors directly observed drug adminis-
tration at the health facility throughout treatment. The treatment regimens and outcomes have
been presented in detail elsewhere [20]. Treatment outcomes were assessed using WHO defi-
nitions [19] and were recorded in routine treatment profiles. Treatment success is defined as

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 4 / 11

 MDR-TB and TB Recurrence

either cure or treatment completed. Cure is defined as a patient whose sputum smear or cul-
ture is positive at the beginning of the treatment but smear- or culture-negative in the last
month of treatment and on at least one occasion before this. Treatment completed need not
meet the criteria for cure or failure. Failure is defined as sputum smear-positive at 5 months or
later during treatment. Death is defined as a patient who dies for any reason during the course
of treatment (the cause of death during TB treatment was not recorded).Recurrence was defined
as a new clinical and/or microbiological diagnosis of TB in any patient who had correctly com-
pleted treatment for their first episode. Participants who had smoked before acquiring TB were
considered smokers. We defined harmful alcohol consumption for males 60g of pure alcohol
and females 40g of pure alcohol on average per occasion.

Data management and statistical analysis

All data were double entered in EpiData 3.1 (The EpiData Association, Odense, Denmark,
2008), and internal consistency was determined. Internal discrepancies were checked against
the original forms by the first author. Statistical inference followed standard procedures for
categorical data [21]. Pearson’s ! 2 test or Fisher’s exact test was used to test for differences in
proportions. Two-sided p-values of <0.05 were considered significant. The overall recurrence
rates, expressed as cases per 1,000 person-year (PY), were compared at two-year intervals. The
follow-up period, from the date of TB treatment completion under DOTS until recurrence,
death, transfer, completion of follow-up or the end of the study, was computed as the time
passed since the end of TB treatment. Cox proportional hazards regression was performed with
time dependant covariate in relation to TB recurrence, using a forward inclusion approach.
Variables significantly correlated in the univariate model with p-value <0.05 and variables of
epidemiological interest were included in the multivariate model. Hazard ratios (HR) and their
95% confidence intervals (CI) were used to assess association. We plotted cumulative incidence
curves, unadjusted and adjusted by age and other covariates over drug resistance status. Stata
software (Version 12; Statacorp) was used for data analysis and preparation of graphs.

Ethical considerations
The original 2001 MDR-TB surveillance survey was approved by the Ethics Committee of the
Department of Health of Henan Province, based on Chinese national ethical regulations. The
follow-up study in 2010 was approved by the Ethics Committee of the Tuberculosis Control
and Prevention Institute of Henan Provincial Center for Disease Control and Prevention and
by the Human Research Ethics Committee of the Australian National University on 12 Novem-
ber, 2009 (Protocol 2009/553). Information sheets and consent forms were provided to partici-
pants, and consent was obtained from all study participants. Participation was voluntary, and
confidentiality of data was maintained.

Results
Attributes of the study population
The median age of the study population was 49 years (IQR 20–84). Among the study popula-
tion, 73.1% were male. A statistically significant difference in recurrence rate between MDR
and non-MDR-TB patients was seen after 9 years (61.3% versus 27.9%; p<0.001). There was
no significant difference in marital status between recurrent cases and others. The two groups
were similar in occupation; most (⇡85.0%) were farmers. Recurrent TB cases were less edu-
cated (61.1% versus 44.2%, p = 0.02), and had non-statistically-significant differences from
other cases in smoking (30.7% versus 22.7%, p = 0.21) and drinking alcohol (19.4% versus

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 5 / 11

 MDR-TB and TB Recurrence

12.8%, p = 0.20). Slightly more recurrent TB cases had diabetes compared to those who did not
have recurrence (p = 0.55). There was a trend by group of working outside for cash following
TB treatment completion (5.2% versus 3.2%), although the difference was not statistically sig-
nificant. Most patients (⇡90%) paid for treatment out-of-pocket, although 88% received some
financial help from community and government. Patients with recurrence were more likely to
live in houses with fewer than three bedrooms (33.3% versus 22.2%; p = 0.08). Recurrence was
more common in those with annual household incomes less than 10,000 Yuan (63.9% versus
37.4%; p<0.001) (Table 1).

Table 1. Attributes of the study population by long-term recurrence to 2010a.

Patient attributes Total n = 234 (%) Free of TB n = 165 (%) Recurrence n = 69 (%) p-value
Median age (years) (IQRb) 49 (20–84) 47 (23–84) 53.5 (20–86) 0.33
Sex
Female 63 (26.9) 48 (27.9) 15 (24.2)
Male 171 (73.1) 124 (72 1) 47 (75 8) 0.57
Drug resistance status
Non-MDR-TB 148 (63.3) 124 (72 1) 24 (38 7)
MDR-TB 86 (36.7) 48 (27 9) 38 (61 3) < 0.001
Marriage status
Married 185 (79.4) 137 (80.1) 48 (77.4)
Others c 48 (20.6) 34 (19.9) 14 (20.6) 0.65
Occupation
Farmer 200 (85.8) 149 (87.1) 51 (82.3)
Other d 33 (14.2) 22 (12.9) 11 (17.7) 0.34
Education
Middle school 120 (51.3) 96 (55 8) 24 (38 7)
 Primary school 114 (48.7) 76 (44 2) 38 (61 3) 0.02
Smoker 58 (24.8) 39 (22.7) 19 (30.7) 0.21
Alcohol drinker 34 (14.5) 22 (12.8) 12 (19.4) 0.20
Work outside e for cash after TB 11 (4.7) 2 (3.2) 9 (5.2) 0.52
cured
Health insurance
Insured 27 (11.5) 21 (12.2) 6 (9.7)
Own expense 207 (88.5) 151 (87.8) 56 (90.3) 0.59
Community/government offered 195 (88.6) 143 (88.8) 52 (88.1) 0.89
financial help
Number of bedrooms in patient’s home
4 170 (74.9) 130 (77 8) 40 (66 7)
3 57 (25.1) 37 (22 2) 20 (33 3) 0.08
Annual household income (Yuan)
10,000 129 (55.6) 107 (62 6) 22 (36 1)
< 10,000 103 (44.4) 64 (37 4) 39 (63 9) < 0.001
a
Those with missing values were excluded from the comparisons.
b
Interquartile range.
c
Other includes single, divorced and widowed.
d
Other includes worker, teacher, cadre, self-employed, housewife, students retired, no job and others.
e
Patient worked outside hometown for cash as a migrant worker.

doi:10.1371/journal.pone.0168865.t001

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 6 / 11

 MDR-TB and TB Recurrence

Recurrence rates
The overall recurrence rate was 35/1,000 PY (18/1,000 PY among those 10–29 years of age,
and 31, 54, and 39, respectively, for those aged 30–44, 45–59, and 60 years or above). The
recurrence rates were 20/1,000 PY among non-MDR-TB and 65/1,000 PY among MDR-TB
cases. The highest recurrence rates were found between the eighth and ninth year after com-
pletion of treatment (74/1,000 PY), followed by the first two years (48/1,000 PY), and the third
to forth (28/1,000 PY).

Factors associated with TB recurrence

In univariate analysis, recurrence was significantly associated with MDR-TB, lower education
attainment, having fewer than 3 bedrooms in the home, and having an annual household
income less than 10,000 Yuan (Table 2). In multivariate analysis, recurrence was significantly
associated with MDR (HR 2 75; 95% CI 1 58–4 79) and with an annual household income less
than 10,000 Yuan (HR 2.05; 95% CI 1.11–3.80). The mean time for recurrence among MDR-TB
patients was 5.7 years, compared to 7.2 years among non-MDR-TB patients (Fig 3).

Treatment outcomes of patients with recurrent TB on a re-treatment

regimen
All patients with recurrence of TB were treated with a re-treatment regimen. Treatment out-
comes are shown in Table 3: 40.3% (25/69) of recurrent patients were cured, 31.9% (22/69)
completed treatment, 61.3% (38/69) died, 7.2% (5/69) defaulted, 18.8 (13/69) had treatment
failure, and 5.8 (4/69) were lost to follow-up.

Discussion
In our study, about one third of participants (29.5%, 69/234) suffered recurrence after comple-
tion of treatment under DOTS. The overall recurrence rate of the followed-up patients was

Table 2. Factors associated with TB recurrence in the study population, 2010§.

Patient attributes Univariate unadjusted HR (95% CI) p-value Multivariable adjusted HR (95% CI) p-value
Male sex 1 04 (0 58–1 85) 0.89 0 99 (0 55–1 81) 0.98
Age groups (years)
44 1 1
45–59 1.48 (0.78–2.81) 0.23 1.03 (0.52–2.05) 0.93
60~ 1.27 (0.67–2.42) 0.46 0.96 (0.46–1.99) 0.92
Drug resistance status
Non-MDR-TB 1.00 1.00
MDR-TB 3 37 (1 98–5 73) < 0.001 2 75 (1 58–4 79) < 0.001
Education
Middle school 1.00 1.00
 Primary school 1 95 (1 14–3 36) 0.01 1 72 (0 88–3 35) 0.11
Number of bedrooms in patient’s home
4 1.00 1.00
3 1 74 (1 01–3 00) 0.04 0 97 (0 52–1 79) 0.92
Annual household income (Yuan)
10,000 1.00 1.00
< 10,000 2 52 (1 47–4 32) 0.001 2 05 (1 11–3 80) 0.02

§Those with missing values were excluded.

doi:10.1371/journal.pone.0168865.t002

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 7 / 11

 MDR-TB and TB Recurrence

Fig 3. Effect of drug resistance on recurrence over time.

doi:10.1371/journal.pone.0168865.g003

35/1,000 PY, with a much higher rate (65/1,000 PY) among MDR-TB patients. We found that
TB recurrence was strongly associated with MDR-TB infection and patient annual household
income less than 10,000 Yuan. Moreover, MDR-TB patients had a shorter disease-free period
compared to non-MDR-TB patients (5.7 vs 7.2 years, p<0.01). Importantly, the 9-year treat-
ment outcomes at follow-up for the recurrence group were very poor, with many deaths
(61.3%) and a substantial proportion of failed treatments (18.8%).
We found higher recurrence rates than in the UK (around 23/1,000 PY) [4], Malawi (3.1%
of all registered TB patients between 1 July 1999 and 30 June 2000) [22], Vietnam (8.6%, 21/
244 TB patients surveyed) [3], and Shanghai (3.1%, 202/6,442 over a five-year follow-up) [10].
However, the recurrence rate we found was lower than that measured in a study conducted in
Uzbekistan (36.0%, 42/118 patients followed up a median of 22 months) [2]. The recurrence
rate we found among MDR-TB patients was similar to that reported in Heilongjiang Province
(61.0%, 79/129 patients surveyed over a four-year follow-up) [9].

Table 3. Treatment outcomes of patients with recurrent TB by 2010.

Treatment outcome Patients with recurrence n = 69 (%)
Enrolled for treatment 69 (100)
Cured 25 (40.3)
Completed 22 (31.9)
Died 38 (61.3)
Defaulted 5 (7.2)
Failed treatment 13 (18.8)
Lost to follow-up 4 (5.8)
doi:10.1371/journal.pone.0168865.t003

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 8 / 11

 MDR-TB and TB Recurrence

We also found that MDR infection was a strong predictor of recurrence, a finding that was
shown in the Uzbekistan study [2]. Long term outcomes for recurrent cases in our study were
poorer than those reported in Malawi [22]. From findings reported in those studies, poor
long-term outcomes may be closely associated with drug resistance status [2]. The initially-
reported treatment success rate among smear-positive patients was 85.5% and was 76.6% for
MDR-TB patients under DOTS in Henan [20], meeting the WHO targets of 85% and 75% [19,
23]. However, we found that about 30% of patients (61.0% of MDR-TB patients) were again
diagnosed with active TB after completing treatment. Recurrence after treatment completion
is common and the initially reported “cure” rate is not reliable [2].
Our results lead us to question whether the cause of recurrences of disease were true relapses
or reinfection with new strains of TB. If it was the former, then DOTS did not truly cure those
patients [2]. The DOTS program should be re-evaluated to determine whether drug resistance,
poor adherence or low quality drugs are causes for relapse [2].
We believe that our study provides valuable information on the recurrence of TB and
MDR-TB in Henan Province, China, although our study has limitations. We could not follow
up all patients in the 30 counties that were in the baseline survey in 2001. Due to resource limi-
tations, we could not evaluate DOTS in the Province. Some data were self-reported. Annual
household income and socioeconomic status may have been underestimated.
We believe that our study has important implications for TB control in China and world-
wide, especially for countries with high TB burdens [8, 9, 24]. High recurrence rates pose con-
tinuing threats to communities and challenge TB control programs. It is well known that
MDR-TB has poor treatment outcomes [23]; these outcomes will be made worse by high
recurrence rates. Poorer outcomes place a huge social, economic, and psychological burden on
patients, families, and communities.
TB is a disease of poverty, and we think it should be a priority to alleviate the economic bur-
den on TB patients. The Chinese government has designated MDR-TB as one of eight priority
diseases eligible for 70% reimbursement in the country’s rural health insurance program.
However, the reimbursement proportion may need to be increased, and additional financial
assistance may need to be provided to ensure that the poorest and most vulnerable patients
have access to care and are able to complete their treatment.

Conclusion
This study demonstrated very poor long-term outcomes following treatment success for TB
patients in a well-developed DOTS program (100% coverage in 2005) in China. From our
findings, we conclude that in Henan, China, and potentially in other settings with similar
drug resistance burdens [1–5, 7, 17, 25–28], the highest probability of TB recurrence occurs
among the most vulnerable populations—patients with poor economic status and MDR-TB
patients. Treatment outcomes reported in routine surveillance data with short follow-up
time may overestimate treatment success. Treatment failure leads to morbidity and mortal-
ity and hampers TB control. Our findings also suggest that services and management for
MDR-TB in China should be strengthened and NTP for MDR-TB patients should be scaled
up urgently. Tailored interventions to control TB recurrence should be developed and eval-
uated in clinical trials.

Acknowledgments
The authors wish to thank all the research teams in the 17 counties for collecting data in
Henan Province. Wang Guojie, Zhen Xinan and Liu Zhanfeng performed data collection in

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 9 / 11

 MDR-TB and TB Recurrence

the field. Their efforts were critical in ensuring collection of very high quality data. We also
thank Dr Gillian Hall and Dr Lance Rodewald for their helpful comments on the manuscript.

Author Contributions
Conceptualization: AS YS.
Data curation: YS.
Formal analysis: YS.
Funding acquisition: YS.
Investigation: YS.
Methodology: AS YS DH HV.
Project administration: YS.
Resources: YS AS.
Validation: YS DH AS.
Writing – original draft: YS.
Writing – review & editing: YS AS DH HV.

References
1. Millet J, Orcau A, De Olalla P, Casals M, Rius C and Cayla J, Tuberculosis recurrence and its associ-
ated risk factors among successfully treated patients. Journal of Epidemiology and Community Health,
2009. 63(10): p. 799–804 doi: 10.1136/jech.2008.077560 PMID: 19179367
2. Cox H, Kebede Y, Allamuratova S, Ismailov G, Davletmuratova Z, Byrnes G, et al., Tuberculosis recur-
rence and mortality after successful treatment: impact of drug resistance. PLoS Med, 2006. 3(10): p.
e384.eng doi: 10.1371/journal.pmed.0030384 PMID: 17020405
3. Vree M, Huong NT, Duong BD, Sy DN, Van LN, Hung NV, et al., Survival and relapse rate of tuberculo-
sis patients who successfully completed treatment in Vietnam. Int J Tuberc Lung Dis, 2007. 11(4): p.
392–7.eng PMID: 17394684
4. Panjabi R, Comstock GW and Golub JE, Recurrent tuberculosis and its risk factors: adequately treated
patients are still at high risk. Int J Tuberc Lung Dis, 2007. 11(8): p. 828–37.eng PMID: 17705947
5. Chiang CY, Enarson DA, Yu MC, Bai KJ, Huang RM, Hsu CJ, et al., Outcome of pulmonary multidrug-
resistant tuberculosis: a 6-yr follow-up study. European Respiratory Journal, 2006. 28(5): p. 980 doi:
10.1183/09031936.06.00125705 PMID: 16837502
6. Avendano M and Goldstein RS, Multidrug-resistant tuberculosis:Long term follow-up of 40 non-HIV-
infected patients. Can Respir J, 2000. 7
7. Geerligs WA, Altena Rv, Lange WCMd, Soolingen Dv and Werf TSvd, Multidrug-resistant tuberculosis:
long-term treatment outcome in the Netherlands. The International Journal of Tuberculosis and Lung
Disease, 2000. 4(8): p. 758–764 PMID: 10949328
8. Sun Y, Harley D, Vally H and Sleigh A, Comparison of characteristics and mortality in multidrug resistant
(MDR) and non-MDR tuberculosis patients in China. BMC Public Health, 2015. 2015; 15:1027. doi: 10.
1186/s12889-015-2327-8 PMID: 26444417
9. He GX, Xie YG, Wang LX, Borgdorff MW, van der Werf MJ, Fan JH, et al., Follow-up of patients with
multidrug resistant tuberculosis four years after standardized first-line drug treatment. PloS one, 2010.
5(5)
10. Shen G, Xue Z, Shen X, Sun B, Gui X, Shen M, et al., The study recurrent tuberculosis and exogenous
reinfection, Shanghai, China. Emerg Infect Dis, 2006. 12(11): p. 1776–8.eng doi: 10.3201/eid1211.
051207 PMID: 17283636
11. WHO, Global tuberculosis report 2015. 2015, World Health Organization: Geneva, Switzerland. p.
WHO/HTM/TB/2015.22.

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 10 / 11

 MDR-TB and TB Recurrence

12. Chen M, Li RZ., Ruan YZ., Xu CH., Global Fund for MDR-TB Control Project in China-achievement and
experience. 2015, Beijing: People’s Medical Publishing House.
13. Henan Statistics Bureau, Henan Statistical Yearbook 2011. 2012, Henan Provincial Bureau of Statis-
tics: Zhengzhou, Henan Province, China.
14. Du CM, Wang GB, XU JY, Wang GJ, HU HY, Zhen XA, et al., The study on the second round surveil-
lance of drug resistance in tuberculosis and its trends in Henan, China. The Journal of The Chinese
Antituberculosis Association, 2006. 28(2)
15. Paramasivan CN and Venkataraman P, Drug resistance in tuberculosis in India. Indian journal of medi-
cal research, 2004. 120(4): p. 377–386 PMID: 15520487
16. Valadas E and Antunes F, Tuberculosis, a re-emergent disease. European Journal of Radiology, 2005.
55(2): p. 154–157 doi: 10.1016/j.ejrad.2005.04.013 PMID: 15905058
17. Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, et al., Treatment outcomes and survival based on
drug resistance patterns in multidrug-resistant tuberculosis. American Journal of Respiratory and Criti-
cal Care Medicine, 2010. 182(1): p. 113–119 doi: 10.1164/rccm.200911-1656OC PMID: 20224066
18. Xiao DL, Zhao MG and Wang Y, Guidelines for Implementation the National Tuberculosis Control Pro-
gram C.C. National Center for Tuberculosis Control and Prevention, Editor. 2008, Beijing Union Medi-
cal College Press: Beijing.
19. WHO, Treatment of tuberculosis: guidelines. 2009, World Health Organization: Geneva, Switzerland.
p. WHO/HTM/TB/2009.420.
20. Wang GJ, Xu JY, Wang GB, Zhen XA, Gao SY and Du CM, Impact of anti-tuberculosis drug resistance
on treatment outcome of pulmonary tuberculosis patients receiving directly obeserved treatment strat-
egy in Henan Province, China. Chinese journal of tuberculosis and respiratory diseases, 2006. 29(8):
p. 527–530 PMID: 17074265
21. Kirkwood BR and Sterne JC, Essential medical statistics. Second edition ed. 2003, Carlton, Australia:
Blackwell Science.
22. Salaniponi FM, Nyirenda TE, Kemp JR, Squire SB, Godfrey-Faussett P and Harries AD, Characteris-
tics, management and outcome of patients with recurrent tuberculosis under routine programme condi-
tions in Malawi. Int J Tuberc Lung Dis, 2003. 7(10): p. 948–52.eng PMID: 14552564
23. WHO, Multidrug and extensively drug-resistant TB (M/XDR-TB), 2010 Global Report on Surveillance
and Response. 2010, World Health Organiztion: Geneva, Switzerland.
24. WHO, Global Tuberculosis Control: WHO report 2010. 2011, World Health Organization: Switzerland.
p. WHO/HTM/TB/2010.7.
25. Sun XY, Jackson S, Carmichael G and Sleigh AC, Catastrophic medical payment and financial protec-
tion in rural China: evidence from the New Cooperative Medical Scheme in Shandong Province. Health
Economics, 2009. 18(1): p. 103–119 doi: 10.1002/hec.1346 PMID: 18283715
26. WHO, Guidelines for the programmatic management of drug-resistant tuberculosis. 2008, World
Health Oranization: Geneva, Switzerland. p. WHO/HTM/TB/2008.402
27. Gilpin CM, Simpson G, Vincent S, O’Brien TP, Knight TA, Globan M, et al., Evidence of primary trans-
mission of multidrug-resistant tuberculosis in the Western Province of Papua New Guinea. Medical
Journal of Australia, 2008. 188(3): p. 148–152 PMID: 18241170
28. Zhao M, Li X, Xu P, Shen X, Gui X, Wang L, et al., Transmission of MDR and XDR tuberculosis in
Shanghai, China. PloS one, 2009. 4(2): p. e4370 doi: 10.1371/journal.pone.0004370 PMID: 19190774

PLOS ONE | DOI:10.1371/journal.pone.0168865 January 24, 2017 11 / 11