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SUPPLEMENT ARTICLE
The World Health Organization/International Union
against Tuberculosis and Lung Disease Global Project
on Surveillance for Anti-Tuberculosis Drug
Resistance: A Model for Other Infectious Diseases
Mohamed Abdel Aziz and Abigail Wright
Stop TB Department, World Health Organization, Geneva, Switzerland
Tuberculosis remains a global epidemic, with one-third of the population infected and 9 million active cases.
Mono- and multidrug resistance in 6 World Health Organization (WHO) regions have been assessed in 40%
of the global cases diagnosed by positive results of sputum testing. The 2004 report of the WHO Global Project
on Anti-Tuberculosis Drug Resistance Surveillance confirms earlier findings that drug-resistant tuberculosis
is ubiquitous and that multidrug-resistant tuberculosis has increased alarmingly. Control of tuberculosis,
which is undermined by the human immunodeficiency virus (HIV) epidemic, is seriously jeopardized by
multidrug resistant strains, for which treatment is complex, more costly, and less successful. Challenges for
high-burden countries include implementation of the DOTS strategy and management of identified multidrug
resistance with DOTS-Plus. Strengthening of the laboratory network in conjunction with improvement of
surveillance, elucidation of the impact of HIV on transmission of tuberculosis and on amplification of resistance
at individual and population levels, and implementation of private sector policies on drug resistance are
imperative. New diagnostic tools and drugs are needed to expedite early detection and cure of multiresistant
strains.
Since their discovery during the last century, anti-tuberculosis drugs have substantially reduced the mortality and morbidity of tuberculosis in the world. However, these gains are seriously jeopardized by the
emergence and spread of mycobacteria resistant to the
inexpensive and effective first-choice, or “first-line,”
drugs. The World Health Organization (WHO) has estimated that one-third of the population worldwide is
infected with tuberculosis. The estimated incidence of
tuberculosis in 2002 was 8.8 million cases, of which 3.9
million had positive smear and/or culture results [1].
The National Tuberculosis Control Program (NTP) or
its equivalent is organized in many countries to set the
Reprints or correspondence: Dr. Mohamed Abdel Aziz, World Health
Organization, Stop TB Department, Ave. Appia 20, CH-1211 Geneva 27, Switzerland
([email protected]).
Clinical Infectious Diseases 2005; 41:S258–62
2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4104S4-0008$15.00
S258 • CID 2005:41 (Suppl 4) • Aziz and Wright
policy and ensure the prevention and proper management of tuberculosis cases. One of the aims of the NTP
is to minimize the development of drug resistance.
Combination drug therapy, as well as directly observed
intake, were adopted as pillars of the DOTS strategy,
largely to prevent the emergence of drug resistance.
Exposure to a single drug because of poor adherence
to treatment, inappropriate prescription, irregular drug
supply, and/or poor drug quality suppresses the growth
of bacilli susceptible to that drug but permits the multiplication of pre-existing drug-resistant organisms.
This phenomenon is called “acquired resistance.” Subsequent transmission of such bacilli to other persons
may lead to disease that is drug-resistant from the outset, a phenomenon known as primary resistance. Because the terms are somewhat conceptual, the phrases,
“resistance among new cases” and “resistance among
previously treated cases” have been adopted as proxy
measures [2–4]. In addition, the emergence of drug
resistant Mycobacterium tuberculosis has been associated with a
variety of management-, health provider–, and patient-related
factors. In some countries, management-related factors may include the lack of availability of a standardized therapeutic regimen
or poor implementation compounded by frequent or prolonged
shortages of drug supply in areas with inadequate resources or
political instability. Use of anti-tuberculosis drugs of unproven
quality is an additional concern, as is the sale of these medications
over the counter and on the black market. Moreover, incorrect
management of individual cases, difficulties in selecting the appropriate chemotherapeutic regimen with the right dosage, and
patients’ nonadherence to prescribed treatment contribute to the
development of drug resistance [5–7].
Surveillance of anti-tuberculosis drug resistance is therefore
an essential tool for monitoring the effectiveness of tuberculosis
control programs and, through policy development, for improving national and global tuberculosis control.
EVOLUTION OF A GLOBAL SURVEILLANCE
SYSTEM
In the early 1990s, reports of institutional outbreaks of multidrug-resistant (MDR) tuberculosis, often associated with HIV
in hospital populations, in New York and Florida as well as in
countries in Europe and South America highlighted drug resistance as an emerging threat to the control of tuberculosis.
Reports of drug-resistant forms of tuberculosis were many and
varied, making estimates of the magnitude of the problem
nearly impossible [8–20]. Concerned about the lack of reliable
and comparable data about anti-tuberculosis drug resistance,
WHO joined forces in 1994 with the International Union
against Tuberculosis and Lung Disease and other partners to
develop a set of guidelines [21] for the surveillance of resistance
to 4 of the 5 anti-tuberculosis drugs: rifampicin, isoniazid,
ethambutol, and streptomycin.
The guidelines were developed to assist national tuberculosis
programs in adopting country-specific surveillance systems for
resistance to anti-tuberculosis drugs that would measure susceptibility to the first-line drugs. The standardization of sampling methods, laboratory techniques, and data analysis as well
as the application of quality assurance and proficiency testing
methods allow comparability of data between countries.
The global project guidelines are based on the following principles:
1.
The sample of specimens should be representative of
the patients with tuberculosis in the country or geographic
setting under study, and the sample size should be determined
to permit standard epidemiological analysis. It is recommended
that surveillance for resistance to anti-tuberculosis drugs covers
the whole country or geographic area and that the sample size
is derived from the total number of bacteriologically confirmed
cases (i.e., those with positive results of sputum testing or of
culture) in the country.
2.
The patient’s history should be carefully obtained, and
available medical records reviewed to clearly determine whether
the patient has received prior anti-tuberculosis drugs. This is
essential to distinguish between drug resistance among newly
diagnosed cases and drug resistance among previously treated
cases.
3.
The laboratory methods for testing susceptibility to
anti-tuberculosis drugs (DST methods) should be selected from
among those that are internationally recommended. Four DST
methods have been standardized and are widely used throughout the world [4]: the proportion method and its economic
and standard variants, the resistance ratio method, the absolute
concentration method, and the BACTEC 460 radiometric
method.
Comparability of data resulting from any of the above 4
methods is ensured through participation in an international
quality assurance program conducted by the Supranational Reference Laboratory (SRL) Network. SRLs provide technical assistance to the National Reference Laboratory (NRL) during
the preparation, implementation, and evaluation of survey results. Often these relationships continue well beyond the course
of a survey. Currently there are 23 SRLs worldwide. The network is coordinated by the Laboratory of Mycobacteriology of
the Tropical Institute in Antwerp, Belgium.
The quality assurance program consists of 3 levels:
1.
Annually, the coordinating SRL sends a panel of 10
duplicate drug-susceptible and drug-resistant strains to the network. The efficiency, sensitivity, and specificity of DST of the
4 drugs as well as the intralaboratory reproducibility obtained
by the SRLs are evaluated through judicial determination.
Trends of the individual performance of the SRL are monitored
yearly.
2.
The SRL will make an initial assessment of the NRL
and, contingent on adherence to biosafety standards and necessary equipment, will send the coded panel of strains for proficiency testing to the NRL. The results of the NRL are then
compared with the coded results at the SRL to determine
whether a survey can commence or whether further training
is required.
3.
The SRL is also responsible for quality assurance during
the course of a drug resistance survey. A sample of the strains
isolated during the survey is sent from the NRL to the SRL to
be retested. The results should be compared for agreement
between laboratories for each of the 4 drugs. It is recommended
that 100% of the resistant and 10%–20% of the susceptible
strains be sent to the SRL, or no less than 10% of the total
sample. The method and percentage must be previously agreed
Global Anti-Tuberculosis Drug Resistance • CID 2005:41 (Suppl 4) • S259
upon between the NRL and the SRL, and a schedule for the
strain exchange should be arranged (table 1).
Table 1. Coverage of the global project, by World Health
Organization (WHO) region, 1994–2002.
Total in
region for 2001
WHO region, parameter
RESULTS
African Region
Total settings
The global project resulted in the production of reports in 1997,
2000, and 2004 [2, 3, 22–24]. The first report included data
from 35 geographic settings (a geographic setting is defined as
a country or subnational setting—e.g., a province, district, or
oblast) collected between 1994 and 1997, and the second report
provided data on 58 geographic settings involved in the global
project between 1997 and 1999.The most recent report includes
data from 77 geographic settings collected between 1999 and
2002. To date, the global project has collected data on DST
results from areas representing 40% of the tuberculosis cases
worldwide confirmed by positive results of sputum testing.
The third report gives a global overview of the magnitude
and distribution of resistance to anti-tuberculosis drugs and
compares the prevalence of resistance to any drug, monoresistance, and multidrug resistance across 6 WHO regions. The
third report analyzes trends in resistance to anti-tuberculosis
drugs between 1994 and 2002, explores determinants of resistance, estimates the magnitude of the multidrug resistance in
the participating countries, and describes the most prevalent
patterns of drug resistance. Data from the 77 included geographic settings are distributed as follows: data from new cases
collected from 74 settings, previously treated cases from 66
settings, and combined cases (i.e., new and previously treated
cases) from 69 settings. The study of the dynamics of resistance
over time summarizes data on new cases from 106 settings, on
previously treated cases from 94 settings, and combined cases
from 96 settings (figure 1).
Data from the third report indicate that the prevalence of
resistance to any anti-tuberculosis drug among new cases
ranged from 0% in a few western European countries to 57.1%
in Kazakhstan (median, 10.2%). Prevalence of MDR tuberculosis among new cases ranged from 0% in Andorra, Cambodia, Iceland, Luxembourg, Malta, New Zealand, Oman, Scotland, Slovenia, and Switzerland to 14.2% of all new cases
confirmed by positive result of smear testing in Kazakhstan.
The median prevalence of resistance among settings surveyed
since 1994 is between 1% and 2%; however, estimates taking
into account areas not yet surveyed but likely to have higher
prevalence of resistance put the global prevalence at 3.2% [25]
(this estimate incorporates all newly detected cases including
relapse cases). In general, high prevalences of drug resistance
have been reported from countries with a poor history of control of tuberculosis. Countries of the former Soviet Union and
China have consistently reported the highest prevalences of
resistance.
S260 • CID 2005:41 (Suppl 4) • Aziz and Wright
Project
total (%)
…
Total countries
Population
All tuberculosis cases
a
New tuberculosis cases
24
46
17 (37)
655,515,000
217,418,000 (33)
811,172
394,785 (49)
375,997
186,139 (50)
Region of the Americas
Total settings
…
Total countries
Population
All tuberculosis cases
a
New tuberculosis cases
18
44
18 (41)
842,442,000
802,922,000 (95)
229,873
218,603 (95)
129,536
119,926 (93)
Eastern Mediterranean Region
Total settings
…
Total countries
Population
All tuberculosis cases
5
23
5 (22)
496,422,000
174,076,000 (35)
165,060
a
New tuberculosis cases
68,924
11,480 (7)
8022 (12)
European Region
Total settings
…
Total countries
Population
All tuberculosis cases
a
New tuberculosis cases
39
51
36 (71)
874,221,000
476,395,000 (54)
368,136
121,552 (33)
86,012
41,107 (48)
Southeast Asian Region
Total settings
…
Total countries
Population
All tuberculosis cases
a
New tuberculosis cases
6
10
3 (30)
1,559,819,000
166,100,000 (11)
1,414,845
156,999 (11)
561,901
79,363 (14)
Western Pacific Region
Total settings
…
Total countries
Population
All tuberculosis cases
a
New tuberculosis cases
17
36
11 (31)
1,702,487,000
730,926,000 (43)
824,023
400,105 (49)
379,783
193,017 (51)
World
Total settings
…
Total countries
Population
All tuberculosis cases
a
New tuberculosis cases
109
210
90 (43)
6,130,906,000
2,567,837,000 (42)
3,813,109
1,303,524 (34)
1,602,153
627,574 (39)
a
New cases means cases confirmed by positive result of sputum
smear testing.
PUBLIC HEALTH IMPLICATIONS AND FUTURE
PLANS
Ten years have elapsed since the WHO and its partners
launched the global project on Anti-Tuberculosis Drug Resistance Surveillance. Primarily because of the global project, the
prevalence and patterns of drug resistance from areas representing 40% of worldwide cases confirmed by positive results
of sputum testing have been assessed. The SRL network has
Figure 1. World Health Organization/International Union against Tuberculosis and Lung Disease Global Project coverage, 1994–2002. The designations
used and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Dashed lines represent approximate border lines for which there may not yet be full agreement.
accomplished 10 rounds of proficiency testing, the guidelines
for the surveillance of drug resistance have been updated, and
the software used for data entry and analysis, “SDRTB4,” has
been enhanced and a fourth version released in 2003.
In addition to prevalence data generated from drug resistance
surveys, the global project has effected some fundamental improvements in infrastructure for national control of tuberculosis. One example is strengthening of the capacity of the NRL
in participating countries through collaboration between the
NRL and the SRL and participation in an international quality
assurance program. Surveillance activities have also stimulated
cooperation among peripheral laboratories, promoted establishment of a functioning laboratory network within the country, and strengthened synergism between the laboratory network and care providers within the NTP.
The observed increase in prevalence of MDR tuberculosis in
some countries is especially alarming, because treatment of such
cases is much more complex, prolonged, and expensive, even
with the advent of DOTS-Plus and the Green Light Committee.
(The Green Light Committee reviews project applications for
DOTS-Plus pilot projects; projects accepted by the committee
are then granted access to preferentially priced second-line antituberculosis drugs.) In addition, treatment success is lower than
for drug-susceptible cases. High and increasing prevalence of
MDR tuberculosis poses a global threat to control of tuberculosis. Preventive and curative strategies for drug resistance
are available. High-quality implementation of the DOTS strategy is crucial in preventing or minimizing the emergence of
drug resistance. In addition, it is the most cost-effective public
health intervention known to date [26]. The DOTS-Plus strategy to treat identified cases of MDR tuberculosis with the appropriate use of second-line drugs has also been shown to be
feasible and effective in low-resource settings [27].
Information on drug resistance is urgently needed from
countries with a high burden of tuberculosis and those where
a high prevalence of drug resistance is expected because of
historically poor tuberculosis control. It should be noted that
without improvement of the laboratory networks in these countries, it will be difficult, if not impossible, to implement or
prioritize DST for surveillance and/or patient care. Therefore,
high priority must be given to the improvement of laboratory
networks, including quality of smear microscopy, culture, and
DST techniques. Proper implementation of good laboratory
practices, including biosafety measures, should constitute a
main focus of a national strategic plan for strengthening the
laboratory network. In addition, the managerial skills of the
Global Anti-Tuberculosis Drug Resistance • CID 2005:41 (Suppl 4) • S261
head of the NRL must be sufficient to provide constant supervision and high-quality performance of the network. This
will benefit not only the tuberculosis programs but also other
infectious disease programs that rely on the laboratory component, using the same health infrastructure and, in the majority of cases, the same laboratory technicians.
Along with continued expansion of baseline surveillance into
new geographic areas, as well as the monitoring of trends over
time, specific research is required to answer questions regarding
determinants of resistance, interactions between multidrug resistance and HIV, virulence, and transmission. Research into
and development of new diagnostic tools and new tuberculosis
drugs are essential to shorten the length of time to diagnosis
and treatment and to identify and cure cases of drug-resistant
tuberculosis. Although the prospects for new drugs and diagnostics are promising, it appears that a vaccine against tuberculosis will not be available in the near future.
Acknowledgments
We are grateful to EuroTB for their participation and contribution of
European drug resistance surveillance data. This project could not have
succeeded without the support of national authorities and the institutions
that host each of the national and international laboratories.
Financial support. United States Agency for International Development. Laboratory training activities were funded by the Tuberculosis Coalition for Technical Assistance.
Potential conflicts of interest. M.A.A. and A.W.: no conflicts.
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