Clin Chest Med 26 (2005) 197 – 205
The DOTS Strategy for Controlling the Global
Tuberculosis Epidemic
Thomas R. Frieden, MD, MPHa,*, Sonal S. Munsiff, MDa,b
a
New York City Department of Health and Mental Hygiene, 125 Worth Street, New York, NY 10013, USA
b
Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA
In 1997, the Director General of the World Health
Organization (WHO) called the directly observed
treatment, short-course (DOTS) strategy ‘‘the most
important health breakthrough of the decade in terms
of the number of lives it will save’’ [1]. DOTS is
nothing new; Karel Styblo developed the essential
principles of DOTS in the 1980s [1a]. The five
principles of the WHO-recommended DOTS strategy
[2] are:
1. Political and administrative commitment.
2. Case detection, primarily by microscopic ex-
amination of sputum of patients presenting to
health facilities.
3. Standardized short-course chemotherapy given
under direct observation.
4. Adequate supply of good-quality drugs.
5. Systematic monitoring and accountability for
every patient diagnosed.
This article reviews the principles, scientific basis,
and experience with implementation of DOTS and
discusses the relevance of DOTS in the context of
This article is adapted from: Frieden TR. Directly
observed treatment, short course (DOTS): the strategy that
ensures cure of tuberculosis. In: Sharma SK, Mohan A, edi-
tors. Tuberculosis. 2nd edition. New Delhi: Jaypee Brothers
Medical Publishers; 2005 [in press]; with permission.
* Corresponding author.
E-mail address: tfrieden@health.nyc.gov (T.R. Frieden).
0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccm.2005.02.001
multidrug-resistant tuberculosis (MDR-TB) and the
HIV epidemic.
Political and administrative commitment
By any measure, the global burden of tuberculosis
is staggering. There are nearly 9 million new cases
and 2 million deaths from tuberculosis worldwide
every year [3,4]. More than 100 million people have
died of tuberculosis since the tubercle bacillus was
discovered by Koch in 1882 [5]. Cases are likely to
increase, particularly in parts of the world with a
poorly controlled HIV epidemic. Tuberculosis dis-
proportionately affects young adults, impoverishes
families, and undermines economic development [6].
Despite the heavy burden of disease, tuberculosis-
control efforts are often inadequately funded and
supported. Shortages of drugs and equipment are
common, and key posts within tuberculosis-control
programs suffer from low prestige or high turnover
and are often vacant. Physicians, in their role as
community leaders, are responsible for promoting the
existence of effective tuberculosis-control programs
and for supporting and coordinating their own efforts
with these programs. Although tuberculosis control is
a core government function, it cannot be accom-
plished by any one individual or sector. It requires
communication and collaboration among local and
national health authorities, the primary health care
system, hospitals, medical schools, private physi-
cians, nongovernmental organizations, and others.
chestmed.theclinics.com
198 frieden
Diagnosis by sputum microscopy of patients
attending health facilities
Two important concepts are combined in this
aspect of the DOTS strategy: first, diagnosis should
be based primarily on microscopy rather than on
chest radiograph, clinical examination, or culture; and
second, case finding should be done primarily among
patients presenting at health facilities and not by
active case finding in the community.
Sputum microscopy is a highly specific test and
should be the primary tool for diagnosis. In contrast,
the unreliability of chest radiograph is well docu-
mented; 30% or more of patients classified as having
active tuberculosis on the basis of chest radiograph,
even by experts, are found not to have tuberculosis
[7 – 10]. The acid-fast bacillus (AFB) smear also
correlates with severity of disease, infectiousness,
and mortality [11,12] and is a low-cost, appropriate
technology that can be done reliably even in remote
areas [13]. Decisions based on the standard WHO-
recommended diagnosis algorithm [14] are often more
rapid than those based on culture [15]. Technical and
logistic requirements make culture unsuitable as a
primary diagnostic tool in developing countries.
Serologic and amplification tests on sputum samples
are currently more expensive and less informative
than the AFB smear and are not of proven utility in
global tuberculosis control; amplification techniques
can be useful in areas with low tuberculosis
prevalence. Future developments in this area may
further facilitate diagnosis, particularly of smear-
negative and extrapulmonary tuberculosis cases [16].
The second component of this aspect of the DOTS
strategy is the approach to case finding. Active
tuberculosis case finding in the community should
not be undertaken; it usually results in low cure rates
and is of limited or no value in tuberculosis control
[17]. Most patients with active tuberculosis seek care,
especially if care is provided free of charge, and the
few who do not seek care are less likely to complete
treatment [11,18]. In countries or regions with
generalized HIV epidemics, however, programs for
intensified tuberculosis case finding should be im-
plemented in all HIV counseling and testing set-
tings [19].
Standardized short-course chemotherapy given in
a program of directly observed treatment
This principle also has two aspects, both of which
are crucial. The efficacy of short-course, intermittent
treatment has been conclusively demonstrated in
& munsiff
numerous controlled clinical trials, [20 – 24] and is
effective for extrapulmonary tuberculosis [25,26].
Standard short-course regimens can cure more than
95% of cases of new, drug-susceptible tuberculosis
[27]. Most recommended treatment regimens have
two phases: an initial intensive phase with four drugs
lasting 2 months, followed by a 4-month continua-
tion phase with at least two drugs. Corticosteroids
have been shown to be useful in patients with peri-
cardial and meningeal tuberculosis and are recom-
mended in these situations [14,28]. Attempts to
reduce the length of treatment to less than 6 months
have failed, indicating that as of 2005 no practical
regimen shorter than 6 months using currently avail-
able medications is effective for patients with smear-
positive tuberculosis [29,30].
Patients previously treated for tuberculosis may
require a more intensive treatment regimen. In areas
where drug-susceptibility testing is not available, the
WHO re-treatment regimen should be used [14]. In
areas where drug susceptibility can be determined,
the susceptibility results of the isolate should guide
the treatment regimen [28].
It is now well documented that intermittent treat-
ment given two or three times a week is, in general,
as effective as daily therapy. This finding should not
be surprising, because Mycobacterium tuberculosis
doubles in 18 to 24 hours, compared with 12 to
20 minutes for most bacteria [31]. In fact, in one
animal model, intermittent treatment was more effec-
tive than daily treatment [32]. Supervised intermittent
short-course therapy for tuberculosis is shown to be
highly effective and extremely well tolerated in
patients whether or not they are HIV infected [24].
Intermittent treatment should be given only in a
program of direct treatment observation [33].
Once- or twice-weekly dosing with rifamycins in
HIV-infected tuberculosis patients with CD4 cell
counts less than 100/mm3 has been associated with
the development of acquired rifamycin resistance
[34]. The Centers for Disease Control (CDC) and
American Thoracic Society (ATS) now recommend
that patients with HIV-associated tuberculosis not be
treated with once-weekly regimens and that those
with CD4 cell counts of less than 100/mm3 not be
treated with any highly intermittent (ie, once- or
twice-weekly) regimens. The CDC and ATS now
recommend that such patients receive daily therapy
during the intensive phase and daily or thrice-weekly
therapy during the continuation phase, regardless of
whether they are also receiving antiretroviral drugs.
The international relevance of this recommendation
is unclear and should be further examined; thrice-
weekly regimens in the intensive phase are recom-
 the dots strategy for controlling tuberculosis
mended by the WHO and the International Union
Against TB and Lung Disease (IUATLD) and are of
proven efficacy for tuberculosis treatment regardless
of HIV status. If rifabutin is used, its dose may need
to be adjusted depending on the antiretroviral medi-
cations used [28,35].
Drugs can be effective only if they are taken [36].
Virtually all clinical studies of short-course chemo-
therapy were conducted using directly observed ther-
apy [37], and it can be argued that unobserved use of
rifampicin-containing regimens is experimental and
potentially dangerous. In particular, the initial phase
of treatment regimens that include rifampicin should
always be directly observed to ensure adherence and
prevent emergence of resistance to rifampicin [37].
Direct observation is the standard of care for tuber-
culosis in most countries [38]. About one third of
patients do not take medications regularly as pre-
scribed, and it is not possible to predict accurately
which patients will not adhere to treatment [33,36,
39 – 42]. Nonadherence is not related to adverse ef-
fects, dosage, or prior receipt of supervised treatment
[40,43] and is as high with placebo as with active
drugs. Surprise home visits revealed a much greater
degree of nonadherence than did pill counts or urine
tests, despite ongoing efforts to obtain and maintain
the cooperation of patients and their families during
the full course of chemotherapy [44].
Directly observed therapy is the most difficult and
most controversial aspect of the DOTS strategy.
(DOTS is the comprehensive five-point tuberculosis-
control strategy; directly observed therapy is one
essential component of that strategy.) Observation
must be done by a person who is accessible and
acceptable to the patient and who is accountable to
the health system [14]. In some countries, directly
observed therapy is given in hospital for the first
2 months [45]. In other countries, health staff
[46 – 48], community volunteers [49,50], members
of nongovernmental organizations [51], religious
leaders [52], and combinations of health staff and
a broad cross-section of community workers or vol-
unteers [53] have given directly observed therapy.
Each community has particular leaders, and the
challenge in implementing this aspect of the DOTS
strategy is to identify and enlist the support of
these leaders. Even in the unstable environment of
a refugee camp, directly observed therapy has been
shown to be feasible [54].
Directly observed therapy involves more than
merely watching patients as they take medications.
Rather, direct observation succeeds by building a
human bond between the patient and the health care
worker or community volunteer and acknowledging
199
the value of treatment success to patients and to
their communities. It also implies recognition of
the responsibility of the program and of the com-
munity to ensure successful treatment through
showing respect for the patient and by providing
treatment at convenient times and in appropriate fa-
cilities [55].
It may be impossible to arrange directly observed
therapy for some patients, but directly observed
therapy should be possible in more than 90% of
cases in a well-functioning program. When directly
observed treatment is impossible, the patient may
need to be given self-administered treatment, in which
a family member may be able to assist the patient.
Assistance by a family member is unreliable, how-
ever [39,56]. There are no examples of successful
large-scale DOTS programs in which immediate
family members have been used as primary providers
of directly observed therapy. Organizing DOTS,
including directly observed therapy, may not be
simple, but it is the only method that can ensure a
high cure rate on a program basis.
Adequate supply of good-quality drugs
Because long-term treatment with a combination
of drugs is required [57], it is important that sufficient
supplies of all necessary antituberculosis drugs are
available so that patients can complete the prescribed
treatment. In addition, it is important that drugs
are of good quality, with adequate bioavailability. Of
particular concern are the bioavailability of rifampicin
in combination tablets, particularly when combined
with pyrazinamide, and the stability of ethambutol,
which may be compromised by poor-quality pack-
aging or excessive humidity during storage.
Combination tablets of proven bioavailability
have the theoretical advantage of preventing mono-
therapy. Fixed-dose combination (FDC) tablets incor-
porate two or more medications into the same tablet
and prevent providers and patients from using a
single antituberculosis drug. This precaution should
reduce the likelihood of development of drug
resistance and the possibility of physician prescrip-
tion error or patient medication error. FDCs can
also simplify treatment for patients and logistics for
program managers. FDCs of low bioavailability
could result in treatment failure and drug resistance,
however, and FDCs generally have a shorter shelf life
and increase the cost of antituberculosis drugs [14].
The benefits of FDCs on a program basis are difficult
to document, and, of course, FDCs still cannot ensure
that the drugs are taken.
200 frieden
Systematic monitoring and accountability
Although record keeping is often seen as unim-
portant, an effective system of registering patients is
the heart of the DOTS strategy because it ensures
accountability. The information system designed
by Styblo [1a] and recommended by WHO is simple
but remarkably robust, allowing effective program
management as well as operational research.
At each microscopy center, a good-quality micro-
scope and reagents are supplied, and the laboratory
technician is trained, supervised, and included in a
quality control network. Every patient whose sputum
is examined is recorded in the tuberculosis laboratory
register. Every patient whose sputum is found
positive for AFB and started on treatment is re-
corded in the tuberculosis register, with all patient
outcomes recorded.
Quarterly reporting of diagnosed cases allows
simple but revealing analysis of diagnostic quality
and the descriptive epidemiology of tuberculosis.
Smear-positive patients are monitored for sputum
conversion to negative at the end of the intensive-
treatment phase, and this conversion rate is monitored
as an early indicator of program effectiveness.
Finally, treatment outcomes are systematically
recorded in one of six strictly defined categories
[14]. The global target for successful treatment of
new smear-positive patients is 85% or more [2].
Information in the tuberculosis laboratory register
and the tuberculosis register can be easily checked for
internal consistency and consistency between records
and can also be externally verified by reviewing spu-
tum slides, interviewing patients and health workers,
and monitoring consumption of drugs and supplies.
Results of the directly observed treatment, short
course strategy
The DOTS strategy has been implemented suc-
cessfully in many countries and contexts. Through
2003, DOTS has been implemented in 182 of
211 countries, covering 77% of the world’s popula-
tion [3]. In 132 countries, including most of the
industrialized world, DOTS is available to more than
90% of their populations [3]. Average treatment
success among all national DOTS programs is 82%,
close to the 85% global target [3]. By 2005, more
than 20 million patients have been treated under
DOTS, with an expected case detection rate of close
to 50% [3]. While the case detection rate has been
increasing over the past decade, it is still below the
70% target [3].
& munsiff
In Baltimore, Maryland, DOTS achieved a
marked reduction in case rates despite a high rate
of HIV infection [58]. In New York City, by 1991,
half of tuberculosis patients were HIV-infected, and
one in five had MDR-TB; [59]; DOTS, in addition
to an MDR-TB control program, resulted in a rapid
decrease in both tuberculosis and in multidrug re-
sistance [60]. Application of universal directly
observed therapy and subsequent adoption of short-
course chemotherapy were associated with a sub-
stantial decline in tuberculosis in Beijing, China, and
in Cuba to levels below those of some industrialized
countries [47,61]. In Peru, where DOTS was intro-
duced in 1990, high rates of case detection and cure
have decreased the incidence of pulmonary tuber-
culosis by at least 6% per year [62]. In China,
prevalence of smear-positive tuberculosis fell 32%
more between 1990 and 2000 in areas where DOTS
was implemented than in non-DOTS areas [63]. Ef-
fective DOTS programs have been established and
have functioned well even in the context of civil war
[45,46]. In addition, DOTS has been shown to be
highly cost effective [45,64].
Multidrug-resistant tuberculosis
The emergence of drug resistance is a symptom of
ineffective tuberculosis control [65]. If patients take
appropriately prescribed antituberculosis treatment,
development of resistance is extremely rare. In
contrast, in situations where prescribing practices,
case holding, or both are poor, drug resistance can
emerge. Effective treatment programs can prevent
drug resistance [66,67] and may even result in a
decrease in drug resistance if it has emerged [60,
68 – 74]. Treatment of MDR-TB is difficult, expen-
sive, and often unsuccessful. Treatment of MDR-TB
may be important for tuberculosis control in some
contexts, but it should be undertaken only with the
appropriate expertise and resources [65].
In most contexts, preventing development of
MDR-TB by ensuring cure of new smear-positive
patients is a much higher public health priority than
treatment of MDR-TB. Low cure rates among new
tuberculosis cases will result in the creation of drug-
resistant cases at a faster rate than these cases can be
cured, even if unlimited resources are available [75].
For disease control, if multidrug resistance is present
in congregate facilities (eg, prisons, hospitals) where
immunosuppressed (eg, HIV-infected or malnour-
ished) individuals are present, it is essential to diag-
nose patients with MDR-TB promptly and to treat
them effectively to avoid rapid spread of the disease.
 the dots strategy for controlling tuberculosis
Where resources permit (eg, targets for case detection
and treatment success are met and resources are in
place to continue DOTS implementation), treatment
of MDR-TB can save lives and prevent further spread
of disease.
There were an estimated 273,000 cases of MDR-
TB worldwide (3.1% of all tuberculosis cases) in
2000. Most MDR-TB is estimated to be concentrated
in 10 countries [76]. These data may underestimate
the number of MDR-TB cases worldwide, however,
because MDR-TB has been found in most regions of
the world that have been surveyed [77]. Systematic
surveys of several areas of the world with high
tuberculosis incidence, such as most parts of sub-
Saharan Africa and most of Asia, have not yet been
done. Resources need to be directed at areas with
the highest burden of this disease. There is limited
experience treating MDR-TB in resource-limited
settings, but successful programs can be imple-
mented [78]. International collaboration and re-
sources probably will be required to implement
such programs [79].
Although MDR-TB can be successfully treated in
a variety of settings, including community-based
treatment by trained community health workers
[78], treatment should be given only under a program
of directly observed therapy in conjunction with
clinicians who are expert in the management of
MDR-TB. All attempts should be made to obtain
susceptibility results so that regimens can be tailored
for individual patients. Most studies of MDR-TB
treatment have used individualized regimens [80].
Patients must be treated with a regimen of at least
three to five antituberculosis medications to which
the strain is known or likely to be susceptible, in-
cluding an injectable agent and a fluoroquinolone
[14,81]. Although longer use of injectable medica-
tions is associated with significant adverse effects,
longer-term injectable therapy increases culture con-
version and survival rates in persons with MDR-TB
[82]. Intermittent regimens should not be used. The
drugs for treating MDR-TB are much more expensive
and have markedly more adverse effects than stan-
dard drugs [83]. The duration of treatment is 18 to
24 months; patients need to be monitored carefully,
because the risk of default can be high.
HIV
Infection with HIV is the most potent known risk
factor for progression to active tuberculosis among
adults [84]. In outbreaks of tuberculosis in wards for
AIDS patients in the United States, the median time
201
from tuberculosis exposure to disease was 3 months,
and in some outbreaks more than one third of
exposed patients developed tuberculosis [85].
The HIV epidemic is a stress test for tuberculosis-
control programs and can relentlessly reveal program
weaknesses. The increase in tuberculosis incidence in
Africa is strongly associated with the prevalence of
HIV infection [86]. Tuberculosis case rates increased
approximately twice as fast in countries with high
HIV infection rates, but the increase was lower in
countries with good-quality tuberculosis-control ser-
vices. Improving the quality of national tuberculosis
programs can mitigate HIV-associated tuberculosis
[87]. Where prevalence of HIV infection is high,
tuberculosis treatment alone cannot reverse the rise in
tuberculosis incidence. At present, the most effective
way to address HIV-associated tuberculosis is
through a sound DOTS program coupled with com-
prehensive, effective HIV prevention and care that
incorporates active case finding in settings where
HIV counseling and testing are offered [19,88 – 92].
In settings with high incidences of HIV and
tuberculosis, diagnosing active tuberculosis in HIV-
infected persons is challenging. Sputum smear-
negative and extrapulmonary tuberculosis are more
common in HIV-infected persons [90,93]. In such
settings, consideration should be given to using ra-
diographs and, if feasible, mycobacterial cultures to
assist the clinician in diagnosing tuberculosis if spu-
tum smears are negative.
Recommended treatment regimens are similar for
all tuberculosis patients, whether HIV-infected or
uninfected [27], and patients with HIV respond well
to standard antituberculosis treatment and do not need
additional drugs [90,94,95]. Death during antituber-
culosis treatment is more common in HIV-infected
individuals but is primarily from non – tuberculosis-
associated causes [33]. Patients with HIV infection
and tuberculosis survive longer if given short-course
chemotherapy with rifampicin-containing regimens
than if given non – rifamycin-containing regimens
[96] and longer still if short-course chemotherapy is
given in a program of directly observed therapy
[97,98]. In addition, antituberculosis regimens con-
taining rifampicin can be administered safely with
several effective, highly active antiretroviral drugs,
making it easier to deliver simultaneous treatment for
tuberculosis and HIV [35,90,99]. Rifabutin, a more
expensive alternative to rifampicin, can be used with
most antiretroviral regimens with some dose adjust-
ments [35].
Tanzania and Malawi have had DOTS programs
for more than 10 years. Despite high rates of HIV
infection (which is present in more than 60% of tu-
202 frieden
berculosis patients in some sub-Saharan African
countries, including Malawi, Zimbabwe, Ethiopia,
and Botswana [3]), there has been no evidence of
an increased rate of relapse among HIV-infected
patients, and rates of drug resistance remain low
[66,67]. Avoiding the creation of drug-resistant tu-
berculosis is the best way to prevent the spread of
such strains.
Summary
The technology to control tuberculosis has been
known for decades. The DOTS strategy can double
cure rates. Successful global implementation of
DOTS could save millions of lives over the next
10 years. Success will require effective governmental
programs along with active communication, collabo-
ration, and participation on the part of the health
care system and governmental and nongovernmen-
tal sectors.
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