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RESPIRA l ()R\
MEDICINE
l.’NIVERSriA
of
WALES

DIPLOMA in TUBERCULOSIS
& CHEST DISEASES D.T.C.D. (Wales)

Leading article
Date of next course:-

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Professor l)J Shale
Section of Respiratory Medicine
University of Wales College of Medicine
l.landough Hospital
Penarth, South Glamorgan
CF64 2XX, UK

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Surveillance of resistance to antituberculosis drugs in develbpfi^Uiidntries
P. Nunn. M. Felten
Tuberculosis Programme. World Health Organization. Geneva. Switzerland

S U M MA R Y. Resistance to antituberculosis drugs is caused by poor management of tuberculosis control. It
gives rise to treatment failure, relapse, further transmission of resistant tuberculosis, and multidrug-resistant
I1 tuberculosis. Widespread occurrence of multidrug-resistant tuberculosis would constitute a major threat to
tuberculosis control in resource-poor countries. Although the impact of HIV on drug resistance is not yet
fully understood, it is likely to exacerbate problems caused by drug resistance. In particular. HIV-related
adverse effects of thiacetazone. together with the risks of transmission of HIV by parenteral administration
of streptomycin, reduce the armamentarium available to tuberculosis control programmes in high HIV
prevalence countries, and could encourage the development of resistance to the remaining drugs. While the
prime need is to ensure, by good management and supervision, that resistance does not occur in the first place,
surveillance of drug resistance is essential to determine the current scale and nature of the drug resistance
problem, as well as to define the correct solutions.

/• or prosoecius and application form p/ease ^rjte/(elfphonf

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October 1994 to March 1995
Course content:- Pulmonary pathology, mycobacterial disease, pulmonary
infections, HIV and AIDS, asthma, lung cancer, occupational and interstitial
diseases. Epidemiology and statistics relating to respiratory diseases.
The course will include teaching in clinical respiratory medicine and appropriate
laboratory experience. An elective period in a clinical or laboratory setting will be
arranged according to the individual needs.

Tel: (0222)705187
Fax:(0222)712284

3;
Tubercle and
Lung Disease

Applications are invited for the above six month full-time postgraduate diploma
course for overseas doctors.

COLI.EfJE
of MEDK INF.

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Tuhtrdf and Lung Dtseasf (19941 75,165-167
C 1994 Longman Group l-td
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R E S U M E. La resistance aux drogues antituberculeuses est provoquee par une prise en charge inadequate de
la lutte contre la tuberculose. dont resultent des echecs du traitement. des rechutes, une transmission accrue
d'une tuberculose resistante et une tuberculose resistant a plusieurs drogues. La survenue etendue d’une
tuberculose resistant a plusieurs drogues serait une menace majeure pour la lutte antituberculeuse dans les
pays depourvus -e ressources. Bien que I’impact du VTH sur la resistance aux antibiotiques ne soit pas encore
completement connu, il est susceptible d'exacerber les problemes crees par cette resistance. En particulier, les
effets nuisibles du thiacetazone associe au VTH. plus les risques de transmission du VTH par I’administration
parenterale de streptomycine. reduisent les armes dont on dispose pour les programmes de lutte anti­
tuberculeuse dans les pays de haute prevalence de VTH. et pourraient encourager le developpement de la
resistance aux autres drogues. Tandis que la premiere necessite est de s’assurer tout d’abord. par une prise en
charge et une surveillance adequates. qu'une resistance ne se produit pas, la surveillance de la resistance est
importante afin de determiner le niveau courant et la nature du probleme de la resistance aux drogues, et
egalement de definir les solutions adequates.

R ESU M EN. La resistencia a los medicamentos antituberculosos es causada por un manejo deficiente del
control de la tuberculosis. Esto produce un aumento de los fracasos del tratamiento. de las recaidas, de
la transmision ulterior de bacilos de la tuberculosis resistentes y del ntimero de tuberculosis multirresistentes.
La amplitud de la aparicidn de tuberculosis multirresistentes deberia ser considerada como una amenaza
importante para el control de la tuberculosis en los paises de escasos recursos. Aunque aiin no esta totalmente
esclarecido el impacto del VIH sobre la resistencia a los medicamentos. es probable que exacerbe los problemas
causados por la resistencia a los medicamentos. En particular, los efectos adversos de la tioacetazona ligados
a la infeccion con VIH. junto con los riesgos de transmission de la infeccion VIH por la administracion
parenteral de estreptomicina. reducen las armas disponibles para el control de la tuberculosis en los paises con
alia prevalencia de infeccion VTH y puede influir en el desarrollo de resistencia a los medicamentos restantes.
Aunque la necesidad primordial es que la resistencia no aparezca. por un buen manejo y supervision del
tratamiento, la vigilancia de la resistencia a los medicamentos es esencial para determinar la dimension actual
y la naturaleza del problema de la resistencia y para definir las soluciones apropiadas.

FOR ALL YOUR LABORATORY NEEDS
Correspondence to: Dr Paul Nunn. Operational Research Unit.
Tuberculosis Programme. World Health Organization. CH-1211
Geneva 27. Switzerland.
BDH laboratory Supplies, Poole, Dorset. BHI5 ITD. England. Fax: +44 202 666856. Tel: +44 202 660444. Telex: 41186

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Surveillance of resislance lo anlituberculosis drugs in developing countries 165

164 Tubercle and Lung Disease

ANTITUBERCULOSIS DRUG RESISTANCE:
CAUSES
What is generally understood by drug resistance is that a
patient infected with resistant strains of Mycobacterium
tuberculosis will fail to respond to treatment with the
drug concerned. There are more precise and complex
laborafory ’Hefinitions,1- but they are less suitable for
the purposes of this paper. Resistance to antituberculosis
drugs is the inevitable result of poor management’ of
tuberculosis control.’ Poor management takes many
forms: most commonly, poor supervision of the patient's
drug-taking, as well as the prescription of regimens with
an insufficient number of drugs to which the patient's
organisms are likely to be susceptible, inadequate dose
or duration of therapy, and poor drug supplies, such that
drugs are taken irregularly. In the past, patients have
taken much of the blame for poor compliance.4 but it is
now recognised that tuberculosis services and their staff
are not entirely innocent.5'’ Drug resistance is thought
by some to be a measure of medical malpractice. Either
way. such deficiencies lead to patients acquiring resist­
ance. If they then transmit the resistant organisms to
their contacts, and if those contacts later develop tuber­
culosis also, then these latter cases are said to have
primary resistance.

THE IMPACT OF ANTITUBERCULOSIS DRUG
RESISTANCE

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Whatever tuberculosis programmes might do to cause
drug resistance it is clear that drug resistance can do
considerable harm to tuberculosis treatment. Failure of
treatment, which is commonly defined as the persistence
of positive cultures for M. tuberculosis at the end of the
treatment period, is more likely to occur if the initial
organisms were resistant. Moreover, the more potent
the drug, and the more drugs to which an organism is
resistant, the greater the chances of treatment failure.
Probably the best of the very few studies in this area
was conducted by the British Medical Research Council
(BMRC) trials in Africa. Hong Kong and Singapore.
Of 11 patients with isolates resistant to rifampicin. 9
of whom also had organisms resistant to another drug
or drugs, 5 (45%) patients failed on treatment and a
further 3 (27%) had a subsequent relapse. On the other
hand, resistance to just isoniazid and/or streptomycin
led to chemotherapy failure in only 12% of 264
patients.

ML'LTIDRL'G-RESISTANCE
In recent years attention has focused on multidrug-resist­
ant (MDR) strains of M tuberculosis. MDR strains are
usually defined as those that are resistant io at least rifainpicin and isoniazid, and often to other drugs as well.
UTilIe occasionarMDR strains" fitivg been RbTate'd-ffoiii

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time to time over the past few decades, it is outbreaks
of MDR tuberculosis in the United States wfilchhave
Brought it into the limelight."15 These outbreaks have
been characterised by an association with the human im­
munodeficiency virus (HIV) and by anjtlarminglyjiigh
mortality, often over 80%, despite the availability of a
full range of reserve drugs. Widespread occurrence of '
MDR. especially primary MDR. would constitute a
major threat to tuberculosis control, particularly to
resource-poor countries, since effective treatment would
become impossibly expensive."’
However, there are grounds for some optimism. Rates
of resistance do not rise inexorably. In Styblo's classic
study in Kolin. in the former Czechoslovakia.” for
example, the introduction of stronger control measures,
especially supervision of all patients in hospital, ensured
that almost all patients completed their therapy. The
prevalence and incidence of resistance declined. Never­
theless. the single most important measure against re­
sistance is to ensure that it does not happen. This is
achieved by making certain that all patients complete a
full course of adequate treatment.

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THE ROLE OF HIV
The impact of HIV on drug resistance is not yet fully
understood. The MDR outbreaks in the US suggest that
HIV might be associated with antituberculosis drug re­
sistance. HIV-associated tuberculosis in some societies,
such as parts of the US’ and Zaire."1 is associated with
poorer adherence to therapy than in the case of patients
with tuberculosis alone, and this could lead to the acqui­
sition of resistance. HIV-infected tuberculosis patients
are up lo 20 times more likely than HIV-negative pa­
tients to have household contacts who are themselves
HIV infected1’ and these contacts are particularly sus­
ceptible to contracting tuberculosis.2"'1 which would
likely be resistant if the source case also had resistant
disease. On the other hand, the few studies, in the US,'”'
Haiti’’ and Africa.24 '' that have so far measured resist­
ance levels in more representative groups of patients
have not found an excess of resistance in the HIV­
positive groups.
One can intuitively see that the impact of resistance
will depend on the number and efficacy of the drugs
available to treat tuberculosis. There are. in current use
in the developing world. 6 main drugs for the treatment
of tuberculosis; isoniazid (H). rifampicin (R). pyrazina
mide (Z). ethambutol (E). streptomycin (S) and thiacetazone (T). The first 3 are the most essential. Streptomycin
is given parenterally, and therefore constitutes a risk
for HIV and hepatitis B virus transmission in those areas
where sterilization of injection equipment cannot be
guaranteed. The World Health Organisation (WHO)
does not therefore recommend it for use in areas with a
high prevalence of HIV infection.2'’ However, the risk
has never been quantified for tuberculosis control pro­
grammes with sufficient supplies and equipment. Fur­

thermore. though, the cost of streptomycin has also in­
creased considerably over the past few years. In addi­
tion. HIV infection has been shown greatly to increase
the risk of severe, and potentially fatal, cutaneous hyper­
sensitivity reactions in patients treated with thiacetazoneA'' It is therefore advised not to use this drug
either in individual patients known or suspected to be
infected with HIV. The armamentarium available for
treating tuberculosis is thus somewhat reduced in high
HIV prevalence areas.
Further, there is a possibility that withdrawal of thiacetazone might actually create resistance to more power­
ful drugs. If the commonly used regimen of 2SHRZ/
6TH (an initial phase of 2 months of daily SHRZ.
followed by 6 months of a continuation phase of T and
H) is altered to 2EHRZ/6EH in some areas, then a pro­
ponion (unknown) of those patients with isoniazid
resistance will, in effect, receive monotherapy in the
continuation phase. Ethambutol resistance is therefore
probable in a percentage (unknown) of patients so
treated. Since the retreatment regimen recommended by
the International Union Against Tuberculosis and Lung
Disease (lUATLD)1" and WHO consists of 2SHRZE/
HRZE/5HRE. the continuation phase will again, in
effect, be monotherapy, this lime with rifampicin. Ri­
fampicin resistance in a proportion (again, unknown) is
the likely result. This is the domino theory of resistance.
Surveillance will at least help to determine the present
unknowns in this scenario.
It is already clear that new. effective, low-cost
antituberculosis drugs are urgently needed in the light
against tuberculosis in both developing and industrial­
ized worlds.

Korea.’ conducted nationwide surveys at 5 or 10 year
intervals to assess the extent of their tuberculosis prob­
lems. Ongoing surveillance was conducted in Algeria.16
Representative information on drug resistance was in­
cluded in each of these surveys. In East Africa, it was
clearly not a major problem, with resistance to one or
more drugs varying from 7-10% between 1964 and
1984. In Korea, primary resistance to one or more drugs
rose to 31%c of isolates tested in I960, but fell to 15%
in 1990 with the introduction of improved tuberculosis
control. Acquired resistance was as high as 75% in
1980. falling to 47% in 1990. Apart from these 4 studies,
which also had their share of methodological problems,
the majority of published work has suffered from at
least one of 3 major deficiences. making interpretation
difficult, if not impossible: selection bias (in favour of
patients referred to major hospitals and thus more likely
to have resistant disease); failure to distinguish clearly
between those patients who had had previous treatment
from those who had not; and the use of non-standard
or unclear laboratory methods. Our current level of igno­
rance of the scale and nature of drug resistance in the
developing world is therefore profound, although we
know that HIV is plentiful, and that MDR exists there
(M. Kinyanjui and W. Githui. personal communication).
For those industrialized countries with large tubercu­
losis burdens among immigrant populations, such as the
Netherlands. Switzerland" and Canada, information on
resistance levels in the countries of origin of their immi­
grants is essential for proper formulation of domestic
treatment policy. The risk of drug resistance in immi­
grants can be 10 times that of native bom patients.1
AIMS OF SURVEILLANCE

SURVEILLANCE FOR ANTITUBERCULOSIS
DRUG RESISTANCE
Until recently, few countries iiy the world, rich or poor,
considered it necessary to carry out systematic surveil­
lance for antituberculosis drug resistance. The USA. for
example, ceased surveillance in 1986. although it was
resumed in 1993. It was generally maintained in some
other countries in the industrialized world that the rec­
ommended treatment regimens were designed to suc­
ceed even in the presence of resistance to one or two of
the commonly used drugs; the minority ot patients who
failed to respond to treatment could be investigatedfor
resistance as the need arose; surveillance was expensive,
resources were limited, and. in any case, tuberculosis
was disappearing fast. The occurrence of MDR. and
the rising incidence of tuberculosis in many Western
countries'1 ” due to HIV. immigration and the failure to
maintain adequate health services in deprived inner
cities, has led to a reexamination of this position.
Likewise, in the developing world, in spite of a gen­
eral failure to control tuberculosis, surveillance for drug
resistance was not an issue until recently. Nevertheless,
a number of countries, such as Kenya." Tanzania" and

The potential benefits of suitable surveillance for drug
resistance are many. At an international level, surveil­
lance could determine the geographical extent and sever­
ity of resistance in given countries or regions, and thus
determine the need for major, international changes in
treatment policy. Such information would also deter­
mine the extent of the need for international research
into new chemotherapeutic agents, or new combinations
of drugs. At a national level, a surveillance system
would provide a useful indicator of tuberculosis control
programme performance and assessment of the need for
changing current treatment policy, identify districts or
health centres in need of support, and determine the risk
factors for resistance.
But there are potential disadvantages. By diverting
scarce resources to resistance surveillance, the essential
tuberculosis control targets of curing 85% of all new
smear-positive cases diagnosed and finding 70% of all
cases could be jeopardised. However, it is in precisely
those countries with poor programme performance that
resistance could be predicted. National resources should
then, perhaps, focus on achieving the targets, and donor
agencies on resistance surveillance.

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166

Tubercle and Lung Disease

RECOMMENDATIONS
The Tuberculosis Programme at WHO has developed a
strategy which will determine the nature and extent of
antituberculosis drug resistance in regions of the devel­
oping world. Countries with viable tuberculosis control
programmes will be encouraged and assisted to develop
their own surveillance systems using guidelines for sur­
veillance drawn up by the Programme, which avoid the
defects, mentioned above, of many previous resistance
surveys. With the collaboration of the IUATLD. it is in­
tended to establish a network of supra-national reference
laboratories to provide the quality control and standardi­
zation of susceptibility testing that will be essential for
international comparison. At the same time, much
needed suppon will be given to national reference labo­
ratories in developing countries to develop their own
capacity for work on drug resistance.

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CONCLUSIONS

Antituberculosis drug resistance, and especially multidrug­
resistance, constitutes a major threat to tuberculosis
control programmes. This danger is amplified by the
presence of HIV. Our current state of knowledge about
the extent and severity of resistance, especially in the
developing world, is woefully inadequate. Surveillance
for drug resistance is therefore essential. WHO is taking
the initiative, together with the IUATLD. io set up such
a system.

References

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