Chemotherapy of tuberculosis under program conditions

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Title
Chemotherapy of tuberculosis under program conditions
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SI ( I ION of
KI SPIKA IORY
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DIPLOMA in TUBERCULOSIS
& CHEST DISEASES D.TC.D. (Wales)

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Editorial

BDH

Chemotherapy of tuberculosis under program conditions
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With special relevan' j to ’ndia

P. R. J. Gangadharam

Mycobacteriology Research Laboratories. University of Illinois at Chicago Colleye of Medicine. Chicago, USA

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Tubercle and
Lung Disease

October 1994 to March 1995

For prospectus and application form please 'vriie/telephont

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Course content:- Pulmonary pathology, mycobacterial disease, pulmonary
infections, HIV and AIDS, asthma, lung cancer, occupational and interstitial
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The course will include teaching in clinical respiratory medicine and appropriate
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Tt^rcle and Lung Diuau (1994) 75,'241 -244
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Tuberculosis, once a life-threatening disease, is now a
curable one, thanks to powerful drugs and. more im­
portantly. the development of highly useful regimens.
Many of these contributions, aptly called 'landmarks'1
have provided sufficient armamentarium in our hands to
achieve complete (100%) success in controlling this dis­
ease. Equally important is the National Tuberculosis
Program (NTP), which has demonstrated practical utility
in many developing countries. Many classical clinical
investigations and the NTP have their origin in India, a
country to which the world owes a great deal in this
domain, as Grzybowski has suggested.'
A series of epidemiological studies have indicated
that there has been a slight reduction in the prevalence
of tuberculosis in India as a consequence of chemo­
therapy and NTP activities. J The reduction is. however,
only gradual and limited, and is perhaps influenced by
local situations. The incidence of primary drug resist­
ance (PDR), the 'epidemiological.yard stick’ indicated
by Canetti.' also shows a reduction. For instance in
Madras, a study by Krishnaswami & Rahim'' showed
PDR rates to be slightly lower than the figures obtained
10 years before by the author' from that center using
the same techniques and source of patient populations.
More recent studies" conducted in other regions have
also indicated reductions in PDR rates.
However, some authorities suggest that if a certain
amount of failure is to be anticipated and only marginal
effort is to be expected, as has been seen in India, the
use of costly regimens should be questioned.While
such a philosophy may have some realistic basis, one
may wonder w hether such a defeatist attitude is juslified
with today's therapeutic armamentarium provided Iw the
short course chemotherapy (SCC) regimen, which could,
achieve nearly 100% clinical outcome. With the use of

Correspondence lo: Professor Paitisapu R J. Gangadharam. Professor
of Medicine. Microbiology and Pathology. Director of
Mycobacteriology Research. University of Illinois at Chicago. R35 S
Wolcott (M/C 79<)>. Rm E709.Chicago. It. 60612. USA

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241

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SCC and drugs like rifampin, no one need suffer from
tuberculosis, much less die of it. Delivery of alxwl_50
doses of drugs under a well-organized SCC program
should yield the expected maximum results Several
studies completed, even under program conditions in
developing countries, have in fad proved this.1®7” Some
of these1415 were done in India with the guidance and
collaboration of the Tuberculosis Research Center
(TRC). Titus the belief that one should gel poorer
results in program (field) conditions in comparison to
the ideal control clinical study settings, may not be so
with powerful SCC regimens. This may be valid with
less effective regimens, as was shown extensively by
Frimodl-Moller and by the studies done by the National
Tuberculosis Institute (NTI).
In just such a situation, delivering a blow to the hope
of achieving success w ith SCC regimens and in support
of suggestions made by Chakraborty,4'' a recent study"'
from India by the TRC demonstrated utter failure of
SCC in a District Tuberculosis Program. An SCC regi­
men consisting of rifampin 450 mg. isoniazid MX) mg
and pyrazinamide 2 gm given twice weekly under
supervision for 2 months, followed by rifampin 450 mg
and isoniazid 600 mg twice a week for the next 4
months, all doses given under supervision, gave an
outcome of high mortality, persistent sputum positivity
and a high degree of acquired drug resistance. As
Grzybowski2 indicated, the way this study was con­
ducted and the results obtained, constitute an unmiti­
gated disaster'. Only about 40% of patients took more
than 80% of their treatment, and a slightly larger propor­
tion took less than 50%. More than a quarter of patients
died and another quarter were persistently positive
bacteriologically. with a high degree of resistance to iso­
niazid (60-80%) and rifampin (12%). Overall, the out­
come of this study gave results which are much lower
than the most pessimistic estimates anywhere in the
world and are very similar to those seen in the pre­
chemotherapy era.
In discussing their results, the authors"' mention that

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Tubercle and Lung Disease

no special measures beyond letter posting, a routine de­
faulter action recommended by the NTP, were adopted.
It is not clear how efficiently this letter posting was done
and what its outcome was; nor was it discussed what
alternative measures were adopted besides verification
of the addresses.” Blaming non-compliance as the chief
reason for the appalling results in their study, they hoped
that they could have achieved much better results in
comparison to several other field studies from develop­
ing countries reported in the literature.15-15
Non-compliance on the part of the patient in taking
the prescribed drugs for the prescribed period is a classic
problem and has received extensive attention in the
literature (see the excellent reviews by Fox)."11'' The
TRC authors16 also followed suit and were ready to
blame patients' non-compliance as the main reason for
the failure of their study. On the other hand, it is difficult
to appreciate the role of compliance in a situation where
all drugs were administered ‘under supervision'. In fact
the only recourse of 'supervision' in this study was the
treatment card!
Since the findings of this study.16 monitored by the
TRC which has an extensive 'track-record of clinical
trials', might influence the thinking and implementation
of tuberculosis programs in India and perhaps in other
developing countries, a closer scrutiny of the findings
and projections is warranted.
In this analysis, besides the patient, whom the authors
first blame for his non-compliance, other key factors
should be considered. Certainly the patient plays an
important role. A non-compliant patient is a danger
not only to himself but also to the community because of
the spread of drug-resistant bacilli. While earlier litera­
ture""’ has given some common reasons, chief among
them being indolence, more recent experience gives
slightly different perspectives. The reasons for noncompliance are vastly different betweeh patTents from
developed and developing countries. In the developed
countries, the most common reasons are drug abuse,
alcohofism. homelessness and lack of civic respohsibifiiy.7" Even though the TRC group16 has suggested
following the US experience.-’”-’1 the problems that are
faced in India will be very different.
In developing countries, although indolence may play
a role". Ifie most common reasons are economic, and
prioritization of the patients' ownjieeds. Most patients
are poor and many are daily wage earners and cannot
forego a day's wages, nor afford to travel with their
meager financial resources to the clinic to get their treat­
ment. ” On the other hand, given that a good proportion
of the patients are conscious of their disease and would
like to be cured, and that the treatment can be taken to
places convenient to them (residence or work), it should
not be difficult to achieve success.
!
With SCC one needs to give about 50 doses twice
a week. If the health authorities deliver the pills to the
patients, most will swallow them in their presence. Such
treatment achieved success in a well organized system in
Bohemia.-" In this study, intermittent chemotherapy was

Chemoiherapy of luberculosis under program conditions

delivered to the patient either in his place of residence,
place of work or other convenient place at scheduled
intervals and maximum efficiency was reached. Such a
system can be organized in any part of the world. Some
authorities24 have questioned that such an approach
could only be feasible in urban or semi-urban communi­
ties but not in rural areas, mainly due to transport and
access problems. Now such fears need not be deterring
factors because of the enormous global improvement in
communications; in many developing countries, particu­
larly India, even the remotest villages have been con­
nected by road and by other communications including
television. In such situations, it should not be impossible
for a committed health worker to visit patients twice a
wecTrT>y”rfianual or motorized bicycle or scooter, dis­
tribute the drugs and see that the patients swallow the
pHTS in his presence. As a practice, the patient should
be asked to talk a few words (like the 'name, number
and rank' expression used in the army, to make sure that
the pills are swallowed), lest they spit them out. as has
been shown in field experience in Assam.’5
Even the most remote villages in any pan of the
country could be covered, although there may be some
areas which are difficult to reach; such places will be
very small in number and with very few patients to cater
to. Several years ago. Signal-’6 expressed such optimism:
'To control tuberculosis in. for instance, the vastness of
deserts, the depths of Amazonian jungle or the remote
foot-hills of the Himalayas is a formidable task. But
those who live in such places are only a tiny fraction of
the total world population.' Even then, attempts can be
made to get the patients to the nearest major village or
township where the treatment can be administered twice
weekly. Again, one need not be tired of stressing that
with a system with fool-proof, honest, conscientious
effort, success can be achieved.
The second important point to be considered in the
analysis of the recent study16 is the quality, stability and
proper and timely supply of the drugs. Many of these
aspects are poorly respected in the mass application of
chemotherapy in many countries, and particularly in
India. Quite often, the purchasing authorities bid for
the cheapest source and not all drugs are procured at the
same time. If they are imported, a prolonged stay in a
hot and humid environment before clearance by cus­
toms. due to bureaucratic red tape, will influence the
stability of the drugs. Many of these points have been
reported in tuberculosis conferences in India and have
been discussed by Fox.’' Chaulel’" and myself.-’''
By far the most important point in the success of
chemotherapy of tuberculosis is the implementation of
supervision, which is not necessarily confined to the
patient, but to (he whole hierarchy of the health distri­
bution personnel, from the directors, doctors, nurses and
pharmacists to the field workers. If each person is doing
his or her duly properly and conscientiously, success is
inevitable. In other words, supervision is not only to see
that the patients lake the drugs, which is the ultimate
purpose, but the quality control of everybody's responsi-

bility by the proper authorities, strictly implemented and
enforced at every stage. While many reports show ideal­
istic regimens in operation, in actual practice they can
fail to achieve good results unless properly and honestly
conducted.
As one example, a urine test which was found to be
useful50 was reported to be giving many false-positive
results and therefore branded as utterly useless under
field conditions." When the basic data of the study were
analyzed, it was recognized that about 50% of the
participating centers did not even collect any urine
specimen, and in others the collected specimens were
not tested.52 The technicians were bold enough to mark
the results in the work book without even looking at the
samples! Such examples, many of which might not be
seen in technical literature or aired in conferences, will
perhaps explain that even the best method of treatment
or procedure will not give the expected results unless
properly conducted and supervised.
The necessity of thorough supervision and motivation
on the part of all health personnel in carrying out their
duties according to the protocol was underlined several
years ago by Bouillon." who stated that: 'the default of
the patient was a minor matter in comparison with that
of the people responsible for the public relations aspect
and delivery of the services'. More recently. Chaulel.54
in attempting to identify those responsible for non-com­
pliance in developing countries, stated: 'non-compliance
with antituberculosis chemotherapy is less often due to
the patient's failure >o comply with treatment than to
—other factors. These factors are not abstract entities or
forced and uncontrollable situations; these are people,
meh and women, who are not doing the jobs to which
,V^'.
’hey have been assigned and for which they are paid’.
Most of these important aspects of non-compliance on
'
the part of the health delivery system officials have been
totally ignored or concealed in many cases due to
’bureaucratic and governmental controls. In connection
with this, it is worth referring to an example given by
philosophers in India: 'While we point our forefinger of
complaint at somebody, let us realize that three fingers
point towards us!' In the present context, when we
blame the patient, let us realize that we. the health deliv­
ery personnel, are to be blamed to a greater extent. As
Sbarbaro" said in a brilliant editorial, instead of blaming
the patients, 'physicians and health professionals heal
and correct themselves'.
Besides the irresponsibility on the part of the health
delivery machinery, other serious reasons which contri­
bute to the failure of treatment in many developing
I countries are the dishonest and illegal practices in drug
i distribution at various levels. Even though the drugs are
i supposed to be delivered lolhe patients, in many cases
I they may not reach them, but will only find their way
I via the black market or to selfish profit-making indi/ viduals. It would not be an exaggeration to suspect that
in~some“cases, similar to the unfortunate experience
with the urine tests cited earlier, the drugs might not
have been procured; only the records will log entries of

243

purchase and distribution to the patient. For instance,
tri flie study from the TRC.16 the only evidence ot drug
consumption was the treatment card. Several years ago.
Signal-’6 and Chauletu expressed similar concerns, but
these have not been seriously considered by tuberculosis
treatment officials. Such malpractice is more likely to
occur with SCC regimens involving costly drugs..such,
as rifampin and pyrazinamide. rather than the inexpen­
sive drugs such as isoniazid and thiacetazone. On these
grounds, one can add further support to Chakraborty's41'
claim that in a potentially ineffectent system of drug
distribution and drug consumption, a cheaper regimen
will be less tempting to those involved in malpractice.
Maybe some of the depot-type drug delivery systems1'’ ”
involving only one-or two administrations-may offer
some hope in the future.
To sum up. one can easily hope that with a committed
learn, we can take the treatment to the patient, even
in the remotest part of the country, and see that they
swallow the pills in our presence. What we need are
sincerity, commitment and a good supply of drugs. After
all. making this work for 50 doses on twice weekly
administration is not an impossible task. By doing so.
we can prove that tuberculosis is really a curable dis­
ease. On the other hand, if these problems are not solved
we cannot achieve success, even if some super drugs are
introduced tomorrow.

Acknowledgement
I thank Mrs Madhavi Paiuri for her excellent secretarial assistance.

References
Toman K What were the main landmarks tn the development of
tuberculosis chemotherapy. In: Toman K. ed. Tuberculosis case­
finding and chemoiherapy. Geneva: WHO. 1979: pp 75-76.
2. Grzybowski S. Drugs are not enough: failure of short course
chemoiherapy in a district in India. Tubercle Lung Dis 1993:
74: 145-146
3. Grzybowski S. Tuberculosis: a look at the world situation. Chest
19X3: X4: 756-771.
4. Chakrabony A K. Chaudhuri K. Sreenivas T R. Krishnamunhy
M S. Channabasavaiah R. Tuberculosis infection in a rural
population of South India: 23 year trend Tubercle Lung Dis
1992; 73: 213-2IX.
Canetti G. The eradication of tuberculosis. Theoretical problems
and practical solutions. Tubercle 1962: 43: 301-321.
6. Knshnaswami K V. Rahim M A. Primary drug resistance in
pulmonary tuberculosis. Indian J Chest Dis 1976; 2X: 233.
7. Indian Council of Medical Research First Drug Resistance
Investigation. Prevalence of drug resistance in patients with
pulmonary tuberculosis presenting for the first time with
symptoms at chest clinics in India. Part I: findings in urban
climes among patients giving no history of previous
chemotherapy. Indian J Med Res 1968: 56: 1617-1630.
X. Tnvedi S S. Desai S G. Primary anlilubcrculosis drug resistance
and acquired rifampicin resistance in Gujarat. India. Tubercle
I9XX; 69: 37-42.
Jagota P. Chakraborty A K. Balasangameshwara V H. Case­
holding in tuberculosis programme - epidemiological priorities
and operational alterations. NTI Bulletin 1993; 29: 1-9.
It). Kumaresan J A. Maoganer E T. Case holding in patients with
tuberculosis in Botswana. BMJ 1992; 305.
11 Manaid F. Tan F. Sbarbaro J A. Iseman M D. Community based
short course treatment of pulmonary tuberculosis in a developing

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Tubercle and Lung Dneaic (1994) 75, 245-250
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244 Tubercle and Lung Disease

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nation: initial report of an eight-tnonlh largely intermittent
regimen in a population with a high prevalence of drug
resistance. Am Rev Respir Dis 1990: 142: 1301-1305.
fl2 Zhang 1. X. Kan G Q Tuberculosis control programme in
'^"Beijing. Tubercle Lung Dis 1992; 73: 162-166.
.UJMathur S R. Intermittent short course chemotherapy for
' pulmonary tuberculosis (a pilot study report), l.ung India 1983:
rs I: 219-223.
\U/Rangaswamy V, Venkatasubramanian N. Short course
chemotherapy under service conditions. Lung India 1984;
-s’: 175-179.
Qs/ Padmanabhan V K. A study of short course chemotherapy for
pulmonary tuberculosis under programme (Held) conditions in
Pandichcry. Lung India 1989; 7: 79-83.
16. Dana M M. Radhamam M P. Selvaraj N et al. Critical
assessment of smear-positive pulmonary tuberculosis patients
after chemotherapy under the district tuberculosis programme.
Tubercle Lung Dis 1993; 74: 180-186.
17 Knshnaswami K V. Satagopan M C. Somasundaran P R.
Tripathy S P. Radhaknshna S. Fox W. An investigation of the
accuracy of the home address given by patients in an urban
community in South India. Tubercle 1979; 60: 1-11.
18. Fox W Self-administration of medicaments a review of
published work and a study of the problems Bull Int Union
Tuberc Lung Dis 1961; 32: 307-331.
19. Fox W. Compliance of patients and physicians: experience and
lessons from tuberculosis. BMJ 1983: 287: 33-35. 101-105.
20. 'Reichman L B Compliance in developed nations. Tubercle 1987.
68 (Suppl.): 25-29
21 Brudney K. Dobkin J Resurgent tuberculosis in New York City
human immunodeficiency virus, homelessness and the decline ol
the Tuberculosis Control Programs. Am Rev Respir Dis 1991.
144:745-749.
, 22 Pamra S P. Problems of tuberculosis in developing countries In
J Stead W W. Dutt A K. eds. Clinics tn Chest Medicine:
Tuberculosis. Philadelphia: W. D. Saunders. 1980: pp 265-271.
23. World Health Organization Collaborating center lor tuberculosis
chemotherapy . Prague. A comparative study of daily and twiceweekly combination regimens of tuberculosis chemotherapy,
including a comparison of two durations of sanatorium treatment.

1. First report: the results of 12 weeks. Bull World Health Organ
1971;45:573-591.
24. Pamra S P Discussion on standard chemotherapy and its
application in the tuberculosis programme. Bull Int Union Tuberc
Lung Dis 1972; Suppl. 2: p 58.
25. Gilroy A B. Proguanil-resistant Plasmodium falciparum in
Assam. Am Trop Med Parasit 1952: 121-126.
. 26,. Signal J R Failure to control tuberculosis: a personal review.
Tubercle 1982; 63: 171-174.
27. Fox w. Tuberculosis in India: past, present and future. Indian J
Tuberc 1990; 37: 175-213.
28. Chaulct P The supply of antituberculosis drugs and national
•"'.drugs policies. Tubercle Lung Dis 1992; 73: 295-304.
t29^Gangadharam P R J. Drug resistance in tuberculosis; its not
always the patient's fault! Tubercle Lung Dis 1993. 74: 65-67.
30 Gangadharam P R J. Nair C N. Subbiah T V. A simple paper
test for detecting isoniazid in urine. Indian J Tuberc 1962;
9: 219-223.
31 East Afncan/Bntish Medical Research Council. Third
Thiacctazone investigation. Isoniazid with thiacetazone in the
treatment of pulmonary tuberculosis in East Africa - third
Investigation Tubercle 1966; 47: 1-32.
32. Macfadycn D M. Heffernan J F. Urine testing for isoniazid in the
supervision ol outpatient oral chemotherapy for pulmonary
tuberculosis. The failure of a routine service. Bull World Health
Organ 1967; 36: 847-852.
s 33jRouillon A. Problems in organizing effective ambulatory
^'-'treatment of tuberculosis patients, motivation. Bull Int Union
Tuberc Lung Dis 1972; 47: 68-83.
34. Chaulct P Compliance with antituberculosis chemotherapy in
developing countries. Tubercle 1987; 68 (Suppl.I: 19-24
35 Sbarbaro J B. The nature of man and physician. Am Rev Respir
Dis 1981; 123: 147.
36 Gangadharam P R J. Ashtckar D R. Farhi D C. Wise D L
Sustained release of isoniazid in vivo from a single implant of a
biodegradable polymer Tubercle 1991; 72: 115-122.
37 Gangadharam P R J. Kailasam S. Srinivasan S. Wise D L.
Experimental chemotherapy of tuberculosis using single dose
treatment with isoniazid in biodegradable polymers. J Antimicro
Chemothcr 1994: in press.

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Tubercle and
Lung Disease

4-, 5- and 6-month regimens containing isoniazid, rifampicin, pyrazinamide
and streptomycin for treatment of pulmonary tuberculosis under program
conditions in Hong Kong
S. L. Chan*. P. C. Wong1, C. M. Tam*

^Tuberculosis and Chest Senice. Wanchai Chest Clinic. Hong Kong. 'Grantham Hospital. Aberdeen. Hong Kong.
fWanchai Chest Clinic. Hong Kong

S U M M A R Y. Setting: Ten full time urban government chest clinics in Hong Kong.
Objective: To assess the effectiveness of 4-. 5- and 6-month fully supervised thrice-weekly regimens containing 4
months of isoniazid, rifampicin, pyrazinamide and streptomycin followed by nil. 1 or 2 months of isoniazid and
rifampicin for the treatment of smear-negative culture-negative, smear-negative culture-positive and smear­

positive pulmonary tuberculosis.
Design: Retrospective study of the 3 antituberculosis treatment regimens given under program conditions
during a 6-month period in 1983.
Results: Of the 1616 patients assessed. 953 (59%) completed their treatment strictly as planned. 443 (27%) had
their treatment prolonged. 107 (7%) had their treatment modified and 113 (7%) defaulted or did not complete
their treatment as planned. There were 2 treatment failures at the end of chemotherapy. At 60 months of
follow-up. 67 patients died. 2 from the sequelae of tuberculosis. Of 1287 patients assessable up to 60 months, a
total of 47 (3.7%) patients relapsed and were eventually treated successfully. 11 (20%) relapses occurred
among the 55 patients who had defaulted and did not complete treatment as planned.
Conclusion: The effectiveness of the 3 treatment regimens depended very much on the patient’s adherence to
treatment. Th. necessity of prolongation of treatment is not known and requires further assessment.
R ESU M E. Cadre: Dix dispensaires thoraciques urbains gouvernementaux. a plein temps, a Hong Kong.
Objet: Evaluer I'efficacite de regimes hautement surveilles, administres trois fois par semaine pendant une
duree de 4, 5 et 6 mois respectivement. consistant en 4 mois de isoniazide. rifampicine. pyrazinamide et
streptomycine, suivis d’arret. 1 ou 2 mois de isoniazide et rifampicine. pour le traitement d’une tuberculose
pulmonaire frottis negatif et culture negative, frottis negatif et culture positive, ou frottis positif.
Schema: Etude retrospective des trois regimes antituberculeux appliques dans les conditions du programme

pendant une periode de 6 mois en 1983.
Resultats: Des 1616 patients evalues, 953 (59%) ont termine leur traitement exactement comme prevu.
pour 443 (27%) leur traitement a ete prolonge, pour 107 (7%) leur traitement a ete modifie. et 113 (7%)
ont abandonne ou n’ont pas termine le traitement prevu. II y a eu deux echecs de traitement a la fin de la
chimiotherapie. Apres 60 mois de suivi. 67 patients etaient decedes. 2 de sequelles de la tuberculose. Des 1287
patients qu’il a ete possible d’evaluer apres 60 mois. au total 47 (3.7%) patients ont rechute et ont ete soignes
avec succes par la suite. 11 (20%) rechutes sont survenues chez les 55 patients qui avaient abandonne et qui

St

n'avaient done pas termine le traitement prevti.
Conclusion: I.'efficacite des trois regimes de traitement dependait en effet de I’adherence des patients a
leur traitement. La necessite de prolonger le traitement n’est pas prouvee et demande une evaluation

strep

supplementaire.

__________________________________________________

R E S U M E N. Marco de referenda: Diez, dispensarios urbunos v gubernamentales que trabajan a tiempo

completo en enfermedades respiratorias en Hong-Kong.

St
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Correspondence to: Dr S. L. Chan. Consultant Chest Physician.
Tuberculosis and Chest Service. Wanchai Chest Clinic. Kennedy
Road. Hong Kong.

Paper received 5 October 1992. Final venion accepted in September
1993

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245

164 Tubercle and Lung Disease
ANTITUBERCULOSIS DRUG RESISTANCE:
CAUSES

time to time over the past few decades, it is outbreaks
of MDR tuberculosis in the United States which havT
brought it into the limelight." 15 These outbreaks have
What is generally understood by drug resistance is that a
been characterised by an association with the human im­
patient infected with resistant strains of Mycohacierium
munodeficiency virus (HIV) and by an alarmingly high'
ti<bci< ulosi.s will fail to respond to treatment with the
mortality, often over 80^, despite the availability of a
drug concerned. There are more precise and complex
full range of reserve drugs. Widespread occurrence of
laboratory definitions,1- but they arc less suitable for
MDR. especially primary MDR. would constitute a
the purposes of this paper. Resistance to antituberculosis
major threat to tuberculosis control, particularly to
drugs is the inevitable result of poor management of
resource-poor countries, since effective treatment would
tuberculosis control.’ Poor management takes many
become impossibly expensive.16
forms: most commonly, poor supervision of the patient’s
However, there are grounds for some optimism. Rates
drug-taking, as well as the prescription of regimens with
of resistance do not rise inexorably. In Styblo’s classic
an insufficient number of drugs to which the patient's
study_ in Kolin. in the former Czechoslovakia.” for
organisms are likely to be susceptible, inadequate dose f example, the introduction. of
control1 measures,
. vstronger
-.
or duration of therapy, and poor drug supplies, such that/ especially supervision of all patients in hospital, ensured
nr. fnVm,
1.,
on,.
I,.........
|hat
pa|ien|s COmp|eted |heir th^tipy. TI1C '
drugs are taken irregularly, In the past, patients have
taken much of the blame for poor compliance.4 but it is
prevalence and incidence of resistance declined. Never­
now recognised that tuberculosis services and their staff
theless. the single most important measure against re­
are not entirely innocent.'* Drug resistance is thought
sistance is to ensure that it does not happen. This is
by some to be a measure of medical malpractice Either
achieved by making certain that all patients complete a
way. such deficiencies lead to patients acquiring resist­
lull course of adequate treatment.
ance. If they then transmit the resistant organisms to
their contacts, and if those contacts later develop tuber­
THE ROLE OF HIV
culosis also, then these latter cases are said to have
primary resistance.,
The impact of HIV on drug resistance is not yet fully
understood. The MDR outbreaks in the US suggest that
THE IMPACT OF ANTITUBERCULOSIS DRUG
HIV might be associated with antituberculosis drug re­
RESISTANCE
sistance. HIV-associated tuberculosis in some societies,
such as parts of the US" and Zaire.1* is associated with
Whatever tuberculosis programmes might do to cause
poorer adherence to therapy than in the case of patients
drug resistance it is clear that drug resistance can do
with tuberculosis alone, and this could lead to the acqui­
considerable harm to tuberculosis treatment. Failure of
sition of resistance. HIV-infected tuberculosis patients
treatment, which is commonly defined as the persistence
are up to 20 limes more likely than HIV-negative paof positive cultures for M. luberculoxis at the end of tlnS^ —
lients to have
— household contacts who arc themselves
treatment period, is more likely to occur if the initial
HIV infected" and these contacts are particularly sus­
organisms were resistanjz Moreover, the more potent
ceptible to contracting tuberculosis.-'"-1 which would
the drug, and the more drugs to which an organism is
likely be resistant if the source case also had resistant
resistant, the greater the chances of treatment failure.
disease. On the other hand, the few studies, in the US.
Probably the best of the very few studies in this anra
Haiti and Africa?4 that have so far measured resist­
was conducted by the British Medical Research Council
ance levels in more representative groups of patients
(BMRC) trials in Africa. Hong Kong and Singa|x>re.
have not found an excess of resistance in the HIV­
< >1 II patients with isolates resistant to rifampicin. 9
positive groups.
of whom also had organisms resistant to another drug
One can intuitively sec that the impact of resistance
or drugs. 5 (45%) patients failed on treatment and a
will depend on the number and efficacy of the drugs
further 3 (27%) had a subsequent relapse. On the other
available to treat tuberculosis. There are. in current use
hand, resistance to just isoniazid and/or streptomycin
in the developing world. 6 main drugs for die irgguaient
led to chemotherapy failure in only 12% of 264
of tuberculosis: isoniazid (H). rifampicin (R), pyrazinapatients.
midc (Z). ethambutol (E), streptomycin (S) and thiaceta
zone (T). The first 3 are the most essential. Streptomycin
is given parenterally, and therefore constitutes a risk
Ml LTII)Rl'(;-RESISTANCE
tor HIV and hepatitis B virus transmission in those areas
where sterilization of injection equipment cannot be
In recent years attention has focused on multidrug-resist- (F guaranteed. The World Health Organisation (WHO)
ant (MDR) strains ol M. tuberculosis.'MDR strains are
does not therefore recommend it for use in areas with a
usually defined as those that arc resistant to at least rihigh prevalence of HIV infection. However, the risk
lampicin and isoniazid, and often to other drugs as well.
bus never been quantified for tuberculosis control pro­
While occasional MDR strains have been isolated from
grammes with sufficient supplies and equipment. Fur­

Surveillance of resisiance to antituberculosis drugs in developing countries 165

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 thiacetazdhe.-'’w 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 thiacetaz.one might actually create resisiance to more power­
ful drugs. If the commonly used regimen of 2SHRZ/
6TH (an initial phase of 2 months of daily SIIRZ.
followed by 6 months of a continuation phase of T and
Hi is altered to 2EHRZ/6EH in some areas, then a pro­
ponion (unknowni of those patients with isoniazid
resisiance 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 tlUATLD)" and WHO consists of 2SHRZE/
HRZE/5IIRE. the continuation phase will again, in
effect, lx- monotherapy, this time 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 fight
against tuberculosis in both developing and industrial­
ized worlds.

Korea,' conducted nationwide surveys at 5 or 10 year y
intervals to assess the extent of their tuberculosis prob-P
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% 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
diiTicuh. if not impossible: selection bias fin 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 resisiance 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 I.
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 ol 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 born patients."
AIMS Ol Sl'RVEILLANCE

SURVEILLANCE FOR AM U UBERCULOSIS
DRUG RESISTANCE
Until recently, few countries in 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 resisiance to one or two of
the commonly used drugs: the minority of patients who
failed to respond to treatment could be investigated for
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 unltT recently. Nevertheless,
a number of countries, such as Kenya." Tanzania" and

fhe 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 dings. At a national level, a surveillance system
would provide a useful indicator of tuberculosis control
programme performance and assessment of the need for 1
changing current treatment policy, identify districts or/
health centres in need of suppon. and determine the risk
factors for resistance.
But there arc 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% ol all
jeopardised. However, itit is in
in precisely
cases could be jeopardised.
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.

a

166

Surveillance of resistance to antituberculosis drugs in developing countries

Tubercle and Lung Disease

RECOMMENDATIONS

resistant tuberculosis at AIDS centre. Lancet 1990;
336:440-441.
12. Chawla P. Klapper P. Kamholz S. Pollack A. Heurich A. Drug­
resistant tuberculosis in an urban population including patients al
risk for human immunodeficiency virus infection. Am Rev
Respir Dis 1992; 146: 280-284. '

with earlier surveys in 1964 and 1974. Tubercle 1989;
-x. 70:5-20.
35. Tanzanian/British Medical Research Council. Tuberculosis in
s—' Tanzania - a national survey of newly notified cases. Tubercle
^1985; 66: 161-178.
f 36.
ilahbal F. Khaled S. and Tazir M. The interest of follow-up

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
13. Centers for Disease Control. Transmission of multidrug-resistani
oping world. Countries with viable tuberculosis control
tuberculosis among immunocompromised persons in a
correctional system - New York. 1991. MMWR 1992:
programmes will be encouraged and assisted to develop
41:507-509.
their own surveillance systems using guidelines for sur­
14. Beck-Sague C. Donley S. Hutton M et al. Hospital outbreak of
veillance drawn up by the Programme, which avoid the
multidrug-rcsistant Mwobacterium tuhrrculosis infections.
JAMA 1992; 268: 1280-1286.
defects, mentioned above, of many previous resistance
# 15. Friedcn T. Sterling T. Pablos-Mendcz A. Kilbui
im J. Cauthen G.
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tended to establish a network of supra-national reference
York City. N Eng J Med 1993; 328: 521 -526.
laboratories to provide the quality control and standard!- 51116. Mahmoudi A. Iseman M. Pitfalls in the care of patients with
tuberculosis: common errors and their association with the
zation of susceptibility testing^at will be essential for
acquisition of drug resistance. JAMA 1993: 270: 65-68.
international comparison. At the same time, much ^17. Styhlo K. Dankova D. Drapela J cl al. Epidemiological and
-—clinical study of tuberculosis in the district of Kolin.
needed support will be given to national reference labo­
Czechoslovakia: report for the first 4 years of lite study.
ratories in developing countries to develop their own
1961-64. Bull World Health Organ 1967: 37: 819-874'
capacity for work on drug resistance.
18. Perriens J H. Colcbunders R L. Karahunga C el al. Increased

CONCLUSIONS

Antituberculosis drug resistance, and especially mullidrugrcsistance, constitutes a major ihreal 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. to set up such
a system.

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