- Email: [email protected]
Controlled clinical trial of a regimen of two durations for the treatment of isoniazid resistant pulmonary tuberculosis
Tubercle (1988) 69, 0 Longman Group
5-14 UK Ltd. 1988
CONTROLLED CLINICAL TRIAL OF A REGIMEN OF TYVO DURATIONS FOR THE TREATMENT OF ISONIAZID RESISTANT PULMONARY TUBERCULOSIS 0.
Babu Kenya
Swai, Medical
J. A. Aluoch, Research
Institute,
Janet Medical
Research
Council
Cardiothoracic
W. A. Githui, Respiratory
Diseases
H. Darbyshire,
Epidemiology
Group,
R. Thiong’o, Research
E. A. Edwards
Centre,
Nairobi,
Kenya
A. J. Nunn Brompfon
Hospital,
Wham
Road, London SW3 6HP
Summary Patients with pulmonary tuberculosis who were failures of primary chemotherapy with strains resistant to isoniazid or to isoniazid and streptomycin were allocated at random to receive a regimen of rifampicin and ethambutol for 6 (4RE) or 9 months (7RE), supplemented in both treatment series by streptomycin plus pyrazinamide for the first 2 months. The patients were treated in hospital for the first 2 months and thereafter treatment was supervised on a daily basis in the nearest health institution by an appointed member of staff or at home by responsible members of the community. A total of 306 patients was admitted and 226 patients remained for analysis at the end of chemotherapy, 179 with a strain resistant to isoniazid alone and 47 with a strain resistant to isoniazid and streptomycin. There were only two failures at the end of chemotherapy, one in the 6-month series who had resistance to both isoniazid and streptomycin pretreatment, and one in the g-month series who had resistance to isoniazid alone. For the 144 patients with initial resistance to isoniazid alone assessed up to 30 months, the relapse rates were low in both series: 4 % for the 72 patients in the 6-month series and 3 % for the 72 patients in the g-month series. However, for the 34 patients with resistance to both drugs, three of the 14 in the 6-month but none of 20 in the g-month series relapsed.
R&urn6 Des malades presentant une tuberculose pulmonaire, pour lesquels une premiere chimiotherapie avait echoue et dont les souches bacillaires Btaient resistantes vis-avis de I’isoniazide ou de I’isoniazide et de la streptomycine, ont bte repartis de facon aleatoire en deux groupes pour recevoir un regime comportant la rifampicine et I’ethambutol soit pendant 6 mois, soit pendant 9 mois, regime auquel etait ajoute dans les deux cas de la streptomycine et du pyrazinamide durant les deux premiers mois. Les patients on ete hospitalises pendant les deux premiers mois du traitement et ensuite I’administration du traitement a 6te supervisee tous les jours dans le centre de Sante le plus proche par un membre du personnel design6 pour cette tdche, ou a domicile par des personnes responsables appartenant a la communaute. Au total, 306 malades ont 6th admis dans I’btude; 226 restaient pour analyse a la Correspondence Nairobi, Kenya.
to: Director, Kenya Medical Research Institute, Respiratory Diseases Research Centre, P.O. Box 47855,
6
Swai
and others
fin de la chimiotherapie, dont 179 presentant des souches resistant a I’isoniazide seul, et 47 presentant des souches resistant a I’isoniazide et a la streptomycine. Deux echecs seulement ont 6te constates a la fin de la chimiotherapie: I’un dans la serie de 6 mois; le malade Btait resistant a la fois a I’isoniazide et a la streptomycine, et I’autre dans la serie de 9 mois; le malade etait resistant a I’isoniazide seulement. Chez les 144 malades qui presentaient une resistance a I’isoniazide seul et qui ont ete dtudies apres 30 mois, le taux des rechutes etait bas dans les deux series, 4 % pour les 72 malades de la serie de 6 mois et 3 % pour les 72 malades de la serie de 9 mois. Par contre, parmi les 34 malades qui presentaient une resistance vis-a-vis des deux medicaments, 3 malades ont rechute parmi les 14 trait& pendant 6 mois mais aucun parmi ceux trait& pendant 9 mois. Resumen Los enfermos que presentaban una tuberculosis pulmonar cuya primera quimioterapia habia fracasado y cuyas cepas bacilares eran resistentes a la isoniacida o a la isoniacida y estreptomicina fueron distribuidos al azar en dos grupos para recibir un esquema terapeutico que incluia rifampicina y etambutol, ya sea durante 6 meses o durante 9 meses, suplementado en ambos cases con estreptomicina y pirazinamida durante 10s dos primeros meses. Los pacientes fueron hospitalizados durante 10s dos primeros meses y luego la administration del tratamiento fue supervisada todos 10s dias en el centro de salud m&s cercano por un miembro del personal designado especialmente o a domicilio por un miembro de la comunidad. Se incluyo en el estudio un total de 306 pacientes, de 10s cuales quedaron 226 para el analisis al final de la quimioterapia; 179 presentaban cepas resistentes a la isoniacida sola y 47 presentaban cepas resistentes a la isoniacida y a la estreptomicina. Al final de la quimioterapia se constatb solo 2 fracasos, uno en la serie de 6 meses, con cepas resistentes tanto a la isoniacida coma a la estreptomicina y el otro en la serie de 9 meses, con cepas resistentes solo a la isoniacida. En 10s 144 pacientes que presentaban una resistencia a la isoniacida sola y que fueron evaluados 30 meses despues, la tasa de recaidas era baja en las dos series: 4 % para 10s 72 enfermos de la serie de 6 meses y 3 % para 10s 72 enfermos de la serie de 9 meses. Por otra parte, en el grupo de 34 pacientes con resistencia a ambos medicamentos, presentaron recaidas 3 de 10s 14 enfermos de la serie de 6 meses y ninguno de 10s de la serie de 9 meses. Introduction The success of standard daily chemotherapy for tuberculosis depends on the long term provision of adequate regimens and on the continued co-operation of the patient in selfadministration of the drugs. In Kenya the standard regimen is daily thiacetazone plus isoniazid for 12-18 months, with an initial streptomycin supplement for l-2 months. This has been shown to have a success rate of over 90 % in controlled clinical trials in patients with fully sensitive strains initially who remain under treatment [I, 21.’However, in routine programme conditions, a considerable proportion of patients stop taking drugs long before the end of the prescribed period or take them in an irregular fashion. Consequently the success rate is much lower, of the order of 70 % in Kenya in 1974 131 and as low as 50 % in some other countries [4]. Failures of standard treatment frequently occur with the
lsoniazid
resistant
tuberculosis
7
emergence of strains of tubercle bacilli resistant to isoniazid. The long duration of treatment is a major factor leading to default. Other factors operating in developing countries include long distance between the patient’s home and the treatment centre, inadequate or intermittent supplies of drugs and lack of education about the disease. Lack of interest of the staff in the disease and a failure to enthuse and encourage the patients to be regular in their attendances and in taking their medicament regularly are common and often no attempt is made to involve the family in the patient’s management. The primary objective of a case-finding and treatment programme is to diagnose and cure all new cases which present to the services. However, many more cases exist in the community which remain undiagnosed by the routine services. When a high level of success is achieved in primary chemotherapy, these are the next priority group for casefinding and treatment. A stage in the programme will be reached when the success rate of diagnosis and treatment of new cases is satisfactorily high and the country can afford sufficient drugs and manpower resources to introduce retreatment regimens for the patients who have failed on standard chemotherapy. The phasing of these activities requires important administrative decisions. As failure cases are often irregular in drug taking, the ideal approach for such retreatment is to aim at organising it on a fully supervised basis from the start. In this study patients known to have strains resistant to isoniazid or to isoniazid and streptomycin were allocated at random to receive a regimen of rifampicin and ethambutol for 6 or 9 months, supplemented in both regimens by streptomycin plus pyrazinamide for the first 2 months. All patients were known to have been failures of standard chemotherapy and daily supervised chemotherapy was considered to be feasible for them. The results during treatment and the bacteriological relapse rates up to 30 months are presented, that is a follow-up of 24 months after stopping chemotherapy for the 6-month and 21 months for the g-month regimen.
Materials Selection
and methods
of patients
Eligible patients were aged 15 years or more, with sputum positive on smear at the local laboratory and confirmed on culture at the Reference Laboratory in Nairobi, the strains being resistant to isoniazid, or to isoniazid and streptomycin. They were considered to be co-operative and had agreed to stay in hospital for the first 2 months. They also had an address which could be visited by hospital staff, and it had been established that outpatient treatment on a daily supervised basis would be possible at a conveniently situated health unit or, if not, with the help of local community leaders. Patients who lived more than 3 km from a health unit and whose treatment could not be supervised by a local community leader were not eligible. Also excluded were those in very poor general condition or who required additional measures for survival, those with coexisting extra-pulmonary lesions other than lymphadenopathy, and those with nontuberculous disease likely to prejudice the response to or assessment of treatment.
Pretreatment
investigations
Two sputum specimens were collected and sent to the Reference Laboratory in Nairobi for smear, culture and sensitivity testing. A postero-anterior chest radiograph was taken before treatment was started.
8
Swai
and others
Allocation
of treatment
Suitable patients were allocated at random to one of the two durations of the regimen in the Research Centre in Nairobi by entering their name in the space alongside the next serial number in a special register. A treatment card was completed with the patient’s name and serial number and sent to the participating centre for the start of chemotherapy for the allocated duration. All patients received the same initial 8-week daily intensive phase of streptomycin (S), pyrazinamide (Z), rifampicin (R), and ethambutol (E) and this was followed by either rifampicin plus ethambutol daily for 4 months (4RE series) or rifampicin plus ethambutol daily for 7 months (7RE Series). Drug dosages were as follows: Streptomycin Pyrazinamide Rifampicin Ethambutol
1 .O g daily or 0.75 g for those aged over 40 years or weighing 33 kg or less pretreatment. 1.5 g for patients weighing less than 50 kg pretreatment and 2.0 g for heavier patients. 450 mg for patients weighing less than 50 kg pretreatment and 600 mg for heavier patients. 25 mg/kg for the first 8 weeks and 15 mg/kg thereafter.
Patients were admitted to the nearest Provincial Hospital for the first 8 weeks, all drugs being given together as a single daily dose. To ensure complete regularity during the outpatient phase patients received the drugs under the direct supervision of an appointed member of staff in the health unit nearest to their home. In the few cases where supervision was undertaken by a community leader or a school teacher, they were given instructions on the procedures for drug administration and recording. In all cases of side effects or default the District Hospital was informed and appropriate action was taken. Investigations
during
treatment
and
follow-up
All patients were assessed monthly up to 12 months and then 3-monthly up to 30 months. At each visit a report was made and sent to the Research Centre giving details and reasons for any departure from the allocated regimen and any suspected adverse reactions. One sputum specimen was collected at each visit and examined at the Research Centre by smear and culture; sensitivity tests to streptomycin, isoniazid and rifampicin were performed on any positive cultures occurring after 3 months of chemotherapy. A chest radiograph was taken at the end of chemotherapy. Ophthalmological examinations were not performed routinely but provisions were made for the patients to be seen by the provincial physician in cases of suspected ethambutol toxicity. Bacteriological
procedures
The procedures used for smear, culture, sensitivity and identification tests were the standard British Medical Research Council techniques [5-71. Resistance to isoniazid was defined as growth of 20 colonies or more on 0.2 mg/l or more of isoniazid in at least one culture, resistance to rifampicin as growth on 32 mg/l rifampicin in at least one culture and to ethambutol growth on 5.6 mg/l of ethambutol in at least one culture. Resistance to streptomycin was defined as a geometric mean minimal inhibitory concentration (MIC) of 32 mg/l. Results A total of 306 patients
(152 4RE, 154 7RE) was admitted
to the study between
October
1978
lsoniazid and March 1982 from outpatient treatment.
five
Provincial
Hospitals
which
resistant
co-ordinated
tuberculosis
the
inpatient
9 and
Exclusions In all, 56 (27 4RE, 29 7RE) patients were excluded pretreatment, 29 (13 4RE, 16 7RE) for bacteriological reasons. Of the 29,2 (1 4RE, 1 7RE) had strains sensitive to isoniazid, for 10 (4 4RE, 6 7RE) all cultures were negative, contaminated or no specimens were collected, 11 (5 4RE, 6 7RE) had no sensitivity test results; two patients (1 4RE, 1 7RE) had strains resistant to isoniazid and rifampicin; three (1 4RE, 2 7RE) had strains resistant to isoniazid and ethambutol and one (4RE) had a strain resistant to isoniazid, rifampicin and ethambutol. Thirteen patients (6 4RE, 7 7RE) died before starting treatment. Nine (4 4RE, 5 7RE) could not be traced to start treatment and five (4 4RE, 1 7RE) were excluded for miscellaneous reasons. During treatment a further 24 patients (12 4RE, 12 7RE) were excluded. Ten (1 4RE, 9 7RE) missed a substantial amount of treatment (defined as 2 weeks or more in the 2-month initial intensive phase or 6 weeks or more for the 6-month regimen or 9 weeks or more for the 9month regimen) on account of default or error and six patients died (5 4RE, 1 7RE). A further eight patients (6 4RE, 2 7RE) had insufficient bacteriology for assessment of response at the end of chemotherapy. After exclusions, there remain 226 (113 4RE, 113 7RE) patients for analysis of whom 179 (91 4RE, 88 7RE) had a strain resistant to isoniazid alone and 47 (22 4RE, 25 7RE) a strain resistant to both isoniazid and streptomycin. Deaths Of the six patients who died during treatment, five (4 4RE, 1 7RE) died of tuberculosis, three (all 4RE) in the first 3 weeks, one (4RE) in the fourth month of a severe haemoptysis and the fifth (7RE) during the third month of car pulmonale. The remaining patient (4RE) died in the second month of acute renal failure of uncertain aetiology although drug toxicity could not be excluded. Condition
on admission
Of the 226 patients in the main analysis, 162 (72 %I were male and 114 (50 %) were aged 35 years or more on admission. All patients had at least one positive smear result at the local laboratory and 93 % had a positive smear in the reference laboratory. Considering the first smear result in the reference laboratory 30 (13 %I were negative, 72 (32 %I were scanty, 64 (28 %) were moderate and 60 (27 %I were heavily positive. Pretreatment postero-anterior chest radiographs were assessed for 102 (46 %I of the 226 patients (the others had either unassessable radiographs or they had been taken more than 6 months before the start of treatment). The independent assessor classified the extent of the disease as involving more than one lung field in 33 %. Obvious cavitation was present in 75 %, 25 % being slight, 20 % moderate, and 30 % extensive [81. The findings in the 4RE and 7RE series were broadly similar. Culture
results
during
chemotherapy
In the first 6 months all patients received the same chemotherapy, namely rifampicin and ethambutol with streptomycin and pyrazinamide in addition for the initial 2 months. At 1 month, 59 % of 177 patients with isoniazid resistance assessed had a negative culture (based on the first or only specimen) and at 2 months 96 % of the 170 patients assessed;
10
Swai
and others
the findings were similar for the patients with resistance to both isoniazid and streptomycin (Table I). At 3 months and subsequently 95 % or more of patients had negative cultures. Status
of patients
on completion
of chemotherapy
Of the 226 patients assessed, only two patients (1 4RE, 1 7RE) have been classified as having an unfavourable status (Table II), their sputum being culture positive at the end of chemotherapy. One (7RE) who had an isoniazid-resistant strain pretreatment, was culture negative at months 2 and 3 but positive again at month 4 to month 9 with no further resistance emerging. In the other (4RE) who had a strain resistant to both isoniazid and streptomycin pretreatment, rifampicin resistance emerged at month 3, and ethambutol at month 7. A further nine patients (2 4RE, 7 7RE) have been classified as having a doubtful status at the end of chemotherapy. Eight (1 4RE, 7 7RE) had resistance to isoniazid alone initially and one (4RE) to both drugs. Of the two patients in the 4RE series, one had a positive culture of more than 20 colonies growth at month 6 and the other had one colony growth in each of the two specimens at 6 months. Of the seven patients in the 7RE series one had a growth of more than 20 colonies and another had a growth of seven colonies at month 8, but they both had negative cultures at month 9. A third patient had 5 and 10 colonies respectively at month 7. The remaining 4 patients had one positive culture of less than 20 colonies growth and one negative at 8 or 9 months. There was no evidence of the emergence of further resistance in any of the patients classified as doubtful. Table
I.
Bacteriological
results
during
Initial resistance to: lsoniazid
the first 3 months Month
alone
lsoniazid and streptomycin
Number of patients assessed
Culture-negative No.
%
1 2 3
177 170 159
104 164 155
59 96 97
1 2 3
46 45 42
30 44 40
65 98 95
*Patients in both the 4RE and 7RE treatment same chemotherapy.
Table
II.
Status
Initial resistance to: lsoniazid
lsoniazid and streptomycin All patients
series
received
the
at end of chemotherapy. Series
alone
of chemotherapy.*
Total patients assessed
Status Favourable
Doubtful
Unfavourable
4RE 7RE
91 88
90 80
1 7
0 1
4RE 7RE
22 25
20 25
1 0
1 0
226
215
9
2
lsoniazid Exclusion
from
relapse
resistant
tuberculosis
11
analysis
All patients were to be followed to 30 months, that is 24 months after stopping chemotherapy for the 4RE series and 21 months for the 7RE series. Of the total 224 patients with a favourable or doubtful status at the end of chemotherapy 46 patients were excluded, seven (4 4RE, 3 7RE) died; three patients in the 4RE series died of car pulmonale and one of unknown cause in the 23rd month with negative cultures up to her last attendance at 16 months. Of the three 7RE patients, one died from gastroenteritis with severe dehydration, the second in a road traffic accident and the third at home of unknown cause. The remaining 39 patients (22 4RE, 17 7RE) had defaulted. Of the 22 patients in the 4RE series 13 had been followed up to at least 20 months when specimens collected were negative, and the remaining nine defaulted between months 7 and 12. Nine of the 17 7RE patients were followed up to 20 months and eight defaulted between 10 and 16 months. They were all clinically well at their last clinic visits and sputum cultures were negative. There remain 178 patients (86 4RE, 92 7REI for the relapse analysis. Definition
of relapse
Bacteriological relapse after stopping chemotherapy was defined as two or more cultures of at least 10 colonies growth obtained at different months in any 3-month period or three or more positive cultures of any growth at different months in any 4-month period. Bacteriological
relapses
Of the 144 patients (72 4RE, 72 7RE) with strains resistant to isoniazid alone pretreatment, five (3 %) patients (3 4RE, 2 7RE) relapsed (Table Ill) at months 2, 9, 20, 2, and 18, respectively after stopping chemotherapy. Of the 34 patients (14 4RE, 20 7RE) with pretreatment strains resistant to isoniazid and streptomycin, three (all in the 4RE series) relapsed at month 5, 8, and 19 after stopping chemotherapy. The sensitivity pattern for the relapse strains for all patients was the same as the pretreatment strains. Resistance to the other drugs, namely rifampicin and ethambutol, did not occur. Six patients (3 4RE, 3 7RE) were excluded from the main analysis for having strains resistant to rifampicin, ethambutol or both drugs in addition to isoniazid pretreatment. At the end of chemotherapy they all had a favourable status. During follow-up, however, two patients (both in the 4RE series), one of whom had a strain resistant to isoniazid and rifampicin and the other to isoniazid, rifampicin, and ethambutol, relapsed 2 months after
Table
III.
Bacteriological
Initial resistance to:
lsoniazid
Regimen
alone
lsoniazid and streptomycin Figures Figures
relapses
in s&are in round
after stopping
chemotherapy.
Number of patients assessed
Bacteriological
4RE 7RE
72 [II 72 [71
3 WI 2 [Ol
4RE 7RE
14 20
111 IO1
No.
3 0
IO1
brackets are patients whose status at the end of chemotherapy brackets are percentages based on less than 25 patients.
relapses %
Month after stopping chemotherapy
4 3
2 2
9 18
20
(21)
5
8
19
(0) was
doubtful.
12
Swai
and others
stopping chemotherapy four patients remained Adverse
with a strain resistant to all the three drugs. The status of the other favourable up to the end of follow-up.
reactions
Only two (0.8 %) of the 283 (142 4RE, 141 7RE) patients who started chemotherapy were reported to have possible adverse reactions and in only one of them (7RE) was the regimen modified. This patient developed a hypersensitivity reaction to streptomycin on the third day. Desensitisation was not attempted and streptomycin was discontinued. The other patient (4RE) complained of arthralgia during the fifth week, suspected to be caused by pyrazinamide but he responded to acetyl salicylic acid without modification of chemotherapy. No ocular toxicity was reported though the centres were expressly advised to refer any patients with visual problems during chemotherapy to the Provincial Physician.
Discussion In Kenya, where the standard chemotherapy regimen for new tuberculosis patients is isoniazid plus thiacetazone for 12-18 months with an initial streptomycin supplement, resistance among those who fail or relapse is usually to isoniazid and the strain is almost invariably still sensitive to streptomycin because it is given for the first 2 months only [2]. Hence, when regimens of rifampicin and ethambutol supplemented with streptomycin and pyrazinamide in the initial phase are used as in the present study, the organisms are likely to be sensitive to three or all four drugs. In this study, there were only two failures during chemotherapy. Also, the bacteriological relapse rates at 30 months after start of chemotherapy were low and similar, 4 % in the 6- and 3 % in the g-month series for patients with initial resistance to isoniazid alone. For those with initial resistance to both isoniazid and streptomycin relapse occurred in three of 14 patients on the 4RE regimen and none of 20 on the 7RE regimen, suggesting a possible advantage for the longer duration. The overall relapse rates for the patients with single and double drug resistance combined were thus 7 % for the 6-month and 2 % for the g-month series. If either could be introduced in routine programme conditions with adequate supervision, it is likely that it would achieve far better results than the much less acceptable 18-month retreatment regimen previously developed in Kenya [9, IO]. This regimen, which was introduced in Kenya in 1970, consisted of PAS plus pyrazinamide orally once daily for 18 months, with streptomycin lg intra-muscularly daily for the first 6 months. Although highly effective in patients with initial isoniazid resistance, it has practical limitations especially that of daily injections for 6 months. Further, the problems related to PAS, namely the inconvenience of administration and the frequency of unpleasant side effects, and in recent years the difficulty in obtaining supplies (as is also the case with cycloserine), have made it difficult to apply routinely. The retreatment regimens used previously in many countries, and still used in some, based on ethionamide, pyrazinamide and cycloserine not only have substantial risks of serious drug toxicity but also high incidence of unpleasant side effects [I 1, 121, leading to poor compliance and low levels of success. Some countries developed effective intermittent retreatment regimens based on rifampicin and ethambutol which make it easier to ensure full supervision of every dose [13]. Few developing countries, however, have organised intermittent or daily supervised chemotherapy, even in first-line treatment. Tackling the problem of patients with drug-resistant strains following initial treatment with a standard regimen is not a high priority in most developing countries. The prevention of failure in new cases brought under treatment for the first time is a more rational approach than producing failures and then spending scarce resources on their retreatment. A survey
lsoniazid
resistant
tuberculosis
13
carried out in Kenya in 1974 showed that the treatment success rate in new cases was of the order of 70 % [3]. Fox, however, has reported that in many developing countries the success rate achieved by routine treatment services may be as low as 50 % with regimens which in carefully conducted controlled clinical trials are near 100 % effective [4]. In the 1974 survey in Kenya [14] 10.1 % of 702 patients who had no history of previous chemotherapy had a strain resistant to isoniazid (7.3 %) or to streptomycin (1.4 %) or to both drugs (1.4 %). In contrast, in 82 patients who had previous chemotherapy, 28 % had a strain resistant to isoniazid (17 %) or to streptomycin (0 %) or both drugs (11 %I. The incidence of drug resistance, mainly due to non-compliance and irregularity of drug taking, increased with the duration of chemotherapy. The reason for concentrating on curing the new cases is obvious. The gap between the potential of regimens and what they achieve in routine service conditions has long been a matter of concern. The role of patient compliance and the failure of the health services to motivate patients has led in some countries to the full supervision of every dose of the chemotherapy by health services staff. This may not be easy to organise and, in many rural areas with limited resources, totally impractical unless efficient primary health care can be organised. This has, however, been achieved to some extent in selected retreatment patients in this pilot study, in those who live near health units. Patients in both urban and rural areas need adequate supervision of the retreatment regimen, but this may be difficult to implement if full supervision is not ensured. Clearly, it is necessary to try an effective intermittent regimen under full supervision in order to obtain practical experience of the problems encountered and how they might be overcome. When the primary health care service is efficient the implementation of intermittent oral regimens using community health workers and other responsible members of the community becomes a real prospect.
Acknowledgements The authors wish to thank all the staff in the co-operating hospitals which included Infectious Diseases Hospital, Nairobi, Provincial General Hospital at Machakos, Kisumu and Nyeri, and the Port Reitz Chest Hospital at Mombasa. Some of the patients were referred from district hospitals in Meru, Embu, Kitui, Kirinyaga, Kilifi, Kwale, Kakamega, Siaya, and Kericho. The continued support of the Ministry of Health is acknowledged. We are particularly grateful to the Director of Medical Services, Dr W. Koinange, for arranging for the supply of part of the drugs used in this study’from Ministry of Health. Special thanks are due to Professor Wallace Fox and Professor D. A. Mitchison for their valuable advice. The independent assessment of chest radiographs was undertaken by Dr J. R. Bignall.
References 1 East African/British Medical Research Council Third Thiacetazone Investigation. lsoniazid with thiacetazone (thioacetazone) in the treatment of pulmonary tuberculosis in East Africa-Third Investigation: The effect of an initial streptomycin supplement. Jubercle 1966; 47: l-32. 2 East African/British Medical Research Council Fifth Thiacetazone Investigation. lsoniazid with thiacetazone in the treatment of pulmonary tuberculosis in East Africa - Fifth investigation. Jubercle 1970; 51: 123-51. 3 Second East African/British Medical Research Council Kenya Tuberculosis Survey Follow-up. Tuberculosis in Kenya: Follow-up of the second (1974) national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. Jubercle 1979; 60: 125-49. 4 Fox W. The modern management and therapy of pulmonary tuberculosis. Proc Roy Sot Med 1977; 70: 4-15. 5 East African/British Medical Research Council ThiacetazoneIDiphenyI-thiourea Investigation. Comparative trial of
14
6 7
8 9 10
11 12 13
14
Swai and others isoniazid in combination with thiacetazone or a substituted diphenylthiourea (SU1906) or PAS in the treatment of acute pulmonary tuberculosis in East Africans. Tubercle 1960; 41: 399-423. Allen BW, Baker RJ. Mycobacteria: Isolation, identification and sensitivity testing. 1968; Butterworths, London. British Medical Research Council Co-operative Study. Co-operative controlled trial of a standard regimen of streptomycin, PAS and isoniazid and three alternative regimens of chemotherapy in Britain. Tubercle 1973; 54: 99-129. Simon G. Radiology in epidemiological studies and some therapeutic trials. Br Med J 1966; 2: 491-4. East African/British Medical Research Council Retreatment Investigation. Streptomycin plus PAS plus pyrazinamide in the retreatment of pulmonary tuberculosis in East Africa. Tubercle 1971; 52: 191-8. East African/British Medical Research Council Retreatment Investigation: Second Report. Streptomycin plus PAS plus pyrazinamide in the retreatment of pulmonary tuberculosis in East Africa-Second report. Tubercle 1973; 54: 283-90. British Tuberculosis Association. Ethionamide. pyrazinamide and cycloserine in the treatment of drug resistant pulmonary tuberculosis. Tubercle 1963; 44: 195-214. International Union Against Tuberculosis. A comparison of regimens of ethionamide, pyrazinamide and cycloserine in retreatment of patients with pulmonary tuberculosis. Bull Inr UnionTuberc 1969; 42: 7-57. Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council Retreatment Investigation. A controlled clinical trial of daily and intermittent regimens of rifampicin plus ethambutol in the retreatment of patients with pulmonary tuberculosis in Hong Kong. Tube&e 1974; 55: l-27. Second East African/British Medical Research Council Kenya Tuberculosis Survey. Tuberculosis in Kenya: A second national sampling survey of drug resistance and other factors, and a comparison with the prevalence data from the first national sampling survey. Tubercle 1978; 59: 155-77.
5-14 UK Ltd. 1988
CONTROLLED CLINICAL TRIAL OF A REGIMEN OF TYVO DURATIONS FOR THE TREATMENT OF ISONIAZID RESISTANT PULMONARY TUBERCULOSIS 0.
Babu Kenya
Swai, Medical
J. A. Aluoch, Research
Institute,
Janet Medical
Research
Council
Cardiothoracic
W. A. Githui, Respiratory
Diseases
H. Darbyshire,
Epidemiology
Group,
R. Thiong’o, Research
E. A. Edwards
Centre,
Nairobi,
Kenya
A. J. Nunn Brompfon
Hospital,
Wham
Road, London SW3 6HP
Summary Patients with pulmonary tuberculosis who were failures of primary chemotherapy with strains resistant to isoniazid or to isoniazid and streptomycin were allocated at random to receive a regimen of rifampicin and ethambutol for 6 (4RE) or 9 months (7RE), supplemented in both treatment series by streptomycin plus pyrazinamide for the first 2 months. The patients were treated in hospital for the first 2 months and thereafter treatment was supervised on a daily basis in the nearest health institution by an appointed member of staff or at home by responsible members of the community. A total of 306 patients was admitted and 226 patients remained for analysis at the end of chemotherapy, 179 with a strain resistant to isoniazid alone and 47 with a strain resistant to isoniazid and streptomycin. There were only two failures at the end of chemotherapy, one in the 6-month series who had resistance to both isoniazid and streptomycin pretreatment, and one in the g-month series who had resistance to isoniazid alone. For the 144 patients with initial resistance to isoniazid alone assessed up to 30 months, the relapse rates were low in both series: 4 % for the 72 patients in the 6-month series and 3 % for the 72 patients in the g-month series. However, for the 34 patients with resistance to both drugs, three of the 14 in the 6-month but none of 20 in the g-month series relapsed.
R&urn6 Des malades presentant une tuberculose pulmonaire, pour lesquels une premiere chimiotherapie avait echoue et dont les souches bacillaires Btaient resistantes vis-avis de I’isoniazide ou de I’isoniazide et de la streptomycine, ont bte repartis de facon aleatoire en deux groupes pour recevoir un regime comportant la rifampicine et I’ethambutol soit pendant 6 mois, soit pendant 9 mois, regime auquel etait ajoute dans les deux cas de la streptomycine et du pyrazinamide durant les deux premiers mois. Les patients on ete hospitalises pendant les deux premiers mois du traitement et ensuite I’administration du traitement a 6te supervisee tous les jours dans le centre de Sante le plus proche par un membre du personnel design6 pour cette tdche, ou a domicile par des personnes responsables appartenant a la communaute. Au total, 306 malades ont 6th admis dans I’btude; 226 restaient pour analyse a la Correspondence Nairobi, Kenya.
to: Director, Kenya Medical Research Institute, Respiratory Diseases Research Centre, P.O. Box 47855,
6
Swai
and others
fin de la chimiotherapie, dont 179 presentant des souches resistant a I’isoniazide seul, et 47 presentant des souches resistant a I’isoniazide et a la streptomycine. Deux echecs seulement ont 6te constates a la fin de la chimiotherapie: I’un dans la serie de 6 mois; le malade Btait resistant a la fois a I’isoniazide et a la streptomycine, et I’autre dans la serie de 9 mois; le malade etait resistant a I’isoniazide seulement. Chez les 144 malades qui presentaient une resistance a I’isoniazide seul et qui ont ete dtudies apres 30 mois, le taux des rechutes etait bas dans les deux series, 4 % pour les 72 malades de la serie de 6 mois et 3 % pour les 72 malades de la serie de 9 mois. Par contre, parmi les 34 malades qui presentaient une resistance vis-a-vis des deux medicaments, 3 malades ont rechute parmi les 14 trait& pendant 6 mois mais aucun parmi ceux trait& pendant 9 mois. Resumen Los enfermos que presentaban una tuberculosis pulmonar cuya primera quimioterapia habia fracasado y cuyas cepas bacilares eran resistentes a la isoniacida o a la isoniacida y estreptomicina fueron distribuidos al azar en dos grupos para recibir un esquema terapeutico que incluia rifampicina y etambutol, ya sea durante 6 meses o durante 9 meses, suplementado en ambos cases con estreptomicina y pirazinamida durante 10s dos primeros meses. Los pacientes fueron hospitalizados durante 10s dos primeros meses y luego la administration del tratamiento fue supervisada todos 10s dias en el centro de salud m&s cercano por un miembro del personal designado especialmente o a domicilio por un miembro de la comunidad. Se incluyo en el estudio un total de 306 pacientes, de 10s cuales quedaron 226 para el analisis al final de la quimioterapia; 179 presentaban cepas resistentes a la isoniacida sola y 47 presentaban cepas resistentes a la isoniacida y a la estreptomicina. Al final de la quimioterapia se constatb solo 2 fracasos, uno en la serie de 6 meses, con cepas resistentes tanto a la isoniacida coma a la estreptomicina y el otro en la serie de 9 meses, con cepas resistentes solo a la isoniacida. En 10s 144 pacientes que presentaban una resistencia a la isoniacida sola y que fueron evaluados 30 meses despues, la tasa de recaidas era baja en las dos series: 4 % para 10s 72 enfermos de la serie de 6 meses y 3 % para 10s 72 enfermos de la serie de 9 meses. Por otra parte, en el grupo de 34 pacientes con resistencia a ambos medicamentos, presentaron recaidas 3 de 10s 14 enfermos de la serie de 6 meses y ninguno de 10s de la serie de 9 meses. Introduction The success of standard daily chemotherapy for tuberculosis depends on the long term provision of adequate regimens and on the continued co-operation of the patient in selfadministration of the drugs. In Kenya the standard regimen is daily thiacetazone plus isoniazid for 12-18 months, with an initial streptomycin supplement for l-2 months. This has been shown to have a success rate of over 90 % in controlled clinical trials in patients with fully sensitive strains initially who remain under treatment [I, 21.’However, in routine programme conditions, a considerable proportion of patients stop taking drugs long before the end of the prescribed period or take them in an irregular fashion. Consequently the success rate is much lower, of the order of 70 % in Kenya in 1974 131 and as low as 50 % in some other countries [4]. Failures of standard treatment frequently occur with the
lsoniazid
resistant
tuberculosis
7
emergence of strains of tubercle bacilli resistant to isoniazid. The long duration of treatment is a major factor leading to default. Other factors operating in developing countries include long distance between the patient’s home and the treatment centre, inadequate or intermittent supplies of drugs and lack of education about the disease. Lack of interest of the staff in the disease and a failure to enthuse and encourage the patients to be regular in their attendances and in taking their medicament regularly are common and often no attempt is made to involve the family in the patient’s management. The primary objective of a case-finding and treatment programme is to diagnose and cure all new cases which present to the services. However, many more cases exist in the community which remain undiagnosed by the routine services. When a high level of success is achieved in primary chemotherapy, these are the next priority group for casefinding and treatment. A stage in the programme will be reached when the success rate of diagnosis and treatment of new cases is satisfactorily high and the country can afford sufficient drugs and manpower resources to introduce retreatment regimens for the patients who have failed on standard chemotherapy. The phasing of these activities requires important administrative decisions. As failure cases are often irregular in drug taking, the ideal approach for such retreatment is to aim at organising it on a fully supervised basis from the start. In this study patients known to have strains resistant to isoniazid or to isoniazid and streptomycin were allocated at random to receive a regimen of rifampicin and ethambutol for 6 or 9 months, supplemented in both regimens by streptomycin plus pyrazinamide for the first 2 months. All patients were known to have been failures of standard chemotherapy and daily supervised chemotherapy was considered to be feasible for them. The results during treatment and the bacteriological relapse rates up to 30 months are presented, that is a follow-up of 24 months after stopping chemotherapy for the 6-month and 21 months for the g-month regimen.
Materials Selection
and methods
of patients
Eligible patients were aged 15 years or more, with sputum positive on smear at the local laboratory and confirmed on culture at the Reference Laboratory in Nairobi, the strains being resistant to isoniazid, or to isoniazid and streptomycin. They were considered to be co-operative and had agreed to stay in hospital for the first 2 months. They also had an address which could be visited by hospital staff, and it had been established that outpatient treatment on a daily supervised basis would be possible at a conveniently situated health unit or, if not, with the help of local community leaders. Patients who lived more than 3 km from a health unit and whose treatment could not be supervised by a local community leader were not eligible. Also excluded were those in very poor general condition or who required additional measures for survival, those with coexisting extra-pulmonary lesions other than lymphadenopathy, and those with nontuberculous disease likely to prejudice the response to or assessment of treatment.
Pretreatment
investigations
Two sputum specimens were collected and sent to the Reference Laboratory in Nairobi for smear, culture and sensitivity testing. A postero-anterior chest radiograph was taken before treatment was started.
8
Swai
and others
Allocation
of treatment
Suitable patients were allocated at random to one of the two durations of the regimen in the Research Centre in Nairobi by entering their name in the space alongside the next serial number in a special register. A treatment card was completed with the patient’s name and serial number and sent to the participating centre for the start of chemotherapy for the allocated duration. All patients received the same initial 8-week daily intensive phase of streptomycin (S), pyrazinamide (Z), rifampicin (R), and ethambutol (E) and this was followed by either rifampicin plus ethambutol daily for 4 months (4RE series) or rifampicin plus ethambutol daily for 7 months (7RE Series). Drug dosages were as follows: Streptomycin Pyrazinamide Rifampicin Ethambutol
1 .O g daily or 0.75 g for those aged over 40 years or weighing 33 kg or less pretreatment. 1.5 g for patients weighing less than 50 kg pretreatment and 2.0 g for heavier patients. 450 mg for patients weighing less than 50 kg pretreatment and 600 mg for heavier patients. 25 mg/kg for the first 8 weeks and 15 mg/kg thereafter.
Patients were admitted to the nearest Provincial Hospital for the first 8 weeks, all drugs being given together as a single daily dose. To ensure complete regularity during the outpatient phase patients received the drugs under the direct supervision of an appointed member of staff in the health unit nearest to their home. In the few cases where supervision was undertaken by a community leader or a school teacher, they were given instructions on the procedures for drug administration and recording. In all cases of side effects or default the District Hospital was informed and appropriate action was taken. Investigations
during
treatment
and
follow-up
All patients were assessed monthly up to 12 months and then 3-monthly up to 30 months. At each visit a report was made and sent to the Research Centre giving details and reasons for any departure from the allocated regimen and any suspected adverse reactions. One sputum specimen was collected at each visit and examined at the Research Centre by smear and culture; sensitivity tests to streptomycin, isoniazid and rifampicin were performed on any positive cultures occurring after 3 months of chemotherapy. A chest radiograph was taken at the end of chemotherapy. Ophthalmological examinations were not performed routinely but provisions were made for the patients to be seen by the provincial physician in cases of suspected ethambutol toxicity. Bacteriological
procedures
The procedures used for smear, culture, sensitivity and identification tests were the standard British Medical Research Council techniques [5-71. Resistance to isoniazid was defined as growth of 20 colonies or more on 0.2 mg/l or more of isoniazid in at least one culture, resistance to rifampicin as growth on 32 mg/l rifampicin in at least one culture and to ethambutol growth on 5.6 mg/l of ethambutol in at least one culture. Resistance to streptomycin was defined as a geometric mean minimal inhibitory concentration (MIC) of 32 mg/l. Results A total of 306 patients
(152 4RE, 154 7RE) was admitted
to the study between
October
1978
lsoniazid and March 1982 from outpatient treatment.
five
Provincial
Hospitals
which
resistant
co-ordinated
tuberculosis
the
inpatient
9 and
Exclusions In all, 56 (27 4RE, 29 7RE) patients were excluded pretreatment, 29 (13 4RE, 16 7RE) for bacteriological reasons. Of the 29,2 (1 4RE, 1 7RE) had strains sensitive to isoniazid, for 10 (4 4RE, 6 7RE) all cultures were negative, contaminated or no specimens were collected, 11 (5 4RE, 6 7RE) had no sensitivity test results; two patients (1 4RE, 1 7RE) had strains resistant to isoniazid and rifampicin; three (1 4RE, 2 7RE) had strains resistant to isoniazid and ethambutol and one (4RE) had a strain resistant to isoniazid, rifampicin and ethambutol. Thirteen patients (6 4RE, 7 7RE) died before starting treatment. Nine (4 4RE, 5 7RE) could not be traced to start treatment and five (4 4RE, 1 7RE) were excluded for miscellaneous reasons. During treatment a further 24 patients (12 4RE, 12 7RE) were excluded. Ten (1 4RE, 9 7RE) missed a substantial amount of treatment (defined as 2 weeks or more in the 2-month initial intensive phase or 6 weeks or more for the 6-month regimen or 9 weeks or more for the 9month regimen) on account of default or error and six patients died (5 4RE, 1 7RE). A further eight patients (6 4RE, 2 7RE) had insufficient bacteriology for assessment of response at the end of chemotherapy. After exclusions, there remain 226 (113 4RE, 113 7RE) patients for analysis of whom 179 (91 4RE, 88 7RE) had a strain resistant to isoniazid alone and 47 (22 4RE, 25 7RE) a strain resistant to both isoniazid and streptomycin. Deaths Of the six patients who died during treatment, five (4 4RE, 1 7RE) died of tuberculosis, three (all 4RE) in the first 3 weeks, one (4RE) in the fourth month of a severe haemoptysis and the fifth (7RE) during the third month of car pulmonale. The remaining patient (4RE) died in the second month of acute renal failure of uncertain aetiology although drug toxicity could not be excluded. Condition
on admission
Of the 226 patients in the main analysis, 162 (72 %I were male and 114 (50 %) were aged 35 years or more on admission. All patients had at least one positive smear result at the local laboratory and 93 % had a positive smear in the reference laboratory. Considering the first smear result in the reference laboratory 30 (13 %I were negative, 72 (32 %I were scanty, 64 (28 %) were moderate and 60 (27 %I were heavily positive. Pretreatment postero-anterior chest radiographs were assessed for 102 (46 %I of the 226 patients (the others had either unassessable radiographs or they had been taken more than 6 months before the start of treatment). The independent assessor classified the extent of the disease as involving more than one lung field in 33 %. Obvious cavitation was present in 75 %, 25 % being slight, 20 % moderate, and 30 % extensive [81. The findings in the 4RE and 7RE series were broadly similar. Culture
results
during
chemotherapy
In the first 6 months all patients received the same chemotherapy, namely rifampicin and ethambutol with streptomycin and pyrazinamide in addition for the initial 2 months. At 1 month, 59 % of 177 patients with isoniazid resistance assessed had a negative culture (based on the first or only specimen) and at 2 months 96 % of the 170 patients assessed;
10
Swai
and others
the findings were similar for the patients with resistance to both isoniazid and streptomycin (Table I). At 3 months and subsequently 95 % or more of patients had negative cultures. Status
of patients
on completion
of chemotherapy
Of the 226 patients assessed, only two patients (1 4RE, 1 7RE) have been classified as having an unfavourable status (Table II), their sputum being culture positive at the end of chemotherapy. One (7RE) who had an isoniazid-resistant strain pretreatment, was culture negative at months 2 and 3 but positive again at month 4 to month 9 with no further resistance emerging. In the other (4RE) who had a strain resistant to both isoniazid and streptomycin pretreatment, rifampicin resistance emerged at month 3, and ethambutol at month 7. A further nine patients (2 4RE, 7 7RE) have been classified as having a doubtful status at the end of chemotherapy. Eight (1 4RE, 7 7RE) had resistance to isoniazid alone initially and one (4RE) to both drugs. Of the two patients in the 4RE series, one had a positive culture of more than 20 colonies growth at month 6 and the other had one colony growth in each of the two specimens at 6 months. Of the seven patients in the 7RE series one had a growth of more than 20 colonies and another had a growth of seven colonies at month 8, but they both had negative cultures at month 9. A third patient had 5 and 10 colonies respectively at month 7. The remaining 4 patients had one positive culture of less than 20 colonies growth and one negative at 8 or 9 months. There was no evidence of the emergence of further resistance in any of the patients classified as doubtful. Table
I.
Bacteriological
results
during
Initial resistance to: lsoniazid
the first 3 months Month
alone
lsoniazid and streptomycin
Number of patients assessed
Culture-negative No.
%
1 2 3
177 170 159
104 164 155
59 96 97
1 2 3
46 45 42
30 44 40
65 98 95
*Patients in both the 4RE and 7RE treatment same chemotherapy.
Table
II.
Status
Initial resistance to: lsoniazid
lsoniazid and streptomycin All patients
series
received
the
at end of chemotherapy. Series
alone
of chemotherapy.*
Total patients assessed
Status Favourable
Doubtful
Unfavourable
4RE 7RE
91 88
90 80
1 7
0 1
4RE 7RE
22 25
20 25
1 0
1 0
226
215
9
2
lsoniazid Exclusion
from
relapse
resistant
tuberculosis
11
analysis
All patients were to be followed to 30 months, that is 24 months after stopping chemotherapy for the 4RE series and 21 months for the 7RE series. Of the total 224 patients with a favourable or doubtful status at the end of chemotherapy 46 patients were excluded, seven (4 4RE, 3 7RE) died; three patients in the 4RE series died of car pulmonale and one of unknown cause in the 23rd month with negative cultures up to her last attendance at 16 months. Of the three 7RE patients, one died from gastroenteritis with severe dehydration, the second in a road traffic accident and the third at home of unknown cause. The remaining 39 patients (22 4RE, 17 7RE) had defaulted. Of the 22 patients in the 4RE series 13 had been followed up to at least 20 months when specimens collected were negative, and the remaining nine defaulted between months 7 and 12. Nine of the 17 7RE patients were followed up to 20 months and eight defaulted between 10 and 16 months. They were all clinically well at their last clinic visits and sputum cultures were negative. There remain 178 patients (86 4RE, 92 7REI for the relapse analysis. Definition
of relapse
Bacteriological relapse after stopping chemotherapy was defined as two or more cultures of at least 10 colonies growth obtained at different months in any 3-month period or three or more positive cultures of any growth at different months in any 4-month period. Bacteriological
relapses
Of the 144 patients (72 4RE, 72 7RE) with strains resistant to isoniazid alone pretreatment, five (3 %) patients (3 4RE, 2 7RE) relapsed (Table Ill) at months 2, 9, 20, 2, and 18, respectively after stopping chemotherapy. Of the 34 patients (14 4RE, 20 7RE) with pretreatment strains resistant to isoniazid and streptomycin, three (all in the 4RE series) relapsed at month 5, 8, and 19 after stopping chemotherapy. The sensitivity pattern for the relapse strains for all patients was the same as the pretreatment strains. Resistance to the other drugs, namely rifampicin and ethambutol, did not occur. Six patients (3 4RE, 3 7RE) were excluded from the main analysis for having strains resistant to rifampicin, ethambutol or both drugs in addition to isoniazid pretreatment. At the end of chemotherapy they all had a favourable status. During follow-up, however, two patients (both in the 4RE series), one of whom had a strain resistant to isoniazid and rifampicin and the other to isoniazid, rifampicin, and ethambutol, relapsed 2 months after
Table
III.
Bacteriological
Initial resistance to:
lsoniazid
Regimen
alone
lsoniazid and streptomycin Figures Figures
relapses
in s&are in round
after stopping
chemotherapy.
Number of patients assessed
Bacteriological
4RE 7RE
72 [II 72 [71
3 WI 2 [Ol
4RE 7RE
14 20
111 IO1
No.
3 0
IO1
brackets are patients whose status at the end of chemotherapy brackets are percentages based on less than 25 patients.
relapses %
Month after stopping chemotherapy
4 3
2 2
9 18
20
(21)
5
8
19
(0) was
doubtful.
12
Swai
and others
stopping chemotherapy four patients remained Adverse
with a strain resistant to all the three drugs. The status of the other favourable up to the end of follow-up.
reactions
Only two (0.8 %) of the 283 (142 4RE, 141 7RE) patients who started chemotherapy were reported to have possible adverse reactions and in only one of them (7RE) was the regimen modified. This patient developed a hypersensitivity reaction to streptomycin on the third day. Desensitisation was not attempted and streptomycin was discontinued. The other patient (4RE) complained of arthralgia during the fifth week, suspected to be caused by pyrazinamide but he responded to acetyl salicylic acid without modification of chemotherapy. No ocular toxicity was reported though the centres were expressly advised to refer any patients with visual problems during chemotherapy to the Provincial Physician.
Discussion In Kenya, where the standard chemotherapy regimen for new tuberculosis patients is isoniazid plus thiacetazone for 12-18 months with an initial streptomycin supplement, resistance among those who fail or relapse is usually to isoniazid and the strain is almost invariably still sensitive to streptomycin because it is given for the first 2 months only [2]. Hence, when regimens of rifampicin and ethambutol supplemented with streptomycin and pyrazinamide in the initial phase are used as in the present study, the organisms are likely to be sensitive to three or all four drugs. In this study, there were only two failures during chemotherapy. Also, the bacteriological relapse rates at 30 months after start of chemotherapy were low and similar, 4 % in the 6- and 3 % in the g-month series for patients with initial resistance to isoniazid alone. For those with initial resistance to both isoniazid and streptomycin relapse occurred in three of 14 patients on the 4RE regimen and none of 20 on the 7RE regimen, suggesting a possible advantage for the longer duration. The overall relapse rates for the patients with single and double drug resistance combined were thus 7 % for the 6-month and 2 % for the g-month series. If either could be introduced in routine programme conditions with adequate supervision, it is likely that it would achieve far better results than the much less acceptable 18-month retreatment regimen previously developed in Kenya [9, IO]. This regimen, which was introduced in Kenya in 1970, consisted of PAS plus pyrazinamide orally once daily for 18 months, with streptomycin lg intra-muscularly daily for the first 6 months. Although highly effective in patients with initial isoniazid resistance, it has practical limitations especially that of daily injections for 6 months. Further, the problems related to PAS, namely the inconvenience of administration and the frequency of unpleasant side effects, and in recent years the difficulty in obtaining supplies (as is also the case with cycloserine), have made it difficult to apply routinely. The retreatment regimens used previously in many countries, and still used in some, based on ethionamide, pyrazinamide and cycloserine not only have substantial risks of serious drug toxicity but also high incidence of unpleasant side effects [I 1, 121, leading to poor compliance and low levels of success. Some countries developed effective intermittent retreatment regimens based on rifampicin and ethambutol which make it easier to ensure full supervision of every dose [13]. Few developing countries, however, have organised intermittent or daily supervised chemotherapy, even in first-line treatment. Tackling the problem of patients with drug-resistant strains following initial treatment with a standard regimen is not a high priority in most developing countries. The prevention of failure in new cases brought under treatment for the first time is a more rational approach than producing failures and then spending scarce resources on their retreatment. A survey
lsoniazid
resistant
tuberculosis
13
carried out in Kenya in 1974 showed that the treatment success rate in new cases was of the order of 70 % [3]. Fox, however, has reported that in many developing countries the success rate achieved by routine treatment services may be as low as 50 % with regimens which in carefully conducted controlled clinical trials are near 100 % effective [4]. In the 1974 survey in Kenya [14] 10.1 % of 702 patients who had no history of previous chemotherapy had a strain resistant to isoniazid (7.3 %) or to streptomycin (1.4 %) or to both drugs (1.4 %). In contrast, in 82 patients who had previous chemotherapy, 28 % had a strain resistant to isoniazid (17 %) or to streptomycin (0 %) or both drugs (11 %I. The incidence of drug resistance, mainly due to non-compliance and irregularity of drug taking, increased with the duration of chemotherapy. The reason for concentrating on curing the new cases is obvious. The gap between the potential of regimens and what they achieve in routine service conditions has long been a matter of concern. The role of patient compliance and the failure of the health services to motivate patients has led in some countries to the full supervision of every dose of the chemotherapy by health services staff. This may not be easy to organise and, in many rural areas with limited resources, totally impractical unless efficient primary health care can be organised. This has, however, been achieved to some extent in selected retreatment patients in this pilot study, in those who live near health units. Patients in both urban and rural areas need adequate supervision of the retreatment regimen, but this may be difficult to implement if full supervision is not ensured. Clearly, it is necessary to try an effective intermittent regimen under full supervision in order to obtain practical experience of the problems encountered and how they might be overcome. When the primary health care service is efficient the implementation of intermittent oral regimens using community health workers and other responsible members of the community becomes a real prospect.
Acknowledgements The authors wish to thank all the staff in the co-operating hospitals which included Infectious Diseases Hospital, Nairobi, Provincial General Hospital at Machakos, Kisumu and Nyeri, and the Port Reitz Chest Hospital at Mombasa. Some of the patients were referred from district hospitals in Meru, Embu, Kitui, Kirinyaga, Kilifi, Kwale, Kakamega, Siaya, and Kericho. The continued support of the Ministry of Health is acknowledged. We are particularly grateful to the Director of Medical Services, Dr W. Koinange, for arranging for the supply of part of the drugs used in this study’from Ministry of Health. Special thanks are due to Professor Wallace Fox and Professor D. A. Mitchison for their valuable advice. The independent assessment of chest radiographs was undertaken by Dr J. R. Bignall.
References 1 East African/British Medical Research Council Third Thiacetazone Investigation. lsoniazid with thiacetazone (thioacetazone) in the treatment of pulmonary tuberculosis in East Africa-Third Investigation: The effect of an initial streptomycin supplement. Jubercle 1966; 47: l-32. 2 East African/British Medical Research Council Fifth Thiacetazone Investigation. lsoniazid with thiacetazone in the treatment of pulmonary tuberculosis in East Africa - Fifth investigation. Jubercle 1970; 51: 123-51. 3 Second East African/British Medical Research Council Kenya Tuberculosis Survey Follow-up. Tuberculosis in Kenya: Follow-up of the second (1974) national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. Jubercle 1979; 60: 125-49. 4 Fox W. The modern management and therapy of pulmonary tuberculosis. Proc Roy Sot Med 1977; 70: 4-15. 5 East African/British Medical Research Council ThiacetazoneIDiphenyI-thiourea Investigation. Comparative trial of
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6 7
8 9 10
11 12 13
14
Swai and others isoniazid in combination with thiacetazone or a substituted diphenylthiourea (SU1906) or PAS in the treatment of acute pulmonary tuberculosis in East Africans. Tubercle 1960; 41: 399-423. Allen BW, Baker RJ. Mycobacteria: Isolation, identification and sensitivity testing. 1968; Butterworths, London. British Medical Research Council Co-operative Study. Co-operative controlled trial of a standard regimen of streptomycin, PAS and isoniazid and three alternative regimens of chemotherapy in Britain. Tubercle 1973; 54: 99-129. Simon G. Radiology in epidemiological studies and some therapeutic trials. Br Med J 1966; 2: 491-4. East African/British Medical Research Council Retreatment Investigation. Streptomycin plus PAS plus pyrazinamide in the retreatment of pulmonary tuberculosis in East Africa. Tubercle 1971; 52: 191-8. East African/British Medical Research Council Retreatment Investigation: Second Report. Streptomycin plus PAS plus pyrazinamide in the retreatment of pulmonary tuberculosis in East Africa-Second report. Tubercle 1973; 54: 283-90. British Tuberculosis Association. Ethionamide. pyrazinamide and cycloserine in the treatment of drug resistant pulmonary tuberculosis. Tubercle 1963; 44: 195-214. International Union Against Tuberculosis. A comparison of regimens of ethionamide, pyrazinamide and cycloserine in retreatment of patients with pulmonary tuberculosis. Bull Inr UnionTuberc 1969; 42: 7-57. Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council Retreatment Investigation. A controlled clinical trial of daily and intermittent regimens of rifampicin plus ethambutol in the retreatment of patients with pulmonary tuberculosis in Hong Kong. Tube&e 1974; 55: l-27. Second East African/British Medical Research Council Kenya Tuberculosis Survey. Tuberculosis in Kenya: A second national sampling survey of drug resistance and other factors, and a comparison with the prevalence data from the first national sampling survey. Tubercle 1978; 59: 155-77.