Controlled Trial of 6-Month and 9-Month Regimens of Daily and Intermittent Streptomycin plus Isoniazid plus Pyrazinamide for Pulmonary Tuberculosis in Hong Kong'1
The Results Up to 30 Months
HKK 250/1
HONG KONG CHEST SERVICE/BRITISH MEDICAL RESEARCH COUNCIL OCT 1977
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IN EX
2
SUMMARY
A comparison was made between 6-month and 9-month regimens of streptomycin plus isoniazid plus pyrazinamide given daily, 3 times a week, or twice a week in the treatment of newly diagnosed, smear-positive pulmonary tuberculosis in Chinese patients.
At 6 months, the twice-weekly regimen was marginally inferior; treatment failed for 5 (4 per cent) of 126 patients with drug-susceptible strains before treatment compared with 2 (1 per cent) of 141 on the 3-times-weekly regimen and none of 137 on the daily regimen. The results for patients with pretreatment strains resistant to isoniazid, to streptomycin, or to both drugs were not as good, treatment failing for 10 (30 per cent) of 33 on the daily regimen, 15 (37 per cent) of 41 on the 3- times-weekly regimen, and 14 (39 per cent) of 36 on the twice-weekly regimen.
In contrast, the relapse rates after chemotherapy were similar for patients with drug-susceptible and drug-resistant strains before treatment and for patients on the daily and intermittent regimens. By 30 months, 35 (21 per cent) of 167 patients with susceptible strains who were treated for 6 months and 10 (6 per cent) of 179 treated for 9 months had relapsed, all with strains still suscep- tible to isoniazid and streptomycin. The relapse rates for patients with resistant strains were 7 (24 per cent) of 29 and 1 (4 per cent) of 26, respectively. Drug toxicity was not a special problem.
Introduction
We report here the results of a study to compare 6-month and 9-month regimens of streptomycin plus isoniazid plus pyrazinamide given daily, 3 times a week, or twice a week, from the start of chemotherapy, to Chinese patients in Hong
(Received in original form December 21, 1976 and in revised form February 22, 1977)
1 From the Hong Kong Chest Service and the British Medical Research Council.
2 Requests for reprints should be addressed to the MRC Tuberculosis and Chest Diseases Unit, Bromp- ton Hospital, London SW3 6HP, England, or to Dr. W. G. L. Allan, Wanchai Chest Clinic, Kennedy Road, Wanchai, Hong Kong.
Kong with newly diagnosed smear-positive pul- monary tuberculosis.
Treatment in Hong Kong is usually given ful- ly supervised in outpatient clinics. Therefore, there was a special interest in short-course regi- mens with drugs given intermittently from the start of treatment. Rifampin was not investigated because, at the time the study was planned, its in- termittent administration in the dosages then in use was known to cause a high incidence of immu- nologic reactions. It was also considered at that time too expensive for routine use even in bacte- riologically confirmed disease in Hong Kong. The streptomycin plus isoniazid plus pyrazinamide combination was chosen because it had proved effective in East Africa (1), but because its daily administration there for 6 months had been fol- lowed by an appreciable relapse rate, it was de-
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 115, 1977
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HONG KONG CHEST SERVICE/BMRC
cided in Hong Kong to study, at random, two durations of chemotherapy, 9 months as well as 6 months.
The main early findings (2, 3) of the present study were that the daily and 3-times-weekly regimens when given for 9 months produced ex- cellent results for patients with drug-susceptible strains of tubercle bacilli before treatment, and that the twice-weekly regimen was only margin- ally less effective. For patients with resistant strains before treatment, the results were unsat- isfactory during chemotherapy, but the early re- lapse rates after chemotherapy were similar to those for patients with susceptible strains. Drug toxicity was not a special problem on any of the regimens.
The present report gives the final results up to 30 months from the start of chemotherapy.
Materials and Methods
Patients admitted and treatment regimens. Chinese patients at least 15 years of age with newly diagnosed smear-positive pulmonary tuberculosis and without a history of previous chemotherapy were allocated at random to treatment with streptomycin plus iso- niazid plus pyrazinamide, given daily (SHZ regimen), 3 times a week (S,H,Z, regimen), or twice a week (SHZ2 regimen). At 5 months, a second random allocation was made to a 6-month or 9-month dura- tion of chemotherapy. Patients in the daily treatment group (SHZ) who were allocated to the 9 months' duration received their drugs 3 times a week during the last 3 months.
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The drug dosages were as follows: Streptomycin: g, for patients less than 40 years of age; 0.75 g for older patients, in all 3 regimens. Isoniazid: 300 mg
daily; 15 mg per kg body weight per dose in both intermittent regimens. Pyrazinamide, SHZ regimen: 1.5 g for patients weighing less than 110 pounds (49.9 kg); 2 g for heavier patients. Pyraz nide, SHZ, regimen: 2 g for patients weighing less than 100 pounds (45.5 kg); 2.5 g for heavier patients. Pyrazinamide, SHZ, regimen: 3 g for patients weighing less than 100 pounds (45.5 kg); 3.5 g for heavier patients.
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In all 3 regimens, all 3 drugs were given at the same time in a single dose. All patients received their chemotherapy under the direct supervision of the staff, either in hospital or in an outpatient clinic.
Assessment of progress. Monthly progress reports were made on each patient. In the London labora- tory, 3 sputum specimens were examined by smear and culture before treatment. As a routine, 2 speci- mens a month were examined from months 1 to 6 and at 9 months; 1 specimen a month at months 7, 8, 10 to 24, and at months 27 and 30. Additional specimens were examined if there was any doubt about the bacteriologic status after 24 months. Posi- tive cultures were identified and their drug suscep- tibilities determined. Urine samples collected at each monthly assessment were tested for acetyl isoniazid and for pyrazinamide. The serum alanine transami- nase concentration was measured monthly during chemotherapy. The bacteriologic and biochemical methods used were listed in a previous report (2).
Drug susceptibility tests. All susceptibility tests were done by the indirect method on slopes of Löwenstein-Jensen medium. Resistance to isoniazid was defined as growth (20 colonies or more) on 0.2 μg per ml or more of isoniazid in one culture, Resis- tance to streptomycin was defined before treatment as growth on 16 μg per ml (before inspissation) or more of streptomycin in one culture or on 8 μg per ml in each of 2 cultures, and during treatment as growth on 16 μg per ml or more.
TABLE 1
BACTERIOLOGIC STATUS DURING CHEMOTHERAPY
Patients Treated
for 6 months
Patients Treated
Unfavorable
Status
for 9 Months
Failures Arising
in Months
7, 8, and 9
Total (no.) (%) * (B)
Estimated Failure Rate during
9 Months
of Chemo-
therapy
(%) (A+B)
Pretreatment Strain
Regimen
Total
at 6 Months
(no.) (%) (A)
SHZ
137
0
70
Susceptible
S3H3Z3
141
2+
1
69
S2H2Z2
126
5
4
78
1
1
← 55
Resistant to isoniazid, to
SHZ
33
10
30
18
0
(0)
30
streptomycin, or to both drugs
S3H3Z3 S2H2Z2
41
15
37
21
1
(5)
42
36
14
39
21
2
(10)
48
Definition of abbreviations: SHZ = daily treatment with streptomycin plus isoniazid plus pyrazinamide; S2 H2Z2 = twice-weekly treatment; S3 H3Z3 = treatment 3 times a week. *Percentages in parentheses are based on fewer than 25 observations.
† One patient had a favorable bacteriologic status at 9 months.
CONTROLLED TRIAL OF 6- AND 9-MONTH TUBERCULOSIS REGIMENS
TABLE 2
BACTERIOLOGIC RELAPSES BY 30 MONTHS IN PATIENTS WITH DRUG-SUSCEPTIBLE STRAINS BEFORE TREATMENT
Favorable
Status
729
Bacteriologic Relapses*
at End of
Total
Relapses, months
Duration of Chemotherapy
Chemo-
Regimen
therapy
(no.)
(%)
7-9
10-12
13-15
16-30
SHZ
60
11
18
6 months
S3H3Z3
68
16t
24
21
9
S2H2Z2
39
8
21
A
SHZ
65
9 months
S3H3Z3
S2H2Z2
65
49
34 3
5
6
6
5 a 6
22-
4
2
0
41
1
2
1
0
1
0
1
1
For definition of abbreviations, see table 1.
*All were with strains susceptible to isoniazid and to streptomycin. *One patient became culture-negative again without further chemotherapy.
Results
Population studied. Six hundred twenty patients (209 SHZ, 218 SHZ, 193 S,H,Z) were ad- mitted. The intake to the SHZ, regimen was stopped 8 weeks before stopping intake to the other 2 series because treatment for a few pa- tients had already failed. Those still receiving twice-weekly chemotherapy were allocated to 9 or 12 months' treatment instead of 6 or 9. Pa- tients allocated to 12 months' chemotherapy are included in the analyses up to 9 months in table 1 but are excluded from the relapse analyses in tables 2 and 3. The 22 SHZ and 23 S2H2Z ̧ pa- tients admitted after the SH2Z, intake had been stopped are included throughout. Hence, fewer S2H Z2 than SHZ and S2HÖZ, patients were available for the analyses of relapse after chemo- therapy.
Of the 620 patients, 38 (13 SHZ, 12 S2H2Z3, 13 S2H2Z) were excluded for pretreatment rea-
sons (2): 24 had negative or contaminated cul- tures, the mycobacteria from 10 were not Myco- bacterium tuberculosis, and 4 were excluded for miscellaneous reasons. Another 68 (26 SHZ, 24 SH2Z, 18 S2H2Z2) were excluded for reasons encountered during chemotherapy: 19 (8 SHZ, 8 SHZ, 3 SH1Z2) defaulted, 33 (included in analyses of adverse reactions) had their chemo- therapy modified because of drug toxicity, 4 died of causes unrelated to tuberculosis, 7 had insufficient bacteriologic results available for as- sessment, and 5 were excluded for miscellaneous reasons. There remained 404 patients (137 SHZ, 141 SHZ, 126 SH2Z2) with fully susceptible strains before treatment and 110 (33 SHZ, 41 SHзZ ̧, 36 SH2Z) with pretreatment strains re- sistant to isoniazid, to streptomycin, or to both drugs. Of these, 346 (125 SHZ, 133 SH2Z, 88 S2H2Z1⁄2) and 55 (17 SHZ, 22 S2H3Z3, 16 S2H2Z2), respectively, had a favorable bacteriologic status
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TABLE 3
BACTERIOLOGIC RELAPSES BY 30 MONTHS IN PATIENTS
WITH PRETREATMENT STRAINS RESISTANT
TO ISONIAZID, TO STREPTOMYCIN, OR TO BOTH DRUGS
Duration of Chemotherapy
6 months
9 months
Regimen
Favorable Status
at End of
Chemotherapy
Bacteriologic Relapses*
(no.)
(%)
SHZ
7
2
S3H3Z3
13
1
S2H2Z2
9
A
(29)
(8)| 24
(44).
SHZ
10
S3H3Z3 S2H2Z2
9
7
00-
(0)
(0)
(14).
For definition of abbreviations see table 1.
* Percentages in parentheses are based on fewer than 25 observations.