Tubercle ORIGINAL

ADVERSE

REACTIONS

STREPTOMYCIN,

Hong Kong Tuberculosis

REGIMENS

PYRAZINAMIDE

IN HONG

81-95

ARTICLES

TO SHORT-COURSE

ISONIAZID,

57 (1976),

AND

CONTAINING RIFAMPICIN

KONG

Treatment Services/British

Medical Research Council*

Summary Three studies of drug toxicity were made in Chinese adults with pulmonary tuberculosis admitted concurrently to short-course antituberculosis regimens. The first was of streptomycin plus isoniazid plus pyrazinamide given daily (SHZ regimen), three times a week (S,H,Z, regimen) or twice a week (S,H zZz regimen). The second was of pyrazinamide in the SHZ regimen and PAS in the standard daily combination of streptomycin plus isoniazid plus PAS (SPH regimen). The third was of the SHZ regimen and these 3 drugs plus rifampicin daily (SHRZ regimen). In study 1 (174 SHZ, 185 S,H 3Z3, 182 S,H zZ, patients), the incidence of arthralgia was associated with the number of doses per week (P < 0.001). The incidence of other reactions, most of which were cutaneous or vestibular, or symptomless increases in the serum alanine transaminase (AIT) concentration, was similar on all 3 regimens. In study 2 (142 SHZ, 137 SPH patients), hepatic reactions occurred not on the SPH regimen (P < 0.002), serum AIT concentrations were a higher range on the SHZ regimen, and 2 patients had jaundice. reactions were more frequent on the SPH regimen (P = 0.06). commoner on the SHZ regimen (P < 0.05).

on the SHZ but distributed over Gastrointestinal Arthralgia was

In study 3 (38 SHZ, 41 SHRZ patients), the incidence of hepatic reactions, jaundice and arthralgia was similar in the 2 regimens. On the pyrazinamide regimens combined, hepatic reactions were marginally more frequent in patients with Australia antigen or antibody either before or during chemotherapy (P = 0.09). Serum uric acid concentrations were higher in patients on daily than on intermittent pyrazinamide (P < 0.005), and in patients with arthralgia on the daily pyrazinamide regimen than in matched controls (P = 0.07). R&urn6 Trois etudes sur la toxicite medicamenteuse ont Bte realisees chez des malades adultes chinois atteints de tuberculose pulmonaire, mis concurement a des regimes antituberculeux de courte duree. La premiere etude etait celle d’un regime comportant streptomycine, isoniazide et pyrazinamide administres tous les jours (regime SHZ), trois fois par semaine (regime S,H 3Z3) ou deux fois par semaine (regime S ,H zZ,). La seconde etude Btait celle du pyrazinamide dans le regime SHZ et du PAS dans I’association quotidienne standard de streptomycine, isoniazide et PAS (regime SPH). La troisieme etude Btait celle du regime SHZ et de ces trois drogues associees a la prise, dgalement quotidienne, de rifampicine. * Reprints may be obtained from MRC Tuberculosis from Dr W. G. L. Allan, Wanchai Polyclinic, Kennedy

and Chest Diseases Unit, Brompton Road, Wanchai, Hong Kong.

Hospital,

London,

SW3 6HP or

82

Hong Kong/B.M.R.C. Dans l’etude no 1 (174 malades SHZ, 185 S,H 3Z3, 182 S,H 2Z2), la frequence des arthralgies s’est montree en rapport avec le nombre de doses hebdomadaires (P < 0,001). La frequence des autres reactions, la plupart cutanees ou vestibulaires, ou I’augmentation, non accompagnee de symptiimes, de la concentration des transaminases alanines seriques (AIT) a Bte la mame pour les 3 regimes. Dans l’etude no 2 (142 malades SHZ, 137 SPH), des reactions hepatiques sont apparues chez les sujets recevant le regime SHZ mais pas chez ceux recevant le regime SPH (P < 0,002) ; les concentrations seriques d’AIT Btaient reparties sur un &entail plus large parmi les sujets du groupe SHZ, et 2 malades ont presente un ictere. Des reactions gastrointestinales sont apparues plus souvent chez les sujets du groupe SPH (P = 0,06). Les arthralgies ont 6th plus frequentes chez ceux du groupe SHZ (P < 0,OS). Dans I’btude no 3, (38 malades SHZ, 41 malades SHRZ), la frequence des reactions hepatiques, des icteres et des arthralgies a 6te la meme pour les 2 regimes. Si I’on regroupe I’ensemble des regimes contenant du pyrazinamide, les reactions hepatiques ont 6te a peine plus frequentes chez les malades pot-teurs d’antigene ou d’anticorps australien, avant ou au tours de la chimiotherapie (P = 0,OS). Les concentrations seriques d’acide urique ont 6te plus elevees chez les malades recevant le regime avec pyrazinamide quotidien que chez ceux ou cette drogue dtait administree de facon intermittente (P < 0,005) et chez les malades presentant des arthralgies sous regime quotidien comportant du pyrazinamide que chez leurs temoins apparies (P = 0,07). Resumen Se hicieron tres estudios sobre toxicidad de las drogas en pacientes chinos adultos con tuberculosis pulmonar incorporados a esquemas de cotta duration. El primer esquema fue con estreptomicina, isoniazida y pirazinamida diarios (regimen SHZ), tres veces por semana (S,H,Z,) 6 dos veces por semana (SzH,Zz). El sequndo esquema fue, uno con pirazinamida (SHZ) y otro con PAS (SPH), diarios. El tercero, fue, uno con SHZ y el otro agregando rigampicina (SHRZ). En el estudio 1 artralgias se asocio de otras reacciones, sericas sin sintomas,

(174 SHZ, 185 &H,Z,, 182 S2H2Z, pacientes) la incidencia de con el ntimero de dosis por semana (P < 0,001). La incidencia la mayoria cutaneas o vestibulares, o aumento de transaminasas fue similar en 10s 3 esquemas.

En el estudio 2 (142 SHZ, 137 SPH) hubo reacciones hepaticas en SHZ pero no en SPH (P < O,OOZ), hubo alteraciones de las transaminasas sericas en et esquema SHZ y dos pacientes tuvieron ictericia. Las alteraciones digestivas fueron m&s frecuentes en el esquema SPH (P = 0,06). Las artralgias fueron mas comunes en el esquema SHZ (P < 0,05). En el estudio 3 (38 SHZ, 41 SHRZ) la incidencia de reacciones hepaticas, ictericia y artralgias fue similar en 10s 2 esquemas. En 10s esquemas con pirazinamida las reacciones hepeticas fueron m&s frecuentes en 10s pacientes con antigen0 australiano o anticuerpos presentes antes o durante la quimioterapia (P = 0,OS). La concentration de kido lirico en suero fue mayor en 10spacientes con pirazinamida diaria que intermitente (P < 0,005) y en 10s pacientes con artralgias que recibian pirazinamida en 10s controles pareados (P = 0,07).

Adverse reactions to drug regimens

83

Introduction In studies of 6-month regimens of chemotherapy for the treatment of newly-diagnosed smear-positive pulmonary tuberculosis in East Africa, daily regimens of streptomycin plus isoniazid with either rifampicin or pyrazinamide as a third drug rendered all patients culture negative during chemotherapy and were followed by low relapse rates (East African/British Medical Research Councils, 1972, 1973a, 1974a). Furthermore, the 4-drug combination of streptomycin plus isoniazid plus rifampicin plus pyrazinamide eliminated tubercle bacilli more rapidly in the early weeks of treatment than did the 3-drug combination of streptomycin plus isoniazid plus rifampicin (East African/British Medical Research Councils, 1974b), suggesting that the 4-drug combination would be particularly effective in preventing relapse. There were thus reasons to suppose that both rifampicin and pyrazinamide had important roles in shortcourse chemotherapy. Pyrazinamide has not been widely used in first-line chemotherapy because of its reported toxicity in some early studies when given in high daily dosage (McDermott and others, 1954; Phillips and Horton, 1956). The purpose of the present paper is to report the drug toxicity encountered in a study of 6- and g-month regimens of streptomycin plus isoniazid plus pyrazinamide in Hong Kong STUDY

1

SHZ, S3H3Z3,S2H2Z2 STUDY 2 SHZ, SPH STUDY 3

SHZ, SHRZ t

v

f

im

j S3H3Z3

I

_~.__ S2H2 Z2 t

i

SHZ

SPH ___I

Month 6

7

8

1972 --__ Year Figure 1

Periods during which patients were admitted to the 3 studies.

84

Hong Kong1B.M.R.C.

(Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1975), and to investigate the toxicity of pyrazinamide and of pyrazinamide plus rifampicin when given together with streptomycin plus isoniazid. Plan of the Investigation The patients were Chinese adults with newly-diagnosed smear-positive pulmonary tuberculosis in Hong Kong, admitted to studies between 1 June 1972 and 25 March 1974 (Fig. I). Study 1

Patients in the first study had been allocated at random to 3 short-course regimens of streptomycin plus isoniazid plus pyrazinamide given daily (SHZ regimen), three times a week (S aH 3Z3 regimen) or twice a week (S ,H ,Z, regimen) for either 6 or 9 months, at random, in a therapeutic trial (Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1975). A total of 541 patients (174 SHZ, 185 S,H,Z,, 182 S,H,Z,), admitted between 1 June 1972 and 21 May 1973, was assessed up to 6 months and 259 (74 SHZ, 82 S,H,Z,, 103 S,H zZ2) up to 9 months. A comparison was therefore made between daily and intermittent regimens of streptomycin plus isoniazid plus pyrazinamide. Study 2

In the second study, the toxicity of standard regimen of daily streptomycin were compared. A total of 279 patients 1972 and 25 March 1974 was assessed

pyrazinamide in the SHZ regimen and of PAS in a plus isoniazid plus PAS for 6 months (SPH regimen) (142 SHZ, 137 SPH), admitted between 1 December up to 6 months.

Study 3

In the third study, the effect of adding rifampicin to the SHZ combination was investigated. A regimen of streptomycin plus isoniazid plus pyrazinamide daily for 6 months, plus rifampicin for the first 4 months (SHRZ regimen) was compared with the SHZ regimen daily for 6 months. A total of 79 patients (38 SHZ, 41 SHRZ), admitted between 1 October 1973 and 25 March 1974, was assessed up to 6 months. Drug dosages

The drug dosages were : - 1 .O g (0.75 g for patients aged 40 years or more) in both daily and intermittent regimens. lsoniazid - 300 mg daily ; 15 mg/kg body weight in both intermittent regimens. Streptomycin

- 1.5 g (2.0 g for patients weighing 50 kg or more) daily; 2.0 g (2.5 g for patients weighing 45 kg or more) three times a week; 3.0 g (3.5 g for patients weighing 45 kg or more) twice a week. PAS - 10 g sodium salt daily. Rifampicin - 450 mg daily.

Pyrazinamide

Laboratory Tests Liver function

tests

The serum alanine transaminase (AIT) concentration was measured monthly on all patients, using the calorimetric method (Reitman and Frankel, 1957). The normal range for the Hong Kong laboratories is 2 - 15 IU/I.

Adverse reactions to drug regimens

85

Australia antigen and antibody

In order to find out whether suspected hepatic toxicity was associated with past or present virus B infection, blood samples from the 252 patients admitted to the SHZ, SaH3Z3, S,H,Z, and SPH regimens between 8 January 1973 and 1 October 1973 were collected pretreatment and monthly up to 6 months and tested for Australia antigen and antibody, using the counterelectrophoresis method (Alter, Holland and Purcell, 1971). Serum uric acid concentration

To investigate the effect of the rhythm of pyrazinamide administration and of its dosage on the serum uric acid concentration, samples of serum were obtained pretreatment and immediately before a supervised dose of the regimen monthly up to 6 months from all patients on the SHZ, S3H,Z, and S,H,Z, regimens admitted to the study on or after 8 January 1973. They were stored in liquid nitrogen and the uric acid concentrations were measured by Folin’s phosphotungstate method (Henry, Sobel and Kim, 1957) on selected samples at the end of the study. Pyrazinamide

serum half-lives

The half-lives of pyrazinamide in the serum of a random sample of 35 patients allocated in study 1 to treatment with the S2H2Z, regimen were determined from the fall in pyrazinamide serum concentrations during the period 3 to 24 hours after dosage with 3.0 or 3.5 g pyrazinamide (Ellard 1969).

Study 1

Results

Adverse reactions in the first 6 months

The nature, incidence and month of onset of the main adverse reactions in study 1 are shown in the left-hand section of Table I. An indication of the severity of the reactions is obtained from the modifications to chemotherapy made in their management, shown in the right-hand section of the table. A distinction is made between patients who had one or more drugs terminated in the sixth month and those before the sixth month, because drugs were sometimes terminated in the sixth month for comparatively mild reactions in patients allocated to stop chemotherapy at 6 months, Drugs stopped in the sixth month were also sometimes reintroduced after 6 months in patients allocated to 9 months of chemotherapy. Adverse reactions occurred in 50 (29 per cent) of the SHZ patients, 46 (25 per cent) of the S,H,Z, and 39 (21 per cent) of the S,H,Z, patients, most of them (31, 33 and 30, respectively) starting in the first 3 months. The majority were successfully managed without any modification to the regimen, or with a temporary interruption, and only 12 (7 per cent), 6 (3 per cent) and 9 (5 per cent) patients respectively had one or more drugs terminated, 5, 3 and 5 respectively in the sixth month. Cutaneous reactions. Cutaneous reactions were, in general, mild, only 13 patients (3 per cent of the SHZ, 1 per cent of the S3H3Z3 and 3 per cent of the S,H,Z,) having one or more drugs terminated. One SHZ patient developed severe exfoliative dermatitis in the third month, with mucosal involvement, hepatosplenomegaly and abnormal liver function tests. All 3 drugs were terminated, steroids were given and the patient recovered.

1

S2”2Z2

323

S2”2Z2

S3’-‘3Z3

SHZ

S2”2Z2

S3”

SHZ

S2V2

S3”&3

SHZ

S2”2Z2

S3V3

SHZ

25

13 5 2

8 14 3

11 16 11

0

132511 1 2

0

7 3 I

1

1

421100 532211 200010

5 8 2

4

321104 3 5 150302

4

6 7 3

6 9 6

10 IO 7

0

0

2

7

12 6 2

of onset

6 4 321320 904012

15 16 20

123456

Month

13 6 9

21

29

50

46 39

23 11 16

%

No.

Patients with reactions

One patient developed severe exfoliative dermatitis.

Arthralgia

Vestibular

Hepatic2

Cutaneous

SHZ

Any

S3”3Z3

Regimen

Adverse reaction

1 1

2

2

3 6 3

0

0

0

0

4 1 4

5 2 I

3 6 1

0 0 0

3 3 4

10 10 9

%

3 1 0

2 3 1

5 12 7

12 4 3

21 22 13

No.

2 1000 0

1110 2 1000

3 6 4

7 2 2

12 12 7

%

Temporary interruption ___

to chemotherapy

z Defined in text, page 87.

9 4 2

5 11 2

0 0 0

5 5 8

17 18 17

No.

None --

Modrfication

000

1

000

635 422 422

631 2 533

12 6 955

Total ~ No.

1

II

7 3

%

0

5 3

In 6th month

0 0 0

1 0 0

0 0 0

3 0 1

4 0 1

S

0 0 0

0 0 0

0 0 0

0 0 1

H

0 0 0

Drug(s)

to chemotherapy

Drugs terminated

Table I. Study 1 : Incidence of adverse reactions in first 6 months and modifications management (based on 174 SHZ. 185 S,H 3Z3 and 182 S,H zZ, patients)

I 0 0

0 0 0

3 4 3

1 1 0

5 5 3

Z

0 0 0

0 0 0

0 0 1

0 0 1

0 0 1

SZ

0 0 0

0 0 0

3’ 0 0

2’ 1 3

31 f 3

SHZ

made in their

h

n

c m L.

Adverse reactions to drug regimens

87

Hepatic reactions. In the absence of jaundice, an hepatic reaction is defined in this report as a modification to the regimen made for a symptomless increase in the serum AIT concentration ; this was invariably to a level above 60 IU/I. Reactions occurred in 11 (6 per cent) of the SHZ, 16 (9 per cent) of the S3H sZs and 11 (6 per cent) of the S,H ,Z, patients, in 6, 12 and 6, respectively, during the first 3 months. On each of the 3 regimens, hepatic reactions were more frequent in patients on the higher pyrazinamide dosage, that is the heavier patients (P r-=0.04, Cochran’s test), but there was no association between the incidence of reactions and the (P > 0.25) (Ellard, 1969). Analyses pyrazinamide dosage in mg/kg (P > 0.25) or mg/kg om65 of the AIT concentrations (not tabulated here) showed no difference between the 3 regimens in the pretreatment or each of the monthly distributions of results. Analysis of the clinical action taken showed no difference in the way patients with higher values were managed on the 3 regimens. The proportion of patients at each month with a concentration of 40 IU/I or more ranged from 1 to 4 per cent on the daily regimen and from 0 to 9 per cent on both intermittent regimens. Only 1 patient (SSH3Z3) became jaundiced. This occurred in the second month of chemotherapy. The pyrazinamide was terminated and the hepatitis resolved during the next 2 months, Vestibular reactions. Vestibular reactions, all attributed to streptomycin, were in general mild and infrequent, only 5 per cent of the SHZ, 8 per cent of the S3H,Z, and 2 per cent of the S,H zZ, patients having episodes, most of which started during the first 3 months. Arthralgia. The pyrazinamide dosages in mg/kg body weight were 30-49 daily (median 36), 39-72 three times a week (median 49) and 53-100 twice a week (median 73). Arthralgia occurred in 13 (7 per cent) of the SHZ patients, 5 (3 per cent) of the S,H,Z, and 2 (1 per cent) of the S,H,Z, patients (P < 0.001 for the association with the number of doses per week). The episodes started during the first 3 months in 6, 4 and 1 patients respectively. Most reactions were stated to have responded to symptomatic treatment with analgesic, antiinflammatory or uricosuric drugs or with allopurinol, and only 1 patient (SHZ) had pyrazinamide terminated. Acute gouty arthritis did not occur. Miscellaneous reactions. Other reactions, not shown in the table, occurred in 33 patients (5 SHZ, 15 SaH3Z3, 13 S2H zZ,). Twelve patients had gastrointestinal reactions, 10 had febrile reactions, 8 had episodes of headache and 3 of circumoral paraesthesia. One S,H,Z, patient had streptomycin and pyrazinamide terminated for a gastrointestinal reaction, and another isoniazid for a febrile reaction ; the remaining reactions were trivial. Adverse reactions after 6 months Of the 74 SHZ, 82 S,H 3Z3 and 103 S,H 2Z2 patients who received chemotherapy by random allocation up to 9 months, only 4 (5 per cent), 4 (5 per cent) and 3 (3 per cent) respectively had reactions starting after 6 months, and only 1 (SHZ) had a drug terminated (pyrazinamide for a raised serum AIT concentration). Study 2 Adverse reactions In study 2 (Table II), reactions during the 6 months occurred in 46 (32 per cent) of the SHZ and 31 (23 per cent) of the SPH patients (P = 0.09), in 31 and 23 respectively during the first 3 months. Cutaneous and vestibular reactions occurred with a similar frequency on the 2 regimens and are not tabulated. The incidence of hepatic and gastrointestinal reactions and of arthralgia is shown in the table.

0

1110010 711210644

3 9

4 12

SHZ SPH

SHZ SPH

Gastrointestinal

Arthralgia

1 Defined in text, page 87.

0 -

3 2

1322220 ---__--

4 2

8 0

8 1

6 1 -

022112434 0000101

10 5

7 2

12 0

14 16

9 11

10

6 8

2

5 -

23 14

3 0

1 3

4 _

16 10

%

No.

SHZ SPH

8 4

%

No.

Hepatic’

32 23

%

None

46 31

No.

123456

0 0

2 2

7 -

14 6

No.

Total

oo-

1 10

54 --

10 4

%

1

5 0

ln 6th month

-

0 0

0 -

6 0

S

Z

-

2 -

4 -

4 -

Drug(s)

to chemotherapy

Drugs terminated

modifications

to chemotherapy

and

Temporary interruption

SHZ SPH

-

Any

Month of onset

Regimen

Adverse reaction

Patients with reactions

Modification

Table II. Study 2: Incidence of adverse reactions in first 6 months management (based on 142 SHZ and 137 SPH patients)

-

2

-

5

P

-

0

_

1

SP

made

_ -

0 _

3

4 -

SHZ

in their

5

z

E

5

3

2

Adverse reactions to drug regimens

89

Hepatic reactions. Hepatic reactions occurred in 12 (8 per cent) of the SHZ patients but in none of the SPH patients (P < 0.002). On the SHZ regimen, 6 of the 12 reactions started during the first 3 months. Two SHi! patients became jaundiced, one in the third and the other in the fourth month. One had pyrazinamide terminated and the other all 3 drugs. Liver function tests in both were normal again 2 months later. Five other SHZ patients had one or more drugs terminated for a raised serum AIT concentration, 3 of them pyrazinamide and the other 2 all 3 drugs. Analyses of the monthly distributions of the serum AIT concentration measured in the laboratory in which most of the estimations were made (Government Institute of Pathology) showed a wider scatter, with more high values (Table Ill) on the SHZ than on the SPH regimen.

Table Ill. Study 2: Proportions of or more measured in one laboratory Regimen

AIT full

Percentage

patients

with

monthly

AIT concentrations

of 3OlU/I

Patients assessed

of patients at month -

0

1

2

3

4

5

6

(range)

SHZ

30-39 40 or more

4 2

6 4

IO 10

4 4

2 4

5 7

5 7

55-42

SPH

30-39 40 or more

2 2

0 0

2 0

2 2

0 0

0 0

4 0

52-46

Gastrointestinal reactions. Gastrointestinal reactions (Table II) occurred in 4 (3 per cent) of the SHZ patients, but in 12 (9 per cent) of the SPH patients (P = 0.06). Two SHZ patients had pyrazinamide terminated and 2 SPH patients, PAS. The others were successfully managed with no more than a temporary interruption of chemotherapy. Arthralgia. Eight (6 per cent) of the SHZ patients had episodes of arthralgia compared with only 1 of the SPH patients (P < 0.05). On the SHZ regimen, 4 of the 8 episodes started during the first 3 months. Study 3 Adverse reactions In study 3 (Table IV) reactions during the 6 months were reported in 15 (39 per cent) of the SHZ patients and 11 (27 per cent) of the SHRZ patients, in 13 and IO, respectively, during the first 3 months. The incidence of hepatic reactions and of arthralgia is shown in the table. Cutaneous, vestibular and gastrointestinal reactions also occurred with a similar frequency in both regimens but are not tabulated. Hepatic reactions. Hepatic reactions occurred in 4 (11 per cent) of the SHZ and 3 (7 per cent) of the SHRZ patients, in 3 and 2, respectively, in the first 3 months. Four patients (2 SHZ, 2 SHRZ) became jaundiced, the SHZ patients being the 2 described in study 2 above. Both the SHRZ patients with jaundice, in the second and fourth months, had rifampicin and pyrazinamide terminated and liver function tests reverted to normal within 2 months. Of the 2 SHZ patients with an hepatic reaction but without jaundice, 1 had pyrazinamide terminated, the other had a temporary interruption of chemotherapy. The SHRZ patient without jaundice had pyrazinamide and rifampicin terminated.

SHZ SHRZ

Arthralgia

1 Defined in text, page 87.

SHZ SHRZ

SHZ SHRZ

Any

Hepatic’

Regimen

Adverse reaction

Patients with

7 4

3 6

123456

3 0

Month of onset

0 0

1 1

1 0 0 0 3 0

2 2 0 0 1 0

1

1

1 0

7 1

5 5

No.

2

3

3 0

18 2

%

No.

%

None

1

0

3 3

6 8

Total ___ No.

2

00

8 7

16 20

%

0

0 0

1 0

In 6th month

0

-

0 0

2 4

S

Drug(s)

1

-

2 0

2 1

Z

to chemotherapy

Drugs terminated

modifications

to chemotherapy

and

Temporary interruption

Modification

Table IV. Study 3: Incidence of adverse reactions in first 6 months management (based on 38 SHZ and 41 SHRZ patients)

0

-

_ 3

3

RZ

made

0

-

1 0

2 0

SHZ

in their

-9

0

CD

Adverse reactions to drug regimens

91

Arthralgia. Two SHZ patients and 2 SHRZ patients had episodes of arthralgia, 1 and 2, respectively, in the first 3 months. Only 1 patient (SHRZ) had pyrazinamide terminated. Australia antigen and antibody Results of Australia antigen and antibody tests were analysed from 243 patients (77 SHZ, 60 S,H 3Z3, 34 S,H ,Z,, 72 SPH). All had results available pretreatment and at 5, 6 or 7 months, and none had more than 2 consecutive months during the first 6 months without results. None had missed more than 6 weeks of their pyrazinamide or PAS for any reason other than hepatic reactions, all those with hepatic reactions being included. Pretreatment, 13 patients (4 SHZ, 4 S,H,Z,, 2 S,H,Z,, 3 SPH) had antigen detected in their serum, and 4 (1 SHZ, 3 S,H,Z,) antibody. Antigen was detected for the first time during chemotherapy in only 2 patients (both SHZ) and antibody in none. Thus, on the 3 pyrazinamide regimens combined, 16 patients had either antigen or antibody detected either before or during chemotherapy. Four (25 per cent) of these had hepatic reactions compared with 13 (8 per cent) of 155 with no antigen or antibody (P ==0.09). No patient in either group had jaundice. Of 3 SPH patients with antigen or antibody and 69 without, none had an hepatic reaction. There was thus no more than a suggestion that virus B infection had predisposed to hepatic reactions on the pyrazinamide regimens. Serum-uric acid concentrations Serum uric acid concentrations (Table V) were measured on the specimens taken pretreatment and at 2 and 5 months, in a random sample of 20 patients from each of the SHZ, S,H,Z, and S,H,Z, regimens who had received their allocated regimen without interruption. The pretreatment mean concentrations were similar for all 3 regimens. At 2 and 5 months the mean concentration on the SHZ regimen was higher than on either the S,H,Z, (P < 0.005) or the S,H,Z2 (P < 0.001) regimen, and at 5 months the mean on the S,H,Z, regimen was significantly higher than that on the S,HzZ, regimen (P < 0.05). The means did not alter significantly between months 2 and 5 on any of the 3 regimens. Table V. Serum uric acid concentrations (based on 20 patients received their allocated regimen without interruption) Month

0

Regimen

SHZ S3H3Z3 SzH2Z2

2

SHZ S3H3Z3 SzHzZ2

5

SHZ

from each regimen who

Serum uric acid concentration Mean (mg/700ml)

Standard deviation

4.2 4.4 5.2 12.6 7.4 7.7 14.5

1.5 1.8 1.3 4.4 2.4 2.2 4.2 5.2 3.1

S3H3Z3

9.4

S2H2=2

7.2

Serum specimens which had been taken in the 4 weeks before the onset of arthralgia (Table VI) were available from 8 patients (5 SHZ, 2 S,H,Z,, 1 S,H,Z,). The mean concentration from the 5 patients on the daily regimen was higher than the mean from pairs of

92

Hong Kong/B.M.R.C.

Table VI. Serum uric acid concentrations control patients

Regimen

SHZ

V-G SzHzZ2

in

patients

Serum uric acid concentration

in mg/ 100 ml

Patient with arthralgia’

controlpatients”

35.4 33.8 15.1 23.1 18.3 7.9 7.9 5.5

Matched 1

2

Mean

14.8 17.5 15.0 22.5 12.1 8.3 6.2 6.8

19.8 16.5 16.9 13.2 12.3 4.4 13.4 11.6

17.3 17.0 16.0 17.8 12.2 6.4 9.8 9.2

with

arthralgia

1 Measured on specimens taken within 4 weeks before the onset of symptoms. same time after the start of chemotherapy as the specimen from the patient with

and

2 Measured

in pairs of matched

on specimens

taken

at the

arthralgia.

control patients on the sams regimen, randomly selected from those who had specimens available at the same time after the start of chemotherapy (P = 0.07). In contrast, the serum uric acid concentrations from the 3 patients with arthralgia on the intermittent regimens were lower and were similar to those of the control patients, suggesting a different mechanism for the arthralgia. Pyrazinamide serum half-lives The pyrazinamide serum half-lives determined in 35 of the patients allocated in study 1 to treatment with the S,H,Z, regimen ranged from 6 to 17 hours (median 9 hours). Discussion It has been suggested that in the short-course chemotherapy of pulmonary tuberculosis, rifampicin and pyrazinamide may have special sterilizing actions against bacilli relatively unaffected by other drugs. The evidence for this arises in part from experimental work on animals and in part from clinical trials (Fox and Mitchison, 1975). Rifampicin is widely used in daily first-line chemotherapy, but daily pyrazinamide has been reported to cause a high incidence of toxicity (McDermott and others, 1954; Allison, 1956 ; Phillips and Horton, 1956; Macleod, Hay and Steward, 1959; United States Public Health Service, 1959). However, the early reports of pyrazinamide toxicity in primary chemotherapy often concerned large daily dosages given for long periods. In other studies, the drug had been given in combination with toxic drugs such as ethionamide and cycloserine in reserve regimens to patients, many of whom had already had toxicity to primary chemotherapy or had been unto-operative in taking their treatment (British Tuberculosis Association, 1963; International Union Against Tuberculosis, 1969). In contrast, toxicity has not been a major problem with pyrazinamide in moderate daily dosage (20-30 mg/kg body weight) in combination with streptomycin (Velu and others, 1964; East African/British Medical Research Councils, 1969), or with streptomycin plus PAS (East African/British Medical Research Councils, 1973b) or intermittently in combination with streptomycin (East African/British Medical Research Councils, 1969) or with streptomycin plus isoniazid (Tuberculosis Chemotherapy Centre, Madras, 1970), the dose size being increased with the interval between doses to a maximum of 90 mg/kg once a week.

Adverse

reactions

to drug regimens

93

The present study has shown that during 6 months of streptomycin plus isoniazid plus pyrazinamide the median dosage of the latter drug being 36 mg/kg daily, 49 mg/kg three times a week and 73 mg/kg twice a week, the incidence of adverse reactions in Hong Kong patients was not unduly high and most were mild. Furthermore, although the majority of reactions started during the first 3 months, shortening the period of pyrazinamide administration could be expected to reduce the incidence of adverse reactions even further. This is particularly true of arthralgia during daily pyrazinamide administration and of hepatic reactions during daily and intermittent administration. In both these instances, a substantial proportion of the reactions started during the second 3 months of chemotherapy. In this context, it is also relevant that a very low incidence of adverse reactions to pyrazinamide was reported when alternating 4-week courses of daily streptomycin plus pyrazinamide (40 mg/kg body weight) and daily isoniazid plus PAS were given (Corpe and Blalock, 1964; Huggin, 1970). In the present study there was a slight suggestion that virus B infection had predisposed to raised serum AIT concentrations (P = 0.09). It is possible that not only previous virus B hepatitis but also other types of hepatitis might render the liver more susceptible to damage by pyrazinamide. This is a matter which clearly requires further investigation. There was a clear tendency for serum AIT concentrations to be higher during treatment with the pyrazinamide regimens than with the PAS-containing control regimen. However, many increases in serum AITconcentration were transient, even in the absence of any modification to the regimen, and transient increases during antituberculosis chemotherapy are, in any case, common and usually unimportant (Baron and Bell, 1974). Five (0.7 per cent) patients out of a total of 668 on pyrazinamide regimens became jaundiced, 4 on daily and the fifth on three times weekly pyrazinamide. There was no association between the incidence of hepatic reactions and the pyrazinamide dosage corrected for body weight. Although pyrazinamide, isoniazid and rifampicin are all known to be hepatotoxic to some patients, there was no evidence in the present study that the addition of daily rifampicin to daily streptomycin plus isoniazid plus pyrazinamide increased the risk, but the numbers observed were small. More information on this will become available in current studies. The commonest symptom attributed to pyrazinamide was arthralgia, and this was considerably less common on the intermittent regimens than on the daily regimen. The administration of pyrazinamide increases the serum uric acid concentration (Cullen, Le Vine and Fiore, 1957 ; Gleason, Street and Khan, 1957). This increase is caused by pyrazinoic acid, a major metabolite of pyrazinamide which reduces the renal elimination of uric acid (Weiner and Tinker, 1972; Fanelli and Weiner, 1973). Studies described in the accompanying paper (Ellard and Haslam, 1976), showthat the renal elimination of uric acid is partially inhibited for periods of up to 48 hours after a therapeutic dose of pyrazinamide. In the present study, the serum uric acid concentrations were significantly higher during daily chemotherapy than when doses were given at intervals of 2 days or more (P < 0.005), and were higher in patients with arthralgia on daily pyrazinamide than in matched controls (P = 0.07). Furthermore, the incidence of arthralgia was associated with the number of doses of pyrazinamide a week (P ( 0.001). These findings provide strong circumstantial evidence that the renal uric acid retention caused by pyrazinoic acid is responsible for the arthralgia during the daily administration of pyrazinamide. During intermittent administration, when serum uric acid concentrations were lower and were the same for patients with arthralgia as for matched controls, the mechanism of the arthralgia may have been different. Acute gouty arthritis did not occur, and the joint pain was successfully managed in most patients by symptomatic treatment with analgesic, antiinflammatory or uricosuric drugs or with allopurinol, with or without a temporary interruption of pyrazinamide administration. In conclusion,

short-course

regimens

including

isoniazid

and pyrazinamide

can sometimes

94

Hong Kong1B.M.R.C.

gives rise to hepatic reactions when the pyrazinamide is administered in dosages of about 35 mg/kg body weight daily, 50 mg/kg three times a week or 70 mg/kg twice a week, as well as arthralgia. The incidence of arthralgia is lower during intermittent than during daily administration, and the incidence of hepatic reactions is not obviously increased by the addition of rifampicin. Further comparisons between regimens containing pyrazinamide and control regimens without the drug are now in progress. Acknowledgements In Hong Kong, the medical and laboratory staffs, the Medical Social Workers, Health Visitors and Health Auxiliaries and the nursing, radiological, technical, secretarial and administrative staffs of the following hospitals, chest clinics and laboratory co-operated in the study. From the Anti-Tuberculosis and Thoracic Diseases Association : Ruttonjee Sanatorium : - Sister M. Aquinas, Sister M. Gabriel, Dr S. L. Chan, Dr S. Virdi ; Grantham Hospital : Dr P. A. L. Horsfall, Dr Michael Chan, Dr K. S. Cheung, Dr S. H. Tsang, Dr Pau Wei, Dr William Chen, Dr K. C. Tang, Dr H. S. Chau, Dr R. P. Saksena. From the Junk Bay Medical Relief Council : Haven of Hope Sanatorium :-Dr P. K. Jenkins, Dr R. G. B. Graham, Dr Mary A. Ashton, Dr David Lum, Dr W. B. Whitehill. From the Government Chest Service: Wanchai Chest Clinic : - Dr J. M. Titmas, Dr K. W. Loke, Dr Albert Fong ; Sai Ying Pun Chest Clinic : Dr J. C. Luan, Dr J. M. Chau; Shaukiwan Chest Clinic: - Dr A. Abraham, Dr C. H. Ng; Yaumatei Chest Clinic : - Dr George Kwong, Dr S. S. Leong ; Kowloon Chest Clinic : - Dr E. L. Wang, Dr P. P. Cheung ; Shek Kip Mei Chest Clinic: - Dr W. C. Loke, Dr S. W. Fung ; Kwai Chung Chest Clinic: - Dr P. G. Lindsay; Kowloon Hospital : - Dr H. Y. Wong, Dr Francis Au. From the Government Pathological Institute : - Dr T. B. Teoh. The Australia antigen investigation was carried out in the Kowloon Hospital Pathological Institute by Dr Shum Hay. In London, the serum uric acid concentrations and pyrazinamide measured by Dr G. A. Ellard and Miss P. T. Gammon at the Medical for Laboratory Studies of Tuberculosis.

serum half-lives were Research Council Unit

The investigation was co-ordinated in the Wanchai Chest Clinic and in the Unit for Laboratory Studies of Tuberculosis and the Tuberculosis and Chest Diseases Unit of the British Medical Research Council. In Hong Kong the co-ordinator was Dr W. G. L. Allan, and Mr William Chan then Mr Chan Yat-lun and Mr Chiu Wan-yin were the co-ordinating secretaries. Dr Dip Singh and Dr S. C. Pang were independent assessors. In London the co-ordinator was Dr D. J. Girling of the Medical Research Council Tuberculosis and Chest Diseases Unit. The report was prepared on behalf of the co-operating Wallace Fox and Mr A. J. Nunn.

physicians

All those co-operating are grateful to the Director of Medical Kong, for his permission to publish the findings.

by Dr D. J. Girling,

Dr

and Health Services, Hong

References Allison, S. T. (1956). Pyrazinamide-isoniazid in low dosage in treatment of pulmonary tuberculosis. American Review of Tuberculosis and Pulmonary Diseases, 74,400. Alter, H. J., Holland, P. V., 8 Purcell, R. N. (1971). Counterelectrophoresis for detection of hepatitis-associated antigen. Methodology and comparison with gel diffusion and complement fixation. Journal of Laboratory and Clinical Medicine, 77,1000. Baron, D. N., 8 Bell, J. L. (1974). Serum enzyme changes in patients receiving antituberculosis therapy with rifampicin or p-aminosalicylic acid plus isoniazid and streptomycin. Tubercle, 55,115. British Tuberculosis Association (1963). Ethionamide, pyrazinamide and cycloserine in the treatment of drug-resistant pulmonary tuberculosis. Tubercle, 44,195. Corpe, R. F., & Blalock, F. A. (1964). Alternating regimens of streptomycin-pyrazinamide, isoniazid-para-aminosalicylic acid at Battey State Hospital. American Review of Respiratory Disease, 90.262.

Adverse-reactions Cullen. J. H.. Le Vine, M.. Et Fiore, J. M. (1957). Journal of Medicine, 23.567.

Studies

of the hyperuricemia

produced

to drug regimens by pyrazinamide.

95

American

East African/British Medical Research Councils (1969). A controlled comparison of four regimens of streptomycin plus pyrazinamide in the retreatment of pulmonary tuberculosis. Tubercle, 60.81. East African/British Medical Research Councils (1972). Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lance?, 1.1079. East African/British Medical Research Councils (1973a). Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Second Report. Lancet, 1.1331. East African/British Medical Research Councils (1973b). Streptomycin plus PAS plus pyrazinamide in the retreatment of pulmonary tuberculosis in East Africa : Second report. Tubercle, 54,283. East African/British Medical Research Councils (1974a). Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third Report. Lancet, 2, 237. East African/British Medical Research Councils (1974b). Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lsncet, 2,llOO. Ellard, G. A. (1969). Absorption, metabolism and excretion of pyrazinamide in man. Tubercle, 50,144. Ellard, G. A., b- Haslam, R. M. (1976). Observations on the reduction of the renal elimination of urate in man caused by the administration of pyrazinamide. Tubercle, 57, 97. Fanelli, G. M.. Et Weiner, I. M. (1973). Pyrazinamide excretion in the chimpanzee. Relation to urate disposition and the actions of uricosuric drugs. Journalof Clinicallnvestigation, 52,1946. Fox, W., & Mitchison, D. A. (1975). Short-course chemotherapy for pulmonary tuberculosis. American Review of ReSpir8tOry Disease, 111,325. Gleason, D. F., Street, J. P., Et Kahn, K. A. (1957). Effects of pyrazinamide on serum and urine uric acid. Transactions of the 16th Conference on the Chemotherapy of Tuberculosis. Veterans Administration -Armed Forces, page 239, Washington. Henry, R. J., Sobel, C., B Kim, J. (1957). A modified carbonate-phosphotungstate method for the determination of uric Journalof C/inica/Patho/ogy, 28,645. acid and comparison with the spectra-photometric uricase method.American Hong Kong TuberculosisTreatment Services/British Medical Research Council (1975). Controlled trial of 6- and g-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Tubercle, 56,81. Huggin, P. M. (1970). Ethambutol in primary chemotherapy. Proceedings of the XXth International Tuberculosis Conference, New York, 2-6 September 1969. Bulletin of the international Union Against Tuberculosis, 43, 310. International Union Against Tuberculosis (1969). A comparison of regimens of ethionamide pyrazinamide and cycloserine Bulletin of the International Union Against Tuberculosis, in retreatment of patients with pulmonary tuberculosis. 42.7. MacLeod, H. M., Hay, D., Et Stewart, S. M. (1959). The use of pyrazinamide plus isoniazid in the treatment of pulmonary tuberculosis. Tubercle, 40, 14. McDermott, W., Ormond, L., Muschenheim, C., Deuschle, K., McCune, R. M., Tompsett, R., Et Stern, K. (1954). Pyrazinamide-isoniazid for pulmonary tuberculosis. American Review of Tuberculosis, 89,319. Phillips, S., 8 Horton, G. E. (1956). Pyrazinamide-isoniazid. Comparison with isoniazid-para-aminosalicylic acid in active pulmonary tuberculosis with the choice of regimens determined by chance. Americ8n Review of Tuberculosis and Pulmonary Diseases. 73.704. Reitman, S., 8 Frankel, S. (1957). A calorimetric method for the determination of serum glutamic oxalacetic and glutamic American JournalofClinicalPathology, 28,56. pyruvic transaminases. Tuberculosis Chemotherapy Centre Madras (1970). A controlled comparison of a twice-weekly and three once-weekly regimens in the initial treatment of pulmonary tuberculosis. Bulletin of the WorldHealth Organization, 43,143. United States Public Health Service (1959). Sequential use of paired combinations of isoniezid, streptomycin, paraaminosalcyclic acid and pyrazinamide. American Review of Respiratory Disease, 80,627. Velu, S., Dawson, J. J. Y., Devadatta, S., Fox, W., Kulkarni, K. G., Mohan, K., Ramakrishnan, C. V., Et Stott, H. (1964). A controlled comparison of streptomycin plus pyrazinamide and streptomycin plus PAS in the retreatment of patients excreting isoniazid-resistant organisms. Tubercle, 45,144. Weiner, I. M., &Tinker, J. P. (1972). Pharmacology of pyrazinamide, metabolic and renal function studies related to the mechanism of drug-induced urate retention. JOUrn8lOfPharm8cOlOgy 8ndExpefimental Therapeutics, 180,411.