TNAG-0655-FCO40-804-Development-of-medical-and-health-services-in-Hong-Kong-1977 — Page 14

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CONTROLLED TRIAL OF 6- AND 9-MONTH TUBERCULOSIS REGIMENS

of chemotherapy. The distributions of the se- rum alanine transaminase concentrations dur- ing hemotherapy are shown in table 5. The distations for the 3 regimens were very sim- ilar and they have therefore been amalgamated in this table.

Vestibular reactions. Vestibular reactions, all attributed to streptomycin, were, in general, mild. They were reported in 5 per cent of the SHZ patients, 8 per cent of the SHZ patients, and 2 per cent of the S2HZ patients, most of them starting during the first 3 months of che- motherapy.

Arthralgia. Arthralgia occurred in 13 (7 per cent) of the SHZ patients, 5 (3 per cent) of the SHZ3 patients, and 2 (1 per cent) of the S2H2Z2 patients. There was a highly significant associ- ation between the number of doses per week and the incidence of arthralgia (P < 0.001). The pyrazinamide dosages in mg per kg body weight were 30 to 49 daily (median, 36), 39 to 72 three times a week (median, 49), and 53 to 100 twice a week (median, 73).

Miscellaneous reactions. Other reactions, not shown in table 4, occurred in 33 patients: 12 had gastrointestinal reactions, 10 had febrile re- actions, 8 had headache, and 3 had circumoral paraesthesia.

Adverse Reactions after 6 Months

Of the 74 SHZ, 82 SHÖZ, and 103 S2H.Z patients who received chemotherapy up to 9 months, only 4 (5 per cent), 4 (5 per cent), and 3 (3 per cent), respectively, had reactions start- ing after 6 months, and only one (SHZ) had a drug terminated (pyrazinamide, for a raised se- rum alanine transaminase concentration). The distributions of serum alanine transaminase con- centrations at months 7, 8, and 9 are shown in table 5.

Discussion

This study has shown that 9-month regimens of streptomycin plus isoniazid plus pyrazinamide given daily or 3 times a week to newly diagnosed Chinese patients with drug-susceptible pulmo- nary tuberculosis achieve good results as assessed up to 30 months and have an acceptable inci- dence of adverse reactions. These 2 regimens could be useful in countries with a low preva- lence of initial drug resistance and where the routine treatment services obtain a poor response to regimens of conventional duration, especially if rifampin is considered to be too expensive for inclusion in first-line regimens. The same drug

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combination given twice a week was less good during chemotherapy, but the relapse rate after this regimen was as low as that following the other two. Failure during chemotherapy was in- variably associated with the emergence of iso- niazid resistance but all the relapses after che- motherapy were with fully drug-susceptible strains. For patients with pretreatment strains resistant to isoniazid, to streptomycin or to both drugs, the failure rates during chemotherapy were high on all 3 regimens, but, in marked con- trast, the relapse rates after chemotherapy were no higher than they were for patients with fully drug-susceptible strains before treatment.

These findings show that the combination of streptomycin plus pyrazinamide is not good at preventing the emergence of drug resistance, confirming previous clinical studies of this com- bination with or without isoniazid (4-6). This is probably because streptomycin but not pyra- zinamide is active against tubercle bacilli in a neutral or alkaline environment, whereas pyra- zinamide but not streptomycin is active in an acid environment (7, 8). Thus, mutant bacilli resistant to one of these 2 drugs may not be in- hibited by the other. A similar explanation prob- ably lies behind the high failure rate among pa- tients with pretreatment strains resistant to iso- niazid, to streptomycin, or to both drugs. In- deed, the failure rate was high even for patients with pretreatment strains resistant to streptomy- cin alone, in sharp contrast with the low failure rates for such patients treated with short-course regimens containing rifampin (9, 10).

Although the intermittent regimens of strep- tomycin plus isoniazid plus pyrazinamide were not fully effective in preventing the emergence of drug resistance, nevertheless they were good sterilizing regimens. Indeed, all three 9-month regimens, daily and intermittent, were equally effective in eliminating fully susceptible strains of bacilli from the sputum, as shown by the equally low relapse rates in all 3 series. The re- lapse rates after the 6-month regimens, although higher, were also similar in all 3 series. The in- cidence of initial resistance to pyrazinamide is very low in Hong Kong patients (unpublished observations from the reference laboratory). Fur- thermore, the relapse rates after chemotherapy among patients with pretreatment strains resis- tant to isoniazid, to streptomycin, or to both drugs were no higher than those among patients with strains susceptible to these 2 drugs. This means that pyrazinamide is almost certainly the most effective drug in the sterilizing activity of the regimens, a finding that provides clinical con-