1 n 1965, Fuchs 1 reported a study of 3,200 Veterans

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1 Prophylaxis with in Inactive Tuberculosis* A Veterans Administration Cooperative Study XII Abraham Falk, M.D., and George F. Fuchs, M.D., F.C.C.P. Based on a study indicating a significant rate of reactivation of tuberculosis in Veterans Administration patients with inactive disease, a cooperative study was initiated to determine the prophylactic effect of isoniazid on the rate of reactivation. A randomized double-blind study was designed, utilizing three regimens, two with isoniazid and one with placebo only. Two consecutive years of taking pills in one of the three regimens was followed by five years of observation. A total of 7,036 patients with inactive disease, some of whom bad received prior chemotherapy, were entered into the study. Only 63 reactivations of tuberculosis were found, for a total rate of reactivation of 9/1,000 (less than 1 percent) over the seven-year period. Although no significant differences in the rate of reactivation were found among any of the regimens, there was a significant reduction in the rate of reactivation among those who had not received any prior chemotherapy and received isoniazid (INH) in this study, compared with those who received placebo only. 1 n 1965, Fuchs 1 reported a study of 3,200 Veterans Administration patients with inactive tuberculosis observed during a five-year period ( 1957 to 1962), which revealed an overall rate of reactivation of For editorial comment, see page 4 tuberculosis of 6.3 percent during that period. The combined rate for those with moderately advanced or far advanced disease was 9.1 percent. Fifty-two percent of the group had received antituberculosis chemotherapy, but only one-third of these had received adequate chemotherapy, defined as 18 months of treatment with no less than two drugs. On the basis of this report prior to publication and other data available to the Veterans Administration, it was decided by a group of consultants and Veterans Administration physicians from the program for tuberculosis to initiate a cooperative study to determine whether a course of therapy with isoniazid ( INH) would reduce the rate of reactivation of tuberculosis in a group of patients with inactive tuberculous disease. The effectiveness of a one-year course of therapy with isoniazid was also to be compared with a two-year course. 0 From the Veterans Administration Hospital, Minneapolis ( Dr. Faile) and the Veterans Administration Hospital, San Francisco (Dr. Fuchs). Supported by the Medical Research Service of the Veterans Administration. Associate Professor of Medicine, University of Minnesota, Minneapolis. Manuscript received August 16; revision accepted April 15. Reprint requests: Dr. Falk, VA Hospital, Minneapolis FALK, FUCHS MATERIALS A!'llD METIIODS The Veterans Administration cares for a large number of veterans with service-connected disability for tuberculosis incurred during or attributable to military service. Outpatient clinics exist in all states for the follow-up care of these patients, who are usually seen on an annual basis. Physicians experienced in treating tuberculosis are in charge of the clinics, and it was from this group that the 11 investigators entered the cooperative study. The location of the clinics in cities such as New York, Chicago, Dallas, and Los Angeles assured an adequate geographic distribution of the patients. Veterans with a diagnosis of pulmonary tuberculosis, classified as inactive by the then-current National Tuberculosis Association's Diagnostic Standards and Classification of TubercukJsis of 1961, were eligible for the study on a voluntary basis, provided they had not received any antituberculosis chemotherapy within the previous 12 months. Admission to the study was also limited to those patients who could reasonably be expected to cooperate in all aspects of the study. Excluded were those patients with known chronic alcoholism, mental incompetence, personality disorders, or other factors which, in the opinion of the investigators, would affect the cooperation of the patient. It was not believed that such exclusions would bias the study, as relatively few such individuals did volunteer, and the number excluded was small. A randomized double-blind system was devised, using a series of coded numbers for the regimens of treatment, to which the patients were assigned consecutively by each investigator. The code remained unknown to the investigators until the completion of the study. All medications were supplied and similarly coded from a central pharmacy, and the pills of isoniazid and placebo were prepared to be identical in size, shape, color, and taste. Patients were required to return the containers from their medication on each visit. The number of pills remaining, based on the previous supply and expected use during

2 the interval, was used by the investigator as an index of the patient's compliance and continuance in the study. Urinary lesuntt lor producls of isonlazlj m e t a ~ owas l lnoi s m a requirement of the study. Patients were randomly assigned to one of the following three regimens: ( 1) regimen 1, consisting of two consecutive years of therapy with isoniazid ( 300 mg in a single daily dose); ( 2) regimen 2, consisting of one year of therapy with isoniazid ( 300 mg in a single daily dose), followed by one year of receiving the placebo in a single daily dose; and ( 3) regimen 3, consisting of two consecutive years of receiving the placebo in a single daily dose. The initial examination on entrance into the study required a chest x-ray film and bacteriologic study, including culture of sputum or gastric contents for tubercle bacilli. Similar studies were required at six-month intervals for the first 24 months (pill-taking period) and yearly thereafter for a fiveyear period of observation. Reports were submitted to a central coordinator on a mark-sense code form, were reviewed for correctness and additional coding, and were processed through an optical scanner that produced a punched card for input into a computer. A total of 7,036 patients were entered into the study between December 1964 and December 1968, the majority of them in 1965 and The distribution of patients among the regimens is shown in Table 1. The patients were predominantly white men, with only 127 women in the entire group. Seventy-eight percent were in the group aged 30 to 50 years, and 16 percent were in the group aged 51 to 70 years. The age distribution of patients among the three regimens was essentially similar. Distribution of patients by the extent of disease at the start of the study was balanced among the regimens. Sixty percent of the patients had minimal disease, 31 percent had moderately advanced disease, and 9 percent had far advanced disease. Tuberculosis had been inactive for 5 to 20 years or more in 95 percent of the patients in each of the regimens. fu:sults Completion of the pill-taking aspects of the study for all patients ended on Dec 31, Completion of pill taking was defined as the termination of pill taking by the patient and does not imply completion of the duration required by the study. It was not expected that all patients would complete the period of pill taking or the subsequent five-year period of observation; however, 73 percent of all patients completed 24 months of pill taking and 78 percent completed more than 12 months. This degree of compliance was similar among the three regimens, and 81 percent of all patients under study were observed Table 1-Di rribulion of Paliem. a m Re«imen. o ~ and by Race ~ Race 2yr 1yr Placebo Total White 1,657 1,969 1,822 5,448 Negro ,191 Other Total 2,166 2,553 2,317 7,036 Table 2--Reaclillalion. of Tuberculo.i Grouped by Character of E11idence ~ 2 yr 1 yr Placebo Total Evidence Bacteriologic only Bacteriologic and roentgenographic Total reactivations Rate of reactivation per 1,000 patients for five years or more. There were 1,918 patients ( 27 percent of the entire group) who discontinued pill taking during the study for various reasons, the majority during the first six months. Nausea was given as a cause in 7 percent, and this complication occurred with equal frequency in the three regimen. Rash was noted in 44 patients on the regimens of isoniazid, and rash occurred in eight patients who received placebo only. Of the 1,918 patients, 673 ( 35 percent) were listed as uncooperative, without explanation. The remainder and largest group failed to continue pill taking for such reasons as intercurrent illness. change of residence, or death and because of various subjective complaints. The distribution of these factors was essentially similar among the three regimens. The criteria for reactivation of tuberculosis were the finding of a positive culture for tubercle bacilli or evidence of unfavorable roentgenographic change, or both. Although unfavorable roentgenographic change was initially included as a criterion of reactivation of tuberculosis, subsequent information on the unreliability of this test led to the acceptance of bacteriologic findings as the sole measure of reactivation. Ninety-nine reactivations of tuberculosis were initially reported. All were reviewed by a referee who did not know the regimen of treatment, and many of the chest x-ray films were also reviewed at periodic meetings of the investigators, to whom the regimens were also unknown. Twenty-six cases were excluded, leaving a total of 73 reactivations diagnosed by positive findings on bacteriologic culture, chest x-ray film, or both. The elimination of ten reactivations of tuberculosis diagnosed only by the roentgenographic criterion leaves a total of 63 reactivations under the revised criteria (Table 2). The 26 exclusions were cases reported by the investigators as reactivations (chiefly bacteriologic) and occurred during the first year of the study (pilltaking period). Review by the referee resulted in PROPHYWIS WITH INH IN INACTIVE TUBERCULOSIS 45

3 exclusion due to such factors as positive cultures of sputum within the year prior to entry into the study or positive bacteriologic findings from the initial specimen on entry into the study. Reported reactivations based on roentgenographic changes were excluded after comparison with chest x-ray films taken at and prior to entry into the study, which demonstrated significant instability of the pulmonary lesions. Since neither the investigator nor the referee knew the regimen of treatment of any of the patients during the study, this did not bias their evaluations. of tuberculosis included five instances of extrapulmonary disease and two deaths from tuberculosis. The extrapulmonary foci were separate instances of meningitis, cold abscess, epidural abscess, epididymitis, and miliary-meningeal tuberculosis. Of the two deaths, one was due to miliary tuberculosis, with extensive adrenal involvement, occurring during the sixth month of therapy with isoniazid. This patient had not had previous chemotherapy, and his disease had been inactive for 15 years. The other death was due to far-advanced pulmonary disease in a patient who had completed only two months of therapy with isoniazid and who died 11 months later. Seven years previously, he had received 12 months of a threedrug regimen (including isoniazid) and had been classified as having inactive disease for five years prior to entrance into the study. There was no predominance of this group of reactivations in any of the three regimens. Table 2 groups the reactivations by the nature of their evidence and by regimen. Seventeen accepted reactivations occurred in the group receiving two years of therapy with isoniazid, 20 occurred among those receiving one year of therapy with isoniazid, and 26 occurred among those who received placebo only. There were no statistical differences in the rate of reactivation of tuberculosis among any of the regimens. The rate of reactivation for the entire seven-year period of the study and the entire population under study was only 9/1,000, or slightly more than 1/1,000/yr. During the first and second years (pill-taking period), there were 22 reactivations of tuberculosis (Table 3), and there were 41 reactivations in the subsequent five years. The number of reactivations in the regimen providing one year of therapy with isoniazid was notably greater after the second year, compared with the regimen providing two years of therapy with isoniazid. Thirty-two of the patients with reactivations (50 percent) had completed the required 24 months of pill taking. Of these, 20 ( 63 percent) were receiving the regimens containing 48 FALK, FUCHS Table 3-Reactillations of Tuberculosis by l' ear of ReJimen,---A Year and Data 2 yr 1 yr Placebo First year of pill taking No. of cases 2,135 2,523 2,285 No Rate per 1,000 patients Survivorship, percent* Second year of pill taking No. of cases 2,080 2,440 2,223 No Rate per 1,000 patients Survivorship, percent* Observation after second year** No. of cases 1,499 1,767 1,615 No Rate per 1,000 patients Survivorship, percent* *Survivorship represents actuarial percentage without reactivation to given time from beginning of study. **Rate based on entire period of observation after second year of study. isoniazid. Table 3 also indicates the rate of reactivation of tuberculosis in each regimen, based upon the number at risk at the beginning of each period. The three regimens have essentially equal percentages of subjects observed for corresponding periods of time. The times at which patients were lost to observation were also equally distributed among the three regi- Table 4-Rates of Reac.ti11ation amonij Re«imens Based on P r e ~ ~ Chemotherapy i o u s Including Regimen and Data None Previous Chemotherapy Without Unknown, 2 yr No. of cases No Rate per 1,000* , 1 yr No. of cases No Rate per 1,000* Placebo only No. of cases No Rate per 1,000* Total No. of cases 2,389 2,803 1, *Rates based only on number of patients at entry into study.

4 mens by length of observation. The percentage without reactivation of tuberculosis at the given time (survivorship) is essentially equal for all regimens and periods of time. Of the 63 reactivations of tuberculosis (Table 4), 35 patients had had known previous chemotherapy, which included isoniazid in 25 patients. Forty percent of all patients in the study had received prior therapy with isoniazid. Of these, 78 percent had received isoniazid for 13 to 24 months or more, and the numbers were essentially equally distributed among the three regimens. The majority ( 75 percent) had received isoniazid within the three-year period prior to the year immediately preceding entry into the study. Overall rates of reactivation of tuberculosis in the patients receiving the isoniazid-containing regimens were not significantly different, whether or not previous chemotherapy included isoniazid or no previous chemotherapy had been given. There was a significant difference in rates of reactivation in the placebo-treated group between those who had received prior chemotherapy (with or without isoniazid) and those previously untreated ( P = ). (Chi-square statistics were calculated by R X C Contingency Table Analysis Program 2.) Review of the 63 reactivations of tuberculosis (Table 5) found that only 23 patients had received prior adequate chemotherapy (adequate chemotherapy being defined as at least 18 months of therapy with two drugs). The remaining 40 patients had received either inadequate or no previous chemotherapy. It would appear that prior adequate chemotherapy did affect the number of reactivations in this group. Prophylaxis with isoniazid resulted in a 60 per- Table S--Reaeti11adoru of Tuberculoaia Grouped by Prior Chemotherapy Prior Chemotherapy Regimen Adequate Inadequate None Total, 2 yr , 1 yr Placebo only Total Table 6--EDect of Prophyla:ria with laonia1jid on Rate of Reacti11ation of Tuberculoaia Data Rate of reactivation per 1,000 cases Placebo only Regimens with isoniazid Percent reduction With Prior No Prior Chemotherapy Chemotherapy cent reduction in the rate of reactivations per thousand (Table 6) for those who had not received prior chemotherapy, compared with those previously untreated who received placebo only in this study; however, among those who had received prior chemotherapy, there was no reduction in the rate of reactivation of those receiving the isoniazidcontaining regimens, compared with those who received placebo only. The possibility that patients who had received prior therapy with isoniazid had developed resistance to the drug may be a factor, but information on resistance was not part of the study, and this factor could not be evaluated. The data were also analyzed to determine the possible influence of other factors on the rate of reactivation of tuberculosis. One-third of the patients had thoracic surgical procedures prior to entering the study, of which approximately half were pulmonary resections. The distribution of these procedures was essentially similar for each of the regimens, and no significant relationship between prior surgery and reactivation could be determined. Similarly, the effect of the maximum extent of the original disease or the extent of the disease at the start of the study was not significant in any regimen. There were 357 deaths reported during the study. The major causes were cardiovascular disease ( 34 percent), accidental deaths ( 11 percent), bronchogenic carcinoma ( 7 percent), nonpulmonary carcinoma (14 percent), and nontuberculous pulmonary disease ( 12 percent); and the causes were equally distributed among the regimens. Deaths rates were 4/ 1,000 in the two-year regimen of therapy with isoniazid, 6.5/1,000 in the one-year regimen of therapy with isoniazid, and 4.4/ 1,000 in the regimen of placebo only. The differences between the regimen of placebo and the one-year regimen of isoniazid were significant ( P = ). The increased death rate in the one-year regimen of isoniazid and the number of reactivations in this regimen could not be satisfactorily explained. Such factors as age, extent of disease, race, or cause of death were not dissimilar compared with the other two regimens. The number of patients entered in the one-year regimen of isoniazid was somewhat greater than in either of the other two regimens, but no fault in the procedure of randomization could be found. Previously prepared randomized and coded log books were provided to each investigator for the consecutive and dated entry of patients into the study. The design was such that proper randomization could not be avoided, and review of these log books found no evidence to the contrary, especially since the code was unknown to the investigators. PROPHYLAXIS WITH INH IN INACTIVE TUBERCULOSIS 47

5 DISCUSSION Our study confirms others reviewed by Johnston and Wildrick, 3 which indicate that the risk of reactivation after completion of 18 months of two-drug therapy is small. Stead and Jurgens 4 found a rate of reactivation of 0.8 percent within three years following 18 months of effective therapy, compared with a rate of 18 percent for a similar group that had received inadequate chemotherapy. Grzybowski et als reported a rate of reactivation of 0.8 percent among 234 patients in the five years following good chemotherapy (one year of treatment with two drugs), compared with a rate of nearly 5 percent during the first five years after reaching inactive status of those who had received inadequate therapy. After 20 years, the total rate of relapse in the latter group had reached 27 percent. A subsequent study by Grzybowski et al, 6 comparing prophylactic treatment of 1,536 patients with inactive disease to 840 untreated control patients, found an annual rate of reactivation of tuberculosis in the treated group of 0.7 percent and a rate of 4.9 percent in the untreated control group. Approximately 90 percent in each group had not had any previous chemotherapy. The higher rate of reactivation of tuberculosis reported by Fuchs 1 was derived from a clinical population different from that entered in this study, reflecting an essentially closed group of patients who were at the highest risk of reactivation during the five-year period after having reached inactive status. By contrast, in this study, 95 percent of the patients had been classified as having inactive disease for five years or more, while only 50 percent of the patients in Fuchs' study had been so classified for the same period of time. The lower rate in this study represents the residual patients of later years who were least likely to have reactivation of tuberculosis. In a Public Health Service tria!t of prophylaxis with isonazid vs placebo in patients known to have had previously active tuberculosis without chemotherapy, there was a 51 percent reduction in the five-year rate of reactivation for the isoniazid-treated group. This compares with a 60 percent reduction in the rate of reactivation for a similar group in this study. For those patients previously known to have active disease who were treated, the reduction in the rate of reactivation with prophylaxis with isoniazid was 17 percent. We found no reduction for a similar group in our study. In an International Union against Tuberculosis trial 8 of preventive treatment with isoniazid in per- sons with fibrotic pulmonary lesions not previously treated or known to be active, there was an 88 percent reduction in reactivations, compared with those receiving placebo, at the end of the first year of the study. The patients in this study were a special population, predominantly men with known previous tuberculosis (inactive for five years or more in 95 percent). Sixty-six percent of the patients had received prior chemotherapy, and all had been regularly followed by the Veterans Administration since the onset of their disease. While no significant overall differences were found in the rates of reactivation of tuberculosis among the three regimens, there was a significant reduction in the rate of reactivation among those who had not received any prior chemotherapy and received isoniazid in this study, as compared with a similar group who received placebo only. The rate of reactivation for the entire period of the study was only 9/1,000, which suggests, in retrospect, that this group as a special population was not sufficiently at risk for such a study. Large-scale prophylaxis of persons with inactive disease who have previously received adequate chemotherapy does not appear to be of value. Our findings suggest that for this, or similar populations, prophylaxis with isoniazid would best be directed toward those individuals with inactive disease not previously treated or inadequately treated. ACKNOWLEDGMENT: We acknowledge the efforts of the following investigators who provided the cases in this study: Drs. Helen Bemfield, Walter D. Coddon, John B. Devine, George F. Fuchs, Paul K. Maier, George W. Post, Dina B. Rappaport, H. Charles Shock, Benjamin Schwartz, Solomon Schwartz, and Joseph Tedesco. REFERENCES 1 Fuchs GF: Criteria for prophylaxis in active tuberculosis. Arch Environ Health 10: , HP 9810A STAT PAC ( vol 2). Loveland, Colo Hewlett Packard Co, pp Johnston RF, Wildrick KH: "State of the art" review: The impact of chemotherapy in the case of patients with tuberculosis. Am Rev Respir Dis 109: , Stead WW, Jurgens GH: Productivity of prolonged followup after chemotherapy for tuberculosis. Am Rev Respir Dis 108: , Grzybowski S, McKinnon V, Tuteur I, et al: in active pulmonary tuberculosis. Am Rev Respir Dis 93: , Grzybowski S, Ashley MJ, McKinnon NE, et al: In Canada: A trial of chemoprophylaxis in inactive tuberculosis: Can Med Assoc J 101: , Ferebee SH: Controlled chemoprophylaxis trials in tuberculosis: A general review. Adv Tuberc Res 17 :28-106, Krebs A: First year efficacy of three durations of treatment. Bull Int Union Tuberc 49: , FALK, FUCHS