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Madras study of supervised once-weekly chemotherapy in the treatment of pulmonary tuberculosis: Clinical aspects
76
T U 1~i: R C LI::. S U e P Z,!:;M!~S l"
~IADRAS STUDY TREATMENT
OF SUPERVISED OF I ' U L M O N A R Y
O N C E - V V E E K L Y C H F M O I ' I - I F . R A P Y IN T I I E TUBERCULOSIS" CI.IN1CAI, ASPECTS
By N. K. M:!x(:)x lkom the 7"tdwrcuhzvis Ctwmothc,'ap)' (~,ntre, Ma~h"ar. Indk~
'~ "'" (] ][i [I [) ~ [ t16 Tuberculosis ( ~" , h ~."m t The first c o n t i ' o ~ t study o f i n t e r m i t t e n t I c n c m o t h c r , ~ .') carried therapy Centre \~,~',"-~"ac o m p a r i s o n o f s t r e p t o n l y c i n plu,~ isoniazid given together twice-weekly with a s t a n d a r d oral daily regimen of i~,onjazid plus PAS, in the twicc-weekIr regimen, streptomS.cin was given in a dosa~,e of 1 t~. t o g e t h e r witi~ isoniazid in a dosage of approxinlatelv 14 ,, wei~zht T h e twice-weekly,, regim'en was fi)und to be at ,cast as effective as the daily " - , "; both in the a t t a i n m e n t o f b a c ( e r i o l o g i c a l l y - qu)r, s -~ " disease -" ....... ztl one year . .vcovera a n d also in its rn a. )"n t c9n a" ))-s u b s e q u e n t (Ibur-vear) period o f l\'dlow-up. The results of two further controlled trials of intermittent chcn'totherapy' u n d e r t a k e n a( the Centre are presented,
()nee-Weekly StreptonDein and lsoniazid In th.e iirst, the twice-weekly regimen of streptomy~:in plu~ isoniazid (SHI",V:j was c ~ m p a r c d with once-~Leeklv streptomycin Flu., isoniazid (,. !t(.)\~. }. In. th.e S H T W regimen, s t r e p t o m y c i n in a.high d o , a g e of ! g. or in a. low dos:U~c of t11:'75 ~z. plt~,; ; . . .body-weight, were given togelhcr t~alc~-~.c,.kly. --,, "," ' " N :[ t C ) W reai.,nen, the isoniazid lS.. mg.:'kg In t,tc same drugs in the same dosages were gi\:en logei.he.F onl.v once-weeTzly. In boih tl:c regim,:n,;.psrid o x i n e 6 rag. was a d m i n i s t e r e d with each dose of isoniazid. The xllocation of the patit,'nls to the txvo regimens and t,) the high and the lmv st, rcptornycln do~tge was d o n e at raitdon], l h e reason l\)r investigating the low d o s a a e of strclpt~rn)cir~, .mtmcly 0"75 g.. was in pi~rz [t:c,~us, e ' ~:"" o f an uncerIaiI~ty a b o u t the t0.xicitv o f I ~..,, <,{" streptomycin in the previotts study. In all, 286 p a t i e n t s with nev~'ly diagnosed, p u l m o m t r y tubereulo~,b, x~cre a d m i t t e d to l he c o m p a r i son. Forty-six pat~ent,a were excluded from the ~]~ain anatvsis, mainly on ar unt of initial d r u e rc,.,sta.~c . After these excltisio~ls, the:'e remain 2d{)pat)ents in th.e main amtly~,is. The two series were similar in the extent-of disease a n d the great majority.0J" p,~tients had .advan9s .. '," were also simil,tr ~n ~u..l.,~ct ced and c.avila'ted d~,.casc with. a positive s:..mt:a~ ," . ,. .Tile ~.r~,.~, --,~-v--. of age. sex ,. C I '.,s iv. gVil'.'; e r a' g,,. weiaht a n d weight: T h e . a ; '.' . . . o f. all . pata:nts .- " in the two s, 39 kg. (N5 lb.) All patients, were treated on an out-palient basis a l t e n d i n g the (;entre twice-weekly or onc.'e...on~,tz.~d weekly f o r their drugs. At each attendance, they t o o k their dose of i~ " ' ' u,~der the supervision o f a clinin nurse and then rec~eived an iz~jedtion o f streptomycin. The sludv was cc hdu,A.cd "doubleblind' in respect o f streptomycin dosao_,e so that no o t h e r memlwer of the clinic or the labora~,ory staff or lhe patienls knew the d os;~ges ol" streptomycin, All p a t i e n t s were followed up by serial . r a d i o g r a p h s and every m o n t h by bacteriological, e x a m i n a l i o n s o f three, s p u t u m :~pecimens, , " . ., ./k.:a, . 9 'x Practically all patients showed some rao~ograpme ~mprovemcnt. I m p r o v e m e n t was considerable or exceptional' in 76"." of pat:ient~ on tl~e twice-weekly regimen c o m p a r e d with 60':!.ii o n . t h e onceweekly, reg~men--,a statistically" signifidant difference (IP<0.01). In 'contrast, i m p r o v e m e n t in cavitatioh was b r o a d l y ' s i m i l a r in b o t h series" cavitation d i s a p p e a r e d in 49 o,,.:,,and .:- 43. o,.:.,,,.,a n d became li~ss in 47 o / a n d 47 ':'/ /' Quiescent d~.:.ease, t h a t is, all c u h u r e s ne~zative a.t 10, 11 a n d 12 m o n t h s , was attained by 92"~;oF patiefits on the twice-weekly, compared with 71 ~ of patients on the once-weekly regimen--a signifiant difference (P <0".01): active disease (that is, patients with. two or more positive cultures in the last .......
9
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ONCll-
W E E K I..Y ( ' i t I - ' M O T H I R A
PY
77
tllrce montl~s and natients Whos.e chemotherapy was changed lbr deterioration during the year) 8 '.?i~ and 2 8 , and tub~:~culous deata . , 1,o,, and ! 7% . Thus, the twice-v,,eekly regimen proved again to be of high. ctticacv: in contrast the once-weekly regimen proved unsatisl~ctorv. Streptomycin
Doxe a n d lsoniazid Inactivation
Halt" the patients in both the twice-weekly and the c-,nce-xsecklv'" ' " 9 series had received a high dosage of streptomycin and the other half a low dosage of streptomycin. The isoniazid inactivation rate was dctermincd tk~r all patients in the study. The condition on admission to treatment was similar l\'~r the slow and the rapid inactivators of isoniazid and for.the high and low dosage patients. Further th.e proporti.on of patients on the idgh do.v,~t:'j" wa,~ similar in the slow and- rapit~ inactivators and the proportion of slow inactiva'tors was similar.in the high and the low dosage patients. We shall tlterel\'~re examine the influence of these t w o ['actors. (,11 rc',t~,rfl-~C. . t o t r e a t m e ~ l t w i t h eg.ich o[" the two regimens. In the twice~ceklvregimen91'!~,ot'lheslowcomr)arcdwith. 92 ,,ofthe rapid inactivators and 91 ,, on the high de, sage and 92 ",, on the low dosage had quiescent disease. This shows that neither the isonia/id im~ctix':~ti{)n rate nor the streptomycin dosage inlluenced ~ts elticacy. lt'tus the tv0iee~aceklv rceim0n proved to bc both highly effective ttnd robust, in contrast, for the once-weekl,,: re-linen. S2 ",, of the .,,[o\~ compared v,ith 6',)':,i o1" the rapid inactivators had quiescent disease--a ,,igniticant d~tl'crcncc. C'~)n-.idcring .,,trcptomvsin dosage. 76'!;, on the high dosage and 67 {',; on the 1~)~ d{~.,,agc had quie,,cent disca,,c .... :t n{)n-signiticant diffc-ence. Thus the once-weekly regimen was ncitl,cr rohu,I n~r satisfactory.
Modilie~l Once-Weekly Regimens In the next :tudy, ~hich xvas in htct ~Lcontinuation of the study ~ust reported, two modilications of tllc r regimen ,.vevc made. one by adding a third drug. pyrazinamidc, and the other by ,,z,ix ing an initml da~l~ cour.,,c of strel'~tom\'cin plus i,,oniazid ll.)r four weeks. l h c lir~,t Ix~t) rcgiincns. SHIVv and SI-I()W. ~ve l~a\.e already considered. In the thiM. S H Z O W . in addilioi~ to ~,trep/om.vcin plus i',~>ni;mzid in the same dosages a.,, before, pyrazinamide 90 mg./kg. ~a,, ~i,o .gixcn at the ,,amc lime oncc-~eckly. In the fourth, S H / S H O W , streptomycin I g. or II .7r ~-."i~tu.,, i,,onktzid ill a unil'orm dosa,,ee of 400 me.. were given daily. R)r l\Sur weeks followed by tl~c t~l~cc-',~.ccklx rcginicn of,,trcpto.nL~cin plus isoniazid l\~r the remaining 48 weeks. In all the lout regimc1,s, pyrid~:xine 6 rag. was administered with every dose of isoniazid. In all. ~.-,. p;.tticnts v~crc admitted to the comparison Fiftv-l'our r)atlents ]lave been excluded from the main an,tlxsc." " .. ',, mainly,, for initial drtle., rcsi.stan~.,..-.~ After these exclusions there remain 394 patients for compari.~on. "lhc condition of the patients on admissic,n was similar in the four series. The two series were also similar in respect of age, sex and weight. lmpro\cmenl was considerable or exceptional. . in 78",, of S H T W patients. 73",,, of S H / S H O W . 65",, of SHZ()W and 57 '7, of SH()W patients. The differences Between S H O W and either of the lirst two regimens are statistically significant ( P < 0 - 0 1 , P<0-05). Bacteriologically quiescent dl ease was hi,.zhest (95",) on the twice-weekly re,,imen, compared with 8,'4':;; on SH/SH()W. and 66 {5, on SHOW. The differenc, e between S H T W and S H / S H O W and between S H Z O W and S H O W are sligh.t and not statisticallysignificant. In contrast, the differertees between either SHTW or S H / S H O W regimens and either,SH ZOW or S H O W are highly signiticant. Thus. the S H T W regimen proved yet again to be highly effective and the S H / S H O W was almost as el]'cctivc. On the other hand. the S H O W regimen p r o v e d t o be of poor efficacy and the addition.of" pyrazinamide resulted in little extra benefit. We shall now consider tim influence of isoniazid inactivation rate and of streptomycin dosage i r~ response to treatment. The condition on admission to treatmm~twas similar for the rapid and th.z slow inactivators of isoniazid and in the high and the. low dosage patients. For lhe S H T W regimen, 97 o,,.o,of the slow compared with 91%/,.,,of the rapid inactivators and 94'}4;
7b'.'
TUBERCLF.
SUPPLEMINT
on the high dosage compared with 96.",,i on the low dosage had quiescent disease, showing that neither isoniazid inactivation rate nor streptomycin dosage affected it,; efficacy. Thus the SHTW regimen again proved ~o be not only highly effective but also robust. in contrast, tbr the S|-I/SHOW regimen 95";; of the slow compared with 76"',, of the rapid inactivators had quiescent disease, a signilicant ditTerence, she,wing that the regimen is not robust in that its efficacy is influenced by isoniazid inactivation rate. P, egarding, streptomycin dosage, 92"".,, o11 the high compared with 84').~, on the low had quiescen', disease .....a non-significant dilTercnee. For the S | t O W regimen, 76".i of slow compared with 56'i, of rapid inactivators had quiescent disease, a substantial dilTerencc and addition of pyr,azinamide did not o,,:ercome this defect: thus for SHZ()W regimen. 87 ", of the slow compared with 5.3 ",, of the rapid had quiescent d i s c a s e ~ a significant di tlcrencc. Reg:t rding streptomycin dosage for the SHOW regimen, 69", I on tile high compared with 63",, on th.e low had quiescent di,,-', c,tsc,- a ngaa-signilicant dilTerence. For the SHZ(.)\~, tee.linen reduction in streplom.~cin dosage did not affect if: efficacy, for 72",, on the high compared with 78"] on the low dosage had quiescent disease. l'oxicity Streptom,cin toxicity was not a prc,~blem, as reduction in do.,,agc was nccc sarx in only live patients oll the high and three on the low dosage. Streptomycin ,,va,~discontin~Jcd in two of the live patients on high dosage. Conclusion In conclusion, these t~vo .,,tudics ha,,c rcailirmed the high efficacy (,f the twice-~vcckly regimen ()i" streptom3cin plus isoniazid. Moreover. th,ey ha~.e sh~);~n that it 1,~ at robust t-eeinlcn in that it,, efficacy is uninltuenccd by the rate of irtactivaticm of isoniazid in the p,iticnts and by minor cil:.[n .ec,, in streptomycin dosage. In contrast, the once-weekl\ regimen of streptomycin plus isoniazid proved to be unsatisfactory and addition o!" a. third drug. p3'razinanaide. 1.o it rcsultcd in little extra l~nefit. On the other hand. the addition of daily streptom.,,'cin plus i,,oniazid for an initial period of four weeks enh;mccd its ellicacy ~o almost that of the t~vic,.'-~cckly reeimcn, l t()~vever, it proved to be "marginal chemotherapy' in that the rate of inactivation of isoniazid and possibly also s)rcptomycin dosage were critical for the etIicacy of the regimen. It may. thcrcfo'rc, prnvc less clTccti:e in communities wt~ere rapid inactivators of i~oniazid arc more frequent and possibly al,,o in patients heavier than in Madras.
M A D R A S S T U D Y O F S U P E R V I S E D ONCE-V~I:,EKI21' C'I-IEMOTHERAi:)Y IN T H E T R E A T M E N T O F P U L S I O N A R Y TUBERCUIX),'SIS": L A B O R A T O R Y A S P E C T S By S, P. TRI)'AT~]'V .front the I'Mwrculo.~is Chc)m)thcrapy C),ntrr'." ,~Iadras. huh'a
In these trials there were four regimens: in the tirst trial, two regimens, SHTW and SHOW, were comt:mred: in the s.econdtrial: lbur regimens, SHTW, SHOW, SFtZOW and SH/SHOW, were compared. We shall now consider the results cf isoniazid and streptomycin sensitivity te:sts in a total of 461 patients admitted to bofh trials. Three specimens of sputum were examined by smear a n d c u l t u r e at each month, of treatment. Sensitivity tests for streptornycin and isoniazid were set up
on one positive culture at each month from tl~ree months onwards. A culture was reported as resistant to isoniazid if the minimal inhibitory concentration (MIC) was I !J.g./ml. or more, i.e., if the culture yielded at least 20 colonies on isoniazid 0.2 p.g./ml. Resistance to streptomycin was reported if tile resistance ratio ( R R ) was eig",~.' or more, or an RR of four was followed by an R R o f a t least four.
T U 1~i: R C LI::. S U e P Z,!:;M!~S l"
~IADRAS STUDY TREATMENT
OF SUPERVISED OF I ' U L M O N A R Y
O N C E - V V E E K L Y C H F M O I ' I - I F . R A P Y IN T I I E TUBERCULOSIS" CI.IN1CAI, ASPECTS
By N. K. M:!x(:)x lkom the 7"tdwrcuhzvis Ctwmothc,'ap)' (~,ntre, Ma~h"ar. Indk~
'~ "'" (] ][i [I [) ~ [ t16 Tuberculosis ( ~" , h ~."m t The first c o n t i ' o ~ t study o f i n t e r m i t t e n t I c n c m o t h c r , ~ .') carried therapy Centre \~,~',"-~"ac o m p a r i s o n o f s t r e p t o n l y c i n plu,~ isoniazid given together twice-weekly with a s t a n d a r d oral daily regimen of i~,onjazid plus PAS, in the twicc-weekIr regimen, streptomS.cin was given in a dosa~,e of 1 t~. t o g e t h e r witi~ isoniazid in a dosage of approxinlatelv 14 ,, wei~zht T h e twice-weekly,, regim'en was fi)und to be at ,cast as effective as the daily " - , "; both in the a t t a i n m e n t o f b a c ( e r i o l o g i c a l l y - qu)r, s -~ " disease -" ....... ztl one year . .vcovera a n d also in its rn a. )"n t c9n a" ))-s u b s e q u e n t (Ibur-vear) period o f l\'dlow-up. The results of two further controlled trials of intermittent chcn'totherapy' u n d e r t a k e n a( the Centre are presented,
()nee-Weekly StreptonDein and lsoniazid In th.e iirst, the twice-weekly regimen of streptomy~:in plu~ isoniazid (SHI",V:j was c ~ m p a r c d with once-~Leeklv streptomycin Flu., isoniazid (,. !t(.)\~. }. In. th.e S H T W regimen, s t r e p t o m y c i n in a.high d o , a g e of ! g. or in a. low dos:U~c of t11:'75 ~z. plt~,; ; . . .body-weight, were given togelhcr t~alc~-~.c,.kly. --,, "," ' " N :[ t C ) W reai.,nen, the isoniazid lS.. mg.:'kg In t,tc same drugs in the same dosages were gi\:en logei.he.F onl.v once-weeTzly. In boih tl:c regim,:n,;.psrid o x i n e 6 rag. was a d m i n i s t e r e d with each dose of isoniazid. The xllocation of the patit,'nls to the txvo regimens and t,) the high and the lmv st, rcptornycln do~tge was d o n e at raitdon], l h e reason l\)r investigating the low d o s a a e of strclpt~rn)cir~, .mtmcly 0"75 g.. was in pi~rz [t:c,~us, e ' ~:"" o f an uncerIaiI~ty a b o u t the t0.xicitv o f I ~..,, <,{" streptomycin in the previotts study. In all, 286 p a t i e n t s with nev~'ly diagnosed, p u l m o m t r y tubereulo~,b, x~cre a d m i t t e d to l he c o m p a r i son. Forty-six pat~ent,a were excluded from the ~]~ain anatvsis, mainly on ar unt of initial d r u e rc,.,sta.~c . After these excltisio~ls, the:'e remain 2d{)pat)ents in th.e main amtly~,is. The two series were similar in the extent-of disease a n d the great majority.0J" p,~tients had .advan9s .. '," were also simil,tr ~n ~u..l.,~ct ced and c.avila'ted d~,.casc with. a positive s:..mt:a~ ," . ,. .Tile ~.r~,.~, --,~-v--. of age. sex ,. C I '.,s iv. gVil'.'; e r a' g,,. weiaht a n d weight: T h e . a ; '.' . . . o f. all . pata:nts .- " in the two s, 39 kg. (N5 lb.) All patients, were treated on an out-palient basis a l t e n d i n g the (;entre twice-weekly or onc.'e...on~,tz.~d weekly f o r their drugs. At each attendance, they t o o k their dose of i~ " ' ' u,~der the supervision o f a clinin nurse and then rec~eived an iz~jedtion o f streptomycin. The sludv was cc hdu,A.cd "doubleblind' in respect o f streptomycin dosao_,e so that no o t h e r memlwer of the clinic or the labora~,ory staff or lhe patienls knew the d os;~ges ol" streptomycin, All p a t i e n t s were followed up by serial . r a d i o g r a p h s and every m o n t h by bacteriological, e x a m i n a l i o n s o f three, s p u t u m :~pecimens, , " . ., ./k.:a, . 9 'x Practically all patients showed some rao~ograpme ~mprovemcnt. I m p r o v e m e n t was considerable or exceptional' in 76"." of pat:ient~ on tl~e twice-weekly regimen c o m p a r e d with 60':!.ii o n . t h e onceweekly, reg~men--,a statistically" signifidant difference (IP<0.01). In 'contrast, i m p r o v e m e n t in cavitatioh was b r o a d l y ' s i m i l a r in b o t h series" cavitation d i s a p p e a r e d in 49 o,,.:,,and .:- 43. o,.:.,,,.,a n d became li~ss in 47 o / a n d 47 ':'/ /' Quiescent d~.:.ease, t h a t is, all c u h u r e s ne~zative a.t 10, 11 a n d 12 m o n t h s , was attained by 92"~;oF patiefits on the twice-weekly, compared with 71 ~ of patients on the once-weekly regimen--a signifiant difference (P <0".01): active disease (that is, patients with. two or more positive cultures in the last .......
9
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.
/ 13,
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O"
"1,~
t
,
"
'
.'
ONCll-
W E E K I..Y ( ' i t I - ' M O T H I R A
PY
77
tllrce montl~s and natients Whos.e chemotherapy was changed lbr deterioration during the year) 8 '.?i~ and 2 8 , and tub~:~culous deata . , 1,o,, and ! 7% . Thus, the twice-v,,eekly regimen proved again to be of high. ctticacv: in contrast the once-weekly regimen proved unsatisl~ctorv. Streptomycin
Doxe a n d lsoniazid Inactivation
Halt" the patients in both the twice-weekly and the c-,nce-xsecklv'" ' " 9 series had received a high dosage of streptomycin and the other half a low dosage of streptomycin. The isoniazid inactivation rate was dctermincd tk~r all patients in the study. The condition on admission to treatment was similar l\'~r the slow and the rapid inactivators of isoniazid and for.the high and low dosage patients. Further th.e proporti.on of patients on the idgh do.v,~t:'j" wa,~ similar in the slow and- rapit~ inactivators and the proportion of slow inactiva'tors was similar.in the high and the low dosage patients. We shall tlterel\'~re examine the influence of these t w o ['actors. (,11 rc',t~,rfl-~C. . t o t r e a t m e ~ l t w i t h eg.ich o[" the two regimens. In the twice~ceklvregimen91'!~,ot'lheslowcomr)arcdwith. 92 ,,ofthe rapid inactivators and 91 ,, on the high de, sage and 92 ",, on the low dosage had quiescent disease. This shows that neither the isonia/id im~ctix':~ti{)n rate nor the streptomycin dosage inlluenced ~ts elticacy. lt'tus the tv0iee~aceklv rceim0n proved to bc both highly effective ttnd robust, in contrast, for the once-weekl,,: re-linen. S2 ",, of the .,,[o\~ compared v,ith 6',)':,i o1" the rapid inactivators had quiescent disease--a ,,igniticant d~tl'crcncc. C'~)n-.idcring .,,trcptomvsin dosage. 76'!;, on the high dosage and 67 {',; on the 1~)~ d{~.,,agc had quie,,cent disca,,c .... :t n{)n-signiticant diffc-ence. Thus the once-weekly regimen was ncitl,cr rohu,I n~r satisfactory.
Modilie~l Once-Weekly Regimens In the next :tudy, ~hich xvas in htct ~Lcontinuation of the study ~ust reported, two modilications of tllc r regimen ,.vevc made. one by adding a third drug. pyrazinamidc, and the other by ,,z,ix ing an initml da~l~ cour.,,c of strel'~tom\'cin plus i,,oniazid ll.)r four weeks. l h c lir~,t Ix~t) rcgiincns. SHIVv and SI-I()W. ~ve l~a\.e already considered. In the thiM. S H Z O W . in addilioi~ to ~,trep/om.vcin plus i',~>ni;mzid in the same dosages a.,, before, pyrazinamide 90 mg./kg. ~a,, ~i,o .gixcn at the ,,amc lime oncc-~eckly. In the fourth, S H / S H O W , streptomycin I g. or II .7r ~-."i~tu.,, i,,onktzid ill a unil'orm dosa,,ee of 400 me.. were given daily. R)r l\Sur weeks followed by tl~c t~l~cc-',~.ccklx rcginicn of,,trcpto.nL~cin plus isoniazid l\~r the remaining 48 weeks. In all the lout regimc1,s, pyrid~:xine 6 rag. was administered with every dose of isoniazid. In all. ~.-,. p;.tticnts v~crc admitted to the comparison Fiftv-l'our r)atlents ]lave been excluded from the main an,tlxsc." " .. ',, mainly,, for initial drtle., rcsi.stan~.,..-.~ After these exclusions there remain 394 patients for compari.~on. "lhc condition of the patients on admissic,n was similar in the four series. The two series were also similar in respect of age, sex and weight. lmpro\cmenl was considerable or exceptional. . in 78",, of S H T W patients. 73",,, of S H / S H O W . 65",, of SHZ()W and 57 '7, of SH()W patients. The differences Between S H O W and either of the lirst two regimens are statistically significant ( P < 0 - 0 1 , P<0-05). Bacteriologically quiescent dl ease was hi,.zhest (95",) on the twice-weekly re,,imen, compared with 8,'4':;; on SH/SH()W. and 66 {5, on SHOW. The differenc, e between S H T W and S H / S H O W and between S H Z O W and S H O W are sligh.t and not statisticallysignificant. In contrast, the differertees between either SHTW or S H / S H O W regimens and either,SH ZOW or S H O W are highly signiticant. Thus. the S H T W regimen proved yet again to be highly effective and the S H / S H O W was almost as el]'cctivc. On the other hand. the S H O W regimen p r o v e d t o be of poor efficacy and the addition.of" pyrazinamide resulted in little extra benefit. We shall now consider tim influence of isoniazid inactivation rate and of streptomycin dosage i r~ response to treatment. The condition on admission to treatmm~twas similar for the rapid and th.z slow inactivators of isoniazid and in the high and the. low dosage patients. For lhe S H T W regimen, 97 o,,.o,of the slow compared with 91%/,.,,of the rapid inactivators and 94'}4;
7b'.'
TUBERCLF.
SUPPLEMINT
on the high dosage compared with 96.",,i on the low dosage had quiescent disease, showing that neither isoniazid inactivation rate nor streptomycin dosage affected it,; efficacy. Thus the SHTW regimen again proved ~o be not only highly effective but also robust. in contrast, tbr the S|-I/SHOW regimen 95";; of the slow compared with 76"',, of the rapid inactivators had quiescent disease, a signilicant ditTerence, she,wing that the regimen is not robust in that its efficacy is influenced by isoniazid inactivation rate. P, egarding, streptomycin dosage, 92"".,, o11 the high compared with 84').~, on the low had quiescen', disease .....a non-significant dilTercnee. For the S | t O W regimen, 76".i of slow compared with 56'i, of rapid inactivators had quiescent disease, a substantial dilTerencc and addition of pyr,azinamide did not o,,:ercome this defect: thus for SHZ()W regimen. 87 ", of the slow compared with 5.3 ",, of the rapid had quiescent d i s c a s e ~ a significant di tlcrencc. Reg:t rding streptomycin dosage for the SHOW regimen, 69", I on tile high compared with 63",, on th.e low had quiescent di,,-', c,tsc,- a ngaa-signilicant dilTerence. For the SHZ(.)\~, tee.linen reduction in streplom.~cin dosage did not affect if: efficacy, for 72",, on the high compared with 78"] on the low dosage had quiescent disease. l'oxicity Streptom,cin toxicity was not a prc,~blem, as reduction in do.,,agc was nccc sarx in only live patients oll the high and three on the low dosage. Streptomycin ,,va,~discontin~Jcd in two of the live patients on high dosage. Conclusion In conclusion, these t~vo .,,tudics ha,,c rcailirmed the high efficacy (,f the twice-~vcckly regimen ()i" streptom3cin plus isoniazid. Moreover. th,ey ha~.e sh~);~n that it 1,~ at robust t-eeinlcn in that it,, efficacy is uninltuenccd by the rate of irtactivaticm of isoniazid in the p,iticnts and by minor cil:.[n .ec,, in streptomycin dosage. In contrast, the once-weekl\ regimen of streptomycin plus isoniazid proved to be unsatisfactory and addition o!" a. third drug. p3'razinanaide. 1.o it rcsultcd in little extra l~nefit. On the other hand. the addition of daily streptom.,,'cin plus i,,oniazid for an initial period of four weeks enh;mccd its ellicacy ~o almost that of the t~vic,.'-~cckly reeimcn, l t()~vever, it proved to be "marginal chemotherapy' in that the rate of inactivation of isoniazid and possibly also s)rcptomycin dosage were critical for the etIicacy of the regimen. It may. thcrcfo'rc, prnvc less clTccti:e in communities wt~ere rapid inactivators of i~oniazid arc more frequent and possibly al,,o in patients heavier than in Madras.
M A D R A S S T U D Y O F S U P E R V I S E D ONCE-V~I:,EKI21' C'I-IEMOTHERAi:)Y IN T H E T R E A T M E N T O F P U L S I O N A R Y TUBERCUIX),'SIS": L A B O R A T O R Y A S P E C T S By S, P. TRI)'AT~]'V .front the I'Mwrculo.~is Chc)m)thcrapy C),ntrr'." ,~Iadras. huh'a
In these trials there were four regimens: in the tirst trial, two regimens, SHTW and SHOW, were comt:mred: in the s.econdtrial: lbur regimens, SHTW, SHOW, SFtZOW and SH/SHOW, were compared. We shall now consider the results cf isoniazid and streptomycin sensitivity te:sts in a total of 461 patients admitted to bofh trials. Three specimens of sputum were examined by smear a n d c u l t u r e at each month, of treatment. Sensitivity tests for streptornycin and isoniazid were set up
on one positive culture at each month from tl~ree months onwards. A culture was reported as resistant to isoniazid if the minimal inhibitory concentration (MIC) was I !J.g./ml. or more, i.e., if the culture yielded at least 20 colonies on isoniazid 0.2 p.g./ml. Resistance to streptomycin was reported if tile resistance ratio ( R R ) was eig",~.' or more, or an RR of four was followed by an R R o f a t least four.