The treatment of patients with initial isoniazid resistance 2011 INTERTB Meeting, St George s, London Patrick Phillips, MRC Clinical Trials Unit DA Mitchison, AJ Nunn. 21 st October 2011
Outline Background Monotherapy with isoniazid or rifampicin Bacterial populations during treatment Isoniazid alone in the continuation phase Outcomes of treating patients with initial isoniazid resistance The effect of adding drugs in the continuation phase Conclusions
Abbreviations Isoniazid: INH / H Ethambutol: EMB / E Rifampicin: RIF / R Streptomycin: STR / S Pyrazinamide: PZA / Z
Background Estimated 14% of incident TB cases with INH resistance outside Eastern Europe 45% in Eastern Europe (Jenkins, PLoS One, 2011) 2009 WHO treatment guidelines recommend adding EMB in the continuation phase in areas with high levels of INH resistance: 2ERHZ/4HR 2ERHZ/4HRE How do outcomes compare in those with initial resistance to INH? What are the risks of further acquired RIF resistance during standard therapy?
Monotherapy with isoniazid or rifampicin Total Cultures with resistance at month: 1 2 3 4 Patients with resistant strains INH (daily for 12m) 1 84 15% 56% 76% 97% 47% at 12 mo. RIF (daily for 60 days 2 49 7% 94% 100% - 33% at 3 mo. 1 Madras TB Chemotherapy Centre, Bull WHO. 1960. 2 Nitti V, Antibiot Chemother. 1970.
Bacterial populations during treatment A population of at least: 3.5 x 10 6 is needed for a single mutant resistant to INH to occur 3.1 x 10 8 is required for a mutant resistant to RIF to occur (David HL, Appl. Microbiol., 1970)
Bacterial populations during treatment Example from OFLOTUB Phase II Rustomjee R et al., 2008 Before treatment At 8 weeks Patients 213 18 Mean 7.05 2.46 No patient had a residual bacterial population at 8 weeks sufficiently large to contain RIF resistant Max. SD 9.25 0.95 4.19 0.95 mutants. Content of viable M. tuberculosis before and after an initial 2-month phase of 4-drug therapy. log CFU/ml sputum
Isoniazid alone in the continuation phase In a randomised controlled trial in Tanzania (T/BMRC, 1996), two 7 month regimens were compared: HRZ (6 weeks) / H (24 weeks) HRZ (30 weeks) Of the 266 patients (135 H; 131 H(RZ)): Only 1 patient in each series had a positive culture at month 7 with the emergence of INH resistance. Thus, failure and emergence of resistance was a rare phenomenon despite a shorter than usual intensive phase.
Outcomes of treating patients with initial isoniazid resistance Review of randomised trials including patients with initial INH resistance Illustrative, not systematic BMRC trials and IUATLD Studies A and C Broadly similar trial design and conduct, so high level of homogeneity 9 trials, 13 regimens
Outcomes of treating patients with initial isoniazid resistance All six month regimens: 4-drug intensive phase Daily or 3-weekly continuation phase of RH Unfavourable outcome is bacteriologically confirmed failure or relapse
Outcomes of treating patients with initial isoniazid resistance Study Regimen INH susceptible INH resistant Assessed Unfav (N) Assessed Unfav (N) Algeria 1 2HRZE/4HR 131 4 15 0 Algeria 2 2SHRZ/4HR 488 15 19 0 East Africa 5 2SHRZ/4HR 166 4 11 2 Singapore 1 2SHRZ/4HR 80 2 2 0 Singapore 2 2SHRZ/4H 3 98 2 5 0 Singapore 2 1SHRZ/5H 3 94 1 7 0 Singapore 3 2SHRZ(C)/4H 3 46 3 0 0 Singapore 3 2SHRZ(S)/4H 3 47 0 0 0 Singapore 3 1SHRZ(C)/5H 3 42 2 3 1 Singapore 3 1SHRZ(S)/5H 3 46 1 1 0 HK Rifapentine 2SHRZ/4H 3 165 7 7 0 IUATLD Study A 2EHRZ/4HR 190 7 23 1 IUATLD Study C 2EHR/4HR 1005 52 (5%) 127 11 (9%) Total 2598 100 (4%) 220 15 (7%)
Outcomes of treating patients with initial isoniazid resistance Unfavourable outcomes: INH-susceptible: 100 (4%) INH-resistant: 15 (7%) p=0.083 (Mantel-Haenszel test, stratified by trial) Acquisition of RIF resistance: INH-susceptible: 3 (6%) of 51 INH-resistant: 2 (22%) of 9 p=0.105 (Mantel-Haenszel test) High proportion of patients from IUATLD Study C, but no evidence of heterogeneity between trials (p=0.31)
Sub-group analysis by HIV status HIV Status HIV Negative Study INH susceptible INH resistant Assessed Unfav (N) Assessed Unfav (N) IUATLD Study A 130 5 (4%) 15 0 (0%) IUATLD Study C 944 44 (5%) 118 9 (8%) Overall 1074 49 (5%) 133 9 (7%) Acquired RIF resistance 0 (0%) / 26 1 (17%) / 6 HIV Positive IUATLD Study A 5 0 (0%) 3 0 (0%) IUATLD Study C 60 9 (15%) 9 2 (22%) Overall 65 9 (14%) 12 2 (17%) Acquired RIF resistance 0 (0%) / 2 0 (0%) / 0 On the limited evidence, HIV infection can only partly be responsible for the apparent increased risk of an unfavourable result in those with initial INH resistance.
Sub-group analysis by type of unfavourable outcome Unfavourable outcomes that were treatment failures: MRC studies: 2 (5%) of 44 Study A: 5 (10%) of 52 Study C: 23 (20%) of 115 Increase in Study C due to: Less frequent bacteriology About half failures/relapses not based on robust bacteriology
The effect of adding drugs in the continuation phase Study Regimen INH susceptible Assessed Unfav (N) Assessed INH resistant Unfav (N) Singapore 1 2SHRZ/4HRZ 78 0 2 0 Hong Kong 4 2S 3 H 3 Z 3 / 4H 3 S 3 (Z 3 ) 633 22 55 6 Hong Kong 3 6H 3 S 3 Z 3 151 2 14 0 Hong Kong 3 6H 3 E 3 Z 3 160 4 14 2 Hong Kong 3 6HREZ 163 2 19 0 Hong Kong 3 6H 3 E 3 S 3 Z 3 152 1 15 0 Total 1337 31 (2%) 120 8 (7%) Acquired RIF resistance 2 (6%) / 31 2 (25%) / 8
Conclusions 1. The bacterial population is likely too small after 2- months of treatment for RIF-resistant mutants to exist Unless bacterial re-growth is allowed to occur in the continuation phase Mutants resistant to INH are ~100 times more prevalent than those resistant to RIF. 2. The favourable rate in patients with initial INH resistance is not much lower than those without initial INH resistance: 93% compared with 96%. 3. This is strengthened by the Tanzanian trial showing that the development of resistance was very rare with INH alone in the continuation phase.
Conclusions 4. The addition of PZA, STR or EMB or a combination to the continuation phase did not reduce the occurrence of an unfavourable outcome or the proportion of failure strains that were resistant to RIF. 5. However, there could be a role for PZA in the continuation phase as there is limited evidence that it could prevent treatment failure. 6. Randomised controlled trials are needed to indentify the best treatment for patients with mono- and poly-drug resistance.
References Mitchison DA, Phillips PPJ, Jindani A, Lienhardt C, Nunn AJ. Outcomes of treatment with a rifampicin/isoniazid continuation in patients with organisms initially resistant to isoniazid. 2011. [Submitted] Jenkins HE, Zignol M, Cohen T. Quantifying the burden and trends of isoniazid resistant tuberculosis, 1994-2009. PLoS One. 2011; 6(7): e22927. Madras Tuberculosis Chemotherapy Centre. A concurrent comparison of isoniazid plus PAS with three regimens of isoniazid alone in the domiciliary treatment of pulmonary tuberculosis in South India. Bull WHO. 1960; 23: 535-85. David HL. Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Microbiol. 1970; 20(5): 810-4. Nitti V. Experimental and clinical studies on the antituberculous activity of rifampicin alone or combined with other drugs. Antibiot Chemother. 1970; 16: 444-70. Tanzania/British Medical Research Council. A controlled trial of a 4-weekly supplement of rifampicin, pyrazinamide and streptomycin in the continuation phase of a 7-month daily chemotherapy regimen for pulmonary tuberculosis. Tanzania/British Medical Research Council Collaborative Investigation. S Afr Med J. 1996; 86(8): 960-5. Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2008; 12: 128-38(11).