1. Guy E. Thwaites, M.R.C.P., Nguyen Duc Bang, M.D., Nguyen Huy Dung, M.D.,Hoang Thi Quy, M.D., Do Thi Tuong Oanh, M.D., Nguyen Thi Cam Thoa, M.D.,Nguyen Quang Hien, M.D., Nguyen Tri Thuc, M.D., Nguyen Ngoc Hai, M.D.,Nguyen Thi Ngoc Lan, Ph.D., Nguyen Ngoc Lan, M.D., Nguyen Hong Duc, M.D.,Vu Ngoc Tuan, M.D., Cao Huu Hiep, M.D., Tran Thi Hong Chau, M.D., Dexamethasone for the Treatment of Tuberculous Meningitis in Adolescents and Adults R1. 하효정 / Pf. 임효석 N Engl J Med 2004;351:1741-51.

2. Introduction Tuberculous meningitis : the severest form of infection with Mycobacterium tuberculosis : Corticosteroids reduced CSF inflammation & time to recovery in patients with tuberculous meningitis A meta-analysis of all randomized controlled trials : Corticosteroids were effective in reducing the risk of death in children But not in patients over 14 years of age  Purpose Therefore, we conducted a double-blind, placebo controlled trial to determine whether adjunctive dexamethasone therapy improves the outcome in patients over 14 years of age who have tuberculous meningitis, with or without HIV infection.

3. Methods (1) - 1 Study Participants Two centers in Ho Chi Minh City, Vietnam Over 14 years of age with clinical evidence of meningitis (Nuchal rigidity + CSF abnormalities) Tuberculous meningitis Definite : Acid-fast bacilli were seen in the CSF Probable : One or more of the following 1. Suspected active pulmonary tuberculosis on chest radiography 2. Acid-fast bacilli found in any specimen other than CSF 3. Clinical evidence of other extrapulmonary tuberculosis

4. Methods (1) – 2 Study Participants Tuberculous meningitis was defined as … “possible” in patients with at least four of the following 1. A history of tuberculosis 2. Predominance of lymphocytes in the CSF 3. Duration of illness (> 5days ) 4. CSF glucose/plasma glucose < 0.5 5. Altered consciousness, 6. Yellow CSF 7. Focal neurologic signs Patients were not eligible ….. 1. Corticosteroids were contraindicated 2. Had received more than one dose corticosteroid 3. More than 30 days of antituberculosis chemotherapy

5. Methods (2) Laboratory investigations CSF specimens : stained and cultured by pyogenic bacteria, fungi, and mycobacteria Isolates of M. tuberculosis : tested for susceptibility to INH, RFP, PZA, ETB, SM antibodies to HIV and hepatitis B surface antigen, CD4 lymphocyte counts

6. Methods (3) -1 Treatments 3 months [oral INH (5 mg/kg), RFP (10 mg/kg), PZA (25 mg/kg), and IM SM (20 mg/kg) ] 6 months [ INH, RFP, PZA at the same daily doses] In the case of HIV infected patients …. 1. Ethambutol (20 mg/kg) SM 2. Added to the regimen for 3 months

7. Methods (3) - 2 Treatments Patients were stratified on entry according to the British Medical Research Council criteria ( Gr. I, II, III) Each grade : (randomly) dexamethasone sodium phosphate vs placebo day Grade II or III : IV treatment (4weeks) (0.4, 0.3, 0.2, 0.1)  Oral treatment (4weeks) (4,3, 2, 1) Grade I : IV treatment (2weeks) (0.3,0.2)  Oral treatment (4weeks) (0.1 mg/kg, 3,2, 1)

8. Methods (3) Assessment of outcome Primary outcome : Death or severe disability 9 months after randomization (the Rankin scale & the simple questions) Required help with everyday activities  Yes : severely disabled  No : Ask the illness had left them with any other problems  Yes : Intermediate  No : Good The Rankin scale : Good (0), Intermediate (1, 2), severe disability (3, 4, 5) Patients were assessed at 1, 2, 6 and 9 months after randomization

9. Methods (3) Assessment of outcome Secondary outcome : Coma-clearance time Fever-clearance time Time to discharge from the hospital Time to relapse The presence of focal neurologic deficit These outcome measures were assessed daily by means of clinical examination by the principal investigator or by the physicians trained to assess disability.

10. Methods (4) Statistical Analysis The outcomes : Intention to- treat analyses & Prespecified subgroup analyses. Survival experiences : Kaplan–Meier The equality of the survival distributions : The log-rank test The RR of death between the treatment groups : Cox regression The combined outcome of death or severe disability : Chi-square test The OR for the outcome : Logistic regression Times to fever clearance, coma clearance, relapse, and discharge : Kaplan–Meier estimates & log-rank test

11. RESULTS

12. RESULTS (1) April 4, 2001, to March 29, 2003

13. RESULTS (2)- Baseline characteristics of the patients M. Tuberculosis in CSF or another : 170 patients (31.2%)  99 (58.2% ) susceptible to all first-line (placebo : Dexa = 51 : 48 )  60 (35.3 %) resistant to SM,INH, or both (placebo : Dexa =29 : 31)  1 mono-resistant to RFP (in the dexamethasone )  10 (5.9%) resistant to at least INH,RFP (placebo : Dexa =3 : 7)

14. RESULTS (3) -Analysis of the primary outcome 0.27 0.96 0.44

15. RESULTS (3) - Analysis of secondary outcomes Time to fever clearance : significantly shorter ( 9 vs 11 ; P=0.03), Time to coma clearance : no significant difference ( 9 vs. 11 ;P=0.23) The time to hospital discharge : no significant difference (44 vs. 54 ; P=0.57) Relapse occurred in 89 patients (16.3 %) : 41 (15.0%) vs 48 (17.7 %) (P=0.42), Time to relapse : no significant difference ( 41 vs 38 ;P=0.12) Hemiparesis resolved : 36 of 48 patients (75.0 %)  30 of 37 patients (81.1 %) Paraparesis resolved : 19 of 28 (67.9 %) vs 9 of 11 (81.8 %) In patients without…. Hemiparesis : 14 of 226 (6.2 %) vs 11 of 234 (4.7%) (P=0.48) Paraparesis : 11 of 246 (4.5%) vs 11 of 260 (4.2 %) (P=0.89) Hearing loss or Reduced visual acuity : no significant difference

16. RESULTS (4)- Prespecified subgroup analyses  Fatality rate : HIV infected > uninfected (65.3 % vs.28.4 %, P<0.001)

17. RESULTS (6) - Adverse events Significantly more adverse events : 214 of 271 vs 186 of 274, P=0.005 More severe in the placebo group :45 of 271 vs 26 of 274, P=0.02 Drug dose or regimen was altered : 81 vs 62

18. Discussion The results of this study show that adjunctive treatment with dexamethasone improved survival in patients over 14 years of age with TB meningitis, but when the outcome measure was broadened to death or severe disability, there was no significant benefit. Dexamethasone did not affect the incidence or resolution of hemiparesis, paraparesis, or quadriparesis, which are the most common causes of severe disability due to tuberculous meningitis Dexamethasone may improve outcomes by reducing the frequency of adverse events that necessitate a change in the antituberculosis-drug dose or regimen — severe clinical hepatitis, in particular Studies of pulmonary tuberculosis showed that corticosteroids reduced the incidence of severe drug-hypersensitivity reactions ( but, has not been documented for other forms )

19. Discussion The 98 HIV-infected patients recruited to our trial were severely immunocompromised, and none were treated with antiretroviral drugs  ? ? The numbers of HIV-infected patients were too small for us to confirm or reject confidently a treatment effect, and the results may not be generalizable to populations with access to antiretroviral drugs.  Future studies should include patients who are taking antiretroviral drugs, and such patients should be monitored carefully for opportunistic infections.

20. CONCLUSION In summary, this study provides clinical evidence that early treatment with dexamethasone and antituberculosis drugs improves survival among patients over 14 years of age with tuberculous meningitis, regardless of disease severity. However, dexamethasone probably does not prevent severe disability in the survivors.

21. Thank you !