Systematic Review and Meta-Analysis of Treatment of Latent TB Infection to Reduce Progression to Multidrug-Resistant Tuberculosis

Transcription

1 Systematic Review and Meta-Analysis of Treatment of Latent TB Infection to Reduce Progression to Multidrug-Resistant Tuberculosis Suzanne M. Marks, Sundari R. Mase, Sapna Bamrah Morris Brown Bag Presentation to CDC/DTBE, August 20, 2015

2 Background Current guidance is based on expert opinion Evidence-based recommendations are lacking because published data consist of small observational studies TB incidence in contacts treated for presumed MDR LTBI is unknown Treatment discontinuation due to adverse effects has not been systematically documented

3 Current Guidance CDC. Management of Persons Exposed to Multidrug-resistant Tuberculosis. MMWR. 1992;41(RR- 11): no clinical data exist on the risks and benefits of regimens that do not include INH or RIF Persons at high-risk of progressing to TB (HIV+, immunosuppressed) treatment with 2 drugs since efficacy of preventive monotherapy with alternative drugs has not been demonstrated Persons who are not at high risk of progression, 2 options: No preventive therapy and provide clinical follow up for signs and symptoms Treatment with 2 drugs other than INH or RIF. If the source case strain is < 100% INH resistant, INH should be used If the source case strain is < 100% RIF resistant, RIF should be used Potential alternative regimens: 6-12 months (12 months for HIV+, immunosuppressed) of treatment with 2 drugs to which the isolate of the presumed source case is susceptible PZA/EMB (EMB to be used with caution in children) PZA/FQ FQ should only be used in children or pregnant females if potential benefits justify the potential side effects PAS, ETH, CYC are not recommended because of their high frequency of side effects and relatively low efficacy CDC. Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection. MMWR. 2000;49(RR-6): PZA/EMB or PZA/FQ for 6-12 months if the isolate is susceptible to these drugs 2 drugs to which the isolate of the presumed source case is susceptible

4 Current Guidance Curry National Tuberculosis Center. Drug-Resistant Tuberculosis: A Survival Guide for Clinicians LEV or MOX and a 2 nd susceptible drug; LEV or MOX alone Young children with presumed MDR-LTBI should be treated with a 2 to 3 drug regimen for 12 months, including a FQ if appropriate (monitor for joint pain, swelling, or decreased range of motion) ECDC Guidance: Management of Contacts of MDR TB and XDR TB Patients Cites 3 studies: Attamna, Kritski, and Schaaf it is not possible with the available evidence to support or reject preventive therapy Bob Horsburgh: ATS/CDC/IDSA LTBI group Current recommendations for treatment of contacts of patients with MDR-TB are based on expert opinion and do not meet GRADE criteria.[15,16] Therefore, we recommend neither for or against such treatment. WHO Guidelines on the management of LTBI serious limitations of the quality of evidence prevent drawing any recommendations on MDR-TB preventive therapy as a public health measure. Strict clinical observation and close monitoring for the development of active TB disease for at least two years is preferred over the provision of preventive treatment for contacts with MDR-TB cases.

5 Study Objectives To assess, using systematic review and metaanalysis, whether MDR-LTBI treatment is significantly associated with lower TB incidence among persons having contact with infectious MDR-TB patients and evidence of or presumed LTBI, compared with no medical treatment To examine treatment completion and adverse effects (AE)

6 Study Methods (1) Conducted a systematic review in Dec of published studies in English or Spanish of patients having contact with infectious MDR-TB cases, who had documented or presumed (for children <5 years of age or living with HIV) LTBI, treated or untreated MDR-TB LTBI Considered patients effectively treated if they were on one medication to which their MDR- TB strain was likely to be susceptible

7 Study Methods (2) Abstracted TB incidence data from studies presenting data both on patients treated and untreated, only on patients treated, and only on untreated patients. TB incidence was calculated as a proportion of persons treated versus untreated, and not by time, because only a few studies reported incidence by person-time. Selected studies that compared treatment versus non-treatment outcomes. We performed meta-analysis on data from studies reporting any TB incidence to estimate the pooled random effects relative risk (RR) of TB incidence and its 95% confidence using EpiSheet. Abstracted data on treatment completion, when available Abstracted data on adverse effects, and aggregated individual level adverse effect data by regimen, when available

8 Search Methods Searched publications through December 2014 in Pubmed, Embase, Cochrane Library, Google Scholar, Google Manually searched references of review articles Reviewed titles and abstracts, followed by reviewing full-texts of selected articles

9 Search Fields ("tuberculosis, multidrug-resistant"[mesh Terms] OR ("tuberculosis"[all Fields] AND "multidrug-resistant"[all Fields]) OR "multidrugresistant tuberculosis"[all Fields] OR ("multidrug"[all Fields] AND "resistant"[all Fields] AND "tuberculosis"[all Fields]) OR "multidrug resistant tuberculosis"[all Fields]) AND contacts[all Fields] AND ("therapy"[subheading] OR "therapy"[all Fields] OR "treatment"[all Fields] OR "therapeutics"[mesh Terms] OR "therapeutics"[all Fields])

10 Systematic Literature Review Inclusion Criteria Published journal articles that presented data on: contacts to patients with infectious MDR TB who have documented or assumed LTBI treatment of MDR TB LTBI

11 Exclusion Criteria Case reports with N < 10 Studies only reporting on diagnosis or treatment of MDR TB disease

12 95 references identified Systematic Review Process 64 references excluded after review of titles and abstracts: Studies reporting just MDR TB disease treatment Studies reporting diagnostic evaluations Case reports (<10 patients) 6 review articles excluded Full text reviewed for references 25 (23 articles and 2 conference abstracts) met inclusion criteria 22 articles full text reviewed 2 conference abstracts requested 1 article excluded due to insufficient data 6 articles included comparison of LTBI treatment vs. no treatment 16 articles analyzed separately: 10 single treatment arm 6 no treatment 2 conference abstracts describing treatment not obtained for review

13 6 Excluded Review Articles: References Manually Search for Inclusion 1. CDC. Management of persons exposed to multidrugresistant tuberculosis. MMWR Recomm Rep Jun 19;41(RR-11): European Centre for Disease Prevention and Control. Management of contacts of MDR TB and XDR TB patients. Stockholm: ECDC; Fraser A, Paul M, Attamna A, et al. Drugs for preventing tuberculosis in people at risk of multipledrug-resistant pulmonary tuberculosis. Cochrane Database Syst Rev 2006; CD

14 6 Excluded Review Articles: References Manually Search for Inclusion 4. Fraser A, Paul M, Attamna A, Leibovici L. Treatment of latent tuberculosis in persons at risk for multidrugresistant tuberculosis: systematic review. IJTLD 2006; 10: Langendam MW(1), Tiemersma EW, van der Werf MJ, Sandgren A. Adverse events in healthy individuals and MDR-TB contacts treated with anti-tuberculosis drugs potentially effective for preventing development of MDR-TB: a systematic review. PLoS One. 2013:8(1): e doi: /journal.pone Van der Werf MJ(1), Langendam MW, Sandgren A, Manissero D. Lack of evidence to support policy development for management of contacts of multidrugresistant tuberculosis patients: two systematic reviews. IJTLD. 2012: 16(3):

15 10 Studies of Only LTBI Treatment 1. Feja K, McNelley E, Tran C S, et al. Management of pediatricmultidrug-resistant tuberculosis and latent tuberculosis infections in New York City from 1995 to Pediatr Infect DisJ 2008; 27: Freier G(1), Wright A, Nelson G et al. Multidrug-resistant tuberculosis in military recruits. Emerg Infect Dis. 2006;12(5): Garcia-Prats AJ, Zimri K, Mramba Z, et al. Children exposed to multidrug-resistant tuberculosis at a home-based day care centre: a contact investigation. Int J Tuberc Lung Dis 2014; 18 (11): Horn DL, Hewlett D Jr, Alfalla C, et al. Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis. N Engl J Med Apr 28;330(17): Lou H X, Shullo M A, McKaveney T P. Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population. Pharmacotherapy 2002; 22: Miramontes R, Lambert L, Haddad MB, et al. Public health response to a multidrugresistant tuberculosis outbreak among Guatemalans in Tennessee, South Med J Sep;103(9): doi: /SMJ.0b013e3181eba Papastavros T, Dolovich LR, Holbrook A, et al. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. CMAJ 2002;167 (2) Ridzon R, Meador J, Maxwell R, et al. Asymptomatic hepatitis in persons who received alternative preventive therapy with pyrazinamide and ofloxacin. Clin Infect Dis Jun;24(6): Seddon JA(1), Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis 2013; 57: Younossian AB(1), Rochat T, Ketterer JP, Wacker J, Janssens JP. High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis. Eur Respir J Sep;26(3):462-4.

16 6 Studies of No Effective LTBI Treatment 1. Amanullah F, Ashfaq M, Khowaja S, et al. High tuberculosis prevalence in children exposed at home to drug-resistant tuberculosis. IJTLD. 2014; 18: Bayona J, Chavez-Pachas AM, Palacios E, et al. Contact Investigations as a Means of Detection and Timely Treatment of Persons with Infectious Multidrug-resistant Tuberculosis. IJTLD. 2003: 7(12):S501 S Becerra MC, Franke MF, Appleton SC, et al. Tuberculosis in Children Exposed at Home to Multidrug-resistant Tuberculosis. Pediatr Infect Dis J. 2013; 32: Kritski AL, Marques MJ, Rabahi MF, et al. Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 1996:153(1): Nitta AT(1), Knowles LS, Kim J, et al. Limited transmission of multidrugresistant tuberculosis despite a high proportion of infectious cases in Los Angeles County, California. Am J Respir Crit Care Med Mar 15;165(6): Pineiro Perez R, Mellado Pena MJ, Mendez Echevvaria A, et al. Exposicion a tuberculosis multirresistente: estudio y seguimiento de nueve ninos. An Pediatr (Barc). 2008;68(5):490-5.

17 6 Studies Comparing LTBI Tx vs. No Effective Tx 1. Bamrah S, Brostrom R, Fred D, et al. Treatment for Multidrug-Resistant Latent Tuberculosis Infection Federated States of Micronesia, IJTLD. 2014:18(8): Denholm JT(1), Leslie DE, Jenkin GA, et al. Long-term follow-up of contacts exposed to multidrug-resistant tuberculosis in Victoria, Australia, IJTLD. 2012:16(10): Schaaf et al. Evaluation of Young Children in Contact with Adult Multidrugresistant Pulmonary Tuberculosis: A 30-month Follow-up. Pediatrics. 2002; 109: Adler-Shohet et al. Management of Latent Tuberculosis Infection in Child Contacts of Multidrug-resistant Tuberculosis. Pediatric Infectious Disease Journal. 2014; 33: Attamna A, Chemtob D, Attamna S, et al. Risk of tuberculosis in close contacts of patients with multidrug resistant tuberculosis: a nationwide cohort. Thorax Mar;64(3): Williams B, Ramroop S, Shah P, et al. Management of Pediatric Contacts of Multidrug Resistant Tuberculosis in the United Kingdom, Pediatric Infectious Disease Journal. 2013;32:

18 Comparison Study #1 Bamrah S, Brostrom R, Dorina F, et al. Treatment for Multidrug- Resistant Latent Tuberculosis Infection Federated States of Micronesia, IJTLD. 2014:18(8): Setting: Chuuk, Micronesia Time period: Subjects: N=119 with LTBI of contacts of MDR-TB patients, median age of those starting treatment was 24 Study type: Prospective observational study with 3 years of follow up n=104 received 12 months daily treatment (mostly FQ: MOX/LEV alone, MOX/LEV with EMB, LEV with ETH) 93 (89%) completed Outcomes: No (0%) TB cases; 56 (54%) had AE (nausea, dizziness/headache, fatigue), 4 (4%) stopped due to AE (2 nausea, 1 muscle/joint pain, 1 HAV) n=15 refused LTBI Tx or discontinued Tx within 2 weeks. Outcomes: 3 (20%) TB cases

19 Details of Comparison Study #1 : Bamrah et al.

20 Comparison Study #2 Denholm JT, Leslie DE, Jenkin GA, et al. Long-term follow-up of contacts exposed to multidrug-resistant tuberculosis in Victoria, Australia, IJTLD. 2012:16(10): Setting: Victoria, Australia Time period: Subjects: N=49 with LTBI of 570 contacts to MDR-TB patients, median age 27 Study type: Retrospective review, retrieved isolates of index cases, ~5 years of follow up n=11 received effective ( 1 med to which their strain was susceptible) treatment with 1-2 meds for 6-9 months treated mostly MOX alone or with EMB; PZA with EMB, INH, or RIF; CIP alone or with PZA 9 (82%) completed Outcomes: No (0%) TB cases; 2 (18%) stopped due to AE (1 itching, 1 nausea) n=38 considered not effectively treated Outcomes: 2 (5%) TB cases

21 Details of Comparison Study #2 : Denholm et al.

22 Comparison Study #3 Schaaf et al. Evaluation of Young Children in Contact with Adult Multidrug-resistant Pulmonary Tuberculosis: A 30-Month Followup. Pediatrics 2002; 109:765. Setting: Western Cape Province, South Africa Time period: Subjects: N=105 children < 5 yrs. of age, household contacts Study type: prospective observational study with 30 months of follow up n=41 received 3-4 drug combinations of INH/PZA/EMB/ETH (6 with OFL) for 6 months 41 (100%) completed 6 months Outcomes: 2 (5%) TB cases; 30 (73%) AE gastrointestinal due to ETH n=64 no treatment Outcomes: 13 (20%) TB cases

23 Details of Comparison Study #3 : Schaaf et al.

24 Comparison Study #4 Adler-Shohet et al. Management of Latent Tuberculosis Infection in Child Contacts of Multidrug-resistant Tuberculosis. Pediatric Infectious Disease Journal. 2014; 33:664 Setting: Orange County, California Time period: ? Subjects: N=31 with LTBI Study type: prospective observational with 2 years of follow up n=26 LTBI treatment of LEV and PZA for 9 months 15 (57%) completed Outcomes: No (0%) TB cases; 26 (100%) AE, 11 (42%) stopped due to AE n=5 no treatment Outcomes: No (0%) TB cases

25 Details of Comparison Study #4: Adler-Shohet et al.

26 Comparison Study #5 Attamna A, Chemtob D, Attamna S, et al. Risk of tuberculosis in close contacts of patients with multidrug resistant tuberculosis: a nationwide cohort. Thorax Mar;64(3):271. Setting: Israel Time period: Subjects: N=470 TST+ contacts, median age 29 Study type: retrospective cohort matched to MDR TB registry to identify incident cases, median of 6 years of follow up n=12 LTBI treatment, mainly with CIP and PZA, Tx length? Completion unknown % Outcomes: No (0%) TB cases; no data on AE n=458 no treatment Outcomes: No (0%) TB cases

27 Comparison Study #6 Williams B, Ramroop S, Shah P, et al. Management of Pediatric Contacts of Multidrug Resistant Tuberculosis in the United Kingdom, Pediatric Infectious Disease Journal. 2013;32: Setting: UK Time period: Subjects: N=12 children with LTBI Study type: retrospective review with 2 years of follow up n=8 LTBI treatment with 2 effective drugs for 6-12 months 8 (100%) completion Outcomes: No (0%) TB cases; unknown AE n=4 no treatment Outcomes: No (0%) TB cases

28 Outcome of TB Incidence

29 Data from 3 Comparison Studies Having Any TB Incidence, Outcome=TB incidence Study TB No TB Total Bamrah LTBI Tx No LTBI Tx Bamrah Total Denholm LTBI Tx No LTBI Tx Denholm Total Schaaf LTBI Tx No LTBI Tx Schaaf Total Bamrah RR= CI ( ) Denholm RR= CI ( ) Schaaf RR= CI ( ) Pooled RR=0.08 CI ( )

30 Results of Meta-analysis of 3 Studies (Denholm, Bamrah, Schaaf) Pooled Random Effects Relative Risk=0.179 ( )

31 Assessment of Heterogeneity of the 3 Studies: p=0.214 Assessment of Heterogeneity of the 3 Studies p=0.214: relatively homogenous Possible reasons for some heterogeneity: Sample size (49, 119, 105) Overall TB incidence: 4% Australia (Denholm) 3% Chuuk (Bamrah) 14% South Africa (Schaaf)

32 Data from 3 Additional Comparison Studies, Outcome=TB incidence Study TB No TB Total Adler-Shohet LTBI Tx No LTBI Tx Adler-Shohet Total Attamna LTBI Tx No LTBI Tx Attamna Total Williams LTBI Tx No LTBI Tx Total

33 Data from 4 LTBI Tx-only Studies and 6 No Effective Tx Studies, Outcome=TB incidence 6 Studies of No Effective Treatment TB no TB Total Amanullah Bayona Becerra Kritski Nitta Pineiro-Perez Total Treatment-only Studies TB no TB Total Feja Garcia-Prats Miramontes Seddon Total Pooled RR=0.48 ( )

34 Outcome of Treatment Completion

35 Study Data from 5 Comparison Studies, Outcome=Treatment Completion Tx months Completed Tx Incomplete Tx Total Adler-Shohet Bamrah Denholm Schaaf Williams Overall Tx Completion 166/190 = 87%

36 Study Data from 8 Treatment-only Studies, Outcome=Treatment Completion Tx months Completed Tx Incomplete Tx Total Feja Garcia-Prats Horn Lou Miramontes? Papastavros Ridzon Seddon Overall Tx Completion 262/443 = 59%

37 Outcome of Adverse Effects (AE)

38 Data from 4 Comparison Studies, Outcome=Stopping of Tx due to Adverse Effects Study AE Tx Stop No Tx Stop Total Adler-Shohet Bamrah Denholm Schaaf Overall AE Stop = 17/182 = 9%

39 Data from 8 Tx-only Studies, Outcome=Stopping of Tx due to Adverse Effects Study AE Tx Stop no AE Tx Stop Total Feja* Garcia-Prats Horn Lou Papastavros Ridzon Seddon Younossian Overall AE Stop = 89/347 = 26% *Feja had 51 started on LTBI Tx, but medical records reviewed for AE of only 22, and no regimen-specific data

40 Regimen-specific Data from 11 Studies, Outcome=Adverse Effects by Regimen % % Total 11 studies n AE AE stop AE AE stop PZA/INH % 0% PZA/INH/ETA % 0% PZA/EMB % 50% PZA/EMB/RIF % 0% PZA/EMB/INH % 0% PZA/EMB/INH/ETA % 0% PZA/EMB/ETA % 0% PZA/FQ % 67% PZA/FQ/INH % 67% PZA/CIP % 0% Any PZA regimen % 51% FQ % 8% FQ/EMB % 0% FQ/EMB/INH % 1% FQ/ETA % 0% Any FQ regimen % 2% ETA/EMB % 0% ETA/EMB/INH % 0% CIP % 100% All regimens % 20% Schaaf mentioned 30 children had AE from ETA, but didn t specify the specific regimen (but none were FQ/ETA) that caused the AE, so those data are not included above

41 Adverse Effects, Stratified by Studies of Children Aged <15 versus Those of Other Ages From 11 studies presenting data on adverse effects by regimen: 4 were in children aged < 15 years 13/277 = 5% AE treatment stop 7 were in persons having a median age > 15 years of age 88/230 = 38% AE treatment stop

42 Limitations Overall quality of evidence was very low Few studies reported the outcomes of interest

43 Cost-effectiveness: Holland DP, Sanders GD, Hamilton CD, Stout JE. Strategies for Treating Latent Multiple- Drug Resistant Tuberculosis: A Decision Analysis. PLoS ONE. 2012;7(1):e Decision analysis of 6 month MDR LTBI Tx regimens: PZA/EMB MOX MOX/PZA MOX/EMB MOX/ETH MOX/PA-824 Efficacy estimates from mouse models; toxicity from various studies, but excluding Bamrah, and assumed toxicity for MOX and MOX/EMB Range of AE stop was 4%-67% MOX alone was lowest cost; MOX/EMB was incrementally cost effective Hypothetical regimen of low toxicity and modest efficacy was cost effective vs. no MDR LTBI treatment

44 Details from Holland et al. Cost-effectiveness Analysis

45 Estimated Direct Costs by Regimen, Including AE costs 2014$ Daily Doses for 9 mo. Tot Med Cost Cost/Dose DOT/ clinic visits Supplies %AE AE Cost ($169 per episode without hosp in 2010$, from Holland) % AE Stop AE Cost ($5677 for 7 days hosp in 2010$, from Taylor assumption, if AEstop then hosp) AE health system cost Total Direct MDR LTBI Daily by DOT Regimens assume 10% of AEstop are hosp PZA/EMB 270 $ 889 $ 3 $ 83 64% $ % $ 318 $ 440 $ 1,413 PZA/MOX or LEV 270 $ 1,532 $ 6 $ 83 85% $ % $ 424 $ 586 $ 2,201 MOX or LEV alone 270 $ 1,235 $ 5 $ 83 81% $ 154 8% $ 48 $ 202 $ 1,520 MOX/EMB 270 $ 1,738 $ 6 $ 83 16% $ 31 0% $ - $ 31 $ 1,852 MOX/ETA 270 $ 2,183 $ 8 $ 83 58% $ 110 0% $ - $ 110 $ 2,377 Total Direct MOX/ETA MOX/EMB MOX or LEV alone PZA/MOX or LEV PZA/EMB $- $500 $1,000 $1,500 $2,000 $2,500

46 Summary of Findings Very few studies met the inclusion criteria Results should be cautiously interpreted We found, by using meta-analysis, some empirical evidence suggesting effectiveness of LTBI treatment in preventing progression to MDR-TB disease We also found high discontinuation rates due to adverse effects and toxicity in those patients taking PZA containing MDR-LTBI regimens (especially PZA/FQ)

47 Discussion Trials are needed, but TB incidence in low incidence settings is too low Adverse effects by regimen: Nix PZA regimens? Cost effectiveness greatest with FQ or FQ/EMB

48 Detection of 1 Incident MDR TB Case ~100 MDR-TB cases in the U.S. per year ~80%=80 cases/year are infectious (pulmonary, sputum smear positive) ~ 20 contacts/case = 1600 MDR TB contacts ~30% to 40% have LTBI = 480 to 640/year Estimated TB incidence is /year (Walter) to /year (Shea)» MDR TB incidence = 0.15 to 0.54 cases per year» So, it would take 2 to 7 years to detect one incident MDR TB case

49 Power Calculation: Michael Chen Numeric Results for testing H0: P = P0 versus H1: P > P0 Test Statistic: Exact Test Proportion Proportion Given H0 Given H1 Target Actual Reject H0 Power N (P0) (P1) Alpha Alpha Beta If R>=This Assumptions: The upper and lower bounds for the rate are and per year, respectively. The average rate is.00058/yr; The average rates for 3, 5 &10 years are:.00174,.0029 &.0058, respectively; The cluster effect is negligible; The chance of developing TB disease is constant throughout years Interpretations: In a 3-year follow-up with average rate of.00174/3-years, a sample size of about 900 is needed for rejecting the rate=0 with 80% power; In a 5-year follow-up with average rate of.0029/5-years, a sample size of about 550 is needed for rejecting the rate=0 with 80% power; In a 10-year follow-up with average rate of.0058/10-years, a sample size of about 300 is needed for rejecting the rate=0 with 80% power.