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Transcript
Tuberculosis Treatment: Challenge for
the New Millennium
Jean B. Nachega, M.D., M.P.H.
Research Associate
Johns Hopkins University
Center for Tuberculosis Research
Baltimore, Maryland, USA
Global Status of TB
TB is the second leading infectious cause of death in the world,
after the Human Immunodeficiency Virus
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1/3 world population is infected with TB
In 1997, 8 million new cases of TB & rate of 136/100,000
3 million deaths per year
<40% of cases are reported to WHO
24% of all preventable life-years lost annually due to TB
Raviglione MC. Et al. JAMA 1995;273:220-6
WHO,Global TB Control: WHO Report 1999, Geneva, 1999, 179pp
Global Status of TB (Cont’d.)
80% of all cases worldwide occur in S S Africa &
S E Asia
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The biggest burden of TB is in SE Asia
~3 million TB cases/year occur in S E Asia
~3 million/year occur in SS Africa
Over a 1/4 of a million TB case/year occur in East Europe
Case and deaths are increasing in former Soviet Union
Raviglione MC. Et al. JAMA 1995;273:220-6
WHO,Global TB Control: WHO Report 1999, Geneva, 1999, 179pp
Factors contributing to TB
Prevalence/Incidence
HIV is contributing to large escalations in the global
incidence of TB
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HIV infection/MDR-TB
Poorly TB programs > lack of funding
Poor technology for diagnosing & Rx. TB
Urbanization and migration
Health sector reform/change
Harries AD., Lancet 1990; 335: 387-390
TB and HIV/AIDS
TB is the leading killer of HIV/AIDS patients
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Worldwide, 35 million people are HIV+ (~40-50% TB+)
22% of all TB deaths occur in HIV-infected people
TB is the leading AIDS-related opportunistic infection
High rate of reactivation (10%/year) and primary TB
Risk of TB correlates with positive PPD & low CD4
Selwyn PA et al. JAMA, 1992; 268:504-9
Antonucci G. et al., JAMA, 1995; 274:143-8
Havlir D. and Barnes P., NEJM, 1999;340, 367
TB and HIV/AIDS: Copathogenicity
• Mortality rate of TB/HIV+ patients is x4 Vs TB/HIV• Immune activation from TB enhances systemic and local HIV
replication
• Change in HIV viral load is seen before and after TB Rx
• TB is the leading AIDS-related opportunistic infection
Havlir DV ans Barnes PF., NEJM 1999, 340 (5) 367-73
TB and HIV/AIDS (Cont’d.)
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Rare pulmonary cavitation (0-6%)
Increase extrapulmonary TB (40-70%)
Bacteremia & Nl Chest x-rays (10-22%)
Low Se. AFB smears from sputum (40-60%)
MDR-TB
Chaisson RE and Slutkin G.,JID, 1989,159, (1), 96-100
Havlir D. and Barnes P., NEJM, 1999;340, 367
Effectiveness of TB Therapy in HIV infection
Reference
Population
Regimen
Relapses
Perriens et al.
Zaire
NEJM 1995; 332:779
HIV +
HIV -
IRZE2/IR4
IRZE6/IR6
IRZE2/IR4
8%
1%
5%
Kassim et al..
Cote d’ivoire
AIDS 1995; 9: 1185
HIV +
HIV -
IRZE2/IR4
IRZE2/IR4
3%
3%
Chaisson et al.
Haiti
Am JR CritC Med
1996;154:1034
HIV +
HIV -
IRZE2/IR4, 3x/wk
IRZE2/IR4 3x/wk
5%
3%
USPHS RPT Trial Gr.
United States
Am JR Crit C Med
1998;157: A 467
HIV +
IRZE2/IR4. 2x/wk or
IRPT4 weekly
10%
Author
Setting
WHO-IUATLD Global TB Drug Resistance
Study: 1994-97
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22 supranational laboratories
35 participating centers
50,000 TB patients
20% of global population represented
Systematic sampling of new cases of TB
WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance, 1994-1997
WHO-IUATLD Global TB Drug Resistance
Study: 1994-97
• Primary Drug Resistance:
Median: 10% Range: 2.0% -40.6%
• Acquired Drug Resistance:
Median: 36% Range: 5.3%-100%
WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance, 1994-1997
M. Tuberculosis Drug Resistance Genes
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INH: katG, inhA, kasA
RMP: rpoB
EMB: embA, embB, embC
PZA: pncA
SM: rrs, strA, rpoL
Zhang Y et al..1992,; 358:591-3
Telenti A.et al.1993; Lancet 1993; 341: 647-50
Sreevatsan S. et al. 1997; 41: 636-40.
The DOTS Strategy (WHO,1993)
DOTS is the best therapy against TB
(78-96% cure rate)
• Directly Observed Treatment,
Short course
The DOTS Regimen (WHO,1993)
DOTS is 6 month therapy
• Intensive phase (daily, 2 mo) :
INH, RMP, PZA, EMB
• Continuation phase (3 times a week, 4 mo):
INH & RMP
The DOTS Strategy (WHO,1993)
Combines five elements
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Government commitment to TB Control
Microscopy services for diagnosis
Short course Rx (6mos)/ supervised 1st 2 mo
Drug supply
Recording/reporting system
Benefits of DOT(S)
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Decrease rate of Rx failure/relapse
Prevent secondary spread
Decrease probability of drug resistance
Cost effective
The DOT Strategy (1980s)
Supervision of all doses of TB medication by a
health team member
• Directly Observed Treatment
TB in Baltimore, USA
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Historically, the TB epicenter of the US
1900s: William Osler, M.D.’s Campaign
1902: Cases rates : 2,000/100,000
1930s: Highest TB cases and deaths rates
1970: Mayor William Donald Schaeffer
Chaulk P et al., 1995, JAMA, 274 (12), 945-51
Graham NM et al., Arch Internal Med 1996; 156:889-94
DOT in Baltimore, USA
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1973-88: Glasser D., M.D., DOT Concept
1976-81: Clinic based DOT, 25% of all cases
1980-92: Community DOT, 70% of all cases
1993-Present: On average 90% of all cases
Chaulk P et al., 1995, JAMA, 274 (12), 945-51
Graham NM et al., Arch Internal Med 1996; 156:889-94
DOT in Baltimore:
Clinical Significance
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12 mo completion rate (CR)
CR: 90%/year in 1985-92 & 95-98% in ‘95-97
Relapse rate: 2%-5%/year
Drug resistance very low: 0.05%
Chaulk P et al., 1995, JAMA, 274 (12), 945-51
Graham NM et al., Arch Internal Med 1996; 156:889-94
DOT in Baltimore:
Epidemiological Significance
• 1978-95: 67% decrease TB incidence
• 1978-92: City rate for TB fell from 2nd to 23rd
Chaulk P et al., 1995, JAMA, 274 (12), 945-51
DOT in Baltimore:
Political Significance
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Sustained > 22 years /3 governors, 3 mayors
International endorsement
Effective DOT models patient-centered
Important role outreach, incentives, language
1993: WHO introduces “DOTS”
Chaulk P et al., 1995, JAMA, 274 (12), 945-51
TB in New York City, USA
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1982-90: Dramatic resurgence of TB
Mostly MDR-TB & attributable to HIV
Response: funding/surveillance/ control
Ext. use of DOT & preventive Rx in
HIV+/PPD+
• Prevention of nosocomial transmission
Frieden TR., et al. NEJM 1995; 333:229-233
Alternatives to DOT
• Treatment Supervised by Family
• Community Supervised Treatment
• Intermittent Supervised Treatment
BRAC Program in Bangladesh (1984)
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CHWs actively screen villages for chronic cough
Enrollment of patients with + sputum smears
Drug free of charge but 200 taka deposit
First 2 mo of CHWs supervised Rx
Weekly clinic visit for take home drug for 6 mo
Mushtague A et al., Lancet 1997; 350: 169-72
Treatment Outcomes: BRAC TB Program
1992-94
N=3497
1995
N=68
1996
N=2729
1997
N=1628
*2833 (81%)
1301(85%)
2312(85%)
1463 (90%)
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1(<1%)
6 (<1%)
0 (0%)
336 (10%)
126 (8%)
233 (9%)
99(6%)
Failure
51(2%)
43 (3%)
52 (2%)
22 (1%)
Defaulted & other
277(8%)
54 (4%)
126 (5%)
44 (3%)
Outcome
Cured
Completed
Died
*Includes cured & completed cases
Adapted from Mushtague A et al., Lancet 1997; 350: 169-72
Community DOT based program in
Hlabisa, South Africa: Results 1991-94
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90% managed in community
> ½ supervised by non-Health Worker
Case holding by non-HW as good as by HW
85% of surviving patients completed Rx
Cost of community Rx = cost of 5d in Hospital
Wilkinson D. et al., Am J Public Health, 1996; 86: 1094-97
Family Supervising TB Rx
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366 smear+ TB Patients 10/96-9/97
Self selected supervised vs self administered Rx
Family member supervising most of the Rx
Overall cure rate: 80%
Supervised cure rate: 85%
Akkship et al. Int J TLD 1999; 3:1061-65
Effectiveness of TB Therapy in HIV infection
Reference
Population
Regimen
Relapses
Perriens et al.
Zaire
NEJM 1995; 332:779
HIV +
HIV -
IRZE2/IR4
IRZE6/IR6
IRZE2/IR4
8%
1%
5%
Kassim et al..
Cote d’ivoire
AIDS 1995; 9: 1185
HIV +
HIV -
IRZE2/IR4
IRZE2/IR4
3%
3%
Chaisson et al.
Haiti
Am JR CritC Med
1996;154:1034
HIV +
HIV -
IRZE2/IR4, 3x/wk
IRZE2/IR4 3x/wk
5%
3%
USPHS RPT Trial Gr.
United States
Am JR Crit C Med
1998;157: A 467
HIV +
IRZE2/IR4. 2x/wk or
IRPT4 weekly
10%
Author
Setting
Concurrent treatment of TB and HIV
• Pansusceptible MTB, DOT at least 6 mo
• Assess clinical and bacteriologic response, if non
satisfactory longer course e.g. 9 mo is preferable
• Pyridoxine 25-50 mg/d or 50-100 mg twice weekly
for all HIV+ patients on INH
• If RMP/RFB resistance, INH/EMB/PZA for a
minimum of 18 mo (12 mo after culture conversion)
• No PI or NNRTI in RMP containing regimen
Havlir DV ans Barnes PF., NEJM 1999, 340 (5) 367-73
Concurrent treatment of TB and HIV
• NNRTI have diverse effects on CYP 450
• Nevirapine is an inducer, delaverdine an inhibitor
and efavirenz both an inducer and an inhibitor
• NRTI are not metabolized by CYP 450
• INH, EMB, PZA and SM are not CYP450 inducer
and can be taken with all ARV drugs
Havlir DV ans Barnes PF., NEJM 1999, 340 (5) 367-73
Rates of TB in HIV+/PPD+
According to Rx Regimen
Reference
Regimen
Annual Rate
RR
Pape JW et al.
Haiti
Lancet ’93:
342:268
INH QD 12mo
Vit. B6 (Placebo)
1.7%
10%
0.17
1
Whalen CC et al.
Uganda
NEJM ’97:
337(12),801
INH OD, 6mo
INH/RIF QD 3mo
INH/RIF/PZA QD 3mo
Placebo
1.1%
1.3%
1.7%
3.4%
0.32
0.41)
0.42
1
Halsey NA. et al.
Haiti
Lancet ’98:
351:786
INH 2X/wk, 6mo
RIF/PZA 2X/wk, 2mo
1.7
1.8
1
1.1
Mwinga A. et al.
Zambia
AIDS ’98:
12;2447
INH2X/wk, 6mo
RIF/PZA 2X/W, 3mo
Placebo
2.3
2.7
9.8
0.62
0.58
1
Author
Setting
Treatment of Latent TB: INH Regimen
• CDC now recommends at least 6 mo of INH
• Therapy for 9 months appear sufficient
• Therapy for >12 months does not provide
additional protection
• Daily regimen (300mg) or twice weekly (1015 mg/kg up to 900mg)
Summary I
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To date DOT(S) is the best Rx of TB
DOT(S) alone is not enough to control TB
Need for timely case finding and surveillance
Need for Screening & preventive Rx in high
risk population (HIV, Household contacts)
Summary II
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Prevention of institutional transmission
Integration of HIV/AIDS and TB prevention
Simplification of TB management
New drugs to overcome MDR-TB
A statistic is not just a number, it is a
number with a teardrop on it
Wade Hampton Frost, M.D.