· individual and pooled risk differences from head-to-head trials comparing rifampin durations of...
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HIV
24 11 2 ( )
HIV
HIV RNA
AIDS/HIV ,1997,
Fig. 1 The life cycle of M. tuberculosis.
D G Russell et al. Science 2010;328:852-6
The life cycle of M. tuberculosis.
HIV
HIV TB TB HIV
HIV TB WHO 2011
AIDS 13% WHO 2011
HIV,TB
3
Estimated global tuberculosis case detection
McNerney R et al. J Infect Dis. 2012;205:S147-S158
( )
HIV 10%/生涯 HIV感染
％年
Daley CL, et al. N Engl J Med 326;231, 1992
Diedrich C R , Flynn J L Infect. Immun. 2011;79:1407-17
Proposed mechanism of HIV-induced reactivation of latent TB. (Stage 1)
Necrotic granuloma functioning “normally” in an individual with latent TB.
(Stage 2) HIV enters the granuloma and induces functional changes within T cells and macrophage
JAMA 274;143-148, 1995
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.
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.
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H-,W-CAST (-), G-CAST (1+)
[ ] WBC 10200 /μl ( Band 41%, Seg 51 , Lymph 1 ,
Mono 7 , Eosino 0%, Baso 0% ), Hb 8.2 g/dl, Plt 13.8 /μl
[ ] PT 96 , APTT 32.3sec, FNG 374 mg/dl, FDP 326 ng/ml
[ ] TP 8.2 g/dl, Alb 2.1 g/dl, TB 0.7 mg/dl, BUN 21.5 mg/dl,
Cr 1.2 mg/dl, UA 10.0 mg/dl, Na 134.8 mEq/l, K 4.7 mEq/l,
Cl 103 mEq/l, Ca 7.5 mg/dl, LDH 389 IU/l, AST 31 IU/l, ALT 26
IU/l, ALP 426 IU/l, CRP 21.70 mg/dl
[ ] 1,3- -D- <2.8 pg/ml, 0.2,
, CM-IgG 16.0 index, CM-IgM 0.2 index,
2 14 1.5cm .
.
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- TB-PCR: :
.
• TB lymphadenitis
• pleural TB
• TB meningitis
• osteoarticular TB
• genitourinary TB
• abdominal TB
• cutaneous TB
• ocular TB
• TB pericarditis and breast TB
A negative smear for acid-fast bacilli, lack of granulomas on histopathology and
failure to culture Mycobacterium tuberculosis do not exclude the diagnosis of EPTB.
HIV感染を伴うTB治療HIV .
2HREZ + 4HR .
.
RFP EFV .
DOTS .
服薬するかどううか 性、年齢、人種、教育、経済状態に関係なし
Akolo C, et al. Cochrane Databese Syst Rev 2010; CD000171
MMWR 49:185-189, 2009
CD4
ART .
CD4
2 ART .
CD4
ART .
HIV
リファマイシン系薬剤
プロテアーゼ阻害剤
NNRTI PI
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CYP3A4
CYP3A4
代謝
肝臓、腸管におけるCYP3A4の誘導
CYP3A4の抑制
HIV (RFP, RBT)
4 12 HAART 4 24
(5/15) (6/25)
Follow up CT
Immunopathological かつ Protective immunity
during anti-tubercular treatment and HAART
Walburger A, et al. Science 304;1800-4, 2004
Dysregulated helper T-cell type 1 (Th1) expansion?
Kedzierska K, et al. J Immunol, 168 、2895–903、2002
Sumatoh, HR, et al. Mycobacterial antibody levels and immune restoration
disease in HIV patients treated in South East Asia.
Biomark Med, 5;847-853, 2011
Shelburne
1) HIV
2) ART
HIV-RNA
CD4 HIV-RNA
3)
3)
Shelburne SA, et al. AIDS 19:399-406, 2005
Haddow LJ, et al. Clin Infect Dis 49:1424-32, 2009
Haddow
Paradoxical IRIS
免疫再構築症候群発症と結核治療からART開始期間との関係
Lawn SD, et al AIDS 21;335-341, 2007
• ART導入後にIRISを発症する頻度16.1%
(3.1~39.1%)
Muller M, et al. Lancet Infect Di 10;251-61, 2010
2週間以内の早期ART開始 新たなAIDS指標疾患の発症、 IRIS合併、死亡率 Zolopa AR, et al. PLoS ONE 4:e5575, 2009
早期ART開始は死亡率を有意に Abdool Karim SS, et al. N Engl J Med 365;1491-1503, 2011
Kaplan–Meier Curves for Survival without an AIDS-Defining Illness
Abdool Karim SS, et al.N Engl J Med 365:1492-1501、2011
2HRZS + 4HRZ 0 %
2HRZS + 4HR 2.5%
2HRZE + 4HR 2.5%
2HRZS + 2HRZ 11.4%
2HRZS + 2HR 7.8%Am Rev Respir DIS 1988 137: 1147~1150
10 5
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persisters
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.
PZA .
PZA .
persister .
6
Individual and pooled risk differences from head-to-head trials comparing rifampin durations of 9
months and 6 months for the treatment of active tuberculosis in patients with human
immunodeficiency virus.
Ahmad Khan F et al. Clin Infect Dis. 2012;55:1154-1163
© The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases
Society of America. All rights reserved. For Permissions, please e-mail:
World Health Organization. 4th edition. ed. Geneva: World Health
Organization; 2010. Stop TB Dept. Treatment of tuberculosis: guidelines.
Khan FA, et al. Clin Infect Dis 50;1288, 2010
rifamycins
+ for 6 months,
+ daily dosing in the intensive phase,
+ ART (regardless of CD4 lymphocyte count)
HIV感染を伴う活動性結核の治療における リファマイシン系薬の重要性
Recurrent TB: relapse or reinfection? The effect of HIV in a
general population cohort in Malawi.
Crampin, AC, et al. AIDS. 24(3):417-426, January 28, 2010.
Nelson Aalen curves showing
cumulative hazards of
(a)recurrent culture-positive tuberculosis,
(b)Relapse
(c)reinfection
HIV感染者は新たな結核菌に感染して発病しやすい
Clin Infect Dis 54;784-91, 2012
B
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in vivo
: )in vitro
BCG, PPD
50-90 %
20-40 %
89 %
98 %
2 1
IGRAs
QFT-In Tube
(QFT or TSPOT)
TST と IGRAsの違い
8
結核の感染診断
LTBI LTBI
IGRAs (QFT or TSPOT-TB)
共にBioassay
μ
HIV ---- 5mm
HIV --- 10mm
IGRAs HIV .
HIV感染における結核の感染診断
HIV
. Sutherland P, et al.AIDS 20;821, 2006
BCG
NTMHIV
CattamanchiA, et al. J Aquir Immune Defic Syndr377;1588, 20
Pai M, et al Ann Intern Med 149;177, 2008
CD4+細胞数が少ないと、偽陰性がある.
特にCD4+ cell < 200
LTBI治療により免疫能が回復し、陽転することあり.
Akolo C, et al. Cochrane Database Syst Rev 2010 CD000171
JAMA 274;143-148, 199591
350
200-350
200
T reatment of latent tuberculosis infection in H IV infectedpersons (Review)
Akolo C, Ade ti fa I , She ppe rd S, Volmin kJ
LTBI .
HIV LTBI 1.3% .
Foster S, et al. AIDS 11:919,2007
Cohen T, et al. Proc Natl Acad Sci USA 103,7042: 2006
Harries AD, et al. Lancet 375, 1906 11:919,2010
HIV LTBI HIV 30~100 reactivate
Selwyn PA, et al. N Engl J Med 320:545,1989
Wood R, et al. J Acquir Immune Defic Syndr 23,75: 2000
Cochrane Database Syst Rev 2010; CD000171
LTBI TST
Cochrane Database Syst Rev 2010; CD000171
LTBI治療
T reatment of latent tuberculosis infection in H IV infectedpersons (Review)
Akolo C, Ade ti fa I , She ppe rd S, Volmin kJ
Harries AD, et al. Lancet 375, 1906 11:919,2010
Selwyn PA, et al. N Engl J Med 320:545,1989
Wood R, et al. J Acquir Immune Defic Syndr 23,75: 2000
Cochrane Database Syst Rev 2010; CD000171
T reatment of latent tuberculosis infection in H IV infectedpersons (Review)
Akolo C, Ade ti fa I , She ppe rd S, Volmin kJ
INH, INH RFP, RFP+PZA
INH 6~9
P<0.0001 P<0.0001P<0.009
A( INH)
Fall and Rise
RFP 10-8
INH EB SM KM 10-6
TH CS 10-3
106
結核の発病診断
LTBI
J Infect Dis 205; S147-158,2012
0 21 3 4 5 6 7
(検査時間：hr)
8
TB
PCR
TRC
TB、AV、INT
TB、AV、INT
2.5時間
MAC
抽出 増幅・検出
TB : 結核菌群検査MAC : MAC 検査MKS : M. kansasii 検出
TBMACMKS
MKS
4時間
PCR
LAMP
9
Boehme CC, et al. NEJM 363; 1105-1115,2010
RFP
Lancet Infect Dis 12:201-9, 2012
Predicted outcome of breath test for active pulmonary TB
A specified target value of NPV or PPV may be achieved by selecting a cutoff point
on the ROC curve
Point-of-care breath test for biomarkers of active pulmonary tuberculosis
Phillips M,et al. Tuberculosis 92, 314 – 320, 2012
PLoS Med. 2012 July; 9(7): e1001270.
AntiretroviralTherapyforPreventionof TuberculosisinAdults with HIV: A Systematic Review and Meta-AnalysisAmi tabh B. Suthar 1*, Stephen D. Lawn 2,3 , Julia del Amo 4, Haileyesus Getahu n5, Christ opher Dye 6 ,
Del phine Scul ier 5, Timoth y R. Ste rling 7, Richard E. Chaisson 8 , Brian G. Williams 9, Ant hony D. Harries 10,11 ,
Reub en M. Gran ich 1
PLoS Med 9;e1001270, 2012
Kirk O, et al. Am J Respir Crit Ca
Girardi E, et al. J Acquir Immune Defic Syndr 26;326-331, 2001
AntiretroviralTherapyforPreventionof TuberculosisinAdults with HIV: A Systematic Review and Meta-AnalysisAmi tabh B. Suthar 1*, Stephen D. Lawn 2,3 , Julia del Amo 4, Haileyesus Getahu n5, Christ opher Dye 6 ,
Del phine Scul ier 5, Timoth y R. Ste rling 7, Richard E. Chaisson 8 , Brian G. Williams 9, Ant hony D. Harries 10,11 ,
Reub en M. Gran ich 1
Antiretroviral therapy use and hazard of tuberculosis by baseline CD4 count.
Suthar AB, et al. PLoS Med. 2012 July; 9(7): e1001270.
Antiretroviral therapy use and hazard of tuberculosis by baseline CD4 count.
Suthar AB, et al. PLoS Med. 2012 July; 9(7): e1001270.
場所 地域 罹患率 菌側因子 virulence factor
ホスト因子 疾患感受性遺伝子 免疫状態 基礎疾患
他因子 感染と発病の連続性
場所 地域 罹患率 菌側因子 virulence factor
ホスト因子 疾患感受性遺伝子 免疫状態 基礎疾患
他因子 感染と発病の連続性
+ HIV
常に結核感染の有無を判断する.
結核は空気感染 いつどこで感染するかわからない！
・監獄入所者 ・密集地域 ・ 薬物中毒 ・ 結核患者との接触歴
罹患率(地域） 個々の症例の背景経済状況
