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TB/HIV Coinfection Page 1 of 20
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TB and HIV
Julie Higashi MD, PhDTB Controller/Deputy Health OfficerSan Francisco Department of Public Health
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Estimated HIV Coinfection in Persons Reported with TB, United States, 1993 – 2013*
*Updated as of June 11, 2014.
Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group.
% C
oin
fect
ion
0
10
20
30
40
50
60
70
All Ages Aged 25 ‐ 44
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TB/HIV Coinfection Page 2 of 20
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What changes with HIV?
Multiple effects of HIV infection on the course of TB infection and disease
TB/HIV Coinfection Page 3 of 20
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Reactivation RiskHIV+20x
Source: Murray & Nadell’s Text of Respiratory Medicine
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TB Diagnosis in HIV positive
Symptoms – may have typical symptoms, but may be asymptomatic
Sputum microscopy (smear) – low threshold to get sputum for testing
Chest X-ray – may be normal, even with disease
Xpert MTB/RIF Assay
MTB Culture
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TB Diagnosis in HIV: Look for active disease aggressively
• Ambulatory HIV+ adults w/ CD4>200 enrolled in a TB vaccine trial• 10/500 w/ subclinical TB (2%)
• 274 HIV+, ART-naïve ambulatory patients in South Africa• 18 (8.5%) asymptomatic, but MTB culture+
TB/HIV Coinfection Page 4 of 20
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TB Diagnosis in HIV: U.S.
• 22% HIV infected with n=31 normal CXRs vs. 5% non HIV infected with n=22 normal CXRs• HIV more likely to be symptomatic (93%) than non HIV infected (68%) with normal CXR
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TB Diagnosis in HIV: U.S.
• 22% HIV infected with n=31 normal CXRs vs. 5% non HIV infected with n=22 normal CXRs• HIV more likely to be symptomatic (93%) than non HIV infected (68%) with normal CXR
Bottom line – lower threshold to collect sputa for HIV than non HIV with normal CXR
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TB Diagnosis in HIV: Microscopy
Overall sensitivity of sputum microscopy ~50%
Lower in HIV+
0%
5%
10%
15%
20%
25%
30%
35%
0-50 51-100 101-150 151-200 201-250 251-300 301-350 351-400 401-450 451-500 >500
CD4 Cell Count (cells/μL)
% N
egat
ive
AF
B S
mea
r
Chamie et al, IJTLD, 2010Chamie, IJTLD 2010
TB/HIV Coinfection Page 5 of 20
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TB Diagnosis in HIV: Chest x-ray
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
0-50 51-100 101-150 151-200 201-250 251-300 301-350 351-400 401-450 451-500 >500
CD4 Cell Count (cells/μL)
% w
ith
Cav
itat
ion
0%
5%
10%
15%
20%
25%
30%
35%
0-50 51-100 101-150 151-200 201-250 251-300 301-350 351-400 401-450 451-500 >500
CD4 Cell Count (cells/μL)
% N
orm
al C
he
st
X-r
ay
(p<0.001, for trend)
(p<0.001, for trend)
Chamie et al, IJTLD, 2010Chamie, IJTLD 2010
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Xpert MTB/RIF Assay
In HIV positives – pooled sensitivity for Xpert in culture positive cases is only 79%
Boehme, NEJM, 2010; Theron AJRCM 2011
Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults., Cochrane Review, 2014
Non HIV
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What is new in …
Timing of ART start in TB patients
TB IRIS
Use of ART drugs in TB patients
TB/HIV Coinfection Page 6 of 20
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Case 1: TB and low CD4
23 Brazilian man, recently moved to US
Presents with fever, night sweats, severely debilitated
Wasted, diffuse lymphadenopathy
AFB smear positive
Newly diagnosed HIV+
CD4 count is 2 cells/μL
He is started on RIPE
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When to start ART?
Competing Risks in the timing of ART during TB treatment
Adapted from: W. Burman, CROI - Boston, 2011
“Immediate” ART (<2 weeks) “Early” ART (<2 months)Benefits• Risk of OIs
Risks• Drug-drug Interactions• IRIS risk• pill burden, and
possible adherence• Could decrease ART
efficacy
Benefits• Risk of IRIS
Risks• OIs
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TB treatment
TB treatment
ART
ART
Study week
80 24
HIV+TB
Primary endpoint
Trial Design for 3 RCTs: CAMELIA, STRIDE, and integrated arms of SAPIT
“Immediate” ART(within 2 weeks))
“Early” ART(2-3 months)
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
TB/HIV Coinfection Page 7 of 20
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Key characteristics of trials of timing of ART during TB treatment
Study Setting Key enrollment criteria
Median CD4 (IQR)
Primary endpoint
CAMELIA Cambodia Smear +, CD4 < 200
25 (10 - 56) Death
STRIDE Multi-national Clinical TB, CD4 < 250
77 (36 – 145) AIDS or death
SAPIT South Africa Smear +, CD4 < 500
150 (77 – 254) AIDS or death
Blanc, Vienna, 2010, Havlir, CROI, 2011, Karim , CROI, 2011 Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
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02468
1012141618
CAMELIA STRIDE SAPIT
Immediate Early
Effect of ART timing on death (CAMELIA) or death/AIDS (STRIDE, SAPIT)
34% ↓p=0.004
19% ↓p=0.45
11% ↓p=0.73
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
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All studies showed significant reduction in death/AIDS among those with CD4 < 50
0
5
10
15
20
25
30
CAMELIA STRIDE SAPIT
Immediate Early
34% ↓p=0.004
42% ↓p=0.02
68% ↓p=0.06
Blanc, Vienna, 2010, Havlir, CROI, 2011, Karim , CROI, 2011
TB/HIV Coinfection Page 8 of 20
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When to start ART?
Competing Risks in the timing of ART during TB treatment
Adapted from: W. Burman, CROI - Boston, 2011
“Immediate” ART (<2 weeks) “Early” ART (<2 months)Benefits• Risk of OIs/Death
Risks• Drug-drug Interactions• IRIS risk• pill burden, and
possible adherence• Could decrease ART
efficacy
Benefits• Risk of IRIS
Risks• OIs
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TB IRIS Greater in Immediate vs. Early Arms
02468
1012141618
STRIDE SAPIT
IRD
Immediate Early
p=0.009
p=0.02
IRIS
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HIV RNA and CD4 Responses Similar at 48 weeks
N 370 380 361 365 355 349 349 347 331 332 N 368 379 357 364 350 347 346 343
333 333
CD4 change from entry 156 cells/mm3
No difference between armsHIV RNA suppression 74% at 48 weeksNo difference between arms
Toxicity similar between Arms
TB/HIV Coinfection Page 9 of 20
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No differences in TB Rx response by ART use
No TB therapy failures occurred in either study arm
TB recurrences:
ART = 3
No ART = 4 (p=.5)
25
50
75
10
00
0 2 4 6
% M
TB
Cul
ture
Pos
itive
Time to MTB Culture Negative
025
5075
100
0 2 4 6
% A
FB
Sm
ear
Pos
itive Time to AFB Smear Negative
ART & TB Rx Response Smear+/Culture-Does immediate ART enhance clearance of TB?
No difference in time to TB culture negative
No difference to AFB smear negativity
Chamie, CID, 2010
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Case 1: TB and low CD4
• Start within 2 weeks of TB therapy
• Anticipate TB IRIS as a complication
23 Brazilian man, recently moved to US
Presents with fever, night sweats, severely debilitated
Wasted, diffuse lymphadenopathy
AFB smear positive
Newly diagnosed HIV+
CD4 count is 2
He is started on RIPE
Key Points
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Case 2: TB and high CD4
47 yo latino male in ER with cough and weight loss
Chest radiograph consistent with TB, AFB+
Initially refuses HIV test
Seen in TB clinic, starts on 4 drug therapy, with rifampin
On the day he starts TB Rx, agrees to HIV test
HIV + and CD4 680
Is ART necessary? If so, when?
TB/HIV Coinfection Page 10 of 20
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SAPiT Study
642 HIV+ adults in Durban, South Africa
AFB smear + pulmonary TB
CD4 count <500
Randomized to
• ART during TB therapy at 2 weeks
• ART during TB therapy after induction
• ART after TB therapy completion (“sequential therapy”)
Karim S, et al. New Engl J Med 2010
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Mortality reduced when ART started during vs. after TB treatment: SAPIT
Karim S, et al. New Engl J Med 2010
HR: 0.44, p<0.003
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DHHS HIV Rx Guidelines - 2015
• “Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
• ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.”
TB/HIV Coinfection Page 11 of 20
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Case 2: TB and high CD4
• Get HIV genotype• Start ART when
genotype returns & ideally by 8 weeks of TB treatment
• ART regimen may require replacing rifampin with rifabutin
47 yo latino male in ER with cough and weight loss
Chest radiograph consistent with TB, AFB+
Initially refuses HIV test
Seen in TB clinic, starts on 4 drug therapy, with rifampin
On the day he starts TB Rx, agrees to HIV test
HIV + and CD4 680
Is ART necessary? If so, when?
Key Points
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Török M E et al. Clin Infect Dis. 2011;52:1374-1383
TB meningitis: No benefit to immediate ART
58% mortality at 9 months
Torok, CID, 2011
Significantly more Grade 4 adverse events in immediate ART arm
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Case 3: Clinical worsening after ART
29 yo man w/ HIV p/w fevers, diarrhea, abd pain
Dx’d with TB ileitis (cx+)
CD4 310, VL=385,000
Started on TB therapy, then ART (EFV, tenofovir/emtricitabine: “Atripla”) within 2 weeks
Comes to clinic 4 weeks after ART start: diarrhea, abd pain have resolved; complains of neck swelling & pain
CD4 is now 615, VL=83 Terminal ileum granulomas
TB/HIV Coinfection Page 12 of 20
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Case 3
FNA: AFB smear + necrotizing, granulomatous inflammation
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TB IRIS – A constant challenge to the clinician
Paradoxical TB IRIS: New or worsening or recurrent symptoms/signs and or radiographic manifestions of TB after ART • Fever, lymphadenopathy, enlarging CNS lesion, respiratory
decompensation
• Median onset 2 weeks
• Higher risk with lower CD4 cell count , higher HIV RNA
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Paradoxical TB IRIS
Diagnosis: • Improvement of TB symptoms on TB treatment prior to ART
• Deterioration with features of worsening TB soon after starting ART; and
• Demonstration of a CD4 and/or HIV viral load response to ART
AND
• Exclusion of alternative causes for deterioration such as a bacterial infection or an additional OI, a drug reaction, poor adherence, or resistance to TB treatment.
Occurs in up to 25% of TB/HIV cases starting ART
Meintjes, G. et al Curr HIV/AIDS Rep, Nov. 2012
TB/HIV Coinfection Page 13 of 20
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Differential Diagnosis of TB IRIS
Drug resistant TB
Other opportunistic infection
Non adherence
Malabsorption
Drug reactions
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Case 4: Clinical worsening after ART
25 female pulmonary TB, fevers, wasting, diffuse lymphadenopathy
CD4 29
Started on TB therapy, then Atripla within 2 weeks
Initial improvement
Comes to clinic 3 weeks after ART start with headache, fever, meningismus and stridor
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Patient has TB IRIS with compression of trachea
Steroids recommended for life threatening situations such as airway compromise, respiratory failure and enlarging mass lesions
For not life threatening TB IRIS, a 4 week course reduced hospitalization and procedures
More extended duration of prednisone may be required
ART should be continued
There is no diagnostic test for TB IRIS, although there are biomarkers associated with higher risk
Meintjes, AIDS, 2010
TB/HIV Coinfection Page 14 of 20
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Patient also has cryptococcal meningitis
Positive CrAg in CSF
Always consider other opportunistic infections in the setting of TB IRIS
HIV-TB cohort in Uganda
• 26% mortality
• Risk factor for death: no ART, anergy, undiagnosed cryptococcal disease
Worodria, JAIDS, 2011
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Cases 3 & 4: Clinical worsening after ART
• Continue ART and TB treatment
• Start steroids• Look for and
treat OIs• Monitor closely
Key Points
www.niaid.nih.gov
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HIV Treatment is TB prevention
CIPRA HT001: Starting ART between 200-350 vs. < 200 reduced TB by 50%
HPTN 052: Early ART in HIV+ patient with CD4 ≥ 350 led to a 47% reduction in risk of TB
Severe NEJM 2010, Grinstein B, et al. 6th IAS MOAX0105, 2011
TB/HIV Coinfection Page 15 of 20
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ART & TB Drug Interactions
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ART and TB Drug Interactions– General Principles
Rifampin potent inducer of CYP3A and interacts with a number of ART drugs
Rifabutin is a less potent inducer of CYP3A than rifampin and preferred TB rifamycin agent when rifampin cannot be used
ART+ TB treatment regimens may call for adjustment of ART dose, rifabutin dose or both
Data covering all possible drug interactions are incomplete
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What ART to start?
NRTIs (“nukes”) generally have no drug interactions with TB treatment & should be a part of most ART regimens (e.g. Truvada, Epzicom)
Non nucleoside reverse transcriptase inhibitors (NNRTI’s): Efavirenz (EFV) and Nevirapine (NVP), both reduced with rifampin coadministration • EFV AUC 78% of normal & NVP AUC 69% of normal
EFV-based ART equivalent effect with or without TB treatment in South African cohort
Limited data on Rifabutin+EFV and concern for increased toxicity with required increased Rifabutin dosing (450 mg QD)
Boulle JAMA 2008, Brennan-Benson AIDS 2005
EFV + Rifampin is preferred HIV/TB regimen
TB/HIV Coinfection Page 16 of 20
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FDA recommendation to EFV to 800
Previously recommended increasing EFV to 800 mg when coadministered with RIF if weight >50 kg (http://packageinserts.bms.com/pi/pi_sustiva.pdf)
Very limited evidence to support this
One study of HIV/TB coinfected Spanish patients• EFV troughs and AUC on average decreased 22-25% if EFV 600
• Highly variable and EFV levels went UP with RIF in some patients
• EFV 800 mg+RIF associated with same levels as EFV 600 without RIF
Lopez Cortes 2002, Boulle JAMA 2008, Friedland JAC 2006, Manosuthi AIDS 2006NIH/CDC OI Guidelines 2013
Current Recommendation: Dose EFV at 600 mg daily (standard dosing)
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Nevirapine: Alternative NNRTI
NVP decreased by RIF more than EFV
Concern for subtherapeutic NVP if already on rifampin during lead-in NVP dosing • NVP standardly dosed at 200 mg daily for 2
weeks followed by 200 mg BID to allow enzyme induction and reduce hypersensitivity
Therefore NO lead-in dosing with NVP recommended if already on Rifampin• May increase risk of NVP hypersensitivity
Boulle JAMA 2008, Brennan-Benson AIDS 2005
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When NNRTIs may not be an option
NNRTI resistance • Transmitted drug resistance (up to 8% NNRTI drug
resistance in HIV treatment naïve patients in US)
• Drug resistance relatively easily acquired due to low genetic barrier
NNRTI intolerance
Pregnancy
Age < 3 (EFV not available)
HIV-2 – NNRTI’s not effective
TB/HIV Coinfection Page 17 of 20
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Alternatives to NNRTIs
Ritonavir boosted protease inhibitors
Integrase inhibitors ( Raltegravir)
CCR5 Antatogists ( Maraviroc)
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PROTEASE INHIBITORS
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Rifamycin effect on protease inhibitors
0
20
40
60
80
100
120
LPV/RTV
ATZ/R
TV
LPV/RTV
ATZ/R
TV
% o
f n
orm
al c
on
ce
ntr
ati
on
s
AUCtrough
Rifampin
Rifabutin
Cannot coadminster Protease inhibitors with RIFAMPIN
TB/HIV Coinfection Page 18 of 20
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Rifabutin and Protease inhibitors
All PIs increase Rifabutin concentrations
Current recommendation: Decrease Rifabutin from 300 mg daily to 150 mg daily for boosted PIs
CAUTION: Rifabutin dose would then be inadequate if patient stopped Protease inhibitor!
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Another Caution: Rifampin resistance with PI/rifabutin
3 cases of relapse with acquired rifampin resistant TB, while on boosted PI + rifabutin 150 mg QOD TB regimen
7 of 10 patients on Kaletra/ Rifabutin 150 QOD subtherapeutic rifabutin AUC• One acquired Rifamycin resistance
Jenny Avital CID, 2009, Boulanger CID 2010
Higher dose of rifabutin now recommended with protease
inhibitors - 150 mg QD (vs. QOD)
Jenny Avital CID, 2009, Boulanger CID 2010, NIH/CDC OI Guidelines 2013
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INTEGRASE INHIBITORS
TB/HIV Coinfection Page 19 of 20
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Raltegravir (RAL) or Dolutegravir (DTG) + Rifampin
Current recommendations to increase RAL to 800 mg BID and DTG to 50 mg BID• Compensates for AUC decrease but trough
remains low
No dose adjustment of RAL or DTG needed if co-administered with Rifabutin
Watch for fixed dose combinations including RAL or DTG
Brainard ICAAC 2008Braininard, J Clin Pharm, 2011; Dooley, JAIDS, 2013
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RALTEGRAVIR DRUG RESISTANCE: 4 in 400 bid vs 1 in 800 BID
TAKE HOME : DOUBLE THE DOSE OF RALTEGRAVIR GIVEN WITH RIFAMPIN
Grinsztejn IAS 2012 ANRS 12-180 REFLATE
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Dose Adjustments with ART and TB Medications
Rifampin Rifabutin
Efavirenz Increase rifabutin
Nevirapine No NVP lead in
Etravirine
Rilpivirine Increase RPV
DRV/r or ATZ/r Decrease rifabutin
Lopinavir/r Increase LPV/r Decrease rifabutin
Raltegravir Increase RAL
Elvitegravir No data* (prob ↓RFB)
Dolutegravir Increase DTG No data
Maraviroc Increase MVC
NNRTI
PI
HIV+ pts with RIF-sensitive TB should only be treated with a regimen not containing a rifamycin if they have had a serious event that is highly likely to be due to the drug.
IntI
TB/HIV Coinfection Page 20 of 20
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Conclusions
CO-TREATMENT OF HIV AND TB SAVES LIVES
ART should be started immediately (within 2 weeks of TB therapy) in TB/HIV patients with <50 CD4 cells
ART should be started between 2 weeks and 2 months in all other patients with HIV and TB, even those with high CD4
TB IRIS has broad differential and remains a challenging management problem
Rifamycins have multiple interactions with ART, and special modifications of dosing of ART and/or TB regimen may be required
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Thank you!
Acknowledgements:
• Dr. Gabe Chamie, MD, Division of HIV/AIDS, UCSF
• Dr. Annie Leutkemeyer, Division of HIV/AIDS, UCSF
Disclosures: None
Thank you for your time and attention!
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