HIV and TB CO-INFECTION

Susan Swindells MBBSNebraska AIDS Education &

Training CenterUniversity of Nebraska Medical Center

Opportunistic Infections Highest Priority Worldwide

Tuberculosis

Andrew Speaker

Emergence of XDR TB

• 17,690 isolates worldwide 2004-5, 20% MDR, 2% XDR • Latvia- 19% of MDR TB cases • S. Korea- 15% of MDR TB cases• Latin America-6% of MDR TB cases• USA-4% MDR TB cases• Africa-<1% MDR TB cases• India? China?

High Prevalence and Mortality from Extensively Drug-Resistant (XDR) TB

in TB/HIV Coinfected Patients in Rural South Africa

NR Gandhi, A Moll, R Pawinski, U Lalloo, AW Sturm, K Zeller, J Andrews, G Friedland

Yale University School of Medicine, New Haven CT USANelson R. Mandela School of Medicine, Durban, South Africa

Philanjalo, Tugela Ferry, KwaZulu Natal, South Africa

Results

1539 Patients with Isolates sent

544 (35%)Culture-Positive for M.tb

995 (65%) Culture-Negative

221 (41%)Resistant to INH and RIF

(MDR TB)128 cases of MDR TB in US in 2004

53 (24% of MDR, 10% Culture-Positive)Resistant to all tested drugs

(XDR TB)

347 cases XDR TB worldwide

Days since Sputum Collected

2402101801501209060300

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Survival from Sputum Collection

Mortality

• 52 of 53 (98%) XDR TB patients died• Median survival from sputum collection 16 days (range

2-210 days)

• 2 healthcare workers died with confirmed XDR TB

– 4 other workers died with suspected XDR TB

• 64% of patients hospitalized for any cause before onset of XDR TB

• 26/30 (87%) XDR TB isolates genetically similar

• 86% HIV-infected

•Majority of patients infected with the same KZN strain•Databases 1994 to 2005 searched for resistance patterns in isolates of M.TB with KZN strain fingerprint.•In 1994, KZN strain cases with MDR TB, with some STM resistance•From 1994, MDR isolates found with resistance to additional drugs•First XDR isolate in 2001•Resistance to up to 7 drugs developed in a decade.

Evolution of the extensive drug resistant (XDR) KZN strain of M.TB in KwaZulu-Natal

Courtesy of G. Friedland

Survival by level of resistance

4002000

observationperiod

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4-censored3-censored2-censored1-censored4321group

Survival Functions

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observationperiod

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Survival Functions

1= non-MDR 2 = MDR

3 = 4/5 XDR 4 = 6 XDR

NonDR=57 MDR=52 XDR=61

Courtesy of G. Friedland

Tuberculosis and HIV Disease and TB Drug Resistance-A Perfect Storm

• Enormous cost of worldwide neglect of TB• Lack of resources, basic research, modern

diagnostics and new treatments• Estimated $20 billion needed in next decade• Areas of high TB and HIV prevalence particularly

vulnerable– Failing TB programs – Poverty/crowding/migration– Primitive infection control– Lack of interaction with HIV programs

XDR TB: High Research Priority Global XDR TB Task Force met Oct ’06

Revised case definition: Occurrence of TB with isolates resistant to INH

and RIF plus any fluroquinolone and at least one of three injectable 2nd-line drugs (amikacin, kanamycin, capreomycin)

MMWR Nov 3, 006/55(43);1176

Interaction of HIV & TB Lifetime risk of disease with MTB infection:

10-20% Annual risk with HIV co-infection 10% Leading cause of death with HIV in sub-Saharan

Africa Occurs at all CD4 levels Risk of TB increases soon after HIV infection

Incidence doubled in 1st year after infection in SA gold miners [Sonnenberg et al; JID 2005]

Reinfection and reactivation

Unanswered questions in Management of HIV/TB co-infection When to start ART What to start Optimal diagnostic tests Role of INH prophylaxis How to prevent drug resistant TB IRIS issues Pregnancy Drug-drug interactions

Estimated TB incidence rates, 2004

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2005. All rights reserved

0 - 2425 - 4950 - 99100 - 299

No estimate300 or more

Estimated new TB cases (all forms) per 100 000 population

A global view of HIV infectionA global view of HIV infection38.6 million people [33.4‒46.0 million] living with HIV, 2005

2.4

Estimated HIV prevalence in new adult TB cases

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2005. All rights reserved

HIV prevalence in TB cases, 15-49 years (%)

0 - 45 - 1920 - 4950 or moreNo estimate

ANTIRETROVIRRAL THERAPY

0

MONTH ON ARV

964862

TB in patients receiving ART

NEW TB

Undiagnosed TB

Activation of latent TB

IRISTransmitted TB

New Pulmonary TB

Treatment failure

Recurence

Reinfection

Courtesy of F. Scano, WHO

TB Skin Testing

≥ 5 mm positive in HIV-infected 55% HIV+ pts in sub-Saharan Africa TST+ Can be read after 2 -7 days

[personal communication R.Chaisson]

TB Diagnosis WHO strategy using sputum smears misses half

of incident cases at 1st presentation Misses extra-pulmonary disease 5% detection in children HIV-infected pts more likely smear-negative

Multiple visits and months of delay common Lack of standardized diagnostic tests to

in/exclude TB in ART clinical trials/rollout programs

Smear negative TB in PLHIV

• Higher chance for smear negative disease– SN pulmonary = 24 – 61%– Extrapulmonary = 4 – 40%

• Autopsy studies = 14 – 54%

• Scale of problem is underestimated– Studies are institution based– Most TB services look for smear positives– Early death before diagnosis is established

Getahun H et al Lancet 2007 DOI:10.1016/S0140-6736(07)60284-0

Key changes in the new policy

• Vigilance and flexibility to start empiric treatment for suspected extrapulmonary TB in peripheral health facilities

• TB care should include HIV care – HIV staging (clinical , immunological)– PCP treatment– Co-trimoxazole preventive therapy

• Clinical management of extrapulmonary TB be included as TB control programme activity

• Recording and reporting of SN TB improved

Clinical Predictors of Active TB in Rural Uganda (n=1995) Sign/symptom

Cough ≥ 3 weeks BMI ≤ 18 Night sweats Fever ≥ 1 month Weight loss Lymphadenopathy

Sensitivity 76% 67% 63% 59% 58% 37%

Sensitivity and specificity improved with 1 or more of: cough, fever, lymphadenopathy, BMI

Were et al; CROI 2007 abstr# 848

Role of DOTS Directly Observed Treatment Short-Course Public health based Passive detection using sputum smear Standardized regimens 6-8 months with

DOT for at least first 2 Targets: 70% detection, 85% cure

2006

ReferenceReferenceLabLab

PeripheralPeripheralLabLab

FIND Product Deliverables 2006-2013FIND Product Deliverables 2006-2013

ClinicClinicHealth postHealth post

2007 2008 2009 2010 2011 2012 2013

% A

ccess after 5 years

95%

70%

10-40%

Liquid culture

MTB & DST

Phage based

resistance test

Automated

NAAT

LED Fluor

Microscopy POC

NAAT

Urinary AG

detection Reader b

ased

LAT Flow

Speciation

test

Urinary

NAAT

Improved AG/AB

strip te

st

Role of INH CDC recommends for TST ≥ 5 mm WHO recommends INH for all HIV+ in high

prevalence countries Most of Asia and Africa do not use: officially

discouraged in S. Africa and India Limited resources to screen for active disease Concern about drug resistance

INH preventive therapy (IPT)

IPT reduces risk of TB in HIV+ people by 62% in PPD+ By 36% overall

Evidence of survival benefit in children and in adults in cohort studies

Benefit of IPT may wane after 1-2 years in high prevalence settings

Efficacy of IPT in HIV+ Adults: Risk of TB

• 11 randomised trials with 8,130 HIV+ participants overall reduction in TB = 36%, reduction PPD+ = 62%

Woldehanna and Volmink, Cochrane Review 2006

0.95

0.64

TB incidence

Death

Relative Risk (Fixed)95% CI

Reference1.0

Treatment of Latent TB in HIV+ Patients and Survival

in Brazil

Pinho, AIDS 2001

TB Preventive Therapy and Drug Resistance

• Review of 13 IPT trials with ~35,000 participants shows low risk of selecting resistance (RR 1.45, 95% CI 0.85-2.47)

• For INH-resistant LTBI, rifampin effective• For MDR or XDR exposure, no regimen has been

shown to be effective• Drugs with potential utility:

– Linezolid– Clofazimine– Amoxicillin/clavulanic acid

Balcells et al. EID 2006;12:744; Nuermberger et al. AJRCCM 2005;172:1452

MDR TB Treatment Peru, Philippines & Eastern Europe cohort

data N = 729 70% success rate Required individualized regimens with at least 4

drugs including 1 injectable + fluroquinolone

MDR-TB can be treated in resource poor countries (but not very poor ones)

Nathanson et al; Emerg Inf Dis Sep 2006

Discovery - 17 Preclinical - 4 Clinical Testing - 5

Dihydrolipoamide Acyltransferase InhibitorsNIAID, Cornell University

DipiperidinesSequella Inc.

InhA InhibitorsGlaxoSmithKline, TB Alliance

Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance

MacrolidesTB Alliance, University of Illinois at Chicago

Methyltransferase inhibitorsAnacor Pharmaceuticals

Translocase I InhibitorsSequella Inc., Sankyo

Synthase Inhibitor FAS20013FASgen Inc.

Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID, TBRU

Diarylquinoline R207910Johnson & Johnson

Proprietary Compound Otsuka

Natural Products Exploration NIAID, TAACF, California State University, University of Auckland

Nitroimidazole PA-824 Chiron Corporation, TB Alliance

Diamine SQ-109Sequella Inc.

GatifloxacinOFLOTUB – TDR, Tuberculosis Research Centre, NIAID, TBRU

Cell Wall InhibitorsNIAID, Colorado State University

Novel Antibiotic ClassGlaxoSmithKline, TB Alliance

Picolinamide ImidazolesNIAID, TAACF)

PleuromutilinsGlaxoSmithKline, TB Alliance

Pyrroles(TB Alliance, Private Sector Partner)

QuinolonesKRICT/ Yonsei University, NIAID, TAACF, TB Alliance

Proprietary CompoundsAstraZeneca

Thiolactomycin AnalogsNIAID, NIH

Nitroimidazole Analogs Novartis Institute for Tropical Diseases, NIAID, TB Alliance

Nitrofuranylamides NIAID, University of Tennessee

Pyrrole LL-3858Lupin Limited

Role of VaccinesRole of Vaccines

Pre or post exposure vaccines could Pre or post exposure vaccines could decrease disease/deathdecrease disease/death

Use in combination with antibiotics?Use in combination with antibiotics?

Role of ART: WHO Guidelines 2006 for ART Initiation

Stage IV illness TB ; serious bacterial infections if CD4

<350 Before CD4 count falls to 200 Start ART treatment 2 - 8 weeks after

TB for active disease

WHO Guidelines

PreventionPreventionOptimal timing of ART initiation in those on Optimal timing of ART initiation in those on

TB treatment?TB treatment?

EARLY DELAYED

IRISPill BurdenDrug-drug interactionsToxicityCost

Increased disease progression and death

Cape Town cohort of 264 pts on ART and Cape Town cohort of 264 pts on ART and

770 not; 1992-2001770 not; 1992-2001 [Badri Lancet 2002][Badri Lancet 2002]

On ARTOn ART NotNot RRRR P valueP value

CD4 countCD4 count # cases # cases (incidence)(incidence)

# cases # cases (incidence)(incidence)

<200<200 5 (3.4%)5 (3.4%) 41 (17.5%)41 (17.5%) 0.180.18 <.0001<.0001

200-350200-350 2 (1.7%)2 (1.7%) 27 (12%)27 (12%) 0.120.12 <.0001<.0001

>350>350 2 (2%)2 (2%) 14 (3.6%)14 (3.6%) 0.360.36 0.780.78

OverallOverall 9 (2.4%)9 (2.4%) 82 (9.7%)82 (9.7%) 0.190.19 <.0001<.0001

Rifampin Interactions: Is dose adjustment required?

• EFV and NVP are reduced 20-40% with rifampin1,2,3,4

• Small PK studies support dose increase of EFV (800 mg) and NVP(300 mg bid) 5,6

• Large interpatient variability due to genetic determinants of metabolism7

• Clinical outcome studies to date do not support dose adjustment of EFV or NVP

1Ribera, JAIDS, 2001; 2Lopez-Cortes, Clinical PK, 2002; 3Manosuthi, AIDS, 2005 ; 4Manosuthi, CID, 2006

5 Lopez-Cortes, Clinical PK, 2002; 6Ramachandran, JAIDS, 2006; 7Haas, AIDS, 2004; Friedland J, Antimicrob. Chemotherapy 2006.

TB-IRIS: Incidence and Risk Factors

Lawn et al; AIDS 2007

TB-IRIS: Incidence and Risk Factors

Risk of IRIS high with low CD4 count and early treatment

Most cases self-limiting Mortality rate low (1%)

Lawn et al; AIDS 2007

Conclusions

ART reduces TB risk, but not enough Risk of selecting for resistance with IPT

appears low Active TB can be ruled out by clinical or

laboratory screening in most patients Need for improved diagnostics

Treatment of TB and HIV concurrently is complex

TB Control in HIV-Endemic Areas Requires Reassessment of traditional approaches to TB

control (active vs passive case finding, DOTS) Development of new tools and technologies Increased drug availability and new drugs;

shorter, simpler regimens Vaccine? Joint approaches with HIV-related programs Earlier access to ART