Exciting developments in TB diagnosis, prevention, and

treatment

Amita Gupta MD MHSAssociate Professor of Medicine and International Health

Center for Clinical Global Health Education

Johns Hopkins University agupta25@jhmi.edu

XI HIV/AIDS Johns Hopkins/Brazil Conference, April 19, 2013

Overview

• Epidemiology

• Novel diagnostics

• Management

– When to start ART

– Drug interactions

– TB-associated IRIS

– Drug resistant TB

• Prevention of TB

– INH, ART

– Novel regimens

– Vaccines

Disclosures

• I receive funding from the

– US National Institutes of Health

– Indian Department of Biotechnology and Indian Council of Medical Research

– Gilead Foundation

– Ujala Foundation

– World Health Organization

• Any opinions expressed are my own and not of any of my sponsors.

Epidemiology

Trends in Estimated TB incidence rates overall (green) and among HIV-positive (red), selected

high-burden countries, 1990–2010

Global TB Control, WHO Report 2011

Brazil TB snapshot

• In 2011, 74892 cases reported

• 71337 new and 10045 retreatment

– 40294 smear +

– 12683 smear -

– 8278 unknown

– 10017 extrapulmonary

– 2450 among <15 year olds

– 566 MDR TB

• Financing $86 million USD, 91% domestic source

74%69%46%

Global TB Control, WHO Report 2012

HIV testing, treatment for HIV-positive TB patients and prevention of TB among people

living with HIV in BRICS countries

HIV+/TB incidence

rate/100,000

TB pts with

known HIV*

% of TB pts tested

for HIV

% HIV+

%

started on CPT

% started on ART

No. screen

ed for TB*

No. on IPT*

Brazil 16 49 58 20 - 80 - -

Russia 9 79 - - - - - -

India 94 689 45 9 91 59 386 -

China 13 209 23 2 - 36 - -

South Africa

330 323 83 65 76 44 1256 373

Global TB Control, WHO Report 2012

*Number are in thousands

TB Diagnosis

TB Diagnosis

• Only 65% of TB cases diagnosed and treated globally

• <5% cases tested for MDR

• Diagnostic delays increase mortality

New Diagnostics

LED microscopy

Line probe assays

Urine Lam Dipstick

Boehme CC et al. N Engl J Med2010;363:1005-1015

Sensitivity 68-98% Specificity 99-100%

Proportion of results reported to clinics from time of sputum collection

Time to treatment

Smear-,cx+ 56 days vs 5 days

Median time to

detection

0 days MTB/RIF

1 day smear

16 days liquid cx

30 days solid cx

DST-RIF Resistance

1 day MTB/RIF

20 days LPA

106 days standard

phenotyping

Boehme Lancet 2011

Lawn & Zumla, Exp Rev Anti-Infect Ther 2012

452 children

• <15 years old

• 24% HIV+

• 6% AFB smear+

• 16% Cx+

• 13% MTB/RIF+

• MTB/RIF detected twice as many TB cases compared to smear 76% vs 38%

(all smear+ and 61% of smear-)

– Testing a second sputum in smear (-) cases increased sensitivity by 28%

– Specificity 99%

– Median 1 day vs 12 days for cx

Lancet ID 2011

Determine TB Urine Lipoarabinomannan (LAM) Antigen detection

• ELISA

• Newer Lateral flow point of care assay (like a pregnancy test)

• LAM -17.5kd glycolipid protein in MTB cell wall released from active or degrading MTB cells in urine

Neg Intermed+ Strong+

Urine LAM

• Overall sensitivity: 50%

• Specificity: 50-100%

• Urinary excretion of LAM correlates with MTB burden and hence shows prognosis

• Cross reactivity with Candida spp and normal oral flora containing LAM-like molecules

• Poor sensitivity and specificity in pleural, pericardial, CSF

Dheda et al, 2013

Urine TB LAM detection in HIV+ depends on CD4 count

Dheda PLOS 2010; Shah JAIDS 2009; Lawn AIDS 2009; Lawn Lancet ID 2011; Minion Eur Resp J 2011

Sensitivity highest in HIV+ with

advanced immunosuppression

Among 101 culture confirmed TB patients with median CD4 60, Uganda

Shah et al, CROI 2013

“Niche clinical utility” rapid TB screening tool for HIV+ with low CD4, starting ART in high TB/HIV burden settings

TB diagnosis in children

• Further diagnostic studies needed

– Xpert in different TB/HIV settings, extrapulmonary TB

– LAM being evaluated but appears to be low yield

– String test, stool test being evaluated

• Consensus statements for evaluation of TB diagnostics in children

– Graham JID 2012; Cuevas JID 2012

TB Treatment

WHO/photographer Jean Chung http://stoptb.org/resources/photos/

When to treat TB

in setting of ART?

Initiation of ART during vs. after TB

treatment: SAPIT

Abdool Karim S (2010) NEJM 362: 697.

Significant survival benefit to providing ART during TB treatment rather than waiting until completion of TB treatment

Key characteristics of trials of timing

of ART during TB treatment

Study Setting ART start

Key

enrollment criteria

Median CD4 (IQR)

Primary endpoint

CAMELIA(Blanc, ANRS)

Cambodia2 wks vs.

8 wks

Smear +, CD4 < 200

25 (10 - 56)

Death

STRIDE(Havlir, ACTG)

Multi-national

2 wks vs.

8-12 wks

Clinical TB, CD4 < 250

77 (36 – 145)

AIDS or death

SAPIT(Abdool-Karim,

CAPRISA)

South Africa

1st 4 wks vs.

8-12 wks

Smear +, CD4 < 500

150 (77 – 254)

AIDS or death

AIDS 2010 abstract THLBB106, CROI 2011 abstract 38, CROI 2011 abstract 39LB

Abdool Karim NEJM 2010; Blanc NEJM 2011; Havlir NEJM 2011

For patients who get TB, early ART reduces

death (CAMELIA) or death/AIDS (STRIDE, SAPIT)

34% ↓p=0.004

19% ↓

p=0.45

11% ↓

p=0.7334% ↓

p=0.004

42% ↓

p=0.02

68% ↓

p=0.06

CD4 < 50Overall

Abdool Karim NEJM 2010; Blanc NEJM 2011; Havlir NEJM 2011

Viral suppression – no effect of timing of ART on suppression at end of TB treatment

ART switches – higher in immediate arm of SAPIT

Risk of IRIS with ART during TB treatment

A5221/ STRIDE3 CAMELIA1 SAPIT Integrated2

N 806 660 429

CD4+ (IQR) 77 (36,145) 25 (11,56) 150 (77, 254)

IRIS 8% 25% 14%

Earlier vs.

later ART10% vs. 5%

33% vs.14%

(p<0.05)

20% vs. 8%

(p<0.001)

Severe IRIS,

earlier vs.

later ART

3% (13/405) vs. 2%(6/401),

No IRIS deaths

Severity data not

available,

7 deaths(6 immediate)

7%(15/214) vs 2%(4/215),

2 deaths (immediate)

1 Laureillard IAS 2011 WEAX0104, Blanc NEJM 2011,

2 Naidoo IAS 2011 WEAX01051, Karim NEJM 2011

3 Luetkemeyer, CROI 2012, Havlir NEJM 2011

Timing of ART in patients with TB

• Advanced AIDS (CD4 < 50): immediate ART (within 2 weeks) improves survival

– Increased risk IRIS, including fatal IRIS

– Overall survival benefit despite this

• CD4 > 50: early ART (~ 2 months) provides good balance of competing risks of death/AIDS vs. IRIS

• Caveats

– CNS involvement – no benefit to immediate therapy, and there may be increased risk* (Torok, CID, 2011)

Which drugs to use?

Nucleus

Cyt

opla

sm

PXR

RXR

RIF

RIF PXR RXR

CYP3A4proximalpromoter

Phase II enzyme

regulatory genes

PGPregulatory

gene

MDR1 proteinregulatory

gene

DNA

mRNA

CYP 3A4XRE

Dooley (2008) JID 198: 948.

RIFAMPIN: A promiscuous inducer of metabolizing enzymes

Important Drug Interactions with

Rifampin• NRTIs (AZT, 3TC, TDF, etc.)

– No significant interactions

• NNRTIs (EFV, NVP, rilpivirine, etravirine)

– RIF decreases NVP exposure 40-50%,

– EFV decreases 20-35% but effects highly variable. In some levels of EFV actually increased (TT genotype)

– RIF decreases rilpivirine 80%-> do not coadminister

– RIF decreases etravirine->do not coadminister

• Protease inhibitors (LPV/r, DRV/r, ATV/r, etc.)

– RIF decreases exposure >80%, in most cases

– Increasing the PI dose can lead to hepatotoxicity

• CCR5 Inhibitors (Maraviroc)

– RIF reduces maraviroc exposure by 63%

• Integrase inhibitors (RAL)

– RIF reduces raltegravir exposure by 40-60%Slide Courtesy of Kelly Dooley, JHU

Antiretroviral Interactions Rifampin

All PIs PIs � >75% NOT RECOMMENDED

(DOUBLE DOSE of PIs being

studied but toxicities a concern)

All NRTIs No significant interactions No dose change

NNRTIs

EFV EFV � 26%

CYP2B6 TT genotype �EFV

(more common in Blacks/

African and Indians)

EFV 600mg once daily

(FDA recommends 800mg

for>50kg but no clinical evidence

to support the need for this)

NVP � 20%-58%

ETR Significant � DO NOT USE

RPV RPV AUC� 80% DO NOT USE

Integrase inhibitors

RAL RAL AUC � 40%, cmin 61% 800mg BID*

EVG/COB/TDF/FTC Significant � expected DO NOT USE

MVC AUC � 64% Not recommended but if

necessary 600mg BID if no CYP3a

inhibitor present

Raltegravir + rifampin

Wenning (2009) AAC 53: 2852.

Virologic suppression with RAL

800 once-daily vs. 400 mg twice-daily (HIV patients without TB)

RAL 400 mg twice-daily alone

RAL 800 mg twice-daily with RIF

Eron, CROI 2011, Abstract # 150LB

Recommendation: Raltegravir at a dose of 800 mg twice daily with rifampin is an acceptable alternative. Employ with caution, though, because clinical significance of lower troughs is unknown

Slide Courtesy of Kelly Dooley, JHU

Efavirenz vs Raltegravir for HIV/TB: REFLATE Phase II Trial

• 153 HIV/TB pts (most Brazilian)

• 3 arms

• EFV 600mg QD

• RAL 400mg BID

• RAL 800mg BID

Proportion with VL<50 at 48 weeks: 73% EFV vs 75% RAL 400 vs 65% RAL 800

Grinsztejn et al Poster 853, CROI 2013

Lopinavir/ritonavir + rifampin

Day 0: LPV/r at a dose of 400/100 twice daily alone

Day 21: LPV/r at a dose of 800/200 twice daily together with rifampin

Day 15: LPV/r at a dose of 600/150 twice daily together with rifampin

Recommendation:For patients already taking LPV/r who require RIF, gradual increase in LPV/r dose to double the dose may be effective.

Decloedt (2011) AAC 55: 3195.Slide Courtesy of Kelly Dooley, JHU

Antiretrovirals and RifabutinARV Interaction/ PK

effect

Rifabutin Recommended dose

PIs

ATV/r Rifabutin 150mg once daily

OR

300mg three times a week.

Monitor for antimycobacterial

activity and consider TDM

DRV/r

FPV/r

LPV/r

SQV/r

TPV/r

NRTIs

AZT

TDF

d4T

ABC

No interaction No dose change

5mg/kg daily (max dose 300mg

once daily)

Rifabutin + Boosted PIs – some issues

• Bidirectional drug interactions– RBT is metabolized by cytochrome P450 (CYP) 3A4, so you

have to decrease the dose when you give it with CYP3A4 inhibitors, like ritonavir, to avoid toxicities

• Expensive, not widely available

• Efficacy data is scanty– Clinical trials comparing RBT to RIF were largely conducted

among patients not taking ARVs

– Reports of rifamycin resistance in patients receiving 150mg every other day (Jenny-Avital et al, CID 2009)

HKCS/BMRC 1992; Gonzalez-Montaner 1994; McGregor 1996; Rowinska-Zakrzowska 1992; Schwander 1995

We don’t know what dose of RBT to give when RBT is given together with a PI.

Boosted PI + rifabutin

Among 16 patients receiving rifabutin plus LPV/r:•6 with Grade 3 hepatitis•3 with Grade 3 neutropenia•1 with Grade 2 uveitis

Recommendation:Boosted lopinavir together with rifabutin is an option. Dosing RBT at 150 mg daily is likely necessary to achieve therapeutic concentrations

Caveats:•Monitor for hepatotoxicity and neutropenia•If you stop the ARVs, make sure to adjust the RBT dose back to 300 mg daily

Naiker, CROI 2011, abstract 650. Slide Courtesy of Kelly Dooley, JHU

Antiretroviral Interaction/PK effect RIFABUTIN

Integrase inhibitors

RAL NO DOSE CHANGE

EVG/COB/TDF/FTC DO NOT USE

NNRTIs

EFV RFB AUC � 38% Rifabutin 450-600mg once

daily or 600mg 3 times/wk

NVP RFB AUC� 17% No dose change

ETR RFB and metabolite � 17%

ETR AUC � 37%

If ETR with PI/r->DO NOT USE

300mg once daily if no PI

RPV RPV AUC �46% DO NOT USE

Other

MVC MVC �possible If strong CYP3A inducer , MVC

300mg BID

If strong CYP3A inhibitor

MVC 150mg BID

T20 No interaction No dose change

Overlapping toxicities

Adverse Reaction TB Drugs HIV Drugs

Rash PZA, RIF, INH NNRTIs, ABC,

T/S

Hepatotoxicity INH, RIF, PZA PIs, NVP

Nausea RIF, PZA, INH RTV, AZT,

APV

Cytopenias RBT, RIF AZT, T/S

CNS INH EFVNot to mention pill burden and coordination of services…..

Slide Courtesy of Kelly Dooley, JHU

Available guidance

http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/PDF/tbhiv.pdf

http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

What are the co-treatment options?

• Efavirenz-based ART with rifampin-containing

TB treatment -preferred

• Nevirapine + rifampin- alternative• NVP should be given at 200 mg twice daily

throughout co-treatment

• Raltegravir + rifampin

• Super-boosted lopinavir or double-dose

lopinavir/ritonavir + rifampin

• Protease inhibitor + rifabutin

• Triple/quadruple NRTI + rifampin

Slide Courtesy of Kelly Dooley, JHU

NC002 Phase II PA-824, moxifloxacin, PZA novel combination for both Drug Sensitive TB and MDR TBNC003 PA-824, TMC207, PZA and clofazimine

MDR TB

• Pulmonary MDR TB: Phase IIb TMC207

(bedaqualline) Diacon NEJM 2009; IUATLD 2010 Berlin

– 13% HIV+ of 47 patients

– At 8 weeks, addition to TMC207 to OBR increased sputum culture

conversion from 9% to 48%

– At 24 weeks (8 weeks of TMC207 +OBR then standard treatment vs

standard treatment) 58% vs 79%

• 9 month Bangladesh regimen Van Deun Am J Resp Crit Care

Med 2010

– Observational study of 206 patients (almost all HIV-negative)

– No prior second-line TB treatment

– 9 months of Gatifloxacin, clofazamine, ethambutol, PZA with 4 month

intensive phase of prothionamide, kanamycin, high dose INH

– Relapse-free cure 88%

– Infrequent and manageable AEs

14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide,

and moxifloxacin combinations: a randomised trial Andreas H Diacon MD a d , Rodney Dawson MD e, Florian von Groote-Bidlingmaier MD d, Gregory Symons

MBChB e, Amour Venter NatDipTech b, Prof Peter R Donald MD c, Christo van Niekerk MD g, Daniel Everitt MD f, Helen Winter PhD h, Piet Becker PhD i, Carl M Mendel MD f, Melvin K Spigelman MD f

The Lancet Volume 380, Issue 9846, Pages 986 - 993, September 2012

Linezolid for Treatment of Chronic Extensively Drug-Resistant TuberculosisMyungsun Lee, M.D., Jongseok Lee, Ph.D., Matthew W. Carroll, M.D., Hongjo Choi, M.D., Seonyeong Min, R.N., Taeksun Song, Ph.D., Laura E. Via, Ph.D., Lisa C. Goldfeder, C.C.R.P., Eunhwa Kang, M.Sc., Boyoung Jin, R.N., Hyeeun Park, R.N., Hyunkyung Kwak, B.S., Hyunchul Kim, Ph.D., Han-Seung Jeon, M.S., Ina Jeong, M.D., Joon Sung Joh, M.D., Ray Y. Chen, M.D., Kenneth N. Olivier, M.D., Pamela A. Shaw, Ph.D., Dean Follmann, Ph.D., Sun Dae Song, M.D., Ph.D., Jong-Koo Lee, M.D., Dukhyoung Lee, M.D., Cheon Tae Kim, M.D., Veronique Dartois, Ph.D., Seung-Kyu Park, M.D., Sang-Nae Cho, D.V.M., Ph.D., and Clifton E. Barry, III, Ph.D.

N Engl J Med; 367:1508-1518, October 2012

TB Prevention

Treatment as Prevention: The

case for (latent) TB

IPT

HAART

HAART +IPT

Newer regimens

Isoniazid Preventive Therapy (IPT)

Reduces Risk of TB among PLHIV

Akolo 2010 Cochrane review

HIV+, TST+ received 6 months IPT in Rio de Janeiro (THRio study)2135 pts, 1615 began IPT, 42 developed TB (IR 0.51/100PY)50% of TB occurred within 12 mo of IPT stopping (almost all among non-completers)

TB incidence: Completed IPT 0.51/100PYIncomplete IPT 1.03/100PYNever had IPT 6.74/100PY

Conclusion: 6 months of IPT may be durable for Brazil

Golub

Number

of Cases

ART reduction in TB risk by baseline CD4 group

Overall (any CD4)65% reduction

CD4 0-19984% reduction

CD4 200-35066% reduction

CD4 >35057% reduction

Suther et al PLOS Med 2012

Combined ART and IPT appears to provide

greater reduction in TB risk

Rangaka AIDS 2012

New WHO IPT Guidelines for HIV+ in high

HIV/TB regions (December 2010)

5/8/2013 57

New WHO TB symptom screening

tool for HIV-infected

• Any current cough, fever, night sweats, or

weight loss

• Meta-analysis of 12 studies

– Sensitivity: 90% in clinical settings

– Negative predictive value: 97.7% and 90% in 5%

and 20% TB prevalence among HIV respectively

– Minimal incremental value of chest Xray

Getahun PLOS Med 2011, WHO Guidance December 2010; Gupta CID 2011

3mo High dose INH/Rifapentine given

weekly is non-inferior to 9 mo INH

900mg INH/900mg RPT weekly for 12 wks

Weekly High Dose 3HP vs 9H in HIV+ not on ART (N=393)

• Enrollment of HIV+ ongoing to assess tolerability

• In MITT analysis, persons receiving 3 HP

– Had higher completion rates (89% vs 65%,p=0.04)

– Fewer AEs (22 vs 40, p=0.004)

– Less hepatotoxicity (2% vs 6%, p=0.03)

• PK studies ongoing to assess RFP and EFV interactions

Sterling AIDS 2012, IAS MOA B0302

Summary TB prevention in HIV+ adults

• IPT, HAART and HAART+IPT all reduce TB

– Adherence important

– More benefit of IPT in TST+

• 6 month INH in HIV+ TST+ appears to offer durable

protection in Brazil setting

• 3RPT/INH: a new safe and effective alternative that

appears potentially superior to 9INH

• Regimen not yet recommended for HIV patients on ART as PK data not available

• Simple TB screen: absence of fever, night sweats, cough, weight loss (with or without CXR) can be used to initiate TB preventive regimen

• ACTG 5279: Phase III trial assessing ultra-short LTBI treatement with daily INH/rifapentine x 4weeks in

What about TB prevention in HIV-infected and

HIV-exposed children?

Conflicting Data on IPT in Children

CHER Study Showed ART Benefit in

Preventing TB in Children

Summary guidance for children• Brazil guidelines

– Contact tracing and IPT are priorities

– Positive TST≥5mm in >2 yrs old BCG vaccinated

children; or non-BCG children or

immunosuppressed ( e.g. HIV+)

– ART to HIV+ children

– TST≥10mm in <2 yrs old BCG vaccinated

• WHO and Brazil guidance

– INH to TB-exposed children <5 years and to HIV-

infected children remains critical

• INH/rifapentine PK and efficacy to be studied

further

The development pipeline for new

TB vaccines, 2012

MV85A/AERAS-485 Phase II RCT in infantsWell tolerated but no efficacyTameris et al , Lancet March 23, 2013

Combination Prevention

WHO Health Organization

Conclusions• TB incidence, prevalence, mortality declining

• Several novel rapid TB diagnostics for TB

– Xpert

– Xpert + LAM in low CD4 group

– Cost-effective

• Need better rates of testing TB patients for

HIV but Brazil doing a great job with ART

• Further Implementation of TB screening and

IPT scale-up needed

• Novel shorter courses for LTBI being studied in

HIV-infected persons on ART

•

Conclusions

• “Co-treatment” – both infections must be treated

• Much progress on timing of ART initiation

– CD4 < 50: immediate (2 weeks)

– CD4 > 50: early (2-3 months)

• Several co-treatment options, but more data needed

– New guidance for daily rifabutin dosing with PI

– RAL and Rifampin appear to be an option

– Guidelines available, Research in progress

• Several new drugs in clinical development for

prevention and treatment of drug sensitive and MDR

TB, so new options are on their way

AcknowledgementsConference organizers

Adriana Andrade, Joel Gallant, Beatriz Grinsztejn, Esaú

Custódio João Filho, Mauro Schechter, Valdiléa G. Veloso,

Claudia Antonaccio

Some slides adapted from Lisa Nelson WHO STOP TB, Kelly

Dooley JHU, Jonathan Golub JHU

EFV + Rifampin – preferred option

Recommendation: Use EFV and rifampin together without dose adjustment of EFV

Boulle (2008) JAMA 5: 530Manosuthi (2009) CID 48: 1752

NVP + rifampin: alternative optionP

rop

ort

ion

with

de

tecta

ble

vir

al lo

ad

Months on ART

TB patients here were on TB treatment then started ART

Patients here were on stable ART and then developed TB

and started TB drugs

TB+HIV

HIV only

Recommendation: If EFV cannot be used, NVP and rifampin is an acceptable alternative. NVP should be given at 200 mg twice daily throughout co-treatment

Boulle (2008) JAMA 5: 530

Bonnet, abstract WELBX05, IAS Rome,