What’s new in HIV-associated tuberculosis? · 2020-02-12 · §4thgeneration IGRA FDA approved...

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Sarah Puryear, MD MPH

What’s new in HIV-associated tuberculosis?December 14, 2019

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Disclosure

I have no relevant financial relationships with any companies related to the content of this course.

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Objectives

§ Select and interpret diagnostic tests for latent tuberculosis infection (LTBI) in HIV-infected patients

§ Design an LTBI treatment plan that accounts for ART drug interactions

§ Identify appropriate methods to screen for LTBI vs. diagnose active TB

§ Describe when to start ART in TB and major rifamycin-ART interactions

§ Manage TB immune reconstitution inflammatory syndrome (IRIS)

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Tuberculosis: A major global health problem

WHO, Global Tuberculosis Report 2019

§ 2018:- 10.0 million

cases/year- 1.5 million

deaths/year

§ #1 cause of death among PLHIV

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Epidemiology of TB in the United StatesTuberculosis Cases in United States, 1980-2015

Centers for Disease Control (CDC). Reported Tuberculosis in the United States, 2015 Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2016.

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Epidemiology of TB in California

California Department of Public Health (CDPH). TB Fact Sheet 2017, Sacramento, CA; 2018.

• California reports 20% of TB cases in the US each year

• >2000 cases annually• LTBI cases estimated at 2.4 million

• 1 in 17 Californians• 1 in 5 foreign-born Californians

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Audience response

How many people have you started on latent TB treatment in the past year?A. None. B. <5C. 5-10D. Who has time to count!?

0A B C D

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Case 1

§ A 41 year-old man from San Francisco presents to your clinic for evaluation. Two weeks ago, he was diagnosed with HIV.

§ Initial labs show:- CD4 120, HIV RNA 75,000 - Interferon gamma release assay (IGRA): Indeterminate

§ He denies any history of TB infection and does not know of any contacts with TB

§ He has experienced homelessness and has had brief periods of incarceration in the past

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Audience Response41M from SF with new HIV (CD4 120, VL 75K) and indeterminate IGRA

What is the correct interpretation of this indeterminate IGRA result and what is your next step?

A. TB infected; rule out active TB and treat him B. TB exposed, uninfected; do nothingC. TB infection cannot be determined; re-test when CD4 is higherD. TB exposed OR BCG vaccinated; obtain a PPD “tie-breaker”E. TB infection cannot be determined; obtain a PPD “tie-breaker”

0A B C D E

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Screening for LTBI in HIV

§ WHO?- All HIV patients, regardless of

risk factors§ WHY?- Increased risk of progression to

active disease- Poor outcomes with active

disease- Effective treatments exist

§ WHEN?- At HIV diagnosis or entry into

care- In those with negative LTBI test

& CD4<200 à repeat after ART started & CD4>200

- If likely ongoing/repeat exposure to active TB: Screen annually

- Recent contact with a known TB case

DHHS OI Guidelines, 2019

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LTBI Treatment and ART reduce risk of TB disease and death in PLHIV

Badje, Lancet Global Health, 2017

Prob

abilit

y of

Dea

th

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Testing for LTBIOption 1: Tuberculin Skin Test Option 2: Interferon Gamma

Release Assay

Neither distinguishes between latent and active disease

Negative does NOT rule out active disease

48 to 72 hours later

≥ 5 mm positivein HIV+ pts

QuantiFERON-TB Gold-Plus ELISA

T-SPOT.TBELISPOT

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TST vs. IGRABoth 65-70% sensitive in PLHIV

Diagnostic Approach

Strengths Limitations

TST§ Vast experience,

abundant data§ Cheaper

§ Requires 2 visits§ False positives possible with BCG*§ Can remain positive after LTBI,

active TB tx

IGRAs§ Requires 1 visit§ Interpretation not

subjective§ More specific than TST§ Unaffected by BCG

§ Technical errors§ Must be processed in 8-30hrs§ False positives with some other

mycobacteria§ Limited data in children, recent TB

exposure, CD4<200§ Can remain positive after LTBI,

active TB tx

*BCG status should NOT affect PPD interpretation

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QuantiFERON-TB Gold-Plus

§ 4th generation IGRA FDA approved 6/2017§ Advances/Advantages1

- Adds CD8+ T cell antigens- Option for single tube blood collection- Non-inferior sensitivity

§ PLHIV2

- Overall sensitivity not affected by HIV status- Lower sensitivity with severe

immunosuppression

1APHL Press Release, 2018. 2Telisinghe, IJTLD, 2017.

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QuantiFERON-TB: Interpretation

Measure IFN-γ by ELISA

Incubate

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Nil (IU/ml)

TB1 minus Nil (IU/ml)

TB2 minus Nil (IU/ml)

Mitogen minus Nil

(IU/ml)

QFT-Plus Result

Report/ Interpretation

≦8.0

≥0.35 and ≥25% Nil

Any Any Positive M. tuberculosis infection likely

Any ≥0.35 and ≥25% Nil

<0.35 OR

≥0.35 and <25% Nil

≥0.5 Negative M. tuberculosis infection NOT

likely

<0.5 Indeterminate Likelihood of M. tuberculosis

infection cannot be determined

>8.0 Any Any

QuantiFERON-TB: Interpretation

QualitativeQuantitative

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...but wouldn’t a tie-breaker help?

§ 294 HIV positive San Franciscans underwent TST & Quanteriferon1

- 30% did not return for PPD follow up- Concordance of tests: 89.3%

§ BUT if one test was positive: only 28% had concordance

1Luetkemeyer, Am J Respir Crit Care Med, 2007; 2Mazurek, MMWR, June 2010.

“…the predictive value of this approach is not clear, and its adoption would be more expensive and more difficult to implement. The routine use of both TST and IGRAs to

screen for LTBI is not recommended in the United States”2

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Case 1 (continued)

§ You start him on Descovy (TAF/FTC) and Dolutegravir§ 3 month labs demonstrate: - CD4 is 230, VL undetectable- Repeat QuantiFERON positive

§ He is asymptomatic§ CXR is within normal limits

You decide to treat him for LTBI.

41M from SF with new HIV (CD4 120, VL 75K) and indeterminate IGRA

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Audience Response 41M from SF with new HIV (CD4 230, VL UD) on TAF/FTC/DTG with positive IGRA

Which one of the following regimens do you select to treat LTBI in this patient?

A. Isoniazid, pyrazinamide, rifampin, ethambutol, and pyridoxine for 2 months

B. Isoniazid and pyridoxine daily for 9 monthsC. Isoniazid and pyridoxine daily for 6 monthsD. Isoniazid and pyridoxine plus rifapentine weekly for 3

months

0A B C D

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LTBI Treatment Options

§ Preferred- 9H: INH x 9 months (with B6)

§ Alternative- 3HP: INH + Rifapentine weekly (with B6) †

- 4R: Rifampin x 4 months - 6H: INH x 6 months (with B6)*- 2RZ: Rifampin + Pyrazinamide x 2 months

§ **High risk of hepatotoxicity**

†Rifapentine and isoniazid recommended only with Efavirenz and Raltegravir + ABC/3TC or TDF/FTC.

DHHS OI Guidelines, 2019

H= isoniazidR=RifampinP=RifaPentineZ=PyraZinamide

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Current Guidelines for TB Preventive Therapy

Regimen Adult Dosage Durations, Months Evidence Rating in HIV-Positive Pts

Isoniazid* daily 300 mg/day 9 A IIsoniazid* daily 300 mg/day 6 C IRifampin daily 600 mg/day 4 B IRifapentine + isoniazid*† weekly

Maximum: 900 mg/900 mg

(+/- DOT)3 A II

*Give pyridoxine 10-50 mg/day with isoniazid to prevent neuropathy in HIV-positive pts.†Rifapentine and isoniazid recommended only with Efavirenz and Raltegravir + ABC/3TC or TDF/FTC.

DHHS OI Guidelines, 2019; Borisov, MMWR, 2018.

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Menzies, NEJM, 2018; DHHS OI Guidelines, 2019

• Multinational study of 6063 patients (Only 255 PLHIV)• Completion rate: 78.8% rifampin vs 63.2% INH• Adverse events: 1.5% in rifampin vs. 2.6% INH• TB cases: 0.1/100 person-yrs in RIF vs. 0.11/100 person-yrs in INH

HOTOFF THE PRESS

à DHHS 2019: 4R recommended in LTBI patients who cannot receive INH

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3HP Guidelines Update

§ 2011: 3HP recommended for LTBI in PLHIV NOT on ART§ 2018 CDC updates & 2019 DHHS updates:- As young as 2 years- PLHIV taking ARVs with acceptable drug-drug interactions with RPT- By DOT or self-administered therapy

DHHS OI Guidelines, 2019; Borisov, MMWR, 2018; Sterling (PREVENT TB), AIDS, 2016

HOTOFF THE PRESS

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What is an “acceptable drug-drug” interaction with rifapentine?Rifapentine and Antiretrovirals

§ Efavirenz (n=87)1

- 1HP qD- EFV >1mg/L: 98%à86% (0à4 weeks)- VL undetectable: 93%à95% (0à8 weeks)

§ Raltegravir (n=16)2

- RAL levels measured w/ weekly and daily rifapentine- 900mg qweek rifapentine increased raltegravir AUC 89%- 600mg qD rifapentine decreased trough, not Cmax or AUC- No intolerance observedà Weekly rifapentine + RAL acceptable; daily is not

§ Dolutegravir?

1Podany, CID, 2015; 2Weiner, J Antimicrob Chemotherapy, 2014

No PIs

NRTI Backbone:TDF/FTC

OrABC/3TC

not TAF…more on this later

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Previous study:1

- Trial of DTG + 3HP in HIV negative adults (n=4)- Stopped early 2 with flu-like syndrome and elevated LFTs- Elevated IF-gamma, CRP, INH UC +67%, DGV AUC -47%

1Brooks, CID, 2018; 2Dooley, CROI 2019

HOTOFF THE PRESS

DOLPHIN Study (n=60)

§ HIV+ adults suppressed on EFV-based ART § Switched to DTG qD+TDF/FTC x 8 weeks then started on 3HP§ HP decreased DTG bioavailability by 29%,

- 59/60 with trough levels >DTG IC90§ Viral suppression maintained, no adverse eventsà Dolutegravir may be given with 3HP

Dooley, et al, CROI 2019, Abstract 80LB

DOLPHIN Trial: DOLutegravir +P(rifapentine)-H(isoniazid) INvestigation

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BRIEF-TB: Multinational, randomized, open-label, phase III trial§ Intervention: Rifapentine 600mg + Isoniazid 300 mg QD x 28 days§ Control: Isoniazid 300mg daily x 9 months§ Population: HIV infected, ≥13 years old, without active TB§ Median CD4 470(IQR 346-635), 50% on ART§ Findings: 24 TB cases in 1HP, 29 cases in 9H -à Noninferior§ Completion rates: 97% in 1HP, 90% in 9HàAuthor Conclusion: 1HP safe and effective in preventing TB disease compared to 9H at 156 week follow up

Swindells, NEJM, 2019

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But which regimen should I use? My generalized approach

Is your patient on ART?

Check for medication interactions and contraindicated co-morbidities before initiating any regimen!*Data for 4R in HIV+ patients is inferior to data for 3HP. If using RAL with 4R, increase RAL dose

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No:Are you going to start now?


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Yes:Is it RAL or EFV based w/o TAF?


No:Choose by

frequency, SE, med

interactions tor THIS pt.

(this is rare)

Yes:

Proceed to other side


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No:Can/should you change

their regimen? Do you want

to?

Yes:

3HP or 4R* (Or 9H)

No:Choose by

frequency, SE, med


(this is rare)

Yes:



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No:Can/should you change

their regimen? Do you want

to?

Yes:

3HP or 4R* (Or 9H)

No:Choose by

frequency, SE, med


(this is rare)

Yes:


Yes: Consider RAL or EFV reg (no TAF!) while on

3HP or 4R*(rare)

No:

Choose 9H

(Most common)


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Indications to Treat HIV-positive patients for LTBI

1. New positive LTBI test and negative workup for active TB

2. Close contact with active TB and negative workup for active TB

à BCG history should not affect the decision to treat in HIV positive individuals for LTBI

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Exceptions to Treating LTBI: Pregnancy

- Population: 956 HIV+ women (all but 1 on ART)- Exposure: IPT during pregnancy vs. IPT 12 weeks post-partum- Primary Outcome: Maternal adverse events + Tx discontinuation

§ Occurred in 15.1% immediate group vs 15.2% deferred group

- Adverse pregnancy outcome: 24% immediate, 17% deferred (p=0.01)àIn high prevalence TB setting, safer to defer IPT until 12 weeks postpartum in WLHIV on ART (unless recent TB exposure)

Gupta, NEJM, 2019

HOTOFF THE PRESS

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LTBI Treatment monitoring

§ Baseline LFTs in all HIV-positive individuals on ART§ Repeat LFTs if:- Abnormal LFTs at baseline- Underlying liver disease (HBV, HCV, EtOH, cirrhosis)- Regular EtOH- Concomitant hepatotoxic medications

§ Elevated LFTs—when to stop?- Symptomatic + >3x ULN- Asymptomatic + >5x ULN

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Case 2

§ 27 year old woman from El Salvador is admitted with cough, fevers, and an 18 pound weight loss over the past month

§ Chest x-ray shows a diffuse infiltrate§ HIV test is positive: CD4

30 cells/mm3, viral load pending§ AFB smear of sputum is negative§ PJP negative§ Pregnancy test is negative

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Diagnosis of active TBWith a focus on PULMONARY TB

§ Clinical suspicion is a must!- Pulmonary symptoms: Prolonged cough, hemoptysis,

chest pain- Systemic symptoms: fevers, chills, night sweats,

appetite loss, weight-loss, fatigability§ Testing options- Chest X-ray- Sputum microscopy (AFB smear)- MTB Culture- Xpert MTB/RIF assay

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TB Diagnosis: Chest X-ray§ Obtain a chest x-ray if: positive IGRA /TST, TB exposure, or TB sxs § CXR can be normal in HIV positive individuals with active TB

873 HIV/PTB cases21% normal CXR with CD4<50

1Cain, NEJM, 2010; ; 2Chamie, IJTLD, 2010

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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

hest

X-r

ay2

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TB Diagnosis: Smear 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

AFB

Sm

ear

Chamie, IJTLD 2010

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TB Diagnosis: Culture

§ More sensitive and specific than smear§ Methods- Traditional Culture

§ SLOW

- Rapid culture: BACTEC, MGIT§ 7-12 days§ Problematic for non-sputum

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TB Diagnosis: XpertXpert Assay

§ More sensitive than smear

§ Useful in children and EPTB samples

§ Screens for Rif resistance

Boehme, NEJM, 2010

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Xpert MTB/RIF Performance in HIV +

§ High sensitivity1

- Overall 79% sensitive§ 97% sensitive in smear + / culture +§ 61% sensitive in smear - / culture +- Improves with repeated samples

§ High specificity- Overall 98% specific1

- In US cohorts 99.2% specific2

1Steingart, Cochrane Database Syst Rev, 2014; 2Luetkemeyer, CID, 2016

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Xpert Ultra

§ Two different amplification targets/new design§ Designed to overcome lower sensitivity in smear negative pulmonary

TB§ PTB diagnostic accuracy study: 8 countries- Increased sensitivity (17%) in smear negative PTB- Decreased specificity (98 to 96%)

§ Greater loss in specificity if history of prior TB

- No difference in detection of Rif-resistance- No decrease in sensitivity if HIV+

1Dorman, Lancet ID, 2018

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Case 2 (cont.)27F from El Salvador with new dx HIV (CD4 30, VL pend) presents with pulmonary infiltrates, fever, cough, wt loss x 1 month

§ The GeneXpert returns positive§ No Rif resistance detected§ You start the patient on RIPE therapy

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Audience Response27F from El Salvador with new dx HIV (CD4 30, VL pend) presents with with pulmonary TB now on RIPE

When should antiretroviral therapy be started?

A. In 2 months, when she starts consolidation phaseB. Within 2 weeks of TB therapy startC. After she completes TB therapyD. Within 8 weeks of TB therapy start

0A B C D

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CAMELIA3

ART Timing

1Havlir, NEJM, 2011; 2Abdool Karim NEJM 2011; 3Blanc, NEJM 2011

STRIDE1SAPiT2

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ART Timing

Trial Location Median CD4(IQR)

Arms Effect ofEarlier Rx on Mortality

SAPIT1

(Karim 2010)South Africa

150(77-254)

Integrated (6 wks) vs. Sequential (39 wks)

ê56%(subanalysis 67% in CD4<50)

CAMELIA2

(Blanc 2011)Cambodia 25

(10-56)Immediate (2 wks) vs Early (8 wks)

ê34%

STRIDE3

(Havlir 2011)Multi-national

77(36-145)

Immediate (2 wks) vs Early (8-12 wks)

ê40% in CD4<50 group only

*Studies excluded CNS TB1Havlir, NEJM, 2011; 2Blanc, NEJM 2011; 3Abdool Karim NEJM 2011

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ART Timing: DHHS Guidelines

§ ART recommended in all PLHIV with TB (AI)1

§ CD4 <50 cells/mm3, initiate ART ASAP, within 2 weeks of TB treatment start (AI)1

§ CD4>= 50 cells/mm3, initiate ART within 8 weeks (AI)1

1DHHS OI Guidelines, 2019; 2Torok, CID, 2011.

EXCEPTION: TB meningitis2à early ART associated with increased AE, exercise caution

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Antiretrovirals and anti-TB therapy: It’s complicated!

§ Pill burden: 4 drugs for TB + HIV Meds§ Overlapping toxicities: Common side effects§ Coordination of the programs: TB care and HIV care are

not always linked§ First line TB regimens should contain a rifamycin

(rifampin, rifabutin)- Rifampin potent inducer of metabolizing enzymes and transporters- Rifabutin metabolism inhibited by PIs

Excellent review article: Meintjes, Management of active tuberculosis in adults with HIV, Lancet

HIV, 2019

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Drug-drug interactions: NRTIs and Rifamycins

§ TDF/FTC & ABC/3TC- Can use with rifampin, rifabutin, and rifapentine without dose adjustment

§ TAF

à Do NOT use TAF with Rifamycins..yet

HOTOFF THE PRESS

Custodio, European AIDS Conference 2017, Abstract PS13/4§ BID TAF + rifampin vs. qD TAF alone- Plasma TAF AUC reduced 15% when given with RIF- Trough levels of tenofovir (metabolite) similar

§ TAF qD + Rifampin (n=21) in HIV-negative individuals- Plasma TAF AUC reduced 55%- Intracellular tenofovir levels reduced 36%- HOWEVER, IC levels 4.2 times higher than TDF alone

Cerrone, J Antimicrob Chemother 2019

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Drug-drug interactions: Rifamycins and INSTIs

§ Dolutegravir: RIF reduces plasma levels of DTGà Overcome by BID dosing- Open-label, randomized non-comparative phase IIIb- N= 113 ART-naïve patients with TB/HIV coinfection- DTG BID + 2 NRTIs vs. EFV qD + 2 NRTIs & Rif based TB therapy- Week 48: Suppression 75% in DTG, 82% in EFV (DTG driven by LTFU)à Supports the BID DTG recommendation

§ Bictegravir: - BIC/FTC/TAF qD vs. BIC/FTC/TAF BID + rifampin (n=52)- AUC BIC reduced 61% and trough reduced 80% even with BIDà Co-administration not recommended

Dooley et al, CID, 2019. “INSPIRING” Study

Custodio et al, CROI 2018. Abstract 34

HOTOFF THE PRESS

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Rifampin Rifabutin RifapentineNRTIs

TDF/FTC & ABC/3TCTAF

NNRTIsEfavirenz (increase RFB)

Etravirine (potentially)

Rilpivirine (potentially)

Doravirine (DOR BID)

PI/r Dose 150mg QD

PI/cobi Dose 150mg QD

INSTIRaltegravir (800mg BID)

ElvitegravirDolutegravir (50mg BID)

Bictegravir

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Case 227F from El Salvador with new dx HIV (CD4 30, VL pend) and pulmonary TB, recently started on RIPE and ART

§ Your patient has now been on TB therapy for 20 days and on ART for 10 days

§ She has recurrent fevers and notes worsening dyspnea and cough§ You obtain a repeat CXR, which now shows progression of

pulmonary infiltrates

§ You suspect Immune Reconstitution Inflammatory Syndrome (IRIS)

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Audience Response27F from El Salvador with new dx HIV (CD4 30, VL pend) and pulmonary TB, recently started on RIPE and ART with concern for IRIS

What is the best way to manage her symptoms?

A. Start a course of prednisoneB. Hold ARTC. Start NSAIDSD. Watchful waiting; continue ART and TB therapy

0A B C D

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Paradoxical TB IRIS

Timing:• Typically 1-4 weeks after

ART; most w/in 3 months

Epidemiology:• Incidence estimated at

15.7%1

• Rarely severe or fatal

Predictors:• CD4<50 at ART start• High pre-ART VLà lower on-

ART VL• Severity of disease• Early ART start2 (<30 days)

Treatment:• Mild: NSAIDs• More severe: steroids• Surgical drainage

1Muller, Lancet ID, 2010. 2DHHS OI Guidelines, 2019.

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TB IRIS: Role of Steroids

Prednisone as IRIS TreatmentMeintjes et al, AIDS 2010• RCT of placebo vs. prednisone (1.5/mg/kg/day x2

weeksà0.75mg/kg/day x 2 weeks)• n=110, HIV + non-life threatening IRIS in South Africa• Endpoint: days of hospitalization and outpatient therapeutic

procedures (equiv 1 hospital day)

à Placebo 3 days (IQR 0-9), Prednisone 0 days (IQR 0-3). No increase infections

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TB IRIS: Role of Steroids

Prednisone as IRIS Prevention: PredART Trial1RCT double-blind of placebo vs. prednisone (40mg/day x 2 weeksà20mg/day x 2 weeks) at time of ART start

• n=240, HIV+ naïve pt, CD4≤100, TB Rx start within 30 days• Endpoint: TB-IRIS• Placebo: 46.7% with IRIS, Prednisone 32.5%, RR 0.70 (0.51-0.96; p=0.02)

2019 DHHS OI Guidelines2: Recommends pre-emptive prednisone for patients at high risk of developing TB-IRIS

1Meintjes (PredART Team) NEJM, 2018; 2DHHS OI Guidelines, 2019.

HOTOFF THE PRESS

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Recent Developments in TB Prevention

Tait et. al NEJM, 2019

§ Population: 3289 HIV-negative adults in Africa§ Exposure: 2 doses of the M72/AS01E candidate vaccine vs 2 doses

of placebo, 1 month apart§ Result: Mean 2.7 years' follow-up: - Pulmonary TB: 0.3 versus 0.6 cases per 100 person-years.

§ Overall 36-month efficacy was 49.7%.

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Conclusions

1. Screen all PLHIV for TB at diagnosis or entry into care• Screen high risk patients annually

2. TST or IGRA can be used to screen for LTBI3. Treat LTBI: It prevents TB and reduces mortality4. 9 months of INH is the preferred LTBI treatment regimen;

alternatives exist, but beware of drug-drug interactions5. CO-TREATMENT OF HIV AND TB SAVES LIVES

• Start ART ASAP and <2 weeks in TB/HIV pts with CD4<50

6. Rifamycins have multiple interactions with ART7. Prednisone has a role in prevention and treatment of TB-

IRIS

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Thank you!

• Gabriel Chamie• Diane Havlir

• Annie Luetkemeyer

• Carina Marquez

Special thanks to the following for their contributions to this presentation:

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ANRS 12300 Reflate TB2: RAL vs EFV as initial therapy for people with HIV and active TB

§ Population: ART-naïve HIV/TB co-infected patients on <8 weeks of rifampin-based TB treatment. Excludes TB meningitis. N=456

§ Exposure: RAL 400mg BID +3Tc/TDF vs. EFV 600mg qD+3Tc/TDF§ Non-inferiority margin: -12%

-13.9 3.7-5.1

-12% NI margin

-12 -8 -4 0 4 8

RAL + 3TC/TDFEFV + 3TC/TDF

-16 -14Virologic Nonresponse

HIV-1 RNA < 50 c/mL

No Virologic Data

Patie

nts

(%)

60

100

80

20

40

0

6661

2229

1210

RAL + 3TC/TDFEFV + 3TC/TDF

Virologic Outcomes (FDA Snapshot) RAL-EFV Treatment Difference (95% CI)

Ø At Wk 48, RAL did not meet criteria for noninferior virologic efficacyvs EFV

De Castro, IAS 2019, MOAB0101

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What’s new in HIV-associated tuberculosis? · 2020-02-12 · §4thgeneration IGRA FDA approved...

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