what’s new in tuberculosis?€¦ · 1aphl press release, 2018. 2telisinghe, ijtld, 2017. hot off...

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Sarah Puryear, MD

What’s new in tuberculosis?The Medical Management of HIV/AIDS and Hepatitis Course

December 8, 2018

Disclosure

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

Objectives

§ At the conclusion of this talk, learners will be better able to:- 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)

Tuberculosis: A major global health problem

WHO, Global Tuberculosis Report 2018

§ 2017:- 10.0 million

cases/year- 1.6 million

deaths/year

§ #1 cause of death among PLHIV


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.

Case 1

§ A 41 year-old man from San Francisco presents to yourclinic for evaluation. Two weeks ago, he was diagnosedwith 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 ofany contacts with TB

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

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?

1. TB infected; rule out active TB and treat him

2. TB exposed, uninfected; do nothing

3. TB infection cannot be determined; re-test when CD4 is higher

4. TB exposed OR BCG vaccinated; obtain a PPD “tie-breaker”

5. TB infection cannot be determined; obtain a PPD “tie-breaker”

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 ELISA

T-SPOT.TBELISPOT


TST vs. IGRABoth 65-70% sensitive in PLHIV

Diagnostic Approach

Strengths Limitations

TST§ Vast experience,

abundant data§ Cheaper

§ Requires 2 visits§ Placement & reading require training§ False positives can occur due to

BCG, environmental AFB*§ Can remain positive after LTBI,

active TB tx

IGRAs § Requires 1 visit§ Interpretation not

subjective§ More specific than TST§ Unaffected by BCG

§ Technical errors possible§ Blood 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

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- Screening tests exist- 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, 2017

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.

HOTOFF THE

PRESSCase 1 (continued)

§ You start him on Triumeq (DTG/ABC/3TC)§ 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


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

Which one of the following regimens do you select to treat

LTBI in this patient?

1. Isoniazid, pyrazinamide, rifampin, ethambutol, and

pyridoxine for 2 months

2. Isoniazid and pyridoxine for 9 months

3. Isoniazid and pyridoxine for 6 months

4. Isoniazid and pyridoxine plus rifampin for 3 months

LTBI Treatment Options

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

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

§ **High risk of hepatotoxicity**

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

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

DHHS OI Guidelines, 2017

Current Guidelines for TB Preventive Therapy

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

Isoniazid* daily 300 mg/day 9 A IIIsoniazid* twice weekly 900 mg/d (DOT) 9 B II

Isoniazid* daily 300 mg/day 6 C IIsoniazid* twice weekly 900 mg/d (DOT) 6 C I

Rifampin daily 600 mg/day 4 B IIIRifapentine + isoniazid*† weekly

Maximum: 900 mg/900 mg

(DOT)3 A III

*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, 2017; Borisov, MMWR, 2018.

CDC Guidelines Update

§ 2011: 3HP recommended for LTBI in PLHIV NOT on ART§ 2018 updates:- Ages 2-17 years- PLHIV taking ARVs with acceptable drug-drug interactions with RPT- By DOT or self-administered therapy

DHHS OI Guidelines, 2017; Borisov, MMWR, 2018; Sterling (PREVENT TB), AIDS, 2016

HOTOFF THE

PRESS


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

- No P vs. P-900 qweek vs. P-600 qD- P-900 qweek increased raltegravir AUC 89%- P-600 qD decreased trough, not Cmax or AUC- No intolerance observed

§ Dolutegravir (n=4)3

- 2 with flu-like syndrome and elevated LFTs; study stopped- Elevated IF-gamma, CRP, INH UC +67%, DGV AUC -47%

1Podany, CID, 2015; 2Weiner, J Antimicrob Chemotherapy, 2014; 3Brooks, CID, 2018

No PIs

NRTI Backbone:TDF/FTC

OrABC/3TC

not TAF…more on this later

BRIEF-TB/A5279: INH + Rifapentine x 1 month to prevent TB in PLHIV

Swindells, et al, CROI 2018, Abstract 37LB

§ Multinational, randomized, open-label, phaseIII trial

§ Intervention: Rifapentine 600mg + Isoniazid300 mg DAILY 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 Conclusion: 1HP safe and effective in preventing TB disease compared to 9H at156 week follow up (non-inferior)

Indications to Treat HIV-positive patients for LTBI

1. New positive LTBI test and negative workup for activeTB

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

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

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


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

Golub, CID, 2015; Badje, Lancet Global Health, 2017

IPT x 6 mo

No IPT

Cum

ulat

ive

prob

abilit

y of

TB

Prob

abilit

y of

Dea

th

Case 2

§ 27 year old woman from El Salvador is admitted withcough, fevers, and an 18 pound weight loss over thepast 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

Diagnosis of active 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

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

1

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

ay

2


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

TB Diagnosis: Culture

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

§ SLOW- Rapid culture: BACTEC, MGIT

§ 7-12 days§ Problematic for non-sputum

TB Diagnosis: XpertXpert Assay

§ More sensitive than smear

§ Useful in children and EPTB samples

§ Screens for Rif resistance

Boehme, NEJM, 2010

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


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

HOTOFF THE PRESS

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

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?

1. In 2 months, when she starts consolidation phase2. Within 2 weeks of TB therapy start3. After she completes TB therapy4. Within 8 weeks of TB therapy start

CAMELIA3

ART Timing

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

STRIDE1

SAPiT2


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

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 (AIII)1

1DHHS OI Guidelines, 2017; 2Torok, CID, 2011.

EXCEPTION: TB meningitis2à early ART associated with

increased AE, exercise caution

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

Drug-drug interactions: NRTIs and Rifamycins

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

§ TAF

àDo NOT use TAF with Rifamycins

HOTOFF THE

PRESS

Custudio, 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 76% higher than TDF alone

Cerrone, CROI 2018, Abstract 28LB


Drug-drug interactions: Rifamycins and INSTIs

§ Dolutegravir: RIF reduces plasma levels of DTGà Overcome byBID dosing- Open-label, randomized non-comparative phase IIIb- N= 113 naïve patients with coinfection- DTG BID + 2 NRTIs vs. EFV qD + 2 NRTIs & Rif based TB therapy- Week 24: Suppression 81% in DTG, 89% in EFV 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, CROI 2018. Abstract 33 “INSPIRING” Study

Custodio et al, CROI 2018. Abstract 34

HOTOFF THE PRESS

Rifamycins and ARTRifampin Rifabutin Rifapentine

NRTIsTDF/FTC & ABC/3TC ✔

TAFNNRTIs

Efavirenz (increase RFB)

Etravirine (potentially)

Rilpivirine (potentially)

PI/r Dose 150mg QD

PI/cobi Dose 150mg QD

INSTIRaltegravir (800mg BID)

ElvitegravirDolutegravir (50mg BID)

Bictegravir

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)

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?

1. Start a course of prednisone2. Hold ART3. Start NSAIDS4. Watchful waiting; continue ART and TB therapy


Paradoxical TB IRIS

Timing:• Typically 1-4 weeks after

ART; most w/in 3 months

Epidemiology:• Incidence estimated at

15.7% (case fatality of ~3%)1

• Rarely severe or fatal

Predictors:• CD4<50 at ART start• Higher on ART CD4• 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, 2017.

TB IRIS: Role of Steroids

Prednisone as IRIS Treatment: The PredART trialMeintjes 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

TB IRIS: Role of Steroids

Prednisone as IRIS PreventionRCT 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)• Placebo: median time to IRIS 8 days vs. prednisone 10 days, HR 0.61

(p=0.02)

Meintjes (PredART Team) NEJM, 2018

HOTOFF THE PRESS

Recent Developments in TB Prevention and Treatment

Walker (CRyPTIC Consortium, 100,000 Genomes Project) NEJM, 2018; Van Der Meeren, NEJM, 2018.


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 LTBI

3. 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 interactions

5. 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 ART

7. Prednisone has a role in prevention and treatment of TB-

IRIS

what’s new in tuberculosis?€¦ · 1aphl press release, 2018. 2telisinghe, ijtld, 2017. hot off...

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