The ART of TreatingTB and HIV Co-Infection

Presented by: Kelly Dooley MD, PhDJohns Hopkins University School of Medicine

D I V I S I O N O F

CLINICALPHARMACOLOGY

Kelly Dooley, MD, PhD

Drug-Drug Interaction Satellite WorkshopXIX International AIDS Conference

Sunday 22nd July 2012

2

HIV and TuberculosisEpidemiology

Total Population HIV-Infected PersonsIncidence 8.8 million 1.1 million (13%)

Deaths 1.45 million 0.35 million (24%)

Global Burden of Tuberculosis, 2010

WHO Report 2011 Global Tuberculosis Control

TB Incidence in Africa, 1990 and 2005

Chaisson and Martinson, N Engl J Med 2008;358:1089

Objectives

• Describe the epidemiology of TB/HIV co-infection

• Discuss optimal timing of initiation of ART among patients with TB

• Learn about therapeutic options for co-treatment of HIV and TB

At what point after HIV seroconversion does a patient’s risk for TB increase

compared with the general population?

A. Within the first yearB. After the CD4 decreases below 500 cells/mm3

C. After the CD4 count decreases below 350 cells/mm3

D. After the CD4 count decreases below 200 cells/mm3

E. What, TB hasn’t been eradicated?

At what point after HIV seroconversion does a patient’s risk for TB increase

compared with the general population?

A. Within the first yearB. After the CD4 decreases below 500 cells/mm3

C. After the CD4 count decreases below 350 cells/mm3

D. After the CD4 count decreases below 200 cells/mm3

E. What, TB hasn’t been eradicated?

TB susceptibility among HIV-seropositive persons

Sonnenberg et al. (2005) JID 191: 150.

Study in 24,000 South African gold miners shows risk TB doubles in first year of HIV infection

What is the most effective strategy for prevention of TB disease among

patients with HIV?

A. 6-9 months of isoniazid preventive therapy B. Isoniazid preventive therapy, indefinitelyC. Combination ARTD. INH plus ARTE. Bed nets

What is the most effective strategy for prevention of TB disease among

patients with HIV?

A. 6-9 months of isoniazid preventive therapy B. Isoniazid preventive therapy, indefinitelyC. Combination ARTD. INH plus ARTE. Bed nets

Exposure category

Person-

years

TB case

s

Incidence rate (per 100 PYs)

(95% CI)Incidence rate ratio (95% CI)

Adjusted hazard ratio*

(95% CI)Naïve 2815 200 7.1 (6.2-8.2) REF REFHAART only 952 44 4.6 (3.4-6.2) 0.65 (0.46-

0.91)0.36 (0.25-

0.51)

INH only 427 22 5.2 (3.4-7.8) 0.73 (0.44-1.13)

0.87 (0.55-1.36)

Both 93 1 1.1 (0.2-7.6) 0.15 (0.004-0.85)

0.11 (0.02-0.78)

TOTAL 4287 267 6.2 (5.5-7.0)

TB Rates by ARV and INH Treatment Status in South African Adults with HIV

* Adjusted for age, sex, CD4, prior history of TB, urban/rural

Golub et al, AIDS 2009;23:631-6

Now, to our case

• LS is a 52 year old man from West Africa, living in the U.S. for 12 years

• Diagnosed 1 year ago with HIV in setting of PCP pneumonia

• Reports to clinic with 6 month history of weight loss, 1 month history of productive cough, fevers

• CD4 count of 5 cells/mm3, sputum smear AFB+

Chest radiograph

What should be our overall plan for LS?

A. Start TB treatment, initiate ART after his 6-month TB treatment course is complete

B. Start TB treatment, initiate ART at the end of the intensive phase (after 2 months)

C. Start TB treatment, initiate ART 2-4 weeks laterD. Start TB and HIV treatment concurrentlyE. Fluoroquinolone for community-acquired

pneumonia

What should be our overall plan for LS?

A. Start TB treatment, initiate ART after his 6-month TB treatment course is complete

B. Start TB treatment, initiate ART at the end of the intensive phase (after 2 months)

C. Start TB treatment, initiate ART 2-4 weeks laterD. Start TB and HIV treatment concurrentlyE. Fluoroquinolone for community-acquired

pneumonia

Timing of Initiation of ART for Patients with TB and HIV

SAPIT trial– Concurrent TB and HIV treatment reduces mortality– Improved survival in patients with high or low CD4

counts

CAMELIA, STRIDE, and SAPIT trials– Starting ART within 2 weeks of TB treatment may

reduce risk of mortality or AIDS-defining illnesses– Benefit seen among those with CD4<50 cells/mm3

Abdool Karim S et al. (2010) NEJM 362: 697; NEJM (2011) 365 – Blanc et al., Havlir et al., Abdool Karim et al.

Effects of timing of ART on mortality, by baseline CD4 cell count: SAPIT trial

< 200 200-50002468

1012141618

Integrated Sequential

Mor

talt

iy r

ate

(per

100

per

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year

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Abdool Karim S et al. (2010) NEJM 362: 697.

2/186

6/8622/281

21/137

Effects of ART timing on outcomes in CAMELIA and patients with CD4 < 50 in STRIDE and SAPIT trials

05

101520

2530

CAMELIA STRIDE SAPIT

Immediate Early

34% ↓ p=0.004

42% ↓ p=0.02

68% ↓ p=0.06

Abdool Karim S et al. (2010) NEJM 362: 697; NEJM (2011) 365 – Blanc et al., Havlir et al., Abdool Karim et al.

How hard can it be?

TB Treatment: Rifampin-- we love it, we hate it

Standard TB treatment:• Intensive phase:– isoniazid, rifampin,

pyrazinamide, and ethambutol (HRZE) x 2 months

• Continuation phase:– isoniazid and rifampin

x 4 months

Nucleus

Cyto

plas

m

PXR

RXR

RIF

RIF PXR RXR

CYP3A4proximalpromoter

Phase II enzyme

regulatory genes

PGPregulatory

gene

MDR1 proteinregulatory

gene

DNA

mRNA

CYP 3A4XRE

Dooley et al. (2008) JID 198: 948.

RIFAMPIN: A promiscuous inducer of metabolizing enzymes

How will you treat this patient?For HIV: ARV (plus 2 NRTIs)

For TB: Rifamycin (plus HZE)

A. Efavirenz Rifampin

B. Nevirapine Rifampin

C. Boosted protease inhibitor (double dose)

Rifampin

D. Boosted protease inhibitor Rifabutin

E. Raltegravir (double dose) Rifampin

Co-treatment optionsDrug class

Drug Metabolized by

Rifamycin Issue

NNRTI Efavirenz Nevirapine

CYP2B6CYP3A, 2B6

Rifampin EFV doseNVP lead-in

Integrase inhibitor

Raltegravir UGT1A1 Rifampin RAL dose

Protease inhibitor

Boosted lopinavir

CYP3A Rifabutin(CYP3A substrate)

Rifabutin dose, availability

Double-dose LPV/r

CYP3A Rifampin Toxicity, LPV/r dose

“If Sustiva is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Sustiva to 800 mg once daily is recommended.”

Food and Drug Administration - January 6, 2012

What is the right dose of EFV for people >50 kg taking RIF?

Mean log EFV with RIF

Mean log EFV alone

Proportion with VL>400 copies similar in patients with and without TB

Boulle et al. (2008) JAMA 300: 530

It may depend on your EFV CYP2B6 metabolizer genotype

Ngaimisi et al. (2011) CPT 90: 406

See MOAB0301 and MOAB0302

Nevirapine with RIF: skip the lead-in phase or avoid it altogether?

ART-naïve patients –EFV vs. NVP (with lead-in):More virologic failure among those randomized to NVP

Swaminathan et al. (2011) CID 53: 716

TB+HIV

HIV only

Patients already on NVP (200 BID):Similar proportion of patients with detectable VL comparing those with and without TB

Boulle et al. (2008) JAMA 300: 530

Raltegravir with rifampin: clinical significance of lower trough with BID dosing?

53% reduction in RAL trough with rifampin

Wenning et al. (2009) AAC 53: 2852.

Overall VL≤100K VL>100K

Once-daily 83.2 89.1 74.3

Twice-daily 88.9 91.9 84.2

Virologic suppression with RAL 800 QD vs. 400 mg BID (HIV patients without TB)

With once-daily dosing, trough matters among patients with high viral loads

Eron et al. (2010) Lancet ID 11: 907.

See REFLATE trial: THLBB

Boosted PIs with rifampin: balancing efficacy and toxicity

• Boosted PI concentrations diminished >90% when given with rifampin

• In healthy volunteers, increasing dose of PI results in high rates of hepatotoxicity

• Strategies in patients with HIV/TB (LPV/r):– Double dose (adults): Gradual increase to double dose– Super-boosting (children): mg to mg parity of ritonavir and lopinavir

Acosta 2007, Burger 2006, LaPorte 2004, Schmitt 2009, Haas 2009, Nijland 2008, L’homme 2009, Decloedt 2011, Reitz 2010, Ren 2008, Elsherbiny 2010, Frohoff 2011

Rifabutin + Boosted PIs

• 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, no pediatric formulation

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

patients not taking ARVs

• Coordination of TB/HIV care is absolutely essential to ensure appropriate RBT dosing and prevent TB treatment failureHKCS/BMRC 1992; Gonzalez-Montaner 1994; McGregor 1996; Rowinska-Zakrzowska 1992; Schwander 1995

What is the right dose of rifabutin to give to patients taking PI-based ART?

Naiker et al., CROI 2011, abstract 650.

Clinical course

• You start your patient on TB treatment with HRZE

• You decide you are going to change his rifampin to rifabutin and give him boosted darunavir plus TDF/FTC

• Until the laboratory calls you…..

Your patient has MAI, not TB! He is already taking a boosted protease inhibitor plus 2

NRTI. Now what do you do?

A. Treat MAI with clarithromycin, ethambutol, and rifabutin

B. Treat MAI with azithromycin, ethambutol, and rifabutin

C. Treat MAI with moxifloxacin, ethambutol, and rifabutin

D. Treat MAI with clarithromycin and ethambutolE. Don’t treat it – it’s probably a contaminant

Your patient has MAI, not TB! He is already taking a boosted protease inhibitor plus 2

NRTI. Now what do you do?

A. Treat MAI with clarithromycin, ethambutol, and rifabutin

B. Treat MAI with azithromycin, ethambutol, and rifabutin

C. Treat MAI with moxifloxacin, ethambutol, and rifabutin

D. Treat MAI with clarithromycin and ethambutolE. Don’t treat it – it’s probably a contaminant

Caution with clarithromycin

• Metabolized by 3A4• Inhibitor of 3A4• Can cause QT prolongation with boosted PIs (risk for

sudden death)• Concentrations can be reduced by NNRTI (and it can

increase NNRTI concentrations and associated side effects)

• If a macrolide is required for a patient taking ART for HIV, use azithromycin if it is available….

Available guidance (2012 update coming soon….)

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

Combined regimen for treatment of HIV and tuberculosis

PK effect of the rifamycin on ART

Tolerability / toxicity

Antiviral activity when used with rifamycin

Recommendation(comments)

Efavirenz-based antiretroviral therapy (ART) * with rifampin-containing tuberculosis treatment

Well-characterized, modest decrease in concentrations in some patients

Low rates of discontinuation

Excellent Preferred (efavirenz should not be used during the first trimester of pregnancy)

PI-based ART * with rifabutin-containing tuberculosis treatment

Little effect of rifabutin on PI concentrations, but marked increases in rifabutin concentrations

Low rates of discontinuation (if rifabutin is appropriately dose-reduced)

Favorable, though published clinical experience is not extensive

Preferred for patients unable to take efavirenz † (caution to ensure patients who discontinue PIs do not continue to receive reduced rifabutin dose)

Nevirapine-based ART with rifampin-containing tuberculosis treatment

Moderate decrease in concentrations

Concern about hepatotoxicity when used with isoniazid, rifampin and pyrazinamide

Suboptimal when nevirapine is initiated using once-daily dosing; largely favorable when nevirapine is given twice-daily throughout co-treatment

Alternative for patients who cannot take efavirenz, though efavirenz is preferred (nevirapine should not be initiated among women with CD4>250 or men with CD4>400 cells/µL). Viral load monitoring is recommended.

Raltegravir-based ART* with rifampin-containing tuberculosis treatment

Significant decrease in concentrations with standard dosing

Limited experience

Limited published clinical experience

Alternative at higher doses for patients who cannot take efavirenz and who have baseline viral load <100,000 copies/mL

Recommendations

Other alternativesZidovudine / lamivudine / abacavir / tenofovir with rifampin-containing tuberculosis treatment

50% decrease in zidovudine, possible effect on abacavir not evaluated

Anemia No published clinical experience, but this combination is less effective than efavirenz- or atazanavir-based regimens in persons not taking rifampin

Alternative for patients who cannot take efavirenz or NVP and if rifabutin not available

Zidovudine / lamivudine / tenofovir with rifampin-containing tuberculosis treatment

50% decrease in zidovudine, no other effects predicted

Anemia Favorable, but not evaluated in a randomized trial

Alternative for patients who cannot take efavirenz and abacavir and if rifabutin not available

Zidovudine / lamivudine / abacavir with rifampin-containing tuberculosis treatment

50% decrease in zidovudine, possible effect on abacavir not evaluated

Anemia Early favorable experience, but this combination is less effective than efavirenz- or nevirapine-based regimens in persons not taking rifampin

Alternative for patients who cannot take efavirenz and tenofovir and if rifabutin not available

Super-boosted‡ lopinavir-based ART or double-dose lopinavir/ritonavir based ART with rifampin-containing tuberculosis treatment

Modest decrease in concentrations

Hepatitis Early favorable experience of super-boosting among young children and double-dose among adults already on antiretroviral drugs at the time of rifampin initiation

Alternative if rifabutin not available; double dose an option among adults already taking lopinavir-based ART and virologically suppressed at the time of tuberculosis treatment initiation; super boosting has not been adequately tested in adults but may be effective

Summary: the ART of treating patients with HIV and TB

• Treating HIV and TB concurrently is life-saving, so drug interactions must be managed

• Many knowledge gaps in dosing and expected frequency and severity of toxicities in patients

• Much research in this arena, so new options are likely to be available soon

Thank you for the opportunity to discuss this topic with you today.