TB and HIVManagement

Dr A.L. Pozniak

Chelsea and Westminster Hospital

London, UK

TB incident cases in 2007– 9.27 million incident cases in 2007

• Asia: 55%• Africa 31%• East Med 6%• East Euro 5%• Americas 3%

TB incident cases has been on the increase since 1990s – 9.27 million (2007)– 9.24 million (2006)– 8.30 million (2000)– 6.60 million (1990)

TB Epidemiology

3. TB incidence rate has been falling since 2004– 137 cases per 100,000 (2007)– 142 cases per 100,000 (2004)

4. The rate of decline is less than 1% a year (generally)

5. TB Incident rates are falling in all regions except Eastern Europe

6. Of the total 9. 3 million new TB cases in 2007, 1.4 million also had HIV (TB/HIV cases)

7. 15% of all TB cases in 2007 were co-infected with HIV

8. 85% of all TB cases in 2007 were not co-infected with HIV

9. Out of the 15% TB cases co-infected with HIV:– Africa (79%)– South East Asia (11%)– Other regions (10%)

Tb epidemiology

10. Case detection rate reached 63% in 2007– Americas (73%)– Western Pacific (77%)– South East Asia (69%)– Eastern Med. (60%)– Eastern Euro (51%)– Africa (47%)

11. Treatment success rate reached 85% in 2006

12. TB remains the leading cause of death among PLHIV

13. PLHIV are 20 – 30 times more likely to acquire TB than people without HIV

14. PLHIV with TB are highly vulnerable to MDR-TB and XDR-TB

TB epidemiology

TB/HIVMany Challenges

• When to start Antiretroviral Therapy (ART)

• What ART to start

• Drug interactions

Issues in initiating antiretroviral therapy in

HIV patients with TB

START TB TREATMENT START TB TREATMENT AND HAART AND HAART SIMULTANEOUSLYSIMULTANEOUSLY

START TB TREATMENT START TB TREATMENT FIRST AND DELAY HAARTFIRST AND DELAY HAART

PROS PROS

Lower risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm3)

Avoid overlapping side effects

Avoid PK interactions

Lower pill burden

Lower risk of IRIS

CONS CONS

Overlapping side effects

PK interactions

Higher pill burden

Risk of immune reconstitution disease

Higher risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm3 )

Adapted from J Acquir Immune Defic Syndr 2007; 46: S9-S18.

HAART in TB-HIV: Early or late?

When to Start ART: in TB Immediately?

TB, HIV+CD4<350Or ?<200

TB TREATMENT

ANTIRETROVIRAL THERAPY-WHEN?

Months

1 2 6

Don’t Wait till it’s too lateFurther AIDS

27/188 TB/HIV patients developed further AIDS

On HAART =3

Not on HAART= 24

median CD4 70 cells

90% had median CD4 <100 4 months post TB

16 died only 4 on HAART (3 short term) Dean et al AIDS 2001

a)

Awaiting ART

ART

0.50

0.60

0.70

0.80

0.90

1.00

0 30 60 90 120 150 180

Days from TB diagnosis

Su

rviv

al p

rob

ab

ility

No difference in CD4 count or Stage 4 disease between those starting and not startingNo difference in CD4 count or Stage 4 disease between those starting and not starting

Mortality among patients with prevalent active TB (n=73) initiating ART

Lawn S et al. CROI 2007;Abstract 81Lawn S et al. CROI 2007;Abstract 81

313 HIV-infected patients with ≥ 1 TB episode andwho initiated HAART after TB diagnosis

• Mortality significantly lower at end of follow-up for patients with simultaneous <8W HAART/TB treatment vs delayed HAART

Outcome at End of Follow-up Simultaneous HAART/TB(n = 140)

Delayed HAART (n = 173)

Mortality, % 9.3 19.7*

Other AIDS-defining conditions, % 16.4 13.9

Median HIV-1 RNA, log10 copies/mL (IQR)

3.8 (2.0-4.6) 2.8 (2.0-4.5)

Median CD4+ cell count, cells/mm3 (IQR)

325 (136-482) 321 (173-468)

Velasco M, et al. JAIDS. 2009;50:148-152Velasco M, et al. JAIDS. 2009;50:148-152

*P = .011 vs patients who received simultaneous HAART/TB treatment.*P = .011 vs patients who received simultaneous HAART/TB treatment.

SAPIT Study: Study design and intervention

• Open-label randomised controlled trial

• 3-arm randomisation:

– ART initiated ASAP after diagnosis during intensivephase of TB treatment

– ART initiated after intensive phase

– ART initiated after TB treatment completed

• TB treatment standard regimen

• Co-trimoxazole prophylaxis given to all patients

• ART was ddI/3TC/EFV given OD with TB-DOT

Integrated arm

Karim SA et al. CROI 2009. Abstract 36aKarim SA et al. CROI 2009. Abstract 36a

SAPIT Study: Mortality rates per CD4 count

Reduction in mortality rates is present in patients with CD4 counts above and below 200 cells/mm3

CD4 count

200 cells/mm3 >200 cells/mm3

Integrated arm

• # dead/ py (n)

• Mortality rate

23/281 (273)

8.2 (5.2–12.3)

2/185 (156)

1.1 (0.1–3.9)

Sequential arm

• # dead/ py (n)

• Mortality rate

21/137 (138)

15.3 (9.57–23.5)

6/86 (75)

7.0 (2.6–15.3)

Hazard ratio• Cox regression

0.54 (0.34–0.98)p=0.04

0.16 (0.03–0.79)p=0.02

Karim SA et al. CROI 2009. Abstract 36aKarim SA et al. CROI 2009. Abstract 36a

SAPIT Study: Mortality in sequential arm occurred late

Months After Randomization

Su

rviv

al

1.00

0.90

0.70

0.80

0.95

0.85

0.75

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Post –TB TreatmentContinuationPhase of TBtreatment

IntensivePhase of TBtreatment

Sequential Arm

Integrated Arm

Kaplan-Meier Survival Curve

Karim SA et al. CROI 2009. Abstract 36a.Karim SA et al. CROI 2009. Abstract 36a.

However not all TB is the same!!

Randomised Controlled Trial ofImmediate Versus Deferred Antiretroviral Therapy

in HIV-Associated Tuberculous Meningitis

Torok ME et al

ICAAC 2009

Presentation H-1224

Study design

Immediate ART (n=127)AZT/3TC+EFV for 12 months

Deferred ART (n=126)Placebo for 2 months followed

byAZT/3TC+EFV for 10 months

Randomised, double blind Placebo controlled

Patientsn=253

≥15 yearsHIV-1+

90% male, mostly IDU

Clinically suspected TBMRandomisation stratified by

TBM grade

Anti tuberculous TX: RHZE 3 monthsRH 6 months

+ Corticosteroids Co-trimoxazole for PCP prophylaxis

If CD4<200

Torok ME et al. ICAAC 2009. Abstract H-1224Torok ME et al. ICAAC 2009. Abstract H-1224

Overall survival (Kaplan Meier curves)

0

1.0

0.8

0.6

0.4

0.2

0 3 9 126

Months since randomisation

Placebo

ARV

Torok ME et al. ICAAC 2009. Abstract H-1224Torok ME et al. ICAAC 2009. Abstract H-1224

Severe AEsImmediate ART

(n=127)Deferred ART

(n=126)P

Grade 3 & 4 AE 114 (89.8%) 112 (88.9%) 0.84

Grade 3 & 4 AEs ≤ 2 mths 109 (85.8%) 95 (75.4%) 0.04

Grade 4 AE 102 (80.3%) 87 (69.1%) 0.04

Grade 4 AEs ≤ 2 mths 77 (60.6%) 59 (46.8%) 0.03

Torok ME et al. ICAAC 2009. Abstract H-1224Torok ME et al. ICAAC 2009. Abstract H-1224

Conclusions

• Immediate ART appears not to improve outcomes in HIV-associated TBM patients

• Significantly more severe AEs in the first two months in the immediate ARM

• These data support delayed initiation of ART in HIV-associated TBM

Torok ME et al. ICAAC 2009. Abstract H-1224Torok ME et al. ICAAC 2009. Abstract H-1224

Impact on Survival of Early vs. Late Initiation of HAART In HIV-infected Adults with Newly Diagnosed Tuberculosis

• Methods: CAMELIA (CAMbodian Early vs. Late Introduction of ART)

• An open-labelled randomized clinical trial to compare the impact upon mortality of early (2 weeks) vs. late (8 weeks) HAART initiation after TB treatment onset in treatment-naïve adults with newly diagnosed acid-fast bacilli (AFB) positive TB and CD4+ cell count <200 cells/mm3.

• Patients received standard 6-month TB treatment plus stavudine, lamivudine and efavirenz and were followed through 50 weeks after the last patient was enrolled.

• 661 patients (early, n=332; late, n=329) were enrolled.

• CD4+ cell count 25 cells/mm3 and viral load 5.64 log copies/ml.

Kaplan-Meier Survival Estimates

Early Late

Weeks After Randomization

1.00

0.75

0.50

0.25

0.000 50 100 150 200

Blanc F, et al. 18th IAC; Vienna, July 18-23, 2010; Abst. THLBB106.

P=0.042

N PR/IRIS

Follow-up time*

Incidence** (95% CI) p

Early arm 332 110 2 728.5 4.03 (3.34 – 4.86)<0.0001

Late arm 329 48 3 333.5 1.44 (1.09 – 1.91)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

TB

-re

latd

PR

/IRIS

pro

babi

lity

(%)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

Time aftre TB treatment initiation (weeks)

Early arm Late arm

IRIS significantly more frequent in the early arm

ANRS 1295/12160 - CIPRA KH001/10425 ANRS 1295/12160 - CIPRA KH001/10425 studystudy

* expressed in person-months** per 100 person-months

Time after TB treatment initiation (weeks)

When to start HAART

BHIVA TB-coinfection Guidelines, consultation Draft 2010BHIVA TB-coinfection Guidelines, consultation Draft 2010

CD4 count, cells/μL When to start HAART

<100 As soon as practical

100–350

As soon as practical, but can wait until after completing 2 months TB treatment especially when there are difficulties with drug interactions, adherence and toxicities

>350 At physician discretion1

Treatment of drug sensitive TB

• 90% of MTB dead in 2 days when regimen includes INH

• 99% of MTB dead in 14 days when regimen also includes RIfampicin

• If INH and RIF and PZA given in first 2 months then total course of TB treatment is 6 months

• Debate whether HIV + should be treated for longer

• ? Quinolones will shorten to 4 months

If we are treating both HIV and TB..

• Have we enough evidence to give clear treatment recommendations for HIV and TB coinfection?

• What are the major drug issues for clinicians

• 1. NNRTIs and rifampicin• 2. Pis and rifampicin and rifabutin

Rifampicin

• The major problem is the use of rifampicin with HAART

• But at present it is an essential part of the solution for TB

Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002

CYP3A4 Regulation

• PXR: pregnane X receptor; RXR: retinoid X receptor

• In vitro models now exist for identifying drugs that bind PXR

Rifampicin

• Induces: CYP1A2, CYP2C8, CYP2C9, CYP2E1, 2C19, 3A4

• Induces P-gp activity

• Induces phase II metabolism (transferase enzymes)

• … rifampin brings broad changes in the pattern of gene expression, rather than increased expression of a small N of metabolic enzymes. Clinicians and researchers who use and study rifampin and other drugs that induce drug metabolism should be alert to the possibility of multiple effects

Rae et al. 2001

Drug-drug interactions TB/HIV

Metabolism

Absorption

Elimination

Metabolism

Rifampicin

↑↑CYP3A4

PIs

NNRTIs

Rifampin Effects on “older” HIV Drugs• Protease inhibitors

– Boosted PIs should not be used with concomitant rifampicin-PK or safety or can they?

• Nonnucleoside reverse transcriptase inhibitors (NNRTI)– Nevirapine 37 % decrease what dose?

– Efavirenz 26 % decrease what dose?

• Reverse transcriptase inhibitors– No significant effect

Enfurvitide

- No effect

NVP and Rifampicin Distributions of plasma nevirapine (NVP) levels

at week 8 and week 12 of therapy

Manosuthi 2006;CID 43:253–5

N=32, ARV naïve, TB/HIV, smear pos, CD4<200, RIF 2-6 weeks

2 weeks 4 weeks 12 weeks

Prospective, randomized, multicenter, open-label, 2-arm study

TDM of NVP

12 hr of NVP

+

Assessments:

++

+

48 weeks

14 days2-6 weeks of TB treatment

24weeks interim analysis

Arm 1: NVP 400 mg/day ( GPOvir Z 1 tab po BID)( GPOvir Z 1 tab po BID)Lead in 14 days with NVP 200 QD

Arm 2: NVP 600 mg/day ( GPOvir Z 1 tab po BID+ NVP 1tab QD)( GPOvir Z 1 tab po BID+ NVP 1tab QD)Lead in 14 days with NVP 200 BID

All patients received AZT+3TC as a

backbone

24-Week Efficacy and safety of Nevirapine: 400 mg versus 600 mg based HAART in HIV-infected Patients with Active Tuberculosis Receiving Rifampicin Clin Infect Dis. 2009 Jun 15;48(12):1752-9.

Summary of adverse events

* disseminated MAC, bloody pleural effusion and liver mass ** cardiomyopathy and heart failure

***

Efavirenz

• PK data

• Standard dose?

• Increased dose?

Population PK modeling in HIV-pts with TB treated with EFV and rifampicin

Soy et al. 2005

• • EFV dose 30% increase (from 600 to 800) adequate

• Body weight important determinant on CL

PK of EFV 800 mg plus rifampicin similar to those of EFV 600 mg without rifampicin

Lopez-Cortes et al. 2002

EFV levels in HIV-infected Thai patients with TB

% o

f pa

tient

s

0

10

20

30

40

50

60

< 1 1-4 > 4

Manisuthi et al. 2005600mg 800mg

Nevirapine and Efavirenz

• What is also important is

• Clinical outcome

• Toxicity

18 month outcomes

• 1,283 started ART while on rifampicin:

• 209 people on nevirapine and 1,074 on efavirenz.

• Those starting NVP with TB rx had a OR(CI) of 2.9(1.8-4.7) of virological failure <400 copies compared with those on EFV or not on TB RX

Boulle JAMA. 2008 Aug 6;300(5):530-9.

Now add this into the mix!!

• P450 2B6 genes-Patients with a TT genotype 20% of the black population cf. 3% of white individuals

have an extended clearance of EFV and are at risk of toxicity

Mean plasma efavirenz area under the curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs 27.6 microg x h/mL, P< .0001) J Clin Pharmacol. 2008 Sep;48(9):1032-40.

• Pregnancy• Chronic Hepatitis• Stopping rifampicin

Nevirapine and Efavirenz

• Quote “Clinical outcome studies to date do not support dose adjustment of EFV or NVP” WHO

• I would say they don’t support not adjusting the dose too!!• Need good clinical trials matching Pk and outcomes• Is the Cmin the right parameter?• Is The accepted Cmin for efficacy set too high?

Boosted PIs and Rifampin Interaction

Lopinavir/rit

•Ritonavir 400 bid required•GI toxicity and lipid perturbation•High rates of elevated transaminase1 (5/7 dropouts) 1/10 low trough concentrations

plus recent Pk study2

-LFT problems

Saquinavir/rit

1La Porte, AAC, 2004Berger AIDS. 2008 May

11;22(8):931-5.

•Early studies from SA suggested could be used •SQV 1000/rit100 BID•39% hepatitis•Transaminase elevations 20x upper normal2

Arch Drug Inf. 2009

Mar;2(1):8-16.

PI Rifampicin Rifabutin Comment

ATV ATV Cmin by 93% (300/100), 80%(300/200), 60% (400/200)

rifabutin AUC (205%) 1) Avoid co-adm. with rifampicin2) Reduce rifabutin dose**

FPV APV AUC by 82% rifabutin AUC (193%) 1) Avoid co-adm. with rifampicin

2) rifabutin dose*** or ** if boosted

DRV No Data do not use

RBT and metabolite increase 1.5X and increase in DRV57%

1) Avoid co-adm. with rifampicin

2) rifabutin dose***

LPV/r LPV AUC by 75%; increased doses to 400/400 or 800/200 bid

compensate

rifabutin AUC (303%), 1) > toxicity during co-administration of rifampicin and increased dose of LPV/r

2) rifabutin dose**

NFV NFV AUC by 82% NFV AUC by 32%; rifabutin AUC (207%)

1) Avoid co-adm. with rifampicin

2) TDM of NFV; rifabutin dose**

SQV SQV AUC by 84%; induction partly compensate by SQV/r 400/400 mg bid

SQV AUC by 43%; compensated by r

1) Hepatotoxicity during co-administration of rifampicin and SQV/r

2) rifabutin dose in presence of r**

TPV/r TPV by 80% TPV; rifabutin AUC (190%), Cmax (70%), and Cmin (114%)

1) Avoid co-adm. with rifampicin

2) rifabutin dose**

*25-O-desacetyl-rifabutin**150 mg every other day or 150 mg 3 times per week*** 150 mg every other day or 300 mg 3 times per weekr = ritonavir; AUC = area under the curve; Cmax and Cmin= maximum and minimum concentrations; TDM = therapeutic drug monitoring

HAART Dose TB Dose therapy

4NRTI No change RIF No changenevirapine 200 mg bd RIF 600 mg odefavirenz* 6-800 mg od RIF 600 mg od

TB Treatment RegimensRIFAMPICIN / HAART

*Dose adjusted?

Rifabutin

• As “potent” as rifampicin but no long-term data for comparison

CYP3A4 CYP3A4Rifabutin

Active metabolites (i.e. 25-O-desacetyl,

31-hydroxy)

• CYP3A4 inhibitors increase rifabutin levels

Can be administered With PIs

Given at a dose of 150mg 3xWK

Expensive! Cost of 4 days of rifabutin = cost of an entire rifampin regimen

Toxicity: marrow suppression, arthralgias, uveitis

Dosing: Dose adjustments of ART regimens ? Dose with boosted PIs

Benefits Limitations

What about Rifabutin?

TB Treatment RegimensRifabutin

HAART Dose TB Dose therapy

4NRTI No change RBT No changeBoosted PI No change RBT 150? mg 2-3/7nevirapine 200 mg bd RBT 300 mg odefavirenz 600 mg od RBT 450 mg od

PI Rifampicin Rifabutin Comment

TMC 125

No data Small decreases

↓ etravirine

↓ rifabutin

↓ 25-Odesacetylrifabutin

use normal doses unless given with PI when 125 levels may be decreased significantly

TMC 278

APV AUC by 82%AUC, Cmax and Cmin decr by 80/69/89%;

Cmin by 49% Avoid co-adm. with rifampicin\?double dose 278 with rbt

Raltegravir

reduced the Cmin AUC and C max of MK-0518 by 61%, 40% and 38% respectively

no dose adjustment ?Avoid co-adm. with rifampicin-use with caution

Elvitegravir

Levels of EVR do not use

Not done

MRV 6.6-fold increase in CYP3A4 induction with rifampin

no dose adjustment Double dose of maraviroc may compensate

DRV Not done Increase DRV (57%)Increase AUC of 25-O-da-rifabutin 881%

increase AEs

T20 No change No change Can use

r = ritonavir; AUC = area under the curve; Cmax and Cmin= maximum and minimum concentrations; TDM = therapeutic drug monitoring

Newer HIV drugs

TB/HIVMany Challenges

• When to start Antiretroviral Therapy (ART)

• What ART to start

• Drug interactions

TB and HIV

Dr A.L. Pozniak

Chelsea and Westminster Hospital

London, UK