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TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

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Page 1: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB and HIV

Dr A.L. Pozniak

Chelsea and Westminster Hospital

London, UK

Page 2: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Chemopreventative therapy

Treatment and side effects

What with… when…

IRIS

MDRTB

Page 3: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK
Page 4: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB and HIV

• Chemopreventative therapy

• Is it useful in HIV ?

Page 5: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10 20

Favours isoniazid Favours controlTuberculin skintest positive patients

INH for TB/HIVTuberculin skin test positive patients

All Studies

Risk ratio & 95% CI

Page 6: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10

Favours isoniazid Risk ratio & 95% CI Favours controlTuberculin skintest negative patients

Isoniazid (INH) for TB/HIVTuberculin skin test negative patients

All Studies

Page 7: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Effect of INH on TB incidence in HIV+

-30

-10

10

30

50

70

90

Uganda Zambia Kenya Zambia US Mexico Haiti pooled

all TST+ TST- / anergic

% reduction in TB incidence, INH vs. placebo

*P<0.05

Bucher, AIDS 1999;13:501

*

*

***

*42%

*60%

*

Page 8: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK
Page 9: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Efficacy of other TBPT regimes in HIV+

Country, reference

Regime, population

Incidence of TB

RR

(95% CI)

US, Mexico, Haiti, BrazilJAMA 2000;283:1445

2RZ vs. 12H

N=1583, TST+0.8 vs. 1.1per 100 pyrs

0.72(0.4-1.31)

HaitiLancet 1998;351:786

2RZ2 vs. 6H2

N=750, TST+

5.4% vs. 5.1% at 3yrs

1.1

UgandaAIDS 2001;15:2137

3HR vs. 6H 3RHZ vs. 6H

N=1554, TST+

na 0.72 (0.42-1.25)

0.60 (0.32-1.12)

NB RX deaths in HIV neg with2RZ3

Page 10: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

1995Uganda

1995Rwanda

1995 Zambia

1997Thailand

1998Uganda

1999 Brazil

HIV seroprevalence

in study population (%)

HIV+ persons

entering the PT process

(%)

Those entering the process who started PT

(%)

235347

100100100

Adherence(%)Year Country

159534

10051

100

301238893875

62--

697061

Proportion of Individuals Dropping Out of Preventative Therapy (PT) in

Feasibility Studies

Page 11: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Who should receive TB preventive therapy?

• effect of TBPT only demonstrated in TST+ • Proportion HIV patients TST+ small• TST difficult to perform

– requires return after 48hrs– requires skilled staff– lack of tuberculin– risk of transmission of blood-borne pathogens

• ? not required if high prevalence of latent TB (prisoners, miners, household contacts etc)

Page 12: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Secondary preventive therapyPost treatment prophylaxis

• In industrialised countries, risk of relapse and reinfection after TB treatment low, hence “secondary PT” not required

• in regions with high TB prevalence, risk of reinfection may be significant

Page 13: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Contribution of reinfection to recurrent TB in gold miners in South Africa

0

5

10

15

20

all recurrence relapse reinfection

all HIV-pos HIV-neg

Incidence of recurrent TB

Sonnenburg et al, Lancet 2001;358:1687 & Lancet 2002;359:1619-1620

Page 14: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Efficacy of secondary TB preventive therapy

Country, reference

Population Incidence of recurrent TB (PT vs. placebo)

% reduction

(95% CI)

DR CongoNEJM 1995;332:779

HIV+ pts completing TB Rx, randomised to 6RH2 vs. placebo

1.9% vs. 9%at 18m

na

Côte d’IvoireChemotherapy 1999;45:452

HIV+ pts completing TB Rx, randomised to INH & SP vs. placebo for <2y

2.1 vs. 7.0per 100 pyrs

70%(6-91)

HaitiLancet 2000;356:1470

HIV+ pts completing TB Rx, randomised to 12H vs. placebo

1.4 vs. 7.8per 100 pyrs

82%(17-96)

South AfricaBarcelona 2002 ThPeB7275

Observational cohort: HIV+ pts on INH/CTX vs. no INH/CTX

8.6 vs. 19.1 per 100 pyrs

55% (22-74)

Page 15: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Advantages of secondary TBPT

• in settings of high TB transmission:– eligible patients easier to identify– HIV test done at TB diagnosis– sputum smear done routinely at

treatment completion - no need to re-screen for active TB

– if giving primary TBPT, why exclude people with previous TB?

– But ? lifelong

Page 16: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Effect of CD4 count on risk of TBamong HIV-infected people

0

5

10

15

20

Italy US South Africa

>350 200-350 <200

Incidence of TB (per 100 pyrs)

Antonucci JAMA 1995;274:143; Markowitz Ann Int Med 1997;126:123; Badri Lancet 2002;359:2059

Page 17: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Effect of HAART on TB incidence

Country, reference

Population TB incidence w/o HAART (per 100pyrs)

adj. % red.

(95% CI)

USAIJTLD 2000;4:1026

16032 pyrs 0.19 80% (50-90%)

ItalyAIDS 2000;14:1985

2272 pyrs

62% asymptomatic, 7% TST+

0.79 overall 92%(12-99%)

BrazilClin Infect Dis 2002:34:543

N=255,

CD4<15%8.4 80%

(-13 –96%)

South AfricaLancet 2002;359:2059

375 pyrs HAART, 770 pyrs no HAART

9.7 81%(62-91%)

Page 18: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Operational use of TB secondary prophylaxis

• In countries with significant rates of reinfection

• For patients enrolling into HIV treatment programmes whose CD4 is < 200

• Once CD4 has risen prophylaxis stopped

Page 19: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Issues in initiating antiretroviral therapy in

HIV patients with TB

Page 20: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Drug-drug interactions TB/HIV

Metabolism

Absorption

Elimination

Metabolism

CYP3A4

PIs

NNRTIs

Page 21: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Drug-drug interactions TB/HIV

Metabolism

Absorption

Elimination

Metabolism

Rifampicin

↑↑CYP3A4

PIs

NNRTIs

Page 22: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK
Page 23: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Rifampin Effects on HIV Drugs• Protease inhibitors

– Saquinavir 80 % decrease

– Ritonavir 35 % decrease

– Indinavir 92 % decrease

– Nelfinavir 82 % decrease

– Amprenavir 81 % decrease

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

– Efavirenz 26 % decrease

• Reverse transcriptase inhibitors– No effect

Page 24: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

HAART Dose TB Dose therapy

3/4NRTI No change RIF No changerit/saq 1000mg/100 mg RIF 600 mg 3/7rit/saq 1600mg/100 mg RIF 600 mg od

nevirapine 200 mg bd RIF 600 mg 3/7nevirapine 300 mg bd RIF 600 mg odefavirenz 800 mg od RIF 600 mg od

TB Treatment RegimensRIFAMPICIN / HAART

Page 25: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Rifabutin dosage 300mg/day

Rifabutin dosage 150mg/day

RBT(Rifabutin)/Rifapentine for Treatmentof Pulmonary Tuberculosis

Patientsn

Regimen

South Africa

Argentina/Thailand/Brazil

Hong Kong

2HRZE/4HR**2RbHZE/4RbH *2RbHZE/4RbH

2RHZE/4HE(2)**2RbHZE/4RbHE(2)

10698

175171174

2HRSZ(3)+4HR(3)4HRp(1)4HRp(1)*2-3

190199203

3.85.1

0.61.21.2

3.27.59.4

Every 2nd or 3rd dose omitted

Bacteriologicalrelapse %

R = rifampicin, Rp = rifapentine, Rb = rifabutin

E = ethambutol, Z = pyrazinamide, H = isoniazid

Page 26: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB Treatment RegimensRifabutin

HAART Dose TB Dose therapy

3/4NRTI No change RBT No changenelfinavir 1750 mg bd RBT 150 mg odindinavir 1000 mg tds RBT 150 mg odamprenavir 1200 mg bd RBT 150 mg odBoosted PI No change RBT 150 mg 2-3/7nevirapine 200 mg bd RBT 300 mg odefavirenz 600 mg od RBT 450 mg od

Page 27: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Antiretroviral Therapy Options

• Triple or Quad NRTI with Rifampicin• EFV* with Rifampicin • NVP plus intermittent Rifampicin• Ritonavir + saquinavir with Rifampicin • EFV* with Rifabutin• Protease inhibitor (IDV, NFV, APV)* with Rifabutin• Boosted PI plus Rifabutin* Intermittent 2-3/7• ? In complex regimens eg Boosted PI plus NNRTI

*Dose adjusted

Page 28: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB• 109 HIV +ve patients with TB• Only risk factor for TB relapse was low CD4 count

• 98 HIV +ve patients on 2 NRTIs + EFV + rifampicin• Co-administration of EFV + rifampicin was well-tolerated

and immunologically effective

• 98 HIV +ve patients on 2 NRTIs + EFV 600mg + rifampicin• 80% had TB resolution• EFV 600mg was sufficient to treat HIV/TB patients on

rifampicin

Nettles R et al. 10th CROI, Boston MA, February 2003. Abs 137; Patel A et al. 10th CROI, Boston MA, February 2003. Abs 138; Pedral-Samapio D et al. 10th CROI, Boston MA, February 2003. Abs 784

Page 29: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

HepatitisPeripheralNeuro

31 (22%)

3.6

52%

d4T

Rash

19 (13.6%)

-

74%

nevirapine

efavirenz

11 (7.8%)

-

91%

isoniazid

rifampicin

n

Onset months

<2 months

AVR association

TB and HIV Adverse Events

Dean et al AIDS 2001

Page 30: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

AIDS + Drug absorptionMedian AUC

HIV + HIV - P

AIDSN 13 14 -

INH 1248 1062 0.5

PZA 22392 23117 0.5

RIF 3604 1665 0.001 Taylor IUTBLD NB No diff in, TMAX,CMAX 2 hr value NOT reflect CMAX 1998

Page 31: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

How Long to Treat?

TB / HIV

Page 32: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Duration of Treatment HIV/ TB Patients: Data

• 4/6 studies show acceptable (< 5 %) relapse rate with 6-month course

• 2 studies showed > 9 % relapse with 6-month course

• Relapse vs. re-infection

Page 33: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Durationmonths

F/Umonths

Relapse/failure

6

9

51

50

2*

1

* = new infection by RFLP

HIV and TB Duration Rx and Relapse

Page 34: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Duration of Treatment HIV/ TB Patients:

• 6-month course for drug-sensitive, uncomplicated cases

• Longer course for cases with CNS disease• Longer course for MDRTB and with

non-Rifampicin regimens

Page 35: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Examples of TB regimens used in new TB cases

INITIAL PHASE CONTINUATION PHASE

 

2 ERHZ 4 RH

2 SRHZ 4 R3 H3

2 S3 R3 H3 Z3 6 EH

6 R3 H3 Z3 plus S3or E3

Don’t use twice weekly regimens in patients with CD4 counts <100

Page 36: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Antiretroviral Therapy and TB

When to start HAART?

Page 37: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB and HIV: Immediate vs. Delayed HAART

Arguments for delaying potent HIV therapy until TB is treated:1. HIV is a chronic disease.2. Adherence may be compromised.3. Toxicity management is more complex.4. Immune restoration may produce “paradoxical

reactions.”

Page 38: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB and HIV: Immediate vs. Delayed HAART

Arguments for initiating potent HIV therapy at the onset of TB:

1. TB is associated with immune activation, increased HIV replication, and HIV disease progression.

2. Potent antiretroviral therapy can reduce HIV RNA levels, improve immune function and slow HIV disease progression.

3. HIV therapy reduces risk of developing other opportunistic infections

Page 39: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

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 in this group was 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

Page 40: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

TB and HIV:Immediate vs. Delayed HAART

• TB treatment must be given urgently.

• The urgency of HIV treatment depends on predictors of HIV disease progression especially the CD4 cell count.

• <100 cells/mm3 - HAART ASAP• 100-200 cells/mm3 - HAART after 2 months• >200 cells/mm3 - HAART after TB RX finished

Page 41: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

Immune Reconstitution Inflammatory Syndrome (IRIS)

Page 42: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK
Page 43: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

IRIS• Worsening of original disease • No evidence of bacteriological relapse or

recurrence*• May have high fevers – must exclude

concomitant disease • Related to start of ARV not to TB Rx• May respond to steroids /IL-2 and GM-CSF• Often prolonged• Recurrent aspiration –not biopsy

* NB not always the case

Page 44: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

IRIS• Thought to be due to increased proliferation

of peripheral blood mononuclear cells and interferon- response to tuberculous antigens

• ?genetic predisposition• Lack polymorphism in the cytokine gene

TNFA-308*2. • Increased levels of IL-6 have also been

found.

Page 45: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

IRIS

• TB and severe immunosuppresion• Rx HAART• Some patients expand abnormal/anergic

T cell clone• leads to abnormal response decrease IL-2

and cell signalling• Rx with IL-2 and GM-CSF can lead to

resolution of IRIS

Pires et al submitted

Page 46: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

MDR - TB outbreaksMDR - TB outbreaks

• Factors responsible– Inadequate control programmes– Inadequate compliance– Infection control procedure breakdown– Immunosuppressed convergence– Index of suspicion low– Inadequate lab. communication– Infectiousness prolonged

• Factors responsible– Inadequate control programmes– Inadequate compliance– Infection control procedure breakdown– Immunosuppressed convergence– Index of suspicion low– Inadequate lab. communication– Infectiousness prolonged

Page 47: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

MDR – TB outbreak• Argentina 16

2162

102102 88

Resistant to 6 drugsResistant to 6 drugs Resistant to 10 drugsResistant to 10 drugs

HIV Unit

88

Page 48: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

MDR -TB• Mortality

– 87 died prior to Rx starting– 49 died on standard Rx– 10 died on tailored Rx– 16 alive on tailored Rx

• Epidemiology– 77/92 indistinguishable RFLP TYPE– all 77 contact with index case

• Control– cohort nursing– contact tracing cost of 1case

=£60000 in UK

Page 49: TB and HIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

HIV and TBThanks to

SE TB research group

LSTMH

Dr Alison Grant

ICSM

Dr Imami

Chelsea and Westminster Hospital

Prof Gazzard