Challenges of treating two infections (HIV and TB): the ART of HIV/TB management

William Burman MDDenver Public HealthUniversity of Colorado

Case 1

27 y/o man from Ethiopia, admitted with cough, fevers, and 20 lb. weight loss over one month

Sputum - rare AFBHIV-positive, CD4 - 18, viral load > 1,000,000

Dramatic initial improvement with IRZE

Case 1

1. Should antiretroviral therapy be started during TB treatment?

2. When during TB therapy should antiretroviral therapy be started?

3. What regimens can be used for co-treatment of HIV and TB therapy?

Survival of persons with HIV-related TB in the pre-HAART era – San Francisco

N Engl J Med 1991; 324: 289-94

Complicating factors: antiretroviral therapy during TB therapy

Need for coordination between TB and HIV treatment programs

Challenge of adherence to multidrug therapy for both diseases

Overlapping drug toxicity profiles Drug interactions Immune reconstitution (paradoxical)

reactions

SAPiT: Starting Antiretroviral therapy (ART) in three Points in TB

Primary Objective: To determine the optimal time to initiate ARVs

in TB patients

Inclusion Criteria: Smear pulmonary TB HIV positive with CD4 count < 500 cells/mm3 Effective contraception (efavirenz)

Endpoint 10 – all-cause mortality

Karim S, et al. N Engl J Med. 2010;362:697-706

Initiation of ART during vs. after TB treatment: SAPIT

Abdool Karim S, et al. New Engl J Med 2010; 362: 697-706

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

02468

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< 200 200-500

Mort

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iy r

ate

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er

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Integrated Sequential

Abdool Karim S, et al. New Engl J Med 2010; 362: 697-706

2/186

6/8622/281

21/137

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

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< 200 200-500

Mort

alt

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Integrated Sequential

Abdool Karim S, et al. New Engl J Med 2010; 362: 697-706

2/186

6/8622/281

21/137All patients with HIV-TB should receive ART during TB treatment

Competing risks in the timing of ART during TB treatment

Immediate (< 2 wks)

Benefits:• ↓ risk of other OIs

Risks:• ↑ adverse effects• ↑ incidence of IRD

Early (2 months)

Benefiits:• ↓ risk of IRD

Risks:• ↑ incidence of

OIs• feasibility

Mortality

TB treatment

TB treatment

ART

ART

Study week

80 24

HIV+TB

Primary endpoint

General schema for CAMELIA, STRIDE, and integrated arms of SAPIT

“Immediate ART”(within 2 weeks)

“Early ART”(2-3 months)

Key characteristics of trials of timing of ART during TB treatment

Study Setting Key enrollment

criteria

Median CD4 (IQR)

Primary endpoint

CAMELIA Cambodia Smear +, CD4 < 200

25 (10 - 56) Death

STRIDE Multi-national

Clinical TB, CD4 < 250

77 (36 – 145) AIDS or death

SAPIT South Africa

Smear +, CD4 < 500

150 (77 – 254)

AIDS or death

N Engl J Med 365; 2011; 1471-1501

Effect of ART timing on death (CAMELIA) or death/AIDS (STRIDE, SAPIT)

02468

1012141618

CAMELIA STRIDE SAPIT

Immediate Early

34% ↓ p=0.00

4

19% ↓ p=0.45

11% ↓ p=0.73

N Engl J Med 2011; 1471-1501

Relationship between median baseline CD4 count and the effect of immediate ART on death (CAMELIA) or death/AIDS (STRIDE, SAPIT)

0

5

10

15

20

25

30

35

40

CAMELIA STRIDE SAPIT

% d

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ase

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ath

/AID

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0

20

40

60

80

100

120

140

160

Me

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N Engl J Med 2011; 1471-1501

P = 0.004

P = 0.45

P = 0.73

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

0

5

10

15

20

25

30

CAMELIA STRIDE SAPIT

Immediate Early

34% ↓ p=0.00

4

42% ↓ p=0.02

68% ↓ p=0.06

N Engl J Med 2011; 1471-1501

Effects of ART timing on death/AIDS among patients with CD4 > 50 in STRIDE and SAPIT

0

2

4

6

8

10

12

14

STRIDE SAPIT

AID

S o

r death

Immediate Early

p=0.67

p=0.34

N Engl J Med 2011; 1471-1501

Effects of ART timing on Immune Reconstitution Disease among patients with CD4 > 50 in STRIDE and SAPIT

02468

1012141618

STRIDE SAPIT

IRD

Immediate Early

p=0.009

p=0.02

N Engl J Med 2011; 1471-1501

Effect of ART timing on survival of patients with TB meningitis

Median CD4 ~ 40 (16 – 100)

60% + CSF culture

KM survival estimates at 9 months

35.2% in immediate arm

40.3% in deferred arm

Similar in per protocol analysis

Török et al, 41st Union World Conference on Lung Health, Berlin Nov 2010

Early ART

Immediate ART

Hazard ratio 1.1 (95% CI 0.8 – 1.6), p = 0.52

Effect of ART timing on risk of adverse events in patients with TB meningitis

Török et al, 41st Union World Conference on Lung Health, Berlin Nov 2010

p = 0.04

0102030405060708090

100

Grade 3 or 4 Grade 4

Perc

enta

ge o

f pati

ents

Immediate Early

Timing of ART in patients with TB

Advanced AIDS (CD4 < 50): immediate ART (within 2 weeks) improves survival

Markedly increased risk of IRIS, including fatal IRIS events

Overall survival benefit despite IRIS CD4 > 50: early ART (~ 2 months) provides

good balance of competing risks of death/AIDS vs. IRIS

Caveats CNS involvement – no benefit to immediate

therapy, and there may be increased risk (Clin Infect Dis. 2011;52:1374-83)

Programmatic complexities of early ART

Programmatic challenges of immediate ART during TB treatment

Rapid HIV diagnosis Rapid provisional diagnosis of TB Rapid way to identify those in need of

immediate ART: CD4 cell count, BMI, clinical status

ART available in settings where TB is diagnosed (hospital or clinic)

Training in diagnosis and management of IRD events

Adverse events during treatment of HIV-TB

54% (99/167) had adverse events, 34% interrupted TB or HIV therapy Common adverse events

Peripheral neuropathy (21%) - more common with use of stavudine

Skin rash (17%) - TB drugs (16), co-trimoxazole (7), nevirapine (2), other drugs (4)

hepatitis (6%) - TB drugs (6), unknown (5)AIDS 2002;16:75-83

Example of drug-drug interactions in HIV-TB care: atazanavir with rifampin

HIV Medicine 2007;8:131-4

Effect of rifampin on exposure (AUC) of NNRTIs

7869

0

20

40

60

80

100

Efavirenz Nevirapine

% o

f no

rmal

AU

C

Effect of EFV dose (600 vs. 800 mg) on mid-dose levels, patients on RIF

AIDS 2005;19:1481-6, AIDS 2006;20:131-2

Outcomes at 48 wks

On EFV 600 mg – 81% 800 mg – 74%

VL < 50 600 mg – 91% 800 mg – 87%

Virological failure of efavirenz-based ART, among patients with and without rifampin for TB

JAMA 2008; 300: 530-9

6.48

11.5

5.7

8.1

10.4

0

2

4

6

8

10

12

14

6 12 18

Months of co-treatment

%w

ith

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al l

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TB No TB

Case #2 - Intubated in the ED

38 year old man sent from jail – 1 wk of fevers, cough, dyspnea

BP – 85/36 P – 100 T – 38.8 ABG – pH – 7.21, PCO2 – 29, PO2 - 38 Intubated for CV instability, acidosis, hypoxia

PMH – Meds – trim/sulfa, azithro, acyclovir AIDS CD4 – 2, VL – 10,200 Crack cocaine abuse, frequent incarcerations PPD negative 3 mos. prior

Hospital course

Initial treatment – trim/sulfa and prednisone

Sputum DFA – negative for PCP Sputum AFB – strongly positive Started on parenteral INH, RIF, levo,

amikacin Extubated, switched to oral IRZE Culture – susceptible M. tuberculosis

In the ID Clinic

3 weeks into TB treatment – first ID Clinic visit since TB diagnosis

Current TB treatment - IRZE 5 days/wk by DOT

Living situation – SRO provided by TB program

Drug use – clean and sober Interested in ART, but very worried

about side effects and being experimented on

ART history

6 years ago – brief multidrug regimen, no records, patient unable to identify meds

18 months ago – tenofovir / 3TC / EFV Initial suppression to < 50 copies/ml CD4 from 4 to 24 Subsequent virological and

immunological failure 2o nonadherence

Genotype: L100I, K103N (EFV), M184V (3TC)

Patients who cannot be treated with EFV-based ART

Efavirenz intolerance Resistance to efavirenz (other 1st-

generation NNRTIs) Pregnancy (at least for the first 1-2

trimesters) Very young children (< 3 years)

Comparison of the effects of RIF vs. RBT on trough concentrations of boosted PIs

1 2.5

120 113

175

117

0

50

100

150

200

LPV/r ATZ/r DRV/r FPV/r

% o

f n

oo

rmal

tro

ug

h

con

cen

trat

ion

rifampin rifabutin

AAC 2204;48:1553-60, AAC 2006; 50:3336-42, AAC 2010;54:4440-5, AAC 2008;52:534-8,

ND ND

Effect of protease inhibitors on serum concentrations (AUC) of rifamycins

Rifabutin RifampinPI

Ritonavir

Indinavir

Nelfinavir

Amprenavir

Lopinavir/ritonavir

Atazanavir

400%

270%

200%

400%

300%

250%

unchanged

unchanged

NR

NR

NR

NR

Clin Infect Dis 1999; 28: 419-30

Clinical relevance of increased rifabutin concentrations due to ritonavir

Adverse effect% of patients on

ritonavir + rifabutin% of patientson ritonavir

Arthralgia

Joint stiffness

Uveitis

Leukopenia

9.2

4.1

4.7

38

0.6

0

0.6

19

11th International Conference on AIDS; abstract Mo.B171

Rifabutin PK with lopinavir/R in TB patients (n = 16)

PK parameter

RBT 300 mg/day

RBT 150 mg QOD + LPV/r

RBT 150 mg/day+

LPV/r

Median AUC (exposure)

3026 2307 5010

Median Cmax (peak)

297 168 311

Naiker S, et al. 2011 CROI, abstract 650

Rifabutin and TB therapy

Rifabutin is as active as rifampin No dose adjustments of ART needed for

commonly-used drugs (ATZ, lopinavir/R) Decrease RBT from 300 mg daily to 150

mg daily when given with boosted PIs Give remainder of TB drugs daily

Caution – RBT dose would be inadequate if patient stopped PI

HIV, TB drug interaction - summary

Drug interactions in HIV-TB are regrettably complex, but should not prevent HIV-TB co-treatment

Co-treatment regimen of choice: rifampin-based TB treatment + efavirenz-based (standard dose) ART

Drug interactions should be managed, not avoided – use a rifamycin-based regimen

New drug interaction guidelines at http://www.cdc.gov/tb/TB_HIV_Drugs

Case 1 – Chest x-ray response to therapy

Diagnosis 2 months

Case 3 – Chest x-ray response to therapy - II

3 monthsStarted antiretroviral therapy at 8 weeks of TB therapy

Developed fever, cough, left pleuritic chest pain 10 days after starting HAART

Types of immune reconstitution inflammatory syndrome (IRIS) events in HIV-TB

• Hectic fever• New or worsening adenitis - peripheral or central nodes• New or worsening pulmonary infiltrates, including respiratory failure• New or worsening pleuritis, pericarditis, or ascites• Intracranial tuberculomas, worsening meningitis• Disseminated skin lesions• Epididymitis, hepatosplenomegaly, soft tissue abscesses

Association between timing of ART and risk of IRIS event (SAPIT)

Ann Intern Med 2012; 157:313-24

42% hospitalized

22% hospitalized

5% hospitalized

Association between timing of ART and risk of IRIS event (SAPIT)

Ann Intern Med 2012; 157:313-24

Median duration - 71 days

Median duration - 34 days

Median duration – 24 days

IRIS in the CAMELIA study (median CD4 of 25)

Immediate ART increased risk of IRIS (33% vs. 14% for early ART)

Similar timing of IRIS events (14 vs. 16 days after starting ART

6 deaths, all in the immediate arm, were attributed to IRIS events

However, immediate ART was associated with a lower risk of death (8% vs. 14%)

N Engl J Med 2011; 365: 1471-81

IRIS events - implications for use of antiretroviral therapy (ART)

Those who need ART the most (patients with low CD4 cell counts) have higher risk for an IRIS event and for a serious IRIS event

Delaying ART decreases risk of severe paradoxical reactions, but increases risk of another OI or death

Anticipate IRIS events – discuss beforehand with patient and other care providers

Schedule early follow-up after starting ARV - detect and manage IRIS events

Management of IRIS

Anticipate IRIS events – warn patients and other care providers

Rule out other possible causes – bacterial infections, a 2nd OI, inadequate Rx for OI, drug-resistant pathogen

For relatively severe manifestations, prednisone is reasonable 1 mg/kg (1.5 mg/kg with rifampin), tapering

over 4-6 weeks

What’s happening in the clinic? Starting ART in TB patients in London, 1998-2007)

British recommendations (at that time)CD4 < 100 – at 2 weeksCD4 100-200 – at 2 monthsCD4 > 200 – after TB treatment

83 patients eligible to start ART 20 patients (24%) started ART at the

recommended point in TB treatment

Thorax 2008;63:935

Reasons for the delay in starting ART among patients with CD4 < 100

Patient-related reasons: Refused to start Fear of side effects of ART Poor adherence

Physician-related reasons: Serious side effect of TB

treatment Concern about ART side effects /

IRIS Presence of another illness Seriousness of the manifestations

of TB

7 (21%)2 (6%)3 (9%)

8 (24%)6 (18%)4 (12%)5 (15%)

Thorax 2008;63:935

Starting ART during TB treatment – summary of the steps required

Start TB therapy, deal with initial side effects Help patient deal with the diagnosis of two

stigmatizing diseases Start cotrimoxazole, deal with initial side

effects Assess readiness for HAART Coordinate start of ART (~ 2 weeks for CD4

< 50, ~ 2 months for CD4 > 50) Use DOT visits to adherence with HAART Anticipate and manage immune

reconstitution events

Summary – treatment of HIV-related TB: issues with antiretroviral therapy

Should antiretroviral therapy be used during TB treatment?

Yes, for all patients What regimens can be used for co-treatment

of HIV and TB? Preferred: efavirenz-based HAART + rifampin-

based TB treatment Alternative: PI-based HAART + rifabutin-based

TB treatment When should HAART be started?

2 weeks (CD4 < 50 to 2 months after starting TB treatment

Two infections; one patient

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