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HIV and TBAlberto Matteelli

WHO collaborative centre for TB/HIV co-infectionDepartment of Infectious Diseases

Brescia University Hospital, Brescia, Italy

HIV and Co-Infections: HCV, Malaria, TB and Beyond

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Outline of the presentation

1. Rationale for TB/HIV collaborative activities

2. Impact of HAART on TB/HIV co-infection3. Treatment of co-infected patients4. Collision between MDR-TB and TB/HIV

co-infection

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Estimated number of cases

Estimated number of deaths

HIV-associated TB 1.1 million (12%) (range: 1.0–1.2 million)

380,000(range: 320,000–450,000)

0–24

25–49

50–99

100–299

300 and higher

No estimate available

The Global Burden of TB -2009

TB is responsible for one in four AIDS deaths

People living with HIV have an estimated 20 to 30 times greater risk of developing active TB than people without HIV infection.

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Countries with the highest number of deaths from HIV-associated TB

Time to act - Save a million lives by 2015Prevent and treat tuberculosis among people living with HIV. WHO 2011

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A. Establish the mechanism for integrated TB& HIV services Set up coordinating bodies for effective TB/HIV activities

at all levels Conduct surveillance of HIV prevalence among TB cases Carry out joint TB/HIV planning Conduct monitoring and evaluation

B. Decrease burden of TB among PLHIV (the "3 Is") Establish Intensified TB case finding and ensure quality TB treatment Introduce TB prevention with IPT or ART Ensure TB Infection control in health care and congregate

settings

C. Decrease burden of HIV among TB patients Provide HIV testing and counselling to TB suspects & TB patients Introduce HIV prevention methods for TB suspects & TB patients Provide CPT for TB patients living with HIV Ensure HIV prevention; treatment & care for TB patients with HIV Introduce ARVs to TB patients living with HIV

TB/HIV collaborative activities:a 12 points package

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2011 WHO Recommendations oncollaborative TB/HIV activities

"The 3 Is"

1. Infection control

2. Isoniazid preventive therapy (IPT)

3. Intensified TB case-finding

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Reducing TB burden among PLWHA

Isoniazid preventive therapy

Infection control

Intensified case finding

Ada

pted

from

WH

O; 2

009

The 3 Is

Antiretroviral therapy

The 4th I

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VariableAdjusted

Relative Hazard (95%CI)

P-value

HAART after TB Dx 0.45 (0.26-0.79) 0.005CD4 < 200(Time- 200 – 349dependent) 350 – 499

≥ 500

10.46 (0.27-0.79)0.47 (0.26-0.85)0.32 (0.17-0.61)

0.0050.01

< 0.001Sex Male

Female1

1.03 (0.67-1.60) 0.89

Age < 30 30-39 40-49 ≥ 50

10.85 (0.41-1.79)0.80 (0.38-1.69)0.26 (0.09-0.75)

0.670.560.01

Golub et al., AIDS 2008; 22:2527

Recurrent TB and ART in HIV-infected patients in Rio de Janeiro

N=1042 – recurrences in 8.9%

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Impact of HAART on MDR-TB spread and outcome

• During the 90s’, in the pre-HAART era, several MDR-TB outbreaks and high mortality reported among PLWHA in U.S. and Europe

• Large outbreaks virtually disappeared after 1996 in these settings

• In 2006 XDR-TB emerging as a global threat from outbreaks among PLWHA in South Africa, at a time where HAART coverage was marginal

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Unmasking TB by HAART• During the three months following start of ART

there is a spike of TB incidenceNew TB cases reported prior to,

and after ART Initiation

407

1,649

0

400

800

1,200

1,600

2,000

During Care, priorto ART

After Initiation ofART

0

5

10

15

20

25

30

35

Rat

e pe

r 100

0 pe

rson

-yea

rsNumber of TBevents Rate per 1000pyrs

TB cases reported after Initiation of ART

153

9

390

1

10

100

1000

0-3 4-6 7-9 10-12 > 12Follow-up in months

0

5

10

15

20

25

Rat

e pe

r 100

0 py

rs

TB cases rate / 1000 pyrs

Somi G, et al. Rome IAS Conference, 2011

Data from >100,000 PLWHA under programme conditions in Tanzania (2004 – 2009)

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Changes in TB incidence during 3 years of HAART in Europe and North America with regression curve fitted (number of

cases per 1000 person-years of follow-up)

Girardi E, Clin Infect Dis 2005, 41: 1772

Incidence at steady state 150 per 100,000 PYFU ,

which is 10-fold higher than in HIV negative population

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ART in HIV / TB patientsHR for mortality 0.45 (0.26 – 0.79) in patients starting ART during TB therapy regardless of CD4

Trial stopped by the ethical committeeAbdool Karim SS, N Engl J Med 2010; 362:697-706

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CONCLUSION: Mortality was reduced by 34% when HAART was initiated 2 weeks vs 8 weeks after onset of TB treatment

Early (2 weeks) vs. late (8 weeks) initiation of HAART: the CAMELIA study (Blanc et al).

Kaplan-Meier Survival curve

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Timing of ART in HIV / TB patients

WHO recommendation• Start TB treatment first, followed by ART as

soon as possible after starting TB treatment irrespective of CD4 cell count

(strong recommendation – Moderate quality of evidence)

WHO, 2010: ART guidelines

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ART in TB patients by Region, 2008

Region started on ARTAFR 30%

AMR 67%

EMR 55%

EUR 29%

SEAR 35%WPR 28%

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Operationalising ART in TB patients

• Rapid HIV diagnosis• Rapid CD4 determination (or identificatioon of

surrogate markers – BMI,Hb, clinical or radiological signs)

• Avalability of ART (often requires referral and loss during referral or delay)

• Instruct on how to identify and manage IRIS

• Improve communications between • HIV and TB services

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Timing of ART during TB therapy

Trial Sites and patients

Study design and endpoint

Overall results

Results in CD4<50

ACTG 5221 STRIDE study(1)

Multicentre in 4 continents (majority in Africa).

TB suspect or confirmed <250 CD4

Immediate (2 w) Vs. early (8 w)

Death+AIDS events at W48

13.0% Vs.16.1%P=0.45

15.5% Vs. 26.6%

P=0.02

SAPiT continuation phase(2)

One centre in South Africa

Smear+PTB<500 CD4

Early (1-4 w) Vs. late (8-12 w)

Death+AIDS events at W48

6.9 Vs. 7.8 /100 p-yP=0.73

8.5 Vs. 26.3 /100 p-y

P=0.06

(1) Havlir D, et al. Abs 38, 18° CROI, Boston 2011(2) Abdool Karim S, et al. Abs 39LB, 18° CROI, Boston 2011

The Camelia study: the median of the CD4 cellc count of enrolled patients was 25 cells

STRIDE and SAPiT trials: for CD4> 50 there was no trend towards decreased death/AIDS events

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Treatment strategies for TB/HIV co-infected patients

• First choice: standard TB regimen• +• 2NRTI + Efavirenz

• Is a first line option for HIV treatment• In the most widely used first line drug in resource limited settings• Allows for standard TB therapy• Allows for once a day therapy with minimal pill burden (Atripla)• Clinical trials available from South Africa and Thailand

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Effect of RFM on Serum Concentrations of PIs and NNRTI

PI

Saquinavir

Ritonavir

Indinavir

Nelfinavir

Amprenavir

Lopinavir/ritonavir

Atazanavir

80%

35%

90%

82%

81%

75%

not done

NNRTI

Nevirapine

Efavirenz

37-58%

13-26%

What if efavirenz cannot be used ?

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Rifabutin can be used with LOPINAVIR, ATAZANAVIR, FOSAMPRENAVIR, DARUNAVIR, TIPRANAVIR always with RITONAVIR boosting

Rifabutin and HIV drugs of the PI class

RIFABUTIN acceptable substitute for rifampicin, in standard TB regimens but:- not widely available- requires loose drugs

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Rifabutin doses: still debated

• 9/10 patients and 5/5 patients with low Cmax values (<30mg/ml)

• Selection of rifa-R MTBBoulanger C, CID 2009

Khaci H, JAC 2009

Naiker S, 18° ICAAR, 2011

• AUC significantly reduced compared to the standard in 16 TB/HIV patients in South Africa. AUC reverted by 150 mg daily during LPV/r treatment

Ritonavir increases rifabutin levels significantly, requiring a dose reduction to 150 mg every other day (DHHS)This recommendation is derived from PK studies in healthy volunteers

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Drug Interactions: Rifampicin and other HIV drugs

• NNRTIs– Rifampicin decreases Etravirin exposure

“significantly”. Combination not recommended• CCR5 Inhibitors

– Rifampicin reduces maraviroc exposure by 63%. Maraviroc doses could theoretically be doubled but no clinical experience

• Integrase inhibitors– Rifampicin reduces raltegravir exposure by 40-60%.

Raltegravir 800 mg BID suggested, but optimal concentration range of this drug is unknown

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The perfect storm

• Areas of collision between MDR and TB/HIV epidemics already existent:– - South Africa– - Eastern Europe– - Central Asia

Australia, Democratic Republic of the Congo, Fiji, Guam, New Caledonia, Solomon Islands and Qatar reported data on combined new and previously treated cases.

0-<3

3-<6

6-<12

12-<18

>=18

No data available

Subnational data only

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Outcomes of Treatment for MDR TB in the South African DOTS-Plus Program, 2002-2004

Outcome HIV + (N=327)

HIV –/unknown

(N=875)

P value

Successful Rx 38.5% 49.3% <0.001

Failed 4.3% 11.4% <0.001

Defaulted 21.4% 22.6% 0.65

Died 35.8% 16.7% <0.001

Farley, van der Walt, et al., IUATLD World Conference, 2007

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Early diagnosis crucial for MDR-TB among PLWHA

• Diagnostic capacity for MDR-TB inadequate in most countries (7% world-wide). We need;– - high quality culture and 1st and 2nd line DST– - molecular tests– - Cepheid Xpert MTB/RIF

HIV testing does not affect test performanceRachow A, PLoS-ONE 2011; 6: e20458

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Key messages

HAART expansion key to reduce the burden of HIV-associated TB

Improve communications between TB and HIV service to operationalise dual treatment

Actively promote the introduction of rifabutin in resource limited settings after defining appropriate doses

Invest massively in TB lab platform. Widen acces to high quality culture or molecular tests. Use them preferentially for PLWHA who are TB suspect

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THE ITALIAN GOVERNMENT STILL OWES 260 MILLION EUROS TO THE GLOBAL FUND AND

NEVER PLEDGED FOR 2011 - 2013

ITALY:KEEP THE PROMISE, NOW!

FUND THE FUND, NOW! AIDS, TUBERCOLOSIS AND MALARIA WILL NOT WAIT!