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HIV and TB. Alberto Matteelli WHO collaborative centre for TB/HIV co-infection Department of Infectious Diseases Brescia University Hospital, Brescia, Italy. HIV and Co-Infections: HCV, Malaria, TB and Beyond. Outline of the presentation. 1. Rationale for TB/HIV collaborative activities

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hiv and tb
HIV and TB

Alberto Matteelli

WHO collaborative centre for TB/HIV co-infection

Department of Infectious Diseases

Brescia University Hospital, Brescia, Italy

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

outline of the presentation
Outline of the presentation

1. Rationale for TB/HIV collaborative activities

2. Impact of HAART on TB/HIV co-infection

3. Treatment of co-infected patients

4. Collision between MDR-TB and TB/HIV co-infection

slide3

0–24

25–49

50–99

100–299

300 and higher

No estimate available

Estimated number of cases

Estimated number of deaths

1.1 million (12%)

(range: 1.0–1.2 million)

380,000

(range: 320,000–450,000)

HIV-associated TB

The Global Burden of TB -2009

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

TB is responsible for one in four AIDS deaths

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

Time to act - Save a million lives by 2015

Prevent and treat tuberculosis among people living with HIV. WHO 2011

slide5
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")

EstablishIntensified 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

slide6

2011 WHO Recommendations on

collaborative TB/HIV activities

  • "The 3 Is"
  • Infection control
  • Isoniazid preventive therapy (IPT)
  • Intensified TB case-finding
slide7

Reducing TB burden among PLWHA

The 4th I

Antiretroviral therapy

Intensified case finding

The 3 Is

Isoniazid preventive therapy

Infection control

Adapted from WHO; 2009

recurrent tb and art in hiv infected patients in rio de janeiro
Recurrent TB and ART in HIV-infected patients in Rio de Janeiro

N=1042 – recurrences in 8.9%

Golub et al., AIDS 2008; 22:2527

impact of haart on mdr tb spread and outcome
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
unmasking tb by haart
Unmasking TB by HAART
  • During the three months following start of ART there is a spike of TB incidence

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

Somi G, et al. Rome IAS Conference, 2011

slide12

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)

Incidence at steady state 150 per 100,000 PYFU , which is 10-fold higher than in HIV negative population

Girardi E, Clin Infect Dis 2005, 41: 1772

art in hiv tb patients
ART in HIV / TB patients

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

Trial stopped by the ethical committee

Abdool Karim SS, N Engl J Med 2010; 362:697-706

slide14

CONCLUSION: Mortalitywasreducedby 34% when HAART wasinitiated 2 weeks vs 8 weeksafteronsetof TB treatment

Early (2 weeks) vs. late (8 weeks) initiation of HAART:

the CAMELIA study (Blanc et al).

Kaplan-Meier

Survival curve

timing of art in hiv tb patients
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

slide16

ART in TB patients by Region, 2008

Region started on ART

AFR 30%

AMR 67%

EMR 55%

EUR 29%

SEAR 35%

WPR 28%

operationalising art in tb patients
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
timing of art during tb therapy

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

Timing of ART during TB therapy

(1) Havlir D, et al. Abs 38, 18° CROI, Boston 2011

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

treatment strategies for tb hiv co infected patients
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
slide20

What if efavirenz cannot be used ?

Effect of RFM on Serum Concentrations of PIs and NNRTI

PI

NNRTI

Nevirapine

Efavirenz

 37-58%

 13-26%

 80%

 35%

 90%

 82%

 81%

 75%

not done

Saquinavir

Ritonavir

Indinavir

Nelfinavir

Amprenavir

Lopinavir/ritonavir

Atazanavir

slide21

Rifabutin and HIV drugs of the PI class

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

  • RIFABUTIN acceptable substitute for rifampicin, in standard TB regimens but:
  • not widely available
  • requires loose drugs
rifabutin doses still debated
Rifabutin doses: still debated
  • 9/10 patients and 5/5 patients with low Cmax values (<30mg/ml)
  • Selection of rifa-R MTB

Boulanger C, CID 2009

Khaci H, JAC 2009

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

  • 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

Naiker S, 18° ICAAR, 2011

drug interactions rifampicin and other hiv drugs
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

the perfect storm
The perfect storm
  • Areas of collision between MDR and TB/HIV epidemics already existent:
    • - South Africa
    • - Eastern Europe
    • - Central Asia
outcomes of treatment for mdr tb in the south african dots plus program 2002 2004
Outcomes of Treatment for MDR TB in the South African DOTS-Plus Program, 2002-2004

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

early diagnosis crucial for mdr tb among plwha
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 performance

Rachow A, PLoS-ONE 2011; 6: e20458

key messages
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

slide28

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!

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