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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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