1. TB and HIV: from clinical practice to public health action
Alberto Matteelli
Institute of Infectious and Tropical Diseases
University of Brescia, Italy
WHO Collaborative Centre on TB/HIV co-infection

2. Outline of the presentation
Burden of HIV associated TB
Impact of HAART on the epidemiology of HIV associated TB
Diagnostic standards and perspectives for HIV associated TB
How to treat the TB/HIV co-infection (choice of drugs, timing, managemert of IRIS)
Prevention of TB in HIV infected persons (early diagnosis, IPT, ART)
WHO recommended TB/HIV activities

3. How HIV influences the TB natural history
Post-primary TB
Primary TB
M. tuberculosis
First Infection
Latent TB
Re-infection (exogenous)
Reactivation (endogenous)
Progressive Primary TB
Relative risk for TB:
HIV neg. = < 10% per lifetime
HIV pos. ~ 3-7 % per year
HIV positive
HIV influences the TB natural history

4. Sub-Saharan African country
TB/HIV Co-infection Overlap of two populations
Sub-Saharan African country
Infection
with M. tuberculosis
Infection with HIV

5. Estimated HIV prevalence in new TB cases, 2009
1.1 million TB/HIV cases and 400,000 deaths
WHO, Global TB report 2010

6. Estimated TB incidence vs. HIV prevalence in high burden countries
1600
1200
Estimated annual TB incidence
(per 100K adults, 1999)
800
400
The estimated annual TB incidence per 100,000 adults increases in a proportional way with the HIV prevalence in adults, years of age. When HIV prevalence increases by 1%, the TB incidence increases by 26/100,000 per year.
HIV prevalence increases by 1%
TB incidence increases by 26/100k/yr
0.0
0.1
0.2
0.3
0.4
Williams B. 3rd Global TB/HIV Working Group Meeting; Montreux, 4-6 June 2003
HIV prevalence, adults years

7. Impact of HIV on TB in Africa
4/5 of all estimated TB/HIV cases are in Africa
Notified cases per 100,000 pop
Regarding the big challenge of TB/HIV, on the left are the case notifications of selected African countries.
These curves show that, when HIV began to spread in the mid-1980s, TB started increasing fast, reaching many times the original rate.
One can easily imagine the impact on already weak services and realise why TB is the number one killer of PLHIV.
On the right, the pie tells you where the HIV-associated TB cases are: 85% in Africa and 15% in other continents.
We do have interventions that are effective to prevent the burden of TB on HIV and that of HIV on TB. We need the GF to promote their use in a bolder way than today.

8. TB notification rate in 20 African countries* versus HIV prevalence
in sub-Saharan Africa, 1990–2004
Sources: World Health Organization (2006), Global TB database; UNAIDS (2006)
Consistently reporting each year: Algeria, Angola, Botswana, Cameroon, Comoros, Congo, Côte d'Ivoire, Democratic Republic of Congo, Ghana, Guinea, Kenya, Malawi, Mauritius, Mozambique, Nigeria, Senegal, South Africa, Uganda, United Republic of Tanzania, Zimbabwe 20 40 60 80
100
120
140
160
180
200
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004 1 2 3 4 5 6 7 8
TB notification rate
TB notification
rate per 100,000
population
% Adult HIV
prevalence
(15-49)
HIV prevalence
4.5

9. Infection with M. tuberculosis
TB/HIV Co-infection Overlap of two populations
Rich European Country
Infection with HIV
Infection with M. tuberculosis
World Health Organization

10. Estimated HIV prevalence in new TB cases, WHO European Region 2008

11. TB in the HIV era
Most frequent infection associated with HIV world-wide
Can spread to the non-HIV population
HIV can pull and steer the incidence of TB

12. Clinical case 1a
16/03/2010: B V, male, 30 years old, from Romania, working in Italy since 4 years, is prescribed an HIV test because of genital lesions and oral candidiasis. The test result is positive.
31/03/2010: His viro-immunological profile is as follows: CD (14,4%) HIV-RNA 106,000 copies. HIV treatment is prescribed: 3TC/ABC plus LPV/r.
3/05/2010: the patient develops persistent high fever and is admitted to the ward 12

13. A chest X-ray is performed (03/05)
Rx torace in data 03/05:. Alla periferia di entrambi i lobi superiori permangono riconoscibili 2 aree di consolidamento parenchimale di morfologia nodulare (diametro max 1cm). Ampliato l'ilo su base adenopatica. Minima accentuazione dell'interstizio di aspetto micronodulare in sede peri-ilare bilaterale. Non versamento. 13

14. Abdominal CT scan (07/05)
TORACE. Numerosi e diffusi piccoli addensamenti parenchimali alla periferia dei polmoni a distribuzione peribronchiale bilateralmente. Bronchiectasia di 18 mm all'apico posteriore del lobo superiore sinistro. Numerose adenopatie a livello dei vasi epiaortici e mediastiniche in parte colliquate. Bilateralmente linfonodi ascellari aumentati di dimensione. a pancreas, reni e surreni. Splenomegalia a struttura disomogenea (utile ecografia mirata). Numerose adenopatie in parte colliquate lungo le catene lomboaortiche (diametro massimo 34 mm) e a livello del ventaglio mesenterico. Non versamento retro o intraperitoneale. 14

15. Clinical case 1b
TB suspect: sputum and blood samples examined – negative microscopy
M.tuberculosis isolated from sputum and blood on 24/05. Rapid test for rifampicin resistance is negative.
Disseminated TB diagnosed
25/05: TB treatment started with RIFABUTIN 150 mg every other day + INH/ETH/PZA; HAART is continued unchanged
06/06: drug sensitivity testing available: resistance to isoniazid. The drug is removed and the TB regimen continues as planned
The patient is fully adherent to monthly clinical visits, his conditions improves and normalise
25/11: he completes TB treatment (6 months). 15

16. Key features of clinical case 1
HAART is a significant determinant of the risk of TB in HIV infected persons
Smear negative pulmonary TB and extrapulmonary TB is common
Treatment of TB in an HIV infected person is challenging 16

17. TB and HIV in the era of HAART
HAART reduces the incidence of TB by approximately 80% in high and low burden countries
TB incidence in HIV infected persons receiving effective HAART is ~ 10 times higher than that in the background population
HAART may unmask TB in persons with low CD4 cell count
HAART may be key to control MDR epidemics among HIV infected persons 17

19. Recurrent TB and ART in HIV-infected patients in Rio de Janeiro
Variable
Adjusted
Relative Hazard (95%CI)
P-value
HAART after TB Dx
0.45 ( )
0.005
CD4 < 200
(Time – 349
dependent) 350 – 499
≥ 500 1
0.46 ( )
0.47 ( )
0.32 ( )
0.01
< 0.001
Sex Male
Female
1.03 ( )
0.89
Age < 30
30-39
40-49
≥ 50
0.85 ( )
0.80 ( )
0.26 ( )
0.67
0.56
N=1042 – recurrences in 8.9%
Golub et al., AIDS 2008; 22:2527 19

20. Changes in tuberculosis (TB) incidence during 3 years of HAART in Europe and North America with regression curve fitted. TB incidence rate is expressed as number of cases per 1000 person-years of follow-up
Although the incidence tended to decrease with time, it was still 150 per 100,000 PYFU during the third year after starting HAART. Which is 10-fold higher than in HIV negative population
Girardi E, Clin Infect Dis 2005, 41: 1772

21. TB is the commonest illness among PLHIV on ART
With the expansion of ART programmes mainly after 3by5, and with more PLHIV living longer, the importance of TB for HIV policy makers has also immensely increased. This slide shows the distribution of OIs in the first three months of ART initiation in more than 30,000 PLHIV by geographical region. Pulmonary and extrapulmonary TB are now the commonest presenting illness among PLHIV started on ART both in Sub-Saharan Africa and established markets of Europe and North America. More than a quarter of these PLHIV developed TB in the first 3 months of ART initiation in sub-Saharan Africa. Similarly, studies showed that both prevalent and incident TB were common among PLHIV receiving ART and up to 1 in five PLHIV on ART died of TB while on ART. This is also further complicated by the difficulty of co-management TB and AIDS primarily due to drug interactions between anti-TB and ART. Therefore, it is imperative to say that any investment in ART scale-up programme by HIV policy makers need to give due attention for TB prevention, diagnosis and treatment.

22. Incidence of tuberculosis among HIV seropositive patients by timing after initiation of HAART
During the initial months of HAART incident TB cases may arise as a consequence of “unmasking” of previously subclinical disease or the deterioration of a pre-existing disease due to the reconstitution of the immune system (Lawn, 2005)
Dembele M, Int J Tub Lung Dis 2010, 14: 318

23. Incidence of tuberculosis among HIV seropositive patients by timing after initiation of HAART and site of the disease
Dembele M, Int J Tub Lung Dis 2010, 14: 318

24. Lessons for HIV programmes
Start ART at early stage (CD4 350 or below)
Increase capacity to diagnose PTB by improved microbiological tools
Increase capacity to diagnose EPTB (develop algorithms)

25. Improving diagnostic capacity

26. New(er) TB Diagnostic Tools
LED fluorescent microscopy
Liquid culture (e.g. MGIT)
Sensitivity ~50-75% > L-J
Capilia TB
Rapid strip test that detects a TB-specific
antigen from culture
Molecular assays
Cepheid GeneXpert
Hain GenoType MTBDRplus) 26

27. LED microscopy
Molecular assays
Liquid culture

29. Xpert MTB/RIF
Boehme et al. N Engl J Med 2010; 363: 1005

30. Among culture-positive patients, a single, direct MTB/RIF test identified 551 of 561 patients with smear-positive TB (98.2%) and 124 of 171 with smear-negative TB (72.5%). The test was specific in 604 of 609 patients without tuberculosis (99.2%). MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 514 (98.1%) with rifampin-sensitive bacteria.

31. Proportion of TB cases detected and time to detection
Courtesy of C Gilpin

32. Current understanding of Xpert TB contribution to TB control
Increases sensitivity of 30% compared to miscroscopy
Reduces time to start TB treatment
Might have an impact on mortality
Logistic is manageable
Costs per TB case detected increases x 3 times but remains cost-effective with WHO criteria (<1 GDP/capita)
Impact on EPTB and pediatric TB under investigation

33. Treatment of TB in HIV infected persons

34. TB treatment should be started immediately under all circumstances
Strategy for initiation of TB treatment in HIV infected patients with active TB
TB treatment should be started immediately under all circumstances
WHO, 2010: Rapid Advice on ART

35. Treatment of Tuberculosis in HIV Daily or 3 times weekly therapy only
Initial Phase Continuation Phase*
Isoniazid
Rifampin
Pyrazinamide
Ethambutol *
months
*If culture positive at 2 months and cavitation, extend therapy to 9 months
CDC , ATS and Infectious Diseases Society of America Guidelines 35

36. Does 6-month therapy duration increase the risk of relapse ?
Pooled estimate of relapse result stratified by duration of rifampin
DURATION OF RIFAMPIN
N. STUDIES
N. RELAPSES
POOLED RELAPSE RATE (95% CI)
aRR
(95% CI)
2 months 6
40/258
10,8 (0-25,1)
3,6
(1,1-11,7)
6 months 12
100/730
9,8 (0-19,8)
2,4
(0,8-7,4)
> 8 months
20/314
3,3 (0-9,0)
1,0 (reference)
Khan FA, AIDS 2010 (methanalysis) 36

37. Programmatic outcomes for TB/HIV patients are poor
WHO Global TB Report, 2009

38. Choice of HIV drugs

39. ART for HIV/tuberculosis co-infection
WHO recommendation
Use efavirenz as the preferred non nucleoside reverse transcriptase inhibitor in patients starting ART while on treatment
(strong recommendation – High quality of evidence)
WHO, 2010: Rapid Advice on ART

40. Efavirenz, no doubts Advantages
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 40 40

41. EFV dose in TB/HIV co-infection treated with RMP (600 versus 800 mg)
Reduction in EFV levels:20-25%
Clearance of EFV lower in in Afro-Americans and Hispanics than Caucasians (impact on safety profile); body weight also important (60 kg threshold)
In Caucasian > 60 Kg EFV 800 mg + RIF give AUC similar to EFV 600 mg
In Thailand and South Africa studies show effective, pharmacological, clinical, immunological and virologic response with conventional 600 mg EFV dose

42. What if efavirenz cannot be used ?
Effect of RFM on Serum Concentrations of PIs and NNRTI PI
NNRTI
Saquinavir
Ritonavir
Indinavir
Nelfinavir
Amprenavir
Lopinavir/ritonavir
Atazanavir
 80%
 35%
 90%
 82%
 81%
 75%
not done
Nevirapine
Efavirenz
 37-58%
 13-26%

43. Rifabutin and HIV drugs of the PI class
Available data allows for the use of LOPINAVIR, ATAZANAVIR, FOSAMPRENAVIR, DARUNAVIR, TIPRANAVIR always with RITONAVIR boosting
PI blood level adequate to ensure efficacy (but few datafrom clinical trials)
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 43 43

44. Rifabutin 150 mg every other day in association with Lopinavir/r
9/10 patients with low Cmax values (<30mg/ml)
(Boulanger C, CID 2009
Khaci H, JAC 2009)
5/5 patients with low Cmax values (<45mg/ml)
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 44

45. Ryfamicin resistance
Monoresistance described almost exclusively in HIV infected patients
Associated with intermittent ryfamicin use (rifapentine, probably for low drug blood levels)
Rifabutin low blood levels may carry a risk for selection of rifamycin-resistant M.tuberculosis
Current dosing recommendation for rifabutin in association with LPV/r likely to need revision

46. 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

47. Drug Interactions: Rifabutin and other HIV drugs
NNRTIs
No significant interactions with efavirenz and nevirapin (but no advantage over rifampicin). With efavirenz rifabutin dose need to be increased to 450 mg daily
Integrase inhibitors
Rifabutin does not alter raltegravir exposure to a clinically meaningful degree (Brainard DM et al. J Clin Pharmacol 2010)
CCR5 Inhibitors
No clinical data

48. Clinical case 2a
C. L. female, 27 years old, originating from Dominican Republic. Known HIV infection since HBV/HDV co-infections. Default from follow-up and HAART in 2007.
On 06/07/2010 admitted to the clinical ward for fever and cough since three months, irresponsive to antibiotic therapy.
A chest X-ray is performed:
Sputum examination: AFB seen, Pneumocystis jirovecii seen
Molecular test: M.tuberculosis, no resistance markers to rifampicin 48

49. Clinical case 2b Smear positive pulmonary TB PCP
CD4 cell count = 27; HIV-RNA 157,000 copies
On 07/07 starts standard antituberculosis treatment with Rimstar 4 tabs /day
On 26/07 starts HAART using TDF/FTC plus + EFV 800 mg once a day
Discharged on 03/08 in good clinical conditions and no signs of toxicity 49

50. Clinical case 2c
On 16/08 admission to the clinical ward for re-emergence of high fever and cough since 3 days. A lung CT is performed.
TC torace e addome completo 18/08: disseminazione miliare di noduli parenchimali centrolobulari in tutti i settori di entrambi i polmoni, con lieve maggiore tendenza alla confluenza nel segmento antero-mediael del lobo inferiore sx. Non versamento pleurico. Multiple adenopatie con rottura capsulare e tendenza alla confluenza in sede sovraclaveare dx, tra i vasi epiaortici all'emergenza, in loggia paratracheale dx e sottocarenale. Il conglomerato di adenopatie in sede sottocarenale continene una piccola raccolta aerea che sembre essere in continuità con l'artria contenuta all'interno dell'esofago, pertanto si sospetta fistolizzazione. 50

51. Clinical case 2d
Adherence to TB treatment reported as optimal. Drug-sensitive TB
Concomitant opportunistic infections ruled out
Other bacterial infections not detected
CD4 cell count = 54; HIV-RNA 600 copies
On 20/08 metilprednisolone 1,5 mg / Kg /day was started
On 01/09 the patient is discharged afebrile, in good clinical conditions, continuing TB, ARV and steroid treatment at home 51

52. Key features of clinical case 2
Do TB/HIV patients need ART ?
Timing of ARV in TB/HIV patients
The risk of the immune reconstitution syndrome (IRIS) and its relevant characteristics
Management of the IRIS

53. Do TB/HIV patients need ART ?

54. SAPiT Trial: Initiating ART during TB treatment significantly increases survival
ART initiation during TB treatment
(n = 429)
Median 67 days
HIV-pos with TB and CD4+ < 500 cells/mm3
(N = 642)
ART initiation after TB treatment (n = 213)
Median 261 days
Primary Endpoint: mortality rate (any cause)
Abdool Karim SS, N Engl J Med 2010; 362:

55. Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy: the SAPiT trial
HR for mortality in arm A = 0.45 (0.26 – 0.79) p=0.005 for any CD4
HR = 0.54 for CD<200
HR = 0.08 for CD4>200
Trial stopped by the ethical committee
Abdool Karim SS, N Engl J Med 2010; 362:

56. Timing of ART in HIV/tuberculosis patients
WHO recommendation
Start ART in all HIV infected individuals with active tuberculosis irrespective of CD4 cell count
(strong recommendation – Low quality of evidence)
WHO, 2010: Rapid Advice on ART

57. Timing for ARV in TB patients

58. Early (2 weeks) vs. late (8 weeks) initiation of HAART:
the CAMELIA study (Blanc et al).
Kaplan-Meier
Survival curve
CONCLUSION: Mortality was reduced by 34% when HAART was initiated 2 weeks vs 8 weeks after onset of TB treatment

59. 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)
6.9 Vs. 7.8 /100 p-y
P=0.73
8.5 Vs /100 p-y
P=0.06
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
(1) Havlir D, et al. Abs 38, 18° CROI, Boston 2011
(2) Abdool Karim S, et al. Abs 39LB, 18° CROI, Boston 2011

60. ART Initiation in TB Meningitis – A Randomized Trial in Vietnam
Immediate – ART within 7 days after TB initiation
Deferred – ART initiated 2 months after TB initiation
Immediate
Deferred
Number
127
126
Died 76 70
Survival
40%
45%
p=0.52
Torok et al. ICAAC 2009, Abstract H-1224 60

61. Timing of ART in HIV/tuberculosis patients
WHO recommendation
Start TB treatment first, followed by ART as soon as possible after starting TB treatment
(strong recommendation – Moderate quality of evidence)
WHO, 2010: Rapid Advice on ART

62. Optimal timing of ART among TB patients – what is the evidence ?
ART should be started within 2 weeks from TB therapy in TB/HIV patients with CD4 < 50
ART can be delayed up to the end of the intensive phase of TB treatment in TB/HIV patients with CD4>50
What if CD4 cannot be measured – or timely measured ? Unclear at this time

63. Expected mortality should steer decision on optimal timing of combined TB and HIV therapy
Risk of death while awaiting HAART
Risk of death as a consequence of HAART (IRIS)

64. Combined HAART and treatment for tuberculosis
Constraints
Increased rate of paradoxical reactions (IRIS)
Additive toxicity
Reduced adherence
Operational delays

65. Definition of IRIS (A) Antecedent requirements (B) Clinical criteria
• Diagnosis of tuberculosis before starting ART
• Initial response (stabilised or improved) to tuberculosis treatment
(B) Clinical criteria
• Onset of manifestations within 3 months of ART
Plus at least one major or two minor criteria
Major criteria
1) New or enlarging lymph nodes, or similar cold abscesses, 2) New or worsening radiological features of TB; 3) New or worsening CNS TB; 4) New or worsening serositis
Minor criteria
1) New or worsening constitutional symptoms; 2) New or worsening respiratory symptoms; 3) New or worsening abdominal pain
(C) Alternative explanations for clinical deterioration must be excluded if possible
• Failure of tuberculosis treatment because of tuberculosis drug resistance
• Poor adherence to tuberculosis treatment
• Another opportunistic infection or neoplasm
• Drug toxicity or reaction
Meintjes G et al. Lancet ID 2008; 8-516

67. TB IRIS

68. Do patients die because of IRIS ?
3·2% (0·7–9·2) of patients with tuberculosis-associated IRIS died
Muller M, Lancet Infect Dis, : 251 (metanalysis)

69. Management of IRIS Make certain of diagnosis
Rule out MDR TB or new opportunistic infection
TB treatment should be continued
ARV treatment should be continued
Surgical drainage
Non-steroidal anti-inflammatory drugs
Steroids – 1.5 mg/kg prednisone

70. Corticosteroids and IRIS outcome
109 TB/HIV patients with clinical definition of IRIS in South Africa
Randomised, placebo controlled trial of 1.5 mg/kg/day (2 weeks) mg/kg/day (2 weeks)
Cumulative # hospital days 282 Vs. 463
Median # hospital stay 1 Vs. 3 (p=0.05)
Meintjes G, AIDS, 2010

71. Overlap of Adverse Reactions from Drugs Used to Treat TB and HIV Infection
TB Drugs
HIV Drugs
Rash
PZA, RIF, INH
NNRTIs, ABC, T/S
Hepatotoxicity
INH, RIF, PZA
PIs, NVP
Nausea
RIF, PZA, INH
RTV, AZT, APV
Cytopenias
RBT, RIF
AZT, T/S
CNS
INH
EFV

72. Side effects of TB treatment and HIV infection
Most studies demonstrate an increased rate of side effects during TB therapy among HIV infected persons
In randomised trials of combined TB and HIV therapy, toxicity was a very unlikely cause of treatment discontinuation

73. ART in TB patients by Region, 2008
Region started on ART
AFR 30%
AMR 67%
EMR 55%
EUR 29%
SEAR 35%
WPR 28%

74. 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
Prevention of IRIS ?

75. Prevention of HIV associated TB
Early diagnosis
IPT
ARV

76. Policies for regular TB screening among PLWHA
Educating health workers to early recognition of TB symptoms in PLWHA
At every consultation in chronic HIV care:
Searching for signs (cough)
Searching for symptoms (clinical examination)
If necessary: second level investigations (sputum microscopy, Chest X-ray)
WHO 2010 IPT/ ICF recommendations

78. Does the WHO algorithm for Screening HIV Patients work ?
Presence of symptoms – work up for TB
Sensitivity 79%
Specificity 56%
Absence of symptoms – proceed with INH preventive therapy
Negative predictive value 97%
Getahun H et al. Plos Med 2011; in press

79. Treatment of latent tuberculosis infection
Current standard (IPT):
Isoniazid 300 mg /daily for 6-9 months

80. Efficacy of IPT compared with placebo, in reducing the incidence of active TB
Akolo C, et al. Cochrane Review, 2010

81. Treatment of latent tuberculosis infection
Research perspectives:
Shorter regimens
Drugs with no baseline resistance
Well tolerated
In high burden countries, where risk of re-infection is high:
Operationalising IPT

82. Samandari et al., IUATLD Conference, December 2009
Efficacy of 36 vs. 6 months of INH for HIV-infected Adults in Botswana The BOTUSA Trial
Samandari et al., IUATLD Conference, December 2009

84. Can IPT increase resistance to INH ?
There is no evidence that IPT can increase resistance to INH provided that active disease is ruled out
Directly observed administration of INH is not essential, although poor adherence will limit the impact of IPT

85. Is IPT safe ? The Botswana NTP / CDC IPT study
Of 1,762 patients in analysis 19 (1.2%) developed hepatitis (grade 3 or above). One patienst died. (1)
Low rate of severe adverse events after the first six months of IPT: 7 (0.9%) in the 6-IPT arm (placebo) and 11 (1.3%) in the 36-IPT arm (2)
Coadministration with ART slightly increased liver toxicity (RR 1.59 [ ]). Risk greater on nevirapine (RR 2.09 [ ]) than efavirenz (RR 0.96 [ ]).
Clinical monitoring appropriate for safety of IPT
Tedia Z et al, Am J Respir Crit Care Med 2010; 182:278
Samandari T, 40 IUATLD Conference, Cancún, 2009

86. Eligibility for IPT
In areas of high prevalence of TB (>30% infected):
All HIV infected individuals who are not affected by active TB
In areas of lower prevalence of TB (<30% infected):
HIV infected individuals with a positive PPD test who are not affected by active TB
Independently from CD4 cell count
Contraindications 86

87. 36 vs. 6 months of INH for HIV-infected Adults in Botswana -The BOTUSA Trial
Samandari et al., IUATLD Conference, December 2009

88. The probability of a positive TST test is associated to the level of immune suppression
Elzi et al CID 2007

89. Do IGRAs help for screening of LTBI in HIV+ subjects ?
Current evidence suggests that IGRAs perform similarly to the tuberculin skin test at identifying HIV-infected individuals with latent tuberculosis infection. Given that both tests have modest predictive value and suboptimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistic considerations.
Cattamanchi A, et al. JAIDS 2011; 56:230-8

90. TB Rates by ART and INH Treatment Status, 2003-2005
Exposure category
Person-Years
TB Cases
Incidence Rate
(per 100 PYs)
Percent
Reduction
(95% CI)
No Rx
3,865
155
4.01 ( ) -
ART only
11,627
221
1.90 ( )
52%
(41-61%)
IPT only
395 5
1.27 ( )
68%
(24-90%)
Both
1,253 10
0.80 ( )
80%
(9-91%)
Total
17,140
391
2.28 ( )
Golub et al., AIDS 2007;21:1441-8

91. * Adjusted for age, sex, CD4, prior history of TB, urban/rural
TB Rates by ARV and INH Treatment Status in South African Adults with HIV Infection
Exposure category
Person -years
TB cases
Incidence rate (per 100 PYs) (95% CI)
Incidence rate ratio (95% CI)
Adjusted hazard ratio* (95% CI)
Naïve
2815
200
7.1 ( )
REF
HAART only
952 44
4.6 ( )
0.65 ( )
0.36 ( )
INH only
427 22
5.2 ( )
0.73 ( )
0.87 ( )
Both 93 1
1.1 ( )
0.15 ( )
0.11 ( )
TOTAL
4287
267
6.2 ( )
* Adjusted for age, sex, CD4, prior history of TB, urban/rural
Golub et al, AIDS 2009;23:631-6

92. New TB screening and IPT guidelines
TB screening and IPT in tandem
Symptom based clinical algorithm for TB screening developed: 4 simple questions
INH for 6 (strong) and 36 (conditional) months recommended
Pregnant women, children and people receiving ART included
TST is not a requirement
Should be a core function of HIV services

94. WHO recommended TB/HIV collaborative activities

95. Policy on collaborative TB/HIV activities WHO recommendations 2004
A. Establish NTP-NACP collaborative mechanisms
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
Monitor and evaluate collaborative TB/HIV activities
B. Decrease burden of TB among PLHIV (the "3 Is")
Establish Intensified TB case finding
Introduce INH preventive therapy
Ensure TB Infection control in health care and congregate
settings
C. Decrease burden of HIV among TB patients
Provide HIV testing and counselling
Introduce HIV prevention methods
Introduce co-trimoxazole preventive therapy
Ensure HIV/AIDS care and support
Introduce ARVs

96. The 12 points package: what is new?
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
World Health Organization

97. TB/HIV co-infection, WHO European Region 2008
HIV case finding among TB:
• HIV testing coverage = 79% (~ patients)
• HIV prevalence among tested TB = 3% (~ patients)
• Estimated HIV prevalence = 5.6% (~ people)
48% of TB/HIV patients are detected

98. TB/HIV co-infection, WHO European Region 2008
Management of TB/HIV co-infected patients:
• 61 % of TB/HIV patients are covered by CPT
• 9.2 % covered by IPT
• 29% of TB/HIV patients are covered by ARV treatment

99. TB/HIV co-infection, WHO European Region 2008
TB case finding among PLHIV:
• estimated TB prevalence among PLHIV = 1.7%
• screening coverage for TB = ??? (~ )

100. Challenges and response
The Health Structure
Extreme verticality of the TB and AIDS programmes both in service provision and management;
Lack of effective coordinating mechanisms for TB and HIV
The 3 group of activities (A,B, C) are presented into details.

101. Challenges and response TB/HIV/IVDU convergence
The 3 group of activities (A,B, C) are presented into details.

102. Challenges and response TB/HIV in marginalised populations
Prisoners
Migrant people
The 3 group of activities (A,B, C) are presented into details.

103. Challenges and response Convergence of TB/HIV and MDR-TB
Increasing convergence of drug resistant TB and HIV in the region and the lack of understanding of the extent of the problem.
Efforts to address drug resistant TB in the region need to be scaled up and integrated with HIV prevention and treatment services.
TB/HIV Working Group of the Partnership
Focus on European Region, Almaty, May 2010

104. Outcomes of Treatment for MDR TB in the South African DOTS-Plus Program, 2002-2004
HIV +
(N=327)
HIV –/unknown
(N=875)
P value
Successful Rx
38.5%
49.3%
<0.001
Failed
4.3%
11.4%
Defaulted
21.4%
22.6%
0.65
Died
35.8%
16.7%
Farley, van der Walt, et al., IUATLD World Conference, 2007

105. Thank you for your attention