1. Isoniazid Preventive Therapy: A Call to Action
Prof Harry Hausler, Medical Director
Project Integrate, TB/HIV Care Association
School of Public Health, University of the Western Cape
1 October 2009

2. Overview Efficacy of isoniazid preventive therapy (IPT) IPT guidelines
IPT implementation
Reasons for limited implementation
Recommendations

3. Effect of IPT on TB: Meta-analysis of 7 randomised clinical trials (N=4134)
Relative risk, 95% CI
1.0
Placebo
Overall
TST+
TST-
Woldehanna 2004, Cochrane review

4. WHO Guidelines
Recommend 6 months of IPT for HIV+ with a positive tuberculin skin test (TST) who do not have active TB (asymptomatic, normal CXR)
When not feasible to perform TST, also recommended for those living or working in high risk area for TB infection (>30% prevalence of infection)
Weekly Epi Record 1999;74:
Prevalence of TB infection (TST+) in HIV+ in Cape Town was 55% in 2002 Hausler 2007

5. International Advocacy for IPT
WHO 3 I’s meeting, April 2008
Global Leaders Forum, 9 June 2008
WHO HIV/AIDS Department Priority Interventions, IAS Mexico, August 2008
Stop TB Partnership, March 2009
Stop TB Partnership Consensus Statement: “IPT works, IPT is safe, IPT works with ART or by itself. Ensure that all people living with HIV in countries where TB is common are offered IPT”

6. IPT Implementation in 2007 Only 41 countries reported provision of IPT
29,000 people started on IPT - less than 0.1% of the estimated 33 million people estimated to be infected with HIV globally Global TB Report, 2009
In comparison, 3 million on ART globally and 2.1 million on ART in sub-Saharan Africa

7. TB screening, diagnosis and prevention, 2002-2007

8. AFRO implementation of IPT, 2007
One more country in AFRO reporting (8) in 2007 vs 2006
Only <1% of PLHIV put on IPT in AFRO (and globally)
Botswana reported 6042 (39%) of the AFRO PLHIV on IPT, a marked decrease from 19,034 in 2006
South Africa reported 2227 on IPT in 2006, 7869 in 2007 and 6818 (incomplete data) in 2008

9. Prelimanary Report on TB Data 2004 CF & 2003 TO
IPT in South Africa
Indicators
2008
Q1 2009
HIV tested
1,372,167
526,958
HIV-positive
455,150
33%
178,261
34%
Tuberculin (PPD) skin test done
4063
0.9%
978
0.5%
HIV pos started on IPT
6818
1.5%
2185
1.2%
Department of Health, 2009
Prepared by Carina Idema

10. Number started IPT per province South Africa, 2008
DOH, 2009 NB: Missing data for EC, KZN, MP, NW

11. Proportion HIV+ started on IPT South Africa, 2008
DOH, 2009 NB: Missing data for EC, KZN, MP, NW

12. IPT Gap in KwaZulu-Natal
Living with HIV: 1.5 million
TB incidence: 1054/100,000 (1%)/year
Eligible for IPT
25% eligible if use TST: 375,000
40% eligible if no TST: 600,000
10% of co-infected would develop TB with no IPT: 37,500 cases
IPT would prevent 24,000 TB cases per year (64% decrease)

13. South African DOH Guidelines
Only offer if
VCT available
Patients can be effectively screened for TB
Patient can be monitored monthly
IPT does not interfere with detection and cure of sm+ PTB
Local AIDS programme takes responsibility for implementation with strong collaboration with TB programme
Department of Health. TB and HIV/AIDS, 2000 and National ART Guidelines, 2004

14. SA DOH Guidelines, 2004 Eligibility:
HIV+
No TB signs or symptoms (cough, fever, night sweats, pleuritic chest pain, loss of appetite, tiredness and weakness, chest pain, haemoptysis)
CXR not recommended for screening
Positive tuberculin skin test (>5 mm induration)
If one or more symptoms, do not provide IPT and do 2 smears, 1 culture

15. SA DOH Guidelines, 2004 Exclusion criteria: Regimen:
Active liver disease
History of TB treatment in past 2 years
Don’t offer to those on ART but can complete course – needs to be revisited
Regimen:
5 mg/kg (max 300 mg) daily for 6 months

16. SA DOH Guidelines Proposed Revisions 2009
Tuberculin test not required for screening
IPT should be given to those on ART with no symptoms of TB
No need to wait for these revisions to start implementing!

17. Excuses for not implementing IPT
It’s too hard to rule out active TB
IPT worsens drug resistance
It’s not needed if you’re on ART
It’s too toxic

18. Objection 1: It’s too hard to rule out active TB
Claim: It’s too hard to rule out active TB among HIV+ persons
Fact: Although TB diagnosis is more complex in HIV+, symptom screening is very sensitive, especially in immuno-suppressed patients. Nonetheless, some subclinical cases will be missed.

19. Difficulty of TB screening in HIV-infected persons
HIV-infected TB patients often lack classic TB symptoms
Up to 30% of HIV-infected TB patients with pulmonary TB have a normal chest radiograph
Sputum smears may be negative in 50% or more

20. Mohammed, et.al. – South Africa Int J Tuberc Lung Dis 2004;8(6):792-795
Setting
South Africa
Study pop.
129 stage 3 and 4 HIV+ referred for IPT (TB suspects were not referred)
TB def’n
Definite = cx confirmed, probable = smear+, possible = clinical dx with response to treatment
# with TB
11 (9%) with TB (10 culture-confirmed)
Cough
Cough >2 weeks 82% sensitive, 89% specific
Algorithm
Two or more of: measured weight loss (>2.5%), cough, night sweats, or fever (all>2 weeks) Sensitivity 100%, Specificity 88%

21. Kimerling, et.al – Cambodia, Int J Tuberc Lung Dis 2002;6(11):988-994
Setting
Cambodia
Study pop.
441 HIV+ in home care network
TB def’n
Single sputum culture
# with TB
41 (9%) with culture-confirmed TB
Cough
Cough >3 weeks 65% sensitive, 33% specific
Algorithm
Any 1 of: cough>3 wks, hemomptysis, weight loss, fever, night sweats, or weakness – 95% sensitivity, 10% specificity

22. Diagnosis of TB in HIV+
Evaluated different algorithms among 2050 HIV+ from Cambodia, Thailand, Viet Nam:
Newly diagnosed with HIV at VCT
Persons with previous HIV diagnosis newly presenting to HIV clinic or CD4 test site
Persons already enrolled in HIV care, some of whom are already on ART
Sensitivity of cough, fever, weight loss:
CD4<250 – 97%
CD4>250 – 81%
Cain, CROI 2008

23. Objection 2: Resistance
Claim: IPT promotes drug resistant disease and renders first-line therapy less effective when active TB occurs
Fact: There is no strong evidence that IPT promotes drug resistant disease. When active TB occurs among those given IPT, standard four-drug first-line therapy works
Nolan IJTLD 2002;6:952
Mitchison Am Rev Respir Dis 1986;133(3):423-30

24. Does IPT promote isoniazid resistance?
Balcells Emerg Infect Dis 2006;12:744-51

25. Effect of IPT on prevalence of resistance
Isoniazid
Control
Prevalence of resistance: 50%
Incidence of resistance:
10% individuals exposed to INH
Prevalence of resistance: 25%
10% individuals exposed to control
INH-sensitive
INH-resistant
Latent TB
Active TB

26. IPT does not increase resistance
If TB is latent, few organisms, dividing slowly, thus low risk of selection of DR-TB
Early studies of isoniazid monotherapy showed 70% cure MRC Br Med J 1952;2(4787):735-46
Risk of increased resistance, if any, is small:
summary RR = 1.45 (95% CI 0.85, 2.47)
Most resistance arises from suboptimal treatment of active disease, so preventing active disease will reduce resistance
Need for surveillance for resistance

27. Objection 3: IPT not necessary because ART is good enough
Claim: IPT is not necessary because ART alone is good enough in reducing TB incidence
Fact: IPT and ART are synergistic in reducing TB incidence among people with HIV taking both

28. Synergistic effect of IPT plus ART on decreasing TB: Brazil
cases / py
incidence /100py
IRR (95% CI)
Neither
155/3865
4.01
1.0
ART
221/11627
1.90
0.48 ( )
IPT
5/395
1.27
0.32 ( )
ART/IPT
10/1253
0.80
0.20 ( )
Golub AIDS 2007;21:1441

29. Objection 4: Toxicity
Claim: IPT is too toxic for people with HIV (on or not on ART) and has additive toxicity with ART
Fact: IPT is far less toxic than HRZE and has far fewer interactions with ART than R; IPT toxicity is rare and can be managed

30. IPT: hepatotoxicity rare
Uganda RCT
7/931 AST>135u/L (N 7-27 u/L); total 3 stopped with any adverse event Whalen NEJM 1997;337:801
South Africa, routine, pre-ART
1/777 stopped INH with asymptomatic raised AST Grant JAMA 2005;293:
South Africa, ART cohort
IPT not associated with higher risk of hepatotoxicity Hoffmann AIDS 2007;21:1301-8

31. Systems Issues IPT is feasible IPT is cost effective
1576 started out of 4110 in care in PHC sites in Ugu, Bohlabela and Cape Town in SA TB/HIV Pilots ( )
9633 started out of 29,197 in care in 18 PHC sites in Kenya (2004-7), 76% completion Diero et al, PEPFAR HIV Implementers Meeting, Kampala 2008
IPT is cost effective
Cost to prevent TB case ($486-$962) less then the cost of treating TB ($823-$1362) Hausler. Bulletin of WHO 2006;84(7):528-36

32. Summary
Fears about difficult diagnosis, resistance, co-administration with ART and toxicity are unfounded
Need to educate programme managers and clinicians about the scientific evidence

33. Remaining Questions
What is best protocol for excluding active TB in HIV+?
What is optimal duration of IPT?
What is best way to ensure good adherence?

34. Recommendations
Public health leadership should drive implementation at PHC level and ART sites through HIV programme
Implement IPT concurrently with infection control and routine TB screening as part of pre-ART care
HIV community/PHA group must advocate for access to IPT
Guidelines should be revised to remove barriers (TST, allow IPT with ART) and operational research should be done but not as an excuse to delay implementation

35. Call to Action IPT is important pre-ART intervention
Failure to provide IPT is a violation of human rights and will worsen the TB epidemic among people with HIV
TB/HIV Care Association and TAC handed a memorandum to Minister of Health on 24 March 2009 calling for partnerships and implementation of 3 I’s
Let’s just do it!

36. Acknowledgements Kevin de Cock, WHO Haileyesus Getahun, WHO
Reuben Granich, WHO
Alison Grant, LSHTM
Mark Harrington, TAG
Vincent Tihon, BTC