isoniazid preventive therapy: a call to action prof harry hausler, medical director project...
TRANSCRIPT
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
Overview
• Efficacy of isoniazid preventive therapy (IPT)
• IPT guidelines
• IPT implementation
• Reasons for limited implementation
• Recommendations
0.36
0.86
0.67Overall
TST+
TST-
Placebo
Relative risk, 95% CI
Woldehanna 2004, Cochrane review
Effect of IPT on TB:Meta-analysis of 7 randomised clinical trials (N=4134)
1.0
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;74:385-400
• Prevalence of TB infection (TST+) in HIV+ in Cape Town was 55% in 2002 Hausler 2007
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”
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
TB screening, diagnosis and prevention, 2002-2007
444 337 267284 1017
14
2558
44
41
77
71
0
100000
200000
300000
400000
500000
600000
700000
Screened for TB Diagnosed with TB IPT
2002
2003
2004
2005
2006
2007
Collaborative TB/HIV activities, 2002–2007,
GLOBAL PROGRESS
AFRO implementation of IPT, 2007
Countries with reported
policy on IPT (N=17)
Countries reported provision of IPT (N=7)
• 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
IPT in South Africa
Indicators 2008 Q1 2009HIV tested 1,372,167 526,958HIV-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
Number started IPT per provinceSouth Africa, 2008
DOH, 2009 NB: Missing data for EC, KZN, MP, NW
Proportion HIV+ started on IPT South Africa, 2008
DOH, 2009 NB: Missing data for EC, KZN, MP, NW
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)
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
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
SA DOH Guidelines, 2004
• Exclusion criteria:– 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
SA DOH GuidelinesProposed 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!
Excuses for not implementing IPT
1. It’s too hard to rule out active TB
2. IPT worsens drug resistance
3. It’s not needed if you’re on ART
4. It’s too toxic
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.
Objection 1: It’s too hard to rule out active TB
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
Mohammed, et.al. – South AfricaInt 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%
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
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
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
Does IPT promote isoniazid resistance?
Balcells Emerg Infect Dis 2006;12:744-51
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%
Incidence of resistance: 10% individuals exposed to control
INH-sensitive INH-resistant
Latent TB Latent TB
Active TB Active TB
• 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
IPT does not increase resistance
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
Synergistic effect of IPT plus ART on decreasing TB: Brazil
cases / pycases / py incidence incidence /100py/100py
IRR (95% CI)IRR (95% CI)
NeitherNeither 155/3865155/3865 4.014.01 1.01.0
ARTART 221/1162221/116277
1.901.90 0.48 (0.38-0.48 (0.38-0.59)0.59)
IPTIPT 5/3955/395 1.271.27 0.32 (0.10-0.32 (0.10-0.76)0.76)
ART/IPTART/IPT 10/125310/1253 0.800.80 0.20 (0.09-0.20 (0.09-0.91)0.91)
Golub AIDS 2Golub AIDS 2007;2007;211:1441:1441
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
Objection 4: Toxicity
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;293:2719-2725
South Africa, ART cohort• IPT not associated with higher risk of
hepatotoxicity Hoffmann AIDS 2007;21:1301-8
IPT: hepatotoxicity rare
Systems Issues• IPT is feasible
– 1576 started out of 4110 in care in PHC sites in Ugu, Bohlabela and Cape Town in SA TB/HIV Pilots (1999-2002)
– 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
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
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?
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
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!
Acknowledgements
Kevin de Cock, WHOHaileyesus Getahun, WHOReuben Granich, WHOAlison Grant, LSHTMMark Harrington, TAGVincent Tihon, BTC