1. Unit 5: IPT Isoniazid TB Preventive Therapy
Botswana National Tuberculosis Programme Manual Training for Medical Officers

2. Objectives At the end of this unit, participants will be able to:
Describe the role of INH Preventive Therapy (IPT) for HIV-infected persons with latent TB infection
Describe how to appropriately screen eligible patients for IPT

3. IPT: Isoniazid Preventive Therapy
Type of secondary prevention
To prevent development of active TB in HIV positive individuals in whom active TB has been excluded
6-month course of INH
INH= Isoniazid, IPT= Isoniazid Preventive Therapy
The purpose of IPT is to prevent TB infection from progressing to TB disease (reactivation), and it is therefore a form of secondary prevention in the BNTP’s recommended use in HIV positive individuals
Note that the protective efficacy of IPT in people with ”latent” TB infection is about 90% among people who are HIV- and 60% among HIV+ individuals
The duration of prevention may be limited. Botswana is currently conducting a three-year trial to determine how long protection lasts as a proxy for life-long treatment
See Section 3.2 in Botswana National Tuberculosis Programme Manual

4. Rationale for IPT
10% lifetime risk of developing active TB if infected with M. tuberculosis alone
5-10% annual risk of developing active TB if co-infected with HIV
IPT is meant to prevent progression of latent TB to active disease
INH shown to decrease incidence of TB among HIV- infected persons by about 40%
The protection period ranges from <1 year to 3 years*
*Studies conducted in several African countries
Source: Republic of Botswana Ministry of Health. National Tuberculosis Programme Manual. 2007; Sixth Edition.
Discuss reinfection because it lowers the effectiveness of IPT. This is not due to the effectiveness of the drug, rather because once the treatment ended, people were exposed to other TB cases and reinfected
Source: BNTP Manual, 2007.

5. Rationale for IPT in Botswana
HIV prevalence is 17.1% in general population*
TB case rate increased ~ 3-fold in 1990s**
1989: 199 /100,000
2002: 623 /100,000
~80% of adult TB cases are HIV co-infected***
Patients more likely to seek HIV testing if they would receive health benefit such as IPT and ART (1999 KABP study in Botswana)
TB is the leading killer of persons with AIDS in Botswana
These numbers are showing the need for IPT
All districts in Botswana offer IPT to HIV positive individuals
With the help of the IPT strategy, it is hoped that the burden of TB among PLWHA will be reduced
Recent survey from Botswana indicates 84% co-infection with TB/HIV
*Source: Botswana AIDS Impact Survey-II: Preliminary Results. The Republic of Botswana, Central Statistics Office [press release 2004 Dec 16]. Available from:
** Source: BNTP Manual, 2007.
***Source: HIV Medicine Association, Infectious Diseases Society of America, The Forum for Collaborative HIV Research. HIV/TB Coinfection: Basic Facts [fact sheet] Oct.
Sources: *HIV Medicine Association, et al., 2007
** BNTP Manual, 2007.
***BIASII, 2004

6. IPT Effectiveness South African Miners, 2003 IPT usage TB incidence
IPT (n=338)
8.6/100 person years
No IPT (n=221)
19.1/100 person years
INH was given for 6 months to one of two cohorts of South African miners
The cohort that received no INH had a TB incidence of 19.1 cases per 100 person years
The cohort that received INH had a incidence of 8.6 person years, a 55% reduction
Source: Churchyard GJ, Fielding K, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy. AIDS Sep 26; 17(14):
Source: Churchyard GJ, Fielding K, et al., Aurum Health Research, 2003.
Overall 55% reduction in TB incidence

7. IPT Effectiveness Related to ART
TB Incidence in 11,026 HIV-infected patients in Brazil
No INH
Yes INH
No ART
4.01/100 person years
1.27/100
person years
Yes ART
1.90/100 person years
0.80/100
INH alone cut TB incidence dramatically, but there was additional benefit from ART
Source: Golub JE, Sraceni V, Cavalcante SC, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS Jul 11; 21(11): Center for Tuberculosis Research, Johns Hopkins University, Baltimore, Maryland, USA.
Source: Golub JE, et al., Johns Hopkins University 2007.
76% reduction with both INH and ART when adjusted for age, previous TB diagnosis and CD4 count at baseline

8. Assessment for IPT Medical and social history TB Screening questions
Previous exposure to TB
Previous treatment for TB
HIV positive
TB Screening questions
Physical examination
Clinical evaluation of TB suspects
Sputum smear for microscopy and other investigations as indicated
This is the screening algorithm which is the tool most used to determine eligibility to begin IPT
Note: a screening chest radiograph is not necessary
Eligibility to enroll on IPT
Confirmed HIV infection
Exclusion of active tuberculosis to avoid monotherapy, which could lead to the development of INH resistance
Not currently pregnant
No terminal AIDS
No history of hepatitis and no active hepatitis at enrolment
No prior history of isoniazid intolerance
No history of TB in the previous 3 years
Not a habitual treatment defaulter

9. Screening Questions Cough for 2-3 weeks Weight loss Night sweats Fever
Malaise
Shortness of breath
Chest pain
Haemoptysis
Consider EPTB:
Lymphadenopathy
Headache
Abdominal pain or distension
Swollen joints
Backache

10. Patients with Advanced HIV Disease
TB Screening Tests in
Patients with Advanced HIV Disease
This table shows the specificity and sensitivity of a number of screening tests for tuberculosis in patients with advanced HIV disease
Active TB was found in 8.5% of advanced HIV patients
A simple screening instrument, the sputum culture, had a sensitivity of 90.9% and a specificity of 100%.
Source: Mohammed A, Ehrlich R, Wood R, Cilliers F, Maartens G. Screening for tuberculosis in adults with advanced HIV infection prior to preventive therapy. Int J Tuberc Lung Dis. 2004; 8(6): IUATLD
Mohammed A, et al. Int J Tuberc Lung Dis, 2004.

11. Screening Algorithm for IPT
Signs / symptoms of PTB
YES NO
INITIATE IPT
Sputum microscopy x 3 for AFB
TREAT FOR TB
CXR & assessment
Treat for bacterial infection
Good response
Poor response
All negative
ONE positive
TB unlikely
TB likely
This algorithm has been adapted from the BNTP manual
Refer to Handout 5.1

12. IPT Drugs and Dosages Recommended daily dosage: INH:
Adults: 5 mg/kg/day, 300 mg/day max
Children: mg/kg/day, 300 mg/day max
Pyridoxine (B6) co-administered:
25mg orally, daily

13. Preventing Isoniazid Resistant TB
Constant & proper use of the algorithm for the dx of PTB to prevent monotherapy
Screening of patients at each visit
Thorough investigation of those suspected of having TB
Ongoing counselling of patients to maintain adherence
Mono-therapy refers to undiagnosed active TB patients inadvertently placed on IPT because of improper/inadequate screening
Don’t overlook the possibility of (extrapulmonary) TB in patients just because they are not coughing. Consider the results of the entire screening tool and, before starting IPT, pursue additional evaluation in any patient who is not in their baseline health.
Refer to the screening algorithm on Handout 5.1 in the Participant Handbook

14. Emergence of Resistance with Single Drug Therapy of Active TB
Start INH alone
Legend:
Red Line: INH-Sensitive TB organisms
Blue Line: INH-Resistant TB organisms
If active TB is treated with only INH, initially the majority of TB organisms will be sensitive to it (although 1 out of 10 million will be naturally resistant to INH)
During single-drug treatment with INH, the organisms SENSITIVE to INH will die, but those naturally resistant will continue to multiply, and eventually will be larger in # than those sensitive to INH. This is seen between weeks 8 & 10 of therapy in the graph above – where the two lines of sensitive and resistant cross over
By week 24 there are very few INH-sensitive organisms left and many INH-resistant organisms
Essentially, M. tuberculosis bacteria become resistant to INH meaning that the drug is not longer active in killing the organism

15. Reasons to Stop IPT
Patient misses 2 consecutive monthly refill/monitoring appointments
Develops INH intolerance (serious side effect)
Becomes terminally ill
Potentially stop if female patient becomes pregnant
If less than 3 months of IPT, discontinue
If more than 3 months of IPT, continue treatment
Develop symptoms of active TB
INH intolerance:
Jaundice
Severe allergy
Severe skin rash
Note: Jaundice is a rather late sign of drug induced liver injury; ideally therapy could be interrupted in the pre-icteric phase where the risk of progression to fulminant hepatic necrosis is much lower. If resources and education permit, I would suggest advising patients to hold INH and seek evaluation if anorexia/nausea/fatigue lasts greater than 5 days. Depending on resources, either an ALT or AST could be checked (or at least a clinical evaluation be performed) before resuming treatment.

16. Patient Education Point
Ensure HIV positive patients understand the benefits of IPT (55% reduction in TB disease)
Reinforce information at each visit
Assess adherence to therapy, as with TB treatment
Patients should be taught to recognize signs & symptoms of active TB
Discuss side-effects and support patient by problem solving ways to manage minor SEs
Encourage questions
Unit 5: Infection Control and Prevention of TB

17. Key Points
It is important to appropriately screen for signs & symptoms of TB in HIV positive individuals before initiating IPT
HIV positive individuals have a 5-10% chance of developing active TB per year
IPT can prevent TB disease in HIV positive individuals