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

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

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

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.

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. 2004 [press release 2004 Dec 16]. Available from: http://www.cso.gov.bw/ ** 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]. 2007 Oct. Sources: *HIV Medicine Association, et al., 2007 ** BNTP Manual, 2007. ***BIASII, 2004

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. 2003 Sep 26; 17(14): 2063-70. Source: Churchyard GJ, Fielding K, et al., Aurum Health Research, 2003. Overall 55% reduction in TB incidence

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. 2007 Jul 11; 21(11):1441-8. 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

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

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

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):792-795. IUATLD Mohammed A, et al. Int J Tuberc Lung Dis, 2004.

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

IPT Drugs and Dosages Recommended daily dosage: INH: Adults: 5 mg/kg/day, 300 mg/day max Children: 10-20 mg/kg/day, 300 mg/day max Pyridoxine (B6) co-administered: 25mg orally, daily

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

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

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.

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

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