Welcome to I-TECH Nurse Clinical Seminar Series 19 August WHO Recommendations for TB Screening and IPT among People Living with HIV Stacie C. Stender

Objectives Review the WHO 12 point policy package Describe the evolution of global IPT policy and implementation, including WHO guideline development processes Identify evidence-based recommendations for TB screening and IPT in adults and children Determine who is eligible for isoniazid preventive therapy

WHO 12 point TB/HIV policy package 8. HIV testing and counselling 9. HIV preventive methods 10. Cotrimoxazole preventive therapy 11. HIV/AIDS care and support 12. Antiretroviral therapy to TB patients. 5. Intensified TB case finding 6. Isoniazid preventive therapy 7. Infection control for TB 1. TB/HIV coordinating bodies 2. HIV surveillance among TB patient 3. TB/HIV planning 4. TB/HIV monitoring and evaluation Three Is A. Establish the mechanism for collaboration B. Decrease the burden of TB among PLHIV C. Decrease burden of HIV among TB patient

Review: Steps in TB Disease EXPOSURE INFECTION DISEASE DEATH 10% of general population What is the lifetime risk of developing active TB if you have a competent immune system? What is the risk of developing active TB in an individual with HIV and latent TB IPT 50% of HIV infected individuals

Multiple stakeholders in international IPT policy WHO/IUATLD. Tuberculosis preventive therapy in HIV- infected individuals. A Joint Statement of the WHO Tuberculosis Programme and the Global Programme on AIDS, and the International Union Against Tuberculosis and Lung Disease (IUATLD). Wkly Epidemiol Rec 1993,68: WHO & UnionWHO & UNAIDSWHO

Key IPT recommendations ( ) IPT should be provided to TST positives If TST is not feasible IPT should be given to: –PLHIV in areas >30% MTB infection in population –Health workers, prisoners, contacts, miners CXR to exclude active TB until the validity of different screening algorithms established Self administered for 6 months

TB screening among PLHIV, % 3% 4% Poor TB/HIV Integration

Gap between policy & implementation of IPT IPT provision among PLHIV,

2006

2010, the year of… New IPT Guidelines! ? Proper TB/HIV Integration?

Uganda example (2006) Human resources: Medical Officer Laboratory assistant Trained counselor Pharmacy technician Adherence supporters Equipment and logistics: Facilities for TB microscopy Facilities for skin testing (mantoux) Cold chain system Facilities for HIV testing Sustainable supply of anti-TB drugs including isoniazid Sustainable supply of HIV test kits Eligibility criteria for an institution to offer IPT The following are the minimum requirements for an organization/institution to offer IPT Infrastructure: Functional Laboratory X-ray or access to x-ray services Counseling room/space Consultation room Other key issues: If an organization has a TB default rate of greater than 5% it will not be eligible to provide IPT ?

WHO GRADE Quality Assessment Criteria Quality of Evidence Study DesignLower if*Higher if* HighRandomized trial Study quality: -1 Serious limitations -2 Very serious limitations -1 Important inconsistency Directness: -1 Some uncertainty -2 Major uncertainty -1 Sparse data -1 High probability of reporting bias Strong association: +1 Strong, no plausible confounders, consistent and direct evidence** +2 Very strong, no major threats to validity and direct evidence*** +1 Evidence of a dose response gradient +1 All plausible confounders would have reduced the effect Moderate LowObservational study Very LowAny other evidence * 1=move up or down one grade (for example from high to intermediate) 2=move up or down two grades (for example from high to low) ** A statistically significant relative risk of >2 (<0.5), based on consistent evidence from two or more observational studies, with no plausible confounders. *** A statistically significant relative risk of >5 (<0.2) based on direct evidence with no major threats to validity.

Strength of Recommendations Strong: the desirable effects of a recommendation outweigh the undesirable effects. Conditional: the desirable effects probably outweigh the undesirable effects. However, –Data are scant or –Only applicable to specific group/population or setting or –New evidence may change risk to benefit balance or –Benefits may not warrant the cost or resources required

Recommendation 1 : TB screening Adults and adolescents living with HIV should be screened with a clinical algorithm and those who do not report any one of – current cough, – fever, – weight loss or – night sweats are unlikely to have active TB and should be offered IPT. Strong recommendation, moderate quality evidence

Recommendation 2 : TB screening Adults and adolescents living with HIV screened with a clinical algorithm and reported one of the following; – current cough, – fever, – weight loss or – night sweats may have active TB and should be evaluated for TB and other diseases. Strong recommendation, moderate quality evidence

Evidence: individual patient data meta-analysis Inclusion criteria for studies Collected sputum specimens from PLHIV regardless of signs or symptoms; Used mycobacterial culture of at least one specimen to diagnose TB and; Collected data about signs and symptoms. What is the most sensitive clinical algorithm to screen for culture-confirmed TB in people living with HIV?

12 studies Total patients in the 12 datasets (n=29,523) HIV-infected patients (n=10,057) Patients not receiving TB treatment (n=9,870) Patients with sputum smear results (n=9,710) Patients with known TB status (n=9,626) Patients with TB (n=557) Patients without TB (n=9,069) Patients with unknown TB status (n=84) Unknown smear results or sputum smear positive with no culture or negative culture or culture grew NTM (n=160) Patients receiving TB disease or TB infection treatment at screening (n=187) HIV-uninfected patients or those with unknown HIV status (n=19,466) 29,523 10,057 9,626

Top five best performing rules in all subjects Combination rule Sen (%) Spe (%) LR- NPV (95% CI) 5% TB prevalence CC, F, NS, WL ( ) H, F, NS, WL ( ) CC, F, WL ( ) CC, NS, WL ( ) CC, F, NS ( ) CC: cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

Top five best performing rules in all subjects with abnormal CXR Combination rule Sen (%) Spe (%) LR- NPV (95% CI) 5% TB prevalence CC, F, NS, WL, X ( ) CC, F, NS, X ( ) CC, F, WL, X ( ) H, F, NS, WL, X ( ) CC, NS, W,L X ( ) CC: cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

Performance of the best rule (one of current cough, fever, night sweats or weight loss) Setting Sen (%) Spe (%) LR- (%) NPV (95% CI) 5% TB prevalence Community ( ) Clinical ( ) CD4 < ( ) CD4> ( ) CC: cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

Recommendation 3 Adults and adolescents who are living with HIV and: –have unknown or positive TST status and; –unlikely to have active TB should receive IPT for at least 6 months Strong recommendation, high quality evidence

Recommendation 4 Adults and adolescents who are living with HIV in settings with higher TB transmission and: –have unknown or positive TST status and; –unlikely to have active TB should receive IPT for at least 36 months Conditional recommendation, low quality evidence

Recommendation 5 Tuberculin skin test is not a requirement for initiating IPT for people living with HIV Where feasible, TST can be used as people with a positive test benefit more from IPT than those with a negative test Strong recommendation

Evidence for recommendations 3, 4 and 5 OutcomeStudiesPatientsRR (95% CI) Probable, confirmed or possible TB (0.51,0.87) - TST positive (0.22,0.61) - TST negative (0.59,1.26) - TST unknown (0.48,1.52) Confirmed TB (0.47,1.11) - TST positive (0.01, 2.32) - TST negative (0.36,1.61) - TST unknown (0.46,1.36) The effect of IPT is more in TST positives than TST negatives and unknowns (Akollo et al 2010 Cochrane Review)

GRADE analysis table: 36 vs. 6 month IPT RR for Probable TB (95% CI) = 0.50 (0.29 to 0.84) RR for Confirmed TB (95% CI) = 0.48 (0.26 to 0.9) Samanadari et al, unpublished, 2010 Martinson et al, unpublished, 2010 Settings for 36 month should be determined by national guidelines Local context (feasibility, resources, safety and relevance) Higher TB prevalence and transmission

Recommendation 6 Providing IPT to people living with HIV does not increase the risk of developing INH resistant TB. Therefore concerns regarding the development of INH resistance should not be a barrier to providing IPT. Strong recommendation, moderate quality evidence

IPT and drug resistance RR 95% CI 1.45 ( ) (Balcell's et al, 2006)

Concomitant use of IPT with ART No study directly address the issue Contrasting results on immune status and IPT effect –No difference by HIV stage at baseline (Gordin, 1997) –Greater effect when TLC >2/L (Mwinga, 1998) –Not affected by CD4 count (Churchyard, 2003) –IPT+ART= TB IRR 0.20 (0.09–0.91) (Golub, 2007-Brazil) –IPT+ART= TB IRR 0.15 (0.004–0.85) (Golub, 2009-SA) Strong recommendation, low quality evidence

TB screening and IPT algorithm NoYes Not TBTBYesNoOther Dx Screen for TB (any one of the following): Current cough, fever, weight loss, night sweats Investigate for TB and other DxAssess IPT contraindications Person living with HIV Treat for TB Appropriate rx & consider IPT Defer IPTGive IPT Follow up & consider IPT Screen for TB regularly ?

Recommendations for Children: TB screening Children living with HIV who do not have poor weight gain*, fever or current cough are unlikely to have active tuberculosis TB. Strong recommendation, low quality evidence Children living with HIV who have any one of poor weight gain, fever, current cough or contact history with a TB case may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, children should be offered IPT regardless of their age. Strong recommendation, low quality evidence *Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than -3 z-score), or underweight (weight-for-age less than -2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flattening

Recommendations for children: IPT Children over 12 months of age who are living with HIV and who are unlikely to have active TB on symptom based screening and have no contact with a TB case should receive 6 months of INH preventive therapy (10mg/kg) Strong recommendation, low quality evidence In children less than 12 months of age, only those children who have contact with a TB case and who are evaluated for TB (using investigations) should receive 6 months IPT if the evaluation shows no TB disease Strong recommendation, low quality evidence

Summary changes in 2010 Screening for TB only by using symptom based algorithm is sufficient to start IPT for PLHIV No mandatory CXR and TST requirement for IPT Regular screening of those on IPT at every visit Pregnant women, children, those on ART and those who completed TB treatment should receive IPT Conditional recommendation of 36 months IPT for settings with high TB transmission among PLHIV

3Is case: ICF & IPT Mrs. Z, a 26 year old HIV positive pregnant woman comes to the HIV clinic in your hospital for routine care with her 2 year old who is also HIV positive –How would you rule out active TB in Mrs. Z and her child? –Is this considered active or passive case finding? –Would a tuberculin skin test (TST) be done as part of the initial evaluation at your site? –If symptom negative, what dose of INH would you offer Mrs. Z?

Thank You

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