Overview Treatment of latent TB infection Meta-analysis 36 months of IPT Screening for TB Adverse events INH Resistance IPT & ART TST Conclusions

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1 202/03/28 Isoniazid preventive therapy: evidence for safety and efficacy Clinician s course Gavin Churchyard/ Liesl Page-Shipp 6 March 202 Overview Treatment of latent TB infection Meta-analysis 36 months of IPT Screening for TB Adverse events INH Resistance IPT & ART TST Conclusions more people living with HIV NO dying of TB Efficacy of TB preventive therapy among HIV-infected individuals Reference PPD+ PPD- PPD-unknown Overall TB 0.8 Death Relative Risk (Fied) & 95% CI Woldehanna 2004, Cochrane review.02 Reduction in TB incidence with 36 vs 6 months IPT Author Location Intention to treat Martinson Soweto 9% 69% Per Protocol Samandari Botswana All 54% 65% TST+ 93% TST- 9% (Martinson et al. Union conference, 2008, CROI 2009) (Samandari et al. Union Conference. 2009) Reduction in TB incidence with 36 vs 6 months IPT Author Location Intention to treat Martinson Soweto 9% 69% Per Protocol Samandari Botswana All 54% 65% TST+ 93% TST- 9% (Martinson et al. Union conference, 2008, CROI 2009) (Samandari et al. Union Conference. 2009) Cumulative TB incidence rates (%) TST status & cumulative TB incidence Placebo, TST + Placebo, TST - Treatment, TST + Treatment, TST Number of days since starting coded medication TST 0.9% per yr The Botswana IPT Trial: 36 months vs. 6mnths INH for TB prevention in HIV-Infected adults Samandari et al.

2 202/03/28 What was the duration of the benefit of si months IPT? Thibela TB study Cumulative TB incidence rates (%) Treatment days after Placebo 6H Start of coded medication Number of days since starting coded medication The Botswana IPT Trial: 36 months vs. 6mnths INH for TB prevention in HIV-Infected adults All participants analy zed in this graph receiv ed 6 months of IPT prior to day 0 in this graph Samandari et al. Thibela TB To compare the efficacy of isoniazid preventive therapy (IPT) given on a community-wide basis to current standard of care on TB among gold miners in South Africa Study design Cluster-randomised intervention study Cluster-randomised 8 intervention 7 control intervention clusters study 8 intervention and 7 control clusters 80,000 miners Intervention Consenting participants were screened for TB TB screen: symptom check and CXR TB suspect: if or more of cough>2 wks, night sweats, wt loss, CXR suggestive of TB TB investigations: spot sputum for microscopy, culture (MGIT) and organism identification (Tauns) IPT: started if eligible, dispensed monthly (9) Assessed monthly for TB and side effects Feasibility # of consents 27,86 # started on IPT (%) 24,22 (86.9%) All participants have completed their IPT 2

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4 202/03/28 Methods: study-defined AEs AE reporting included hepatitis hypersensitivity peripheral neuropathy convulsions Occurring between first IPT dispensing date two months after last IPT dispensing date AEs: results 2422 participants started IPT 95% male, median age 40 years 30 individuals eperienced 32 possible study defined AEs (0.54%) Suspected hypersensitivity rash 6 Peripheral neuropathy 50 Convulstions 4 Hepatotoicity 7 INH non-related 2 One AE resulted in death: overall risk of death of 4 per 00,000 (0.004%) Risk factors for hepatotoicity Variable Category Hepatotoicity/total (%) Odds ratio (95% CI) Se Male Female 4/23038 (0.06%) /68 (0.09%).4 ( ) Age group (years) < /7763 (0.04%) 7/8203 (0.09%) 5/820 (0.06%) 2.2 ( ).6 ( ) Ethnic group Black Other 4/23794 (0.06%) /425 (0.24%) 4.0 ( ) Baseline weight (kg) < History suggesting HIV care No Antiretroviral therapy No Alcohol use (units/week) /4234 (0.05%) 8/4700 (0.05%) 5/5275 (0.09%) 5/23584 (0.06%) 0/68 (0%) 5/23654 (0.06%) 0/544 (0%) 4/439 (0.03%) 0/7760 (0.3%) /232 (0.04%).2 ( ) 2.0 ( ) (.4-4.5).5 ( ) Risk factors for hepatotoicity Variable Category Hepatotoicity/total (%) Odds ratio (95% CI) Se Male Female 4/23038 (0.06%) /68 (0.09%).4 ( ) Age group (years) < /7763 (0.04%) 7/8203 (0.09%) 5/820 (0.06%) 2.2 ( ).6 ( ) Ethnic group Black Other 4/23794 (0.06%) /425 (0.24%) 4.0 ( ) Baseline weight (kg) < History suggesting HIV care No Antiretroviral therapy No Alcohol use (units/week) /4234 (0.05%) 8/4700 (0.05%) 5/5275 (0.09%) 5/23584 (0.06%) 0/68 (0%) 5/23654 (0.06%) 0/544 (0%) 4/439 (0.03%) 0/7760 (0.3%) /232 (0.04%).2 ( ) 2.0 ( ) (.4-4.5).5 ( ) INH resistance TB after IPT (n=26) Any INH resistance: Mean (95% CI) TB after IPT AIDS. 200 Apr 24;24(7):05-5. Tuberculosis outcomes and drug susceptibility in individuals eposed to isoniazid preventive therapy in a high HIV prevalence setting. van Halsema CL, Fielding KL, Chihota VN, Russell EC, Lewis JJ, Churchyard GJ, Grant AD. First episodes Laboratory sub-study TB after IPT Retreatment episodes Percentage 4

5 202/03/28 INH resistance by treatment arm Botswana background = 9% INH 6H resistance (n=989) new TB 36H patients; (n=006) 8% INH-R epected in Trial if no additional contribution by IPT Drug susceptibility test available 24 4 INH-mono-resistant 3 IPT and ART MDR (INH + RIF) Any INH resistance >36 mo # (%) 4 (7%) 2 (4%) The Botswana IPT Trial: 36 months vs. 6mnths INH for TB prevention in HIV-Infected adults Samandari et al. Effect of IPT and ART on TB incidence Golub. AIDS.2009 TB Incidence ahr (95% CI) /00py No IPT/ART 7. ART ( ) ART/IPT. 0. ( ) Golub et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort.. AIDS 2009, 23: proportion alive Death after IPT & ART Kaplan-Meier survival estimates Deaths PYRS RATE/00 95% CI Never started 227 2, ( ) Star ted INH ( ) analysis time in months Never started on INH Started on INH Golub et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIVinfected adults in South Africa: a prospective cohort. AIDS 2009, 23: INH No Results Multivariable analysis Death Rate /00py Unadjusted analysis (N=3270) Hazard Ratio (HR) % CI (P value) (P<0.00) Adjusted analysis* (N=3094) Hazard Ratio (HR) % CI (P value) P= *Adjusted for age group, baseline WHO stage, baseline CD4 count, year started on ART and previous TB Innes C et al. Effectiveness of isoniazid preventive therapy in reducing mortality in patients on ART. Seventeenth CROI abstract 02, 200 Influence of ART and 36H by TST status TST negative HR (% reduction) TST positive 95%CI HR (% reduction) 95%CI ART alone* 0.44 (56%) 0.2, (56%) 0.2,0.9 36H alone 0.92 (8%) 0.4, (93%) 0.0,0.6 Both 0.40 (60%) 0., (97%) 0.0,0.3 * 300 days of ART The Botswana IPT Trial: 36 months vs. 6mnths INH for TB prevention in HIV-Infected adults Samandari et al. 5

6 202/03/28 Requiring tuberculin skin tests before implementing IPT leads to avoidable and substantial number of TB cases Golub JE et al. 8 th International AIDS Conference, abstract MOAB0305, Vienna, 200. IPT reduces TB/deaths in HIV clinics in Rio Intent To Treat Modified Intent To Treat (Stayers) Outcome Cases HR (95% CI) TB ( ) TB or Death ( ) TB ( ) TB or Death ( ) (B.Durovni, et al. AIS20. Abstract no. WELBB02) p-value <0.00 <0.00 <0.00 Conclusion of evidence Questions? It is feasible to implement IPT at scale Implement 6 months IPT can be delivered safely with clinical monitoring by trained nursing staff IPT not associated with increased INH resistance IPT with ART reduces TB incidence and mortality IPT reduces TB in HIV clinics Requiring TST delays initiation of IPT results in substantial numbers of preventable TB. IPT A. Has not been shown to reduce mortality (death) B. Should be given with ART C. Is contraindicated with any alcohol use D. Is the responsibility of the TB programme 2. IPT and ART A. Once patient controlled on ART, IPT will have no effect B. In asymptomatic patients with CD4 <350, 6 months IPT should be completed before ART initiated C. Randomised controlled trials have shown IPT is effective for patients on ART D. IPT before ART may reduce the risk of IRIS 6

7 202/03/28 3. Tuberculin Skin Test (TST) A. Is not needed in children < 5yrs before IPT is initiated B. Is a pre-requisite for IPT initiation in adults C. IPT is more effective in TST positive individuals D. Can be placed by any cadre of HCW 4. INH resistance A. The TB bacillus divides rapidly, therefor INH resistance can easily develop B. May be the reason why the effect of IPT seems to wane over time C. Is not regarded as a consequence of IPT D. Is not clinically significant 5. Screening for TB A. Clear CXR is essential before starting IPT B. Symptom screen in HIV positive patients includes cough > 2 weeks C. Must occur monthly for patients on IPT D. Is not required at HCT IPT Endorsed by WHO Endorsed by South African Department of Health Remember children!! How? Who should provide: HIV programme with TB TB programme to assist with HIV prevention efforts TB to assist in obtaining INH Part of a package of care } Nutritional support, family planning, CD4 } TB symptom screen } IPT } NB Cotrimoazole to all TB patients Previous PCP Eligibility No active liver disease No alcohol abuse Eclude active TB TB symptom screen Can be given in pregnancy 7

8 202/03/28 TB symptom screen Sensitive TB symptom screen Do you have a cough (>24 hrs.)? Do you have loss of weight? Do you sweat a lot at night? Do you have fever? CXR Adds to sensitivity but additional barrier Not recommended in SA guidelines for asymptomatic pts Valuable in symptomatic pts with negative smears (as per National guidelines) TST OUT!!! Not routine SA DOH IPT Guidelines 200, p.g. 9 If in doubt... DO not give IPT Investigate for Smear positive TB Smear negative TB- NB algorithmn includes CXR Etra-pulmonary TB If all negative Reassess for IPT after 3 months Treatment INH 5mg/kg dly (ma.300mg/day) Vit.B6 (Pyridoine) 25 mg dly Counsel Adherence Seek care if Side effects of INH (esp. hepatitis) Symptoms of active TB Monthly Monitoring TB symptom screen if symptomatic investigate Side effects Counselling Side effects: Hepatitis -3 per 000 NNRTI (NVP) Risk factors-age/liver disease/hep C/alcohol Ask about Nausea and vomiting Dark urine and pale stools Right upper quadrant pain Yellow eyes If hepatitis suspected Stop/ Do LFT (ALT) Refer 8

9 202/03/28 Side effects: Peripheral neuropathy May be eacerbated by Stavudine (D4T) Increase Pyridoine to 00mg dly If severe or worsens- stop INH Hypersensitivity Severe rash CNS Side effects: Rare Hearing voices or seeing things that are not actually there (psychosis) Convulsions Check reasons Adherence Complete 6 months within 9 months If defaults twice, consider stopping Defaulter tracing may not be effective use of resources Counselling Does not need to be taken on a full stomach (do not link it to meals) Patients to understand that they are not receiving TB treatment but only TB prevention No alcohol HIV counseling including Prevention- use of condoms Stay in care- regular monitoring ART as soon as eligible/ continue ART Conclusion It is feasible to implement IPT at scale TB screening, using symptoms and CXR, prior to starting IPT misses very few cases Requiring TST delays initiation of IPT and results in substantial numbers of preventable TB cases occurring IPT can be delivered safely with clinical monitoring by trained nursing staff IPT not associated with increased INH resistance IPT with ART reduces TB incidence and mortality IPT reduces TB in HIV clinics 9