1. Safety Monitoring & Adverse Drug Reactions to Efavirenz and INH Dr Clorata Gwanzura MBChB-UZ, MPH –FETP (UZ)

2. Background Isoniazid Preventive Therapy (IPT) is a key public health intervention aimed at prevention of progression of latent TB infection to active TB disease among people living with HIV Isoniazid Preventive Therapy (IPT) is a key public health intervention aimed at prevention of progression of latent TB infection to active TB disease among people living with HIV Recommended by WHO since 2004 as part of 3 I’s for strengthening TB/HIV collaborative activities Recommended by WHO since 2004 as part of 3 I’s for strengthening TB/HIV collaborative activities In Zimbabwe, the IPT Programme was commissioned by the MOHCC in Dec 2012 In Zimbabwe, the IPT Programme was commissioned by the MOHCC in Dec 2012 Initially as a pilot in 10 sites across 5 provinces from Dec 2012 – Dec 2013 then Initially as a pilot in 10 sites across 5 provinces from Dec 2012 – Dec 2013 then Scaled up in a phased approach from Jan 2014 to date Scaled up in a phased approach from Jan 2014 to date As at end of Dec 2015, approximately 70 000 clients had been offered IPT As at end of Dec 2015, approximately 70 000 clients had been offered IPT

3. Rationale for implementing IPT in Zimbabwe? Rationale for implementing IPT in Zimbabwe? Tuberculosis - most common cause of mortality and morbidity among HIV infected people Tuberculosis - most common cause of mortality and morbidity among HIV infected people 68% HIV co-infection in all TB cases (Global TB Report, 2015) 68% HIV co-infection in all TB cases (Global TB Report, 2015) Multiple studies have shown that IPT reduces TB incidence in HIV infected patients by 33% – 64% Multiple studies have shown that IPT reduces TB incidence in HIV infected patients by 33% – 64% ART reduces the likelihood of developing TB disease, however TB incidence among HIV infected on ART is still greater than in the general population ART reduces the likelihood of developing TB disease, however TB incidence among HIV infected on ART is still greater than in the general population

4. Suspected INH Toxicity Index case, Nov 2014 - Previously well 56 year old HIV +ve female HCW Index case, Nov 2014 - Previously well 56 year old HIV +ve female HCW Suspected severe INH fulminant liver failure, Harare Central hospital Suspected severe INH fulminant liver failure, Harare Central hospital Patient deteriorated & subsequently died on day 5 post admission into ICU Patient deteriorated & subsequently died on day 5 post admission into ICU More suspected cases reported by physicians in Harare province (public & private sector) More suspected cases reported by physicians in Harare province (public & private sector) A total 23 suspected cases reported to the ministry as at end of April 2015 A total 23 suspected cases reported to the ministry as at end of April 2015 MOHCC’s response MOHCC’s response Meetings conducted with Physicians (PAZ) & Public Health Physicians (CPHP) & representatives of PLHIV Meetings conducted with Physicians (PAZ) & Public Health Physicians (CPHP) & representatives of PLHIV Task team comprising of a physician representative, a programme manager, an M&E officer & an MPH officer made to critically investigate cases Task team comprising of a physician representative, a programme manager, an M&E officer & an MPH officer made to critically investigate cases Eight out of total ‘reported’ 23 suspected case records successfully retrieved and analysed Eight out of total ‘reported’ 23 suspected case records successfully retrieved and analysed

5. Characteristics of the 8 Reported Suspected Cases All were female clients, median age 38 years (Q1 = 26.5, Q3 = 43.5) All were female clients, median age 38 years (Q1 = 26.5, Q3 = 43.5) Duration in HIV care 3 - 11 years, latest CD4 ranging from 460 – 987 cells/ml, average 620 c/ml Duration in HIV care 3 - 11 years, latest CD4 ranging from 460 – 987 cells/ml, average 620 c/ml All had been initiated on INH and the duration on IPT up to time of presentation ranged from 3 weeks - 4 months All had been initiated on INH and the duration on IPT up to time of presentation ranged from 3 weeks - 4 months Seven (7) of the cases were on a concurrent Tenolam – E regimen and one (1) was on Tenolam – N Seven (7) of the cases were on a concurrent Tenolam – E regimen and one (1) was on Tenolam – N No additional concurrent medications with hepatotoxic effects No additional concurrent medications with hepatotoxic effects No history of traditional medicines use No history of traditional medicines use

6. Presenting Complains and Management Presenting symptoms - early onset nausea & vomiting followed by yellowing of eyes & skin (jaundice) Presenting symptoms - early onset nausea & vomiting followed by yellowing of eyes & skin (jaundice) Duration from onset of symptoms to presentation for admission ranged from 6 days - 1 month Duration from onset of symptoms to presentation for admission ranged from 6 days - 1 month Three of the clients had been attended to by another HCW prior to presentation for admission (initially managed as acute GE) Three of the clients had been attended to by another HCW prior to presentation for admission (initially managed as acute GE) Three (3) of the suspected cases had death outcomes, 5 completely recovered and were discharged Three (3) of the suspected cases had death outcomes, 5 completely recovered and were discharged Two (2)were on a concurrent Tenolam –E regimen while one (1) was on Tenolam – N Two (2)were on a concurrent Tenolam –E regimen while one (1) was on Tenolam – N Two of the 3 who dies had altered level of consciousness and confusion on admission Two of the 3 who dies had altered level of consciousness and confusion on admission

7. Investigations Done on Admission and Patient Outcomes Patient number Peak Bilirubin Peak ALTPeak ASTPeak INR Length of hospital stay Outcome 14216447761.607 daysAlive 2355191533701.769 daysAlive 3242134912641.868 daysDied 42832897032.8018 daysDied 5446136025002.987 daysDied 6542869328.49 6 daysDied 75013991326 -7 daysAlive 83444811415 -14 daysAlive Five (5) had USS done, two were normal, 1 had duct pathology suggesting a medical pathology and 1 queried liver cirrhosis All 8 patients were hepatitis A, B and C negative

8. Research Questions to be answered? What is the extent of the problem and is the reported incidence of adverse events above what one would expect from INH exposure in general? What is the extent of the problem and is the reported incidence of adverse events above what one would expect from INH exposure in general? What are the current IPT prescribing practices among clinicians? What are the current IPT prescribing practices among clinicians? Is there need to further re-stratify clients eligible for IPT? Is there need to further re-stratify clients eligible for IPT? Who is most affected (sex, CD4, etc)? Who is most affected (sex, CD4, etc)? Could this be pharmacovigilance issue related to the batch of INH medicines in use or not? Could this be pharmacovigilance issue related to the batch of INH medicines in use or not? Is there possibility of interactions with EFV? Is there possibility of interactions with EFV?

9. Next Steps Consultations done & are currently ongoing with colleagues in neighbouring countries implementing IPT (Botswana & SA) Consultations done & are currently ongoing with colleagues in neighbouring countries implementing IPT (Botswana & SA) Impact of IPT program on reduction of incidence of TB infection Impact of IPT program on reduction of incidence of TB infection Analysis of data controlling for increased ART coverage rates Analysis of data controlling for increased ART coverage rates Data reporting tool developed & disseminated to all provinces Data reporting tool developed & disseminated to all provinces MOHCC has commissioned studies which are currently ongoing to answer some of the research questions - ‘Determining the Prevalence and Risk Factors Associated with the Development of Isoniazid Toxicity among Patients on Antiretroviral Therapy at Parirenyatwa Hospital’ MOHCC has commissioned studies which are currently ongoing to answer some of the research questions - ‘Determining the Prevalence and Risk Factors Associated with the Development of Isoniazid Toxicity among Patients on Antiretroviral Therapy at Parirenyatwa Hospital’

10. Next Steps MOHCC working with MCAZ to strengthen pharmacovigilance system for ADRs MOHCC working with MCAZ to strengthen pharmacovigilance system for ADRs Exploring innovative strategies to sensitize HCWs, clients enrolled in care and communities on IPT on the following Exploring innovative strategies to sensitize HCWs, clients enrolled in care and communities on IPT on the following To have a high index of suspicion for potential adverse events, To have a high index of suspicion for potential adverse events, Importance of early presentation to HFs Importance of early presentation to HFs Strengthen reporting of AEs through the MCAZ Adverse Events Reporting System - regular trainings, emails, SMS, whatsapp Strengthen reporting of AEs through the MCAZ Adverse Events Reporting System - regular trainings, emails, SMS, whatsapp

11. Acknowledgements MOHCC AIDS & TB staff MOHCC AIDS & TB staff Dr A Reid, Dr T Gede and other physicians Dr A Reid, Dr T Gede and other physicians Partners – WHO regional country office, CDC Zimbabwe, the Union Partners – WHO regional country office, CDC Zimbabwe, the Union MSF MSF

12. Thank you