I nternational E pidemiologic D atabases to E valuate AIDS

1. Pharmacovigilance & Toxicity Documentation in the Context of Antiretroviral Treatment: Comparative Evaluation of 4 Strategies in a Resource-Constrained Setting P. Braitstein1,2,3; B. Jakait2,3; S. Pastakia2,3,4; R. Karwa4; C. Ngetich3; J. Sidle1,2,3; K. Wools-Kaloustian1,2,3; W. Nyandiko2,3; J. Pandit5; C. Dunscombe6; S. Ollsen7 1. Indiana University School of Medicine, Indianapolis, USA; 2. Moi University School of Medicine, Eldoret, Kenya; 3. USAID-AMPATH Partnership, Eldoret, Kenya; 4. Purdue University School of Pharmacy, Bloomington, USA; 5. Kenya Ministry of Health Drug and Poison Control Board, Nairobi, Kenya; 6. World Health Organization, HIV Department, Geneva, Switzerland; 7. Uppsala Monitoring Centre, Uppsala, Sweden International Epidemiologic Databases to Evaluate AIDS IeDEA East Africa Executive Committee meeting May 2011 Nyeri, Kenya

2. Introduction • Over the past 5 years, millions of HIV-infected people have initiated combination antiretroviral treatment (cART) • In spite of poor infrastructure, widespread under/malnutrition, co-morbidities (e.g. TB, malaria), and HIV stigma • Some have said it’s the largest uncontrolled medical/public health experiment ever undertaken • These factors combined with high genetic diversity mean that toxicities experienced by Africans may be different from those experience by Euro-Americans

3. Why is toxicity documentation important? • Due diligence: using drugs in populations they may not have been tested on, by the millions • Particularly important for pregnant women, infants exposed in utero, and HIV-infected children • Clinical management: side effects affect adherence; adherence affects sustainability of treatment

4. What are the challenges? • Lack of space on data collection forms to ascertain detailed information about toxicities • Lack of time, sensitization, and training on the part of clinicians to adequately ascertain, document, and address adverse effects • Lack of training and resources to adequately diagnose and manage them when they emerge • A large list of possible symptoms and side effects that are impractical to include on data collection forms • A lack of consensus about whether to collect every symptom or just treatment-limiting and/or life-threatening ones • The difficulty of distinguishing between toxicities and symptoms due to co-morbid or underlying disease(s)

5. How to do it? • Only treatment-limiting side effects? • What about those that won’t kill you but make you so miserable you don’t want to take them? • Capture a long list of all possible symptoms/side effects? • Only known? • Only unknown? • Do clinicians have time? Motivation? • What about pharmacists? Peers?

6. Parent Project • With funding from Bill and Melinda Gates, WHO has undertaken a multi-component project around PV and cART • Project objectives: • establish tools and reference standards for monitoring antiretroviral-related adverse events, • strengthen pharmacovigilance capacity in focus countries and cohort collaborators • pilot Cohort Event Monitoring and stimulated spontaneous reporting • develop strategies for the sustainability of PV • assess different data collection methodologies • strengthen capacity for pharmacovigilance for women and infants who receive antiretrovirals to prevent mother to child transmission (PMTCT).

7. USAID-AMPATH Partnership • 72,450 ever started on antiretrovirals • Currently have 45,807, including nearly 5000 children • To-date, toxicity in adults only captured as a reason for switch or discontinuation of treatment • Cause for switch/discontinuation often missing • Actual toxicity almost never described • Toxicity in children began to be captured in 2009 as: Any side-effects attributable to ARV since the last visit? □ Yes □ No If yes, tick all that apply: □ Rash □ Anemia □ Lipo-dystrophy □ Hepatitis □ Neuropathy □ IRIS □ Steven-Johnson syndrome □ Lactic Acidosis □ Diarrhoea □ Persistent Vomiting □Other (specify):

8. In 2010, AMPATH was asked by National AIDS Control Program of Kenya for data on stavudine toxicity to inform decision as to whether to drop it or keep it • We had almost no data (except for probability of stopping or switching) • But more than anyone else in the country • Program Managers realized there was a gap, but how best to capture the information? What information to capture? By whom?

9. Specific Aim • To develop an effective and feasible method for documenting treatment-threatening antiretroviral toxicity in a resource-constrained clinical setting by implementing and comparing various mechanisms for documentation.

10. Primary Research Questions • How complete is the documentation by clinicians in the routine clinical encounter about toxicity? • Are peers or pharmacy personnel ‘better’ at collecting information about toxicity from patients? • How feasible and effective is it for the PPB SADR form to be completed at all switches or discontinuations of cART either by clinicians or pharmacists? • Do patients report more side effects to peers/pharmacy personnel or clinicians?

11. Secondary Research Questions • What is the incidence of and risk factors for treatment-threatening and treatment limiting adverse effects of cART in HIV-infected adults, including pregnant women receiving PMTCT interventions and children, including HIV-uninfected infants or those of unknown HIV status exposed to long term ARVS during breast feeding? • What is the impact of toxicity on patient adherence to cART? • What is the impact of toxicity on patient quality of life? • What are the specific adverse effects that are being experienced by patients and what are their consequences? • What are the results of rechallenge?

12. 4 Strategies A) Routine Clinical Encounter B) Routine Pharmacy Encounter C) In-depth interview by pharmacist D) In-depth interview by HIV-positive peer

13. A) Routine Clinical Encounter • As a reason for switching or discontinuing cART • Screen for side effects for all patients on cART (adults and children) 12C. Side-effects/Toxicity: Any side-effects attributable to any drug that the patient is currently taking? □ Yes □ No If Yes, drug(s) ________________________________________ If yes, tick all that apply: □ Rash □ Anemia □ Lipo-dystrophy □ Hepatitis □ Neuropathy □ IRIS □ Steven-Johnson syndrome □ Lactic Acidosis □ Diarrhea □ Persistent Vomiting □ Other (specify):_______ Severity of the reaction: □ Mild □ Moderate □ Severe □ Fatal □ Unknown Cause of the reaction/Toxicity: □ Certain □ Probable/Likely □ Possible □ Unlikely □ Conditional/Unclassified □ Unassessable/Unclassified • To be done on all patients receiving cART • All data to be entered into AMRS

14. B) “Routine” Pharmacy Encounter • Implement National Pharmacy and Poison Board Suspected Adverse Drug Reaction protocol • Modified to focus only on patients who discontinue or switch medications due to toxicity • Pilot test in AMPATH central clinic at Moi Teaching and Referral Hospital • Clinicians can complete forms themselves or call for a pharmacist to do it • Forms will be compiled, entered into database, and forwarded to national office • The core of the AMPATH Drug Information Centre

15. C & D) In-depth Interviews • Randomly select 1000 patients to be interviewed by a pharmacist or HIV-positive peer at each routine clinical encounter • Same structured questionnaire (~20 minutes) • Will include a symptom screen documenting frequency of symptom, severity, and whether patient believes it’s caused by a particular drug (and if so which) • Will include WHO Quality of Life screen (adults) • Will include adherence assessment (children) • Management strategies (e.g. traditional medicine)

16. Outcome Measures • How complete is the documentation by clinicians in the routine clinical encounter about toxicity? • Compare the prevalence of side effects documented in clinical encounter with that reported during interviews • Compare prevalence of toxicity as reason for treatment discontinuation or switch vs. the number of reports we have from the PPB SADR pharmacy form

17. Outcome Measures • Are peers or pharmacy personnel ‘better’ at collecting information about toxicity from patients? • Prevalence of side effects reported to peers vs. pharmacy staff • Number of symptoms reported, severity of symptoms, impact on QOL • Completeness and accuracy of data recorded

18. Outcome measures • How feasible and effective is it for the PPB SADR form to be completed at all switches or discontinuations of cART either by clinicians or pharmacists? • Number of forms received compared to the number of medication changes/switches in the pharmacy database • The completeness and accuracy of the forms

19. Outcome Measures • Do patients report more side effects to peers/pharmacy personnel or clinicians? • Prevalence of side effects reported to (documented by) the clinicians vs. peers vs. pharmacy staff

20. Timeline • Protocol and budget finalized (March 2011) • Contract needs signing (May 2011) • IRB/IREC (May 2011) • Clinical encounter forms are currently being programmed • PPB SADR form currently being rolled out • Enrolment into interviews (July 2011) • Data collection for 12 months • Analysis to begin from month 6