1. Pharmacovigilance to inform policy: experience in South Africa
Karen Cohen
Division of Clinical Pharmacology
University of Cape Town

2. HIV programmatic pharmacovigilance
Pharmacovigilance: “Detection, assessment, understanding and prevention of short and long term  adverse effects of  medicines”
Clinical studies short
Co-morbidities, concomitant medicines, genetic variability
Risk versus benefit:
early treatment initiation
prevention
Focus on serious adverse drug reactions (ADRs)
Resulting in hospitalisation and death
Treatment limiting ADRs- drug substitutions

3. South African context Largest ARV treatment programme in the world
± 3 million people on ART
High rates of concomitant HIV and TB treatment
Growing burden of non-communicable diseases
Methods:
Hospital-based surveys
Sentinel Cohorts
Spontaneous reporting

4. Hospital-based surveillance
4 South African hospitals in 2013
8.4% medical admissions in SA due to ADR (164/1951) (Worldwide 5.3% of admissions)
ART, TB treatment and/or co-trimoxazole implicated in 34%
In 16% of in-hospital deaths ADR implicated (56/357)
Most commonly implicated: tenofovir, rifampicin, co-trimoxazole
ADR contributed to death of 2.9% of medical admissions (Europe, UK, USA 0.05 to 0.32% of admissions)
Make less busy
Mouton et al 2015 Br J Clin Pharmacol 80(4); Mouton et al 2016 Medicine 95(9);Kongkaew Ann Pharmacother. 2008; 42: 1017 ; Juntti-Patinen et al 2002 Eur J Clin Pharmacol 58; Davies et al 2009 PloS ONE 4:e4439; Pirmohamed et al 2004 BMJ 329 ; Lazarou et al 1998 JAMA 279: 1200

5. Hospital-based surveillance
Top 4 ADRs resulting in medical admission in South African hospitals (n=1951)
Renal impairment (n=24)
Hypoglycaemia
(n=22)
Liver injury
(n=20)
Haemorrhage
(n=19)
Median age (yrs) 41 61 35 67
HIV infection
71% 5%
90%
16%
Commonly implicated drugs
tenofovir (46%)
ACE-I (38%)
insulin (64%)
sulfonylureas(50%)
TB drugs (60%)
efavirenz (20%)
warfarin (68%)
NSAIDs (32%)
Mortality
46%
18%
35%
Median stay
9 days
6 days
10 days
Preventable
77%
15%
58%
Make less busy
ADRs in HIV patients- high mortality, prolonged admission
Importance of looking at all drug exposures
Mouton et al 2016 Medicine 95(9)

6. Sentinel cohorts Robust denominator data
Valuable resource for ADR surveillance
Requires fewer resources than setting up cohorts solely for toxicity surveillance (Cohort event monitoring)
Robust denominator data
Can determine incidence of treatment-limiting ADRs
Can identify risk factors
Cohort collaborations increase study power
Important for studying rare but serious events

7. Data on stavudine toxicity from sentinel cohorts informed policy
Adults on first-line ART in 2 Western Cape cohorts
(Khayelitsha and Gugulethu)
Proportion having drug substituted
Just picture
Time on individual drug (yrs)
2007: 30 mg all weights, point of care lactate meters, avoidance in obesity, education HCW
Dramatic decrease referral rates, severity at admission, mortality
Boulle et al Antivir Ther;12:753; Schutz 2010 AIDS Res Ther, 7:13

8. ARV exposure and diabetes
Diabetes incidence:
13.24 per 1000 PYFU
Associations with diabetes:
Older ager
Higher BMI
Efavirenz, zidovudine and stavudine exposure
Other diabetogenic meds
Percentage with new onset diabetes
Time on antiretroviral therapy (yrs)
Karamchand et al 2016 Medicine 95(9)

9. Spontaneous reporting
Does not give prevalence/incidence
Signal detection
ADRs that trouble HCWs
Guide HCW training and clinical support
Nurse-driven services
Need responsive systems
Telephonic; online reporting in addition to paper-based
Prompt, individualised feedback and clinical support
SA National HIV & TB HCW hotline most frequent ADRs:
Rash (efavirenz)
Liver injury (tuberculosis treatment and efavirenz)
Kidney injury (tenofovir)
Gynaecomastia (efavirenz)
Neuropsychiatric (efavirenz)
Chugley et al 2015 AIDS 29: Njuguna et al 2015 Drug Saf doi: /s

10. Conclusions Pattern of ADRs is different in SA
Large burden of serious ADRs in PLWHA and/or TB
ADRs due to ARVs AND concomitant medicines
Resource limited settings
Create systems that can address multiple questions
Communication and feedback

11. Acknowledgements National Dept of Health SA CDC and PEPfAR
Mukesh Dheda
Yogan Pillay
CDC and PEPfAR
Ehimario Igumbor
Getahun Aynalem
UCT Division of Clinical Pharmacology
Hannes Mouton
Christine Njuguna
Annemie Stewart
Melony Fortuin- de Smidt
Marc Blockman
Gary Maartens
Annoesjka Swart
Jackie Jones
Medicines Information Centre
Hospital sentinel sites
Douglas Wilson
Andy Parrish
Peter Raubenheimer
Karl Technau
UCT School of Public Health
Mary-Ann Davies
Renee De Waal
Ushma Mehta
Andrew Boulle
IeDEA-SA data centre staff
Patients
Health care workers who report

14. Top 5 ADRs causing admission
Renal impairment
Hypoglycaemia
Liver injury
Haemorrhage
Blood dyscrasia
Median age (yrs) 41 61 35 67
HIV infection
71% 5%
90%
16%
79%
Commonly implicated drugs
tenofovir (46%)
ACE-I (38%)
insulin (64%)
sulfonylureas (50%)
TB drugs (60%)
efavirenz (20%)
warfarin (68%)
NSAIDs (32%)
cotrimoxazole (29%)
Mortality
46%
18%
35%
14%
Median stay
9 days
6 days
10 days

15. Adverse drug reaction (ADR)
Pharmacovigilance
Detection, assessment, understanding and prevention of short and long term  adverse effects of  medicines
Adverse drug reaction (ADR)
A response to a medicine which is noxious and unintended, and which occurs at doses normally used in humans (WHO).

16. Tenofovir and renal function monitoring
Incidence of eGFR<30mL/min: 15/1000 person years (95%CI 14 to 17)
Older patients, advanced disease, baseline renal impairment, PI at risk
Implication for monitoring guidelines
De Waal et al TUPEB035

17. Sentinel cohort data for ADR analyses
Data cleaning including record review to resolve queries
Requires resources
Drug starts and stops not always accurately recorded
Reasons for single drug substitutions
Linkage outpatient cohorts to hospitalisation events
Improved recording of pregnancy data in cohorts