Medication safety issues associated with currently used first-line antiretroviral regimens in Uganda

Kay Seden1, Daniel Kiiza2, Eva Laker2, Joseph Walter Arinaitwe3, Catriona Waitt1, Mohammed Lamorde2, Saye Khoo1

1. University of Liverpool, UK; 2. Infectious Diseases Institute, Makerere University, Uganda; 3. AIDS Treatment Information Centre (ATIC), Infectious Diseases Institute, Makerere University, Uganda

19th International Workshop on Clinical Pharmacology of Antiviral Therapy 2018, 22 - 24 May 2018; Baltimore, Maryland, USA

Abstract: 09

Conflict of interest statement

• ML has received research grants from ViiV, Janssen pharmaceuticals NV

• SK has received support for the HIV Drug Interactions website (www.hiv-druginteractions.org) from ViiV

Healthcare, Gilead Sciences, Merck, and Janssen

• All other authors have none to declare

Background: Uganda

Scope for improvement of care quality and medication safety

Background: medication safety issues

• May increase the risk of drug toxicity, or reduce clinical effect of one or more drugs

• Clinically significant drug-drug interactions (CSDDIs) affect 26.7% of Ugandan outpatients taking antiretrovirals (ARVs)1

• In sub-Saharan Africa, recognition and management of DDIs is restricted by patients accessing medicines via separate silos of care, and un-regulated purchase of medicines

Drug-drug interactions

(DDIs)

• May affect quality of life, cause morbidity or mortality

• May affect adherence

• May be under-reported in this setting, or tolerated due to lack of alternative regimens

Adverse drug events

(ADEs)

Seden K, Kiiza D, Laker E, Arinaitwe JW, Waitt C, Lamorde M, Khoo S. Task shifting and mobile technology for HIV drug-drug interaction screening in Uganda. 22nd International AIDS Conference (AIDS 2018), 23-27 July, 2018 in Amsterdam, Netherlands. Abstract: Poster A-899-0383-05296

Technician interviews patient

and completes CRF

Pharmacist receives documents in

shared file for triage

PMSI screening and ADE causality

validation and review

Populate prescriber feedback form

Feedback form received in shared file

Feedback form placed in clinic

notes

Background: study design

Prescriber review/action

Central shared drive

Longitudinal observational study in adults taking antiretrovirals (SAPU)

• Prevalence of medication safety issues (prescribing error, drug interactions, adverse drug reactions)

• Prevalence and cause of medication-related hospital admissions

• Prescriber recognition of medication safety issues

• Feasibility, acceptability and utility of an intervention (via prescriber questionnaire)

Methods & population: early analysis

• Consecutive eligible patients from 3 diverse clinics

• Adult HIV-positive outpatients, taking current first-line ARVs

• DDI screening/severity assessment and assessment of ADE causality was undertaken by pharmacists and clinicians, using standardized tools1,2,3,4

1. University of Liverpool HIV Drug Interaction tool. www.hiv-druginteractions.org. 2. Gallagher RM, Kirkham JJ, Mason JR et al. Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool. PLoS One 2011; 6: e28096.3. U.S. Department of Health and Human Services, National Institutes of Health, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, [July 2017]. https://rsc.tech-res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-adult-and-pediatric-adverse-events-corrected-v-2-1.pdf.

4. Medical Dictionary for Regulatory Activities (MedDRA) version 19.0, www.meddra.org

• Early analysis undertaken to inform patient care locally and internationally

• Data have informed national plans to roll-out dolutegravir

• 469 consecutive patients (50% of total SAPU study recruitment)

• 416 patients taking first-line ARV regimens

Results: patient characteristics

1st line regimen 416 (88.7)TDF/3TC/EFV n(%) 262 (63)ZDV/3TC-EFV n(%) 37 (14.1)ZDV/3TC/NVP n(%) 95 (22.8)TDF/3TC-NVP n(%) 21 (5)ABC/3TC-EFV n(%) 1 (0.2)Female n(%)

Male

287 (69)

129 (31)Time on treatment (months)

median (IQR)

36 (19-57)

Age (years) median (IQR) 35 (28-44)Weight mean (Standard error)

Female

Male

60kg (0.53)

59.7kg (0.67)

60.5kg (0.85)Site CE n(%) 177 (42.5)UD n(%) 135 (32.5)RD n(%) 104 (25)

72% of first-line patients were taking EFV

Majority had been taking first line regimens long-term (75% took 1st line for ≥19 months)

Majority were female (comparable to clinic populations)

Results: summary

Serious

Moderate

Minor

No ADEs

Clinically significant drug interactions

180 (43.3%) of 416 patients on 1st line

regimens reported a current side effect at the

time of interview, which was considered to be

an adverse drug event. 252 ADEs were

reported in total (95%CI 38.5- 48.2%)

25,5%

74,5%

Adverse Drug Events

106 (25.5%) of 416 patients on

1st line regimens had ≥1 CSDDI

(95%CI 21.4- 30.0%)

Patients with CSDDIs more likely to report an ADE (OR 1.86, 95%CI 1.16 - 2.98, p=0.0059)

EFV-based regimen associated with reporting ADEs (OR 1.84, 95%CI 1.15 - 2.98, p=0.007)

but not presence of a CSDDI (OR 0.76, 95%CI 0.46 - 1.27, p=0.2650

Reported/detected ADEs (System Organ Class) Prevalence (%)

All 252

Nervous system/Psychiatric disorders 145 (57.5)

General disorders & administration site conditions 33 (13.1)

Gastrointestinal disorders 31 (12.3)

Skin & subcutaneous tissue disorders 12 (4.8)

Eye disorders 9 (3.6)

Reproductive system & breast disorders 5 (2.0)

Musculoskeletal & connective tissue disorders 4 (1.6)

Investigations 4 (1.6)

Cardiac disorders 3 (1.2)

Blood & Lymphatic system disorder 3 (1.2)

Renal & urinary disorders 2 (0.8)

Ear & labyrinth disorders 1 (0.4)

Results: adverse drug events

Dizziness 83

Headache 18

Neuropathies 17

Somnolence 14

Nightmares 6

Memory impairment 2

Dysgeusia 1

Anxiety 1

Psychosis 1

Insomnia 1

Hallucinations 1

Some ADEs not evaluable due to lack of laboratory

monitoring (renal function, haemoglobin)

72.6% of 252 total ADEs were possibly

or probably related to EFV

Results: adverse drug eventsHigh prevalence and low recognition of persistent nervous system/psychiatric disorder ADEs related to efavirenz1

36% of 300

patients taking

EFV reported

NS/PD ADEs

On average, symptoms had

lasted for ~2 years, and

were ongoing at the time of

analysis

(Median 22 months, IQR 9-

35.3 months)

83.7% of NS/PD ADEs were

not recorded in clinical

notes

(n=123 evaluable reports)

36%

64%

Dizziness accounted

for 64% of symptoms,

affecting 27% of 300

patients on EFV

58% of symptoms

rated by patients at

≥5/10 severity

1. Seden K et al. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy 14 - 16 June 2017, Chicago, USA. (Abstract 55.)

‘When I feel dizzy, I stop my car at the side of the road, until it goes away’

Results: clinically significant drug interactionsAntimicrobials

14,4

21,4

64,2

35.8% of 416 patients on 1st line regimens took

antimicrobials in the previous month

14.4% of 416 patients had a CSDDI between 1st

line ARVs and antimicrobials (accounting for ~40%

of all CSDDIs)

40.3% of 149 patients taking

antimicrobials had a CSDDI

Antimicrobials included: antibiotics, antimalarials, anthelmintics, antivirals

CSDDIs between ARVs and antimicrobials may reduce antimicrobial efficacy, leading to: 1. Inadequate treatment of infection2. risk of resistance

46%

9%

25%

15%

5%

InappropriateindicationInappropriatechoiceInadequateduration

Seden K et al. 19th International Conference on AIDs and STIs in Africa, 4 - 9 Dec 2017, Abidjan, Côte d'Ivoire

Results: clinically significant drug interactionsChronic conditions

Potential for EFV and NVP to decrease exposure to available antihypertensivessuch as amlodipine and nifedipine.

Of 10 patients taking antihypertensives, all

10 had a potential CSDDI. Of these patients,

9/10 had uncontrolled hypertension

Results: clinically significant drug interactionsRisk of contraceptive failure

Of 37 women on 1st line ARV regimens who

reported using hormonal contraceptives, 9

women were exposed to a DDI which put them

at significant risk of contraceptive failure

Results: prescriber awareness & utility of active screening

At baseline study visits, prescribers were asked to detail

any DDIs they were aware of for each patient

Prescribers were aware of only 3.5% of

CSDDIs (n=144)

DDI checks

provided

NEW

information

in 56.1% of

cases (n=214)

Prescribers

changed

Patient

management

in 53.1% of

cases (n=309)

DDI checks

saved time in

68% of cases

(n=200)

DDI checks

added

benefit in

72% of cases

(n=200)

Conclusions & recommendations

• Currently available ARVs for 1st-line regimens in sub-Saharan Africa comprise drugs which are the most

susceptible to CSDDIs, and with the highest propensity to cause ADEs, of all the globally available ARVs.

• Low resource settings are the least able to consistently monitor patients, switch regimens due to toxicity,

or tailor treatment to individuals

1. Compared to currently used 1st-line ARV regimens, roll-out of newer ARVs with lower potential for DDIs and

debilitating ADEs (such as dolutegravir) may:

▪ Reduce the risk of contraceptive failure

▪ Reduce risk of antimicrobial treatment failure and microbial resistance

▪ Reduce significant morbidity due to adverse drug reactions

2. Patients experiencing, or at high risk of debilitating ADEs or CSDDIs related to current first-line ARV regimens

should be prioritised for switching to dolutegravir.

3. Active screening for medication safety issues using task shifting and mobile technology is feasible, acceptable

to prescribers and led to a change in clinical management in more than half of patients screened

Acknowledgements

We would like to thank the staff and patients of all health centres and hospitals involved in the study, for their ongoing commitment to patient safety

Saye Khoo

Catriona Waitt

Mohammed Lamorde

Joseph Walter Arinaitwe

Eva Laker

Daniel Kiiza

Oliver Sapiri

Andrew Luswata

Byron Kawooya

Daniel Oula

This work was jointly supported by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under

the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union.