TARGETED SPONTANEOUS REPORTING FOR
ADVERSE EVENTS RELATED TO ARV:
PRELIMINARY RESULTS FROM VIETNAM
Nguyen Hoang Anh, Nguyen Thi Thuy Van, Le Thi Huong, Masaya Kato,
Tran Ngan Ha
Technical review meeting of country experiences in ARV toxicity surveillance:
sharing preliminary results and lessons learnt, identifying solutions
Geneva, 7-8th November 2013
Viet Nam HIV Overview
Epidemic: “Concentrated epidemic”
– Population (2013): 90 million
– Estimated HIV population (2012): 256,845
– HIV prevalence - age15-49 (2012): 0.46%
– HIV prevalence – PWID (2012): 11.6%
Response
– Harm reduction (NSP, OST), Condom
• People on methadone maintenance (2012):
12,253
– ART rapid scale-up
• People on ART (2012): 72,711
• ART coverage among the eligible (2012):
62%
Data sources: General Statistic Office (population), VAAC/MOH (others)
NATIONAL GUIDELINE FOR HIV/AIDS
DIAGNOSIS & TREATMENT
Switch from AZT/d4T
+ 3TC + NVP to TDF +
3TC + EFV/NVP
PHARMACOVIGILANCE PRACTICE IN VIETNAM
1999: became
full member of
WHO-UMC
2009: Foundation of The
National DI & ADR Center
Achievements
 Control of drug quality problems
 Establishment of spontaneous ADR
reporting system by healthcare workers
 Issued a number of legal documents
relating to ADR monitoring
1994: Foundation of
the 1st ADR center
Strengthening the national PV system to support PHPs
PV
SYSTEM
National
level
Regional
level
effective linkages
GOAL
Develop a national PV system that
effectively links with and supports
PHP’s practice ensuring drug safety
PHP’s SYSTEM
National
level
Regional
level
Healthcare
facilities
Province &
district level
Patients
Patients
PHARMACOVIGILANCE PRACTICE IN HIV/AIDS
PROGRAM: CURRENT SITUATION
 Expansion of ART: 72,711 patients in 2012
 Limited information on adverse events of ARV
 Inadequate training and limited experiences on ARV
toxicity monitoring.
 Frequent change/revision on treatment guidelines
COLLECTING SAFETY DATA RELATED TO ARV
Spontaneous reporting (SR)
Launched in 1994 and mandated by law
since 2005 for healthcare professionals
Number of spontaneous reports related to ARV
received by the National PV Center
2010
2011
2012
No of ARV
reports
16
11
15
Total reports
received
1807
2407
3024
%
0,88
0,46
0,49
COLLECTING SAFETY DATA RELATED TO ARV
Cohort event monitoring (CEM)
Pilot of active surveillance on ARV from 10/2011 to 6/2013
at 5 sentinel sites
Key findings
645 patients; male 60.2%; age: 34.2 ± 7.9, mean of follow-up: 11,4 months
49,1% patients experienced with ADRs
Most common reported ADRs: liver/biliary, skin, CNS, hematology disorders
ADR-induced regimen switching: 14.6%
Risk factors for ADR identified: d4T-based regimen and liver disorders
AZT-based regimen and anemia; NVP-based regimen, CD4 count and skin
disorders, EFV-based regimen, age, clinical stage and CNS disorders.
Challenges: Require more intensive laboring, time
consuming, costly, difficult to maintain in long terms
and not feasible to apply at national wide
COLLECTING SAFETY DATA RELATED TO ARV
Targeted spontaneous reporting (TSR)
Spontaneous
reporting (SR)
Cohort event
monitoring
(CEM)
Targeted spontaneous
reporting (TSR)
Pal S et al. Drug Saf. 2013, 36, 75-81
PILOTING TSR IN VIETNAM
Objectives
 To assess the feasibility of TSR approach in monitoring ARV
toxicity
 To monitor and document adverse events among those
taking ART for prevention and treatment.
 To improve physicians capacity in monitoring and
documenting adverse events related to ARV drug use
Pilot of TSR to monitor adverse events of TDF and EFV
 DienBien và CanTho provinces (from 02/2013 - 12/2013)
 Hanoi (from 05/2013 – 05/2014)
Feasible, affordable and sustainable at restricted-source countries
TSR implementation in Dien Bien and Can Tho
Dien Bien
 “Treatment as Prevention” (TasP study)
among serodiscordant couples:
 HIV positive partners received ART
regardless of CD4 count
 Study couples received standard care
and prevention
 Monitor adverse events related to TDF
and EFV
 Feasibility of TSR in a research
environment.
Can Tho
 DienBien (6 OPCs), CanTho (5 OPCs)
TSR
TSRimplementation
implementationin
inHanoi
Hanoi
(from 05/2013-05/2014)
Ha Noi
•
To monitor toxicity of TDF and EFV
among patients:
-
Newly
treated
TDF/3TC/EFV
-
Switching
from
d4T-based
regimen to TDF/3TC/EFV
with
• To assess feasibility of TSR
approach in monitoring ARV toxicity
in HIV program
• Implement in all 7 out patient clinics
(OPC) in Hanoi
TSR implementation: setting-up
Design a specific ADR reporting form
TSR implementation: setting-up
Development of
guideline on
recording form
TSR implementation: setting-up
Training for healthcare workers
M&E, technical assistance at HIV/AIDS clinics
TSR implementation: data collection
 Detection of adverse events
 Asking patients on ADR that they may encounter in all follow-up
visits (CNS symptoms related to EFV)
 Testing serum creatinine periodically (TDF induced renal toxicity)
 Filling in ADR reporting form
 Doctors identify adverse events (if any) ⇒ fill in the toxicity reporting
form
 Nurses/other healthcare workers fill in the remaining part of the form
 Contact person at OPCs collect all reports and periodically send to
the National DI&ADR Center before the 5th day of the next month
ADR reporting form
Patient
information
to be filled
by nurses
ADR
information
to be filled
by doctors
TSR implementation: data collection
Reporting cycle
National DI&ADR Center
review, assessment
Drug Information
Reporting
ART clinics
Doctors, nurses …
Feedback
WHO UMC
Feedback
Reporting
Adverse events
occurred in
patients
Provincial HIV/AIDS
Center (PAC)
Viet Nam Administration of
HIV/AIDS Control (VAAC)
Making decision
Results: TasP study (DienBien and Can Tho)
Number of
patients
Number of AE
reports
OPC Tuan Giao district
21
0
OPC Muong Ang district
10
3
OPC Muong Lay district
5
2
OPC Muong Cha district
6
2
OPC Dien Bien city
10
0
OPC Dien Bien Hospital
18
14
OPC Thot Not district
8
0
OPC O Mon district
3
0
OPC Cai Rang district
7
0
OPC Ninh Kieu district
5
1
OPC Can Tho General Hospital
5
0
98
22
OPC
Dien Bien
Can Tho
Total
Patients experienced with AEs: 22.45% (all related to EFV)
* Data till September 2013
Results: TasP study (DienBien and Can Tho)
Characteristics of patients experienced with AEs
Gender
Age
CD4 cells count
(cells/mm3)
Not
documented
4%
Female
14%
40-49
18%
20-29
14%
<350
41%
Male
86%
30-39
68%
>=350
55%
Results: TasP study (DienBien and Can Tho)
CNS symptoms related to EFV
AEs related to EFV
Dizziness
Fatigue
Insomnia
Headache
Nausea
Vivid dream
Hot flush
Nightmares
Anxiety
Poor concentration
Depression
Others
Reduce of sexual desire
No of reports
16
16
12
10
8
8
6
5
4
2
2
2
1
%
72.7
72.7
54.5
45.5
36.4
36.4
27.3
22.7
18.2
9.1
9.1
9.1
4.5
Results: TasP study (DienBien and Can Tho)
CNS symptoms related to EFV
No of reports
%
10
12
45.5
54.5
< 1 week
18
81.8%
1 week to 1 month
1
4.55%
1 month - 6 months
1
4.55%
Not documented
2
9.09%
Severity
Grade 1
Not documented
Onset
Results: TasP study (DienBien and Can Tho)
CNS symptoms related to EFV
AE management
Reduce dosage
Stop medicines
Switching regimen
Using other drugs to treat AE symptoms
Others (consultancy, change the time of
taking drugs, taking with a lot of water…)
Not documented
No of reports
0
0
1
0
3
18
%
4.55%
13.64%
81.82%
Results: Pilot in Hanoi
OPC
OPC Ba Đình district
OPC Dong Da district
OPC Hoang Mai district
OPC Thanh Xuan district
OPC Tay Ho district
OPC Ba Vi district
OPC Dong Anh district
OPC Tu Liem district
OPC Long Bien district
OPC Gia Lam district
OPC Ung Hoa district
OPC Son Tay Hospital
OPC Soc Son district
OPC Hospital 09
OPC Dong Da Hospital
OPC Ha ĐOng Hospital
OPC Hà Nội Lung Hospital
Total
Number of patients Number of AE reports
62
22
NA
NA
24
12
7
7
49
5
27
13
90
20
47
37
36
8
19
19
20
20
Not reported
Not reported
12
4
34
19
47
8
34
20
50
8
558
222
Patients experienced with AEs: 39.8% (EFV: 217 cases, TDF: 14 cases)
Results: Pilot in Hanoi
Characteristics of patient experienced with AEs
Gender
Age
>=50
5.4%
40-49
17.6%
Female
28.8%
Male
71.2%
CD4 cells count
(cells/mm3)
Not
documented
0.9%
15-19
0.5%
20-29
18.5%
30-39
58.1%
>=350
28.4%
<350
70.7%
Results: Pilot in Hanoi
CNS symptoms related to EFV
AEs related to EFV
Dizziness
Fatigue
Hot flush
Headache
Insomnia
Vivid dream
Nausea
Anxiety
Nightmares
Poor concentration
Aesthesia
Others
Paranoia
Reduce of sexual desire
Depression
Suicide thought
No of reports
%
129
126
88
82
62
61
59
31
24
21
16
16
6
4
3
2
59.4
58.1
40.6
37.8
28.6
28.1
27.2
14.3
11.1
9.7
7.4
7.4
2.8
1.8
1.4
0.9
Results: Pilot in Hanoi
CNS symptoms related to EFV
No of reports
%
151
47
5
13
69.59
21.66
2.3
5.99
< 1 week
133
61.29
1 week to 1 month
46
21.20
1 month - 6 months
13
5.99
Not documented
25
11.52
Severity
Grade 1
Grade 2
Grade 3
Not documented
Onset
Results: Pilot in Hanoi
Central nervous system AEs
related to EFV
CNS symptoms related to EFV
AE management
Reduce dosage
Stop medicines
Switching regimen
Using other drugs to treat AE symptoms
Others (consultancy, change the time of
taking drugs, taking with a lot of water…)
Not documented
No of reports
%
0
0
10
8
4.61
3.69
148
68.20
50
23.04
Results: Pilot in Hanoi
TDF induced renal toxicity
Creatinin
Patients
Gender before using
code
TDF
78
M
65
209
F
70
76
M
80
6
M
74
117
F
60
55
M
89
243
M
64
73
M
76
226
F
71
206
M
87
152
M
89
112
M
90
104
M
95
139
M
126
Date
Creatinin at time
of reporting
Date
TDF start date
01/11/2012
07/11/2011
19/05/2011
01/11/2012
08/11/2012
08/11/2012
27/05/2013
25/05/2013
15/11/2012
15/11/2012
15/11/2012
09/05/2011
22/11/2012
29/11/2012
160
105
124
161
115
136
125
144
135
166
147
200
123
203
11/07/2013
11/07/2013
11/07/2013
11/07/2013
11/07/2013
18/07/2013
11/07/2013
18/07/2013
18/07/2013
18/07/2013
18/07/2013
18/07/2013
11/07/2013
18/07/2013
05/07/2013
05/07/2013
05/07/2013
05/07/2013
10/07/2013
10/06/2013
18/06/2013
20/06/2013
14/06/2013
14/06/2013
14/06/2013
10/07/2013
21/06/2013
21/06/2013
2 patients need to switch to other regimen
Challenges in AE monitoring and
recording at OPC
 Due to huge workload at OPC: Healthcare workers have
not paid much attention to AEs
 Lack of knowledge and skills among healthcare workers
to detect and assess AEs
 Record and report AEs have not become a routine work
 Transient/mild adverse events has not been recorded by
physicians or not reported by patients.
 Missing data with AEs occurred when patients at home,
only persisted AEs at follow-up visit could be taken into
account by healthcare workers
 Uncompleted and inaccurate information in AE reports
AE report collection
 Technical assistance and close monitoring of Hanoi PAC
have an impact on number of AE reports
 ADR reports from TasP study is less frequent especially in
Can Tho: recording other information of the study may
compromise ADR information recording/reporting
 Reporting channel need to be revised
 OPC intended to send report to PAC (their supervision)
than to ADR centre (as required)
 Weak adherence to timeline of sending reports by some
OPCs
 Loss reports when sending by post office
 ADR reports sent by email were likely more update and
accurate
LESSON LEARNT
1. Feasibility:
 Structured reporting form (clear and simple)
 Increase in number of reports (compared to
spontaneous reporting)
2. Training on detecting, recoding and reporting skills is
vital for success.
3. Providing TA and monitor from provincial level to OPC
is crucial
4. Close communication, feedback between National DI &
ADR Center, VAAC, PAC and OPCs.
RECOMMENDATIONS
 Toxicity monitoring of ARV using TSR approach is
applicable and relevant for concentrated epidemic
and limited resource as Vietnam.
 Training
and
guidelines
are
needed
for
implementation and scale up
 More advocacy on ARV toxicity monitoring is
needed to improve awareness of ARV toxicity
monitoring.
 Support and commitment from HIV program
manager is important
Scaling up
VAAC recommends to implement new reporting form
(based on TSR form) in 5 high burden provinces
Scaling up
VAAC required PACs to
monitor and report AEs
using the national ADR
reporting form (August
2013)
TSR promotes
spontaneous reporting
Collaborations
Provincial AIDS Centre
Thanks for your attention