Medication error

1. Clinical aspects of ADRs in HIV
and ARV toxicity monitoring
approaches
Workshop on management and
reporting of adverse drug reactions
related to ARVs
26 June 2018, Gaborone, Botswana

2. Presentation Outline
1) WHO ARV recommendations
2) Key definitions
3) Major toxicities associated with ARVs used in clinical
practice
4) Clinical management of major ARV toxicities
5) Management of drug-drug interactions
6) DTG related toxicities
– Clinical management of DTG toxicities
– Drug-drug interactions
7) WHO recommended ARV toxicity monitoring approaches
– Routine ARV toxicity monitoring
– Active ARV toxicity monitoring

3. WHO 2016 ARV guidelines recommend DTG as
alternative 1st line regimen in adults & adolescents
DTG=dolutegravir EFV=efairenz
DRV/r=darunavir/ritonavir RAL=raltegravir

4. WHO recommendations on monitoring toxicity - Lab
Guiding principles for ARV toxicity monitoring (WHO
2016 ARV guidelines)
• The availability of laboratory monitoring is not
required for initiating ART
• Symptom-directed laboratory monitoring for safety
and toxicity can be used for those receiving ART
• At the same time several laboratory tests for
monitoring ARV toxicity are advised (but not required)
for specific high-risk people using certain drugs:
• HB test for initiating AZT
• Serum creatinine & eGFR for PLHIV on TDF
• Alanine aminotransferase for initiating NVP

5. Key definitions

6.  Adverse drug reaction (ADR)
 A response which is harmful and unintended, and
which occurs at doses normally used in humans
for the prophylaxis, diagnosis, or therapy of
disease, or for the modification of physiological
function.
 Unlike an adverse event, an ADR is characterized
by the suspicion of a causal relationship
between the drug and the occurrence, i.e. judged
as being at least possibly related to treatment by
the reporting or a reviewing health professional.

7.  Treatment limiting toxicity
 A serious adverse drug reaction that results in
drug/regimen discontinuation or substitution.
Serious Adverse Drug
Reaction (ADR)
ADR causing death, life threatening,
requires or prolongs hospitalization,
disability or permanent damage, or
congenital anomaly/birth defect
Any adverse drug reaction
that leads to treatment
interruption or requires
changing drug/regimen

8.  Routine toxicity monitoring. Monitoring of
treatment limiting ARV toxicities integrated into
monitoring and evaluation of national HIV treatment
programmes using patient monitoring tools and
reporting systems.
 Active toxicity monitoring. A system in which
active measures are taken to detect the presence or
absence of adverse drug reactions through follow-up
after treatment. The adverse drug reactions may be
detected by interviewing patients, preforming specific
investigation or by screening patient records.

9. Adverse Drug Reactions
 Patients frequently experience ADRs or side
effects when they start ARVs including:
 Gastrointestinal (e.g. nausea, diarrhea)
 Body pains
 Headache
 Fatigue
 Rash
 Neuropsychiatric symptoms (e.g. dizziness
or sleepiness)
Slide courtesy of ICAP

10. Major toxicities associated with most used ARVs
Drug Liver
Ren
al
Bone CVD Metabolic
Hematol
ogic
CNS Skin
GI
intolerance
Muscular
ABC
AZT
TDF
EFV
NVP
ATV/r
DRV/r
LPV/r
DTG
RAL
PIs
NNRTIs
NRTIs
INSTIs
most commonly reported adverse drug reactions
CVD= cardiovascular disease CNS=central nervous system GI= gastrointestinal

11. Clinical management of major ADRs associated with ARVs (1)
ARV drug Major types of toxicity Risk factors Suggested management
EFV
Persistent central nervous system
toxicity (such as dizziness,
insomnia, abnormal dreams) or
psychiatric symptoms (anxiety,
depression, mental confusion)
Depression or other mental
disorder (previous or at
baseline)
Daytime dosing
For CNS symptoms, dosing at bed
time. Consider use EFV at lower
dose (400mg/day or integrase
inhibitor (DTG) if EFV400mg is not
effective in reducing symptoms.
Convulsions History of seizure
Hepatotoxicity Underlying hepatic disease
HBV and HCV coinfection
Concomitant use of
hepatotoxic drug
For severe hepatotoxicity or
hypersensitivity reactions, substitute
with another therapeutic class
(integrase inhibitors or boosted PIs).
Severe skin and hypersensitivity
reactions
Risk factor(s) unknown
Gynaecomastia
Risk factor(s) unknown Substitute with another therapeutic
class (integrase inhibitors or
boosted PIs).

12. ARV drug Major types of toxicity Risk factors Suggested management
ABC Hypersensitivity reaction Presence of HLA-B*5701
gene
Do not use ABC in presence of HLA-
B*5701 gene. Substitute with AZT or
TDF.
ATV/r Electrocardiographic abnormalities
(PR and QRS interval
prolongation)
People with pre-existing
conduction system disease
Concomitant use of other
drugs which may prolong
the PR or QRS intervals
Congenital long QT
syndrome
Use with caution in people with pre-
existing conduction disease or who are
on concomitant drugs which may prolong
the PR or QRS intervals.
Indirect hyperbilirubinemia (clinical
jaundice)
Presence of UDP-
Glucuronosyltransferase
1A1*28 (UGT1A1*28) gene
This phenomenon is clinically benign but
potentially stigmatizing. Substitute only if
adherence is compromised.
Nephrolithiasis History of nephrolithiasis Substitute with LPV/r or DRV/r. If boosted
PIs are contraindicated and NNRTIs
have failed in first-line ART, consider
substitute with integrase inhibitors.
Clinical management of major ADRs associated with ARVs (2)

13. Clinical management of major ADRs associated with ARVs (3)
ARV drug Major types of toxicity Risk factors Suggested management
AZT Anaemia, neutropaenia, Baseline anaemia or
neutropaenia
CD4 cell count of ≤200
cells/mm3
Substitute with TDF or ABC
Consider use of low dose
zidovudine. ()
Lactic acidosis or severe
hepatomegaly with steatosis
lipoatrophy, lipodystrophy
myopathy
BMI >25 (or body weight >75
kg)
Prolonged exposure to NRTIs
Substitute with TDF or ABC.
DRV/r Hepatotoxicity Underlying hepatic disease
HBV and HCV coinfection
Concomitant use of
hepatotoxic drugs
Substitute with ATV/r or LPV/r.
When it is used in third-line
ART, limited options are
available.
For hypersensitivity reactions,
substitute with another
therapeutic class.

14. Clinical management of major ADRs associated with ARVs (4)
ARV
drug
Major types of toxicity Risk factors Suggested management
LPV/r Electrocardiographic
abnormalities (PR and
QRS interval
prolongation, torsades de
pointes)
People with pre-existing conduction
system disease
Concomitant use of other drugs which may
prolong the PR or QRS intervals
Congenital long QT syndrome
Hypokalaemia
Use with caution in people with pre-existing
conduction disease or who on concomitant drugs
which may prolong the PR or QRS intervals .
Hepatotoxicity
Underlying hepatic disease
HBV and HCV coinfection
Concomitant use of hepatotoxic drugs
If LPV/r is used in first-line ART for children,
substitute with NVP or RAL for children younger
than 3 years and EFV for children 3 years and
older. ATV can be used for children older than 6
years.
If LPV/r is used in second-line ART for adults, and
the person has treatment failure with NNRTI in
first-line ART, consider integrase inhibitors.
Pancreatitis Advanced HIV disease, alcohol Substitute with another therapeutic class
(integrase inhibitors).
Dyslipidaemia, Cardiovascular risk factors as obesity and
diabetes
Substitute with another therapeutic class
(integrase inhibitors).
Diarrhoea Risk factor(s) unknown Substitute with atazanavir/r, darunavir/r or
integrase inhibitors.

15. ARV
drug
Major types of toxicity Risk factors Suggested management
NVP Hepatotoxicity
Severe skin rash and
hypersensitivity reaction,
including Stevens-
Johnson syndrome
Underlying hepatic disease
HBV and HCV coinfection
Concomitant use of hepatotoxic drugs
High baseline CD4 cell count (CD4
count > 250 cells/mm3 in women or
>400 cells/mm3 for men)
If hepatotoxicity is mild, consider
substitution with EFV including in
children 3 years and older.
For severe hepatotoxicity and
hypersensitivity, and in children under
the age of 3 years, substitute with
another therapeutic class (integrase
inhibitors or boosted PIs) .
RAL Rhabdomyolysis,
myopathy, myalgia
Concomitant use of other drugs that
increase the risk of myopathy and
rhabdomyolysis, including. statins Stop ART. When symptoms are
resolved, substitute with another
therapeutic class (etravirine, boosted
PIs) .
Hepatitis and hepatic
failure
Severe skin rash and
hypersensitivity reaction
Risk factor(s) unknown
Lactic acidosis or severe
hepatomegaly with
steatosis
Prolonged exposure to nucleoside
analogues
Obesity, Liver disease
Clinical management of major ADRs associated with ARVs (5)

16. Clinical management of major ADRs associated with ARVs (6)
ARV
drug
Major types of toxicity Risk factors Suggested management
TDF Chronic kidney disease
Acute kidney injury and
Fanconi syndrome
Underlying renal disease; Older than
50 years old; BMI <18.5 or low body
weight (<50 kg) notably in females;
Untreated diabetes; Untreated
hypertension
Concomitant use of nephrotoxic drugs
or a boosted PI Substitute with AZT or ABC
Do not initiate TDF at eGFR < 50
ml/min, uncontrolled hypertension,
untreated diabetes, or presence of renal
failure
Decreases in bone
mineral density
History of osteomalacia (in adults) and
rickets (in children) and pathological
fracture
Risk factors for osteoporosis or bone
mineral density loss, Vitamin D
deficiency
Lactic acidosis or severe
hepatomegaly with
steatosis
Prolonged exposure to nucleoside
analogues
Obesity, Liver disease

17. • Drug-drug interactions can reduce or increase the efficacy of
ART and/or increase ART-related toxicities.
• Polypharmacy is common among PLHIV and a frequent
cause of stopping or changing HIV therapy.
• Providers should be aware of all drugs used by the patients,
including alternative medicine products such as herbal
remedies, vitamins and dietary supplements - that people
are taking when ART is initiated, as well as new drugs that
are added during treatment maintenance.
Monitoring ADRs- Interactions

18. Major drug interactions associated with ARVs
most used in clinical practice
Drug
Amiodarone
Astemizole/Terfenad
rine
Carbamazepine,/
Phenobarbital/
Phenytoin
Cisapride
Ergotamine/
Dihydroergotamine
Halofantrine/Lumefa
ntrine
Hormonal
contraceptives
Itraconazole/Ketoco
nazole
Lovastatin/Simvastat
in
Methadone
Buprenorphine
Midazolam,/Triazola
m
Sildenafil
Simeprevir
Ombitasvir/paritapre
vir/
ritonavir
+
dasabuvir
Interferon/Ribavirin
Polivalent
cations
(Mg,
Al,
Fe,
Ca
and
Zn
)
Rifampicin
Tenofovir
EFV         
NVP       
ATV/r                
DRV/
r
               
LPV/r                
DTG   
RAL 
PIs
NNRTIs
INSTIs
 increase interacting drug concentration  increase ARV drug concentration
 decrease interacting drug concentration  decrease ARV drug concentration

19. Major drug interactions associated with ARVs &
suggested management (1)
ARV drug Key interactions Suggested management
EFV
Amodiaquine Use an alternative antimalarial agent
Cisapride Use alternative gastrointestinal agent
Methadone Adjust the methadone dose as appropriate
Hormonal contraceptives Use alternative or additional
contraceptive methods
Astemizole and terfenadine Use an alternative anti-histamine agent
Ergotamine and dihidroi-ergotaminne Use alternative antimigraine agent
Simeprevir Use alternative DAA
Midazolam and triazolam Use alternative anxiolytic agent

20. Major drug interactions associated with ARVs &
suggested management (2)
ARV drug Key interactions Suggested management
Boosted PI
(ATV/r, DRV/r,
LPV/r)
Rifampicin Substitute rifampicin with rifabutin
Adjust the dose of LPV/r or substitute with
three NRTIs (for children)
Halofantrine Use an alternative antimalarial agent
Lovastatin and simvastatin Use an alternative dyslipidaemia agent
(e.g. pravastatin)
Hormonal contraceptives Use alternative or additional
contraceptive methods
Metformin Adjust methadone and buprenorphine doses
as appropriate
Astemizole and terfenadine Use alternative antihistamine agent
TDF Monitor renal function
Simeprevir Use alternative DAA
Ombitasvir / paritaprevir /ritonavir + dasabuvir Use alternative DAA

21. Dolutegravir related toxicities

22. Dolutegravir
 Integrase inhibitor
 Effective (rapid viral load suppression)
 Well tolerated
 High genetic barrier to resistance
 Few drug interactions
 Single and as fixed dose formulation (DTG)
 Cheap 75 USD/patient/year
 PEPFAR transition

23.  TB : double dose – 50 mg 12 hrs apart (RTC INSPIRING)
 IRIS: No elevation in RTC (REALITY) rapid immune
reconstitution syndrome
 Pregnancy
– Indication to use only if benefits outweigh risk (FDA and drug packet
insert)
– spontaneous abortion in 13% of women living with HIV taking ART
other than DTG
– 10% in those taking DTG
 Children
– FDA approved for > 30 kg
– EMA approved for > 6 yrs and > 15 kg
Dolutegravir

24. DTG uptake by countries
• By May 2018, 68 LMICs (49%)
informed that have included or are
planning to include DTG in their
national guidelines
o DTG introduced in national guidelines: 24
o DTG introduced in national guidelines and
procurement initiated: 23
o DTG introduction in national guidelines
planned : 21
• Approximately 500 000 PLHIV are
using DTG globally
• Early adoption of DTG in LMIC:
Botswana, Brazil, Kenya and Ukraine
*Source: Global AIDS Monitoring 2018 data and WHO country correspondence
20
55
68
0
10
20
30
40
50
60
70
80
mid 2017 end 2017 mid 2018*
Number of LMICs that adopted
DTG as 1st line option
* preliminary data

25. Source: MoH Botswana, Brazil & Kenya, 2018
Country
Trans
ition
start
PLHIV
on
DTG
M/F
ratio
DTG eligibility criteria % of
reported
DTG
adverse
events
Major DTG AEs
reported (top 3)
DTG
monitoring
tools
Use of VL for
DTG
substitution
ART
naive
NNRTI
intolerance
Stable
on
ART
non
EFV
regimens
Stable
on
ART
EFV
regimen
PW
TB
2
nd
line
3
rd
line
PEP
Toxicity
(PV)
APR
HIVDR
Botswana
May
2016
57,000 40/60          1%
• GI symptoms
• Skin reactions
• Insomnia
?   
Brazil
Jan
2017
100,000 70/30          2%
• GI symptoms
• Skin reactions
• Insomnia
   
Kenya
July
2017
11,000 25/75          7%
• Headache
• Abnormal
dreams
• Insomnia
   
Botswana, Brazil and Kenya have adopted DTG as preferred 1st
line option and have implemented a programmatic transition to
DTG

26. 26 |
Gaps on clinical use of dolutegravir
CNS side effects:
higher than
expected rate of
DTG discontinuation
due insomnia in
some cohort studies
(higher rates
compared with
RCTs) but very low
occurrence of other
side effects.
IRIS in PLHIV
with advanced
HIV disease:
increased risk
observed in
some cohort
studies but not
detected in RCTs
with other
INSTIs (REALITY
trial).
Pregnant/BF
women: limited
safety data, very
high DTG
concentrations in
blood cord at birth
(PK and clinical
studies ongoing)
HIV-associated
TB: need to
double dose if
rifampin is
used
(INSPIRING –
50 mg BID)
Infants and
children:
safety and
dose finding
trial underway.
Very limited
clinical
experience

27. 27 |
DTG-related Adverse Drug Reactions
Batista, et al. #494, CROI 2018
1.3
0.8
0.6 0.5
0.2 0.2 0.1
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Percentile
(%)
Most frequent ADRs
Frequency of ADRs reported by patients taking DTG in Brazil

28. 28 |
Clinical management of major ADRs associated with DTG
ARV drug
Major types of
toxicity
Risk factors
Suggested
management
DTG Hepatotoxicity
Hypersensitivity
reactions
Hepatitis B or C co-
infection
Liver disease
Substitute with
another therapeutic
class (EFV or
boosted PIs).
Insomnia Older than 60 years
Female gender
Consider morning
dose or substitute
with EFV, boosted PI
or RAL.

29. 29 |
• Mary was previously taking TLE but recently changed to DTG
containing regimen
• At her follow up appointment she complains about not being able to
sleep at night
What would you ask Mary?
What advice could you give Mary?
DTG Adverse Event: Case Study - Mary
Slide courtesy of ICAP

30. 30 |
Insomnia and DTG
• Symptoms may improve over
time as the body adjusts
• Take DTG in the morning
Slide courtesy of ICAP

31. 31 |
DTG in a patient with TB Case Study - Charles
 Charles was referred to your clinic after testing positive for HIV at the TB clinic
where he also received TB treatment.
 He reports feeling better after starting TB treatment and is motivated to start
ART today.
 You decide he is ready to start ART and initiate him on DTG regimen and
Cotrimoxazole.
 You also send labs to check his CD4
 You ask him to return in two weeks for follow up.
 What additional considerations are there for Charles starting on DTG
regimen?
Slide courtesy of ICAP

32. 32 |
Immune Reconstitution Inflammatory
Syndrome (IRIS)
• IRIS occurs when someone with severe immunosuppression
has a preexisting infection that was not detected or was
incompletely treated prior to starting ART.
• If the immune system recovers quickly it may cause
worsening of symptoms.
• IRIS does not occur with just DTG and can happen with any
other ART regimen.
Slide courtesy of ICAP

33. 33 |
Hypersensitivity
• Hypersensitivity is
characterized by rash,
constitutional findings, and
sometimes organ dysfunction
• Whenever a patient has a
severe reaction to a drug all
drugs should be stopped until
the patient recovers
• Important to find out the drug
causing hypersensitivity as it
should never again be used
by the patient
Slide courtesy of ICAP

34. 34 |
• Your patient Michael has TB. He is currently
undergoing treatment for his TB and HIV
simultaneously.
• He comes to you complaining of feeling like his
legs and arms are tingling.
• What questions would you ask Michael?
• What do you suspect might be happening?
Adverse Events: Case Study - Michael
Slide courtesy of ICAP

35. 35 |
Drug Interactions with DTG
https://www.hiv-druginteractions.org/checker
Slide courtesy of ICAP

36. 36 |
DTG and Vitamin Supplements
• DTG should also not be given at the same time as supplements
containing Magnesium (Mg), or Zinc (Zn)
• DTG may be given with calcium (Ca) and/or Iron (Fe) if it is also
taken with food. If it not taken with food though DTG should not be
given at the same time
• These may be in multivitamins, certain laxatives or certain antacids
so it is important to know what other tablets your patients are
taking.
• If your patients are taking any of these, advise them to take their
ARVs at least 2 hours before or at least 6 hours afterwards.
Slide courtesy of ICAP

37. 37 |
Other Drug Interactions with DTG:
Case Study - Blessing
• Your patient, Blessing, is ready to be initiated on DTG.
When you take her medical history, you discover that she
has epilepsy.
• She reports that she has been pretty well controlled on
phenobarbital.
 What else would you want to learn from your patient?
 What would you recommend?
Slide courtesy of ICAP

38. 38 |
38
Other Drug Interactions with DTG:
Case Study - Joyce
• Joyce is newly diagnosed with HIV and ready to
initiate ART.
• She also is using family planning and gets shots of
Depo Provera every three months.
• She is concerned because she heard that ART may
make her contraception less effective.
 How would you counsel your patient?
 What would you tell her?
Slide courtesy of ICAP

39. 39 |
Use of DTG and Other Medications
ACTIVITY
Slide courtesy of ICAP

40. WHO recommended approaches
for toxicity monitoring of new
ARVs

41. WHO recommendation on ARV drug
toxicity Monitoring
• With rapid treatment scale up, prolonged exposure
to ARVs & transition to new ARV drugs, clear need
for ARV toxicity monitoring to better understand the
risks of new ARVs under conditions of programmatic
use
WHO recommends enhanced toxicity monitoring &
surveillance to address gaps in safety data of new
ARVs in the 2017 Technical update on Transition
to new antiretroviral drugs in HIV programmes:
clinical & programmatic considerations

42. Why implement ARV toxicity
monitoring?
Adverse drug reactions can lead to
• reduced quality of life
• treatment interruption
• treatment failure
• avoidable morbidity
• deaths
• added costs to the service (e.g.
hospitalization)
…

43. Why implement ARV toxicity
monitoring?
• Expanded use of new ARVs in whom exposure to such
treatment is relatively new and caregivers unfamiliar to
the safety profile
• Early recognition and management of adverse reactions
can improve adherence and treatment outcomes
• Adverse reactions pose a risk not only to the individual
but also to the whole treatment programme. May harm
public confidence in a national treatment programme or
in a new medicine or regimen

44. Routine Active
2 recommended approaches to
toxicity monitoring of new ARVs

45. Routine Active
2 recommended approaches to
toxicity monitoring of new ARVs
Integrated within national M&E system,
(using existing HIV patient monitoring
tools and indicators) & implemented at
all ART sites

46. Routine Active
2 recommended approaches to
toxicity monitoring of new ARVs
Implemented at select ART sites,
complements routine monitoring. Enables
enhanced monitoring & data capture of
ADRs including management & outcomes.

47. 1. Routine ARV toxicity monitoring
 Countries use a standardized approach to integrate ARV
toxicity monitoring within national M&E systems as part
of routine patient monitoring
 Routine ARV toxicity monitoring provides data on the
prevalence and clinical significance of serious toxicities
2013 Technical brief
on surveillance of
ARV drug toxicity in
ART programmes

48. 2017 Consolidated Guidelines for Person
centred monitoring & case based surveillance
 Defines the key toxicity prevalence indicator to be collected
& provides patient monitoring tools to capture treatment
limiting toxicities as part of routine reporting
Standardised tools:
• HIV care & treatment card
• ART register
National ARV toxicity indicator
Indicator Programme relevance and interpretation
Toxicity
prevalence: % of
people receiving
ART with
treatment-limiting
toxicity
Measures how toxicity affects treatment
outcomes. Helps to guide national policy
on ART regimens, diagnosis, strategies for
preventing toxicity, health-care worker
training and retention in care

49. HIV Care & Treatment
Card

50. HIV Care & Treatment Card (1)
 Designed to be completed for all individuals entering
care at a facility and serves as the primary data source
for patient monitoring.
 Toxicities captured using standardised toxicity codes in
the following sections:
Encounter page card:
1) Treatment limiting
toxicities
2) Reasons for missed
doses including toxicity
Front page of card:
1) Drug substitution
within 1st/2nd/3rd line
ART
2) ART interruptions

51. HIV Care & Treatment Card (2)
Front page:
Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. Geneva.
World Health Organization; 2017

52. HIV Care & Treatment Card (3)
Encounter page:

53. ART Register

54. Enter the above codes highlighted in red
for reasons for substitution in the columns
highlighted blue using the code 1 for
toxicity.
Record the corresponding code for treatment
limiting toxicity (codes highlighted in green)
beside it e.g. for GI related adverse drug
reactions the code 1 would be recorded

55. ARV Toxicity Prevalence
Indicator

56. Key ARV toxicity prevalence indicator
• Included in the minimum dataset for HIV patient monitoring
in 2017 WHO patient monitoring guidelines
• Recommended this indicator is captured via electronic
systems using electronic medical records

57. Indicator instructions (1)
Indicator code and
name
ART.12 Toxicity prevalence
Indicator definition Percentage of ART patients with treatment-limiting toxicity
Overview - This indicator measures the impact of toxicities on
treatment outcomes.
- ARV-associated toxicities are among the most common
reason reported for poor adherence to ART, treatment
discontinuation or substitution of drugs.
- Routine monitoring will provide data on prevalence and
clinical significance of serious toxicities, and their impact
on patient outcomes and attrition. It is a new indicator
designated for national programme monitoring in the
WHO 2015 consolidated SI guidelines
Priority level National, subnational, facility
Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO,
Geneva 2017.

58. Indicator instructions (2)
Numerator Definition: number of people living with HIV and on ART
within the past 12 months who substituted a regimen or
interrupted/discontinued treatment due to toxicity
Data source: HIV patient card, ART register
Data elements: ART start date, ART follow-up status, ARV
regimen, date substituted (within first-, second-, third-line
regimen), reason substituted, toxicity/serious drug reaction,
ART no. missed doses, reason for poor adherence
Denominator Definition: ART 3. Numerator: number of people living with
HIV who are currently receiving ART [at the end of the
reporting period]
Data source: ART register
Data elements: ART follow-up status
Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO,
Geneva 2017.

59. Indicator instructions (3)
Data collection
methodology
Denominator: this is the numerator for ART.3 ART coverage1.
Numerator: for all patients identified in the denominator, in the ART
register, look at the last columns on the first page labelled
“substitutions” within first-, second- and third-line regimens. Count
patients if they have substituted within any regimen during the
reporting period (see date), and the reason is “toxicity/serious drug
reactions” (code=1). Similarly, go through the relevant follow-up
months of the ART register (note: months columns will be different
for every cohort; e.g. it could be Months 0–11 for ART cohort
starting January 2015 or Months 11–22 for ART cohort starting
January 2014) and count all patients who have a treatment
interruption (no ARV regimen code recorded). For these patients,
pull out their HIV patient cards and find out the reason for their poor
adherence (ART no. missed doses/why column). Count those with
reason “toxicity/side-effects” (code=1) recorded.
1. For full indicator definition see page 165 of consolidated guidelines on person-centered HIV patient monitoring and
case surveillance. Geneva: World Health Organization; 2017.
http://apps.who.int/iris/bitstream/10665/255702/1/9789241512633-eng.pdf?ua=1,

60. Indicator instructions (4)
Frequency This indicator is best tallied at the end of the year when
tallying ART.3 ART coverage
Disaggregation For each patient, note the sex, age, current TB treatment on
page 1 of the ART register. Also note the ARV regimen
(code) the patient was on when experiencing the toxicity-
related drug substitution and the associated toxicity
category or categories recorded.
• Sex
• Age (less than 15 years old or 15 years and above)
• TB/HIV coinfection
• ARV regimen
• Toxicity categories from minimum dataset
Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO,
Geneva 2017.

61. Factors that support routine toxicity monitoring
of new ARVs
 Updating national patient monitoring system in
adopter countries
 Introducing new indicator on Toxicity prevalence -
% of ART patients with treatment-limiting toxicity
 Introducing electronic medical records to support
reporting
 Updating for adult and children ART patient cards,
ART registers and HIV card
 Using new coding for major toxicities and
treatment substitution/interruption due to
toxicities
 Tools are available in 2017 Guidelines Person-
centred HIV patient monitoring and case
surveillance + web annexes
http://www.who.int/hiv/pub/guid
elines/person-centred-hiv-
monitoring-guidelines/en/

62. 2. Active Toxicity Monitoring
 Provides additional approach to reporting & quantifying the
frequency & seriousness of expected & unanticipated adverse
drug reactions while maintaining simplicity of use, low cost and
linkage to existing M&E and pharmacovigilance systems
Data element Routine toxicity monitoring Active toxicity monitoring
Management ADR Partially
(drug substitutions due to
toxicity captured)
✔
Seriousness of ADR X ✔
Outcome of ADR
(resolved, requires or
prolongs hospitalization,
disability, death etc.)
X ✔

63. Methodology
 Active toxicity monitoring of new ARVs based on consideration of
the following:
• Leveraging existing M&E and pharmacovigilance structures
• Sustainability
• Stakeholder engagement
• Willingness and capacity of ART sites & health care workers to report
& implement
Approach brings cost efficiencies, improved documentation of
clinical practices and integration within the ART programme
Feasible, affordable and sustainable within settings with
limited financial and human resources
Active toxicity monitoring implemented in select number of ART sites

64. ART Site Selection Criteria
Key criteria for site selection:
→ Number of individuals initiating DTG/new ARV drugs: ART sites with the
largest no. of people initiating or transitioning to DTG or other new ARV drugs
→ Availability of electronic medical records: to support data capture and
reporting
→ Human resource capacity: availability, willingness, commitment and capacity
of health care workers to identify, capture and report treatment limiting toxicities
associated with new ARVs
Additional criteria that can be considered for site selection:
→ Laboratory monitoring: for detection, identification and confirmation of
adverse drug reactions as well as assessment of treatment efficacy
→ Data management and record keeping: availability of unique identifiers,
linkage to pharmacy database, longitudinal patient data including medication,
clinical and adverse drug reaction data
→ Outcome ascertainment and follow-up: Follow up of individuals receiving
new ARVs including key populations, pregnant women and children. Ability to
document outcomes important as patients lost to follow up are a source of
selection and ascertainment bias in the evaluation of ADRs related to new
ARVs

65. Data collection
 WHO has developed a generic adverse drug
reaction reporting tool for DTG to enable
standardised reporting of toxicities, drug-drug
interactions and comorbidities that countries can
use
 By focusing on a specific drug and particular ADRs
of interest reporting is kept simple & feasible
without comprising quality
 Going forward additional tools will be produced
for other new ARVs and available for country use
and adaptation
Health care workers managing individuals initiating new ARVs
should be required as well as sensitized and trained to report on
treatment limiting toxicities

66. DTG ADR
Reporting
Form
Section 1: captures
demographic data,
clinical status &
details of indication of
DTG use, TB and
pregnancy status at
onset of ADR

67. Section 1
cont:
Captures existing
comorbidities,
complimentary
laboratory results,
details of ARVs &
concomitant drugs &
medicines at time of
ADR onset

68. Collects information
on ADRs focusing on
CNS ADRs as most
commonly reported
ADRs associated with
DTG.
Section 2
Seriousness,
management &
outcome of ADRs
are also reported in
this section

69. DTG ADR Reporting Form- Section 2 cont.

70. DTG ADR Reporting Form
Section 3: captures key information about the health care worker that
completed the form to facilitate data quality review and enable data issues to be
followed up and addressed.
Instructions provided on
frequency of reporting,
date of submission of
completed forms & key
contact person the form
should be returned to.

71. DTG ADR Reporting Form – Definitions
A serious ADR is an adverse reaction that can cause one of the
following consequences:
 limiting treatment
 death
 life threatening
 requires or prolongs hospitalization
 disability or permanent damage
 congenital anomaly/birth defect
A case that leads to treatment interruption or requires changing
drug or regimen because of an adverse drug reaction is also
considered a serious adverse drug reaction.

72. DTG ADR Reporting Form – Definitions
Definition of immune reconstitution inflammatory syndrome
 Immune reconstitution inflammatory syndrome describes a collection of infectious or
inflammatory conditions associated with paradoxical clinical worsening of pre-existing
infectious processes caused by the host’s regained capacity to mount an inflammatory
response after people living with HIV initiate antiretroviral therapy (ART).
 It usually occurs in the first two months after starting ART among people living with
HIV with severe immunodeficiency and quick immune recovery (rapid increase in CD4
counts and viral load suppression). Immune reconstitution inflammatory syndrome
can present clinically in two types.
 The first is called unmasked immune reconstitution inflammatory syndrome because
of occult and subclinical opportunistic infection and a generally detectable pathogen.
 The second is called paradoxical immune reconstitution inflammatory syndrome and
is characterized by recrudescence or relapse of infection successfully treated
previously and marked antigen-induced immune activation with no or few detectable
pathogens.

73. Data collection & reporting process

74. Data management and analysis
 Data on ADRs related to the use of new ARVs, collected at
the facility level onto a paper form should be entered in a
specifically designed electronic database in order to
facilitate data analysis.
 WHO has developed a data dictionary matched to the
generic DTG ADR reporting form and is developing a simple
data entry interface programme countries can utilise to
securely enter and manage the data they collect on DTG
treatment limiting toxicities
 Going forward this will be expanded to incorporate other
new ARV drugs and made available to countries.

75. Data quality review and control (1)
• Personnel involved in data collection & collation should have these functions
included in their ToR & be allocated time to complete these activities.
• Data flow chart describing how & when different information is collected &
reported, people responsible, formats used, & timing of each step provides
clarity to the data collection process.
• Personnel involved in data collection, including supervisors, should receive
instructions & training & be evaluated in using the formats & record keeping.
• Supervisors should regularly review the ADR reporting forms to ensure that
they are correctly & completely filled out.
• Quality assurance & use of toxicity monitoring data should be included as
part of routine supervisory assessments & as an aspect of service quality at
the ART site.

76. Data quality review and control (2)
• Whenever possible, ADRs related to new ARVs should be
recorded at the time of the patient encounter rather than recorded
later from memory.
• Electronic medical records & database should be used to capture
& manage data.
• The ADR reporting forms should be archived systematically to
allow for verification or record review to confirm aggregated
results, as needed.
• ARV toxicity data have inherent value & should be available for
use & analysis locally (e.g. at site level) to improve the
management of ADRs instead of being reported up for higher level
or central level use only.

77. Data dissemination and use (1)
 Site-level data should be forwarded to the national
level (ART programme/PV unit, MoH) and
aggregated, de-identified and analysed with reports
generated on a regular basis (e.g. quarterly) and
disseminated
 Data should be fedback to ART sites to guide and
provide information on the management of ADRs
related to new ARVs to improve patient outcomes.
 If issues where ADRs could have been prevented
are identified non punitive feedback should be
provided to the ART site and care giver

78. Data dissemination and use (2)
 Communication between reporting levels should be
bi-directional; just as systems for reporting data to
higher reporting levels are established, so should
feedback and data analysis flow regularly back
down
 In order for data on the toxicity of new ARV drugs to
be used effectively it needs to be available in real
time when decisions are made

79. Stakeholder engagement (1)
Stakeholder Role and responsibility
ART site
Health care workers
(Completion &
submission of data
forms)
 Overall responsibility for monitoring ADRs related to new
ARVs and timely documentation using standardised data
reporting forms and submission
Required elements:
 Standardized ADR reporting forms available
 Training and feedback to health care workers on
management of ADRs and reporting
Data entry
clerk/operator
(Input of data)
 Enter and submit data from paper data collection forms into
the electronic database and ensure data security
Required elements:
 Standardised data entry interface programme
 Training, supervision and feedback on data quality

80. Stakeholder engagement (2)
Stakeholder Role and responsibility
National ART Programme, MOH
M&E focal point
(Data analysis &
dissemination)
 Review data reports on ADRs of new ARVs and risk factors and asses and
support data quality
 Aggregate data and generate regular quarterly/annual reports
 Disseminate and feedback information to relevant stakeholders including
reporting ART sites
Required elements:
 National database with data aggregation and report generation features
 Training
 Standard operating procedures for data quality assurance
ART programme manager
(Data use)
 Review reports of ADRs related to new ARVs
 Develop recommendations to address findings and toxicity issues identified by
toxicity monitoring of new ARVs
 Promote the dissemination and communication of priority public health
recommendations including changes to the ART programme emerging from the
toxicity monitoring data as required
Required elements:
 Timely reports summarising available data on new ARV related ADRs and
risk factors
 Effective communication channels

81. Stakeholder engagement (3)
Stakeholder Role and responsibility
Other stakeholders
Partners
(Technical & financial
support)
 Provide technical and financial assistance to
support countries with the implementation of
toxicity monitoring of new ARVs
WHO
(Coordination and
technical support)
 Provide normative guidance, tools, training
materials and technical support to key countries
 Convene partners to support implementation of
active toxicity monitoring

82. WHO technical support for active toxicity monitoring and safe
introduction of DTG and other new ARVs
2. Strengthening routine toxicity
monitoring via HIV patient
monitoring system
1. WHO ARV toxicity
monitoring
implementation tool and
training materials
Global ARV toxicity database
Surveillance of drug safety in pregnancy
General
population inc.
children
Pregnant women
Pregnancy & birth defect
registry

83. 83
Contacts and resources
1. 2017 WHO Technical update: Transition to new antiretroviral drugs in HIV
programmes: clinical and programmatic considerations
http://www.who.int/hiv/pub/toolkits/transition-to-new-arv-technical-
update/en/
2. 2017 WHO Consolidated guidelines on person centred HIV patient
monitoring and case surveillance:
http://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-
guidelines/en/
3. 2015 WHO consolidated HIV strategic information guidelines:
http://www.who.int/hiv/pub/guidelines/strategic-information-
guidelines/en/
4. May 2018 WHO statement on DTG:
http://www.who.int/medicines/publications/drugalerts/Statement_on_DT
G_18May_2018final.pdf?ua=1
Contact HIV/SIP team: Françoise Renaud renaudf@who.int
Contact HIV/SIP: Hiwot Haile-Selassie haileselassieh@who.int