Rational Drug Use
Prescribing, Dispensing,
Counseling and Adherence
in ART Programs
Supported by USAID
Pharmaceutical Management Cycle
Selection
Use
Management
Support
Procurement
Distribution
Policy, Regulations, Laws
Definition of RDU
The rational use of drugs requires that:
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patients receive medications appropriate to their
clinical needs,
in doses that meet their own individual
requirements
for an adequate period of time, and
at the lowest cost to them and their community.
WHO conference of experts, Nairobi 1985
Importance of RDU in the context
of ART
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ART is:
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Complex (a combination of many drugs)
a life treatment
Recent and in constant development
An irrational drug use of ARVs results in the following:
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Treatment failure
Rapid development of drug resistance
Increase of toxicity risk
Wastage of money
The promotion of RDU in the context of ART is a must from day
one!
Many Factors Influence Use of
Medicines
Policy, Legal and Regulatory
framework
Prescriber,
Dispenser &
their
workplaces
Rational
Drug Use
Drug Supply System
Patient &
community
Diagnosis: Aspects that lead to
Irrational Drug Use
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Inadequate examination of patient
Incomplete communication between patient and
doctor
Lack of documented medical history
Inadequate laboratory Resources
Prescription:Types of Irrational Drug
Use
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Under-prescribing
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Incorrect prescribing
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Extravagant prescribing
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Over-prescribing
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Multiple prescribing
Dispensing:Types of Irrational Drug
Use
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Incorrect interpretation of the prescription
Retrieval of wrong ingredients
Inaccurate counting, compounding, or pouring
Inadequate labeling
Unsanitary procedures
Packaging:
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Poor-quality packaging materials
Odd package size, which may require repackaging
Unappealing package
ART Dispensing – Differences?
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Why is dispensing key for the success of ART
programs?
Are there significant differences between dispensing
ARTs and other medicines?
ART Dispensing – Differences?
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A stock-out of one ARV in regimen result in the
cessation of therapy until the drug is available again
Time of taking medicines more important than for
many other medicines
Date of collection of medicines more important –
reflects on adherence
Accurate and complete record keeping is vital
Regimens more complex so knowledge of treatment
guidelines more important.
ART Dispensing needs clear
Dispensing Guidelines
ARV Dispensing – Clear Patient
Presentations
ARV Dispensing Clear Patient
Instructions
Adherence to HAART
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Goal of HAART (Highly Active Antiretroviral
Therapy) is to suppress viral load in the blood to
undetectable levels
Adherence to treatment is critical to obtain full
benefits of HAART:
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maximal and durable suppression of viral replication,
reduced destruction of CD4 cells,
prevention of viral resistance,
promotion of immune reconstitution
slowed disease progression.
Adherence vs Compliance
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Adherence: The act or quality of sticking to
something; steady devotion; the act of adhering
 The
acceptance of an active role in ones health
care
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Compliance: the act of yielding conforming, or
acquiescing
 Lack
of sharing in the decision made between
provider and client
How Much Adherence is Required for
Optimal Results of HAART?
Adherence
>95%
Viral load<400
81%
90-95%
64%
80-90%
25%
<70%
6%
Paterson D.L et al 2000. ann. Int. medicine
Consequences of Poor Adherence
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For the individual:
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From a public Health perspective:
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Treatment failure: incomplete viral suppression, continued
destruction of the immune system, disease progression
Drug resistance: emergency of resistant viral strains
Limited future treatment options: more complex treatment,
more toxicity, uncertain prognosis
Transmission of resistant virus (subsequent HAART failure)
From a health economics perspective:
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Negative impact on the established cost-benefit of HAART –
higher cost to the individual and ART program
Adherence: Why do Patients Miss Doses?
(Barriers to adherence 1)
DID NOT
FORGOT
FAMILY SAID
NO TO
MEDICATION
AWAY
FROM
HOME
TAKING
PILL
HOLIDAYS
UNDERSTAND
INSTRUCTION
S
UNABLE
to CARE
FOR
SELF
RAN
OUT
OF
PILLS
DID NOT
WANT
OTHERS
TO SEE
/ BUSY
SLEPT
IN
FEAR
SIDE
EFFECTS
FELT
ILL
PILLS
DO NOT
HELP
FELT
BETTER
MISSED
Let’s find together a solution for
your problem
• I am listening
• You can trust me
• I understand
• I suggest…
• What do you think?
• I’ll explain to you how to take these
medicines
Other Barriers to adherence
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Communication difficulties
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Discomfort with disclosure
of HIV status
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Literacy levels
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Inadequate knowledge of
HIV disease
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Difficult life conditions
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Alcohol and drug use
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Inadequate understanding of
effectiveness of medications
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Depression and other
psychiatric problems
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Lack of social support
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System barriers
Adherence Multi-disciplinary Roles
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Same message from all!
Doctors
Pharmacist
Adherence
Message for the
patient
Family/
Friends
Adherence
Nurse
Counselor
Social Worker
Adherence to Antiretroviral Therapy in Adults: A guide for Trainers. Horizon/Population Council
Methods and Challenges of Measuring
Adherence (2)
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Self reports
Pill counts
Pharmacy records
Provider estimate
Pill identification test
Biological markers
Electronic devices
Measuring drug levels
Strategies and Tools to Enhance
Adherence (1)
Pre-treatment strategies
• Identification of potential non-adherent and address
the barriers to adherence before first ARV prescription
• Identification of adherence partners/buddy’s (Peer,
friend, family)
• Identification of reminders/tools to help taking pills
Strategies and Tools to Enhance
Adherence (2)
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Treatment adherence-support strategies
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Generation of daily-due review/refill list and ‘flag’ absent
patients
Referral to community-based Healthcare workers and
NGO’s
Use of Directly Administered Antiretroviral Therapy, DAART
Use of incentives and enablers
Recap on Adherence
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A perfect adherence to ART is a must
The consequences of poor adherence are poor health
outcomes and increased health care costs
Adherence is a dynamic process that needs to be
followed up
Patient-tailored interventions are required
Family/friends, community: key factor in improving
adherence
Multidisciplinary approach towards adherence is
needed
Nutrition and ART
HIV
Affects
Nutrition
HIV Affects Nutrition:
• Metabolic changes and wasting
• Reduced food consumption
• Nutrient malabsorption
Nutrition Affects HIV:
• Poor nutrition reduces ability to fight HIV and O.I.s
• Nutritional problems can affect drug compliance
ART
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Nutrition
ART Affects Nutrition
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Drugs can decrease appetite (decrease food intake)
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(AZT can cause nausea, GI disturbances may lead to reduced food intake)
Drugs can cause metabolic changes
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Affects
Indinavir (can raise blood sugar) LPV/RTV (can worsen high triglycerides or
cholesterol levels
Drugs can cause vitamin disturbances (INH depletes Vit. B6)
Nutrition Affects ART
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Food can hinder or help drug absorption
Certain minerals can hinder drug absorption
Certain vitamins can help minimize drug side effects
Alcohol can exacerbate side effects of drugs
Nutrition and ARVs
ARV
Food Effect
Oral Bioavailability
Nevirapine
No effect
> 90%
Efavirenz
Absorption of tabs increased 79% with tabs and
51% with caps with high fat meal. (Avoid high fat
meal)
42%
60%
AZT, ZDV
None ( May be better tolerated with food. Fatty
food may decrease bioavailability (AIDS
1990;4;229)
d4T Stavudine
3TC Lamivudine
None
None
86%
86%
ddI
Levels less than 19% with food (take two hours
before and two hours after meals.)
30-40%
Nutrition and ARVs
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DdI’s absorption reduced by ~55% with food
Indinivair’s absorption is reduced 84% with food.
Food may increase the absorption of Saquinavir by 200%.
Grapefruit juice, increase absorption of Saquinavir by 40-100% (
inhibition of enzyme CYP3A4, which is responsible for its
metabolism).
Taking indinavir with a high fat meal reduces its absorption by
about 77%.
Indinavir taken in combination with ritonavir, food has no effect
on the absorption of indinavir and it may be taken irrespective of
meals.
ARV Therapy in Pregnancy
Source: WHO
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Eligibility criteria for starting HAART in pregnancy will
not differ from other adults
Default first-line regimen for all women will include
nevirapine. Avoid efavirenz.
All pregnant women with a CD4 <200 cells/mm3
should be started on ARVs after the first trimester
ARV Therapy in Pregnancy cont
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Pregnant women with CD4 counts between 200 and
350 CD4 cells/mm3 should be strongly considered for
initiation of HAART after the 1st trimester, with
therapy to be continued for life.
Women who become pregnant while on ARVs should
continue therapy without interruption, including during
the first trimester.
For pregnant women who test HIV-positive during
labour, single-dose nevirapine will be used for PMTCT
per guidelines.
Pediatric ART
HIV in Children & Adults is not the
same
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Control of viral replication in younger children is poor
due to immature immune systems
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Higher levels of HIV RNA reached(2mths) persist for 1yr.
Decline over next few yrs.
Infants have a substantial risk of developing AIDS even
with high CD4 values
In contrast to adults, immunologic & virologic
predictors of progression in asymptomatic HIV-infected
children and infants, are not well defined
Current surrogate markers are not specific enough to
differentiate slow progressors from rapid progressors
in childhood
Children Under-represented in ART
programs
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Of 12,000 patients on HAART in MSF Programs only
700 (6%) Children below 15 years
Mombasa RPM Plus/FHI and Horizons program (August
2004) Adults 186 Children 14 (7.5%)
Namibia (August 2004) Adults 1679 Children 166 (9%)
Haiti 7.2% used for projection.
Vietnam 5% used for projection
WHO 3x5 targets aim at 10-15% of patients on ART as
infants and Children
Clinical, Psychosocial, Programmatic
Obstacles for Paediatric ART
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Obstacles to testing children for HIV
Lack of expertise on paediatric ARV management, especially ‘when to start’:
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Clinical staging non-specific
Prognostic tests poor in young children
Logistics of family clinic approach
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ART Availability
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Cost of individual drugs
– Lack of appropriate paediatric formulations and Fixed Dose Combinations
– Not a priority for pharmaceutical companies
Lack of advocates for children
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Obstacles to HIV Testing in Children
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By families and care-givers
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By health professionals
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fear, stigma, other priorities (Diagnosis of HIV in a child usually implies the
mother is infected even if she is well)
lack expertise to recognise clinical HIV
see no benefit in testing
lack counselling expertise for families
Lack of diagnostic tests for young children under 18 months
(PCR for firm diagnosis)
Disclosure issues (older children)
Obstacles in Clinical Management
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Decision when to start ART
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Differences in disease patterns in resource-poor settings
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lack of good laboratory predictors of HIV progression in younger
children
Laboratory tests for prediction scarce
Lack of specificity of many conditions (new 4-stage WHO guide coming
up)
More overlap with commonly seen infectious diseases
Major effect of malnutrition (predicts mortality independent of
CD4 counts)
Antiretroviral Drugs for Children
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Lack of affordable and appropriate antiretroviral drugs and
formulations for Children
Lack of expertise among health workers to deliver care
As in most areas of medicine availability of treatments for
children lags behind that for adults
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Lack of incentives to manufacture pediatric formulations
Difficulties (perceived and real) in undertaking research in children
Lack of pediatric research expertise among health professionals
Practical difficulties in making and testing appropriate formulations drugs
for children
Obstacles for Pharmaceutical
Companies
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Big Pharma:
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Generic Companies:
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No financial incentives to develop Ped. Formulations (market small and
largely in developing world)
Regulatory and prequalification procedures: perceived high risk of doing
research in children discourages production of pediatric ART
Extension of patent (carrot by FDA); Big stick (failure to grant adult
licence-being proposed by EU)
Also need a business case
Lack of expertise and research ‘know-how’
Pre-qualification issues
Demand Forecasting
Obstacles - Pre-Qualification
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“National and or international regulatory and
prequalification procedures may discourage the
production of specific paediatric ART formulations”
WHO requirements
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Shelf-life studies
Dissolution studies
Bio-equivalence Studies
PK studies in children
Some Barriers to Adherence in
Children
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Lack of liquid formulations of some drugs
High volume
Poor palatability
High pill burden
Frequent daily dosing requirements
Dietary restrictions and toxicity.
Stigma issues: disclosure to family, friends, school
Adherence depends on caregivers (usually old
grandparents)
Challenges
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Appropriate simple ART formulations and combinations relevant
to resource–poor settings urgently needed
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Integration of adult and paediatric treatment and care: FAMILY
APPROACH
Applying and Scaling-up what we already know:
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Industry interest and accelerated PK research
Cotrimoxazole prophylaxis
Nutritional support
Training in paediatric and family-based care for HIV
Strengthen links between access to treatment and operational
research to answer important questions about natural history
and response to ART
Strategies to Improve Use of Drugs3
Educational:
 Inform or persuade
– Health providers
– Consumers
Managerial:
Guide clinical practice
– Information systems/STGs
– Drug supply / lab capacity
Use of
Medicines
Economic:
 Offer incentives
– Institutions
– Providers and patients
Regulatory:
 Restrict choices
– Market or practice controls
– Enforcement
3WHO, Dept. Essential
Drugs and Medicines Policy
To Achieve Optimal Treatment
Outcomes, Patients Need to:
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Understand the diagnosis and correctly assess its
potential impact
Be interested in their health and believe in the efficacy
of the prescribed treatment
Find ways of using the medication that are not more
troublesome than the disease
Changing a Drug Use Problem:
An Overview of the Process
1. EXAMINE
Measure Existing
Practices
(Descriptive
Quantitative Studies)
4. FOLLOW UP
Measure Changes
in Outcomes
(Quantitative & Qualitative
Evaluation)
improve
diagnosis
improve
intervention
3.TREAT
Design & Implement
Interventions
(Collect Data to
Measure Outcomes)
2. DIAGNOSE
Identify Specific
Problems & Causes
(In-depth Quantitative
& Qualitative Studies)
Drug Procurement and Rational Drug Use:
What is the influence of one on another?
Drug Procurement
•Drug Quality Problems
•Unreliable suppliers
•Poor forecasting/bad
quantifications
•Inefficient distribution
system
•Poor inventory
Management
•Incomplete/incorrect
patient record keeping
•Inadequate dispensing
•Bad counseling
•Irrational Prescriptions
•Incorrect Diagnosis
•Absence of Formulary
•Absence of STG
Rational Drug Use
A multi-disciplinary team work is
required to achieve Rational ARV Use !!!
Pharmacist
Counselor /
Treatment
supporter
Doctor
Community
Nurse