Rational Drug Use

Rational Drug Use Prescribing, Dispensing, Counseling and Adherence in ART Programs Supported by USAID

Case Study A 26 yr old female has been on HAART for the past 12 months, with no adherence problems. She comes for her repeat Rx at the pharmacy and when you check the patient records you discover that she is 1 week early for her refill. Further checking reveals that she also collected 1 week early previous month and that her CD4 count has dropped for first time since she started HAART. • What could be the possible causes? • What action would you take at this point?

Pharmaceutical Management Cycle

Objectives • Define Rational Drug Use (RDU) and describe specific relevance to ART programs • Describe the different types of irrational drug use • Identify factors that influence use of ARVs • Discuss strategies and interventions that can improve RDU in ART programs

Definition The rational use of drugs requires that: • 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 • ART is: • Complex (a combination of many drugs) • a life treatment • Recent and in constant development • An irrational drug use of ARVs results in the following: • 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 Patient & community Drug Supply System

Drug Use Process

Diagnosis: Aspects that lead to Irrational Drug Use • Inadequate examination of patient • Incomplete communication between patient and doctor • Lack of documented medical history • Inadequate laboratory Resources

Prescription: Types of Irrational Drug Use (1) Source: Adapted from report by Working Party 1975, Council of Europe, Drug Intel. Clin. Pharm., 10: 94-110, 1976.

Dispensing: Types of Irrational Drug Use • Incorrect interpretation of the prescription • Retrieval of wrong ingredients • Inaccurate counting, compounding, or pouring • Inadequate labeling • Unsanitary procedures • Packaging: • Poor-quality packaging materials • Odd package size, which may require repackaging • Unappealing package

ART Dispensing – Differences? • Why is dispensing key for the success of ART programs? • Are there significant differences between dispensing ARTs and other medicines?

ART Dispensing – Differences? • 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.

Adherence to HAART • 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: • 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 • 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 • Compliance: the act of yielding conforming, or acquiescing • Lack of sharing in the decision made between provider and client

Adherence Viral load<400 >95% 81% 90-95% 64% 80-90% 25% <70% 6% How Much Adherence is Required for Optimal Results of HAART? Paterson D.L et al 2000. ann. Int. medicine

Consequences of Poor Adherence • For the individual: • 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 • From a public Health perspective: • Transmission of resistant virus (subsequent HAART failure) • From a health economics perspective: • Negative impact on the established cost-benefit of HAART – higher cost to the individual and ART program

MISSED DOSES Adherence: Why do Patients Miss Doses? (Barriers to adherence 1) DID NOT UNDERSTAND INSTRUCTIONS FORGOT/ BUSY AWAY FROM HOME FAMILY SAID NO TO MEDICATION TAKING PILL HOLIDAYS UNABLE to CARE FOR SELF RAN OUT OF PILLS SLEPT IN FEAR SIDE EFFECTS DID NOT WANT OTHERS TO SEE FELT ILL • 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 FELT BETTER PILLS DO NOT HELP

Other Barriers to adherence • Communication difficulties • Literacy levels • Inadequate knowledge of HIV disease • Inadequate understanding of effectiveness of medications • Lack of social support • Discomfort with disclosure of HIV status • Difficult life conditions • Alcohol and drug use • Depression and other psychiatric problems • System barriers

Adherence Nurse Adherence Message for the patient Doctors Pharmacist Counselor Social Worker Family/ Friends Adherence Multi-disciplinary Roles • Same message from all! Adherence to Antiretroviral Therapy in Adults: A guide for Trainers. Horizon/Population Council

Methods and Challenges of Measuring Adherence (2) • 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) • Treatment adherence-support strategies • 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 • 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 Nutrition Affects 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 Nutrition Affects • ART Affects Nutrition • Drugs can decrease appetite (decrease food intake) • (AZT can cause nausea, GI disturbances may lead to reduced food intake) • Drugs can cause metabolic changes • 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 • 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

Nutrition and ARVs • 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 PregnancySource: WHO • 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 • 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 • Control of viral replication in younger children is poor due to immature immune systems • 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 • 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 • Obstacles to testing children for HIV • Lack of expertise on paediatric ARV management, especially ‘when to start’: • Clinical staging non-specific • Prognostic tests poor in young children • Logistics of family clinic approach • ART Availability • Cost of individual drugs • Lack of appropriate paediatric formulations and Fixed Dose Combinations • Not a priority for pharmaceutical companies • Lack of advocates for children

Obstacles to HIV Testing in Children • By families and care-givers • fear, stigma, other priorities (Diagnosis of HIV in a child usually implies the mother is infected even if she is well) • By health professionals • 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 • Decision when to start ART • lack of good laboratory predictors of HIV progression in younger children • Laboratory tests for prediction scarce • Differences in disease patterns in resource-poor settings • 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 • 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 • 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 • Big Pharma: • 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) • Generic Companies: • Also need a business case • Lack of expertise and research ‘know-how’ • Pre-qualification issues • Demand Forecasting

Obstacles - Pre-Qualification • “National and or international regulatory and prequalification procedures may discourage the production of specific paediatric ART formulations” • WHO requirements • Shelf-life studies • Dissolution studies • Bio-equivalence Studies • PK studies in children

Some Barriers to Adherence in Children • 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 • Appropriate simple ART formulations and combinations relevant to resource–poor settings urgently needed • Industry interest and accelerated PK research • Integration of adult and paediatric treatment and care: FAMILY APPROACH • Applying and Scaling-up what we already know: • 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

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 Strategies to Improve Use of Drugs3 3WHO, Dept. Essential Drugs and Medicines Policy

Addressing a Drug Use Problem:ARVs at Kenyatta National Hospital (KNH) The situation: • Feb1998, KNH started free ARV treatment to staff • By June 1999, the situation was getting out of hand. • There were no clear guidelines for prescribing and dispensing the ARVs. • There were no proper records. • The buying and supply of ARV was erratic. • A number of prescriptions were not genuine. • There was no follow up on the genuine patients Promoting Rational Use of ARVs at Kenyatta National Hospital, Kenya. Elizabeth Ogile, BPharm Pg Cert EDM & RDU MPSK

Addressing a Drug Use Problem: ARVs at Kenyatta National Hospital (KNH) 2 Actions: • Medical Advisory Committee implemented the following actions: • Only 3 specialists to prescribe ARVs • Prescriptions countersigned by Head of Clinical Services for verification • Dispensing was centralized to one pharmacy. • Only recommended combinations dispensed (guidelines developed) • Computerized record keeping in pharmacy • ARV monitoring form was introduced in March 2001.

Rational Drug Use