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

2. 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?

3. Pharmaceutical Management Cycle

4. 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

5. 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

6. 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!

7. Rational Drug Use Prescriber, Dispenser & their workplaces Drug Supply System Patient & community Many Factors Influence Use of Medicines Policy, Legal and Regulatory framework

8. Drug Use Process

9. 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

10. 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.

11. Prescription: Types of Irrational Drug Use (2) Source: Adapted from report by Working Party 1975, Council of Europe, Drug Intel. Clin. Pharm., 10: 94-110, 1976.

12. Prescription: Types of Irrational Drug Use (3) Source: Adapted from report by Working Party 1975, Council of Europe, Drug Intel. Clin. Pharm., 10: 94-110, 1976.

13. Prescription: Types of Irrational Drug Use (4) Source: Adapted from report by Working Party 1975, Council of Europe, Drug Intel. Clin. Pharm., 10: 94-110, 1976.

14. Prescription: Types of Irrational Drug Use (5) Source: Adapted from report by Working Party 1975, Council of Europe, Drug Intel. Clin. Pharm., 10: 94-110, 1976.

15. 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

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

17. 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.

18. 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.

19. 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

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

21. 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

22. SLEPT IN AWAY FROM HOME RAN OUT OF PILLS FELT ILL FELT BETTER PILLS DO NOT HELP FEAR SIDE EFFECTS DID NOT WANT OTHERS TO SEE FAMILY SAID NO TO MEDICATION FORGOT / BUSY DID NOT UNDERSTAND INSTRUCTION S MISSED DOSES TAKING PILL HOLIDAYS UNABLE to CARE FOR SELF Adherence: Why do Patients Miss Doses? ( Barriers to adherence 1 ) Lets find together a solution for your problem I am listening You can trust me I understand I suggest… What do you think? Ill explain to you how to take these medicines

23. 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

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

25. 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

26. 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/buddys (Peer, friend, family) Identification of reminders/tools to help taking pills

27. 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 NGOs – Use of Directly Administered Antiretroviral Therapy, DAART – Use of incentives and enablers

28. 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

29. Nutrition and ART

30. HIV Nutrition Nutrition Affects HIV: Poor nutrition reduces ability to fight HIV and O.I.s Nutritional problems can affect drug compliance HIV Affects Nutrition: Metabolic changes and wasting Reduced food consumption Nutrient malabsorption Affects

31. ART Nutrition 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 Affects

32. Nutrition and ARVs ARVFood EffectOral Bioavailability NevirapineNo effect> 90% EfavirenzAbsorption of tabs increased 79% with tabs and 51% with caps with high fat meal. (Avoid high fat meal) 42% AZT, ZDV None ( May be better tolerated with food. Fatty food may decrease bioavailability (AIDS 1990;4;229) 60% d4T Stavudine 3TC Lamivudine None 86% ddILevels less than 19% with food (take two hours before and two hours after meals.) 30-40%

33. Nutrition and ARVs DdIs absorption reduced by ~55% with food Indinivairs 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.

34. ARV Therapy in Pregnancy Source: 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

35. 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.

37. Pediatric ART

38. 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

39. 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

40. 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

41. 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)

42. 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)

43. 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

44. 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

45. 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

46. 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)

47. 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

48. 3 WHO, Dept. Essential Drugs and Medicines Policy Strategies to Improve Use of Drugs 3 Economic: Offer incentives –Institutions –Providers and patients Managerial: Guide clinical practice –Information systems/STGs –Drug supply / lab capacity Regulatory: Restrict choices –Market or practice controls –Enforcement Use of Medicines Educational: Inform or persuade –Health providers –Consumers

49. 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

50. 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.

51. Addressing a Drug Use Problem: ARVs at Kenyatta National Hospital (KNH) 3 Results: Reduced false prescriptions from 16% to 2% Compliance with prescription refill dates improved Easier to monitor patients and their medication, Hence strengthening the counselling of patients Lessons Learned: Difficult to control ARV use among own staff Simple regulatory measures can promote rational ARV use.

52. To Achieve Optimal Treatment Outcomes, Patients Need to: 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

53. 1. EXAMINE Measure Existing Practices (Descriptive Quantitative Studies) 2. DIAGNOSE Identify Specific Problems & Causes (In-depth Quantitative & Qualitative Studies) 3. TREAT Design & Implement Interventions (Collect Data to Measure Outcomes) 4. FOLLOW UP Measure Changes in Outcomes (Quantitative & Qualitative Evaluation) improve intervention improve diagnosis Changing a Drug Use Problem: An Overview of the Process

54. Drug Procurement Drug Procurement and Rational Drug Use: What is the influence of one on another? Rational Drug Use 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

55. A multi-disciplinary team work is required to achieve Rational ARV Use !!! Doctor Pharmacist Counselor / Treatment supporter Nurse Community