Initiation and Monitoring of Therapy

1. Initiation and Monitoring of Therapy Unit 8HIV Care and ART: A Course for Physicians

2. Learning Objectives • Define HAART and identify goals of Antiretroviral Therapy (ART) • Describe the preparation and indications for initiation of ART • Describe the first line ART regimens in Ethiopia • Identify the goals and ways of monitoring ART • Explain IRIS and its implications during monitoring

3. History of ART • In 1986 AZT was discovered as the first ARV drug • Reduced viral replication • Effect short lived due to the rapid development of resistance • Dual therapy showed better results than monotherapy • Effect still limited by resistance • In 1996, HAART was introduced • Sustained clinical and virological response seen

4. What is HAART? • HAART stands for Highly Active Anti Retroviral Therapy • Similar to ART (can be used interchangeably) • A combination of at least three effective ARV drugs • Controls HIV replication with reduced risk of resistance development • However, it does not eliminate the virus from the body. It is not a cure

5. Goals of HAART- Primary • Reduce HIV RNA (viral load) to undetectable levels within 4-6 months of ART initiation with durable suppression • Increase CD4 cell count, allowing preservation or improvement of immune function • Reduce HIV related morbidity thereby improving quality of life of the patient • Reduce HIV related mortality

6. Goals of HAART- Secondary • Reduction of the incidence of HIV by: • Increasing uptake of HCT • Prevention of mother to child transmission • Reducing stigma and discrimination through raising community’s hope • Reducing transmission of HIV at the community level

7. What Factors Determine the Success of HAART? • ADHERENCE! • Appropriate preparation for initiation • Use of effective first line regimen • Proper monitoring for side effects and disease progression

8. Introductory Case: Meseret • Meseret, a 25-year-old female, came to the ART clinic after she was referred from the VCT center • She decided to be tested for HIV because she observed significant but unintentional weight loss in the last 2 months • Her boyfriend recently died from chronic couch and marked weight loss and she believes he had underlying HIV infection • She was told that she is HIV positive 3 days ago • What should be done to prepare Meseret for HAART initiation?

9. Preparation for HAART Initiation • Baseline clinical and lab evaluation • Identify and treat OIs • Assess for the presence of indications for ART • Clinical staging • CD4 values • Assess patient readiness • Acceptance of HIV status and benefits of ART • Psychological, financial, socio-cultural issues • Strong adherence counseling • Prepare patient follow-up for after initiation of ART

10. Initial Evaluation for Initiation of ART

11. Introductory Case: Meseret (2) • What should be done in the baseline assessment to evaluate Meseret?

12. The Baseline Assessment • Baseline health history • Physical examination • Clinical staging • Laboratory testing

13. Baseline Health History • Current symptoms • Usual source and pattern of seeking care • Psychiatric or emotional disorders • Surgical history • Date • Recovery status • Review of systems • Past medical illness

14. Baseline Health History (2) • Childhood Illnesses • Varicella • Immunizations • Family Medical History • Medical conditions • Mental health • Sexually Transmitted Infections (STI) • Treatment and follow-up

15. Baseline Health History (3) • Gynecologic and Obstetrical History • Menstrual history • Pregnancy history • Methods of birth control • PMTCT history • Children’s HIV Status

16. Baseline Health History (4) • Medication History • Previous/current medications including HAART • Drug allergy • Adherence history • Assess adherence to care and medications • Assess family/household support • Nutritional History • Access to food • Social history • Patient beliefs and misconceptions

17. Baseline Physical Exam • Do complete physical examination • Special attention to: • Weight • Height (head circumference in children) • Oral cavity • Lymph nodes • Lungs and CVS • Skin: full exam including rectogenital region • Liver and spleen size • For women, pelvic exam and pregnancy status • Funduscopic and neurological evaluation

18. Introductory Case: Meseret (3) • When asked her health history, Meseret reports: • No complaints other than weight loss • Treated for pulmonary TB one year ago • No history of STI • On examination, Meseret looks thin with silky hair. • Weight 42 kg (50 kg 6 months back) • No oral thrush • No other remarkable finding

19. Introductory Case: Meseret (4) • Is Meseret eligible for ART? • What baseline lab tests would you request for Meseret?

20. Baseline Laboratory Testing • HIV antibody test • Hemoglobin or hematocrit and WBC with differential count • Serum ALT or AST, bilirubin • Serum creatinine & BUN • CD4 lymphocyte count • Pregnancy test (women) • Other tests are indicated when appropriate based on patient current and past medical history e.g. CXR, sonography etc

21. Baseline Laboratory Testing (2) • Other tests: • Serum glucose • Amylase • Serum lipids • Viral load testing

22. When to Start ART • Starting Antiretroviral Drugs is NOT AN EMERGENCY! • Criteria for initiation must be met • At least two visits are necessary before initiation to ensure patient readiness

23. Indications for ART • Based on ‘Guidelines for Use of Antiretroviral Drugs in Ethiopia,’ January 2005. • Adapted from the revised WHO guidelines • Can be used in the presence or absence of CD4 values • Uses WHO clinical staging, CD4 count and TLC as appropriate • Designed for: • Physicians and other health-care providers • HIV/AIDS program managers, health planners, and experts working on drug selection and procurement

24. Objectives of the Guidelines • Ensure evidence-based, safe, and rational use of antiretroviral drugs • Provide standardized approach to the use of ARV drugs in the comprehensive HIV/AIDS care in Ethiopia • Serve as a reference resource to health care providers and people living with HIV/AIDS

25. Clinical Criteria for ART Initiation for Adults • If CD4 count available: • WHO stage IV irrespective of CD4 • WHO stage III with CD4 ≤ 350/mm3 • CD4 < 200/mm3 irrespective of the clinical stage • If CD4 count not available: • WHO stage IV irrespective of TLC • WHO stage III irrespective of TLC • WHO stage II with TLC < 1200/ mm3

26. Introductory Case: Meseret (5) • The following lab tests were obtained for Meseret: • Hct: 36% • WBC: 4000/mm3 ; L- 20% • BUN, creatinine and ALT – within normal limits • Urine pregnancy test—negative • CD4- specimen to be sent to regional lab (result expected in 2 weeks) • Is she eligible for ART?

27. Introductory Case: Meseret (6) • Meseret was counseled by the ART nurse about: • Living positively with the virus • Availability of treatment free of charge • Need for 100% adherence • Started with cotrimoxazole 960mg daily • Made appointment to return in two weeks

28. Ethiopian First-Line Regimens

29. Special Considerations in Selecting Regimens • If there is potential for pregnancy, avoid EFV due to teratogenicity • If patient is taking Rifampicin, use EFV instead of NVP • If patient has anemia, use d4T instead of ZDV • Avoid the following in HAART combinations: • d4T+ ZDV due to pharmacodynamic antagonism • d4T+ ddI in pregnancy due to greatly increased risk of lactic acidosis

30. Introductory Case: Meseret (7) • Meseret returned in 2 weeks with enthusiasm to start ART • CD4 = 150/mm3 • What drugs would you start her with?

31. Key Points on Starting ART • Not an emergency • Has to be individualized • Ensure fulfillment of eligibility criteria before initiating • Medical • Emotional • Social • Follow-up • Access to ARVs ensured

32. Monitoring Therapy

33. Goals of Monitoring ART • Detect drug toxicity, interactions and side effects • Evaluate initial response to therapy • Assess adherence • Recognize treatment failure as early as possible

34. Types of Monitoring • Clinical assessment • Laboratory monitoring

35. Clinical Assessment • Conduct physical examination and symptom review at each visit • Compare current status to baseline

36. Clinical Assessment (2) • History • Drug side effects: nausea, vomiting, jaundice, RUQ pain, bad dreams, etc • Symptoms of OIs such as cough, fever, severe headache, etc • Adherence to medications • Physical exam • Take weight at each visit • Look for signs of drug side effects and OIs

37. Laboratory Monitoring • Should be done on regular basis according to Ethiopian Guidelines, and as needed for specific clinical conditions • Detects side effects (toxicity) of drugs before clinical symptoms and signs appear • Used for early detection of response to therapy

38. Laboratory Tests for Toxicity Monitoring • Hgb/Hct • WBC and differential, platelet count • ALT, AST • Other tests • Lipid profile for PI or EFV containing regimens • Blood sugar for PI containing regimens • Creatinine for IDV containing regimens

39. Laboratory Tests for Monitoring Response to Therapy • CD4 testing • Used to monitor immunological response • With successful therapy, it is expected to rise about 50-100/mm3 per year • Viral load testing • Should be done at baseline, three months after initiation to detect early treatment success, and at 6 months to see if viral load is detectable • Successful treatment decreases viral load by at least 1 log at 6-8 weeks and to undetectable levels by 24 weeks

40. Recovery of CD4 Cells Continues for Years after Starting HAART Source: Binquet C, et al. Am J Epidem, 2000.

41. Ethiopian Guidelines for Lab Monitoring

42. Introductory Case: Meseret (8) • Meseret was started on ART after intensive adherence counseling: • Stavudine 30mg BID • Lamivudine 150mg BID • Nevirapine 200mg daily • When should her next appointment be? • What would you do at the time of her next visit?

43. Introductory Case: Meseret (9) • Next visit after 2 weeks • Her evaluation includes: • Symptoms of drug side effects like skin rash and itching, jaundice • Assessment of adherence • Any other new symptom • Look for icterus, skin rash; measure her weight • Do ALT

44. Introductory Case: Meseret (10) • At her two week visit you find: • No complaints except mild itching over the trunk without rash • No jaundice • Good adherence • The dose of NVP increased to 200mg BID

45. Introductory Case: Meseret (11) • At her third post-ART visit (2 months after initiation of ART), she reported a cough of 2 weeks duration • Has associated scanty sputum and low grade fever • Chest is clear • List the differential diagnosis for her current symptoms

46. Introductory Case: Meseret (12) • Differential diagnosis • Pulmonary TB • Upper respiratory tract infection • Pneumonia (PCP, bacterial, fungal)

47. Introductory Case: Meseret (13) • Investigations revealed: • WBC= 5000/mm3; L= 25% • Sputum for AFB negative • CXR showed bilateral lower lung nodular infiltrates with left sided pleural effusion • Pleural fluid analysis revealed lymphocytic & exudative fluid

48. Introductory Case: Meseret (14) • Presumptive diagnosis of Tuberculosis was made. • What went wrong with Meseret?

49. Immune Reconstitution Inflammatory Syndrome (IRIS) • IRIS is the occurrence of an inflammatory condition (OI) a few weeks to 6 months after the initiation of ART due to restoration of immune status • It may manifest as: • A new OI occurring for the first time • Reappearance of a previously treated OI • Flare up of an existing viral infection like viral hepatitis or herpes simplex

50. IRIS (2) • Mechanism: • When effective ART regimen is given, the CD4 cells increase in number rapidly • A previously sub-clinical infection would trigger an inflammatory response and tissue damage • The quiescent infection will become a clinically apparent disease