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

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

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

13. 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. 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. 15 Baseline Health History (3)  Gynecologic and Obstetrical History Menstrual history Pregnancy history Methods of birth control PMTCT history  Children’s HIV Status

16. 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. 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. 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. 19 Introductory Case: Meseret (4)  Is Meseret eligible for ART?  What baseline lab tests would you request for Meseret?

20. 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. 21 Baseline Laboratory Testing (2)  Other tests: Serum glucose Amylase Serum lipids  Viral load testing

22. 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. 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. 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. 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. 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. 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. 28 Ethiopian First-Line Regimens ARV Regimen Usage in Women (of childbearing age or pregnant) Usage in TB co- infection d4T/3TC/NVPYes Not with RIF containing regimen ZDV/3TC/NVPYes Not with RIF containing regimen d4T/3TC/EFVNo Yes ZDV/3TC/EFV Special situation ABC or TDF No Yes

29. 29 selective settings  TDF/3TC/NVP or EFV OR  ABC/3TC/NVP or EFV

30. 30 First-line ARV drugs dosage  Zidovudine (AZT) 300 mg every 12 hours  Lamivudine (3TC) 150 mg every 12 hours  Stavudine (d4T) 30 mg every 12 hours (or 40 mg every 12 hours if patient weighs >60 kg)  TDF 300 mg daily  ABC 300 mg every 12 hours  Nevirapine (NVP) 200mg daily for the first 2 weeks, followed by 200mg every 12 hours  Efavirenz 600 mg daily at night

31. 31 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

32. 32 Introductory Case: Meseret (7)  Meseret returned in 2 weeks with enthusiasm to start ART  CD4 = 150/mm3  What drugs would you start her with?

33. 33 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

34. Monitoring Therapy

35. 35 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

36. 36 Types of Monitoring  Clinical assessment  Laboratory monitoring

37. 37 Clinical Assessment  Conduct physical examination and symptom review at each visit  Compare current status to baseline

38. 38 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

39. 39 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

40. 40 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

41. 41 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

42. 42 Recovery of CD4 Cells Continues for Years after Starting HAART Source: Binquet C, et al. Am J Epidem, 2000.

43. 43 Ethiopian Guidelines for Lab Monitoring RegimenARTLab TestFrequency 1 st line Regimen d4T/3TC/NVP TLC or CD4At baseline and 6 Monthly (if available) ALTSymptom-directed AZT/3TC/NVP TLC or CD4At baseline and 6 Monthly (if available) ALTSymptom-directed HgbAt baseline, 4, 8, and 12 thereafter symptom-directed Alternative 1 st Line Regimen D4t/3TC/EFV* TLC or CD4At baseline and 6 Monthly ALTSymptom-directed Pregnancy TestBaseline, thereafter as indicated AZT/3TC/EFV* Hgb Pregnancy TestBaseline, thereafter as indicated ALTSymptom-directed TLC or CD4At baseline and 6 Monthly

44. 44 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?

45. 45 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

46. 46 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

47. 47 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

48. 48 Introductory Case: Meseret (12)  Differential diagnosis Pulmonary TB Upper respiratory tract infection Pneumonia (PCP, bacterial, fungal)

49. 49 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

50. 50 Introductory Case: Meseret (14)  Presumptive diagnosis of Tuberculosis was made.  What went wrong with Meseret?

51. 51 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

52. 52 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

53. 53 IRIS (3)  Timing: Usually occurs in patients with very low CD4 count (<50/mm3) IRIS usually occurs within 6 months after initiation of effective ART However, some episodes of IRIS have been documented up to 18 months after initiation of ART

54. 54 IRIS (4)  Clinical manifestations Fever is a prominent feature Usually the infections have atypical presentation (Mediastinal lymphadenopathy and pleural/pericardial effusion in TB)  Common infections that manifest with IRS include: Tuberculosis Cryptococcal meningitis Herpes simplex and herpes zoster CMV retinitis Viral hepatitis MAC infection

55. 55 IRIS (5)  Approach to treatment: Recognize the situation is IRIS, not treatment failure Continue ART Start treatment of the specific OI Steroids may be helpful in particularly severe cases of IRIS e.g. severe dyspnea or TBC meningitis

56. 56 IRIS (6)  Implications of IRIS on patient monitoring: IRIS may be easily confused with treatment failure Some features of IRIS may mimic drug side effect and the distinction may be difficult Viral hepatitis presenting as IRIS may be difficult to distinguish from hepatotoxicity due to ARV drugs Patients may feel that they are getting worse with ART Negative effect on adherence

57. 57 IRIS (7)  IRIS versus treatment failure IRIS usually occurs within 3-6 months IRIS occurs in the face of increasing CD4 count Viral load determination is the most reliable way of differentiating the 2 conditions

58. 58 Introductory Case: Meseret (15)  Meseret has TB presenting as IRIS Started on RHZE and pyridoxine She was continued on d4T and 3TC NVP was switched to EFV (800mg)  Showed significant improvement after 1 month of anti-TB treatment

59. Case Studies Handouts 8.2 and 8.3

60. 60 Key Points  The primary goal of ART is to reduce morbidity and mortality by controlling viral replication and improving the immune function  ART may be started after adequate preparation of the patient for ART and based on the presence of indications for treatment  Decision on when to start ART and what to start with is based on the Ethiopian guidelines

61. 61 Key Points (2)  The most important factor that determines the outcome of ART is adherence  Proper and scheduled monitoring is important to detect drug toxicity and treatment failure early  Monitoring involves clinical assessment and laboratory tests  IRIS may be easily confused with treatment failure and drug toxicity