KITSO AIDS Training Program

1. KITSO AIDS Training Program Lecture 4: Principles of ARV Therapy in the Botswana National ARV Program delivered by Dr. Ndwapi Ndwapi, BHP

2. Learning Objectives • To know the goals of ARV therapy. • To know when to start ARV therapy in Botswana. • To know which regimens to use in Botswana. • To know how to monitor ARV therapy in Botswana.

3. What is Antiretroviral Therapy? • ARTAntiretroviral Therapy • ARVAntiretroviral • HAARTHighly Active Antiretroviral Therapy

4. Goals of ARV Therapy • Clinical: Prolong life, improve quality of life, and sustain productivity. • Virologic: Achieve maximal suppression of HIV - Viral load should fall by at least 1.0 log (to at least 1/10th of baseline viral load) by 3 months. - By 6 months viral load should be less than 400. • Immunologic: Reverse immune system damage.

5. Principle 1 The most effective way to suppress HIV replication is the simultaneous initiation of combinations of at least three effective ARV drugs (HAART). The use of at least three ARV drugs for ARV treatment is mandatory under the Botswana National ARV Program.

6. Principle 2 Drugs used in ARV therapy regimens should be used according to the Botswana National ARV Guidelines in the most effective and tolerable pattern that a patient can manage. However, the Guidelines are not a substitute for good clinical decision making.

7. Principle 3 Disease progression differs among HIV-infected persons. The decision to begin treatment should be individualized and based upon three major factors: 1. The degree of HIV-related disease. 2. The degree of HIV-related immunosuppression. 3. A solid adherence plan and a working relationship with the health care system.

8. When to Initiate ARV Therapy Eligibility Criteria: • The presence of an AIDS-defining illness and/or AIDS-defining symptoms, regardless of CD4 count. • A CD4 count less than 200 cells/uL. • Any HIV+ child less than 12 months of age. • HIV+ children over 1 year old who are symptomatic or immunosuppressed. • TRY TO AVOID starting a patient on ARV drugs until acute opportunistic infections are stabilized and patient is discharged from the hospital. e.g., cryptococcal meningitis

9. When to Initiate ARV Therapy (2) • AIDS-defining symptoms and/or illnesses merit ARV therapy, regardless of CD4 count: - KS - TB - Recurrent pneumonia - Recurrent severe bacterial infections - Wasting Syndrome/Chronic fevers - Chronic diarrhea - VZV involving at least 2 distinct episodes or more than one dermatome - Peripheral neuropathy - CA of cervix - Lymphoma - Thrush

10. Before Therapy is Initiated All Patients: • Complete History and Physical, including IPT/TB history • Comprehensive Laboratories ARV-Experienced Patients: • Obtain full treatment history. - What prior regimen/s has the patient taken? - What was the duration of the therapy? - If switched, why? - How was adherence? - Obtain all possible old CD4 and VL results.

11. Longitudinal Monitoring • Monitoring Adherence • Discuss at each visit • Monitoring tolerability of ART • Direct questioning • Clinical assessment and laboratory tests • Monitoring efficacy of ART • Clinical indicators (weight) • CD4 and Viral load measurements

12. Testing Schedule (chest X-ray only if indicated) * SGOT and SGPT if on NVP

13. Full Chemistry • SGOT/AST • SGPT/ALT • Alk Phos • Creatinine • +/-T. Bili • +/- Electrolytes

14. Principle 4 ARV Therapy is a life-long commitment.

15. Clinicians must assess a patient’s understanding and readiness to make a life-long commitment to taking ARV medications before beginning treatment.

16. Principle 5 The more treatment-experienced a patient is, the less likely that subsequent ARV regimens will be effective. The best chance of success with ARV therapy is with the first regimen.

17. ARVs in the Botswana National Program NRTIs NNRTIs PIs Nucleoside Reverse Non-Nucleoside Reverse Protease Inhibitors Transcriptase Inhibitors Transcriptase Inhibitors AZT(Zidovudine)EFV(Efavirenz) LPV/r(Kaletra) 3TC(Lamivudine)NVP(Nevirapine) NFV(Nelfinavir) d4T(Stavudine)SQV(Saquinavir) ddI(Didanosine)RTV(Ritonavir) (AZT+3TC)(Combivir) Special Order: ABC(Abacavir)

18. Mechanism of Action of ARVs • NRTIs and NNRTIs block HIV replication early in its life-cycle by inhibiting reverse transcription. • PIs block HIV replication late in its life-cycle by inhibiting protease-catalyzed assembly of the virus.

19. Mechanisms of Action NRTIs & NNRTIs • NRTIs and NNRTIs inhibit reverse transcriptase by different mechanisms: • NRTIs are false nucleosides and--once incorporated into the DNA chain--terminate further elongation of the DNA chain. • NNRTIs directly inhibit the enzymatic function of reverse transcriptase by binding at the catalytic site.

20. NRTIs(Nucleoside ReverseTranscriptase Inhibitors) AZT (Zidovudine) ddI (Didanosine) d4T (Stavudine) 3TC (Lamivudine) (AZT+3TC) (Combivir) ABC(Abacavir) Reverse Transcriptase Protease RNA RNA RNA CD4 DNA RNA CD4 T -Lymphocyte

21. NNRTIs(Non-Nucleoside ReverseTranscriptase Inhibitors) EFV (Efavirenz) NVP(Nevirapine) Reverse Transcriptase Protease RNA RNA CD4 RNA DNA RNA CD4 T -Lymphocyte

22. Mechanism of Action: PIs • PIs inhibit protease by binding at the catalytic site.

23. PI’s(ProteaseInhibitors) LPV/r(Kaletra) NFV (Nelfinavir) SQV (Saquinavir) RTV (Ritonavir) Protease Reverse Transcriptase RNA RNA RNA CD4 DNA RNA CD4 T -Lymphocyte

24. Botswana Guidelines NRTI’s NNRTI’s PI’s AZT+3TC EFV or NVP ddI + d4T NFV / LPV/r 2 recycled NRTIs* SQV/RTV * Depending on resistance assay and specialist consultation. 1st Line 2nd Line 3rd Line

25. Standard 1st line ARV Therapy 2 NRTIs + 1 NNRTI • (AZT+3TC) + EFV Combivir + Efavirenz • (AZT+ 3TC) + NVP Combivir + Nevirapine - Give NVP to women with reproductive potential and to children less than 3 years of age.

26. Standard Dosages - First Line Therapy (1) • (AZT + 3TC) -- Combivir - 1 tablet BD • EFV -- Efavirenz - 600 mg HS

27. Standard Dosages - First Line Therapy (2) • (AZT+3TC) -- Combivir 1 tablet BD • NVP -- Nevirapine 200 mg BD • Begin NVP, 200 mg OD for two weeks. • After two weeks, increase NVP to 200 mg BD and check LFT’s. • Dose escalation of NVP will reduce the incidence of side effects.

28. Clinical Issues with 1st Line Therapy • Selection of 1st line therapy is simple within national guidelines. (AZT+3TC) + EFV or (AZT+3TC) + NVP • Due to side-effects--for example, anemia--different NRTIs may need to be used for first line therapy. • d4T + 3TC is the alternative NRTI combination for first line therapy when the baseline hemoglobin is <7.5g/dL, or when AZT-associated anemia develops. • 1st line therapy will hopefully work for several years.

29. Changing Regimens In the course of therapy there are two reasons to change regimens: • Toxicity - Adverse reaction to a particular ARV drug in the regimen. CHANGE ONLY THE OFFENDING DRUG, RETAINING ACCOMPANYING ARV DRUGS. Or • TherapyFailure - Inability of the drug regimen to suppress the replication of the HIV virus. CHANGE ENTIRE REGIMEN

30. Principle 6 Therapy failure MUST be addressed promptly, and the patient must not be kept on a failing regimen for a long period of time.

31. Principle 7 Decisions about changing a patient to second or third line regimens should be reviewed with an HIV specialist as soon as possible.

32. Therapy Failure • Virologic: failure to suppress HIV replication, i.e., viral load. • Immunologic: failure to increase CD4 count. • Clinical: occurrence of an OI or other AIDS-defining event.

33. Therapy Failure (2) • For the patient not yet on HAART, decisions about when to initiate ARVs focus on immunologic (i.e., CD4 count) and clinical factors (AIDS-defining illnesses/symptoms). • Once the patient starts HAART, decisions about therapy success or therapy failure focus primarily on the virologic response (i.e., viral load).

34. Therapy Failure (3) • Only rarely will a patient have immunological or clinical failure with an undetectable viral load. Such patients must be reviewed with an HIV specialist before changing regimens. • In general, “therapy failure” means virologic failure, and the two terms are usually used interchangeably.

35. Definition of Therapy (i.e. virologic) Failure • The ARV regimen initially fails to suppress replication—ie., the viral load does not fall by at least 1.0 log by 3 months, and is not less than 400 by 6 months. or • The regimen initially suppressed replication (viral load <400 copies/ml), but at a later date the viral load becomes detectable.

36. Standard 2nd Line ARV Therapy 2NEWNRTIs + NFV or LPV/r d4T + ddI + NFV or LPV/r (stavudine) + (didanosine) + (nelfinavir) or (kaletra) • 2nd Line therapy should be used if a patient’s viral load fails to be < 400 copies/ml after 6 months of therapy, or if viral load initially suppresses but later increases. • If d4T had been part of the first-line regimen because of anemia, and if the patient’s hemoglobin has increased, then AZT/ddI should be the NRTI backbone. If anemia has persisted, consult with HIV specialist about NRTI backbone.

37. Standard Dosages - Second Line Therapy • d4T: If < 60kg, 30mg BD If ≥ 60kg, 40mg BD • ddI: If < 60kg, 300mg OD If ≥ 60kg, 400mg OD • NFV: 1250mg BD (five 250mg capsules/dose) • LPV/r: 400mg/100mg (3 Kaletra capsules) BD

38. 3rd Line or Salvage Therapy 2 Recycled NRTIs + 2 PIs 2 NRTI’s + RTV/SQV • A patient who has failed two regimens will need therapy that takes into account the previous drug history. • Adherence assessment is crucial. • Two new PI’s plus recycled NRTIs. • Always discuss with experienced ARV specialist. • Successful salvage therapy can be difficult to achieve.

39. 3rd Line or Salvage Therapy (2) Genotypic resistance testing should be done to guide choice of drugs for the third line regimen.

40. TB/HIV Co-infection and HAART • Patients with newly diagnosed TB and not on HAART should be treated for TB first, and HAART should be delayed. • Timing of HAART initiation in active TB depends upon CD4 count and clinical condition of the patient. • Patients already on HAART and who develop active TB should continue HAART while ATT is initiated.

41. TB/HIV Co-infection and HAART (2) • Patients on ATT and NVP-containing HAART do not require dose adjustment of NVP. • Patients on ATT and EFV-containing HAART may require dose adjustment of EFV: • If weight > 60 kg, some authorities would not change EFV dose. • Guidelines advise increasing EFV dose to 800mg HS if weight > 60 kg.

42. TB/HIV Coinfection and HAART (3) Because of serious drug-drug interactions between rifampicin and protease inhibitors, patients who develop TB while on second-line regimen must be referred to a specialist for evaluation.

43. Principle 8 Being “naïve” to a class of drugs is the single most important factor in predicting response to future salvage therapy.

44. Principle 9 Adherence strategies between patient and clinician are as important or more important than any choice of ARV drugs.

45. Principle 10 All HIV-infected persons, even those taking ARV medications with viral loads below detectable limits, remain infectious.

46. Final Summary • ARV choices are limited, protect them by • using 3 drugs simultaneously. • promoting adherence. • For any drug change make sure the reasons are clearly documented. • If in doubt, ask the most experienced HIV physician.