1. 1 Introduction to ARV Therapy HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 Learning Objectives By the end of this session, participants should be able to: Identify the main classes of ARV drugs available in Vietnam and explain their mechanisms of action Explain the criteria for starting ART Identify the first line ARV regimens

3. 3 ARV Drug Classes

4. 4 Drug Classes of Antiretrovirals 1. Nucleoside Reverse Transcriptase Inhibitors (NRTI) 2. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) 3. Protease Inhibitors (PI) 4. Fusion/Entry Inhibitors 5. Integrase Inhibitors

5. 5 ARV Drugs Currently Available in the World and Vietnam Nucleoside/ Nucleotide RTI AZT / Zidovudine d4T / Stavudine 3TC / Lamivudine ddI / didanosine ABC / Abacavir TDF / Tenofovir FTC / Emtricitabine Non- nucleoside RTI NVP /Nevirapine DLV / Delavirdine EFV / Efavirenz ETR / Etravirine Protease inhibitors SQV / Saquinavir RTV / Ritonavir IDV / Indinavir NFV / Nelfinavir APV / Amprenavir LPVr / Lopinavir + ritonavir ATV / Atazanavir Fos-Amprenavir DRV / Darunavir TPV / Tipranavir Integrase inhibitors RAL / Raltegravir Fusion/Entry inhibitors MVC / Mariviroc ENF / Enfuvirtide

6. 6 Combination Pills Available in Vietnam AZT + 3TC = LAMZIDIVIR, Combivir D4T + 3TC + NVP = D4T - FDC, NEVITRIO 30, Triamune, GPOvir AZT + 3TC + NVP = AZT - FDC, LAMZITRIO AZT + 3TC + ABC = ABATRIO, Trizivir

7. 7 Review of HIV Lifecycle HIV is an RNA “retrovirus” Virus containing RNA infects the cell Viral enzymes transcribe RNA to DNA (reverse transcription) Viral DNA is integrated into the host cell DNA Cell and viral mechanisms produce viral proteins and viral RNA New virus is produced

8. 8 HIV Lifecycle and ARV Reverse Transcriptase Inhibitors (NRTI + NNRTI) Fusion/Entry Inhibitors Integration Inhibitors Protease Inhibitors (PI) Source: wires.wiley.com-2010

9. 9 Nucleoside Reverse Transcriptase Inhibitors (NRTI) Reverse transcriptase (RT) builds DNA from viral RNA by using human nucleotides NRTI drugs, when present, will be inserted into the growing DNA chain DNA chain containing NRTIs cannot accept new nucleotides This blocks DNA chain production so HIV cannot produce new virus to infect new cells

10. 10 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) NNRTIs attach directly to the reverse transcriptase enzyme. Enzyme with NNRTI attached cannot function normally Production of viral DNA from RNA is blocked Virus is unable to convert RNA into DNA, therefore unable to infect the cell and produce new virus

11. 11 Site of Action of RTIs Reverse Transcriptase Inhibitors (NRTI + NNRTI) Source: wires.wiley.com-2010

12. 12 Mechanism of Action of NRTIs and NNRTIs Source: Nature 2001 Source: Nature, 2001

13. 13 Protease Inhibitors (PI) Infected cell produces large viral proteins (polyproteins) Protease enzyme cleaves polyproteins into enzymes and structural proteins required to make new virus PIs attach to and block protease enzyme The virus particles produced are defective and inactive and are unable to infect new cells

14. 14 Site of Action on Protease Inhibitors Protease Inhibitors (PI) Source: wires.wiley.com-2010

15. 15 ARV Therapy

16. 16 Goals of ARV Therapy Inhibit HIV replication As low as possible (undetectable) For as long as possible Allow recovery of the immune system Prevent opportunistic infection Improve survival, health and quality of life

17. 17 Key Principle of ARV “Triple Therapy” (1) A 3 drug regimen should be chosen for treatment based on the National ARV guidelines Treatment with 1 or 2 drugs should not be started for standard treatment of HIV disease Guidelines for Diagnosis and Treatment of HIV/AIDS, MOH 2009

18. 18 Key Principle of ARV “Triple Therapy” (2) “ Highly Active Antiretroviral Therapy ” is 3-drug ARV therapy with 2 NRTI + NNRTI or 2 NRTI + PI

19. 19 Treatment of HIV Infection With 1 or 2 Drugs Viral Load Limit of detection Time

20. 20 Treatment of HIV Infection with 3 ARVs “Triple Therapy” Viral Load Limit of detection Time

21. 21 15 Patients Progressing to AIDS, by Type of ARV Therapy % Month

22. 22 When to Start ART? ARV therapy is never an emergency Patients with high CD4 are not at risk for OIs and can delay ARV treatment Decide when to start ARV based on: RisksBenefits Allergy Side Effects Adherence Costs Improve immune function Improve quality of life Decrease risk for OIs

23. 23 When to Start ARV in Vietnam Patients with: CD4 ≤ 350 cells/mm³ irrespective of clinical stage Clinical stage 3 or 4 irrespective of CD4 cell count Modification and Supplement to the Guidelines for Diagnosis and Treatment of HIV/AIDS, MOH November 2011

24. 24 Which Antiretroviral Drugs Should You Use?

25. 25 First Line ARV Regimens in Vietnam (1) 2 NRTI + 1 NNRTI Stavudine (D4T) is no longer recommended as a first line ARV Lamivudine (3TC) Tenofovir (TDF) Zidovudine (AZT) Efavirenz (EFV) Nevirapine (NVP) Modification and Supplement to the Guidelines for Diagnosis and Treatment of HIV/AIDS, MOH November 2011

26. 26 First Line ARV Regimens in Vietnam (2) 3TC EFV or NVP + Modification and Supplement to the Guidelines for Diagnosis and Treatment of HIV/AIDS, MOH November 2011 + TDF or AZT

27. 27 First Line ARV Regimens in Vietnam (3) Priority RegimensAlternative Regimens TDF/3TC/EFV TDF/3TC/NVP AZT/3TC/EFV AZT/3TC/NVP Modification and Supplement to the Guidelines for Diagnosis and Treatment of HIV/AIDS, MOH November 2011

28. 28 How to Choose a First Line Regimen

29. 29 Prioritized Regimens: TDF/3TC/EFV TDF/3TC/NVP TDF/3TC are the preferred NRTIs Well tolerated by patients Once-daily dosing Treats hepatitis B in patients with HIV- hepatitis B co-infection

30. 30 First Line Regimen NNRTI: NVP vs. EFV Use EFVUse NVP LFTs > 2.5x normal HBV or HCV co- infection Patient on Rifampin Men, CD4 > 400 Female, CD4 > 250 Pregnancy, 1 st trimester Depression or other mental illness

31. 31 Use for patients who cannot take TDF Suitable choice for patients with: Renal failure Pregnancy Alternative Regimens: AZT/3TC/EFV AZT/3TC/NVP Do not use AZT in patients with severe anemia (Hgb < 8 g/l)

32. 32 Alternative First Line Regimens: AZT + 3TC + TDF For patients who cannot use NVP or EFV However, research shows less efficacy than regimens that contain 2 NRTI + (1 NNRTI or 1 PI) Lower rates of virological suppression Higher chance for developing resistance to NRTI Recommended only when no other ARV regimens are available

33. 33 Small Group Activity: Mini Case Scenarios

34. 34 Key Points NRTI, NNRTI, PI are 3 ARV classes used in Vietnam Only prescribe triple therapy ARV regimens – they are most effective Two priority first ARV regimens in Vietnam: TDF + 3TC + EFV TDF + 3TC + NVP

35. 35 Thank You! Questions?