2. Combination Antiretroviral Therapy for HIV Infection by Ormrat Kampeerawipakorn

3. Outline Introduction Content Factors Contributing to Treatment Failure Why does the combination therapy make sense? Combinations of Antiretroviral Drugs Combinations of Nucleoside analogues (NRTIs) Combinations of NRTIs and non-NRTIs Combinations of Protease Inhibitors and NRTIs and/or NNRTIs Conclusion

4. Introduction Combination Therapy is the use of two or more drugs at the same time for the same disease. multiple agents often have additive or synergistic effects against the disease. has been widely used in the treatment of some infectious diseases and cancers.

5. Background of Anti-HIV drugs In 1987, Zidovudine (AZT) was approved as the first drug specifically to combat HIV and AIDS by FDA. AZT is in the family of reverse transcriptase inhibitor. Others in this class include Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir

6. Nevirapine, the first non-nucleoside analogue (NNRTIs), was approved by FDA in 1996. Other NNRTIs include Delaviridine Efavirenz FDA approved Saquinavir as the first protease inhibitor in late 1995 Other agents in this class include Ritonavir Indinavir Nelfinavir Amprenivir

7. In 1995, the combination of 2 NRTIs was approved to solve the drug resistance problem such as the combinations of AZT and ddI. In 1996, PIs were introduced in combination with 2 NRTIs. The triple antiretroviral therapy had become the standard first-line therapy for HIV infection. It is called “ Highly Active Antiretroviral Therapy ” (HAART).

8. Contents Factors contributing to treatment failure Limited potency of the anti-HIV drugs In single NRTIs treatment, complete suppression of HIV replicate was rarely achieved. AZT works best in cells actively producing new HIV, but is not active in resting-infected cells.

9. Factors contributing to treatment failure (cont.) Poor Adherence Missing doses Reducing the frequency of doses or the number of medications taken Side effects

10. The importance of regular dosing

11. The relationship of a number of dose and viral load in plasma

12. Side Effects Renal colic Diarrhea Nausea, vomiting,dizziness and/or epigastric discomfort Lipodystrophy Anxiety

13. Factors contributing to treatment failure (cont.) Pharmacologic factors Limited penetration of drug into sanctuary site such as central nervous system. Drug-drug interaction Rifampin and Rifabutin reduce PIs level by inducing cytochrome P450 3A activity. In contrast, Ketoconazole enhances the increase level of PIs.

14. Factors contributing to treatment failure (cont.) Drug Resistance is the major factor contributing to treatment failure. Pathogenesis HIV replicates at an extremely rapid rate (1-10 billion copies daily). Each time of replication, an average of one mutant base pair viral genome occurs. There is no error-checking system to repair these spontaneous mutations arising daily. These mutations can make amino acid substitutions at active site of anti-HIV drug in gene.

15. Reverse Transcriptase mutation to NRTIs

16. A highly drug-resistant viral strain

17. What does the combination therapy make sense? The combination therapy can decrease HIV progression better than monotherapy.

18. Rate of Decline of Plasma HIV RNA Concentration After Initiation of Potent Combination Antiretroviral Therapy

19. What does the combination therapy make sense? The combination therapy can decrease HIV progression better than monotherapy. Different anti-HIV drugs can attack the virus in the different ways.

20. HIV Life Cycle Targets of Current and Emerging Therapy

21. What does the combination therapy make sense? The combination therapy can decrease HIV progression better than monotherapy. Different anti-HIV drugs can attack the virus in the different ways. Different drugs can attack virus in different types of cell and in different parts of the body.

22. Some NRTIs and NNRTIs can get inside spinal cords and brain such as AZT, d4T and Nevirapine. AZT and d4T work best in infected cells that are actively producing new copies of HIV. ddI, ddC, 3TC and nevirapine work best in resting cell

23. What does the combination therapy make sense? The combination therapy can decrease HIV progression better than monotherapy. Different anti-HIV drugs can attack the virus in the different ways. Different drugs can attack virus in different types of cell and in different parts of the body. Combinations of anti-HIV drugs may overcome or delay resistance.

24. Reduced mutation in AZT-experience patients after treating with the combinations of Abacavir and AZT

25. Combinations of Antiretroviral Drugs Combinations of Nucleosides Analogues Because of differences in the intracellular activity, NRTIs working in actively infected cells are given with those working in resting cells. Large studies in the US, Europe and Australia showed that AZT plus ddI or AZT plus ddC worked better than AZT alone.

26. n Combinations of Nucleosides Analogues (cont..) ACTG 175 trial (NIAID, United States) showed 50% decline CD4 cell count rate increase significantly in the combinations of AZT/ddI and AZT/ddC group, compared with AZT monotherapy.

27. The 50% decline CD4 cell counts in volunteers in ACTG 175 after treating with monotherapy and combinations of NRTIs

28. n Combinations of Nucleosides Analogues (cont.) ACTG 175 trial (NIAID, United States) showed 50% decline CD4 cell count rate increase significantly in the combinations of AZT/ddI and AZT/ddC group, compared with AZT monotherapy. In treatment-naïve individuals, average peak HIV- RNA reduction increased significantly in combination NRTIs compared with NRTIs monotherapy.

29. Average peak RNA reduction with RTIs monotherapy and combination regimen in anti- HIV-na ï ve individuals.

30. n Combinations of NRTIs and NNRTIs NNRTIs have same target and activity as in NRTIs. The incorporation of NRTIs and NNRTIs shows synergistic effect and is active against AZT-resistant HIV isolates. In the study of Staszewski et al., plasma HIV-RNA level in patients receiving EFV/AZT/3TC decreased greater than in ones receiving EFV/IDV

31. Percentage of patients with plasma HIV-1 RNA level of less than 400 copies/ml according to the combinations of NRTIs/NNRTIs

32. n Combinations of PIs and RTIs Saquinavir was the first protease inhibitor for use in the combination with nucleoside analogues. Several studies showed that the triple drugs (PIs+2NRTIs) given together resulted in a large and longer-lasting reduction in the amount of virus in blood compared with 2 NRTIs combinations or with PIs alone.

33. Mean changes from baseline in serum human immunodeficiency virus (HIV) RNA levels

35. Conclusion The potent antiretroviral regimen now have proven capable of effecting a dramatic suppression of HIV viral replication and a delay in the emergence of drug resistance. Clinical end point studies showed the potential benefit of NRTIs combination in intermediate-stage HIV infection and in treatment-naive individual. The triple drugs (PIs plus RTIs) have the clinical benefit in late-stage HIV infection.

36. Conclusion (Cont.) However, side effects, high cost, large number of pills and complicated dosing schedules can make poor adherence in the HAART regimen. Therefore, it is necessary to develop more potent therapies that have low cost, fewer toxic effects and are easier to administer such as vaccine, fusion inhibitors.

37. The End