An overview of the acquired immune deficiency syndrome (AIDS) caused by the human deficiency virus (HIV) and the drugs used for its treatment, including a classification of the established drugs, the HAART regimen, and investigational approaches

1. Prepared by:
Rawa Muhsin

2. Table of Contents
 Overview of AIDS
 History and Origin
 Transmission
 Pathogenesis and Symptoms
 Complications of AIDS
 Life Cycle of HIV
 Anti-HIV Drugs
 Entry Inhibitors
 Reverse Transcriptase Inhibitors
 Protease Inhibitors
 Integrase Inhibitors
 The HAART Regimen
 Investigational Drugs

3. Global Summary of the AIDS Epidemic - 2009

4. History and Origin of AIDS
 Recognized in 1981
 Causative agent is HIV
 Two types: HIV-1 and HIV-2
 Origin of HIV
Pan troglodytes Cercocebus atys

5. Transmission

6. Pathogenesis and Clinical Disease

7. Complications of AIDS
Opportunistic Infections Neoplasms Ophthalmic Disorders
Dermatological Effects Hematological Effects Heart and CNS Effects

8. Structure of HIV

9. Life Cycle of HIV

10. Classification of Anti-HIV Drugs

11. Entry Inhibitors
 1) Enfuvirtide (Fuzeon®)
 Given SC (peptide)
 Binds gp41
 Injection site reactions
○ Erythema, pain, swelling

12. Entry Inhibitors

13. Entry Inhibitors

14. Entry Inhibitors
 2) Maraviroc (Selzentry®)
 Blocks CCR5
 Metabolized by CYP3A4
 Allergic-type hepatotoxicity

15. Reverse Transcriptase Inhibitors

16. NRTIs
 1) Zidovudine (Retrovir®)
 Thymidine analog
 Glucoronylation
○ Inhibited by probenecid, NSAIDS, etc.
 Hematotoxicity
○ Potentiated by cotrimoxazole
 Myalgia and headache
○ Patient takes NSAIDS

17. NRTIs
 2) Stavudine (Zerit®)
 Zidovudine analog
 Peripheral neuropathy
 3) Abacavir (Ziagen®)
 Guanosine analog
 Hypersensitivity reactions
(anaphylaxis, etc.)
○ Not re-used if hypersensitivity
occurs

18. NRTIs
 4) Didanosine (Videx®)
 Inosine analog
 Orally in fasting state
○ Destroyed by gastric acid
 Pancreatitis
○ Monitor serum amylase
 Peripheral neuropathy
○ Avoid with stavudine

19. NRTIs
 5) Tenofovir (Viread®)
 Adenosine analog
 Food increases absorption
 Highest incidence of interactions
○ Avoid with didanosine
 Nephrotoxic
○ Acute renal failure

20. NRTIs

21. NRTIs
 6) Cytosine Analogs
 Lamivudine (Epivir®)
 Least effective and well-tolerated
 Used with zidovudine to cut maternal
transmission
 Emtricitabine (Emtriva®)
 Widely used
 Hyperpigmentation of palms and soles
 Zalcitabine (Hivid®)
 Not recommended (pancreatitis, etc.)

22. Reverse Transcriptase Inhibitors

23. NNRTIs
 1) Efavirenz (Sustiva®)
 Recommended, effective, well-
tolerated
 Lipophilic
 Dizziness, rash, and CNS effects
 Pregnancy group D
○ Severe CNS defects

24. NNRTIs
 2) Nevirapine (Viramune®)
 Lipophilic
 Inducer of CYP3A4
 Fatal hepatotoxicity, Stevens-
Johnson, etc.
 3) Delavirdine (Rescriptor®)
 Similar to Nevirapine
 Inhibitor of cytochrome P450
 Rash

25. NNRTIs
 4) Etravirine (Inelence®)
 No cross-resistance
 Hypersensitivity
○ Stevens-Johnson, etc.
 No CNS effects
 Pregnancy group B
○ Better than Efavirenz

26. Protease Inhibitors

27. Protease Inhibitors
 Common features
 Fat redistribution
○ Buffalo hump
○ Hyperlipidemia and hyperglycemia
 Inhibitors of CYP3A4
○ Delay metabolism of other drugs
 Resistance in sub-optimal concentrations

28. Protease Inhibitors

29. Protease Inhibitors
 1) Ritonavir (Norvir®)
 CYP3A4 inhibitor
 Used as a booster
 NVD, taste perversion, circumoral
paresthesias
 2) Fosamprenavir (Lexiva®)
 Activated to Amprenavir
 Preferred
 Increased risk for MI
○ Monitor serum lipid

30. Protease Inhibitors
 3) Indinavir (Crixivan®)
 Nephrolithiasis/urolithiasis
 Hyperbilirubinemia
 Prominent fat redistrubtion
 4) Atazanavir (Reyataz®)
 Preferred for once daily dosing
 Give with food; avoid with antacids
 Blocks glucoronyl transferase
○ Hyperbilirubinemia and jaundice

31. Protease Inhibitors
 5) Saquinavir (Invirase®)
 Given with high-fat diet
 Prolongation of QT and PR interval
○ Heart block and arrhythmias
 NVD, abdominal pain, fatigue, etc.
 6) Lopinavir (Kaletra®)
 Preferred
 Prolongs QT interval,
hypercholesterolemia
 Contains alcohol
○ Disulfiram-like reactions with
cephalosporins, metronidazole

32. Protease Inhibitors
 7) Nelfinavir (Viracept®)
 Given with food
 Metabolized by many liver
enzymes
 No extensive metabolism by
CYP3A
○ Not boosted by Ritonavir
 Diarrhea

33. Protease Inhibitors
 8) Salvage Regimen Drugs
 Tipranavir (Aptivus®)
 Uniquely inducer of cytochrome
P450
 Hepatatitis (including fatalities) and
intracranial hemorrhage (rare)
○ In those with existing medical
conditions
 Darunavir (Prezista®)
 Inhibitor of CYP3A4
 Nasopharyngitis, neutropenia, rash

34. Integrase Inhibitors
 Raltegravir (Isentress®)
 Metabolized by UGT1A1
glucuronidation
○ Half-life reduced by
rifampin
 Myopathy, fatigue,
headache, increased serum
creatinine

35. The HAART Regimen
 No cure yet
 Obstacles to treatment
 Nested viruses, side effects, drug interactions, patient’s
compliance
 Two NRTIs and either a protease inhibitor or NNRTI

36. The HAART Regimen

37. Combined Formulas
 Atripla®
 Efavirenz, Emtricitabine, and Tenofovir
 Truvada®
 Emtricitabine and Tenofovir
 Combivir®
 Zidovudine and Lamivudine
 Epzicom®
 Abacavir and Lamivudine

38. Investigational Drugs
 Entry Inhibitors
 AMD070
 PRO-140
 TNX-355
 Vicriviroc
 NRTIs
 Apricitabine
 Elvucitabine
 Fosalvudine
 KP-1461
 Racivir
 NNRTIs
 Rilpivirine
 Integrase Inhibitors
 Elvitegravir

39. Thank you for listening.