The document discusses antiretroviral therapy drugs used to treat HIV, including their mechanisms of action and adverse effects. It provides timelines of drug approvals and describes the classes of antiretrovirals including nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 inhibitors, and integrase inhibitors. It also discusses guidelines for initial treatment regimens and components not recommended, as well as counseling points about adverse effects.

1. Antiretroviral Therapy: Drugs, Mechanism of Action, Adverse Effects Joanne J. Orrick, Pharm.D., BCPS Clinical Assistant Professor University of Florida Faculty, Florida/Caribbean AIDS Education and Training Center [email_address]

2. Disclosure of Financial Relationships Dr. Orrick has received honoraria from Boeringer-Ingelheim and Bristol-Myers Squibb This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

3. Timeline of ARV Approvals 1987: Zidovudine 1987: 1 st NRTI Approved 1995: 1 st PI 1996: 1 st NNRTI 2003: 1 st Fusion Inhibitor The Future: Entry inhibitors, Integrase inhibitors 1995: Lamivudine, Invirase ® 1996: Nevirapine, Ritonavir, Indinavir 2003: T-20, Atazanavir, Emtricitabine, Fosamprenavir 2005: Tipranavir 2006: Darunavir 2007: Maraviroc 1991: Didanosine 1992: Zalcitabine 1994: Stavudine 1997: Delavirdine, Nelfinavir, Fortovase ® 1998: Abacavir, Efavirenz 1999: Amprenavir 2000: Lopinavir/ritonavir 2001: Tenofovir

4. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI’s) Zidovudine (AZT, ZDV, Retrovir  ) 3/87 Didanosine (ddI, Videx  , Videx EC  ) 10/91 Stavudine (d4T, Zerit  ) 6/94 Lamivudine (3TC, Epivir  ) 11/95 Abacavir (ABC, Ziagen  ) 12/98 Combivir  (AZT/3TC) 9/97 Trizivir  (AZT/3TC/ABC) 11/00 Tenofovir (TDF, Viread  )* 10/01 Emtricitabine (FTC, Emtriva  ) 7/03 Epzicom  (ABC/3TC) 8/04 Truvada  (FTC/TDF) 8/04 Agent Approved *A nucleotide reverse transcriptase inhibitor

5. HIV Life Cycle From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com Protease inhibitors (PIs) NRTIs and NNRTI Fusion Inhibitors CCR5 Inhibitors

6. NRTI Mechanism of Action NRTIs must first undergo intracellular phosphorylation to be active NRTIs inhibit the viral reverse transcriptase enzyme Enzyme responsible for transcribing viral RNA into double stranded DNA Clinical Pharmacology 2007. Gold Standard, Inc.

7. NRTI Mechanism of Action NRTIs mimic other nucleosides and are incorporated into the DNA strand They prevent the addition of the natural nucleosides into the DNA strand This halts the production of new virions Clinical Pharmacology 2007. Gold Standard, Inc.

8. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Agent Approved Nevirapine (NVP, Viramune  ) 6/96 Delavirdine (DLV, Rescriptor  ) 4/97 Efavirenz (EFV, Sustiva  ) 9/98

9. HIV Life Cycle From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com Protease inhibitors (PIs) NRTIs and NNRTI Fusion Inhibitors CCR5 Inhibitors

10. NNRTI Mechanism of Action NNRTIs also inhibit the viral reverse transcriptase enzyme but have a different mechanism of action compared to NRTIs NNRTIs bind directly to the reverse transcriptase enzyme Viral RNA double stranded DNA

11. Protease Inhibitors (PIs) Agent Approved Saquinavir-HGC (SQV-HGC, Invirase  ) 12/95 Ritonavir (RTV, Norvir  ) 3/96 Indinavir (IDV, Crixivan  ) 3/96 Nelfinavir (NFV, Viracept  ) 3/97 Saquinavir-SGC (SQV-SGC, Fortovase  ) 11/97 Amprenavir (APV, Agenerase  ) 4/99 Lopinavir/ritonavir (KAL, Kaletra ® ) 9/00 Atazanavir (ATV, Reyataz ® ) 6/03 Fosamprenavir (fos-APV, Lexiva ® ) 10/03 Tipranavir (TPV, Aptivus ® ) 6/05 Darunavir (DRV, Prezista ® ) 6/06

12. HIV Life Cycle From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com Protease inhibitors (PIs) NRTIs and NNRTI Fusion Inhibitors CCR5 Inhibitors

13. PI Mechanism of Action Protease enzyme is responsible for cleaving (cutting up) larger polyproteins into structural proteins and reverse transcriptase enzyme Protease is needed to form a fully mature, functional virus that is able to replicate and produce more virus Protease inhibitors prevent this enzyme from doing its job in the later steps of the viral life cycle Clinical Pharmacology 2007. Gold Standard, Inc.

14. Fusion Inhibitor Enfuvirtide (T-20, Fuzeon ® ) Approved March 2003

15. HIV Life Cycle From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com Protease inhibitors (PIs) NRTIs and NNRTI Fusion Inhibitors CCR5 Inhibitors

16. Fusion Inhibitor Mechanism of Action Inhibits entry of HIV into the CD4 cell T-20 binds to glycoprotein gp41 (a protein on the viral membrane) This binding prevents a change in the shape of the membrane protein and prevents fusion of the virus and the CD4 cell membrane

17. Enfuvirtide - Fuzeon ® Unfortunately, Fuzeon ® is only active when injected subcutaneously This aspect (in addition to its high cost) severely limits it use in the correctional setting

18. Initial Treatment: Preferred Components * Avoid in pregnant women and women with significant pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa. OR NNRTI Option PI Options Tenofovir + emtricitabine** OR Zidovudine + lamivudine** + NRTI Options http://www.aidsetc.org Efavirenz* Atazanavir + ritonavir Fosamprenavir + ritonavir (BID) Lopinavir/ritonavir (BID)

19. Initial Treatment: Alternative Components *Nevirapine should not be initiated in women with CD4 counts >250 cells/mm 3 or men with CD4 counts > 400 cells/mm 3 **Atazanavir must be boosted with ritonavir if used in combination with tenofovir OR NNRTI Option PI Options Abacavir + lamivudine Or Didanosine + (emtricitabine or lamivudine) NRTI Options http://www.aidsetc.org + Nevirapine* Atazanavir** Fosamprenavir Fosamprenavir + ritonavir (QD) Lopinavir/ritonavir (QD)

20. Regimens NOT Recommended Similar resistance profiles; no potential benefit Emtricitabine + lamivudine Increased risk of toxicities such as lactic acidosis and pancreatitis; May be considered when no other options available and potential benefits outweigh the risks. Stavudine + Didanosine Both thymidine analogs; antagonistic Stavudine + zidovudine Comment Agent (s) Components Not Recommended as Part of Regimen

21. Regimens NOT Recommended Contraindications due to propylene glycol content Amprenavir oral solution Potential for additive hyperbilirubinemia Atazanavir + indinavir Amprenavir is active component of both drugs Amprenavir + fosamprenavir Teratogenic Efavirenz in pregnancy Should be combined with ritonavir Saquinavir (Invirase ® ), Darunavir (Prezista ® ), tipranavir (Aptivus ® ) Comment Agent (s) Components Not Recommended as Part of Regimen

22. Choice of ARVs for Treatment of the ARV-Naïve Patient Abacavir + lamivudine + zidovudine (Available as Trizivir ® ) Alternative Triple NRTI Regimen-Based Regimens Only as alternative when PI or NNRTI-based regimens cannot be used

23. ARV Update Tipranavir (Aptivus ® ) Approved June 2005 Darunavir (Prezista ® ) Approved June 2006 Emtricabine/tenofovir/efavirenz (Atripla TM ) Approved August 2006 TMC-125 (Etravirine) Investigational NNRTI-available via expanded access program (EAP) MK-0518 (Raltegravir) Investigational integrase inhibitor available via EAP Maraviroc Investigational CCR5 inhibitor available via EAP Approved August 6 th , 2007

24. Tipranavir (Aptivus ® ) Dosage Form 250 mg capsules Adult Dose 500 mg po bid WITH ritonavir 200 mg po bid Patient Counseling Points Take with food (high fat meal preferred) Antacids may decrease TPV/RTV absorption (25-29%), consider separating dosing Keep in refrigerator or store at room temperature for up to 60 days AEs: Hepatotoxicity-monitor LFTs, closely, rash (8-14%) of patients, diarrhea, nausea, vomiting, rare cases of intracranial hemorrhage Caution with sulfa allergy

25. Darunavir (Prezista ® ) Dosage Form 300 mg capsules Adult Dose 600 mg po bid WITH ritonavir 100 mg po bid Patient Counseling Points Take with food AEs: Rash (7%), abdominal pain, constipation, headache Caution with sulfa allergy

26. One Pill Once Daly! Atripla TM (emtricitabine/tenofovir/efavirenz) Emtricitabine/tenofovir (Truvada ® ) + efavirenz (Sustiva ® ) Approved July 12, 2006 First collaborative effort between 2 companies to develop combination pill for HIV treatment Not new drugs!

27. Maraviroc (Selzentry TM ) First in new class of agents, CCR5 inhibitors Approved August 6 th , 2007 Maraviroc binds to the CCR5 receptor on the membrane of human cells such as CD4 cells. This binding prevents the interaction of HIV-1 gp120 and human CCR5 which is necessary for entry into the cell. Maraviroc does not prevent HIV-1 entry into CXCR4-tropic or dual-tropic cells. www.selzentry.com

28. HIV Life Cycle From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com Protease inhibitors (PIs) NRTIs and NNRTI Fusion Inhibitors CCR5 Inhibitors

29. Maraviroc (Selzentry TM ) Maraviroc is indicated (in combination with other ARVs) treatment-experienced adult HIV-infected p atients Maraviroc is not recommended in patients who have dual/mixed tropic or CXCR4-tropic virus Use of maraviroc should be based on treatment history and tropism assay results The tropism assay is available from Monogram Biosciences, Inc. (For more information go to monogramhiv.com) www.selzentry.com

30. Maraviroc (Selzentry TM ) www.selzentry.com 150 mg po bid CYP3A inhibitors (with or without a CYP3A inducer) Protease inhibitors (except tipranavir/ritonavir) Delavirdine Ketoconazole, itraconazole, clarithromycin Other strong CYP3A inhibitors (e.g. telithromycin, nefazodone) Maraviroc Dose Concomitant Medications

31. Maraviroc (Selzentry TM ) 600 mg po bid CYP 3A inducers (WITHOUT a strong CYP3A inhibitor) Efavirenz Rifampin Carbamazepine, phenobarbital, phenytoin 300 mg po bid Other meds including tipranavir/ritonavir, nevirapine, all NRTIs, enfuvirtide (T-20) Maraviroc Dose Concomitant Medications

32. Adverse effects/precautions Hepatotoxicity may be preceded by a systemic allergic reaction (pruritic rash, eosinophilia) Dizziness/postural hypotension Increased risk of CV events (MI, ischemic events) Maraviroc (Selzentry TM )

33. Antiretroviral Agents: Counseling Points, Adverse Effects

34. NRTI’s Mainly undergo renal excretion EXCEPT Zidovudine (AZT) undergoes glucuronidation Abacavir metabolized by alcohol dehydrogenase Do not have P-450 drug interactions Limited food restrictions Take without regards to meals: zidovudine, lamivudine, stavudine, tenofovir, emtricitabine Take on empty stomach: didanosine (except when given with tenofovir) Class adverse effects Lactic acidosis with hepatic steatosis

35. NRTI Adverse Effects Hypersensitivity reaction: fever, rash, fatigue, malaise, nausea, vomiting, diarrhea, loss of appetite, pharyngitis Abacavir Hyperpigmentation of palms and soles Emtricitabine Bone marrow suppression (anemia/ neutropenia) Nausea Nail discoloration Zidovudine Generally well-tolerated Lamivudine

36. NRTI Adverse Effects Peripheral neuropathy Pancreatitis Increased triglycerides Stavudine GI upset Flatulence Nephrotoxicity Pancreatitis Peripheral neuropathy Diarrhea Tenofovir Didanosine

37. Zidovudine (AZT, Retrovir ® ) Widely held misconceptions among inmates that this was an experimental way to poison HIV+ inmates Perception by inmates that many friends/family died from AZT toxicity in the early years of HIV epidemic can result in reluctance to take this medication Correctional provider should point out: AZT was used in much higher does in those years At currently used doses, toxicity is greatly reduced. AZT immunotherapy, while it was the only available treatment at the time, did not provide an adequate long term response. The perception that people were dying due to AZT was actually people dying of AIDS due to lack of an effective treatment. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, July 2005.

38. The most common side effects are nausea, headache, muscle aches with muscle tenderness due to inflammation, fever and insomnia Headache, muscle aches and insomnia tend to occur more frequently in those patients with advanced HIV infection Zidovudine comes as a 300 mg tablet, 100 mg capsule, strawberry-flavored syrup with 50 mg/5mL and as an intravenous (IV) formulation with 10 mg/mL The standard dose for adults is 300 mg every 12 hours, in combination other anti-HIV therapy 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, July 2005. Zidovudine (AZT, Retrovir ® )

39. Patient Case JK JK is a 50 year old African American male incarcerated due to repeat drug offenses 6 months prior to his incarceration, he found out that he had HIV infection but has not yet been treated He is also known to be co-infected with Hepatitis B and C Medications: none Social History: Divorced, lived alone, 3 grown children, active drug use including IV heroin and crack/cocaine, drank 12 pack of beer per day on weekend, smokes cigarettes 2 ppd, worked as a painter for 10 years but has been disabled due to back injury

40. Patient Case JK Result: Baseline HIV labs: CD4: 305 cells/mm 3 , HIV RNA: 85,650 copies/mL HIV Genotype: pansensitive Other Labs: HepBsAg (+), HepBsAb (-), Hep C Ab (+), CMV IgG (+), Toxo IgG (+) HepBeAg (+), HBV DNA > 10 million copies/mL AST 189, ALT 153 All other labs WNL

41. Patient Case JK What ARV(s) would you include in the regimen to provide activity against HIV and HepB? What other agents have activity against HepB?

42. Black Box Warning SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV AND HAVE DISCONTINUED _______. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE _______ AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

43. Lactic Acidosis with Hepatic Steatosis Rare complication of NRTI therapy Signs/Symptoms: Abdominal distention, abdominal pain, nausea, vomiting, diarrhea, weight loss, difficulty breathing, generalized weakness, myalgias Risk Factors: Stavudine and didanosine use during pregnancy Female gender Obesity Prolonged use of NRTIs

44. NNRTI’s-General Statements Hepatic metabolism-no renal dosage adjustments required Single mutation confers cross resistance to all available NNRTIs Due to pill burden and lack of potency, delavirdine is rarely used Many P-450 drug interactions Class adverse effects: increased transaminase levels rash (nevirapine > delavirdine > efavirenz)

45. NNRTI Adverse Effects Nevirapine: Rash (7%), increased transaminase levels, hepatitis Hepatotoxicty more common in women with pretreatment CD4 + cell counts > 250 cells/mm 3 , men with CD4 + cell counts > 400 cells/mm 3 and patients co-infected with hepatitis B or C Monitor LFTs minimally at baseline, 2 weeks, monthly for the 1 st 3 months in all patients Efavirenz: Rash (1.7%), increased transaminase levels, CNS side effects (e.g. vivid dreams, dizziness, drowsiness)

46. Nevirapine (NVP, Viramune ® ) The most common side effect with Viramune is skin rash that occurs among 17% of patients The majority of severe rashes from Viramune occur within the first four weeks of therapy To decrease the rate of rash, a 14 day "lead-in" dose of one 200 mg tablet daily is used for adults, in combination therapy. The dose can then be increased to 1 tablet bid (if no rash, hepatitis, or other serious adverse effect) Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06

47. Severe, life-threatening hepatotoxicity Often associated with rash Greatest risk in women with CD4 >250 (12-fold greater risk) Increased risk for men with CD4 > 400 (3-fold greater risk) Greatest risk during 1 st 6 weeks (continued risk through 18 weeks) Monitor LFTs closely (e.g. baseline, at 2 weeks, 4 weeks, then monthly for first 3 months) Symptoms: often non-specific, including fatigue, malaise, anorexia, nausea, jaundice Dear Health Care Professional Letter, Feb 2004 Boehringer Ingelheim Nevirapine (NVP, Viramune ® )

48. Although there may be no set policy regarding medical hold when starting this medication, it is advisable to consider not starting nevirapine under the following circumstances*: Immediately prior to an inmate being transferred to another facility Immediately prior to release (EOS) *Unless there is communication with the subsequent medical provider. Nevirapine (NVP, Viramune ® )

49. Efavirenz (EFV, Sustiva ® ) Many patients taking efavirenz can experience nervous system symptoms (for example, dizziness, vivid dreams, decreased concentration, and insomnia) which are generally mild to moderate and resolve after 2 to 4 weeks. Rash is also a potential but uncommon side effect Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06

50. Should be used with caution in patients who have a history of psychiatric illness due to side effects including vivid (sometimes disturbing) dreams, insomnia, somnolence, difficulty concentrating, dizziness, amnesia, confusion or agitation Some concern that efavirenz can trigger cravings in patients with a history of substance abuse Mental health and/or substance abuse supports should be available Should be take before bedtime to avoid daytime difficulties Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06 Efavirenz (EFV, Sustiva ® )

51. PI’s-General Statements Hepatic metabolism-no renal dosage adjustments Resistance usually requires multiple mutations Many drug interactions

52. PI’s-General Statements Food restrictions Take all with food EXCEPT: Indinavir: take on empty stomach when not combined with ritonavir Fosamprenavir: can take with or without food Lopinavir/ritonavir tablets: take with or without food Class adverse effects Hyperglycemia, lipodystrophy, hyperlipidemia (less with atazanavir), increased transaminases

53. PI Adverse Effects GI intolerance, rash Darunavir GI intolerance, hepatitis, rash, intracranial hemorrhage Tipranavir Nausea, diarrhea, pancreatitis Lopinavir/ritonavir Diarrhea Nelfinavir Nephrolithiasis, hyperbilirubinemia Indinavir Hyperbilirubinemia Atazanavir GI intolerance, rash, oral paresthesias Amprenavir/fos-amprenavir GI intolerance Saquinavir GI intolerance, paresthesias, asthenia, taste perversion, hepatitis Ritonavir

54. PIs Containing Sulfa Moieties Darunavir (Prezista ® ) Fosamprenavir (Lexiva ® ) Tipranavir (Aptivus ® ) Above agents are not contraindicated with sulfa allergy History of sulfa allergy did not correlate with rash in studies and patients with history of sulfa allergy were not excluded Use with caution

55. Metabolic Complications Glucose intolerance Rare diabetes, diabetic ketoacidosis Lipodystrophy Central obesity, “buffalo hump”, peripheral fat wasting Hyperlipidemia Hypertriglyceridemia and/or hypercholesterolemia Osteonecrosis, osteopenia, osteoporosis

56. Lipodystrophy Dorsocervical fat pad Aka “Buffalo Hump” Central Obesity Carr and Cooper: New Eng J Med 339, 1296:

57. Lipoatrophy Image courtesy: AIDS Images Library www.aids-images.ch

58. Facial Wasting Hendi, et al. Lipodystrophy, HIV. www.emedicine.com

59. Questions?