COMPLICATIONS OF ANTIRETROVIRAL THERAPY

1. COMPLICATIONS OF ANTIRETROVIRAL THERAPY Michael Thompson PharmD, BCNSP Faculty Florida/Caribbean AETC Professor of Pharmacy Practice College of Pharmacy Florida A&M University

2. Disclosure of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose.

3. Objectives To review mechanisms of action of commonly used antiretroviral agents To discuss common adverse effects associated with antiretroviral use To discuss drug-drug interactions associated with antiretroviral use Highlight the role of the clinician in prevention, detection and monitoring of adverse drug-related outcomes in patients receiving ARVs

5. ART Options NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”) NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, aka “Non-Nukes”) PIs (Protease Inhibitors) Fusion Inhibitors Entry Inhibitors Integrase Inhibitors

6. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Zidovudine (AZT, ZDV, Retrovir?) 3/87 Didanosine (ddI, Videx?, Videx EC?) 10/91 Zalcitabine (ddC, Hivid?) 6/92 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

7. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine (NVP, Viramune?) 6/96 Delavirdine (DLV, Rescriptor?) 4/97 Efavirenz (EFV, Sustiva?) 9/98 Etravirine (Intelence™) 1/08 We currently have 3 non-nucleoside reverse transcriptase inhibitors or NNRTI’s on the market. These are nevirapine, delavirdine and the most recently approved agent, efavirenz or Sustiva. Efavirenz was approved in September of 1998.We currently have 3 non-nucleoside reverse transcriptase inhibitors or NNRTI’s on the market. These are nevirapine, delavirdine and the most recently approved agent, efavirenz or Sustiva. Efavirenz was approved in September of 1998.

8. Protease Inhibitors (PIs) 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 Counting the two saquinavir formulations as one agent (although these formulations are not interchangeable, we now have 5 protease inhibitors or PI’s on the market. The most recently approved agent is amprenavir or Agenerase which was approved in April 1999.Counting the two saquinavir formulations as one agent (although these formulations are not interchangeable, we now have 5 protease inhibitors or PI’s on the market. The most recently approved agent is amprenavir or Agenerase which was approved in April 1999.

9. Fusion and Entry Inhibitors Agent Approved Fusion Inhibitor Enfuvirtide (T-20, Fuzeon?) 3/03 Entry Inhibitor (CCR5 Inhibitor) Maraviroc (Selzentry™) 8/07 Counting the two saquinavir formulations as one agent (although these formulations are not interchangeable, we now have 5 protease inhibitors or PI’s on the market. The most recently approved agent is amprenavir or Agenerase which was approved in April 1999.Counting the two saquinavir formulations as one agent (although these formulations are not interchangeable, we now have 5 protease inhibitors or PI’s on the market. The most recently approved agent is amprenavir or Agenerase which was approved in April 1999.

10. Multi-Class Product Atripla® (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!

11. Problems Associated with Antiretrovirals Adverse Effects Drug Interactions Resistance Genotyping Phenotyping

12. Common Adverse Effects of Antiretrovirals Lactic Acidosis Hepatotoxicity Hyperglycemia Fat Maldistribution Hyperlipidemia Pancreatitis Peripheral Neuropathy Others (bone marrow suppression, gastric intolerance) Common effects due to shared toxicity of mitochondria in human cells

13. Common Adverse Effects of Antiretrovirals Lactic Acidosis Thought to be secondary to mitochondrial damage; associated with hepatic steatosis Increased risk in: females, obesity, prolonged NRTI therapy, nutritional depletion of cofactors/vitamins (riboflavin and thiamine)- required for normal mitochondrial function; HIV itself (lower numbers of cellular mitochondria even prior to NRTI use)

14. Summary of NRTI Related Lactic Acidosis NRTIs prevent DNA elongation and viral reproduction Once incorporated into the viral DNA chain, their presence in the DNA halts transcription These drugs unfortunately can also function as substrates for other enzymes like DNA polymerase gamma; this enzyme is involved in the replication of mitochondrial DNA Disruption of DNA polymerase gamma is thought to result in a wide variety of adverse effects ranging from lactic acidosis to hepatic steatosis

15. Mechanism of Development of Lactic Acidosis in HAART

16. Lactic Acidosis Continued Symptoms: nonspecific GI complaints of nausea, abdominal pain, bloating, nausea and vomiting, diarrhea, anorexia, weakness, tachypnea, myalgia,paresthesia and weight loss with hepatomegaly Labs: hyperlactemia, increased anion gap, elevated aminotransferases, LDH, lipase and amylase Routine testing of lactic acid not recommended due to technical problems in reliably assaying for lactate

17. Adverse Effects: Hepatotoxicity Defined as 3 to 5 times increase in serum transaminases with or without clinical hepatitis All marketed NNRTIs and Protease Inhibitors have been associated with elevations in transaminases

18. Nevirapine Hepatotoxicity Of the NNRTIs, nevirapine has highest incidence of hepatoxicity and patients should be monitored especially throughout the first 18 weeks. Patients with hepatitis B and C may be at increased risk. The two week lead in with nevirapine may reduce incidence of hepatotoxicity. Patients should be monitored every 2 weeks for the first month then monthly for the first 18 weeks. If rash occurs, patients should be monitored for hepatotoxicity as well.

19. Protease Inhibitors can cause hepatoxicity at ANY time during therapy Other antiretrovirals and hepatotoxicity Co infection with Hepatitis C or B, alcohol and stavudine use can increase potential for toxicity

20. Adverse Effects Continued Hyperglycemia Seen in Protease Inhibitors Glucose intolerance and insulin resistance can occur without Diabetes Fat maldistribution Lipodystrophy is part of a metabolic syndrome that includes dyslipidemias, insulin resistance and accelerated bone loss

21. HAART Toxicities: Lipodystrophy Body habitus changes Central fat accumulation Peripheral fat wasting Risk factors Female gender Older age HAART Protease Inhibitor use

22. Lipodystrophy

23. Proposed Case Definition of Lipodystrophy Primary Characteristics Age > 40 years HIV infection > 4 years AIDS (Class C) Increased waist:hip ratio Decreased HDL Change in anion gap Secondary Characteristics Increased total cholesterol Increased triglycerides Decreased lactate

24. Lipodystrophy: Unclear Etiology Mitochondrial toxicity? Interference w/ adipocyte differentiation? Pro-inflammatory activation of the immune system during reconstitution?

25. Lipodystrophy Syndrome: NRTIs versus PIs We have attempted to create a model of the relationship between drug therapies and these clinical endpoints, which allows for ‘overlapping toxicities’ in which both drug classes contribute to a clinical endpoint (the example here being subcutaneous fat wasting), while suggesting that some clinical endpoints are strongly associated with either NRTIs or PIs, with little contribution from the other drug class... In the case of NRTIs, there is no data currently available to suggest that PI therapy modifies the risk of hyperlactataemia. At the other end of the spectrum, PI therapy is strongly associated with risk of dyslipidaemia and insulin resistance. As previously mentioned, there is now increasing evidence to support the concept that subcutaneous fat wasting represents a clinical endpoint where both NRTIs and PIs contribute significantly. Antiretroviral therapy Duration of treatment – Nucleoside RTIs Protease inhibitors – Non-nucleoside RTIs HIV disease course Duration of infection – Viral load suppression Disease progression – Immune reconstitution Other potential risk factors Age – Diet Race – Host genetics Gender – Mitochondrial toxicity variety of clinical factors can predict the development and severity of fat redistribution in patients with HIV infection.• These are data from the HIV Outpatient Study, which looked at 1077 patients visiting 8 clinics in 7 U.S. cities.1 Patients aged 40 and older were discovered to have an increased risk for developing these syndromes. Other time-dependent predictors were the duration of HIV infection and the number of months since the CD4 cell nadir.• Treatment predictors were nucleoside use of greater than 8 months and protease inhibitor use of greater than 2 years’ duration. At the time of this study, non-nucleoside reverse transcriptase inhibitors (NNRTIs) were not widely used.• Other predictors included the nadir CD4 percent and a body mass index loss of greater than 1.0 kg/m2. Gender differences are starting to emerge with the reporting of these syndromes. Whereas original observations were made mostly in men, Mulligan1 has tried to systematically examine the differences between men and women.• Women are more likely to develop the lipohypertrophy-type syndromes, such as increased intra-abdominal and breast fat. They also have an increased prevalence in general when compared to men.• On the other hand, men tend to experience more fat loss, particularly from their extremities. However, both men and women can experience any of these manifestations.Reference:1. Mulligan K. Abnormalities of body composition and lipids associated with HAART: pathogenesis, clinical manifestations, and case definitions. 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA; Jan 30-Feb 2, 2000. Abstract S20. We have attempted to create a model of the relationship between drug therapies and these clinical endpoints, which allows for ‘overlapping toxicities’ in which both drug classes contribute to a clinical endpoint (the example here being subcutaneous fat wasting), while suggesting that some clinical endpoints are strongly associated with either NRTIs or PIs, with little contribution from the other drug class... In the case of NRTIs, there is no data currently available to suggest that PI therapy modifies the risk of hyperlactataemia. At the other end of the spectrum, PI therapy is strongly associated with risk of dyslipidaemia and insulin resistance. As previously mentioned, there is now increasing evidence to support the concept that subcutaneous fat wasting represents a clinical endpoint where both NRTIs and PIs contribute significantly. Antiretroviral therapy Duration of treatment – Nucleoside RTIs Protease inhibitors – Non-nucleoside RTIs HIV disease course Duration of infection – Viral load suppression Disease progression – Immune reconstitution Other potential risk factors Age – Diet Race – Host genetics Gender – Mitochondrial toxicity variety of clinical factors can predict the development and severity of fat redistribution in patients with HIV infection.

26. Lipodystrophy: Treatment Options Switch patient to NNRTI regimen Anti-hyperglycemic agents Metformin and Thiazolidindiones Growth hormone

27. Lipodystrophy Illustrations

28. Severe Wasting

29. Treatment of Facial Wasting

30. Example of Buffalo Hump

31. Other Adverse Effects Pancreatitis Bleeding in Hemophiliacs Skin Rash/Dermatologic Effects Examples NNRTIs (nevirapine, efavirenz) NRTIs (abacavir) Others

32. Steven Johnson Syndrome or Toxic Epidermal Necrolysis http://www.fromthewilderness.com/images/stevenJohnsonSyndrome2.jpghttp://www.fromthewilderness.com/images/stevenJohnsonSyndrome2.jpg

33. Drug Interactions

34. Understanding Drug Interactions with Antiretrovirals Mechanisms of Drug Interactions: Pharmacokinetic Interactions These interactions affect: Absorption of drugs Distribution of drugs Metabolism Elimination of drugs Considered clinically significant if there is more than a 30% change in the blood levels or area under the concentration curve

35. Interactions Affecting Drug Metabolism Most Common Cytochrome P450 is an enzyme system containing many enzyme families The majority of interactions reported involve CYP3A4 Medications can induce OR inhibit the action of enzymes responsible for their own metabolism or the metabolism of other drugs Inducing enzymes result in lower drug levels; Inhibiting enzymes result in increased levels

37. Drug Interactions: HAART Nucleoside and Nucleotide drugs not eliminated via cytochrome P450 therefore these interactions are minimal Drug interactions here may occur via other mechanisms (eg GI absorption, renal elimination)

38. Non-nucleoside Interactions Drugs involved: Efavirenz: can induce or inhibit CYP3A4 (most often acts as an inducer and can also induce others) Nevirapine acts as an inducer to CYP3A4 Delavirdine acts as an inhibitor of CYP3A4 Etravirine is an inducer of CYP3A4 (inhibits CYP2C, and CYP2C19)

39. Protease Inhibitor Interactions All PIs inhibit CYP3A4 Ritonavir is the most potent inhibitor while Saquinavir is the least potent Ritonavir can inhibit other cytochrome P450 inhibitors and can induce CYP1A2 Tipranavir can also be an inducer

40. Other classes Fusion inhibitors and integrase inhibitors are not metabolized by these systems

41. Effects of Food on Absorption of Antiretrovirals Didanosine Levels decrease by 55% Take ½ hour before or 2 hours after meals Efavirenz Empty stomach, food increases levels as high as 39%-79% Amprenavir High fat meal decreases blood levels Can take with food but avoid high fat f-Amp not affected as much

42. Food Effects Continued.. Ritonavir Take with food; increases bioavailability Indinavir Food decreases levels by 77% (not a problem if boosted with ritonavir) Take 1 hr before or 2 hr after or may take with skim milk or low fat meal Nelfinavir Levels increase 2-3 fold with food; Take with food

43. Food Effects Continued.. Saquinavir (eg Fortovase, Invirase) Levels increase 6-fold if taken with food Take with or up to 2 hours after a meal as sole PI or with RTV Lopinavir/Ritonavir (Kaletra) Take with food AUC increased when taken with food

44. Effect of Buffering Agents on PI Concentrations Mechanism PI absorption is related to its solubility properties For weak bases-solubility increases in gastric acid When pH is less acidic, PIs become less soluble to varying degrees ion-trapping mechanisms will cause acidic compounds (weak bases) to accumulate in alkaline compartmentsion-trapping mechanisms will cause acidic compounds (weak bases) to accumulate in alkaline compartments

45. Effect of Buffering Agents on Gastric pH Buffering agents Proton-pump inhibitors (PPIs) Histamine-2 (H2) blockers Antacids calcium carbonate and magnesium hydroxide in didanosine buffered tablets (Videx) Duration of action Decrease in gastric acidity varies by drug class PPI > H2 blockers > antacids  24 - 72h 10 – 12h a few hours

46. Effect of Buffering Agents on Antiretroviral Drug Absorption Didanosine (ddI) Contains buffering agents that can affect absorption of: Atazanavir Tetracyclines Quinolones Itraconazole Proton Pump Inhibitors, H2 antagonists and Antacids Atazanavir absorption decreased Note manufacturer’s dosing recommendation as follows

47. Dosing Recommendations for Use of PPIs with Atazanivir Treatment Naïve Patients PPI max dose equal to 20mg omeprazole given 12 hrs before atazanvir 300mg with ritonavir 100mg Treatment Experienced Patients Avoid use as per manufacturer’s recommendations

48. Examples of Noted Interactions Between Antiretrovirals Efavirenz and Nevirapine Decrease Atazanavir levels Tenofovir and ddI ddI levels are elevated (exact mechanism not known fully) Recommend 250mg ddI-EC (>60 kg) Some reports to suggest decreased virologic control when this combination used as NRTI backbone with EFV or NVP

49. Antiretroviral Interactions Continued Tenofovir and Atazanavir Atazanavir levels are decreased Tenofovir concentrations increased Atazanavir should be boosted with RTV when combined Does not seem to be clinically significant with PIs such as lopinavir/ritonavir (Kaletra) Tenofovir may compete for tubular secretion for wide variety of drugs as well

50. Other Interactions: Maraviroc When given with strong CYP3A inhibitors (with or without CYP3A inducers) including PIs (except tipranavir/ritonavir), delavirdine 150 mg twice daily With NRTIs, tipranavir/ritonavir, nevirapine, and other drugs that are not strong CYP3A inhibitors or CYP3A inducers 300 mg twice daily (i.e. that do not have a net CYP3A inhibition or induction effect) With CYP3A inducers including efavirenz (without a strong CYP3A inhibitor) 600 mg twice daily

51. Drug Interactions with Drugs Used in Treating Addiction Methadone Efavirenz and nevirapine decreases methadone levels; Delavirdine effects unknown Abacavir decreases methadone clearance Methadone decreases stavudine levels but increases zidovudine PIs decrease levels and patients can have symptoms of withdrawal

53. Drug Interactions with Antiretrovirals Antifungal agents Review of specific agents with dosage adjustments Antilipidemic agents Selection of proper agents to avoid interactions. Avoid: simvastatin (Zocor®) and lovastatin (Lescol®) Dosage adjustment: when using rosuvastatin (Crestor®) with lopinavir, do not exceed 10 mg/day of rosuvastatin Antimycobacterial agents Major interactions to consider Management Issues

54. Drug Interactions Continued Anticonvulsants Carbamazepine, Phenobarbital and Phentyoin Effect on serum concentrations of ARV Concomitant effects on anticonvulsant levels

55. Drug Interactions Herbal Products St John’s Wort Kava Kava Other herbals that cause hepatotoxicity Other herbal products to consider

56. Role of the Clinician in Drug Interaction Detection and Prevention Question patients concerning Nonprescription Drug Usage Herbal and Natural Product Usage Use appropriate literature sources to obtain reliable and consistent information www.aidsinfo.nih.gov www.hivinsite.com www.hiv-druginteractions.org Prescribing information on web Communication among providers is key

57. Summary Talk with patients to stress adherence to therapy Review all medications with patients Function in an interdisciplinary environment

61. Mechanism of NRTI Associated Lactic Acidosis: Specifics During normal glycolysis, glucose is converted to pyruvate in the cytosol and is transferred into the mitochondria Once the pyruvate is in the mitochondria, most of it is converted into acetylcoenzyme A, which in turn enters the tricarboxylic acid cycle to form NADH (nicotinamide adenine dinucleotide) NADH is used by the mitochondria to produce ATP through oxidative phosphorylation; DNA polymerase is inhibited in the presence of NRTIs which diminishes mitochondrial function (especially oxidative phosphorylation)

62. Continued Pyruvate and NADH accumulate and the conversion of pyruvate to lactate is enhanced Impaired oxidation leads to decreased fatty acid oxidation resulting in accumulation of free fatty acids Free fatty acids are converted to triglycerides and accumulate in liver causing hepatic steatosis

63. Facial Wasting

64. Adverse Effects Clinical Features of Peripheral Fat Loss Peripheral fat loss in face, limbs, buttocks Accumulation of fat centrally in abdomen and breast and over dorsocervical spine (buffalo hump) Dyslipidemia Elevation in triglyceride and cholesterol levels Can respond to antihyperlipidemics