1. Session 6 BASIC HAART AND DRUG INTERACTIONS Mary Bishop RPH, AAHIVE HIV/AIDS Clinical Pharmacist UofL Healthcare Pharmacy 11/05/11

2. HIV life cycle http://www.youtube.com/watch?v=RO8MP3 wMvqg&feature=player_profilepage http://www.youtube.com/watch?v=RO8MP3 wMvqg&feature=player_profilepage

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5. Goal of Therapy Maximally and durably suppress plasma HIV viral load Reduce HIV-associated morbidity and prolong survival Improve QOL Restore and preserve immune function Prevent HIV transmission

6. 6 Starting Therapy RecommendationStrength AIDS-Defining IllnessAI CD4 < 350AI PregnancyAI HIV-Associated Nephropathy (HIVAN)AII Hepatitis B Virus (HBV) co-infection [when HBV treatment is indicated] AIII CD4 350-500A/BII † CD4 > 500B/CIII ‡ † Panel divided, 55% voted for strong recommendation (A) and 45% voted for moderate recommendation (B) (A/B-II). ‡ Panel divided, 50% favor starting antiretroviral therapy at this stage of HIV disease (B); 50% view initiating therapy at this stage as optional (C) (B/C-III). 6

7. 7 15 YEARS OF “HAART” 24 years since first drug We now have : 7 Nucleoside/tide analogs (4 combos) 5 Non-nucleoside analogs (2 combos) 9 Protease Inhibitors 1 Fusion Inhibitor 1 CCR5 antagonist 1 Integrase Inhibitor

8. 8 What drug to use when? Guidelines – http://AIDSinfo.nih.gov – IAS-USA – WHO Patient assessment and education Genotype

9. 9 Recommended HAART* in Treatment Naïve Patients * highly active ant-retroviral therapy 1 NNRTI + 2 NRTI’s EFV + TDF + FTC (Atripla®) 1 PI (preferable PI/r) + 2NRTI’s ATV/r + TVD DRV/r + TVD 1 INSTI + 2 NRTI’s RAL + TVD Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 37

10. 10 Panel also recommends that medication selection… Individualized based on viral efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and co-morbid conditions. Based on individual patient characteristics and needs, in some instances, an alternative regimen may actually be a preferred regimen for a patient. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 37

11. 11 Adenosine Didanosine (ddI) Tenofovir (TDF) Cytosine Zalcitabine (ddC) Lamivudine (3TC) Emtricitabine (FTC) Guanine Abacavir (ABV) Amdoxovir (DAPD) Thymine Zidovudine (ZDV) Stavudine (d4T) Clin Ther 2000; 22: 685-708 NRTI Structures

12. 12 NRTI’s… Considered the backbone of HAART therapy All but Abacavir need dosing adjustments for renal insufficiency All have black box warnings Short term side effects mostly GI related

13. NRTI’s… Zidovudine AZT(Retrovir®)Marrow suppression Didanosine ddI(Videx EC®)Peripheral neuropathy Stavudine d4T(Zerit®)Peripheral neuropathy Lamivudine 3TC(Epivir®)Headache, Nausea Emtricitabine FTC(Emtriva®)Headache, Nausea Abacavir ABC(Ziagen®)Hypersensitivity

14. 14 NRTI Combinations Truvada (FTC/TNF) or TDV Epzicom (ABC/3TC) or EPZ Combivir (AZT/3TC) or CBV Trizivir (ABC/3TC/AZT) or TZV (No combination products should be used in renally impaired patients CrCl <50ml/min)

15. 15 TDF (Tenofovir) Viread® Nucleotide Reverse Transcriptase 300mg Daily +/- food ADE Asthenia, HA, NVD, flatulence Renal insufficiency, Fanconi syndrome Osteomalacia, decrease in bone mineral density Activity against Hepatitis B Part of Truvada®, Atripla®, and Complera®

16. 16 FTC (Emtricitabine) Emtriva® 200mg daily +/- food Dizziness, HA, Rash, insomnia Hyper-pigmentation/skin discoloration Also has activity against Hepatitis B 184V mutation In Truvada®, Atripla®, and Complera®

17. 17 ABC (Abacavir) Ziagen® 300mg BID or 600mg Q Day +/- food some cohort studies suggest increase risk of MI with recent or current use of ABC but not substantiated with further studies HLA-B*5701 Risk of “hypersensitivity reaction” combination of symptoms »Group 1 Fever »Group 2 Rash »Group 3 GI symptoms »Group 4 Malaise, fatigue »Group 5 SOB, cough, or sore throat

18. 18 3TC (Lamivudine) Epivir® 150mg BID or 300mg daily +/- food Minimal toxicity Approved at 100mg to treat Hepatitis B In Combivir®, Trizivir®, Epzicom® 184V mutation

19. 19 AZT (Zidovudine) Retrovir® Dosed 300mg BID +/- food Recommended in pregnancy (as Combivir®) ADE – Bone marrow suppression, macrocytic anemia, neutropenia – GI intolerance, HA, insomnia, asthenia – Nail pigmentation, palate discoloration – Lactic acidosis and hepatic steatosis

20. 20 Zidovudine Pigmentation Dark discoloration of the upper palate and nails

21. 21 NNRTI’s Class ADR’s –Rash (Can treat through depending on severity) –^LFT’s, Hepatotoxicity Individual drugs –EFV (efavirenz) SUSTIVA® –NVP (nevirapine) VIRAMUNE® –ETV (etravirine) INTELENCE® –RPV (rilpivirine) EDURANT®

22. 22 EFV (Efavirenz) Sustiva® Dosed 600mg Q Day preferable bedtime Empty stomach to reduce side effects CNS side effects False + cannabinoid, benzodiazepine screening assay Pregnancy Category D

23. 23 NVP (Nevirapine) Viramune® 200mg daily x 14 day lead in period then BID +/- food or Daily as XR formulation Rash  SJD Symptomatic hepatitis including necrosis has been reported* Monitor LFT’s at 2,4,6 weeks then q 3 months * ^risk in treatment naive women with CD4> 250mg/dl or treatment naïve men with CD4>400mg/dl

24. 24 Atripla® Efavirenz 600mg+Emtricitibine 200mg+Tenofovir DF 300mg 1 st time two companies worked together 1 po Q HS on empty stomach Not for patients with CrCL<50ml/min Single co-pay?

25. Second generation NNRTI’s (effective in presence of K103N mutation) ETR (Etravirine) INTELENCE® 200mg po BID Rash, hepatotoxicity Salvage therapy CYP3A4 interactions – TPV, FPV, ATV RPV (Rilpivirine) EDURANT® 25mg daily w > 500kcal Rash, depression Don’t use if VL >100,000 D/I: PPI’s Pregnancy Cat. B

26. Battle of monotherapy? Atripla® Empty stomach Pregnancy Cat. D Any viral load CYP metabolism CNS disengagement, D/I with PI DHHS stamp of approval Complera® With food Pregnancy Cat B VL <100,000 CYP metabolism Depression D/I with PPI DHHS approval???

27. Protease Inhibitors Preferred in 2009 Atazanavir (Reyataz®) Darunavir (Prezista®) Preferred in Pregnancy Lopinavir/r (Kaletra®) Alternates… Saquinavir (Invirase®) Ritonavir (Norvir®) Indinavir (Crixivan®) Nelfinavir (Viracept®) Fosamprenavir (Lexiva®) Tipranavir (Aptivus®)

28. 28 Protease Inhibitors Changed HIV from fatal to chronic illness Class toxicities – Short term- N/V/D – Long term- insulin resistance, lipodystrophy, – lipid abnormalities – LFT elevations – ^risk of bleeding with hemophilia Most have drug interactions due to CYP metabolism in the liver requiring dosage adjustments of PI’s or other agent

29. 29 Elevated Lipids (Cholesterol and Triglycerides) Occurs with EFV and PI’s May increase risk for coronary heart disease Treat through or stop medication – “statins” (e.g. atorvastatin) – Fibrate (e.g. fenofibrate or gemfibrozil ) Prevention – Stop Smoking – Diet and exercise – Fish Oil

30. 30 ATV (Atazanavir) Reyataz® Dose is 300mg/100mg ATV/r + food. Lipid sparing if un-boosted Do not use with PPI’s Side effects (well tolerated) Indirect hyperbilirubinemia Nephrolithiasis PR prolongation Mutations at I50V, 84, and 88

31. 31 RTV (Ritonavir) Norvir® Potent CYP3A4 Inhibitor When used as lone PI, dose is 600mg BID (rare) Has 2 formulations – Capsules require refrigeration +/- food – Tablets must be taken with food, no refrigeration Side effects – NVD – Taste perversion – Parasthesias-circumoral and extremities Mutations at 82 and 84

32. 32 DRV (Darunavir) Prezista® ARV Naïve dose – 800mg/100mg po daily + food ARV experienced – 600mg/100mg po BID + food Side effects – Rash (sulfonamide moiety) – Diarrhea, Nausea – Headache – Fever

33. 33 MVC (Maraviroc) Selzentry® Only indicated for CCR5 tropic HIV-1 infection Dose is dependent on other drugs in the regimen – 150mg BID +/- food – 300mg BID +/- food – 600mg BID +/- food

34. 34 MVC continued… Side effects – Abdominal pain – Fever – Dizziness – Musculoskeletal symptoms – Cough, URI – Orthostatic Hypotension

35. Fusion Inhibitors Enfurvitide (Fuzeon ®) T-20 90mg SQ q 12 h $$ Injection site reactions Salvage therapy $$

36. 36 Integrase Inhibitor RAL (Raltegravir) Isentress® 400mg po BID +/- food Approved as 1 st line therapy Metabolism is glucaronidation NOT CYP450 SE – Nausea, Diarrhea – HA – Fever – CPK elevation

37. Which Therapy is Best? The regimen that the patient can take every dose every day At the same time.

38. 38 The Realities of Adherence: Get it right the first time: Establish readiness before initiating ART Anticipate common causes of poor adherence not related to the medication: Mental illness, drug use, homelessness, life instability, poor clinic attendance Pill Fatigue: Even excellent adherence may wane over time; consider pill burden and dosing frequency Tolerability: Side effects, drug interactions Wanted: Simple, tolerable, potent, effective, and forgiving ART regimen

39. CLINICAL SCENARIOS…

40. HIV Management “Co-Medicators” Opportunistic infections Malignancies Drug dependence Psychiatric disorders Neurologic manifestations Metabolic disorders

42. Opportunistic Infection Prophylaxis and Treatment Pneumocystic jiroveci formerly Pneumocystic carinii (PCP) Prophylaxis (CD4 + cell count <200): Bactrim DS 1 PO QD Treatment: Bactrim IV 15 mg/kg/d x 21 d Toxoplasmosis gondii Prophylaxis (CD4 + cell count <100): Bactrim DS 1 PO QD Treatment: Sulfadiazine and Pyrimethamine + folinic acid

43. Opportunistic Infection Prophylaxis and Treatment Mycobacterium avium Complex Prophylaxis (CD4 + cell count <50): Azithromycin 1200 mg PO Q week Treatment: Clarithromycin and Ethambutol Candida albicans Treatment: Fluconazole 100mg po x 7-14 days. Maintenance: Optimum prevention is immune reconstitution, but oral fluconazole is recommended for severe or frequent recurrence. Continuous use is not associated with more resistance than episodic treatment. (ACTG 323)

44. Anxiolytics Avoid: triazolam and midazolam Consider: short-acting agents -Lorazepam (Ativan®) -Oxazepam (Serax®) Consider: Buspirone (Buspar®) Alprazolam (Xanax®) should be used cautiously with ritonavir

45. Tuberculosis Rifampin (RIF) potent inducer of CYP Avoid RIF and PIs Rifabutin should be DOC Adjust rifabutin dose with EFV, ATV, NFV, fPV, IDV, RTV

46. Antidepressants Generally safe Some ARVs may potentiate TCAs, manifesting in pronounced anticholinergic effects Desipramine (Norpramin®) should be avoided SSRIs most common agent of choice, safer in overdose-start low and build as tolerated

47. Psychotropics Generally safe with few exceptions Area of drug development – best to consult references with regards to new agents Concerns regarding metabolic disturbances Avoid pimozide (Orap®) with PIs

48. Anticonvulsants Phenobarbital: potent CYP inducer Phenytoin: highly protein bound (AVOID) CBZ: increased toxicity when combined with PIs and/or CYP induction (AVOID) VPA: some studies have associated use with increases in viral load? Consider: gabapentin, pregabalin, lamotrigine, tiagabine, levotiracetam

49. Hypertension No significant interactions with typical anti- HTN agents ACE-I, ARBs, diuretics, beta-blockers, calcium channel blockers with PIs-√, Avoid bepridil (Vascor®) with PI’s

50. Anti-arrhythmics Use very cautiously in combination with PI’s Amiodarone, encainide, flecainide, propafenone, quinidine

51. Antihyperlipidemics Preferred agents for increased LDL: Pravastatin (Pravacol®) Atorvastatin (Lipitor®) Preferred agent for HyperTG: Gemfibrozil (Lopid®) Fenofibrate (Tricor®) Niacin appears safe – sustained release product (Niaspan®) may be preferred agent due to reduced incidence of hepatic dysfunction, increased serum glucose

52. Erectile Dysfunction Sildenafil, vardenafil, tadalafil Cautions: reduced metabolism when combined with PIs S: 25 mg q48h V: 2.5 mg q72h T: 10 mg q 72h Nitrates, nitrites, “Poppers”

53. Herbal Therapies St. John’s Wort -IDV AUC <50%(CYP3A4 and pGP induction) Garlic -Inhibition of CYP3A4; severe GI A/E with RTV Others: milk thistle, grapefruit juice, ginseng, skullcap

54. Questions 54

55. 55 References www.CDC.gov/HIV www.Medscape.com/hiv-aidshome www.Hopkins-aids.edu http:AIDSinfo.nih.gov Netaccess/Micromedix www.FAETC.org www.lexi.com