1. Antiretroviral Update Sarah Ryan, PharmD February 17, 2010

2. Learning Objectives Adherence counseling Initiating therapy Recommended antiretroviral regimens Antiretrovirals (ARVs) in pregnancy Common adverse effects of ARVs and counseling points Opportunistic Infection prophylaxis Drug Interactions

3. Adherence 95% of ARV doses must be taken for optimal viral suppression –QD regimen – missing no more than 1 dose/month –BID regimen – missing no more than 3 doses/month Inadequate viral suppression can lead to multi-drug and multi-class resistance

5. Initiating Antiretroviral Therapy ARVs should be started in all patients with History of an AIDS-defining illness CD4 < 350 Pregnancy HIV associated nephropathy Hepatitis B coinfection when hep B treatment is indicated

6. Initiating Antiretroviral Therapy (cont’d) CD4 between 350 and 500 –ARV therapy is recommended –Panel is divided in its strength of this recommendation CD4 > 500 –50% of panel favors starting therapy –50% view treatment as optional Patients must be willing to commit to lifelong treatment (risk vs. benefit, adherence)

7. Choosing an Initial Antiretroviral Regimen 3 types of combination regimens NNRTI + 2 NRTIs PI (preferably boosted) + 2 NRTIs INSTI + 2 NRTIs Regimen selection should be individualized - Virologic efficacy- Drug-drug interactions - Toxicity- Resistance testing - Pill burden- Comorbid conditions - Dosing frequency

8. Initial Treatment: Preferred Regimens NNRTI - based - Atripla (efavirenz/tenofovir/emtricitabine) PI - based - Boosted Reyataz (atazanavir) + Truvada (tenofovir/emtricitabine) - Boosted Prezista (darunavir) (once daily) + Truvada INSTI - based - Isentress (raltegravir) + Truvada Pregnancy - Kaletra (lopinavir/ritonavir) (twice daily) + Combivir

9. Initial Treatment: Alternative Regimens NNRTI - based - Sustiva (efavirenz) + Epzicom (lamivudine/abacavir) or Combivir (zidovudine/lamivudine) - Viramune (nevirapine) + Combivir PI - based - Boosted Reyataz (atazanavir) + Epzicom or Combivir - Boosted Lexiva (fosamprenavir) + Truvada (tenofovir/emtricitabine) or Epzicom or Combivir - Kaletra (lopinavir/rtv) + Truvada or Epzicom or Combivir - Boosted Invirase (saquinavir) + Truvada

10. ARV Regimens NOT Recommended Monotherapy Dual-NRTI regimen Triple-NRTI Regimen –Possible exceptions: Abacavir/zidovudine/lamivudine (Trizivir) Tenofovir (Viread) + zidovudine/lamivudine (Combivir)

11. ARV Components NOT Recommended Stavudine (Zerit) + Zidovudine (Retrovir) Stavudine + Didanosine (Videx) Emtricitabine (Emtriva) + Lamivudine (Epivir) Saquinavir (Invirase), Darunavir (Prezista), or Tipranavir (Aptivus) without Ritonavir Etravirine (Intellence) + ritonavir boosted Atazanavir (Reyataz), Fosamprenavir (Lexiva), or Tipranavir Etravirine + unboosted PI

12. Pregnancy ARVs decreased transmission from 20-30% to < 2% 1st line: Kaletra (lopinavir/rtv) + combivir (zidovudine/lamivudine) Most ARVs are Category B or C Avoid: Sustiva (efavirenz), Category D Caution –Viramune (nevirapine) if CD4 > 250 –Videx (didanosone) + Zerit (stavudine) Insufficient data –Prezista (darunavir), Lexiva (fosamprenavir), Aptivus (tipranavir), Fuzeon (enfuvirtide), Selzentry (maraviroc), Isentress (raltegravir), Intellence (etravirine)

13. Adverse Effects and Counseling Points

14. NRTIs Most are excreted renally –Dose adjustments are necessary –Exceptions: zidovudine (Retrovir) and abacavir (Ziagen) Do not have P-450 drug interactions Taken without regard to food –Exception: didanosine (Videx) needs to be taken on an empty stomach unless taken with tenofovir (Viread)

15. Adverse Effects: NRTIs Hypersensitivity reaction – Abacavir (Ziagen) –5% of patients, usually within first 6 weeks –Can be fatal, especially with rechallenge –S/sx: rash, fever, fatigue, malaise, GI or respiratory sx –HLA-B*5701 testing –Abacavir is a component of Trizivir and Epzicom

16. Adverse Effects: NRTIs (cont’d) Abacavir (Ziagen, ABC) –Potential for increased cardiovascular events Zidovudine (Retrovir, AZT) –Bone marrow suppresion Tenofovir (Viread, TDF) –Nephrotoxicity (dose adjust if CrCl<50 ml/min) Emtricitabine (Emtriva, FTC) –Hyperpigmentation of palms and soles Didanosine (Videx, ddI) –Pancreatitis –Reports of noncirrhotic portal hypertension

17. Adverse Effects: NRTIs (cont’d) Mitochondrial dysfunction Lactic acidosis Peripheral neuropathy Hepatic steatosis Lipodystrophy Pancreatitis D-drugs d4T>ddI>ZDV>TDF=ABC=3TC=FTC (stavudine>didanosine>zidovudine>tenofovir=abacavir=lamivudine=emtricitabine)

18. Adverse Effects: Lipodystrophy Associated with HIV-infection, PIs, and NRTIs (especially Zerit, stavudine,d4T) Lipodystrophy syndrome: –Fat accumulation –Insulin resistance –Hyperlipidemia –Fat atrophy

19. PIs Take with food! –Exceptions: Unboosted indinavir (Crixivan) should be taken on an empty stomach –Kaletra (lopinavir/RTV) and Lexiva (fosamprenavir) can be taken with or without food –N/V/D are common AEs –Commonly prescribe antiemetics (promethazine, compazine, metoclopramide) and antidiarrheals (loperamide, lomotil, calcium)

20. Adverse Effects: PIs Atazanvir (Reyataz) –hyperbilirubinemia Indinavir (Crixivan) –kidney stones Nelfinavir (Viracept) –diarrhea Tipranavir (Aptivus) –intracraneal hemorrhage All PIs –elevated LFTs PIs containing sulfa moieties: –Darunavir (Prezista) –Fosamprenavir (Lexiva) –Tipranavir (Aptivus) –Not a contraindication –Use with caution

21. Adverse Effects: NNRTIs Nevirapine (Viramune) –Rash, SJS Dose 200mg qd x 14 days, then 200mg bid –Elevated LFTs, hepatitis, liver failure Higher risk with higher CD4 counts, in women, Hep B or C LFTs q 2 wks x 1 month, monthly x 3 months, then q 3 months Efavirenz (Sustiva) –CNS AEs: abnormal dreams, drowsiness, dizziness, confusion Take on an empty stomach or with a low-fat snack –Rash, elevated LFTs, hyperlipidemia –Teratogenic

22. Fusion Inhibitors Fuzeon (Enfuvirtide, T-20) –90mg BID SQ injection –Used in treatment experienced patients only –Injection site reactions are common

23. CCR5 Inhibitors Maraviroc (Selzentry) –Patients with CCR5 tropic virus –Recently approved in treatment naïve patients –Increased risk of CV events, postural hypotension, hepatotoxicity (can be preceded by hypersensitivity reaction) –Common AEs: cough, fever, URI, rash, sore muscles, abdominal pain, dizziness –Dosing is based on concomitant meds

24. Integrase Inhibitors Raltegravir (Isentress) Now used as part of a first line regimen Common AEs: nausea, headache, diarrhea, fever 400mg bid, with or without food

25. Patient Information New Mexico AIDS Education and Training Center - www.aidsinfonet.org Fact sheets on all ARVs as well as topics such as adherence, resistance, labs, OIs

26. Howie Ganser, RPh Opportunistic Infection Prophylaxis

27. Preventing OIs: Pneumocystis carinii (PCP) CD4 < 200 or oropharyngeal candidiasis 1st choice: –TMP-SMZ, one DS daily –TMP-SMZ, one SS daily Discontinue when CD4 > 200 for  3 months

28. Preventing OIs: PCP (cont’d) Alternatives: –Dapsone 100mg qd –Dapsone 50mg qd + pyrimethamine 50mg weekly + leucovorin 25mg weekly –Dapsone 200mg + pyrimethamine 75mg + leucovorin 25mg weekly –Aerosolized pentamidine 300mg monthly –Atovaquone 1500mg qd –TMP-SMZ one DS three times weekly

29. Preventing OIs: Toxoplasma gondii CD4 < 100 and antibody to Toxoplasma 1st choice: –TMP-SMZ, one DS qd Discontinue when CD4 > 200 for  3 months

30. Preventing OIs: Toxoplasmosis (cont’d) Alternative regimens: –TMP-SMZ, 1 SS daily –Dapsone 50mg qd + pyrimethamine 50mg weekly + leucovorin 25mg weekly –Dapsone 200mg + pyrimethamine 75mg + leucovorin 25mg weekly –Atovaquone 1500mg qd with or without pyrimethamine 25mg qd + leucovorin 10mg qd

31. Preventing OIs: Mycobacterium avium complex CD4 < 50 Discontinue when CD4 > 100 for  3 months 1st choice: –Azithromycin 1200mg weekly –Clarithromycin 500mg bid Alternatives: –Rifabutin 300mg qd –Azithromycin 1200mg qd + rifabutin 300mg qd

32. Drug-Drug Interactions

33. Selected CYP450 Interactions Common Inducers –Nevirapine (Viramune) –Efavirenz (Sustiva) –Rifampin –Rifabutin –Antiepileptics (phenytoin, CBZ, phenobarb) –Herbal supplements (St. John’s Wort, Garlic) Common Inhibitors –Protease Inhibitors –Ketoconazole > Itraconazole > Fluconazole –Delavirdine (Rescriptor) –Efavirenz (Sustiva) –Macrolid abx (erythro > clarithromycin)

34. Selected Substrates of CYP450 CYP 3A4 Substrates –Benzodiazepines –Macrolides (not azithro) –Quinidine –Cisapride (propulsid) –Sildenafil (Viagra) & other ED therapies –PIs –Calcium Channel Blockers –Statins –Methadone CYP 2D6 Substrates –Beta blockers –Tricyclic antidepressants –SSRIs –Haloperidol –Risperidone

35. Protease Inhibitors: Common Drug Interaction Pearls Anxiety/insomnia –Use lorazepam or temazepam –Avoid midazolam and triazolam –Use caution with buspirone and other BZDs Lipid lowering drugs –Use fluvastatin, pravastatin, or rosuvastatin –Use atorvastatin at low-dose with caution –Avoid simvastatin and lovastatin

36. PIs: Common Drug Interaction Pearls (cont’d) Antidepressants –Start low, and go slow! –Avoid fluvoxamine, nefazodone, and St. John’s Wort Anticonvulsants –Interactions not likely with valproic acid, gabapentin, lamotrigine, levetiracetam, topiramate, tiagabine –Avoid carbamazepine and phenytoin

37. PIs: Common Drug Interaction Pearls (cont’d) Antipsychotics –Consider lower starting dose with risperidone, ziprasidone, aripiprazole, haloperidol –Avoid chlorpromazine, thioridazine, and pimozide –Use caution with quetiapine (may have increased levels) and olanzapine (may need higher dose)

38. PIs: Common Drug Interaction Pearls (cont’d) Erectile Dysfunction –Start with low doses –Sildenafil (Viagra) - q 48 hours –Tadalafil (Cialis) and Vardenafil (Levitra) - q 72 hours

39. Miscellaneous Interactions Atazanavir (Reyataz) + Acid-reducing agents –Give at least 2 hours before or 1 hour after antacids –Take 2 hours before or 10 hours after H2 blockers (ie: ranitidine) –With norvir: Administer simultaneously with and/or ≥ 10 hours after H2 blocker –With Tenofovir (Viread, Truvada) and H2 blocker in PI- experienced pts, use Reyataz 400mg + Norvir 100mg –PPIs are not recommended in patients on unboosted Reyataz or PI- experienced pts –PI-naïve patients should not exceed omeprazole 20mg qd administered at least 12 hours prior to boosted Reyataz

40. Drug Interaction Resources www.hivinsite.ucsf.edu www.aidsinfo.nih.gov (DHHS Guidelines) http://depts.washington.edu/madclin/pharm acy/drugs/index.html Micromedex