HIV Medication Overview John J. Faragon , PharmD , BCPS, AAHIV-P Albany Medical Center Hospital NY/NJ AIDS Education a

1. HIV Medication OverviewJohn J. Faragon, PharmD, BCPS, AAHIV-PAlbany Medical Center HospitalNY/NJ AIDS Education and Training Center

2. When to Start

3. DHHS: Changing Criteria for Initiating ART

4. Current Guidelines for Initiating ART – Other Guidelines *If a patient with CD4+ count > 350 cells/mm³ wishes to start ART to reduce the risk of transmission to partners, that wish should be respected and ART started. †With the exception of an HIV-positive partner in a serodiscordant relationship, who should be offered antiretroviral therapy at CD4+ count > 350 cells/mm³ to prevent transmission to the uninfected partner.

5. www.aidsetc.org Potential Benefits of Early Therapy: Supporting Data (2) • CD4 count >500 cells/µL • Cohort study data are not consistent; some show survival benefit if ART initiated early • Other considerations (eg, potential benefit of ART on non-AIDS complications, HIV transmission risk) support recommendation for ART • Data not entirely conclusive, especially for patients with very high CD4 counts…

6. Why treat at CD4 >500 cells/mm3? • Untreated HIV infection and ongoing viremia associated with development of non-AIDS defining diseases such as • Cardiovascular Disease • Renal disease • Liver disease • Neurologic complications • Malignancy www.aidsetc.org

7. Community Viral Load Mirrors Reduced Rate of New HIV Cases in San Francisco • Retrospective analysis of relationship between community viral load (CVL; mean of summed individual HIV-1 RNA results per yr) and new HIV diagnoses P = .005 for association* Mean CVL 30,000 1200 Newly diagnosed and reported HIV cases 25,000 1000 20,000 800 Mean Community Viral Load (copies/mL) Number of Newly Diagnosed HIV Cases 798 15,000 600 642 523 518 10,000 400 434 5000 200 0 0 2004 2005 2006 2007 2008 Yr *Data insufficient to prove significant association with reduced HIV incidence. Das-Douglas M, et al. CROI 2010. Abstract 33. Reproduced with permission.

8. START Study • INSIGHT Network: multinational • Study population: adults with CD4 >500 • Study treatment: • Immediate ART • CD4 <350 • Study endpoints: • Serious AIDS-defining illness, non-AIDS illness, death • Sample size: • N=900 (pilot for feasibility; enrollment completed) • N=3100 (definitive) • Duration: ~6 yrs. http://insight.ccbr.umn.edu- START Protocol Synopsis

9. What to Start

10. www.aidsetc.org Current ARV Medications 26 medications, but we use only about ½ of them usually

11. 8AM 4PM 12 MID 3-Drug Combination ART 1996: Crixivan/Retrovir/Epivir Fasting (1 hour before/2 hours after meals)1.5 liters of hydration/day

12. HIV Lifecycle And Drug Targets Fusion Entry Inhibitors Nukes and Non Nukes Budding Reverse transcription Uncoating Viral DNA Assembly 3’-processing Viral proteins Pre-Integration Complex Integrase Inhibitors Protein chains Viral RNA Integration (strand transfer) Nucleus Translation Transcription Human Genomic DNA Viral DNA RNA Protease Inhibitors

13. DHHS Guidelines Update 2014: Recommended Regimens in ARV Naives Regardless of Baseline CD4 and Viral Load Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14

14. DHHS Guidelines Initial Recommended Regimens - 2014 Atripla 1/day Reyataz/Norvir/Truvada 3/day Prezista/Norvir/Truvada 3/day Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14.

15. DHHS Guidelines Initial Recommended Regimens - 2014 Isentress (BID)/Truvada 3/day Tivicay/Truvada OR Epzicom 2/day OR Stribild 1/day Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14.

16. Atripla Key Points • 3 drugs in one tablet • Efavirenz/tenofovir/emtricitabine • AKA Sustiva+Truvada • Dosed at bedtime usually • Pregnancy Category D • CNS side effects common in first few weeks • Renal side effects possible with tenofovir

17. ReyatazNorvirTruvadaKey Points • 3 pills daily • “Boosted” PI regimen • Dosed once a day with food • GI side effects, minimal effect on lipids • Hyperbilirubinemia, nephrolithiasis • Proton Pump Inhibitor interaction • Renal side effects possible with tenofovir

18. PrezistaNorvirTruvadaKey Points • 3 tablets daily • “Boosted” PI regimen • Dosed once a day with food • GI side effects, minimal effect on lipids • Sulfa moeity • Renal side effects possible with tenofovir • 400mg off market now!

19. Ritonavir (Norvir®, RTV, r) • Dosing / Administration • For PI-boosting: 100-200mg PO BID or daily • Full dose - 600mg PO Q12H (usually wrong) • Take with food to improve tolerability • Refrigerate capsules • Adverse effects • GI effects, taste perversion, circumoral tingling •  [cholesterol] &  [triglycerides] • Drug interactions • Potent CYP3A4 inhibitor and inducer

20. Single-Dose Pharmacokinetics of LopinavirWith and Without Ritonavir Lopinavir/ritonavir Lopinavir Concentration (mg/mL) IC50 wt HIV Lopinavir alone 0 6 12 18 24 30 36 42 48 Time After Dosing (hr) Sham HL, et al. Antimicrob Agents Chemother. 1998;42(12):3218-3224; Lal R, et al., 37th ICAAC, 1997, # I-194

21. Why Norvir Boosted Protease Inhibitors • Less resistance – nearly no resistance reported in naïve trials with all boosted PI regimens currently on guidelines • Lower pill burdens • Reduced frequency – now all are once daily, versus 2-3 times daily for unboosted protease inhibitors • “Ritonaphobia” is the REAL downside

22. IsentressTruvada Key Points • 3 tablets • Isentress dosed twice a day • Once daily dosing possible, but inferior to BID • Well tolerated, no effect on lipids • Renal side effects possible with tenofovir

23. Stribild Key Points • 4 drugs in one tablet • Elvitegravir – a new integrase inhibitor • Cobicistat – a new booster (does the same thing as RTV) • Tenofovir – preferred NRTI • Emtricitiabine – preferred NRTI • Head to head data with Atripla and Reyataz/Norvir/Truvada showed similar results (non-inferior at 48 weeks) Sax P, et al. CROI 2012. Abstract 101. DeJesus E, et al. CROI 2012. Abstract 627.

24. Stribild – Additional Information • Contains cobicistat • Booster for the elvitegravir • Similar to Norvir for drug interactions • Increased creatinine levels due to inhibition of tubular secretion of creatinine back into bloodstream in the kidney • Similar to cimetidine

25. Tubular Reabsorption Substances reabsorbed back into blood from the renal tubule Tubular Secretion Substances secreted from the blood back into renal tubule for elimination Blocking Tubular Secretion Cobicistat BLOCKS tubular secretion of creatinine, causing an increase in blood levels of creatinine X

26. FDA-approved August 12, 2013 Approved for wide range of HIV populations, adults and children aged 12 and above and at least 40kg New integrase inhibitor dosed as a 50 mg tablet Once daily for treatment-naïve patients Twice daily for integrase treatment-experienced patients Can be taken with or without food Pregnancy category B Adverse events > 2% were insomnia and headache Contra-indicated to be given with dofetilide, an anti-arrhythmic Submitted to FDA STR of Epzicom/dolutegravir Tivicay Key Points OR

27. Tivicay Dosing • Treatment naïve or treatment experienced, integrase inhibitor naïve • 50mg once daily • Treatment naïve or treatment experienced, with UGT1A/CYP3A4 inducers: Efavirenz, fosamprenavir/ritonavir, tipranavir, or rifampin • 50mg twice daily • Integrase inhibitor with II resistance • 50mg twice daily • No food restrictions • Separate from cations – ie Magnesium, Calcium, Iron

28. DHHS Guidelines Update 2014: Recommended Regimens, ARV Naives, ONLY if Pre ART Viral Load <100,000 copies/ml Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14

29. CompleraRilpivirine/tenofovir/emtricitabine • STR once daily • Food required • Take antacids at least 2 hours before or at least 4 hours after • Take H-2 blockers at least 12 hours before or at least 4 hours after • PPIs are contraindicated

30. DHHS Guidelines Update 2014Alternative Regimens in ARV Naives Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14

31. Preferred NRTI Backbones in Pregnancy – DHHS Perinatal Guidelines, March 2014 Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 5/2/14

32. Preferred PI, NNRTI Regimens in Pregnancy – DHHS Perinatal Guidelines, March 2014 Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 5/2/14

33. What to Avoid

34. www.aidsetc.org ARV Medications: Should NOTBe Offered at ANY Time • ARV regimens not recommended: • Monotherapy with NRTI* • Monotherapy with boosted PI • Dual-NRTI therapy • 3-NRTI regimen (except ABC + 3TC + ZDV or possibly TDF + 3TC + ZDV) * ZDV monotherapy is not recommended for prevention of perinatal HIV transmission but might be considered in certain circumstances; see Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions toReduce Perinatal HIV Transmission in the United States.

35. www.aidsetc.org ARV Medications: Should NOTBe Offered at ANY Time • ARV components not recommended: • Didanosine + stavudine • Didanosine + tenofovir • Emtricitabine + lamivudine • Stavudine + zidovudine • Darunavir, saquinavir, or tipranavir as single, unboosted PIs • Atazanavir + Indinavir

36. www.aidsetc.org ARV Medications: Should NOTBe Offered at ANY Time • ARV components not recommended: • Efavirenz during first trimester of pregnancy and in women with significant potential for pregnancy • Nevirapine initiation in women with CD4 counts of >250 cells/µL or in men with CD4 counts of >400 cells/µL • Etravirine + unboosted PI • Etravirine + boosted Atazanavir, fosamprenavir or tipranavir • Any combination of 2 NNRTIs

37. PrEP Guidelines

38. 2014 CDC PrEP Guidelines • Guidelines for PrEP were released in May 2014 • Addresses the role of PrEP in the following adult populations • Men who have sex with men • Heterosexual men and woman • Injection Drug Users • Sero-discordant couples • ONLY medication to be used in this setting is tenofovir/emtricitabine (Turvada) http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.

39. Results of PrEP Trials, CDC Center for Disease Control. MMWR. June 14, 2013 / 62(23);463-465

40. 2014 CDC PrEP Guidelines – Recommended Indications for PrEP Use in MSM • Adult man • Without acute or established HIV infection • Any male sex partners in past 6 months • Not in a monogamous partnership with a recently tested, HIV-negative man • AND at least one of the following • Any anal sex without condoms (receptive or insertive) in past 6 months • Any STI diagnosed or reported in past 6 months • Is in an ongoing sexual relationship with an HIV-positive male partner http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.

41. 2014 CDC PrEP Guidelines – Recommended Indications for PrEP Use in Heterosexual Men and Women • Adult person • Without acute or established HIV infection • Any sex with opposite sex partners in past 6 months • Not in a monogamous partnership with a recently tested HIV-negative partner • AND at least one of the following • Is a man who has sex with both women and men (behaviorally bisexual) • Infrequently uses condoms during sex with 1 or more partners of unknown HIV status who are known to be at substantial risk of HIV infection (IDU or bisexual male partner) • Is in an ongoing sexual relationship with an HIV-positive partner http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.

42. 2014 CDC PrEP Guidelines – Recommended Indications for PrEP Use Injection Drug Users • Adult person • Without acute or established HIV infection • Any injection of drugs not prescribed by a clinician in past 6 months • AND at least one of the following • Any sharing of injection or drug preparation equipment in past 6 months • Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months • Risk of sexual acquisition http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.

43. 2014 CDC PrEP Guidelines – Monitoring • All patients receiving PrEP should be seen as follows: • At least every 3 months to • Repeat HIV testing and assess for signs or symptoms of acute infection to document that patients are still HIV negative • Repeat pregnancy testing for women who may become pregnant • Provide a prescription or refill authorization of daily TDF/FTC for no more than 90 days (until the next HIV test) • Assess side effects, adherence, and HIV acquisition risk behaviors • Provide support for medication adherence and risk-reduction behaviors • Respond to new questions and provide any new information about PrEP use http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.

44. 2014 CDC PrEP Guidelines – Monitoring • At least every 6 months to • Monitor eCrCl • If other threats to renal safety are present renal function may require more frequent monitoring or may need to include additional tests • A rise in serum creatinine is not a reason to withhold treatment if eCrCl remains ≥60 ml/min. • If eCrCl is declining steadily (but still ≥60 ml/min), consultation with a nephrologist may be indicated. • Conduct STI testing recommended for sexually active adolescents and adults (i.e., syphilis, gonorrhea, chlamydia) • At least every 12 months to • Evaluate the need to continue PrEP as a component of HIV prevention http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.

45. PEP Guidelines

46. HIV Prophylaxis Following Exposure • The Medical Care Criteria Committee now recommends tenofovir + emtricitabine* plus raltegravir as the preferred initial PEP regimen • excellent tolerability, proven potency, and ease of administration. • Zidovudine is no longer recommended • no clear advantage in efficacy over tenofovir • higher rates of treatment-limiting side effects.

47. HIV Prophylaxis Following Occupational Exposure • Recommendations place emphasis on the importance of initiating occupational PEP as soon as possible, ideally within 2 hours of exposure. • First dose of PEP should be offered while evaluation is underway. • PEP should not be delayed while awaiting source patient or results of the exposed baseline HIV test.

48. Updated Public Health Service Occupational PEP Guidelines, November 2013 Preferred HIV PEP Regimen Raltegravir(Isentress; RAL) 400 mg PO twice daily PLUS Truvada, 1 PO once daily(Tenofovir DF [Viread; TDF] 300 mg + emtricitabine [Emtriva; FTC] 200 mg) Fixed Dose Combination Kuhar DT. Infect Control HospEpidemiol. 2013;34(9):875-92.

49. Resources

50. Web Resources of Interest • DHHS Guideline Tables • http://www.aidsinfo.nih.gov/guidelines/ • NY/NJ AIDS Education and Training Center • http://www.nynjaetc.org/ • University of Liverpool • www.hiv-druginteractions.org • Toronto HIV Clinic • http://www.hivclinic.ca/main/home