1/13/16. Updated April 2015

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1 Bernadette Jakeman, PharmD, PhC, BCPS, AAHIVP Assistant Professor UNM College of Pharmacy Pharmacist objectives: 1. Summarize key updates to the DHHS treatment guidelines. 2. Identify recommended antiretroviral regimens for treatment-naive patients. 3. Describe common side effects and drug interactions associated with the recommended antiretroviral regimens. Technician objectives: 1. Define HAART. 2. Define CD4 cell count and HIV viral load. 3. Explain why combination therapy is required in the management of HIV. Updated April 2015 Approximately 1.2 million people are living with HIV in the US 1 14% of infected patients remain undiagnosed 2 Undiagnosed responsible for 30-50% of new cases 3,4 CDC recommends testing for all patients ages years 5 1. CDC. MMWR June 26, 2015/64(24); Skarbinski J et al. JAMA Intern Med 2015;175: Marks G et al. AIDS 2006;20: CDC MMWR Sept 22, 2006/55(RR14);1-17 A. <100 cells/mm 3 B cells/mm 3 C cells/mm 3 D cells/mm 3 E. >500 cells/mm 3 1

2 Reverse Transcriptase Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs): Non-functional DNA building blocks which interrupts transcriptions Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Binds reverse transcriptase enzyme preventing transcription Integrase Integrase Strand Transfer Inhibitors (INSTIs): Bind viral integrase preventing integration of viral DNA into host genome Protease Protease Inhibitors (INSTIs): Bind viral protease preventing conversion of viral polypeptide into functional viral proteins NRTIs Tenofovir Emtricitabine Abacavir Lamivudine Zidovudine NNRTIs Efavirenz Rilpivirine Etravirine INSTIs Dolutegravir Raltegravir Elvitegravir (with cobicistat booster) PIs (boosted with ritonavir or cobicistat) Darunavir Atazanavir A. One B. Two C. Three D. Four E. Five 2

3 HAART: Combination HIV therapy that suppresses HIV replication and prevents emergence of drug resistance when taken appropriately Composed of 3 active medications from at least 2 classes Commonly includes: 2 NRTIs (backbone) + another medication class (NNRTI, INSTI, PI) >95% adherence required for virologic suppression Early HAART improves outcomes Kitahata MM et al. N Engl J Med.2009;360(18): Lundgren JD et al 2015;373; Estrella M et al. CID 2006;43: Bhaskaran K, et al. Ann Neurol. 2008;63: Lichtenstein K, et al. CID 2010;51: Quinn TC et al. N Engl J Med 2000;342: Therapy recommended for ALL HIVinfected patients, regardless of pretreatment CD4 count CD4 count <350 cells/mm3 (AI) CD4 cell count cells/mm3 (AII) CD4 cell count >500 cells/mm3 (BIII) Proven clinical efficacy Ease of administration (frequency, pill burden) Low drug-drug interaction potential Low side effect profile Baseline resistance testing recommended (GART) 1. Guidelines for the use of an- tiretroviral agents in HIV-1-infected adults and adolescents. DHHS. Available at centgl.pdf. Accessed 1/6/ INSIGHT START Study Group. N Engl J Med 2015;373: Dolutegravir + Abacavir/Lamivudine Superior to Efavirenz/Tenofovir/Emtricitabine INSTI-Based Regimens Dolutegravir/abacavir/lamivudine Dolutegravir + tenofovir/emtricitabine Elvitegravir/cobicistat/tenofovir/emtricitabine Raltegravir + tenofovir/emtricitabine NEW!: Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine PI-Based Regimen Darunavir + ritonavir + tenofovir/emtricitabine 1. Guidelines available at centgl.pdf. Accessed 1/6/ HHS Panel on Antiretroviral Guidelines for Adults and Adolescents Update Nov 18, Accessed 1/6/2015. Walmsley S et al. J Acquir Immune Defic Syndr 2015;70: Walmsley SL et al. N Engl J Med 2013;369:

4 Elvitegravir/Cobicistat/Tenofovir/Emtricitabine Noninferior to Efavirenz/Tenofovir/Emtricitabine One tablet once-a-day regimen for treatmentnaïve patients No pre-treatment viral load restrictions HLA-B*5701 screening required (abacavir) Possible increased cardiovascular risk (abacavir) Reduced tubular secretion of creatinine (dolutegravir, mean SCr increase = 0.15mg/dL)* Avoid coadministration with polyvalent cations Difference 3.6% (95% CI = -1.6 to 8.8) Other ADEs: GI disturbances, headache, insomnia, transaminitis *Triumeq Package Insert Accessed 1/6/2016. Sax PE et al. Lancet 2012;379: COBI Reduces tubular Secretion of Creatinine One tablet once-a-day regimen Cobicistat booster CYP3A4 inhibitor = drug-drug interactions Increases tenofovir concentrations, avoid use in patients with ClCr <70 ml/min Food increases absorption Avoid coadministration with polyvalent cations Other ADEs: diarrhea, nephrotoxicity, decreases in bone mineral density Sax PE et al. Lancet 2012;379: HMG-CoA reductase inhibitors (statins) Hep C protease inhibitors (boceprevir, telaprevir) Macrolides (clarithromycin, erythromycin) Corticosteroids Methadone Rifampin Benzodiazepines PDE5 inhibitors (e.g., tadalafil) Oral contraceptives Tenofovir disoproxil fumarate (TDF) Readily converted in plasma to tenofovir diphosphate Potential ADEs: Proximal tubular uptake and dysfunction of kidney Tenofovir-associated bone loss (alteration of gene expression) Tenofovir alafenamide (TAF) Stable in plasma, resulting in lower plasma tenofovir concentrations Converted intracellularly to tenofovir diphosphate Advantages: may cause less nephrotoxicity and bone effects, smaller pill size 4

5 % Patients with HIV RNA <50 c/mm Δ +2.0% (95% CI: -0.7% to +4.7) Sax PE, et al. Lancet 2015;385; E/C/F/TAF (n=866) E/C/F/TDF (n=867) Success Failure No Data E = elvitegravir; C = cobicistat, F = emtricitabine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate TAF group had smaller decline in egfr (0 08 vs 0 12 mg/dl; p<0 0001) TAF group had less proteinuria (median % change 3 vs 20; p<0 0001) TAF group had smaller reductions in bone mineral density at the spine (mean % change 1 30 vs 2 86; p<0 0001) and hip ( 0 66 vs 2 95; p<0 0001) One tablet once-a-day regimen Approved by FDA November 2015 DHHS Recommend Agent November 2015 Cobicistat booster CYP3A4 inhibitor = drug-drug interactions Avoid use in patients with ClCr <30 ml/ min Food increases absorption Avoid coadministration with polyvalent cations Other ADEs: diarrhea, nephrotoxicity, decreases in bone mineral density TAF/emtricitabine under review Rilpivirine/TAF/emtricitabine under review Darunavir/cobicistat/TAF/emtricitabine GS-9883/emtricitabine/TAF INSTI Advantages Disadvantages Dolutegravir Once-daily dosing Single tablet with abacavir/ lamivudine High resistance barrier Activity against resistant virus Few drug interactions No food requirement Elvitegravir Once-daily dosing Single tablet Raltegravir First INSTI Fewest drug interactions Best ADE profile No food requirement No coformulation with tenofovir/emtricitabine Requires boosting Drug-drug interactions Food requirement Avoid if ClCr <70 ml/min if given with TDF New TAF formulation may require PA BID dosing No single-tablet regimen Lower barrier to resistance NNRTI-based regimen Efavirenz/tenofovir/emtricitabine Baseline resistance 1 Failures due to ADEs requiring switch 2,3 CNS toxicity and suicidality 4 PI-based regimen Atazanavir + ritonavir + tenofovir/emtricitabine Failures due to ADEs requiring switch 5 Regimens with HIV RNA or CD4 cell count restrictions 1. Snedecor SJ et al. PLoS One 2013;8:e Walmsley SL et al. N Engl J Med 2013;369: Rockstroh JK et al J Acquir Immune Defic Syndr 2013;63: Mollan KR et al. Ann Intern Med 2014;161: Lennox JL, et al. Ann Intern Med 2014;161: ADE Resulting in Discontinuation Atazanavir/ ritonavir Raltegravir Darunavir/ ritonavir 95 (15.7%) 8 (1.3%) 32 (5.3%) GI toxicity Hyperbilirubinemia Other hepatic toxicity Rash Metabolic toxicity Renal toxicity Abnormal chem/hem Other Results of study: Cumulative incidence of virologic and tolerability favored raltegravir and darunavir/ritonavir over atazanavir/ritonavir. Lennox JL, et al. Ann Intern Med 2014;161: & supplemental material. 5

6 PI-based regimen Darunavir/cobicistat + tenofovir/emtricitabine Darunavir/cobicistat + abacavir/lamivudine Atazanavir/cobicistat + tenofovir/emtricitabine Once-a-day regimen (combined with other antiretrovirals) Decreases ritonavir pill burden Cobicistat booster CYP3A4 inhibitor = drug-drug interactions Avoid use in patients with ClCr <70 ml/min if used in combination with tenofovir Food increases absorption Other ADEs: nausea, diarrhea, headache, rash, increase in SCr, metabolic side effects Once-a-day regimen (combined with other antiretrovirals) Decreases ritonavir pill burden Cobicistat booster CYP3A4 inhibitor = drug-drug interactions Avoid use in patients with ClCr <70 ml/ min if used in combination with tenofovir Food increases absorption Requires acidic environment for absorption Other ADEs: nausea, diarrhea, headache, rash, hyperbilirubinemia, metabolic side effects, increase in SCr 64yo male w HIV is establishing care in your clinic. He was dx d in 1987 and started HAART (efavirenz + tenofovir + abacavir/ lamivudine) in 1997 (CD4 0 cells/mm 3 ). He has remained on that regimen and has had an undetectable viral load since initiation (17 years). He has had sleep disturbances, insomnia and vivid dreams since starting the medication. He has been taking trazodone and clonazepam for many years now to treat the HAART ADEs. PMH also includes HTN (controlled), stroke in Other medications include amlodipine, ASA, pravastatin. He does not smoke, drink or use illicit drugs. He is an avid cycler. Labs: CDC 699 (36%), HIV RNA undetectable, GART too low to sequence, CBC WNL, SCr 1.12 (ClCr = 68mL/min), AST 16, ALT 32, Hep A Ab negative, Hep B S Ag positive, Hep B S Ab positive, Hep C Ab negative, Toxo IgG negative, TB QF negative, A1c 5.2, Lipids TC 156 TG 82 HDL 63 LDL 77 Which of the following HAART medications is the most likely culprit for the patient s sleep disturbances? A. Efavirenz B. Abacavir C. Lamivudine D. Tenofovir Which of the following is the best option for managing this patient? A. Continue with current regimen since patient has undetectable viral load. B. Obtain resistance testing to determine potential treatment options. C. Discontinue current regimen. Start dolutegravir/abacavir/ lamivudine (Triumeq). D. Discontinue current regimen. Start elvitegravir/cobicistat/taf/ emtricitabine (Genvoya) E. Discontinue current regimen. Start dolutegravir (Tivicay) + darunavir/cobicistat (Prezcobix). 6

7 What are some potential side effects and counseling points that should be discussed with the patient regarding the new regimen? What other potential management issues need to be addressed? Treatment for prevention (HAART) Condom use Tx of sexually transmitted disease Contraception among HIV+ women Perinatal care to prevent transmission Blood supply screening and safety Needle exchange/safety Post-exposure prophylaxis Now available! Guidelines published in May 2014 How does it work? HIV-negative patient High-risk for infection Takes tenofovir/emtricitabine 1 tablet once daily prior to exposure Potential ADEs: nausea, rash, headache, renal toxicity, dyslipidemia Patients who meet high-risk criteria 1 in 4 sexually active HIV-negative MSM 1 in 5 HIV-negative adults who inject drugs 1 in 200 sexually active HIV-negative heterosexual adults 1 in 3 of doctors and nurses have never heard of PrEP (2015 survey) CDC Vital Signs Dec Accessed 1/6/2015 Document prior to use: Negative HIV result & symptoms Normal renal function Educate patient on adherence, ADEs, symptoms of conversion Follow-up at 3 months: HIV test STI assessment Medication and risk reduction counseling Assess renal function Fill prescription every 90 days 7

8 PrEP Study HIV Reduction Overall HIV Reduction in patients with detectable drug concentrations iprex 1 (tenofovir/ emtricitabine) Partners PrEP 2 (tenofovir/ emtricitabine) Bangkok Tenofovir Study 3 44% >90% 75% 90% 49% 74% UNM Truman Health Services has a pharmacist run HIV PrEP clinic For info call: Grant RM et al. N Engl J Med 2010;363: Baeten JM et al. N Engl J Med 2012;367: Choopanya K et al. Lancet 2013;381: