1/13/16 Pharmacist objectives: Summarize key updates to the DHHS - - PDF document

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Bernadette Jakeman, PharmD, PhC, BCPS, AAHIVP Assistant Professor UNM College of Pharmacy bjakeman@salud.unm.edu

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. ¡ www.aidsinfo.nih.gov ¡ Updated April 2015 ¡ Approximately 1.2 million people are living

with HIV in the US1

¡ 14% of infected patients remain

undiagnosed2

§ Undiagnosed responsible for 30-50% of new

cases3,4

¡ CDC recommends testing for all patients

ages 13-64 years5

• 1. CDC. MMWR June 26, 2015/64(24);657-662. 2. http://www.cdc.gov/hiv/pdf/surveillance_report_vol_19_no_3.pdf
• 3. Skarbinski J et al. JAMA Intern Med 2015;175:588–96. 4. Marks G et al. AIDS 2006;20:1447-50. 5. CDC MMWR Sept

22, 2006/55(RR14);1-17

• A. <100 cells/mm3
• B. 100-200 cells/mm3
• C. 200-350 cells/mm3
• D. 350-500 cells/mm3
• E. >500 cells/mm3

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¡ 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

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¡ 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 outcomes1-5

• 1. Kitahata MM et al. N Engl J Med.2009;360(18):1815-26. 2. Lundgren JD et al 2015;373;795-807 . 3. Estrella M et al. CID

2006;43:337-380. 4. Bhaskaran K, et al. Ann Neurol. 2008;63:213-221. 5. Lichtenstein K, et al. CID 2010;51:435-447. Quinn TC et al. N Engl J Med 2000;342:921-929.

¡ Therapy recommended for ALL HIV-

infected patients, regardless of pre- treatment CD4 count

§ CD4 count <350 cells/mm3 (AI) § CD4 cell count 350-500 cells/mm3 (AII) § CD4 cell count >500 cells/mm3 (BIII) ¡ Baseline resistance testing recommended

(GART)

• 1. Guidelines for the use of an- tiretroviral agents in HIV-1-infected adults and adolescents. DHHS. Available at

http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdoles- centGL.pdf. Accessed 1/6/2016.

• 2. INSIGHT START Study Group. N Engl J Med 2015;373:795-807.

¡ Proven clinical efficacy ¡ Ease of administration (frequency, pill

burden)

¡ Low drug-drug interaction potential ¡ Low side effect profile ¡ 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 http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdoles- centGL.pdf. Accessed 1/6/2016. 2. HHS Panel on Antiretroviral Guidelines for Adults and Adolescents Update Nov 18, 2015. https://aidsinfo.nih.gov/news/1621/evg-c-ftc-taf--statement-from-adult-arv-guideline-panel Accessed 1/6/2015.

Dolutegravir + Abacavir/Lamivudine Superior to Efavirenz/Tenofovir/Emtricitabine

Walmsley S et al. J Acquir Immune Defic Syndr 2015;70:515-519. Walmsley SL et al. N Engl J Med 2013;369:1807-1818.

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¡ One tablet once-a-day regimen for treatment-

naïve 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 ¡ Other ADEs: GI disturbances, headache,

insomnia, transaminitis

*Triumeq Package Insert. 2014. https://www.viivhealthcare.com/media/80846/Triumeq-PI-MG.pdf Accessed 1/6/2016.

Elvitegravir/Cobicistat/Tenofovir/Emtricitabine Noninferior to Efavirenz/Tenofovir/Emtricitabine

Sax PE et al. Lancet 2012;379:2439-2448.

Difference 3.6% (95% CI = -1.6 to 8.8)

COBI Reduces tubular Secretion of Creatinine

Sax PE et al. Lancet 2012;379:2439-2448.

¡ 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

¡ 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

www.hiv-druginteractions.org

¡ 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

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§

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)

% Patients with HIV RNA <50 c/mm3 Δ +2.0% (95% CI: -0.7% to +4.7) Sax PE, et al. Lancet 2015;385;2606-2615.

92 4 4 90 4 6 10 20 30 40 50 60 70 80 90 100 Success Failure No Data E/C/F/TAF (n=866) E/C/F/TDF (n=867)

E = elvitegravir; C = cobicistat, F = emtricitabine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

¡ 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
• No coformulation with

tenofovir/emtricitabine Elvitegravir

• Once-daily dosing
• Single tablet
• Requires boosting
• Drug-drug interactions
• Food requirement
• Avoid if ClCr <70 ml/min if given

with TDF

• New TAF formulation may

require PA Raltegravir

• First INSTI
• Fewest drug interactions
• Best ADE profile
• No food requirement
• BID dosing
• No single-tablet regimen
• Lower barrier to resistance

¡ NNRTI-based regimen § Efavirenz/tenofovir/emtricitabine

▪ Baseline resistance1 ▪ Failures due to ADEs requiring switch2,3 ▪ CNS toxicity and suicidality4

¡ PI-based regimen § Atazanavir + ritonavir + tenofovir/emtricitabine

▪ Failures due to ADEs requiring switch5

¡ Regimens with HIV RNA or CD4 cell count

restrictions

• 1. Snedecor SJ et al. PLoS One 2013;8:e72784. 2. Walmsley SL et al. N Engl J Med 2013;369:1807-1818. 3.

Rockstroh JK et al J Acquir Immune Defic Syndr 2013;63:77-85 4. Mollan KR et al. Ann Intern Med 2014;161:1-10. 5. Lennox JL, et al. Ann Intern Med 2014;161:461-71.

Atazanavir/ ritonavir Raltegravir Darunavir/ ritonavir ADE Resulting in Discontinuation 95 (15.7%) 8 (1.3%) 32 (5.3%) GI toxicity 25 2 14 Hyperbilirubinemia 47 Other hepatic toxicity 4 1 5 Rash 7 2 4 Metabolic toxicity 6 2 Renal toxicity 4 Abnormal chem/hem 2 Other 2 3 4

Lennox JL, et al. Ann Intern Med 2014;161:461-71 & supplemental material.

Results of study: Cumulative incidence of virologic and tolerability favored raltegravir and darunavir/ritonavir over atazanavir/ritonavir.

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¡ PI-based regimen § Darunavir/cobicistat + tenofovir/emtricitabine § Darunavir/cobicistat + abacavir/lamivudine § Atazanavir/cobicistat + tenofovir/emtricitabine

¡ Once-a-day regimen (combined with

• ther 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

• ther 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/mm3). 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

• 2013. 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
• ptions.
• 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).

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¡ 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 2015. http://www.cdc.gov/vitalsigns/pdf/2015-11-24-vitalsigns.pdf 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

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PrEP Study HIV Reduction Overall HIV Reduction in patients with detectable drug concentrations iPrEx1

(tenofovir/ emtricitabine)

44% >90% Partners PrEP2

(tenofovir/ emtricitabine)

75% 90% Bangkok Tenofovir Study3 49% 74%

1. Grant RM et al. N Engl J Med 2010;363:2587-2599. 2. Baeten JM et al. N Engl J Med 2012;367:399-410. 3. Choopanya K et al. Lancet 2013;381:2083-2090.

¡ UNM Truman Health Services has a

pharmacist–run HIV PrEP clinic

¡ For info call: 505-272-1312