HIV Management and Antimicrobial Stewardship How a pharmacist can promote patient safety and improve care

April 11, 2014 Andrea Pallotta, PharmD, BCPS, AAHIVP HIV and Infectious Diseases Clinical Specialist Ohio Society of Health-System Pharmacists 75th Annual Meeting

Objectives • Pharmacist objectives – Explain several potential medication errors involving – –

–

antiretrovirals (ART) Describe the mechanism of action, side effects, and pharmacokinetics of commonly used ART Discuss drug-drug interactions between ART and commonly used inpatient medications Identify opportunities for pharmacy involvement in preventing ART-related medication errors

• Technician objectives – Explain several potential medication errors involving ART – Summarize which ART are available in formulations other than –

oral tablets/capsules Identify opportunities for pharmacy involvement in preventing ART-related medication errors

Evolution of HIV Therapy

1996

2008

7 AM

3 PM

11PM

Bedtime

Advances Bring Challenges

Integrase Inhibitors (INSTIs) Isentress

Stribild

Tivicay

(raltegravir or RAL)

(elvitegravir, cobicstat, emtricitabine, tenofovir )

(dolutegravir or DTG)

Complexities of HIV Medicine Potential Causes of Errors

Pharmacy Department

Complicated regimens Combination products and multiple dosage forms Renal and hepatic dosage adjustments

Pharmacokinetic boosters and drug-drug interactions Opportunistic infection prophylaxis

Medication reconciliation

Opportunities for Intervention

Order entry

Order verification Dispensing Chart review and rounding Education

HIV Life Cycle

Figure 128-1: Mandell’s

1. Defining a Complete ART Regimen • 2 to 3 fully active medications from at least 2 classes • Example regimens Combination tablet: Stribild Elvitegravir/cobicistat/ emtricitabine/tenofovir daily Atazanavir 300 mg daily Ritonavir 100mg daily Epzicom (ABC/3TC) daily

Treatment experienced patient: Darunavir 600 mg BID Ritonavir 100 mg BID Etravirine 200 mg BID Raltegravir 400 mg BID Truvada (TDF/FTC) daily

• Pharmacokinetic boosters – Ritonavir: has activity against HIV – Cobicistat: no activity against HIV – Do not count as a fully active agent

• Refer to outpatient regimen or patient when needed Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS. Available at http://aidsinfo.nih.gov/ContentFiles/Adultand AdolescentGL.pdf. Section accessed Feb-Mar 2014.

2. Combination Products • New and old combinations

• Look-a-Like, Sound-a-Like • Renal insufficiency may result in splitting up combination tablets into individual products – Atripla once daily as outpatient – Efavirenz/emtricitabine/tenofovir – AKI with CrCL: 25 ml/min

Other Combinations Efavirenz/emtricitabine/tenofovir (Atripla) Rilpivirine/emtricitabine/tenofovir (Complera) Elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) Emtricitabine/tenofovir (Truvada) Zidovudine/lamivudine (Combivir)

Efavirenz 600 mg daily

Abacavir/lamivudine (Epzicom)

Emtricitabine 200 mg Q72hrs

Abacavir/lamivudine/zidovudine (Trizivir)

Tenofovir 300 mg twice weekly

Lopinavir/ritonavir (Kaletra)

2. Many Dosage Forms • Liquid products NRTIs

PIs

NNRTIs

Abacavir

Darunavir

Nevirapine

Emtricitabine

Fosamprenavir

Etravirine

Lamivudine

Lopinavir/ritonavir

Stavudine

Ritonavir

Zidovudine

Tipranavir

Tablet can be dissolved

• Common ART with pharmacokinetic data supporting “Do not crush or open” – Atazanavir capsules: do not open for administration via gastric tube – Atripla and Kaletra tablets – Nevirapine XR tablets

3. Renal and Hepatic Dosage Adjustments • Renal elimination – NRTIs, except abacavir

• Hepatic metabolism – PIs, NNRTIs, Integrase Inhibitors, maraviroc, abacavir Agent

Effect on Kidney

Comments

Cobicistat

• Blocks tubular secretion of creatinine • Mean creatinine ↑ 0.14 mg/dL (0.1-0.4 mg/dL)

Do not start if: CrCL < 70 ml/min Do not continue if: CrCl drops < 50 ml/min

Ritonavir Dolutegravir

• Blocks tubular secretion of creatinine • Mean creatinine ↑ 0.1 mg/dL

No creatinine clearance limitations

Tenofovir

• Can cause renal impairment, Fanconi’s syndrome

Monitor creatinine, urinalysis, phosphorus

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS. Available at http://aidsinfo.nih.gov/ContentFiles/Adultand AdolescentGL.pdf. Section accessed Feb-Mar 2014.

4. Pharmacokinetic Boosters: Ritonavir, Cobicistat PI toxicity threshold

Plasma Concentration

Boosted PI

PI level required to overcome “resistant” virus

PI monotherapy

PI level required to overcome wild-type virus

Time Figure courtesy of A. Hirsch, PharmD. Louis Stokes VA Medical Center.

4. Common Inpatient Drug-Drug Interactions NNRTIs Substrate

Inhibits

Induces

Efavirenz

3A4, 2B6 (major)

3A4, 2C9, 2C19 (moderate)

3A4(strong) 2B6 (weak)

Etravirine

3A4, 2C9, 2C19 (major)

2C9, 2C19 (moderate)

3A4 (strong)

Nevirapine

3A4 (major) 2B6, 2D6 (minor)

1A2, 2D6, 3A4 (weak)

3A4, 2B6 (strong)

Rilpivirine

3A4 (major)

--

--

• NNRTI affect on other medications: – ↓ azole antifungal, statin concentrations

• Other medications can affect NNRTI concentrations – Rifamycins, phenytoin, carbamazepine, dexamethasone can ↓ NNRTI concentrations Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS. Available at http://aidsinfo.nih.gov/ContentFiles/Adultand AdolescentGL.pdf. Section accessed Feb-Mar 2014.

4. Common Inpatient Drug-Drug Interactions Protease Inhibitors and Cobicistat Drug

Substrate

Inhibits

Atazanavir

3A4 (major)

1A2 & 2C8/9 (weak), 3A4 (strong)

Darunavir

3A4 (major)

2D6 (weak), 3A4 (strong) P-glycoprotein

Fosamprenavir

3A4 (major), 2C9, 2D6 (minor) P-glycoprotein

2C19 (weak), 3A4 (strong)

Lopinavir

3A4 (major)

3A4 (strong)

Ritonavir

1A2, 2B6, 2D6 (minor) 3A4 (major) P-glycoprotein

2C19, 2C9, 2E1 (weak) 2C8, 2D6, 3A4 (strong) P-glycoprotein

Induces

1A2, 2B6, 2C9, 2C19, 3A4 (weak/moderate)

• PIs/cobicistat affect concentrations of: – ↑ statins, azole antifungals, inhaled/intranasal corticosteroids, PDE5 inhibitors concentrations – ↓ ethinyl estradiol concentrations: alternative contraceptive recommended

• Drugs that can affect PI concentrations: – Rifamycins, phenytoin, carbamazepine, dexamethasone ↓ PI concentrations Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS. Available at http://aidsinfo.nih.gov/ContentFiles/Adultand AdolescentGL.pdf. Section accessed Feb-Mar 2014.

4. Common Inpatient Drug-Drug Interactions Acid Suppressing Medications ART

Rilpivirine

Boosted Atazanavir

Unboosted Atazanavir INSTIs

Interaction: PPIs

Interaction: H2 blockers

Interaction: Antacids

Contraindicated

Give H2 blockers 12 hrs before or 4 hrs after RPV

Give antacids 2 hrs before or 4 hours after RPV

Tx naïve only Max omeprazole 20mg daily, separate by 12 hours

Max famotidine 40mg BID in naïve, 20mg BID tx experienced. Administer at same time or 10 hrs apart

ATV 2 hrs before or 1 hr after

Contraindicated

Max famotidine 20mg BID in naïve, no TDF

ATV 2 hrs before or 1 hr after

-

-

Separate by 2-6 hrs

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS. Available at http://aidsinfo.nih.gov/ContentFiles/Adultand AdolescentGL.pdf. Section accessed Feb-Mar 2014.

5. Opportunistic Infection Prophylaxis Opportunistic Infection (OI)

Criteria for Prophylaxis

Recommended Prophylaxis

Alternative Prophylaxis

Pneumocystis pneumonia

• •

CD4 count < 200 Oropharyngeal candidiasis CD4 % < 14% AIDS defining illness

•

• •

CD4 count < 100 and Toxoplasmosis IgG positive

•

• •

Toxoplasmosis gondii encephalitis

Disseminated Mycobacterium avium Complex (MAC) disease

•

• •

CD4 count < 50 Rule out disseminated MAC

SMX/TMP DS or SS daily

• •

• •

SMX/TMP 1 DS daily

Azithromycin 1200 mg weekly or 600 mg BID Clarithromycin 500 mg BID

•

SMX/TMP DS TIW Dapsone 100 mg daily or 50 mg BID Pentamidine inhalation monthly Atovaquone 1500 mg daily

•

Dapsone + pyrimethamine + leucovorin Atovaquone

•

Rifabutin 300 mg daily

Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of OIs in HIV-infected adults and adolescents. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 19, 2014.

Stepwise Approach to Inpatient ART 1. Verify complete and accurate ART regimen

2. Check route of administration (oral vs. via tube) and combination product accuracy

3. Account for hepatic and renal adjustments if needed 4. Evaluate drug-drug interactions 5. Identify indications for OI prophylaxis

Antiretroviral Medication Errors Reference

Institution

N

Yehia BR. CID 2012

John Hopkins 982 bed academic med center CPOE

12 months 380 admissions

29%

Daniels LM. AJHP 2012 Pastakia SD AJHP 2008

University North Carolina 803 bed academic med center CPOE

Pre: 4 months Post: 6 months 146 patients

Pre: 72% Post: 15%

Rao N. HIV Med 2012

Jersey City Medical Center 269 bed academic med center

12 months 90 admissions

52%

Heelon M. AJHP 2007

Baystate Med Center 651 bed academic med center CPOE

Pre: 6 months Post: 7 months 199 admissions

Pre: 17% Post: 24%

John Hopkins Bayview Rastegar DA. CID 2006 354 bed community hospital CPOE

12 months 209 admissions

26%

Cleveland Clinic 1400 bed academic medical center, CPOE

Pre: 10 months Post: 6 months 272 admissions

Sanders J. ICHE 2014

Rate of Med Errors

Cleveland Clinic: Inpatient HIV Stewardship Research

Goal

Primary Objective Secondary Objectives

• Evaluate the incidence of HAART or OI-related medication errors in HIV admissions before and after antimicrobial stewardship interventions

• Rate of resolution of HAART or OI-related medication errors

• Determine the overall incidence of HAART or OI-medication errors • Describe the type of medication errors • Describe time to medication error resolution before and after stewardship interventions Infect Control Hosp Epidemiol 2014;35(3):272-277.

Study Methods Pre-Intervention Jan 2011

Oct 2011

Post-Intervention July 2012

Dec 2012

• Retrospective chart review • 1400 bed, academic, referral center – 11 inpatient infectious diseases consult services – 800 outpatient HIV clinic patients

• Inclusion criteria – Adults (> 18 years) prescribed ART during hospitalization

• Exclusion criteria – Tenofovir or lamivudine monotherapy for hepatitis B infection Infect Control Hosp Epidemiol 2014;35(3):272-277.

Stewardship Interventions • Multi-disciplinary, multi-faceted approach

• Implementation time period: 6 months

Electronic Medical Record Updates

Education

Transitions of Care

Prospective Chart Review Infect Control Hosp Epidemiol 2014;35(3):272-277.

Electronic Medical Record Updates • Systematic review of medication files – 22 files reviewed – 20 modification – Removal or update of dose or frequency buttons – Addition of important prescribing information

Infect Control Hosp Epidemiol 2014;35(3):272-277.

Education • Pharmacists – Competency on ART dosing and drug-drug interactions – ID Monthly – Presentations by HIV/ID pharmacy clinical specialist to pharmacists, residents, and students

• Physicians – HIV noon conference – Fellows HIV practiced based learning lectures – Medical resident education conference

Infect Control Hosp Epidemiol 2014;35(3):272-277.

Transitions of Care • Infectious diseases fellows focusing on continuity of care from inpatient to outpatient – Same outpatient and inpatient ID provider – Post-discharge follow up appointments in ID clinic

• Infectious diseases pharmacist dedicated to HIV clinic – Medication reconciliation – Discharge counseling – Medication procurement assistance

Infect Control Hosp Epidemiol 2014;35(3):272-277.

Prospective Chart Review • Medication list review at time of order verification by staff and clinical pharmacists – Appropriateness and completeness of regimen – Renal or hepatic dosage adjustments – Drug-drug interactions

• Prospective audit and review of all inpatients on ART by an Infectious Diseases trained pharmacist or resident throughout inpatient admission – Appropriateness and completeness of regimen – Renal or hepatic dosage adjustments – Drug-drug interactions – OI prophylaxis indications

• On average, five profile reviews per day Infect Control Hosp Epidemiol 2014;35(3):272-277.

Example Inpatient: Identify Potential Errors • 45 yo male admitted with SOB and fevers

• PMH:

• Inpatient Medications

– HIV/AIDS – CD4/5: 175/11% – VL undetectable – COPD

• Calculated CrCl: 43 ml/min – Ht: 68 in, wt: 65 kg 133

97

13

45 123

4.2

24

2

7.9

111 40.1

• Albuterol 90 mcg 1-2 puff Q4hrs PRN • Atazanavir 300 mg daily • Ciprofloxacin 400 mg Q12hrs • Emtricitabine-tenofovir 200-300 mg daily • Fluticasone-salmeterol 100-50 mcg BID • Gabapentin 800 mg BID • Methylprednisolone 40 mg Q8hrs • Omeprazole 20 mg daily • Piperacillin-tazobactam 3.375g Q6hrs • Ritonavir 100 mg BID • Vancomycin 1g Q24hrs

Patient and Error Demographics Pre-intervention Admissions N=162

Post-intervention Admissions N=110

P value

49 (43-56.3)

49 (41.4-56)

0.822

Gender, male, n (%)

103 (64%)

76 (69%)

0.347

Hospital LOS, days,

4 (2-7)

6 (3.8-8.3)

0.001

28 (17%)

20 (18%)

0.849

Contraindicated drug interaction

14 (8.6)

3 (2.7)

0.072

Major drug interaction

32 (19.8)

1 (0.9)