2016 pharmacotherapy specialty examination review course...

2016 Pharmacotherapy Specialty Examination Review Course: Complex HIV Cases

Douglas Slain, Pharm.D., BCPS, FCCP, FASHP Associate Professor and Infectious Diseases Clinical Specialist

West Virginia University School of Pharmacy Morgantown, West Virginia

Learning Objectives:

At the conclusion of this session, given patient cases, the participant should be able to

• Select the appropriate treatment and monitoring for a complex patient‐case with multipleconditions, including dyslipidemia, acute MRSA infection, and hepatitis B.

• Identify and manage common drug interactions experienced by HIV‐treated patients.• Identify and manage common adverse drug reactions experienced by HIV‐treated patients.• Determine appropriate medication choices for the treatment and prevention of common

opportunistic infections• Discuss quality of life issues in terms of medication therapy for HIV‐infected patients.• Identify and recommend appropriate resource organization/groups to assist a specific patient.

Format: Today’s session will be a highly interactive discussion of the attached case studies.

Premise: Participants in this course are pharmacists who practice in acute care and ambulatory care

settings. You are responsible for evaluating and monitoring the patient’s therapy.

©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.

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PATIENT CASE Date: June, 2016

Initials

ML

DOB/Age

38 yo

Sex

F

Source:

Patient and medical records

Chief Complaint/History of Present Illness (CC/HPI) (including symptom analysis for CC):

Admitted to ICU with respiratory distress and malaise

Past Medical History:

Hepatitis B (chronic)

Hypothyroidism, Hepatitis B (chronic‐no therapy)

Former IV drug user (clean for 2 years)

Current Home Medications Drug Name/Strength/Regimen

Levothyroxine 50 mcg tablet once daily

Pantoprazole 40mg tablet once daily

St. John’s Wort capsule once daily

Multivitamin tablet once daily

Drug Allergies: NKDA

Social History

Completed a methadone program 6 months ago

Still drinks alcohol and smokes marijuana

Has dated off and on, last sexual encounter 2 weeks prior

Has 2 cats at home

Family History

Mother died at age 46 of a

heart attack

Occupation: Currently unemployed

Former bar tender

Review of Systems: Upset stomach at times and frequent bouts of fatigue

Vital Signs: T= 100F, BP= 110/75 mm Hg, RR=30/min, P= 100 bpm Resp: PaO2 = 60 mm Hg

on room air, 02 Sat= 93% Laboratory Data

Na = 139 mEq/L K = 3.5 mEq/L Cl = 99 mEq/L CO3 = 23 mg/dL BUN = 18 mg/dL

SCr = 0.6 mg/dL

WBC: 9.0 x 103 cells/mm3 RBC: 3.5 x 106 cells/mm3 Hgb: 10 g/dL Hct: 40%

Glucose = 100 mg/dL

AST = 15 IU/L ALT = 20 IU/L Total Bilirubin: 0.2 mg/dL


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Presentation Questions 1. Which medication would most likely be “flagged” during the medication reconciliation process?

A. Levothyroxine B. Pantoprazole C. St. John’s Wort D. Multivitamin

2. The preferred Pneumocystis jirovecii pneumonia (PCP) therapy for this patient would be:

A. Intravenous trimethoprim‐sulfamethoxazole x 14 days B. Intravenous trimethoprim‐sulfamethoxazole x 21 days + oral prednisone as a 21‐day

taper C. Intravenous clindamycin + oral primaquine x 14 days D. Oral atovaquone x 21 days and intravenous methylprednisolone as a 10‐day taper

3. When should ML be started on antiretroviral therapy (ART)?

A. Immediately B. After PCP treatment is complete C. After results from an HIV resistance test are available D. After the patient is discharged

4. What antiretroviral therapy should be started for ML?

A. Atazanavir/Ritonavir + Tenofovir DF/Emtricitabine B. Efavirenz/Tenofovir DF/Emtricitabine C. Dolutegravir/Abacavir/Lamivudine D. Rilpivirine/Tenofovir DF/Emtricitabine

5. The team started ML on Dolutegravir/Abacavir/ Lamivudine. What lab tests should have been

performed prior to starting this ART regimen? A. ART phenotypic resistance test, pregnancy test B. ART phenotypic resistance test, tropism test C. ART genotypic resistance test, pregnancy test, HLA‐B*5701 D. ART genotypic resistance test, HLA‐B*5701, tropism test

6. ML has started taking her home medications again. Are there any significant drug interactions

with her regimen of Dolutegravir/Abacavir/Lamivudine ? A. Levothyroxine and pantoprazole B. Pantoprazole C. St. John’s Wort D. Pantoprazole and St. John’s Wort

7. Given that ML has hepatitis B co‐infection, what ART regimen would provide her with two

agents with hepatitis B activity? A. Zidovudine + lamivudine + lopinavir + ritonavir B. Abacavir + emtricitabine + efavirenz C. Tenofovir + emtricitabine + darunavir + ritonavir D. Stavudine + lamivudine + raltegravir


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8. ML is diagnosed with drug‐associated glucose‐6‐phosphate dehydrogenase (G6PD)‐deficiency hemolytic anemia. Which of her current medications probably is the cause?

A. Dolutegravir B. Abacavir C. Lamivudine D. Trimethoprim‐Sulfamethoxazole

9. Following acute treatment for PCP will ML need secondary prophylaxis? If so, what regimen

should she receive? A. A TMP‐SMX double‐strength oral tablet once daily B. A TMP‐SMX double‐strength oral tablet three times per week C. Atovaquone oral solution 1,500mg once daily D. No PCP agents are needed for secondary prophylaxis

10. At her first outpatient clinic appointment, ML’s CD4 count is 45 cells/mm3. Should ML receive

any additional prophylactic therapy at this point? A. Azithromycin 1,200mg orally once weekly B. Fluconazole 200 mg orally once daily C. Dapsone‐based regimen for toxoplasmosis prevention D. No additional prophylactic agents are needed

11. ML’s CD4 count at her 3‐month appointment was 150 cells/mm3. When she returns to clinic 3

months later, her CD4 count has increased to 250 cells/mm3. She has been taking atovaquone daily and azithromycin weekly. She is tired of taking so many medications. Can she stop these agents?

A. No, she must continue both until her CD4 count has been >200 cells/mm3 for 3 months B. He can stop the azithromycin at this point, but must continue the atovaquone C. He can stop the atovaquone at this point, but must continue the azithromycin D. Yes, he can discontinue both drugs


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Antiretroviral Drug Class and Common Adverse Effects and Cautions

Drug Class Adverse effects

Nucleoside reverse transcriptase inhibitors (nucleotide) • Zidovudine (AZT) • Didanosine (ddI) • Stavudine (d4T) • Lamivudine (3TC) • Abacavir (ABC) • Emtricitabine (FTC) • Tenofovir disoproxil fumarate (TDF) • Tenofovir alafenamide (TAF)

• Neuromuscular ▫ Polyneuropathy: d4T, ddI ▫ Myopathy & cardiomyopathy:

AZT, ddI

• Cardiac: risk of MI: abacavir‐? • Hepatic

▫ Steatosis, lactic acidosis: All agents

• Gastrointestinal ▫ Nausea / diarrhea: All agents ▫ Pancreatitis: ddI, d4T

• Hematologic ▫ Anemia / neutropenia: AZT

▫ Mean corpuscular volume: AZT • Nephrotoxicity: tenofovir • Hypersensitivity reaction: abacavir

Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) • Nevirapine • Efavirenz • Etravirine • Rilpivirine

• Rash • Elevated LFTs/hepatitis • Drug interactions (P‐450) • NNRTI cross‐resistance common (i.e.,

K103N single mutation) • CNS side effects*: efavirenz • FDA pregnancy category “D”‐‐avoid in 1st

trimester: efavirenz • QTc prolongation: rilpivirine • Take with large meal: rilpivirine • Avoid proton pump inhibitors: rilpivirine • Dyslipidemia: efavirenz

Protease inhibitors • Ritonavir • Indinavir • Nelfinavir • Fosamprenavir • Tipranavir • Lopinavir/ritonavir • Atazanavir • Atazanavir/cobicistat • Darunavir • Darunavir/cobicistat

• GI intolerance/nausea/diarrhea • Hyperglycemia / insulin resistance • Drug interactions (P‐450) • Fat redistribution / lipid abnormalities

▫ LDL‐C and triglycerides • Osteopenia, osteoporosis, osteonecrosis • Elevated LFTs/hepatitis

• Asymptomatic indirect bilirubin: indinavir, atazanavir

• Nephrolithiasis / renal disease: indinavir • Skin rash/sulfonamide moiety: darunavir,

fosamprenavir, tipranavir • Avoid proton pump inhibitors: atazanavir

Integrase inhibitors • Raltegravir • Elvitegravir • Dolutegravir

• GI effects, headache, CPK elevations • Drug interactions (elvitegravir &

dolutegravir) • Inhibits secretion of SCr: dolutegravir

*dizziness, hallucinations, vivid dreams/nightmares, insomnia, irritability, disorientation, depression, suicidal ideation


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Uncommonly Used Antiretroviral Agents

Fusion inhibitor Enfuvirtide • Injection site reactions • Hypersensitivity reactions

CCR5‐Antagonist Maraviroc Need to perform tropism test on virus

• P‐450 drug interactions • Liver toxicity; theoretical risk of cancer;

rash, joint, and muscle pain

One‐Pill‐Once‐Daily formulations

Trade Name Composition

Atripla efavirenz + emtricitabine + tenofovir (TDF)

Complera rilpivirine + emtricitabine + tenofovir (TDF)

Stribild elvitegravir + cobicistat + emtricitabine + tenofovir (TDF)

Triumeq dolutegravir + abacavir + lamivudine

Genvoya elvitegravir + cobicistat + emtricitabine + tenofovir (TAF)

Opportunistic Infections:

Risk of Opportunistic Infections Based on CD4 Count

CD4 Count (cells/mm3) Opportunistic Infection

<200 Candida (thrush) Kaposi sarcoma

100 ‐ 200 Pneumocystis jirovecii (PCP) Histoplasmosis Progressive multifocal leukoencephalopathy (PML)

50 ‐ 100 Toxoplasmosis Cryptococcal meningitis Cytomegalovirus (CMV)

< 50 Mycobacterium avium complex (MAC)


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References and Recommended Readings Opportunistic Infections 1. Panel on Opportunistic Infections in HIV‐Infected Adults and Adolescents. Guidelines for the

prevention and treatment of opportunistic infections in HIV‐infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (updated December 2015). Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf

Antiretroviral Therapy 1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral

agents in HIV‐1‐infected adults and adolescents. U.S. Department of Health and Human Services (updated January 2016). Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf

2. Mallal S, Phillips E, Carosi G et al. HLA‐B*5701 Screening for Hypersensitivity to abacavir. N Engl J

Med. 2008; 358:568‐79. http://www.nejm.org/doi/full/10.1056/NEJMoa0706135 (accessed 2016 February 20).

3. 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 (Updated August

2015). Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf

4. Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other

anti‐HIV agents. Clin Pharmacokinet. 1998; 35:275‐91. http://www.ncbi.nlm.nih.gov/pubmed/9812178 (accessed 2016 March 1).

5. Cooper RD, Wiebe N, Smith N et al. Systematic review and meta‐analysis: renal safety of tenofovir

disoproxil fumarate in HIV‐infected patients. Clin Infect Dis. 2010; 51:496‐505. http://www.ncbi.nlm.nih.gov/pubmed/20673002 (accessed 2016 March 1).

6. Olin JL, Spooner LM, Klibanov OM. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil

fumarate single tablet for HIV‐1 infection treatment. Ann Pharmacother. 2012; 46:1671‐7. http://www.theannals.com/content/46/12/1671.full.pdf+html?sid=dde8d028‐c17b‐4829‐ab32‐69c05bc36cfb (accessed 2016 March 1).

7. Cahn P, Pozniak AL, Mingrone H et al. Dolutegravir versus raltegravir in antiretroviral‐experienced,

integrase‐inhibitor‐naive adults with HIV: week 48 results from the randomised, double‐blind, non‐inferiority SAILING study. Lancet 2013;382:700‐8. http://www.ncbi.nlm.nih.gov/pubmed/23830355

8. Rodriguez‐Novoa S, Alvarez E, Labarga P et al. Renal toxicity associated with tenofovir use. Expert

Opin Drug Saf. 2010; 9:545‐59. http://www.ncbi.nlm.nih.gov/pubmed/20384533

9. Arya V, Florian J, Marcus KA et al. Does an increase in serum creatinine always reflect renal injury? The case of Stribild. J Clin Pharmacol 2014;54: 279‐81.


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10. Lundgren JD, Babiker AG, Gordin F, et al; INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015; 373:795‐807.

11. Danel C, Moh R, Gabillard D, et al; TEMPRANO ANRS 12136 Study Group. A trial of early

antiretroviral and isoniazid preventive therapy in Africa. N Engl J Med. 2015; 373:808‐22.

HIV Co‐infection with Hepatitis B 1. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009; 50:661‐2.

http://www.ncbi.nlm.nih.gov/pubmed/19714720 (accessed 2016 March 1). 2. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007; 45:507‐39.

http://www.ncbi.nlm.nih.gov/pubmed/17256718 (accessed 2016 March 1). Dyslipidemia and metabolic syndromes in HIV patients 1. Dubé MP, Sprecher D, Henry WK et al. Preliminary guidelines for the evaluation and management of

dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis. 2000; 31:1216‐24. http://www.ncbi.nlm.nih.gov/pubmed/11073755 (accessed 2016 March 1).

2. Aberg JA, Gallant JE, Ghanem KG et al. Primary care guidelines for the management of persons

infected with HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2014; 58(1):e1–34. http://cid.oxfordjournals.org/content/58/1/e1.long

Drug Interactions 1. 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/Adultand AdolescentGL.pdf. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf (accessed 2016 March 1).


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Miscellaneous 1. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004; 69:2599‐606.

http://www.aafp.org/afp/2004/0601/p2599.html

2. Stone VE, Jordan J, Tolson J et al. Perspectives on adherence and simplicity for HIV‐infected patients on antiretroviral therapy: self‐report of the relative importance of multiple attributes of highly active antiretroviral therapy (HAART) regimens in predicting adherence. J Acquir Immune Defic Syndr. 2004; 36:808‐16. http://www.ncbi.nlm.nih.gov/pubmed/15213564

3. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2889–934.

4. Schafer JJ, Gill TK, Sherman EM, McNicholl IR. ASHP guidelines on pharmacist involvement in HIV care. Am J Health Syst Pharm. 2016; 73:e72‐98. http://www.ashp.org/DocLibrary/BestPractices/Guidelines‐Pharmacist‐Involvement‐HIV‐Care.aspx.


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Complex HIV Case

Douglas Slain, Pharm.D., BCPS, FCCP, FASHP

Associate Professor

Infectious Diseases Clinical Specialist

West Virginia University

Morgantown, West Virginia

Disclosure

• I have nothing to disclose related to the content of this presentation.

Learning Objectives• Select the appropriate treatment and monitoring of a complex patient‐

case with multiple conditions, including dyslipidemia, acute MRSA skin infection, and hepatitis B.

• Identify and manage common drug interactions experienced by HIV‐treated patients.

• Identify and manage common adverse drug reactions experienced by HIV‐treated patients.

• Determine appropriate medication choices for the treatment and prevention of common opportunistic infections.

• Discuss quality of life issues in terms of medication therapy for HIV‐infected patients.

• Identify and recommend appropriate resource organizations/groups to assist a specific patient

Case LM is a 38 yr old female admitted to the hospital Medical ICU Unit for respiratory distress and malaise. She is hypoxemic (PaO2 =60 mmHg [room air])

PMH:Hypothyroidism, Hepatitis B (chronic‐no therapy),

former IV drug user (clean for 2 years)

Home meds:Levothyroxine 50 mcg tablet once daily

Pantoprazole 40mg tablet once daily

St. John’s Wort capsule once daily

Multivitamin tablet once daily

Case

Social History

• Currently unemployed

• Former bartender

• Completed a methadone program

• Still drinks and smokes marijuana

• Has dated off and on, last sexual encounter 2 weeks prior

• Has 2 cats at home

Question 1Which medication would most likely be “flagged” for review during the medication reconciliation process?

A. Levothyroxine

B. Pantoprazole

C. St. John’s Wort

D. Multivitamin


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Medication Reconciliation

National Patient Safety Goal.03.06.01

• Medication discrepancies can affect patient outcomes.

• Medication reconciliation is intended to identify and resolve discrepancies—it is a process of comparing the medications a patient is taking (and should be taking) with newly ordered medications.

• The comparison addresses duplications, omissions, and interactions, and the need to continue current medications. The types of information that clinicians use to reconcile medications include (among others) medication name, dose, frequency, route, and purpose.

http://www.jointcommission.org/assets/1/6/2015_npsg_hap.pdf (Accessed March 2, 2016)

Case

• After diagnostic work up she is found to have Pneumocystis jirovecii pneumonia (PCP).

• An HIV test is ordered for her

• The team would like to order PCP treatment for her

Question 2The preferred PCP therapy for this patient would be:A. Intravenous trimethoprim‐

sulfamethoxazole x 14 daysB. Intravenous trimethoprim‐

sulfamethoxazole x 21 days + prednisone as an oral 21‐day taper

C. Intravenous clindamycin + oral primaquine x 14 days

D. Oral atovaquone x 21 days and intravenous methylprednisolone in a 10‐day taper

• Trimethoprim‐sulfamethoxazole(TMP‐SMX) 15‐20 mg/kg/day (based on trimethoprim) divided PO/IV q 6 or 8 hours x 21 days

• Alternatives:

– Clindamycin IV + Primaquine PO

– Atovaquone PO

– Pentamidine IV

U.S. Department of Health and Human Services. Opportunistic infections. December 2015. URL in reference list

Treatment of Pneumocystis jirovecii pneumonia (PCP)

• Prednisone as a 21‐day taper

– 40mg orally twice daily x 5 days

– 40mg orally Daily x 5 days

– 20mg orally Daily x 11 days

• Indicated if:

– PaO2 < 70 mmHg (room air)

– Alveolar‐arterial O2 gradient > 35 mmHg

• Alternative: methylprednisolone IV

Briel M et al. BMC Infectious Diseases. 2005, 5:101., U.S. Department of Health and Human Services. Opportunistic infections. December 2015. URL in reference list

Severe PCP with HypoxiaCD4 Count (Cells/mm3) Opportunistic Infections

>200 Candida (Thrush)Kaposi Sarcoma

100‐200 Pneumocystis jirovecii (PCP)HistoplasmosisProgressive Multifocal Leukoencephalopathy (PML)

50‐100 ToxoplasmosisCryptococcal MeningitisCytomegalovirus (CMV)

<50 Mycobacterium avium complex (MAC)

Adapted from: U.S. Department of Health and Human Services. Opportunistic infections. December 2015. URL in reference list

Risk of Opportunistic Infections Based on CD4 Count


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HIV Life Cycle

http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle. (Accessed 4/10/16)

Case: Day 6

• Patient is still taking PCP therapy and improving from a respiratory standpoint

• ML’s HIV PCR test is positive.

• Her CD4 count= 40 cells/mm3 and HIV RNA = 50,000 copies/mL

Question 3When should ML be started on antiretroviral therapy (ART)?

A. Immediately

B. After PCP treatment is complete

C. After results from a HIV resistance test are available

D. After the patient is discharged

When to start Antiretroviral therapy (ART)?

What ART to start?

• A combination of > 3 antiretroviral drugs that are usually composed of:

– A pair of two nucleoside reverse transcriptase inhibitors

AND– A non‐nucleoside reverse transcriptase inhibitor

OR– A “boosted” protease inhibitor

OR– An Integrase Inhibitor

A Traditional ART Regimen When to start ART?

• ART is recommended for all HIV‐infected individuals, regardless of CD4 cell count, to reduce the morbidity and mortality associated with HIV infection.

• ART may be deferred because of clinical and/or psychosocial factors, but therapy should be initiated as soon as possible.

Lundgren JD, et al. N Engl J Med 2015;373:795-807, Danel C, et al. N Engl J Med 2015;373:808-22. U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and

Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, January 2016. URL in Handout


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• Inflammatory syndrome triggered by supercharged immune system after (after highly active antiretroviral therapy (HAART) initiation).

• Usually occurs during an acute or subacute infection or disease.– MAC– Tuberculosis– CMV– Cryptococcal Meningitis – PCP

• Paradoxical worsening of their underlying opportunistic infection.

• Role of corticosteroids or delay of HAART initiation?

Dhasmana DJ et al. Drugs. 2008; 68:191-208.

Immune Reconstitution Inflammatory Syndrome (IRIS)

Initiating ART in the setting of an acute opportunistic infection

In patients who have:

• AIDS‐associated opportunistic diseases for which there is no effective therapy (e.g.,cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy), improvement of immune function with ART may improve disease outcomes, thus ART should be started as soon as possible.

• Cryptococcal and tuberculous meningitis, for which immediate therapy may increase the risk of serious IRIS, a short delay before initiating ART may be warranted.

• Pneumocystis jirovecii pneumonia, early initiation of ART is associated with increased survival; therefore, therapy should not be delayed


• Maximal and durable suppression of viral load (HIV RNA < 20‐50 copies/mL)– Typically achieved within 12‐24 weeks after initiating ART therapy

• Restoration and/or preservation of immunologic function

• Reduction of HIV‐related morbidity and mortality

• Improvement of quality of life

U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV‐1‐infected adults and adolescents. January 2016. URL in

Handout.

Goals of ART Therapy Keep it simple

• Minimizing number of daily doses (and food restrictions) has correlated with improved adherence, quality of life, and efficacy rates

• ART Simplification: Patients initially on multiple‐dose regimens may be able to switch to single‐dose regimens when viral load is suppressed on older regimens

U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and

adolescents. January 2016 (URL in Handout), DeJesus E, et al. J Acquir Immune Defic Syndr2009;51:163-74, Degroote S, et al Arch Pub Health 2014;72:40.

Question 4What antiretroviral therapy should be started for ML?

A. Atazanavir /Ritonavir + Tenofovir DF /Emtricitabine

B. Efavirenz /Tenofovir DF/ Emtricitabine

C. Dolutegravir /Abacavir / Lamivudine

D. Rilpivirine/Tenofovir DF/ Emtricitabine

Question 5The team started ML on Dolutegravir/Abacavir/ Lamivudine. What lab tests should have been collected prior to starting this ART regimen?

A. ART phenotypic resistance test, pregnancy test

B. ART phenotypic resistance test, tropism test

C. ART genotypic resistance test, pregnancy test, HLA‐B*5701

D. ART genotypic resistance test, HLA‐B*5701, tropism test


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Resistance ‐‐ Genetic Mutation

• Genetic mutations can result in changes in drug target enzymes (reverse transcriptase, protease, or integrase).

• A mutation of concern is one that does not compromise the enzyme functionality, but resists binding to antiretroviral agents.

• Drug activity can be reduced by single or multiple mutations

Resistance Testing

• Genotypic:

– Measures mutations in the reverse transcriptase, protease, and integrase gene that imparts partial or complete resistance.

• Phenotypic:

– Tests the ability of a specific viral strain to grow in vitro in the presence of a specific antiretroviral agent compared with the “wild‐type” virus.

What ART regimens to start with?

But first, a drug class review

• Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Protease Inhibitors (PIs)

• Integrase inhibitors

• Fusion Inhibitors

• Entry (CCR5) Inhibitors

Classes of FDA Approved Antiretroviral Agents

Competitive inhibition of RT enzyme & leads to chain termination

Nucleoside Reverse Transcriptase Inhibitors:

Mimics of natural deoxynucleosides • Zidovudine (AZT)

• Stavudine (d4T)

• Lamivudine (3TC)

• Emtricitabine (FTC)

• Didanosine (ddI)

• Abacavir (ABV)

• Tenofovir*– Tenofovir disoproxil fumarate (TDF)

– Tenofovir alafenamide (TAL)

*Nucleotide agent

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)


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NRTI ‐ Associated Toxicity• Neuromuscular:

– Polyneuropathy d4T, ddI– Myopathy & Cardiomyopathy AZT, ddI

• Cardiac: risk of MI: ABV ?• Hepatic:

– Steatosis, lactic acidosis All agents• Gastrointestinal:

– Nausea / diarrhea All agents– Pancreatitis ddI, d4T

• Hematological: – Anemia / neutropenia AZT– mean corpuscular volume (MCV)* AZT

• Nephrotoxicity: Tenofovir df• Bone mineral density: Tenofovir df

* Not an adverse effect

Mitochondrial Toxicity

• Toxicities:– Hepatic steatosis– Lactic acidosis– Myopathy– Peripheral neuropathy– Pancreatitis

• Role of mitochondria may be more important in certain tissues.

• More common with “d” drugs ddI, and d4T– NRTIs vary in their ability to inhibit mtDNA polymerase.– Different drug levels in different tissues.

Abacavir Hypersensitivity Reaction

• Reported in approximately 5% of patients.• Potentially fatal (hypotension).• Clinical features (within 6 weeks):

– Fever– Rash– Nausea / vomiting / abdominal pain– Malaise / fatigue– Dyspnea– Labs: CPK & LFTs.

• Don’t re‐challenge patient.• Can now genotype patients (HLA‐B* 5701)

Mallal S et al. N Engl J Med. 2008; 358:568-79.

• Nevirapine

• Efavirenz

• Etravirine

• Rilpivirine

• Binds to reverse transcriptase enzyme resulting in blockade of RNA/DNA polymerase activity. Not substrates of the enzyme.

Newer generation NNRTIs

Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Not affected by single K103N mutation

• Activity can be reduced with > 3 NNRTI mutations

• Etravirine 200mg PO Twice Daily

• Rilpivirine 25mg PO Once Daily (in Complera)

– Take with 400 kcal meal

Newer NNRTIs:Etravirine or Rilpivirine

NNRTI Adverse Effects

• Rash All agents

• Elevated LFTs/hepatitis All agents

• CNS side effects*: Efavirenz

• Drug interactions (P‐450). All agents

• QTC prolongation Rilpivirine

• FDA pregnancy Category “D” Efavirenz– Avoid in 1st trimester

• Dyslipidemia: Efavirenz

*dizziness, hallucinations, vivid dreams/nightmares, insomnia, disorientation, depression, suicidal ideation


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• Ritonavir • Indinavir • Nelfinavir• Fosamprenavir • Tipranavir• Lopinavir/Ritonavir (co‐formulated tablet)• Atazanavir• Atazanavir/Cobicistat (co‐formulated tablet)• Darunavir• Darunavir/Cobicistat (co‐formulated tablet)

Protease Inhibitors Protease Inhibitor Adverse Effects

• GI intolerance/nausea/diarrhea All agents

• Hyperglycemia / insulin resistance All agents

• Fat redistribution / dyslipidemia All agents– LDL‐C and Triglycerides

• Osteopenia, osteoporosis All agents

• indirect bilirubin Indinavir, Atazanavir

• Elevated LFTs/hepatitis All agents

• Nephrolithiasis / renal disease Indinavir

• Drug interactions (P‐450). All agents

• Sulfonamide allergy Darunavir, Tipranavir, Fosamprenavir,

U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV‐1‐infected adults and adolescents. January 2016. URL in

Handout.

0

1

2

3

4

5

6

7

8

9

10 IDV 800mg TID

IDV 800mg/RTV 100mgBID

Mean Protein‐adjustedIC50 = 0.071±0.028 mg/L

Br J Clin Pharmacol. 2005; 60:276-86.

0 1 2 3 4 5 6 7 8 9 10 11 12

Indinavir Plasm

a Conc (m

g/L)

Time (hours)

Steady‐State Indinavir (IDV) Concentrations With and Without Ritonavir (RTV)“Boosting”

Cobicistat

• Not an antiretroviral agent• A “booster” for PIs and Integrase Inhibitors• Drug Interactions!• Cobicistat is a selective CYP3A4 inhibitor

– Some inhibition of CYP2D6, – Minimal effect on P‐glycoprotein, OATP1B1, and OATP1B3

• Component of once‐daily combination tablet formulations

• Can interfere with creatinine tubular secretion (May need to stop if CrCL < 30‐50mL/min per package inserts)

Arya et al. J Clin Pharmacol. 2014; 54:279-81.

Dyslipidemia in HIV‐Positive Patients Receiving ART

• Mostly seen with efavirenz or protease inhibitor‐based regimens

• Patients may have underlying risks for dyslipidemia

• Nonpharmacologic therapy.

• Statins are generally preferred drug therapy.

Caution with protease inhibitors and cobicistat!

Stone NJ, et al. J Am Coll Cardiol 2014;63:2889–934. , Dubé MP et al. Clin Infect Dis. 2000; 31:1216-24.

Dyslipidemia Therapy in HIV

Statins • Avoid simvastatin and lovastatin (CYP3A4)

• Prefer pravastatin (if it works)• Often use atorvastatin and rosuvastatin (less CYP3A4 interaction potential) Start at low doses

Fibrates• Generally for triglycerides > 500mg/dLNiacin (2nd line)• Prefer prescription extended‐release formulation

– Limited effectiveness information

Stone NJ, et al. J Am Coll Cardiol 2014;63:2889–934. Dubé MP et al. Clin Infect Dis. 2000; 31:1216-24.


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Raltegravir• Inhibits the enzyme HIV‐1 integrase • 400mg twice daily dosing• Minimal drug interactions• GI effects, headache, CPK elevations

Elvitegravir• CYP3A4 substrate • 150mg Once Daily• Given with cobicistat

Integrase Inhibitors Dolutegravir

• Less lipid effects than efavirenz

• Metabolized by UGT1A1 with some CYP3A.

• Substrate of P‐glycoprotein and other UGTs

• Separate from cation+

medications

• Can ↑ SCrINSTI = Integrase Strand Transfer Inhibitor

UGT = Uridine Diphosphate Glycosyltransferases

Dosing

Question 6ML has started taking her home medications again. Are there any significant drug interactions with her regimen of Dolutegravir / Abacavir / Lamivudine ?

A. Levothyroxine and pantoprazole

B. Pantoprazole

C. St. John’s Wort

D. Pantoprazole and St. John’s Wort

• Cytochrome (CYP) P‐450 Isoenzymes– Primarily CYP3A4

• P‐Glycoprotein

• pH alteration

Antiretroviral Drug Interactions

Substrates Inhibitors InducersPIs Azole antifungals RifampinStatins Macrolides RifabutinMacrolides NNRTIs NNRTIsSome NNRTIs Grapefruit juice Phenobarbital Maraviroc PIs CarbamazepineBenzodiazepines Sertraline PhenytoinAzolesantifungals Fluoxetine St.John’s WortMethadone Cobicistat some PIsElvitegravir Other P‐450 isoenzymes may be involved in interactions

PI=protease inhibitors NNRTI=non‐nucleoside reverse transcriptase inhibitor

US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents., updated January 2016. URL in Handout.

P‐450 CYP3A4 Drug Interactions

US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents., updated January 2016. URL in Handout.

• ART with acid suppression agents– Atazanavir– Rilpivirine

• Budesonide with PIs or Cobicistat– ↑Cor costeroid

• Interactions between NNRTIs, PIs, and Elvitegravir– Unpredictable

• Methadone and protease inhibitors– Lower methadone concentrations

Special Interactions to Watch For


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One “Pill” Once a Day

• Atripla (tenofovir, emtricitabine, efavirenz)

• Complera (tenofovir, emtricitabine, rilpivirine)

• Stribild (tenofovir disoproxil fumarate, emtricitabine, elvitegravir, cobicistat)

• Genvoya (tenofovir alafenamide , emtricitabine, elvitegravir, cobicistat)

• Triumeq (abacavir, lamivudine, dolutegravir)

U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected

adults and adolescents. January 2016. URL in Handout.

“What to Start with”‐ Per Guidelines

Preferred regimens for naive patients (A‐I)

Protease Inhibitor‐Based Regimen

• Darunavir/Ritonavir + Tenofovir DF/Emtricitabine

Integrase Inhibitor‐Based Regimens

• Dolutegravir / Abacavir / Lamivudine (Only if HLA‐B*5701 negative)• Dolutegravir + Tenofovir DF/ Emtricitabine• Elvitegravir / Cobicistat / Tenofovir DF / Emtricitabine (Only if pre‐ART CrCl >

70mL/min)• Elvitegravir / Cobicistat / Tenofovir AL/ Emtricitabine (Only if pre‐ART CrCl >

30mL/min)• Raltegravir + Tenofovir DF/ Emtricitabine

U.S. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV‐1‐infected adults and adolescents. January 2016. URL in Handout.

DF= Disoproxil fumarate, AL= Alafenamide

Question 7Given that ML has hepatitis B co‐infection, what ART regimen would provide her with two agents with hepatitis B activity?

A. Zidovudine + lamivudine + lopinavir + ritonavir

B. Abacavir + emtricitabine + efavirenz

C. Tenofovir + emtricitabine + darunavir + ritonavir

D. Stavudine + lamivudine + raltegravir

Chronic Hepatitis B Treatment

• Controversial

• Treatment clearly indicated:

– ALT levels >2 x upper limit of normal range

– Liver damage on biopsy

– HBV DNA (Viral load) > 2000 IU/mL

Lok ASF et al. Hepatology. 2007; 45:507-39.

Lok ASF et al. Hepatology. 2009; 50:661-2.

ART Drugs with Hepatitis B activity for Co‐Infected Patients

• Tenofovir

• Lamivudine

• Emtricitabine

• Only use these as part of HIV regimen not as monotherapy for Hepatitis B infection

• Guidelines recommend using two agents (Tenofovir + emtricitabine OR lamivudine)

Lok ASF et al. Hepatology. 2007; 45:507-39. Lok ASF et al. Hepatology. 2009; 50:661-2. U.S. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-

infected adults and adolescents. January 2016. URL in Handout.

Acute Hepatotoxicity

• Nearly all available antiretroviral drugs have been associated with some risk for hepatotoxic reactions.

• Many patients co‐infected with hepatitis B or C.

• Treating HIV can improve viral hepatitis

U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. January 2016. URL in handout.


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• Respiratory system greatly improved

• ML reports occasional GI upset and nausea.

• ML is feeling increasingly weak and tired. She reports some difficulty breathing while walking the halls.

Case‐ Day 15 Question 8ML is diagnosed with drug‐associated G6PD‐deficiency hemolytic anemia. Which of his current medications is the likely cause?

A. Dolutegravir

B. Abacavir

C. Lamivudine

D. Trimethoprim‐Sulfamethoxazole

Dhaliwai G et al. Am Fam Physician. 2004; 69:2599-606.

• Sulfa drugs

• Dapsone

• Primaquine

• Nitrofurantoin

• Phenazopyridine

• Nalidixic acid

• Methylene blue

Drug‐Associated Glucose‐6‐Phosphate Dehydrogenase Deficiency Hemolytic

Anemia

Prevention of Opportunistic Infections

Question 9Following acute treatment for PCP will ML need secondary prophylaxis? If so, what regimen should she receive?

A. A TMP‐SMX double‐strength oral tablet daily

B. A TMP‐SMX double‐strength oral tablet three times per week

C. Atovaquone oral solution 1,500mg once daily

D. No PCP agents are needed for secondary prophylaxis

Question 10At her 1st outpatient clinic appointment, her CD4 count= 45 cells/mm3. Should ML receive any additional prophylactic therapy at this point?

A. Azithromycin 1,200mg oral tablet dose once weekly

B. Fluconazole 200mg orally once daily

C. Dapsone‐based regimen for toxoplasmosis prevention

D. No additional prophylactic agents are needed


____________________________________________________________________________________________________________ 19

• Pneumocystis pneumonia (PCP)– CD4 count< 200 cells/mm3 or oropharyngeal candidiasis

– One TMP‐SMX double‐strength (DS) tablet daily

– Dapsone 100 mg orally once daily, one TMP‐SMX single‐strength (SS) tablet once daily

– Atovaquone 1.5 g orally once daily

– Aerosolized pentamidine 300 mg monthly

• Toxoplasmosis encephalitis– CD4 < 100 cells/mm3 and positive anti‐toxoplasma IgG

– One TMP‐SMX DS tablet once daily

– Dapsone 50 mg orally once daily + Pyrimethamine 75mg orally once daily + Leucovorin 25 mg orally once daily

– TMP‐SMZ DS three times a week or one Single Strength tab Daily

– Atovaquone 1.5 g orally once daily

• Mycobacterium avium complex (MAC)– CD4 count < 50 cells/mm3

– Azithromycin 1.2 g orally once weekly

• Tuberculosis– Isoniazid (INH) 300 mg orally for 9 months

U.S. Department of Health and Human Services. Opportunistic infections. December 2015.

URL in reference list

Opportunistic Infection (OI) Primary Prophylaxis

• Pneumocystis pneumonia (PCP)– CD4 < 200 cells/mm3

– TMP‐SMX DS daily or Dapsone 100 mg orally once daily– Atovaquone 1.5 g orally once daily

• Toxoplasmosis encephalitis– CD4 < 100 cells/mm3 and positive toxoplasma IgG– TMP‐SMX DS daily – Dapsone 50 mg orally once daily + Pyrimethamine 75 mg orally once daily +

Leucovorin 25 mg orally once daily• MAC

– CD4 < 50 cells/mm3

– Azithromycin 1.2 g orally once weekly

• Cryptococcal Meningitis– Fluconazole 200‐400 mg orally daily

• CMV – Valganciclovir 900 mg orally once daily +/‐ Ocular implant

U.S. Department of Health and Human Services. Opportunistic infections. December 2015.

URL in reference list

OI Secondary Prophylaxis

• Better responses if CD4 > 200 cells/mm3

• Live vaccines usually avoided– Especially at lower CD4 counts

• Pneumococcal vaccine• Influenza vaccine (NOT live‐attenuated)• Hepatitis B vaccine• Hepatitis A vaccine• Tetanus‐diphtheria‐acellular pertussis (Tdap)

Immunizations

Question 11ML’s CD4 count at her 3 month appointment was 150 cells/mm3. When she returns to clinic 3 months later her CD4 count has increased to 250 cells/mm3. She has been taking atovaquone daily and azithromycin weekly. She is tired of taking so many medications. Can she stop these agents?

A. No, he must continue both until his CD4 count has been > 200 cells/mm3 for 3 months

B. He can stop the azithromycin at this point, but must continue the atovaquone

C. He can stop the atovaquone at this point, but must continue the azithromycin

D. Yes, he can discontinue both

• Pneumocystis pneumonia (PCP)– CD4 > 200 cells/mm3 for 3 months

• Toxoplasmosis encephalitis– CD4 > 200 cells/mm3 for 3 months– CD4 > 200 cells/mm3 for 6 months (secondary prophylaxis)

• Mycobacterium avium complex (MAC)– CD4 > 100 cells/mm3 for 3 months– CD4 > 100 cells/mm3 for 6 months (secondary prophylaxis)

• Cryptococcal meningitis*– CD4 > 100 cells/mm3 for 6 months

• Cytomegalovirus– CD4 > 100 cells/mm3 for 6 months

* Some experts have recommended lifelong use


Discontinuing Opportunistic Infection Prophylaxis

When to Change Therapy

• To simplify regimen

• Toxicity or interaction with other drug(s).

• Failure to maintain undetectable HIV RNA.

– Selection and replication of resistant mutants are more likely to occur as viral load increases.

– Modifiable reasons for failure (nonadherence, interactions, etc. ) MUST be addressed first.


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Why Do Regimens Fail?

• Drug resistance

• Insufficient drug exposure

– Poor adherence

– Low bioavailability

—Poor absorption / drug interactions

– Inability to penetrate viral reservoirs (sanctuary sites)

• Limited antiviral potency

• Progressive immunologic decline

Selection of Resistant Mutants

Wild‐type virus

Drug

Stop Drug

• A better test of resistance than susceptibility.

• Requires a minimum HIV RNA of 500 copies / mL.

• Minor species not accounted for.

• Generally recommended for all HIV patients entering care.

• Testing should be done during a “failed regimen.”

U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV‐1‐infected adults and adolescents. January 2016. URL in handout.

Points to Remember About Resistance Testing

Good Sources of Information for HIV‐Positive Patients

US Department of Health & Human Services

Health Resources and Services Administration (HRSA) HIV/AIDS Services

http://www.hab.hrsa.gov/

– Ryan White Program

• State AIDS Hotlines

• Local support groups

• Your pharmacist

Ryan White Services*

• For limited income HIV‐infected persons without health insurance (Including Medicaid or Medicare)

• Outpatient HIV services (i.e., HIV clinic)

• HIV lab tests

• Emergency dental care

• Outpatient mental health care

• Transportation to HIV medical, pharmacy, dental, and counseling appointments

• Subject to approvals and availability of funds

• HIV medications generally provided through the AIDS Drug Assistance Program (ADAP)

http://www.hab.hrsa.gov/abouthab/aboutprogram.html (Accessed 2016, February 20)

* Not a comprehensive list of services and restrictions.

Summary

• Opportunistic infections have decreased as a result of ART, but they still occur when CD4 counts are low

• Drug interaction potential with ART is very high, and mainly involves CYP3A4 isoenzymes

• Adverse effects from ART are frequently encountered and require close monitoring

• Adherence to ART has correlated with viral load suppression and enhanced outcomes


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2016 pharmacotherapy specialty examination review course...

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