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The ART of Antiretroviral Therapy in Critically-ill Patients with HIV Tyler Finocchio, PharmD, BCPS PGY2 Critical Care Pharmacy Resident Avera McKennan Hospital & University Health Center February 10th, 2018
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Disclosure Statement
I have no disclosures concerning financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation
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Pharmacist Objectives Describe available evidence regarding initiation of antiretroviral therapy (ART) in patients newly diagnosed with HIV with or without Opportunistic Infections Summarize literature on the continuation of ART in the inpatient setting for patients previously diagnosed with HIV and taking a complete antiretroviral regimen Recognize relevant drug-drug interactions between antiretroviral medications and other drugs commonly used in the inpatient setting
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Technician Objectives
Distinguish brand and generic names of HIV medications Recognize available dosage forms of HIV medications
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1981: The Beginning
http://time.com/3503000/behind-the-picture-the-photo-that-changed-the-face-of-aids/
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HIV Therapy
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7 HIV Medications
NRTIs NNRTIs Abacavir (Ziagen®) Delavirdine (Rescriptor®) Didanosine (Videx®) Efavirenz (Sustiva®) Emtricitabine (Emtriva®) Etravirine (Intelence®) Lamivudine (Epivir®) Nevirapine (Viramune®) Stavudine (Zerit®) Rilpivirine (Edurant®) Tenofovir alafenamide INSTIs (Vemlidy®) Raltegravir (Isentress ®) Tenofovir Disproxil Fumerate Elvitegravir (Vitekta®) (Viread ®) Dolutegravir (Tivicay®) Zidovudine (Retrovir ®) Fusion Inhibitor Entry Inhibitor Enfuviritide (Fuzeon®) Maraviroc (Selzentry®)
https://aidsinfo.nih.gov/understandng-hiv-aids/fact- sheets/21/58/fda-approved-hiv-medications
8 HIV Medications
Protease Inhibitors (PIs) Combination Products Atazanavir (Reyataz®) Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine Darunavir (Prezista®) (Genvoya®) Fosamprenavir (Lexiva®) Elvitegravir/cobicistat/tenofovir Indinavir (Crixivan®) disproxil fumerate/emtricitabine Nelfinavir (Viracept ®) (Stribild ®) Ritonavir (Norvir ®) Emtricitabine/rilpivirine/ tenofovir alafenamide (Odefsey®) Combination Products Emtricitabine/rilpivirine/ tenofovir Abacavir/lamivudine disproxil fumerate (Complera®) (Epizicom®) Emtricitabine/tenofovir disproxil Abacavir/lamivudine/ fumerate (Truvada®) dolutegravir (Triumeq®) Emtricitabine/tenofovir Efavirenz/emtricitabine/ alafenamide (Descovy®) tenofovir disproxil fumerate https://aidsinfo.nih.gov/undersating-hiv-aids/fact- (Atripla ®) sheets/21/58/fda-approved-hiv-medications
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Opportunistic Infections
Morris A, Et al. Emerging Infectious Diseases 2004
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HIV Prevalence in the US
http://aidsvu.org/map/
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HIV in South Dakota
https://doh.sd.gov/documents/statistics/ID/Nov2017.pdf
12 Recent Trends
28%
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6047a4.htm
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13 2018: Why are patients with HIV in the ICU? Unaware of HIV or Not in Aware of HIV and Virally Effective Care Suppressed Opportunistic infections Cardiovascular issues
HIV-associated neoplasms Respiratory Failure
Non-HIV related conditions Sepsis
Chronic Kidney Disease
Gastrointestinal bleeding
Liver disease
Neurological conditions
Masur. HIV + Critical Illness: a Primer of ICU Management. 2015
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ICU Admission Diagnoses ICU Admission Diagnosis Based on ART Use in 2009 50
45
40
35
30 25 Total 20 No ART % of of % patients 15
10 ART
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0 AIDS PCP Respiratory Sepsis Neurologic Other associated Failure diagnosis
Powell, et al. CHEST 2009
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Antiretroviral Therapy (ART) in Critically-ill Patients Newly diagnosed with HIV or Not in Effective Care
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Early Initiation of ART Morris Zolopa Abay N= 85 N= 282 N=2272
Year 2003 2009 2015 All HIV+ patients All HIV+ patients Meta-analysis Population admitted to ICU with admitted with HIV+ patients PCP any OI with TB Early ART vs Early ART vs Study Arms Use of ART vs No ART delayed ART delayed ART AIDS Progression/ All cause Endpoint Mortality Death mortality 25% vs 63% 14.2% vs 24.1% 10.1% vs 12.9% Result (P= 0.03) (P=0.035) (P=0.03) PCP: pneumocystis Jiroveci pneumonia Morris, et al. Am J Respir Crit Care Med. 2002 OI: opportunistic infections Zolopa, et al. PLoS ONE. 2009 TB: Tuberculosis Abay, et al. J Int Assoc. Providers of AIDS Care. 2015
17 Immune Reconstitution Inflammatory Syndrome (IRIS)
Paradoxical worsening of infection or unmasking of new infection sites following the initiation of ART
Occurs in up to 30% of patients within 1-8 weeks of starting ART and more often associated with: Lower initial CD4 counts Faster decreases in viral load
Guidelines recommend continuation of ART through IRIS, treating the Opportunistic infection, and possible use of glucocorticoids
Murdoch, et al. AIDS Research and Therapy. 2007
18 ART in Cryptococcal Meningitis (COAT Trial)
177 HIV+, ART Naïve patients with Cryptococcal meningitis in Uganda and South Africa 88 received early ART ( within 1-2 weeks of diagnosis) 89 received delayed ART ( 5 weeks after diagnosis)
Primary Endpoint: Mortality at 26 weeks Early ART: 45% (40 of 88 patients) Delayed ART: 30% (27 of 89 Patients) P = 0.03
No difference in recognized IRIS (20% vs. 13%, P= 0.32)
Boulware, et al. NEJM. 2014
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19 ART in Cryptococcal Meningitis (COAT Trial)
Boulware, et al. NEJM. 2014
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Continuation of ART in Patients Previously Diagnosed with HIV and Virally Suppressed
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ART Continuation
General consensus based on Expert Opinion Continue ART if virally suppressed and minimal risk of drug-drug interactions or toxicity Recommend drug resistance testing for any doubt of patient compliance before continuing Consider drug delivery, dosing, and absorption factors
Holding ART can lead to viral resistance Varying half lives of antiretrovirals Short vs. long term interruptions
Huang, et al. NEJM 2006 Akgun, et al. Semin Resp Crit Care Med 2016
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2006: SMART Trial
CD4 Count Guided Interruptions in ART Continuation of Interruption of P- value ART ART (N=2752) (N=2720) All Cause 30 55 0.007 Mortality OIs Serious 2 13 0.01 Non-serious 18 63 <0.001 Major Cardiovascular, 39 65 0.009 Renal, or Hepatic Disease OI: Opportunistic Infection El-Sadr, Et al. NEJM 2006
23 2012: Continuing HAART in the ICU
Continued ART Stopped ART in P Value in ICU ICU (N=32) (N=59) Mortality at 6 11 27 0.04 months AIDS related 5 20 0.07 Events Viral load at 6 2.42 3.37 0.03 months Viral 8 4 0.02 resistance
Meybeck, et al. AIDS Research and Therapy. 2012
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Drug-Drug Interactions between ART and Other Medications Used in the Inpatient Setting
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ART-Drug Interactions Drug/Drug category Antiretroviral/class Interaction
H2RA Atazanavir Reduced PPIs Nelfinavir concentrations of Rilpivirine ARVs Fentanyl Protease inhibitors Increased sedation Midazolam Protease inhibitors Increased sedation Phenytoin Protease inhibitors ↑ phenytoin; ↓ ARVs Phenobarbital Many ARVs Decreased ARV levels Amiodarone Protease inhibitors Increased QTC NNRTIs Interval Atazanavir, Efavirenz ↑↓ warfarin Warfarin Lopinavir, Darunavir ↑↓ warfarin
Akgun. Semin Respir Crit Care Med. 2016
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ART-Drug Interactions
CHAP. http://hivclinic.ca/downloads/DDI%20tool_English_final.pdf 2016
27 Alternative Forms of Administration Liquid/Oral Suspension Crushable Tablets/Open Available capsules Abacavir Raltegravir Abacarvir Nevirapine Atazanavir Ritonavir Atanazanavir Nelfinavir Darunavir Tenofovir Atripla® Rilpivirine Didanosine Zidovudine Combivir® Stribild® Emtricitabine Dolutegravir Tenofovir Fosamprenavir Emtricitabine Truvada® Lamivudine Etravirine Zidovudine Lopinavir Efavirenz Nevirapine (capsules) Lamivudine
Folsy, Et al. Oral Antiretroviral Administration. 2017
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28 Clinical Conclusion ART should generally be started early in all newly diagnosed HIV+ patients presenting with OIs, or low CD4 Counts Except Cyrptococcal Meningitis
Continue ART in patients admitted to ICU who were on a complete regimen and virally suppressed Improved outcomes, but possible increase in resistance due to absorption abnormalities Interruption in ART can also lead to viral resistance
Always Double check potential drug-drug interactions with ARVs and be aware of alternative methods of administering ARVs to patients in the ICU
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Questions?
30 References
Morris A, Lundgren JD, Masur H, et al. Current Epidemiology of Pneumocystis Pneumonia. Emerging Infectious Diseases. 2004;10(10):1713-1720
Map - AIDSVu. http://aidsvu.org/map/. Accessed January 8, 2018.
Powell K, Davis JL, Morris AM, Chi A, Bensley MR, Huang L,. Surivial for Patients with HIV admitted to the ICU Continues to Improve in the Current Era of Combination Antiretroviral Therapy. CHEST. 2009; 135(1): 11-17
Boulware DR, Meya DB, Muzoora C, et al. Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis. The New England journal of medicine. 2014;370(26):2487-2498. doi:10.1056/NEJMoa1312884.
Murdoch DM, Venter WD, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Research and Therapy. 2007;4:9.
Folsy, M; Hughes, C; Lamb, S; Tseng, A. Oral Antiretroviral Administration: Information on Crushing and Liquid Drug Formulations. 2017. http://hivclinic.ca Accessed January 24, 2018
Canadian HIV/AIDS Pharmacists Network. A Management Tool for HIV Drug-Drug Interactions. 2016. http://hivclinic.ca/downloads/DDI%20tool_English_final.pdf Accessed January 26, 2018
Akgun, K, Miller, R. Critical Care in Human Immunodeficiency Virus-Infected Patients. Seminars in Respiratory and Critical Care Medicine. 2016; 37:303-317.
Masur H. HIV+ Critical Illness: A Primer of ICU management. 2015. http://maryland.ccproject.com/2014/03/07/hiv-critical-illness-primer-icu-management/ Accessed January 14, 2018.
Center for Disease Control and Prevention. Morbidity and Mortality Weekly Report – Vital Signs: HIV Prevention Through Care and Treatment – United States. 2011; 60 (47): 1618-1623. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6047a4.htm Accessed July 12, 2015
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31 References
Abay, s; Deribe, K; Reda, A; Biadgilign, S. The Effect of Early Initiation of Antiretroviral Therapy in TB/HIV – Coinfected Patients: A systematic Review and Meta-Analysis. Journal of the International Association of Providers of AIDS Care. 2015; 14(6) 560-570.
Zolopa, A; Anderson, J; Komarow, L; Sanne, I; et al. Early Antiretroviral Therapy Reduces AIDS Progression/Death in Indviduals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial. PLoSONE. 2009; 4(5):e5575.1-10.
Morris, A; Creasman, J; Turner, J; Luce, J; et al. Intensive Care of Human Immunodeficiency Virus-Infected Patients During the Era of Highly Active Antiretroviral Therapy. American Journal of Respiratory and Critical Care Medicine. 2002. 166: 262-267.
Huang, L; Quartin, A; Jones, D; Havlir, D. Intensive Care of Patients with HIV Infection. New England Journal of Medicine. 2006; 355(2): 173-181.
FDA –Approved HIV Medicines. https://aidsinfo.nih.gov/understandng-hiv-aids/fact- sheets/21/58/fda-approved-hiv-medications. Accessed January 23, 2018.
Meybeck, A: Lecomte, L; Valette, M; Van Grunderbeeck, N; et al. Should Highly Active Antiretroviral Therapy Be Prescribed in Critically-ill HIV-Infected Patietns During the ICU Stay? A Retrospective Cohort Study. AIDS Research and Therapy. 2012; 9:27.
El-Sadr, W; Lundgren, J; Neaton, J; Gordon, F; et al. CD4+ Count-Guided Interruption of Antiretroviral Treatment. New England Journal of Medicine. 2006. 355(22): 2283-2296
South Dakota Department of health. South Dakota Health and Disease Summary November 2017. https://doh.sd.gov/documents/statistics/ID/Nov2017.pdf Accessed January 8, 2018
32 Assessment Question 1 Initiation of antiretroviral therapy should be delayed in patients who present with which opportunistic infection?
A. Pneumocystis Jiroveci Pneumonia B. Toxoplasmosis C. Cryptococcal Meningitis D. Mycobacterium Avium Complex
Assessment Question 2 33 Which of the following outcomes has not been associated with the continuation of antiretrovirals in Critically-ill patients?
A. Decreased mortality B. Decreased AIDS-related events C. Decreased antiretroviral resistance D. Potential drug toxicity due to drug-drug interactions
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Assessment Question 3 34 A 25 yo woman with HIV as been tenofovir/emtricitabine and darunavir/ritonavir for 5 years. She was recently diagnosed with Hodgkin’s Lymphoma for which she is currently being treated by an oncologist. Today, venous doppler reveals she has a lower extremity thrombus for which she will be treated with enoxaparin and transitioned to warfarin. Which of the following would be important regarding this patient’s initial warfarin dosing? A. Initiate half the normal warfarin dose B. Use the standard initial warfarin dose C. Double the initial warfarin dose D. Warfarin is contraindicated with this antiretroviral regimen
Assessment Question 4 35 Which medication is correctly matched to its commonly used brand name?
A. Darunavir (Reyataz®) B. Tenofovir Disproxil Fumerate (Viread®) C. Dolutegravir (Isentress®) D. Emtricitabine (Sustiva®)
Assessment Question 5 36
Which of the following antiretrovirals is available as an oral suspension?
A. Dolutegravir B. Tenofovir alafenamide C. Efavirenz D. Raltegravir
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