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 10 th, 2018 2 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 3 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 1
4 Technician Objectives Distinguish brand and generic names of HIV medications Recognize available dosage forms of HIV medications 5 1981: The Beginning http://time.com/3503000/behind-the-picture-the-photo-that-changed-the-face-of-aids/ 6 HIV Therapy 2
HIV Medications NRTIs Abacavir (Ziagen ) Didanosine (Videx ) Emtricitabine (Emtriva ) Lamivudine (Epivir ) Stavudine (Zerit ) Tenofovir alafenamide (Vemlidy ) Tenofovir Disproxil Fumerate (Viread ) Zidovudine (Retrovir ) Entry Inhibitor Maraviroc (Selzentry ) NNRTIs Delavirdine (Rescriptor ) Efavirenz (Sustiva ) Etravirine (Intelence ) Nevirapine (Viramune ) Rilpivirine (Edurant ) INSTIs Raltegravir (Isentress ) Elvitegravir (Vitekta ) Dolutegravir (Tivicay ) Fusion Inhibitor Enfuviritide (Fuzeon ) 7 HIV Medications Protease Inhibitors (PIs) Atazanavir (Reyataz ) Darunavir (Prezista ) Fosamprenavir (Lexiva ) Indinavir (Crixivan ) Nelfinavir (Viracept ) Ritonavir (Norvir ) Combination Products Abacavir/lamivudine (Epizicom ) Abacavir/lamivudine/ dolutegravir (Triumeq ) Efavirenz/emtricitabine/ tenofovir disproxil fumerate (Atripla ) Combination Products Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya ) Elvitegravir/cobicistat/tenofovir disproxil fumerate/emtricitabine (Stribild ) Emtricitabine/rilpivirine/ tenofovir alafenamide (Odefsey ) Emtricitabine/rilpivirine/ tenofovir disproxil fumerate (Complera ) Emtricitabine/tenofovir disproxil fumerate (Truvada ) Emtricitabine/tenofovir alafenamide (Descovy ) https://aidsinfo.nih.gov/understandng-hiv-aids/factsheets/21/58/fda-approved-hiv-medications https://aidsinfo.nih.gov/undersating-hiv-aids/factsheets/21/58/fda-approved-hiv-medications 8 9 Opportunistic Infections Morris A, Et al. Emerging Infectious Diseases 2004 3
10 HIV Prevalence in the US http://aidsvu.org/map/ 11 HIV in South Dakota https://doh.sd.gov/documents/statistics/id/nov2017.pdf Recent Trends 12 28% http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6047a4.htm 4
2018: Why are patients with HIV in the ICU? 13 Unaware of HIV or Not in Effective Care Opportunistic infections HIV-associated neoplasms Non-HIV related conditions Aware of HIV and Virally Suppressed Cardiovascular issues Respiratory Failure Sepsis Chronic Kidney Disease Gastrointestinal bleeding Liver disease Neurological conditions Masur. HIV + Critical Illness: a Primer of ICU Management. 2015 14 ICU Admission Diagnoses 50 45 40 ICU Admission Diagnosis Based on ART Use in 2009 % of patients 35 30 25 20 15 10 Total No ART ART 5 0 AIDS associated diagnosis PCP Respiratory Failure Sepsis Neurologic Other Powell, et al. CHEST 2009 15 Antiretroviral Therapy (ART) in Critically-ill Patients Newly diagnosed with HIV or Not in Effective Care 5
16 Early Initiation of ART Morris N= 85 Zolopa N= 282 Abay N=2272 Year 2003 2009 2015 Population Study Arms Endpoint Result PCP: pneumocystis Jiroveci pneumonia OI: opportunistic infections TB: Tuberculosis All HIV+ patients admitted to ICU with PCP Use of ART vs No ART Mortality 25% vs 63% (P= 0.03) All HIV+ patients admitted with any OI Early ART vs delayed ART AIDS Progression/ Death 14.2% vs 24.1% (P=0.035) Meta-analysis HIV+ patients with TB Early ART vs delayed ART All cause mortality 10.1% vs 12.9% (P=0.03) Morris, et al. Am J Respir Crit Care Med. 2002 Zolopa, et al. PLoS ONE. 2009 Abay, et al. J Int Assoc. Providers of AIDS Care. 2015 Immune Reconstitution Inflammatory Syndrome (IRIS) Paradoxical worsening of infection or unmasking of new infection sites following the initiation of ART 17 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 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) 18 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 6
ART in Cryptococcal Meningitis (COAT Trial) 19 Boulware, et al. NEJM. 2014 20 Continuation of ART in Patients Previously Diagnosed with HIV and Virally Suppressed 21 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 7
22 2006: SMART Trial CD4 Count Guided Interruptions in ART All Cause Mortality OIs Serious Non-serious Major Cardiovascular, Renal, or Hepatic Disease OI: Opportunistic Infection Continuation of ART (N=2752) Interruption of ART (N=2720) P- value 30 55 0.007 2 18 13 63 0.01 <0.001 39 65 0.009 El-Sadr, Et al. NEJM 2006 2012: Continuing HAART in the ICU 23 Mortality at 6 months AIDS related Events Viral load at 6 months Viral resistance Continued ART in ICU (N=32) Stopped ART in ICU (N=59) P Value 11 27 0.04 5 20 0.07 2.42 3.37 0.03 8 4 0.02 Meybeck, et al. AIDS Research and Therapy. 2012 24 Drug-Drug Interactions between ART and Other Medications Used in the Inpatient Setting 8
25 ART-Drug Interactions Drug/Drug category Antiretroviral/class Interaction H 2 RA PPIs Atazanavir Nelfinavir Rilpivirine Reduced concentrations of ARVs Fentanyl Protease inhibitors Increased sedation Midazolam Protease inhibitors Increased sedation Phenytoin Protease inhibitors phenytoin; ARVs Phenobarbital Many ARVs Decreased ARV levels Amiodarone Warfarin Protease inhibitors NNRTIs Atazanavir, Efavirenz Lopinavir, Darunavir Increased QTC Interval warfarin warfarin Akgun. Semin Respir Crit Care Med. 2016 26 ART-Drug Interactions CHAP. http://hivclinic.ca/downloads/ddi%20tool_english_final.pdf 2016 Alternative Forms of Administration Liquid/Oral Suspension Available Abacavir Atazanavir Darunavir Didanosine Emtricitabine Fosamprenavir Lamivudine Lopinavir Nevirapine Raltegravir Ritonavir Tenofovir Zidovudine Crushable Tablets/Open capsules Abacarvir Atanazanavir Atripla Combivir Dolutegravir Emtricitabine Etravirine Efavirenz (capsules) Lamivudine Nevirapine Nelfinavir Rilpivirine Stribild Tenofovir Truvada Zidovudine 27 Folsy, Et al. Oral Antiretroviral Administration. 2017 9
Clinical Conclusion ART should generally be started early in all newly diagnosed HIV+ patients presenting with OIs, or low CD4 Counts Except Cyrptococcal Meningitis 28 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 29 Questions? References 30 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 10
References 31 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/factsheets/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 Assessment Question 1 Initiation of antiretroviral therapy should be delayed in patients who present with which opportunistic infection? 32 A. Pneumocystis Jiroveci Pneumonia B. Toxoplasmosis C. Cryptococcal Meningitis D. Mycobacterium Avium Complex Assessment Question 2 Which of the following outcomes has not been associated with the continuation of antiretrovirals in Critically-ill patients? 33 A. Decreased mortality B. Decreased AIDS-related events C. Decreased antiretroviral resistance D. Potential drug toxicity due to drug-drug interactions 11
Assessment Question 3 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 34 B. Use the standard initial warfarin dose C. Double the initial warfarin dose D. Warfarin is contraindicated with this antiretroviral regimen Assessment Question 4 Which medication is correctly matched to its commonly used brand name? 35 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 12