marie dorsey, pharm.d., aahivp ospa annual meeting november 8, 2014

Marie Dorsey, Pharm.D., AAHIVP OSPA Annual Meeting November 8, 2014

I do not have any conflicts of interest or financial disclosures

Case Study Medication List: Lopinavir/ritonavir (Kaletra) tenofovir, emtricitabine (Truvada) Sulfamethoxazole/trimethoprim (Bactrim) Pantoprazole (Protonix) Paroxetine (Paxil) Mirtazapine (Remeron) Gabapentin (Neurontin) Lisinopril (Zestril) Simvastatin (Zocor) Insulin glargine (Lantus) Insulin apart (Novolog) *Bob is a 57 yr WM *Dx HIV 1994, AIDS 2000 *CrCl ~ 50ml/min, Scr -1.2 *VL-Non detectable *Diabetes, hypertension, * CD4-196 depression, cognitive delay

Objectives Explore the management of non-AIDS co-morbidities in aging HIV patients Identify useful information for HIV medication management Discuss age-related factors that impact adherence and solutions for improved medication adherence List at least three quick HIV medication resources

Viral Load and CD4 VL -An indicator of how well the medication is working -Drops to non- detectable in 12 weeks if on HIV medication CD4 -An indicator of the immune system response -Increases 50- 100cells/mm 2 per year if on HIV medication

Anti-Retroviral Therapy (ART) Review Five ART Classes: Nucleoside Reverse Transcriptase Inhibitor (NRTI) Protease Inhibitor (PI) Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) Entry Inhibitor (EI) Integrase Strand Transfer Inhibitor (INSTI)

HIV Life Cycle and ART Targets Protease Inhibitor Entry Inhibitor NRTI NNRTI Integrase Inhibitor

DHHS Antiretroviral Therapy Guidelines: May 1, 2014 Recommended Regimens Regardless of Baseline HIV RNA or CD4 Count Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov).www.aidsinfo.nih.gov ^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine: only for patients with pre-ART CrCl 70 ml/min *Abacavir recommended only if HLA-B5701 negative Slide created by Dr. Brian Wood and Dr. David Spach

The Eras of the HIV Epidemic The HIV/AIDS epidemic: major clinical themes over 3 distinct eras, 19812011 Chu C, Selwyn P. J Urban Health 2011:556-566.

HIV and AIDS Current Cases, Diagnoses and Deaths United States 1981-2008 Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. HIV Surveillance United States 1981-2008

HIV Statistics as of 2012 What is the average age of an HIV positive Oregonian? How many Oregonians are diagnosed with HIV each year? How many Oregonians are living with HIV? What percent of people living in the U.S. are >50yrs old? What percentage of people will be over the age of 50 in 2015? CDC HIV Surveillance Report 2011, Oregon Health Authority Epi Profile 2013

Issues Unique to the Aging HIV Positive Patient Late Testing and Diagnosis Diagnosis made later in course of illness Higher transmission risk ART started later Polypharmacy Organ dysfunction Girardi E. J Acquir Imm Def Syndr 2000;25:71

The Factors that Contribute to Increased Morbidity and Mortality in HIV Positive Patients HOST Lifestyle Genetic Aging HOST Lifestyle Genetic Aging HIV Compromised immunity Inflammation despite ART HIV Compromised immunity Inflammation despite ART ART Toxicity ART Toxicity Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Morbity and Mortality Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic

The Factors that Contribute to Increased Morbidity and Mortality in HIV Positive Patients HOST Lifestyle Genetic Aging HOST Lifestyle Genetic Aging HIV Compromised immunity Inflammation despite ART HIV Compromised immunity Inflammation despite ART ART Toxicity ART Toxicity Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurocologic Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurocologic Morbity and Mortality Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic

Compromised immunity Decline in CD4 T cells predict higher risk of morbidity and mortality Immune dysfunction in HIV similar to aging Inflammation despite ART HIV results in low level inflammation Chronic inflammation also occurs in aging ART associated with increase in visceral fat, causing inflammation Are non-AIDS co-morbidities more likely with immune dysfunction and chronic inflammation? Living with HIV = accelerated aging? Phillips AN. AIDS 2008, Casau N. CID 2005;41:855-863 The Contribution of HIV to aging and non-AIDS Co-morbidities

The Factors that Contribute to Increased Morbidity and Mortality in HIV Positive Patients HOST Lifestyle Genetic Aging HOST Lifestyle Genetic Aging HIV Compromised immunity Inflammation despite ART HIV Compromised immunity Inflammation despite ART ART Toxicity ART Toxicity Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurocognitive Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurocognitive Morbity and Mortality Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic

Host Factors that Contribute to Increased Risk of Co-Morbidity Lifestyle Smoking, alcohol Diet, exercise Genetic Family history Aging Renal, hepatic function Neurocognitive function Immune system Co-infections Hepatitis B Hepatitis C HOST Lifestyle Genetic Aging Co-infections HOST Lifestyle Genetic Aging Co-infections Helleberg M. Clin Infect Dis. 2013;56:727-734

The Factors that Contribute to Increased Morbidity and Mortality in HIV Positive Patients HOST Lifestyle Genetic Aging HOST Lifestyle Genetic Aging HIV Compromised immunity Inflammation despite ART HIV Compromised immunity Inflammation despite ART ART Toxicity ART Toxicity Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Systems of Chronic Morbidity Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Morbity and Mortality Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic

ART Toxicity Is anti-retroviral therapy toxic to the body? Most studies exclude patients >50 or those with co-morbid conditions Most studies do not compare ages ART Toxicity ART Toxicity *The newer ART medications have less toxicity *The toxicity from the virus is greater than the toxicity from the medication El-Sadir WM. N Engl J Med 355;22:2283-2296.

Pharmacokinetics in Aging Patients Pharmacokinetics: Absorption - body fat changes Distribution - body fat changes Metabolism - decreased CYP function Elimination - decreased creatinine clearance (ClCr) Dumond JB. HIV Medicine 2013; 12(7):401-409, Wooten JM. South Med J. 2012;105(8):437-445

Side Effects Metabolic (diabetes, lipodystrophy) - PI, NNRTI Osteoporosis Tenofovir (Viread) Cardiac - PI, Abacavir (Ziagen) Renal Tenofovir (Viread) Hepatic - older PIs Central Nervous System efavirenz (Sustiva), dolutegravir (Tivicay) Gastrointestinal - PI Peripheral neuropathy - older NRTIs NNRTI-Non-nucleoside Reverse Transcriptase Inhibitor, PI-Protease Inhibitor NRTI-Nucleoside Reverse Transcriptase Inhibitor

Drug Interactions MedicationPredicted EffectManagement Acid Reducers (Calcium, H2RA, PPI) PI, INSTI, rilpivirineAtazanavir -timing and max dosing requirements, some contraindicated INSTI-separate antacids by 2hr Rilpivirine-omeprazole contraindicated StatinsPI StatinsSimvastatin, lovastatin contraindicated Start with low dose statin Use pravastatin, rosuvastatin Herbals or any medMany unknowns Counsel about necessity St. Johns Wort, Garlic DHHS Guidelines Drug Interaction Charts HIV-druginteractions.org Micromedex or LexiComp INSTI-Integrase Strand Transfer Inhibitor, PI-Protease Inhibitor, H2RA-Histamine-2 Receptor Antagonist, PPI-Proton Pump Inhibitor DHHS Antiretroviral Guidelines 2014

Drug Interactions MedicationPredicted EffectManagement SteroidsPI SteroidUse Beclomethasone Check for adrenal suppression (Cushings Syndrome) NarcoticsPI, NNRTI or NarcoticIncrease or decrease narcotic Methadone PDEIPI PDEISildenafil, Tadalafil, Vardenafil -Start with lowest dose Boosting *Therapeutically necessary Ritonavir PI Cobicistat Elvitegravir Ritonavir given with most PI Cobicistat always given with elvitegravir NNRTI-Non-nucleoside Reverse Transcriptase Inhibitor, PI-Protease Inhibitor PDEI Phosphodiesterase Inhibitor DHHS Antiretroviral Guidelines 2014

Case Study *Bob is a 57 yr WM *Dx HIV 1994, AIDS 2000 *CrCl ~ 50ml/min, Scr -1.2 *VL-Non detectable *Diabetes, hypertension, * CD4-196 depression, cognitive delay Bob states he has been having muscle fatigue and pain. What do you suggest for him? 1. Quit lifting weights and rest 2. Change his ART 3. Discontinue simvastatin and replace it with pravastatin Medication List: Lopinavir/ritonavir (Kaletra) Tenofovir, emtricitabine (Truvada) Sulfamethoxazole/ Trimethoprim (Bactrim) Pantoprazole (Protonix) Paroxetine (Paxil) Mirtazapine (Remeron) Gabapentin (Neurontin) Lisinopril (Zestril) Simvastatin (Zocor) Insulin glargine (Lantus) Insulin apart (Novolog)

The Factors that Contribute to Increased Morbidity and Mortality in HIV Positive Patients HOST Lifestyle Genetic Aging HOST Lifestyle Genetic Aging HIV Compromised immunity Inflammation despite ART HIV Compromised immunity Inflammation despite ART HAART Toxicity HAART Toxicity Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Co-morbidities Renal Hepatic Cardiovascular Endocrine Skeletal Neurologic Morbity and Mortality

Renal Function HIV Associated Nephropathy, IgA nephropathy, glomerulonephritis Chronic kidney disease associated with higher mortality ART effects Tenofovir (Viread)-Fanconi Syndrome Tenofovir Alefenamide Phase III trials, improved efficacy, less SE Atazanavir (Reyataz) renal stones Scherzer R. AIDS 2012 April 24;26(7):867-875, Lucas GM. CID 2014:59(9):e96-e138 Prevalence of abnormal renal function: 30%

Renal Dose Adjustments Drug ClassAdjustments Needed? NRTIYes -except abacavir (Ziagen) PIAtazanavir (Reyataz) and Lopinavir (in Kaletra) in hemodialsis Fusion InhibitorMaraviroc (Selzentry) INSTICobicistat (booster in Stribild) NNRTINo DHHS Antiretroviral Guidelines 2014 NRTI-Nucleoside Reverse Transcriptase Inhibitor, PI-Protease Inhibitor, INSTI-Integrase Strand Transfer Inhibitor, NNRTI-Non Nucleoside Reverse Transcriptase Inhibitor

Case Study * Bob is a 57 yr WM * Dx HIV 1994, AIDS 2000 * CrCl ~ 50ml/min, Scr -1.2 * VL-Non detectable * Diabetes, hypertension, * CD4-196 depression, cognitive delay Medication List: Lopinavir/ritonavir (Kaletra) Tenofovir, emtricitabine (Truvada) Sulfamethoxazole/ Trimethoprim (Bactrim) Pantoprazole (Protonix) Paroxetine (Paxil) Mirtazapine (Remeron) Gabapentin (Neurontin) Lisinopril (Zestril) Pravastatin (Pravachol) Insulin glargine (Lantus) Insulin apart (Novolog) Bobs creatinine clearance decreases to 40 ml/min. What do you suggest For him? 1. Change tenofovir to abacavir 2. Decrease frequency of Truvada 3. Change Bactrim to atovaquone (Mepron) 4. Answers #2 and #3

Liver disease is the most common non- AIDS related cause of death - Up to 18% of all deaths Hepatitis C co-infection (30%) Hepatitis B co-infection (10%) Alcohol abuse Hepatotoxicity from medication- discontinue meds if >10x upper limit of normal Atazanavir (Reyataz) Smith C. AIDS 2010; Price JC Clin Gast Hepat. 2010 Hepatic Function

Cardiovascular Disease (CVD) HIV infected and older adults at increased risk for CVD Higher rates of CVD risk factors in HIV infected: -smoking, dyslipidemia ART improves CVD markers Lower CD4 associated with increased CVD risk SMART Study versus D:A:D Study- conflicting results CVD: -1/3 of serious non-AIDS conditions ~10% of deaths El-Sadir WM. N Engl J Med 355;22:2283-2296,Theibaut R, et al. AIDS. 2010 Jun 19;24(10):1537-48

Cardiovascular Illness and Dyslipidemia Guidelines from HIV Medical Association and AIDS Clinical Trials Group Protease Inhibitors most significant effect Atazanavir (Reyataz) and Darunavir (Prezista) improved impact on lipids Efavirenz (Sustiva) mostly Statins: Use pravastatin (Pravachol), rosuvastatin (Crestor) Start low and titrate up Avoid simvastatin (Zocor), lovastatin (Mevacor) Fibrates: Use fenofibrate (Tricor) Dube MP. Eval of dyslipidemia in HIV. CID 2003

Endocrine Function Diabetes Mellitus Multiple factors contribute to diabetes PI, NNRTI most likely culprits HbA1c in HIV underestimates blood sugar Testosterone Older men often need androgen replacement Menopause Occurs earlier in HIV positive women Hormone replacement may interact with ART Kim, PS, et al. Diabetes Care. 2009

Case Study * Bob is a 57 yr WM * Dx HIV 1994, AIDS 2000 * CrCl ~ 50ml/min, Scr -1.2 * VL-Non detectable * Diabetes, hypertension, * CD4-196 depression, cognitive delay Medication List: Lopinavir/ritonavir (Kaletra) Tenofovir, emtricitabine (Truvada) Atovaquone (Mepron) Pantoprazole (Protonix) Paroxetine (Paxil) Mirtazapine (Remeron) Gabapentin (Neurontin) Lisinopril (Zestril) Pravastatin (Pravachol) Insulin glargine (Lantus) Insulin apart (Novolog) You notice Bob is at increased risk for cardiovascular illness. What do you suggest for him? 1. Discontinue ritonavir (Novir) 2. Change tenofovir to abacavir (Ziagen) 3. Change Kaletra to raltegravir (Isentress)

Skeletal Function: Osteoporosis HIV and aging increases risk Declines in bone mineral density have been observed with the start of most ART Tenofovir main culprit Interventions: Bisphosphonates Vitamin D and calcium Change ART: tenofovir abacavir or raltegravir Brown T Top Antiv Med 2013, Stellbrink HJ. Clin Infect Dis. 2010 Osteopenia and osteoporosis may be 3x higher

Neurologic Function and HIV HIV replicates in the Central Nervous System HIV Associated Neurocognitive Disorders (HAND) ART effect on the Brain: CNS Drug Penetration Effectiveness Score (CPE) Better CPE score = improved CNS viral load Studies non conclusive of clinical effect of CPE scores Efavirenz-high CNS penetration Letendre S. Top Antiviral Med 2011 >50% of HIV patients have some form of HAND >50% of HIV patients have some form of HAND

Neurologic Function and HIV Antiretroviral Therapeutic Threshold Neurotoxicity Threshold Antiretroviral Drug Concentration in the CNS Risk of Neurocognitive Impairment _____________ > ______ > Damage from: -Uncontrolled HIV Replication -Immune activation Letendre S. Top Antiviral Med 2011 Clinical Cognitive Threshold

Neurologic Function and HIV Mental health illness Great risk of morbidity and mortality Depression up to 40% Antidepressant therapy partially reverses medication non-adherence AIDS Survivors Syndrome Lets Kick ASS (AIDS Survivors Syndrome) Re-focusing on living instead of dying Celebrating survival

Medication Adherence Older HIV positive adults may have better adherence than younger Concerns: Neurocognitive function Vision loss, hearing loss Polypharmacy Physical impairment Consequences: Viral resistance Opportunistic Infections Drug toxicity Shortened life-span Becker BW, et al. AIDS Behav. 2011 Nov: 15(8):1888-94, Suarez S, et al. AIDS 2001:15:195-200, Silverberg MJ, et al. Arch Intern Med 2007;167:684-691

Medication Adherence Tools Pharmacist-led medication adherence counseling Pill boxes, alarms, calendars On-line applications mymedschedule.com adultmeducation.com Support from family, friends Referrals to psychiatry or substance use rehabilitation Transportation assistance Prescription mailings

Case Study * Bob is a 57 yr WM * Dx HIV 1994, AIDS 2000 * CrCl ~ 50ml/min, Scr -1.2 * VL-Non detectable * Diabetes, hypertension, * CD4-196 depression, cognitive delay Medication List: Raltegravir (Isentress) Tenofovir, emtricitabine (Truvada) Atovaquone (Mepron) Pantoprazole (Protonix) Paroxetine (Paxil) Mirtazapine (Remeron) Gabapentin (Neurontin) Lisinopril (Zestril) Pravastatin (Pravachol) Insulin glargine (Lantus) Insulin apart (Novolog) Bob is having a difficult time with medication adherence. what do you suggest? 1. A new pillbox 2. Refer to psychiatry 3. Set an alarm for dosing times 4. All of the above

Medication Adherence: Food and Absorption DrugDrug exposure with food Requirement Daruvavir (Prezista) 30%acid Atazanavir (Reyataz) 35-70%Acid/fat Ritonavir (Norvir) 20%acid Etravirine (Intelence) 50%acid Rilpivirine, tenofovir emtricitabine (Complera) 40%Acid/fat Elvitegravir, cobicistat, Emtricitabine, tenofovir (Stribild) 34-87%Fat *Efavirenz (in Atripla)-take before bed and on an empty stomach *Forgetting food may lead to viral resistance and more side effects

Immunizations for HIV+ Adults VaccineDose/FrequencyNotes Influenza0.5ml annuallyInactivated only. Never use live attenuated (intranasal) PneumococcalPCV-13 (Prenvar) x 1 then Pnvax 23 x1, 5yr a part If CD4>200 Hep BRecombivax HB 40ug x 3 or Engerix B 2-20ug doses x 4 If sAG neg and sAB60 and CD4>200 CDC Adult Immunization Schedule U.S. 2014.

Resources Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents, Department of Health and Human Services 2014. Http://www. http://aidsinfo.nih.gov/guidelines North West AIDS Education and Training Center. Http://www. http://depts.washington.edu/nwaetc/ HIV-druginteractions.org HIVinsite.ucsf.edu The HIV and Aging Consensus Project. Recommended Treatment Strategies for Clinicians Managing Older Patients with HIV. American Academy of HIV Medicine. 2013. www.aahivm.org/hivandagingforumwww.aahivm.org/hivandagingforum Marie Dorsey, Pharm.D., AAHIVP: [email protected]

Conclusions Diagnosing and starting ART early will prolong life Consider recommendations for HIV patients according to co-morbidities Check for drug interactions Assist patients with medication adherence The interplay between HIV, aging, drug effects and co- morbidities is not well understood and more studies are needed

Do not regret growing older. It is a privilege denied to many. ~Unknown

References Becker BW, Thames AD, Woo E, et al. Longitudinal change in cognitive function and medication adherence in HIV-infected adults. AIDS Behav. 2011 Nov;15(8):1888-94 Brown T. Challenges in the Management of Osteoporosis and Vitamin D Deficiency in HIV Infection. Topics in Antiviral Medicine 2013; 21(3); 115-118 Casau N. Perspective on HIV Infection and Aging: Emerging Research on the Horizon. CID 2005; 41:855-863 Center for Disease Control and Prevention. Morbidity and Mortality Weekly Report. HIV Surveillance United States 1981-2008. June 3, 2011 60(21);689-693. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6021a2.htm. Accessed October 2014 Center for Disease Control and Prevention. Recommended Adult Immunization Schedule United States 2014. http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule.pdf. Accessed September 15, 2014 Dumond JB, Adams JL, Prince HA, et al. Pharmacokinetics of Two Common Antiretroviral Regimens in Older HIV-Infected Patients. HIV Medicine 2013 14(7):401- 409 El-Sadir WM, Lundgren JD, Neaton JD, et al. CD4+ Count-Guided Interruption of Antiretroviral Treatment. The strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 355;22:2283-2296. Girardi E. Increasing proportion of late diagnosis of HIV infection among patients with AIDS in Italy following introduction of combination antiretroviral therapy. J Acquir Immune Defi Syndr 2000;25:71 Helleberg M et al. Clin Infect Dis. 2013;56:727-734 Kim PS, Woods C, Georgoff P, et al. A1C underestimates glycemia in HIV infection. Diabetes Care. 2009;32:1591-1593

References Letendre S. Central Nervous System Complications in HIV Diseasae: HIV-Associated Neurocognitive Disorder 2011. Top Antiviral Med 19(4):137-142 Lucas GM, Ross MJ, Stock PG, et al. Clinical Practice Guideline for the Management of Chronic Kidney Disease in Patients Infected with HIV: 2014 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2014; 59(9):e96-e138. Oregon Health Authority, Public Health Division, HIV/STD/TB Program, HIV Data and Analysis. Epidemiologic Profile of HIV/AIDS in Oregon. 2013. https://public.health.oregon.gov/DiseasesConditions/CommunicableDisease/DiseaseSurveillanceData/HIV Data/Documents/EpiProfile.pdf. Accessed September 12, 2014. 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. May 1, 2014. Available at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed September 2014http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008;22:2409-2418h, C, Lundgren JD, Thiebaut R, et al. Factors associated with specific causes of death amongst HIV-positvie individuals in the D:A:D Study. AIDS. 2010 Jun 19;24(10):1537-48 Silverberg MJ, Leyden W, Horberg MA, et al. Older age and the response to and tolerability of antiretroviral therapy. Arch Intern Med. 2007;167:684-691.) Stellbrink HJ, Orkin C, Arribas JR et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults:48 week results from the ASSERT study. Clin Infect Dis. 2010;51(8):963 Suarez S. Baril L, Stankoff B. et al. Outcome of patients with HIV-1 related cognitive impairment on highly active antiretroviral therapy. AIDS 2001;15:195-200 Virus (HIV)-Infected Adults Receiving Antiretroviral Therapy: Recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group.Clin Infect Dis. 2003;37 (5):613-627 Wooten JM. Pharmacotherapy Considerations in Elderly Adults. South Med J. 2012;105(8):437-445

marie dorsey, pharm.d., aahivp ospa annual meeting november 8, 2014

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