HIV for the Non-ID Pharmacist

Disclosures HIV for the Non-ID Pharmacist I have nothing to disclose at this time Carmen Faulkner-Fennell, PharmD, BCPS (AQ-ID) Clinical Pharmacy Specialist--Infectious Diseases Greenville Hospital System March 23 rd, 2012 Objectives Why Is This Important? Interpret clinical relevance of laboratory tests routinely ordered in the HIV population Identify reasons for initiating or discontinuing HIV therapy in the hospital setting Identify common medication errors and drug interactions that can occur when patients on HIV therapy are hospitalized and discuss ways to prevent those errors Establish a baseline knowledge of HIV medications and recognize common HIV regimen components Because These Patients are in Your Hospital! HIV Therapy is Rarely Initiated in Hospital Setting Patient specific factors Willingness to begin therapy Adherence barriers Modifiable risk factors Baseline laboratory values Resistance testing Up to 24% baseline Other STDs Reason for admission Opportunistic Infection Patient would benefit from initiation of ART Exceptions due to risk of immune reconstitution inflammatory syndrome (IRIS) Mycobacterium avium complex (MAC) Cryptococcal meningitis 1

CASE KG is a 53 year old white male admitted to your hospital for shortness of breath (SOB), fever, cough, nausea and malaise. Past medical history significant for hypertension, type 2 diabetes, HIV, and hyperlipidemia. Home medications include: Atorvastain Atazanavir Ritonavir Tenofovir/Emtricitabine (Truvada) CASE ER physician orders Ceftriaxone 1 gm IV Q24h Azithromycin 500 mg IV Q24h Admitting physician calls pharmacy the next day to ask if IV trimethoprim/sulfamethoxazole (SMZ/TMP) is available Wants to start patient on empiric therapy for pneumocystis jiroveci, previously pneumocystis carinii, (PCP) pneumonia Laboratory Tests Commonly Ordered in Hospitalized HIV Patients CD4 Count and Viral Load Laboratory Test Definition Measured Normal (HIV negative) What it Means CD4 count Number of CD4 cells circulating i l in i the body Cells/mm 3 500-1000 An indicator of immunei function HIV RNA (Viral Load) Amount of virus circulating in the blood Copies/mL Undetectable < 20-75 Level of HIV viremia http://www.healthhype.com/wp-content/uploads/hiv-timecourse.png Laboratory Tests Commonly Ordered in Hospitalized HIV Patients Laboratory Test Definition Measured Normal What it Means (HIV negative) CD4 count Number of CD4 cells circulating in the body Cells/mm 3 500-1000 An indicator of immune function HIV RNA (Viral Load) Amount of virus circulating in the blood Copies/mL Undetectable < 20-75 Level of HIV viremia CD4 percentage % of functional % ~ 40 % An indicator of lymphocytes that are immune function CD4 cells B-Lymphocytes 1000 500 Lymphocytes T-Lymphocytes CD4 Percentage = 50 25 % CD4--start immune response protects the body from infectious invaders CD8--destroy other infected cells and produce antiviral substances 250 250 750 http://www.cdc.gov/hiv/surveillance/resources/reports/2010supp_vol16no1/pdf/hivaids_ssr_vol16_no1.pdf Absolute CD4 vs CD4% CD4 count Can change due to factors that alter total WBC and lymphocyte percentages Bone marrow suppressive agents Acute infections (typically causes decrease in CD4) Falsely elevated Splenectomy Coinfection with human T- lymphotropic virus type I Falsely decreased Use of alpha-interferon CD4 percentage Stable Currently not incorporated into the guidelines CD4 count Used to determine when opportunistic infection prophylaxis is needed Used to help determine when therapy should be initiated 2

Which Number Should I Review? In a stable outpatient with HIV CD4% and Corresponding CD4 Count* CD4 % CD4 Count > 29% 500 14-28% 200-499 < 14% 200 *An Estimate In a patient with an acute infection Have to review both numbers Our patient CD4 count = 195 CD4 % = 22% PCP unlikely given his non-acutely ill CD4 count is likely above 200 PCP prophylaxis not on home medication profile Opportunistic Infection (OI) Prophylaxis CD4 Count OI Pathogen Prophylaxis Medications < 200 Pneumocystis jiroveci <100 Toxoplasma gondii With + anti-toxoplasma IgG Mycobacterium avium < 50 complex (MAC) *Do not use in G6PD deficiency SMZ/TMP DS 1 PO Qday Dapsone 100 mg PO Qday* Atorvaquone 1500 mg PO Qday SMZ/TMP DS 1 PO Qday Dapsone 50 mg PO Qday* + pyrimethamine 50 mg PO Qweek + leucovorin 25 mg PO Qweek Atorvaquone 1500 mg PO Qday + pyrimethamine 25 mg PO Qweek + leucovorin 10 mg PO Qweek Azithromycin 1200 mg PO Qweek HIV Surveillance Supplemental Report 2010;16(No. 1) Opportunistic Infection (OI) Treatment CD4 Count OI Pathogen Treatment Medications < 200 Pneumocystis jiroveci <100 < 50 *Do not use in G6PD deficiency Toxoplasma gondii With + anti-toxoplasma IgG Mycobacterium avium complex (MAC) SMZ/TMP 15-20 mg IV or PO divided daily Atorvaquone 750 mg PO BID Clindamycin IV or PO Q6h or Q8h + primaquine* 15-30 mg PO Qday Sulfadiazine 1 or 1.5 gm PO QID + pyrimethamine 50 or 75 mg PO Qday + leucovorin 10-20 mg PO Qday Clindamycin 600 mg IV or PO Q6h + pyrimethamine 50 or 75 mg PO Qday + leucovorin 10-20 mg PO Qday Clarithromycin 500 mg PO BID + ethambutol 15 mg/kg PO Qday +/- rifabutin 300 mg PO Qday Azithromycin 500 mg PO Qday + ethambutol 15 mg/kg PO Qday +/- rifabutin 300 mg PO Qday What is G6PD? Glucose-6-Phosphate Dehydrogenase Protects erythrocytes from oxidative stress G6PD Deficiency GdA- 8-20% of normal enzyme activity Population: African, ~10% in African Americans GdMed- < 5% of normal enzyme activity Population: Iran, Iraq, India, Pakistan, Greece, Sardinia Certain medications can cause a drug induced hemolysis Dapsone, primaquine, +/- SMZ/TMP (not GdA-) Back to the CASE Based on the patient s CD4 count and % the physician no longer wants to use SMZ/TMP Physician is unsure if patient should receive the pneumococcal and influenza vaccines as recommended in your hospital s pneumonia protocol Pneumococcal and Influenza 23-Valent Pneumococcal polysaccharide vaccine (PPSV23) All adults > 65 years or 19-64 with underlying medical conditions Another dose indicated if vaccine received prior to 65 5 years after first dose persons 19-64 with asplenia and/or immunocompromising conditions Influenza Vaccine (Trivalent Inactivated Vaccine (TIV)) Recommended annually Persons with advanced AIDS may not induce protective antibody titers MMWR: September 3, 2010 / 59(34);1102-1106 MMWR: August 6, 2010 / 59(rr08);1-62 3

CASE Prescriber determined that patient received Influenza vaccine in October 2011 Patient vaguely remembers a pneumonia shot about 10 years ago CASE The patient is doing well 48 hours later and the physician decides to restart the patients antiretroviral therapy (ART) Atazanavir 400 mg PO Qday Ritonavir i 600 mg PO twice a day The patient was also started on DVT and SUP (stress ulcer prophylaxis) Heparin 5000 units SubQ Q8h Pantoprazole 40 mg PO Qday HIV Therapy Interruptions CASE Situation Severe or life-threatening toxicity or inability to take PO meds Interruption for < 1-2 days Planned short-term interruption (>2-3 days): y) ART have similar half-lives, food NOT required for absorption Planned short-term interruption (>2-3 days): ART have similar half-lives, food required for absorption Planned short-term interruption (>2-3 days): ART have different half-lives *Typically an issue with non-nucleoside reverse transcriptase inhibitors (NNRTI): Efavirenz, etravirine, nevirapine Management of HIV therapy Stop all ART simultaneously, regardless of half life Hold all ART Give meds with sip of water if possible If not possible stop and start all ART simultaneously If patient unable to eat, stop all ART simultaneously Restart ART when patient eating Stagger discontinuation of ART based on half-life The patient is doing well 48 hours later and the physician decides to restart the patients ART Atazanavir 400 mg PO Qday Ritonavir 600 mg PO twice a day The patient was also started on DVT and SUP (stress ulcer prophylaxis) Heparin 5000 units SubQ Q8h Pantoprazole 40 mg PO Qday Medication Errors in Hospitalized Patients 247 admissions of 189 HIV infected patients 60 ART errors in 41 patients 21.7% had at least 1 error 75% of errors occurred at admission HIV Medicine 2011;12(8):494-99 Percent HIV Medication Errors Don t Happen in My Hospital October 2010-October 2011 42% of patients on ART had an error in their regimen that was corrected by the GHS antimicrobial stewardship team Most common errors Incorrect doses of HIV meds Significant drug interactions 14% had > 2 errors in their regimen 4

Back to the Patient Current HIV regimen Dose in when treatment ritonavir Atazanavir 400 mg PO Qday naïve was the patients only protease without ritonavir inhibitor, boosting NOT the Ritonavir 600 mg PO twice a day boosting dose DVT and SUP Heparin 5000 units SubQ Q8h Pantoprazole 40 mg PO Qday Ritonavir Boosting Extremely potent inhibitor of CYP3A4 Added to most other protease inhibitors (PI) (except nelfinavir) to boost Increase drug exposure Prolong half-life No longer used as a sole PI Not as potent as newer PIs Gastrointestinal intolerance (especially with high doses) Since HIV Drug Classes Were Mentioned http://www.edidik.com/wp-content/uploads/2010/09/hiv_biology.gif Includes nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) AND Non-nucleoside (NNRTIs) Includes fusion inhibitors AND chemokine receptor type 5 (CCR5) antagonist Currently Available HIV Medications by Class NRTIs PIs Fusion Inhibitor Abacavir (ABC) Atazanavir (ATV) Enfuvirtide (T20) Didanosine (ddi) Darunavir (DRV) Combination Formulations Emtricitabine (FTC) Fosamprenavir (FPV) All NRTIs Lamivudine (3TC) Indinavir (IDV) Combivir (3TC + ZDV) Stavudine (d4t) Lopinavir/Ritonavir i i (LPV/r) Epzicom (3TC + ABC) Tenofovir (TDF) Nelfinavir (NFV) Trizivir (3TC+ ZDV + ABC) Zidovudine (ZDV/AZT) Ritonavir (RTV or r) Truvada (FTC + TDF) NNRTIs Saquinavir (SQV) Combination Formulations Delavirdine (DLV) Tipranavir (TPV) NRTIs + NNRTIs Efavirenz (EFV) Integrase Inhibitor Atripla (EFV + TDF + FTC) Etravirine (ETR) Raltegravir (RAL) Complera (RPV + TDF + FTC) Nevirapine (NVP) CCR5 Antagonist Rilpivirine (RPV) Maraviroc (MVC)* *Requires a tropism assay prior to use Currently Available HIV Medications-Renal Adjustments NRTIs PIs Fusion Inhibitor Abacavir (ABC) Atazanavir (ATV) Enfuvirtide (T20) Didanosine (ddi) Darunavir (DRV) Combination Formulations ALL combination products have components that require renal adjustment, typically requires switching to individual components Emtricitabine (FTC) Fosamprenavir (FPV) All NRTIs Lamivudine (3TC) Indinavir (IDV) Combivir (3TC + ZDV) Stavudine (d4t) Lopinavir/Ritonavir i i i (LPV/r) Epzicom i (3TC + ABC) Tenofovir (TDF) Nelfinavir (NFV) Trizivir (3TC+ ZDV + ABC) Zidovudine (ZDV/AZT) Ritonavir (RTV or r) Truvada (FTC + TDF) NNRTIs Saquinavir (SQV) Combination Formulations Delavirdine (DLV) Tipranavir (TPV) NRTIs + NNRTIs Efavirenz (EFV) Integrase Inhibitor Atripla (EFV + TDF + FTC) Etravirine (ETR) Raltegravir (RAL) Complera (RPV + TDF + FTC) Nevirapine (NVP) CCR5 Antagonist Rilpivirine (RPV) Maraviroc (MVC) Typical HIV Regimen Based on Most Recent Guidelines Typically at least 3 medications (not including the ritonavir booster in PI based regimens) Typically 2 NRTIs NNRTI Based PI Based Integrase Based (INSTI) Pregnancy Preferred EFV +TDF+FTC + FTC ATV/r + TDF + FTC DRV/r + TDF + FTC RAL + TDF/FTC LPV/r + ZDV + 3TC Alternative EFV + ABC +3TC RPV +TDF/FTC or ABC/3TC ATV/r + ABC + 3TC DRV/r + ABC + 3TC FPV/r + TDF/FTC or ABC/3TC LPV/r + TDF/FTC or ABC/3TC RAL + ABC + 3TC 5

Only 5 NRTIs Listed on Chart NRTI(S) Typical Dose(s) Comments FTC (Emtricitabine) 200 mg PO Qday 3TC can be substituted for FTC and vice versa TDF (Tenofovir) 300 mg PO Qday Caution in renal insufficiency Do NOT use with unboosted atazanavir FTC/TDF (Truvada ) 1 tablet PO Qday COMBINATION ABC (Abacavir) 300 mg PO BID or Caution in high risk cardiovascular disease Caution in i patients t with HIV RNA >100,000 000 600 mg PO Qday Do NOT use if positive for HLA-B*5701 3TC (Lamivudine) 150 mg PO BID or FTC can be substituted for 3TC and vice versa 300 mg PO Qday ABC/3TC (Epzicom ) 1 tablet PO Qday COMBINATION ZDV (or AZT) (Zidovudine) 300 mg PO BID Nausea/Vomiting Headache Macrocytic anemia, bone marrow suppression ZDV/3TC (Combivir ) 1 tablet PO BID COMBINATION Abacavir Hypersensitivity Reaction Major histocompatibility complex (MHC) class I allele Associated with hypersensitivity reaction to abacavir All patients must be screened prior to initiation History of reaction or HLA-B*5701 positive should be recorded as an abacavir allergy Allergy does not apply to other NRTIs Only 2 NNRTIs and 1 INSTI Listed on Chart NNRTI(S) Typical Dose(s) Comments EFV (Efavirenz) 600 mg PO Qday (bedtime) Rash Neuropsychiatric symptoms Contraindicated in 1 st trimester EFV + TDF + FTC (Atripla ) 1 tablet PO Qday (bedtime) COMBINATION- 1 PILL ONCE A DAY! RPV (Rilpivirine) 25 mg PO Qday Use of proton pump inhibitors is contraindicated Caution in patients with HIV RNA >100,000 RPV + TDF + FTC (Complera) 1 tablet PO Qday with meals COMBINATION- 1 PILL ONCE A DAY! Use of proton pump inhibitors is contraindicated INSTI Typical Dose(s) Comments RAL (Raltegravir) 400 mg PO BID CPK elevation, rhabdomyolysis 800 mg PO BID Dose if given in combination with rifampin Only 4 PIs Listed on Chart Not Including Ritonavir as a Booster PI Typical Dose(s) Comments ATV/r (Atazanavir/ Ritonavir (RTV) boosting) DRV/r (Darunavir) FPV/r (Fosamprenavir) LPV/r (Lopinavir/Ritonavir) ONLY available as combination Kaletra ATV 300 mg PO Qday + RTV 100 mg PO Qday DRV 800 mg PO Qday + RTV 100 mg PO Qday DRV 600 mg PO BID + RTV 100 mg PO BID FPV 1400 mg PO Qday + RTV 100-200 mg PO Qday FPV 700 mg PO BID + RTV 100 mg PO BID LPV 400 mg PO BID + RTV 100 mg PO BID LPV 800 mg PO Qday + RTV 200 mg PO Qday Indirect hyperbilirubinemia Avoid with antacid therapy Contraindicated with > 20 mg omeperazole equivalent/day Use with no DRV mutations DRV active against highly resistant strains Use with at least 1 DRV mutation ti DRV active against highly resistant strains Dose for PI naïve patients Sulfonamide moiety Dose for PI experienced patients Sulfonamide moiety Dose recommended in pregnancy GI intolerance GI intolerance Back to the Patient Current HIV regimen Atazanavir 400 mg PO Qday Ritonavir 600 mg PO twice a day DVT and SUP Heparin 5000 units SubQ Q8h Pantoprazole 40 mg PO Qday Antacids/PPIs/H2 Antagonists and HIV Medications Atazanavir Atazanavir boosted with ritonavir Fosamprenavir Rilpivirine Antacids H2 Antagonists PPIs Do not exceed dose equivalent to Contraindicated famotidine 20 mg (naïve) BID or 20 mg (experienced) Qday Space 2 hours prior or 10 hours Give ATV 2 after hr prior Or 1 Do not exceed dose equivalent to Do not exceed dose hr after famotidine 40 mg (naïve) BID or 20 equivalent to omeprazole 20 mg (experienced) BID mg/day (txment naïve) give Space 2 hours prior or 10 hours 12 hours apart after AVOID with treatment experienced patients Give FPV with or 2 hr prior of 1 hr after Give antacids 2 hr prior or 4 hr after Give 2 hours prior to H2s, consider boosting with ritonavir Give H2s 12 hours before or at least 4 hours after No significant effect Contraindicated 6

Atazanavir Concentrations and PPIs CASE Your change ART to: Atazanavir 300 mg PO Q24h Ritonavir 100 mg PO Q24h AND discontinue the PPI since the patient does not qualify for stress ulcer prophylaxis The physician now wants to know if there are any potential issues restarting atorvastain Topics in HIV Medicine 2005;13:64-70. Statin Therapy and HIV Medications All boosted protease inhibitors can cause lipid abnormalities Increase LDL, TG, HDL Efavirenz can cause lipid abnormalities Increase LDL, TG, HDL HIV patients should be identified early and treated for hyperlipidemia PI therapy and Statins Statin Effect on Statin Dosing Recommendations Atorvastatin AUC increased Start 10 mg/day, titrate, monitor Fluvastatin None No adjustment needed Lovastatin Significant AUC increases Contraindicated Pitavastatin Significant AUC increases Contraindicated with all ritonavir boosted PIs Pravastatin DRV/r increases AUC 81% Start 20 mg/day, titrate, monitor with DRV therapy only Rosuvastatin AUC increased Start 5 mg/day, titrate, monitor Simvastatin Significant AUC increases Contraindicated FDA Med Watch Communication 3/1/2012 NNRTIs and Statins Most NNRTIs (EFV, ETR, RPV) can reduce statin concentrations Adjust statin doses according to lipid responses Do not exceed maximum daily doses 7

Other Drug Interactions PIs and NNRTIs Substrates of CYP3A4 [PIs] will be altered CYP inhibitors or inducers NNRTIsCan act as inhibitors or inducers EFV is a mixed inhibitor or inducer NRTIs No transformation via CYP pathway Other routes of hepatic metabolism CCR5 Inhibitor (MVC) Substrate of CYP3A enzymes and P-glycoprotein Strong CYP inhibitors increase [MVC] Strong CYP inducers decrease [MVC] Integrase Inhibitor (RAL) Strong inducers of uridine diphosphate (UDP)- glucuronosyltransferase (UGT)1A1 enzymes decrease [RAL] Fusion Inhibitor (T20) No significant interactions ART with Rifampin and Rifabutin ART Med Rifampin Dose Adjustment NNRTI: Nevirapine NNRTI: Efavirenz NNRTI: Etravirine Decrease [NVP] Decrease [EFV] Decrease [ETR] (expected) No dose adjustment for [NVP] No dose adjustment for [EFV] Co-administration NOT Recommended PIs Decrease [PI] Co-administration NOT Recommended Maraviroc Decrease [MVC] Increase MVC dose if therapeutically necessary Raltegravir Decrease [RAL] Double RAL dose if therapeutically necessary Rifabutin Decrease [RIF] Decrease [RIF] Dose Adjustment Increase rifabutin Increase rifabutin??? Administer rifabutin Increase [RIF] Possible Decrease [MVC] Minimal effects on [RAL] Dose adjust rifabutin 150 mg PO QotherD May need to dose adjust rifabutin based on other medications Administer rifabutin Other Medication Interactions Warfarin Monitor INR closely with PIs and NNRTIs Salmeterol Do NOT administer with PIs Phenytoin/Phenobarbital/Carbamazepine Etravirine and rilpivirine use contraindicated Once daily lopinavir/ritonavir should not be used May decrease maraviroc levels Questions to Consider When Entering ART Medications in the Hospital Is the patient on a complete regimen? Typically at least 3 agents Remember there are several combination medications Ritonavir as a boosting agent does not count Are the HIV meds (or all components) ordered on formulary? Do not enter part of a regimen until all meds can be given If patient taking own medication, verify all components Are there any specific drug-drug interactions? Patient taking own medication may require a manual drug interaction check Acid suppressing meds and statins Are there administration issues? With or without food, timing, feeding tube, etc Strategies to Avoid ART Medication Errors in the Hospital Review all patients with ART medications profiled Dosing errors Medication omissions Medication interactions Call patient s pharmacy or clinic to determine appropriate regimen Review the most current guidelines aidsinfo.nih.gov Updated every 6-10 months Consequences of medication errors Errors carried over into outpatient treatment ART dosing errors Medication omissions Interacting medications Insufficient or inappropriate regimens Drug-resistant infection Toxicity HIV for the Non-ID Pharmacist Carmen Faulkner-Fennell, PharmD, BCPS (AQ-ID) Clinical Pharmacy Specialist--Infectious Diseases Greenville Hospital System March 23 rd, 2012 8