Learning Objectives. Pre Assessment Questions. Faculty Disclosure. HIV Continuing Education, Do We Need It Now?

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1 HIV Continuing Education, Do We Need It Now? Faculty Disclosure. Kathleen K. Graham, Pharm.D HIV Clinical Research Pharmacist Children s Diagnostic & Treatment Center Clinical Affiliate Associate Professor Nova Southeastern University Ft. Lauderdale, FL Dr. Graham has no relevant financial relationships in relation to this activity. She has indicated that off label use of medication will not be discussed during her presentation. Learning Objectives Pre Assessment Questions Upon completion of this program pharmacists (or pharmacy technicians) will be able to: Know the current HIV CE licensure requirement Know the current HIV statistics Know the most recent ARV agents Know the recent DHHS guidelines Know the guidance on pre exposure prophylaxis True or False? The Florida HIV/AIDS CE licensure requirement changed in 2006 Florida is #2 as 2009 in incidence of new HIVinfections Florida has less heterosexual transmission than the rest of the country While the mortality has gone down, the number of people living with HIV is on the rise Dade, Broward and Palm Beach counties make up over ½ the cases in Florida Pre Assessment Questions True or False? There are currently 20 FDA approved antiretroviral medications on the market 6 new antiretroviral agents have been approved since the change in HIV CEU requirements The new DHHS guidelines recommend starting ARV in asymptomatic patients when CD4>500 Resistance to ripilvirine leads to cross resistance to the NNRTI class Change in AIDS Continuing Education Requirements (House Bill 699) 2006 Current regulations require licensed pharmacists to obtain 1 hour of the Florida Department of Health approved HIV/AIDS continuing education each biennial renewal period. House Bill 699 revises the HIV/AIDS requirement by requiring the course to be completed only once during the initial biennium of licensure. It appears that no other AIDS continuing education will be mandatory after completion of the first program. The 3 hour initial HIV/AIDS program will, however, remain as requirement and condition of initial licensure. The bill has been signed into law by the governor and will take effect on October 1, 2006.

2 Do I need HIV for my renewal now? Current Florida requirement 1 hour of HIV CE is required for all Florida pharmacists renewing their licenses for the first time. After that, there is no HIV requirement for relicensure Changes in Management of HIV/AIDS since 2006 Changing epidemiology Florida #1 DHHS Guideline changes 6 New Antiretroviral agents approved Pre exposure Prophylaxis (PrEP) Truvada What does this mean to Florida Pharmacists? More people than ever will be receiving Antiretroviral Therapy Pharmacists play a major role in the prevention and management of HIV/AIDS What is the role of the pharmacist in HIV/AIDS? Appropriate combinations of ARV Appropriate doses Drug Interactions Adherence counseling Side effect management Patient education HIV Testing programs Changes in Management of HIV/AIDS since 2006 Changing epidemiology Florida #1 DHHS Guideline changes 6New Antiretroviral agents approved Pre exposure Prophylaxis (PrEP) Truvada New HIV Infections and Cummulative People Living with HIV/AIDS

3 Florida is #1 incidence of New HIV infections 2009 Florida 5775* California 4886 New York 4649 Texas 4291 Georgia 2073 Pennsylvania 1736 North Carolina 1719 Illinois 1708 Maryland 1400 New Jersey 1252

4 Underlying Factors for Disparities Pre existing HIV in community Unprotected anal or vaginal intercourse between serodiscordant or untested partners Multiple partners, concurrent partners Late diagnosis and treatment Homophobia Stigma, discrimination, racism Underlying Factors for Disparities Homelessness Binge drinking Depression, partner violence, childhood sexual abuse, substance use Prevention burnout, HIV/AIDS complacency STDs Social/sexual mixing patterns of high and low risk persons Florida HIV/AIDS Death Rates Per 100,000 Population Florida ADAP WAITING LIST ENROLLMENT FOR SEPTEMBER & OCTOBER, There has been an 80% decline from 1995, (the peak of HIV resident death rates) to 2009 Total 1500 ALACHUA 20 BAY 10 BREVARD 16 BROWARD 230 CHARLOTTE1 CITRUS 1 CLAY 4 COLLIER 19 COLUMBIA 2 DADE 408 LEE 23 LEON 16 LEVY 1 MANATEE 21 MARION 14 MARTIN 6 MONROE 6 OKALOOSA 1 ORANGE 95 OSCEOLA 17 Changes in Management of HIV/AIDS since 2006 Changing epidemiology Florida #1 DHHS Guideline changes 6New Antiretroviral agents approved Pre exposure Prophylaxis (PrEP) Truvada DHHS Indications for Initiation of HAART in HIV 1 Infected Patients History of AIDS defining illness CD4 count <200 cells/mm3 CD4 count cells/mm3 CD4 count cells/mm3 Pregnant women Persons with HIV associated nephropathy Persons with Hepatitis B co infection requiring treatment for HBV CD4 count >500 not well defined. Weigh risk vs. benefit DHHS GUIDELINES: October, 2011,

5 HAART and Survival Based on Initial CD4+ Cell Count Modeled data from ART Cohort Collaborative 10,855 patients included 934 progressed to AIDS or died IDUs excluded from Hazard ratio for AIDS (95% CI) Hazard ratio for AIDS or death (95% CI) model CD4+ < 200 vs ( ) 2.93 Sterne J, et al. CROI Abstract 525. ( ) CD4+ < 350 vs ( ) 1.26 ( ) Cumulative Probability of AIDS/Death According to CD4+ Count at Initiation of HAART ath Probability of AIDS or Dea cells/mm cells/mm cells/mm Years Since Initiation of HAART Changes in Management of HIV/AIDS since 2006 Changing epidemiology Florida #1 DHHS Guideline changes 6New Antiretroviral agents approved Pre exposure Prophylaxis (PrEP) Truvada 6 New Antiretroviral Medications since 2006 Maraviroc Darunavir Raltegravir Etavirine Rilpivirine Complera CCR5 Inhibitor: Maraviroc Maraviroc (MVC, Selzentry ) First in new class of agents, CCR5 inhibitors Approved August 6 th, 2007 Indications not recommended in patients who have dual/mixed tropic or CXCR4 tropic virus tropism assay results required The tropism assay is available from Monogram Biosciences, $2000 Only effective against R5 virus Adverse effects/precautions Hepatotoxicity may be preceded by a systemic allergic reaction (pruritic rash, eosinophilia) Dizziness/postural hypotension Increased risk of CV events (MI, ischemic events) Ritonavir is not needed as booster Protease inhibitors for naïve and experienced patients Darunavir (DRV, TMC114, Prezista ) High barrier to resistance Take with food Side Effects: Rare: Abdominal pain, constipation, Rare: Headache Asymptomatic increase in Amylase Rash (7%) Sulfhydryl moiety May use in patients with sulfa allergy Higher incidence of rash than other PI s Rash often resolves with continued use Very rare SJS Integrase Inhibitor: Raltegravir Raltegravir (RAL, Isentress ) First in new class of agents, integrase inhibitors Approved September, 2007 Approved September, 2007 Indications Naïve patients 1 st regimen (in combination with other ARVs) Treatment experienced adult HIV infected patients (in combination with other ARVs) Rarely has adverse effects headache, CK elevation Metabolized by glucuronidation; no significant drug interactions

6 Non Nucleosides: Etravirine Etravirine (Intelence,TMC 125, ETV) BID dosing FDA approval January 18 th 2008 For use in patients t with resistance it to nevirapine i and efavirenz Active against K103N virus 13 TMC125 resistance associated mutations (TMC125 RAMs) have been identified the greatest added benefit in the TMC125 versus placebo group was seen in patients with <3 TMC125 RAMs 86% patients had <3 TMC125 RAMs in the DUET trial Except for rash, incidence and severity of AEs with TMC125 were similar to placebo Non Nucleosides: Rilpivirine and Compleratm Rilpivirine (Edurant,TMC 278, RPV) FDA approval May 20, mg 1 tablet once daily MUST TAKE WITH FOOD Pregnancy category B Substrate of CYP 3A4 Side effects: depression, insomnia, headache, rash (less CNS vs. efavirenz) Contraindicated Inducers: Carbamazepine, phenytoin, phenobarbital, rifampine, rifabutin, St. John s wort Proton pump inhibitors: esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole ) Drug Interactions Protease inhibitors (increase rilpivirine concentrations no dose change) H2 blockers and antacids, must space apart from rilpivirine Reduced efficacy in patients with baseline HIV RNA >100,000 copies/ml Cross resistance to all other NNRTI s is possible COMPLERA FDA approval August 10, nd 1 pill once a day. Rilpivirine in combination with tenofovir and emtricitabine Rilpivirine: ECHO and THRIVE Results Antiretroviral Drug Classes Approved by the FDA for HIV Treatment Week 48 Outcome Rilpivirine (n = 346) ECHO THRIVE Pooled Efavirenz (n = 344) Rilpivirine (n = 340) Efavirenz (n = 338) Rilpivirine (n = 686) Efavirenz (n = 682) Treatment failure, % Virologic Adverse events NRTI NNRTI PI II EI, FI Nucleoside and nucleotide reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Integrase Inhibitors Entry Inhibitors, Fusion Inhibitors Fusion Inhibitors HIV Virions CD4 Receptor HIV Replication Cycle and Sites of Drug Activity NRTIs Viral RNA CCR5 or CXCR4 co-receptor CCR5 Antagonist Attachment Uncoating and Fusion NNRTIs Reverse Integrase Transcriptase Unintegrated double stranded Viral DNA Reverse Transcription Integrase Inhibitors Nucleus Integrated viral DNA Cellular DNA Viral mrna Integration Transcription Protease Inhibitors Protease gag-pol polyprotein Translation New HIV particles Capsid proteins and viral RNA Assembly And Release Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11 Antiretrovirals: 27 FDA approved medications Non Nucleoside Reverse Transcriptase Inhibitors Nevirapine (NVP) Efavirenz (EFV), Etravirine (ETV), Rilpivirine(RPV) * Nucleoside Analogues Tenofovir, (TDF), Abacavir (ABC), Lamivudine (3TC) Zidovudine (ZVD), Stavudine (D4T), Didanosine (DDI) Protease Inhibitors Darunavir (DRV), Lopinavir (LPV), Ritonavir (RTV), Indinavir (IDV), Saquinavir i (SQV), Nelfinavir Nlfi i(nfv) (NFV), Fosamprenavir (FPV) Entry Inhibitors Enfuvirtide (T20) Maraviroc (MVC) CCR5 antagonist Integrase Inhibitor Raltegravir (RAL) Combinations Combivir, Epzicom, Truvada, Trizivir, Atripla, Complera * Delavirdine (DVL) is also an NNRTI, however it is not recommended for use in the DHHS guidelines

7 2011 DHHS Recommended Regimens for Treatment Naive Patients: (Oct. 2011) NNRTI + 2 NRTIs or boosted PI + 2 NRTIs or II + 2 NRTIs NRTI NNRTI PI II Preferred TDF/FTC EFV* -ATV/RTV QD -DRV/RTV QD -LPV/RTV BID + ZDV/3TC (pregnancy) Alternative RPV** -ATV/RTV QD TDF/FTC EFV -DRV/RTV QD ABC/3TC ** -FPV/r -LPV/RTV BID/QD RAL RAL Changes in Management of HIV/AIDS since 2006 Changing epidemiology Florida #1 DHHS Guideline changes 6New Antiretroviral agents approved Pre exposure Prophylaxis (PrEP) Truvada *Except during 1st trimester of pregnancy or in women with high pregnancy potential. Use only if HLA- B*5701 negative. ** Caution in with HIV-RNA >100,000 DHHS guidelines. Available at: iprex: PrEP in HIV Negative, At Risk MSM and Transgender Women Current CDC Guidance on PrEP N = 2499 subjects randomized to oral TDF/FTC or placebo 44% reduction in HIV acquisition through 136 wks previously reported [1] Update: 42% risk reduction through 144 wks [2] AEs of PrEP mild, time limited [2] Headache (4%), nausea (2%), weight loss (2%) Only 9% of seroconverters had detectable drug levels vs 51% of nonseroconverters [2] No evidence of resistance in seroconverters [2] 1. Grantww RM, et al. N Engl J Med. 2010;363: Grant R, et al. CROI Abstract What does PrEP Mean to Pharmacists? More people taking antiretroviral therapy Now HIV negative and positive Must test negatives often when on PrEp! Pharmacist can take a role in educating and testing Efficacy of HIV Prevention Strategies From Randomized Clinical Trials Study ART for prevention; HPTN 052, Africa, Asia, Americas PrEP for discordant couples; Partners PrEP, Uganda, Kenya PrEP for heterosexual men and women; TDF2, Botswana Medical male circumcision; Orange Farm, Rakai, Kisumu PrEP for MSMs; iprex, Americas, Thailand, South Africa Sexually transmitted diseases treatment; Mwanza, Tanzania Microbicide; CAPRISA 004, South Africa HIV vaccine; RV144, Thailand Efficacy (%) Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print]. 100 Effect Size, % (95% CI) 96 (73-99) 73 (49-85) 63 (21-84) 54 (38-66) 44 (15-63) 42 (21-58) 39 (6-60) 31 (1-51)

8 On the Horizon TEST AND TREAT?? HPTN 052: Multivariate Analysis of Factors Associated With Linked Transmissions Variable HR 95% CI Treatment, immediate vs delayed Baseline CD4+ count, per 100 cells/mm 3 decrease Baseline HIV-1 RNA, per1log 10 copies/ml increase Baseline condom use, 100% vs < 100% Sex of infected partner, male vs female % of transmissions occurred from infected patient with CD4+ cell count > 350 cells/mm 3 All transmissions occurred prior to starting ART 82% of transmissions occurred in African patients Cohen MS, et al. IAS Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print]. On the Horizon Hepatitis C Protease inhibitors for HIV/HCV Co infection? Boceprevir and Telaprevir Currently FDA approved for HCV mono infectiononlyonly Preliminary studies in HIV co infection Role for Pharmacist Drug Interactions Patient management Patient education Boceprevir (SCH ) Dose: 800 mg po TID CYP 3A4 substrate and inhibitor HCV Protease Inhibitors Telaprevir (VX 950) Dose 750 mg po q 8 hours CYP 3A4 substrate bt t and inhibitor Effect of HAART on CYP450 isoenzymes Drug Drug Interactions With HCV PI, Telaprevir, and ART in Healthy Volunteers Substrate of Inhibitor of Inducer of Non-nucleoside Reverse Transcriptase Inhibitors 3A4 > 2B6 3A4, 2C9/19 Efavirenz/etravirine 3A4 nevirapine 3A4, 2B6 3A4, 2B6 Protease Inhibitors darunavir 3A4 3A4 atazanavir 3A4 3A, 1A2, 2C8 fosamprenavir 3A4 3A4 indinavir 3A4 3A4 lopinavir 3A4 3A4, 2D6 nelfinavir 3A4, 2C9/19, 2E1 3A4 2D6, ritonavir 3A4 > 2D6 3A4>2D6 >2C19>>2A6>1A2>2E1 3A4, 2C9, 1A2 saquinavir 3A4 3A4 tipranavir 3A4 2C9>3A4>2C19>2D6>1A2 3A4,2C19,1A2 Krikorian JOURNAL OF PHARMACY PRACTICE ;4: ; Aptivus package insert; ; ; Among PIs evaluated, ATV/RTV had lowest impact on telaprevir exposure ATV/RTV reduced telaprevir AUC by 20% Telaprevir increased ATV AUC by 17% Change in PK Parameter, % C min C max AUC* Effect of ART on TVR exposures ATV/RTV DRV/RTV FPV/RTV LPV/RTV Effect of TVR on ART exposures ATV DRV FPV LPV *AUC 8hr for effect of antiretroviral drug on telaprevir; AUC tau for effect of telaprevir on antiretroviral drug. Van Heeswijk R, et al. CROI Abstract

9 Drug Drug Interactions With HCV PI, Boceprevir and ART in Healthy Volunteers Reduced mean trough concentration of BOC when coadministered with EFV Clinical implications not yet clear No significant drug drug interactions with TDF or RTV and BOC Rti Ratio Eti Estimate, t % (90% CI) C max AUC C min Effect of ART on boceprevir exposure RTV100 mg QD 73 (57 93) AUC T : 81 (73 91) NR RTV 100 mg BID 66 (56 78) AUC T : 82 (75 88) NR TDF 105 (98 112) AUC 0 8hr : 108 ( ) NR EFV 92 (78 108) AUC 0 8hr : 81 (75 89) 56 (42 74) Effect of boceprevir on ART exposure TDF 132 ( ) AUC 0 8hr : 105 ( ) NR EFV 111 ( ) AUC Kasserra C, et al. CROI Abstract hr : 120 ( ) NR Drugs Contraindicated with HIV And HCV Protease Inhibitors Antiarrythmics Flecainide (Tambocor) Quinidine Opiate analgesics Fentanyl (Duragesic) Meperidine (Demerol) GI motility Cisapride (Propulsid Benzodiazepines Midazolam (Versed) Triazolam (Halcion) Ergotamines Illicit drugs Ecstacy Herbals St. John s Wort Take Home Points l HIV/AIDS is on the rise in Florida and more living each year l New DHHS guidelines more taking ARV l Multiple New agents approved each year for HIV and co infections l PrEP Now HIV ( ) on ARV, Test and Treat? l Chance for multiple drug interactions l Know inducers, inhibitors and substrates l Know contraindicated agents l Ask about OTC s, Herbals and Illicit drug use l Educate patients on adherence and resistance HIV testing, prevention and medication management a major role for Pharmacists! Biennial HIV CEU in Florida Do we need it now?? Post Assessment Questions Post Assessment Questions True or False? The Florida HIV/AIDS CE licensure requirement changed in 2006 Florida is #2 as 2009 in incidence of new HIV infections Florida has less heterosexual transmission than the rest of the country While the mortality has gone down, the number of people living with HIV is on the rise Dade, Broward and Palm Beach counties make up over ½ the cases in Florida True or False? There are currently 20 FDA approved antiretroviral medications on the market 6 new antiretroviral agents have been approved since the change in HIV CEU requirements The new DHHS guidelines recommend starting ARV in asymptomatic patients when CD4>500 Resistance to ripilvirine leads to cross resistance to the NNRTI class

10 Resources www hiv druginteractions org druginteractions.org aids.edu