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1. HIV Treatment Update Todd Correll, PharmD, BCPS Clinical Pharmacy Specialist, Infectious Diseases/HIV University of North Carolina Hospitals November 2006
5. Indications for Antiretroviral Initiation TREAT >100K c/mL >350 cells/mm 3 Asymptomatic Defer therapy <100K c/mL >350 cells/mm 3 Asymptomatic Offer treatment; pros vs cons Any value 200 to 350 cells/mm 3 Asymptomatic TREAT Any value <200 cells/mm 3 Asymptomatic AIDS TREAT Any value Any value Symptomatic (AIDS) Recommendation HIV RNA CD4 cell count Clinical Category
11. GS 934: Study Design TDF QD FTC QD Efavirenz QD (N = 255) Non inferiority Trial, Primary Endpoint < 400 c/mL at Week 96 Time to Loss of Virologic Response (TLOVR) CBV BID Efavirenz QD (N = 254) Week 144 Stratification by HIV RNA >10,000 c/mL Any CD4 count Adequate Renal and Hepatic Function at baseline FTC/TDF Fixed dose combination tablet was not used Gallant JE, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. TUPE0064. ARV-naïve patients randomized 1:1 Week 144 * FDA-required endpoint, similar to ITT Missing = Failure, Switch = Failure. Requires confirmation for success, used by FDA for presentation in U.S. Prescribing Information of newly approved antiretrovirals 241 Median CD4 (cells/mm³) 233 5.0 Median Viral Load (log 10 copies/mL ) 5.0 37 Age (Median) 36 87% Male 86% Baseline Characteristics
18. EFV vs. LPV/r vs. LPV/r + EFV 96 Week Outcomes (ITT) Patient Percent Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THLB0204. EFV vs. LPV: p=0.006 EFV vs. LPV/EFV: p=0.5 LPV vs. LPV/EFV: p=0.13 CD4+ Cell Count Change from BL: +239 vs. +285 vs. +268 (p=0.01) EFV vs. LPV: p=0.003 EFV vs. LPV/EFV: p=0.123 LPV vs. LPV/EFV: p=0.183
19. Time to Virologic Failure Adjusted p values (threshold for significance <0.016) LPV/EFV vs LPV: 0.13 LPV/EFV vs EFV: 0.5 LPV vs EFV: 0.006 Log Rank P-Values: A vs B p=0.099; A vs C p=0.371; B vs C p=0.004 Regimen Censored Failed Total MEDIAN A – LPV+EFV 177 73 250 - B – LPV+3TC+NRTI 159 94 253 - C – EFV+3TC+NRTI 190 60 250 - Proportion Not Failed Time in Weeks From Randomization Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THLB0204. 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 1.0 0.8 0.6 0.4 0.2 0.0 LPV EFV LPV/ EFV
20. Time to Regimen Completion Proportion Not Failed Time in Weeks From Randomization Adjusted p values (threshold for significance <0.016) LPV/EFV vs LPV: 0.13 LPV/EFV vs EFV: 0.5 LPV vs EFV: 0.02 Log Rank P-Values: A vs B p=0.101; A vs C p=0.708; B vs C p=0.028 Regimen Censored Failed Total MEDIAN A – LPV+EFV 145 105 250 133 B – LPV+3TC+NRTI 126 127 253 106 C – EFV+3TC+NRTI 156 94 250 - Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THLB0204. 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 1.0 0.8 0.6 0.4 0.2 0.0 LPV EFV LPV/ EFV
21. ARV Resistance Mutations (Preliminary Analysis) +some genotype assays pending ++30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V, 90M Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THB0204. * P < 0.05 compared to LPV; ** P<0.05 compared to EFV; *** P<0.05 compared to LPV/ EFV 2 0 0 Major PI mutations ++ 2** 2** 8 20 52 94 LPV 2 10*** Mutations in 2 classes 27* 16 NNRTI mutations 4 11*** NRTI mutations 18 13 Any PI mutations 39 33 Genotypic assays + 73 60 Observed VF LPV/ EFV EFV Patient Samples
33. NRTIs *dose reduce for renal dysfunction † dose reduce for weight <60 kg 125,200,250,400mg cap, pwdr for soln 200mg cap 150, 300mg tab, oral soln 300mg tab, 100mg cap, iv oral soln Dosage forms Pancreatitis, peripheral neuropathy, LA/HS Well tolerated Well tolerated Fatigue, malaise, HA, myalgia, anemia, GI Common Side Effects 400mg EC qd * † Didanosine (ddI) Videx Truvada, Atripla 200mg qd* Emtricitabine (FTC) Emtriva Combivir, Epzicom, Trizivir 150mg bid * or 300mg qd Lamivudine (3TC) Epivir Combivir, Trizivir 300mg bid * Zidovudine (ZDV/AZT) Retrovir Combos Standard Dose* Drug
34. NRTIs * dose reduce for renal dysfunction † dose reduce for weight <60 kg hypersensitivity Trizivir, Epzicom 300mg tabs, oral soln 300mg bid, 600mg qd Abacavir (ABC) Ziagen Few SEs, potential renal dysfxn. Truvada, Atripla 300mg tabs 300mg qd* Tenofovir (TDF) Viread Peripheral neuropathy, Dylipidemia, Lipodystrophy Pancreatitis, LA/HS 15,20,30,40 mg cap,oral soln 40mg bid * † Stavudine (d4T) Zerit Common Side Effects Combos Dosage forms Standard Dose* Drug
35. NRTI Combination Products * Use of individual components instead of combination products may necessary in patients with renal dysfunction. 600/300 mg tablet 1 tablet QD* Epzicom (ABC + 3TC) 300/200 mg tablet 1 tablet QD* Truvada (TDF + FTC) 300/150/300 mg tablet 1 tablet BID* Trizivir (AZT + 3TC + ABC) 300/150 mg tablet 1 tablet BID* Combivir (AZT + 3TC) Dosage Form Standard Dose Drug
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40. FDA Black Box Warnings http://aidsinfo.nih.gov/guidelines/adult/AA_032304.pdf Warning NNRTI ■ None EFV ■ None DLV ■ Severe, life-threatening hepatotoxicity including fulminant and cholestatic hepatitis, hepatic necrosis & hepatic failure. ■ Severe, life-threatening, and even fatal skin reactions. Monitor intensely during the first 12 wk to detect hepatotoxicity and skin reactions. NVP
41. NNRTIs Vivid dreams, drowsiness, CNS SEs, rash (including Stevens Johnson) CYP3A inducer, potency similar to PIs 50, 100, 200mg cap, 600mg tab 600 mg qhs Efavirenz (EFV) Sustiva rash, hepatotoxicity CYP3A inducer, auto inducer 200mg tabs, Oral susp 200 mg qd x 14 d then 200 mg bid Nevirapine (NVP) Viramune rash Suboptimal data on efficacy; potent CYP3A inhibitor 100mg tab, 200mg cap 400 mg tid Delavirdine (DLV) Rescriptor Common AEs Combos Dosage forms Standard Dose Drug
59. MAC Rifabutin has drug interactions with PI; dose reductions may be necessary Clarithromycin 500 mg BID + ethambutol 20 mg/kg QD ± rifabutin 300 mg QD* N/A Azithromycin 1200 mg Q week Treatment of Choice D/C therapy if a minimum of 12 months of MAC therapy, pt is asx and CD4 count > 100 cells/mm3 for at least 6 months Fluoroquinolone Amikacin Treatment N/A N/A Secondary Prophylaxis CD4 count >100 cells/mm3 Clarithromycin 500 mg BID Primary Prophylaxis Discontinue Alternative
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63. Cryptococcus Amphotericin B 0.7 mg/kg + flucytosine 100 mg/kg/d x 14 days Fluconazole 400 mg QD x 6 weeks Fluconazole 200 mg None Treatment of Choice Fluconazole 800 mg QD Treatment CD4 > 100-200 x 6 months Secondary Prophylaxis N/A None Primary Prophylaxis Discontinue Alternative
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Notes de l'éditeur
The Department of Health and Human Services (DHHS) Guidelines are based on sound science and recommend preferred and alternative regimens. Preferred regimens may be PI- or NNRTI-based in combination with an optimized backbone regimen typically containing dual nucleosides. Older HAART regimens required patients to adhere to complex dosing schedules involving multiples pills taken several times daily, whereas, the new HAART regimens have simplified dosing and pill schedules down to streamlined once daily fixed dose regimens, in order to facilitate better patient adherence. Reference 1. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/guidelines. Revision October 29, 2004. Accessed March 31, 2005.