1. HIV Treatment Update Todd Correll, PharmD, BCPS Clinical Pharmacy Specialist, Infectious Diseases/HIV University of North Carolina Hospitals November 2006

3. HIV Life Cycle Illustration by David Klemm

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

9. Preferred Combination Regimens: DHHS Oct, 2006 Nevirapine Atazanavir Fosamprenavir Fosampreanvir/r (QD) Lopinavir/r (QD) Abacavir/lamivudine Didanosine + lamivudine Alternative Efavirenz Atazanavir/r Fosamprenavir/r (BID) Lopinavir/r (BID) Tenofovir/emtricitabine Zidovudine/lamivudine Preferred NNRTI OR PI 2 NRTI

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

12. Proportion < 400 c/mL (TLOVR) r 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 10 0 Weeks TDF+FTC+EFV 75%* CBV+EFV 62% p = 0.004 *95% CI: (+4.3%, +21.1%) % Responder Gallant J, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. TUPE0064 . B L 8 1 6 2 4 3 2 4 0 4 8 6 0 7 2 8 4 9 6

13. Proportion < 50 c/mL (TLOVR) % Res pon d e r 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 TDF+FTC+EFV 67%* CBV+EFV 61%* p = 0.16 *95% CI: (-2.3%, +15.0%) Weeks % Responder Gallant J, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. TUPE0064. B L 8 1 6 2 4 3 2 4 0 4 8 6 0 7 2 8 4 9 6

14. Mean Absolute Change in CD4 count from Baseline Mean Change (cells/ m m 3 ) 0 5 0 10 0 15 0 20 0 25 0 30 0 B L 8 1 6 2 4 3 2 4 0 4 8 6 0 7 2 8 4 9 6 Weeks 270 TDF+FTC+EFV 237 CBV+EFV p = 0.036 n = 255 238 234 223 218 209 199 177 184 172 166 n = 254 222 216 199 188 175 164 145 149 149 142 Mean Change (cells/mm 3 ) Gallant J, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. TUPE0064 .

15. Resistance Development through Week 96 Gallant J, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. TUPE0064. p = 0.017 p = 0.036 Excludes patients with baseline NNRTI-R mutations (n = 487) 0 0 K65R 1 0 TAMs 9 2 M184V/I 18 10 EFV-R 20 10 Any Resistance 7 4 Wild Type 29 14 Genotypes CBV+EFV (n = 243) TDF+FTC+EFV (n = 244)

17. Baseline Characteristics Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THLB0204. 51 52 51 51 HIV RNA >10 5 (%) 42 34 25 178 65 77 LPV N=253 N/A 181 65 82 LPV/EFV N=250 42 34 24 42 34 24 NRTI (%) ZDV TDF d4T XR 190 182 CD4 (median) 60 64 Non-white (%) 81 80 Male (%) EFV N=250 Total N=753

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

30. NNRTI ’ 87 ’ 91 ’ 92 ’ 94 ’ 95 ’ 96 ’ 97 ’ 98 ’ 99 ‘ 00 ’ 88 ’ 89 ’ 90 NRTI PI Approved Antiretrovirals Norvir Invirase Crixivan Fortovase Kaletra Viracept Ziagen Combivir Videx Hivid Zerit Epivir Trizivir Rescriptor Sustiva Viramune ’ 01 Viread Emtriva Reyataz ‘ 02 ‘ 03 ’ 93 Agenerase Lexiva Truvada Epzicom FI AZT Aptivus Prezista Atripla Fuzeon

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

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

43. Atripla Bioequivalence TFV FTC EFV

46. Protease Inhibitors Take with food 2 (700mg) tabs BID 2 (700mg) tabs + 2 (100 mg) caps QD 1 (700mg) tabs + 1 (100 mg) caps BID 1400 mg BID 1400 mg + RTV 200 QD 700 mg + RTV 100 mg BID Fosamprenavir (Lexiva) Liquid contains propylene glycol Avoid concomitant with ritonavir liquid Available as 50 mg capsules and liquid 600 mg + RTV 100 mg BID 1200 mg + RTV 200 mg QD Amprenavir (Agenerase) Drink 7-8 glasses of water per day 2 (400mg) caps + 1(100mg cap) BID 2 (400 mg) caps TID 800mg + RTV 100 BID 800 mg TID Indinavir (Crixivan) Take with food 2(625mg) tabs BID 3(250mg) tabs TID 1250 mg BID 750 mg TID Nelfinavir (Viracept) Take with food 2(500mg) caps/ 1(100mg cap) BID 1000 mg + RTV 100 mg BID Saquinavir (Invirase) Dosing info Pill burden Dose Drug

47. Protease Inhibitors Take with food 2 (300mg) tabs + 1 (100 mg) caps BID 600mg + RTV 100mg BID Darunavir (Prezista) Take with food 2 (250mg) caps + 2( 100mg cap) bid 500mg + RTV 200mg BID Tipranavir (Aptivus) Take with food; avoid PPI 2 (200mg) QD 2 (150mg) + 1 (100mg) QD 400mg QD 300mg + RTV 100mg QD Atazanavir (Reyataz) Take with or without food 4 tabs QD 2 tabs BID 400mg/100mg QD 400mg/100mg BID Lopinavir/ritonavir (Kaletra) Dosing info Pill burden Dose Drug

48. Protease Inhibitors 3A inhibitor, 3A substrate ----------- N/V, rash, HA Darunavir 3A and UGT1A1 inhibitor; 3A substrate good/86% ↑ bilirubinemia Atazanavir 3A inhibitor/ substrate; 2D6 inhibitor Poor/99% GI symptoms, rash Lopinavir/ritonavir 3A inhibitor/ substrate Unknown/99% GI symptoms ↑ LFTs, lipids, rash Tipranavir 3A inducer/ substrate Poor/90% GI symptoms, rash Fosamprenavir 3A substrate 30%/60% Nephrolithiasis; GI intolerance Indinavir P450 inhibitor/inducer/ substrate 20-80%/99% diarrhea Nelfinavir 3A substrate 4%/98% GI intolerance Saquinavir Metabolizing enzymes Bioavailability/ Protein Binding Side Effects Drug

55. Common Opportunistic Infections Cryptococcus meningitis MAC CMV < 50 cells/mm 3 Toxoplasmosis gondii < 100 cells/mm 3 PCP < 200 cells/mm 3 Thrush < 250 cells/mm 3 Tuberculosis VZV HSV Recurrent bacterial infections < 500 cells/mm 3 Opportunistic Infection CD4 cell count

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

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