21st Century Therapy: Advances in Antiretroviral Options PROGRAM DIRECTOR Anton L. Pozniak, MD, FRCP Consultant Physician Department of HIV and Genitourinary Medicine Chelsea and Westminster Hospital London, United Kingdom FACULTY Kathleen E. Squires, MD Professor of Medicine Director, Division of Infectious Diseases Jefferson Medical College Thomas Jefferson University Philadelphia, Pennsylvania

clinicaloptions.com/hiv Refining Antiretroviral Regimens Timeline of Antiretroviral Development AIDS 1st reported ddI ddC d4T 3TC, SQV RTV, IDV, NVP NFV, DLV, ZDV/3TC, SQV-gc EFV, ABC APV LPV/RTV, ddI-EC, ZDV/3TC/ABC TDF EFV-600, 3TC-300, d4T-XR ENF, NFV 625, ATV, FTC, FPV ABC/3TC, TDF/FTC, ddI generic SQV 500, TPV, ZDV generic, LPV/RTV tabs ZDV Reformulations Coformulations DRV, TDF/FTC/EFV

clinicaloptions.com/hiv Refining Antiretroviral Regimens 21st Century: Era of Reformulations, Coformulations, New Approaches YearReformulationCoformulationNew AgentsNew Approaches 2000ddI-EC LPV/RTV ZDV/3TC/ABC 2001TDF 2002 EFV-600 3TC-300 d4T-XR* 2003 NFV 625 FPV ATV FTC ENF Fusion inhibitor 2004ddI generic ABC/3TC TDF/FTC Entry inhibitors 2005 SQV 500 ZDV generic LPV/RTV tabs TPVIntegrase inhibitors 2006TDF/FTC/EFVDRVMaturation inhibitor *Not available commercially.

clinicaloptions.com/hiv Refining Antiretroviral Regimens Dosing Evolution of HIV Drugs AgentOriginal Daily DosingCurrent Daily Dosing ZDV2 ddI1 d4T1 3TC1 EFV1 NFV4 SQV APV4 LPV/RTV (SQV/RTV) (FPV/RTV)

clinicaloptions.com/hiv Refining Antiretroviral Regimens Approved Fixed-Dose Coformulated NRTIs FormulationDosing Studies Giving Insight About Use 2-drug coformulations ZDV/3TC1 tablet twice daily ACTG 384 ACTG 5095 ABC/3TC1 tablet once daily CNA CNA KLEAN TDF/FTC1 tablet once daily GS903 ABT418 GS934 3-drug coformulations ZDV/3TC/ABC1 tablet twice dailyACTG 5095

clinicaloptions.com/hiv Refining Antiretroviral Regimens Other Approved Coformulated Drugs FormulationDosing Studies Giving Insight About Use 2-drug coformulations LPV/RTV2 tablet twice daily M M ABT418 3-drug coformulations TDF/FTC/EFV1 tablet once dailyGS934

clinicaloptions.com/hiv Refining Antiretroviral Regimens Potential Advantages of Fixed-Dose Formulations  Reduced pill burden  Increased adherence  Improved patient satisfaction  Reduced risk of dosing errors  Reduced pharmacy copays (US)  Allowance for once-daily administration

clinicaloptions.com/hiv Refining Antiretroviral Regimens Fixed-Dose NRTIs: Comparison ZDV/3TCABC/3TCTDF/FTC Advantages  Long history of data  Lower rates of fat atrophy than d4T-containing regimens  Better adherence with coformulation than with separate drugs  Single pill once daily  Wide range of experience with third agents  No significant drug- drug interactions  No long-term toxicity  No mitochondrial toxicity  Single pill once daily  Long intracellular half-life  Good results paired with EFV and LPV/RTV  No mitochondrial toxicity Disadvantages  Twice-daily dosing  Adverse effects –Higher levels than other FDCs –Anemia –Mitochondrial toxicity  ABC hypersensitivity reaction  TDF has several drug- drug interactions  TDF associated with low risk of renal impairment  FTC hyperpigmentation

clinicaloptions.com/hiv Refining Antiretroviral Regimens First Regimen Failure EFV + ZDV + 3TC NFV + ZDV + 3TC EFV + ddI + d4T NFV + ddI + d4T Weeks Probability That the Endpoint Has Not Yet Been Reached Initial regimen First Virologic Failure Weeks Probability That the Endpoint Has Not Yet Been Reached Initial regimen Weeks P =.02 for initiation with EFV vs NFV EFV + ZDV + 3TC NFV + ZDV + 3TC EFV + ddI + d4T NFV + ddI + d4T ACTG 384: Time to First Regimen Failure and VF by Initial Regimen Robbins GK, et al. N Engl J Med. 2003;349:

clinicaloptions.com/hiv Refining Antiretroviral Regimens  Peripheral limb fat declined below baseline level with both ZDV/3TC and ddI/d4T  Lipoatrophy delayed with ZDV/3TC compared with ddI/d4T Weeks ZDV + 3TC ddI + d4T Percent Change in Limb Fat ACTG 384/5005S: Limb Fat Changes Dubé MP, et al. AIDS. 2005;19:

clinicaloptions.com/hiv Refining Antiretroviral Regimens < 50 copies/mL< 200 copies/mL Subjects With HIV-1 RNA Suppression at Week 48, % Level of Virologic Suppression Combined EFV arms Triple-NRTI arm  Randomized, double-blinded study in antiretroviral-naive patients, N = 1147 –ZDV/3TC/ABC –ZDV/3TC + EFV –ZDV/3TC/ABC + EFV  167 patients developed virologic failure –21% in the triple-NRTI arm –11% in the combined EFV arms (P <.001) Gulick RM, et al. N Engl J Med. 2004;350: ACTG 5095: Efficacy

clinicaloptions.com/hiv Refining Antiretroviral Regimens 0 BL 95% CI: -6.3% to 7.9% VL < 50 copies/mL (%) Week  CD4+ cell increase: 209 for ABC; 155 for ZDV (P =.005)  Withdrawal from study due to adverse events: 14% for ABC; 18% for ZDV  Adverse events –ABC arm: more hypersensitivity reaction –ZDV arm: more nausea, vomiting, fatigue, and anemia ABC (n = 324) ZDV (n = 325) Week 48, ITT Exposed Analysis DeJesus E, et al. Clin Infect Dis. 2004;39: ABC/3TC vs ZDV/3TC Combined With EFV (CNA )

clinicaloptions.com/hiv Refining Antiretroviral Regimens Week 48, ITT Exposed Analysis ABC QDABC BID Patients With HIV-1 RNA < 50 copies/mL (%) Moyle GJ, et al. J Acquir Immune Defic Syndr. 2005;38: ZODIAC (CNA 30021): Once- vs Twice- Daily ABC/3TC With EFV  N = 770 antiretroviral-naive patients randomized to –3TC + EFV + ABC once daily (n = 384) vs –3TC + EFV + ABC twice daily (n = 386)  Similar efficacy and safety at Week 48 –Grade 3/4 hypersensitivity reaction: 5% with once daily, 2% with twice daily (P =.02)

clinicaloptions.com/hiv Refining Antiretroviral Regimens KLEAN: FPV/RTV vs LPV/RTV as Initial Therapy  Phase IIIb, randomized, open-label, 48-week study  FPV/RTV 700/100 mg BID (n = 434) vs LPV/RTV SGC (400/100 mg BID) (n = 444) –Plus ABC/3TC (600/300 mg) QD  No difference in virologic outcome overall or stratified by baseline VL or CD4+ count  CD4+ gain: +176 (FPV/RTV) vs +191 (LPV/RTV) (ITT-E) VL Suppression at Wk 48 (%) FPV/ RTV LPV/ RTV TLOVR Analysis FPV/ RTV LPV/ RTV < 400 c/mL< 50 c/mL Eron JJ Jr, et al. Lancet. 2006;368:

clinicaloptions.com/hiv Refining Antiretroviral Regimens GS934: HIV RNA < 400 and < 50 copies/mL at Week 96 (TLOVR) Weeks Responders (%) 0 BL ZDV/3TC* < 400: 62% TDF + FTC* < 400: 75% P (< 400) =.004 TDF + FTC* < 50: 67% ZDV/3TC* < 50: 61% P (< 50) =.19 Gallant J, et al. IAC Abstract TUPE0064; Pozniak A, et al. J Acquir Defic Immun Syndr. 2006;epub. *All arms + EFV

clinicaloptions.com/hiv Refining Antiretroviral Regimens GS934: Changes in Renal Function and Limb Fat  Significantly higher glomerular filtration rate (by MDRD calculation only) in ZDV/3TC vs TDF + FTC arm –108 vs 100 mL/min/1.73 m 2 at Week 96; P =.006 –Difference not clinically significant –No significant decline over time within each arm Mean Changes in Limb Fat by DEXA in Patients With Data at Week 48* n = Pozniak A, et al. J Acquir Defic Immun Syndr. 2006;epub. TDF/FTC ZDV/3TC ‡ 6.0† 8.1‡ 7.4† Total Limb Fat (kg) *No baseline DEXA data available. †P =.034 ‡P <.001 TDF + FTC 48 weeks TDF + FTC 96 weeks ZDV/3TC 48 weeks ZDV/3TC 96 weeks

clinicaloptions.com/hiv Refining Antiretroviral Regimens Fixed-Dose NRTIs: Resistance ZDV/3TCABC/3TCTDF/FTC Resistance  Resistance mutations appear gradually and predictably  Can have “resensitizing” effect  TAMS may emerge after failure  Maintenance of M184V with continued 3TC use may confer continued virologic benefit  Well-studied resistance pattern  ABC initially selects for M184V mutation  If no thymidine analogue in regimen –ABC can select for L74V mutation –ABC less often selects for K65R mutation  ABT418 –M184V observed in 4 of 23 patients (17%) –K65R not observed –LPV resistance not observed  GS934 –M184V and EFV mutations occurred –No TAMs –No K65R

clinicaloptions.com/hiv Refining Antiretroviral Regimens  Advantages –Highly potent regimen associated with excellent activity –TDF/FTC/EFV single tablet, once daily, no food restrictions* –Components have long half-lives –Neither NRTI believed to cause mitochondrial toxicity  Disadvantages –TDF has several significant drug-drug interactions –Low incidence of renal impairment attributed to TDF –EFV adverse effects are barriers to use in a small number of patients –Low barrier to EFV resistance TDF/FTC/EFV: Advantages and Disadvantages *Recommended to be taken on an empty stomach.

clinicaloptions.com/hiv Refining Antiretroviral Regimens Patients Who Should Not Be Offered TDF/FTC/EFV  Women who either intend to become pregnant or who are not reliably preventing pregnancy  Patients with preexisting renal insufficiency  Patients who are intolerant of EFV  Patients with reverse transcriptase inhibitor mutations  Patients at risk for prolonged interruptions in therapy

clinicaloptions.com/hiv Refining Antiretroviral Regimens Improvement in PI Convenience  LPV/RTV coformulation  Improvements in dosing and food restrictions  Improvements in tolerability  Improvements in pill burden

clinicaloptions.com/hiv Refining Antiretroviral Regimens PIs Indicated for Once-Daily Therapy AgentFDA Approved for Patient Population LPV/RTVAntiretroviral-naive patients only ATVAntiretroviral-naive patients only (except those also receiving TDF) ATV/RTVBoth antiretroviral-naive and antiretroviral- experienced patients FPV/RTVAntiretroviral-naive patients only

clinicaloptions.com/hiv Refining Antiretroviral Regimens Evolution of PI Dosing APV FPV FPV/RTV ATVATV/RTV or IDV IDV/RTV None Light meal Empty stomach None

clinicaloptions.com/hiv Refining Antiretroviral Regimens Evolution of PI Dosing (cont’d) NFV SQV/RTVSQV LPV/RTV SGC or LPV/RTV Tablet or With food With food With food NoneWith food With food

clinicaloptions.com/hiv Refining Antiretroviral Regimens ACTG 5142: Outcomes at Week 96 (ITT) VL < 50No VF No Regimen Completion VL < 200 Patients (%) P =.041 P = Riddler S, et al. IAC Abstract THLB0204. LPV/RTV + 2 NRTIs EFV + 2 NRTIs LPV/RTV + EFV  EFV + 2 NRTIs superior to LPV/RTV + 2 NRTIs in coprimary endpoint of time to virologic failure (P =.006)  EFV + 2 NRTIs not significantly different to LPV/RTV + 2 NRTIs in coprimary endpoint of time to regimen completion (P =.02)  LPV/RTV + 2 NRTIs superior to EFV + 2 NRTIs in CD4+ cell count change CD4+ cell count (cells/mm 3) Median CD4+ Change P =.01

clinicaloptions.com/hiv Refining Antiretroviral Regimens Key Developments Affecting Treatment Approaches  Drugs with new targets –Entry inhibitors –Integrase inhibitors –Maturation inhibitors

clinicaloptions.com/hiv Refining Antiretroviral Regimens Estimated Timeline for New Antiretrovirals PA-457 PI NNRTI NRTI Maturation inhibitor Maraviroc GS-9137 TMC278Etravirine Apricitabine Brecanavir Integrase inhibitor Entry inhibitor (anti-gp120, CCR5) CXCR4 inhibitors MK-0518 TNX-355 Vicriviroc

clinicaloptions.com/hiv Refining Antiretroviral Regimens MK-0518 vs EFV in Treatment-Naive Patients: VL < 50 copies/mL at Week 24 *P <.001 for MK-0518 at each dose vs EFV Week MK mg39 MK mg40 MK mg41 MK mg40 EFV Patients With VL < 50 copies/mL (%) * * Markowitz M, et al. IAC Abstract THLB0214.

clinicaloptions.com/hiv Refining Antiretroviral Regimens PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy  Randomized, phase IIa study of PA day monotherapy in 32 HIV-infected patients –Median 1 log 10 VL reduction with PA mg/day  Treatment response correlated with plasma exposure and trough  Maximum response not seen yet with doses studied  No resistance seen to date in clinical studies  PA-457 resistance has been identified in vitro Median Change in HIV-1 RNA at Day 10 (log 10 copies/mL) PL (n = 8) 25 (n = 6) 50 (n = 6) 100 (n = 6) 200 (n = 6) PA-457 Dose (mg/day) (P =.02) (P =.004) (P <.0001) Beatty G, et al. ICAAC Abstract H-416d. Smith P, et al. CROI Abstract 52.

clinicaloptions.com/hiv Refining Antiretroviral Regimens Integrase Inhibitors: GS-9137  10-day monotherapy study  N = 40, HIV positive, HCV negative/HBV negative  Antiretroviral naive or experienced but off treatment  Randomized 1:1 vs placebo  Dosing –200 mg BID –400 mg BID –800 mg QD –800 mg BID –50 mg/RTV 100 mg QD  PK studies –Days 1 and 10 –Trough sampling through Day 21  No serious adverse events  Once-daily dosing with RTV to be investigated in phase II trial with experienced patients BL BID 400 BID 800 BID 50 + RTV QD Placebo 800 QD Day Log 10 Change HIV-1 RNA Dosing DeJesus E, et al. CROI Abstract 160LB.

clinicaloptions.com/hiv Refining Antiretroviral Regimens Summary  Considerable evolution has occurred in antiretroviral therapy leading to the ability to design simplified initial regimens –Reformulation of existing agents –Development of coformulations of 2 or more agents –Approval of new agents –Identification of novel agents and new approaches to therapy