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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
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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 198119841994 1992 1991 1985 19871995 1996 19971999 1998 2000 2001 2002 2003 2005 2004 2006
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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.
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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 4 6 12 4 2 2 3 9 9 16 6 (SQV/RTV) (FPV/RTV)
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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 30024 CNA 30021 KLEAN TDF/FTC1 tablet once daily GS903 ABT418 GS934 3-drug coformulations ZDV/3TC/ABC1 tablet twice dailyACTG 5095
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clinicaloptions.com/hiv Refining Antiretroviral Regimens Other Approved Coformulated Drugs FormulationDosing Studies Giving Insight About Use 2-drug coformulations LPV/RTV2 tablet twice daily M98-863 M97-720 ABT418 3-drug coformulations TDF/FTC/EFV1 tablet once dailyGS934
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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
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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
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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 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0163248648096102128144160 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;349:2293-2303. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0163248648096102128144160
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clinicaloptions.com/hiv Refining Antiretroviral Regimens 1632486480 Peripheral limb fat declined below baseline level with both ZDV/3TC and ddI/d4T Lipoatrophy delayed with ZDV/3TC compared with ddI/d4T -20 -15 -10 -5 0 5 10 15 Weeks ZDV + 3TC ddI + d4T Percent Change in Limb Fat ACTG 384/5005S: Limb Fat Changes Dubé MP, et al. AIDS. 2005;19:1807-1818.
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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 74 89 83 61 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) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Gulick RM, et al. N Engl J Med. 2004;350:1850-1861. ACTG 5095: Efficacy
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clinicaloptions.com/hiv Refining Antiretroviral Regimens 0 BL 95% CI: -6.3% to 7.9% VL < 50 copies/mL (%) 100 80 60 40 20 8162440 32 48 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) 70 69 Week 48, ITT Exposed Analysis DeJesus E, et al. Clin Infect Dis. 2004;39:1038-1046. ABC/3TC vs ZDV/3TC Combined With EFV (CNA 300024 )
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clinicaloptions.com/hiv Refining Antiretroviral Regimens Week 48, ITT Exposed Analysis 0 10 20 30 40 50 60 70 80 90 100 ABC QDABC BID Patients With HIV-1 RNA < 50 copies/mL (%) 66 68 Moyle GJ, et al. J Acquir Immune Defic Syndr. 2005;38:417-425. 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)
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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 (%) 0 20 40 60 80 100 FPV/ RTV LPV/ RTV 65 66 TLOVR Analysis FPV/ RTV LPV/ RTV 71 73 < 400 c/mL< 50 c/mL Eron JJ Jr, et al. Lancet. 2006;368:476-482.
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clinicaloptions.com/hiv Refining Antiretroviral Regimens GS934: HIV RNA < 400 and < 50 copies/mL at Week 96 (TLOVR) Weeks 20 40 60 80 100 8162432404860728496 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 2006. Abstract TUPE0064; Pozniak A, et al. J Acquir Defic Immun Syndr. 2006;epub. *All arms + EFV
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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 = 51 49 Pozniak A, et al. J Acquir Defic Immun Syndr. 2006;epub. TDF/FTC ZDV/3TC 0 2 4 6 8 10 5.5‡ 6.0† 8.1‡ 7.4† Total Limb Fat (kg) 49 44 *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
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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
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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.
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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
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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
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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
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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
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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
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clinicaloptions.com/hiv Refining Antiretroviral Regimens ACTG 5142: Outcomes at Week 96 (ITT) VL < 50No VF No Regimen Completion VL < 200 Patients (%) 0 20 40 60 80 100 P =.041 P =.003 67 54 86 77 76 60 93 89 73 61 92 83 Riddler S, et al. IAC 2006. 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 0 100 200 300 CD4+ cell count (cells/mm 3) 285 241 268 Median CD4+ Change P =.01
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clinicaloptions.com/hiv Refining Antiretroviral Regimens Key Developments Affecting Treatment Approaches Drugs with new targets –Entry inhibitors –Integrase inhibitors –Maturation inhibitors
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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 20062007200820092010 MK-0518 TNX-355 Vicriviroc
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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-0518 100 mg39 MK-0518 200 mg40 MK-0518 400 mg41 MK-0518 600 mg40 EFV38 37 0248121624 0 20 40 60 80 100 Patients With VL < 50 copies/mL (%) * * Markowitz M, et al. IAC 2006. Abstract THLB0214.
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clinicaloptions.com/hiv Refining Antiretroviral Regimens PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy Randomized, phase IIa study of PA-457 10-day monotherapy in 32 HIV-infected patients –Median 1 log 10 VL reduction with PA-457 200 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 -0.8 -0.4 0 -1.2 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) +0.03 +0.05 -0.17 (P =.02) -0.48 (P =.004) -1.03 (P <.0001) Beatty G, et al. ICAAC 2005. Abstract H-416d. Smith P, et al. CROI 2006. Abstract 52.
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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 BL1234710111421 -2.5 -2.0 -1.5 -0.5 0 200 BID 400 BID 800 BID 50 + RTV QD Placebo 800 QD Day Log 10 Change HIV-1 RNA Dosing DeJesus E, et al. CROI 2006. Abstract 160LB.
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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
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