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Co nowego na zjazdach CROI, ICAAC. EACS

Explore the latest recommendations for first-line HIV treatment, including new treatment strategies, medications, complications, and co-infection management. Get insights from European, American, and Polish guidelines.

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Co nowego na zjazdach CROI, ICAAC. EACS

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  1. Co nowego na zjazdach CROI, ICAAC. EACS

  2. Leczenie pierwszego rzutuNowe strategie leczeniaNowe lekiPowikłania leczeniaKoinfekcje

  3. Leczenie pierwszego rzutu&strategie leczenia

  4. Rekomendacje europejskie (EACS)Rekomendacje amerykańskie (DHHS)Rekomendacje polskieKiedy zacząć ?

  5. 0.12 0.10 0.08 0.06 0.04 0.02 0.00 3 0 4 5 1 2 HAART and Survival Based on Initial CD4+ Cell Count Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART • Modeled data from ART Cohort Collaborative • 10,855 patients included • 934 progressed to AIDS or died • IDUs excluded from model 101-200 cells/mm3201-350 cells/mm3351-500 cells/mm3 Probability of AIDS or Death Years Since Initiation of HAART Sterne J, et al. CROI 2006. Abstract 525.

  6. ATHENA National Cohort 1000 1000 800 800 600 600 400 400 200 200 0 0 0 240 144 48 96 192 288 336 0 1 2 3 4 5 Weeks From Starting HAART CD4+ Cell Count Response Based on Baseline CD4+ Cell Count Johns Hopkins HIV Clinical Cohort • Magnitude of CD4+ cell count increase greatest if therapy started at low CD4+ cell counts, but greater likelihood of CD4+ cell count normalization with earlier therapy Mean CD4+ Cell Count (cells/mm3) Years on HAART Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.

  7. 0.25 0.20 0.15 0.10 0.05 0.00 0 18 36 54 72 Związek pomiędzy śmiertelnością a supresją wiremii Proportion of Detectable Viral Loads Over6-18 Months After Initiation of HAART • Prospektywne, Danish HIV Cohort Study • N = 3919 HIV(+) • HAART ≥ 18 miesięcy • Podzieleni na grupy w zależności od proporcji wykrywalnej wiremii w ciągu 18 miesięcy od włączenia leczenia • Większe ryzyko śmierci u osób z niepełną lub brakiem supresji 100% (all values VL ≥ 400) 1%-99% (of values VL ≥ 400) 0% (all values VL < 400) Cumulative Mortality Months After Baseline (baseline = 18 months after HAART initiation) Lohse N, et al. ICAAC 2005. Abstract H-515.

  8. Kiedy rozpoczynać HAART : HOPS Cohort Dane z kohorty >8000pts, obserwacja od 1993 • U pacjentów, którzy zaczynali HAART przy wyższym CD4+ • Mniejsza śmiertelność, mniej OI • Lepsza odpowiedź CD4+ na HAART • Rzadziej niewydolność nerek, neuropatia i lipoatrofia • Lepszy efekt immunologiczny u osób stale leczonych HAART vs STI • Korzyści z leczenia nawet u osób, którzy rozpoczynali leczenie z CD4+ 350-500 kom/mm³i > 500 kom/mm³ Lichtenstein KA, et al. CROI 2006. Abstract 769.

  9. Rekomendacje europejskie (EACS)Rekomendacje amerykańskie (DHHS)Rekomendacje polskieCzym zacząć ?

  10. HIV RNA < 400 c/mL and < 50 c/mL Through Week 48 (ITT) 100 < 400 c/mL 86% 85% 75% 80 70% 60 < 50 c/mL Responders (%) 40 20 0 BL 2 4 12 16 24 32 40 48 8 Weeks Difference estimate (95% CI): 1.5 (-8.2 to 11.1)Difference estimate (95% CI): 1.5 (-7.0 to 17.0) ATV 300/RTV (n = 95)ATV 400 (n = 105) Boosted vs Unboosted Atazanavir in Antiretroviral-Naive Patients • Randomization 1:1 • ATV 400 mg QD (n = 105) • ATV/r 300/100 mg (n = 95) • Both with d4T-XR 100 mg QD + 3TC 300 mg QD • Trend for more virologic failure in ATV arm* • Patients with VF • ATV: n = 10 • ATV/r: n = 3 • Mean CD4+ count change • ATV: +224 • ATV/r: +189 *Not powered to determine if ATV noninferior to ATV/r Malan N, et al. CROI 2006. Abstract 107LB.

  11. ACTG 5095: Założenia badania • Porównanie 2- vs 3 lekowego NRTI backbones i zestawu 3-NRTI vs zawierające EFV • Ramię 3-NRTI przerwano po analizie danych pokazujących mniejsza efektywność w stosunku do ramion zawierających EFV Median follow-up: 144 weeks 3-NRTI arm Zidovudine/lamivudine/abacavir Antiretroviral-Naive VL ≥ 400 copies/mL (N = 82) 3 NRTIs + EFV arm Zidovudine/lamivudine/abacavir + efavirenz 2 NRTIs + EFV arm Zidovudine/lamivudine + efavirenz Gulick RM, et al. ICAAC 2005. Abstract H-416a.

  12. Ni stwierdzono różnicy w: Czasie osiągnięcia supresji Liczbie niepowodzeń terapeutycznych Proporcji z VL < 200 or < 50 c/mL Odpowiedzi CD4+ Profilu oporności Podobne rezultaty u osób z VL > 100,000 Czynniki niepowodzenia wirusologicznego HCV (HR: 1.57) Black race (HR: 1.67) Płeć,wiek, CD4+ nie ma wpływu ACTG 5095: EFV + ZDV/3TC vs EFV + ZDV/3TC/ABC jako terapia inicjująca 100 80 60 Virologic Failures* (%) 40 25 26 20 0 ZDV/3TC/ABC + EFV (n = 383) ZDV/3TC + EFV (n = 382) * Virologic failure defined as 2 consecutive VL ≥ 200 copies/mL at ≥ Week 16. Gulick RM, et al. ICAAC 2005. Abstract H-416a.

  13. Otwarte, randomizowane, pilotażowebadanie N = 30 naive men LPV/r (400/100 BID) + SQV (800 BID) or ZDV/3TC (300/150 BID) Podobne wyniki w 48 tygodniu Nie różnią się objawami ubocznymi Mniejsza liczba tabletek nowych postaciLPV/r and SQV Potrzeba więcej badań nad efektywnością dual-PI NRTI-Sparing Initial Therapy: LPV/r + SQV Compared With LPV/r + NRTIs 100 78% 80 77% 60 Patients With HIV-1 RNA < 50 copies/mL (Observed Data) (%) 40 20 LPV/r + SQV LPV/r + ZDV/3TC 0 0 12 24 48 36 Week n = 13 13 n = 10 9 Cameron DW, et al. ICAAC 2005. Abstract H-523.

  14. Odpowiedź na NNRTIs vs PIs u pacjentów z zaawansowanym AIDS • Poprzednie badania sugerowały różnice w efektywnościpomiędzy NNRTIs a PIs u pacjentów z zaawansowaną chorobą • Jednak oparte na badaniach obserwacyjnychi porównaniu różnych badań • Randomizowane badanie porównujące EFV vs IDV/r unieleczonychz CD4+ < 100 kom/mm3 • Nie ma statystycznychróżnic w odpowiedziwirusologicznej • Nie ma statystycznych różnic w odpowiedzi CD4+ w 24 miesiącu Miro JM, et al. EACS 2005. Abstract PS1/4.

  15. < 50 at Wk 48 100 < 400 at Wk 48 80 74% 65% 62% 55% 60 % of Subjects 40 20 0 ITT M=F OT 300 231 n = Mean log drop: 3.72 4.20 DART: Use of TDF + ZDV + 3TC in Resource-Limited Settings • Potential advantages of regimen • No refrigeration • No hypersensitivity • No pregnancy concerns • No rifampin interactions • Randomized trial: clinical + lab vs clinical monitoring alone in 3315 naive pts starting ZDV/3TC + TDF • 48-wk results presented on 300 pts in virology substudy • BL median CD4+, 100 cells/mm3 • BL median VL, 279,910 copies/mL Kaleebu P, et al. IAS 2005. Abstract WeOaLB0203.

  16. Rekomendacje europejskie (EACS)Rekomendacje amerykańskie (DHHS)Rekomendacje polskieJak zmieniać? ?

  17. Zmiana na prostszy schemat • SWAN study: efektywność i bezpieczeństwozmiany zreżimu PI BID i/lub≥ 3 tabl/dizenniena ATV (n = 253) lub ATV/r,jeśli z TDF (n = 25) • Kryteria wejścia: na stabilnym HAART z PI-, na 1stlub 2ndzestawie, VL < 50 przez ≥ 3 months • Randomizowano na dwie grupy-zmiana lub pozostanie na dotychczasowym leczeniu • Patiencji, którzy otrzymali ATV: • Utrzymali supresję wirusologiczną • Mieli poprawę profilu liidów • Total cholesterol, -16% vs +1% with comparator PI (P < .0001) • Triglycerides, -38% vs +1% with comparator PI (P < .0001) Gatell JM, et al. IAS 2005. Abstract WePe6.3C15.

  18. Leczenie podtrzymujące monoterapią PI • Monoterapia podtrzymująca stanowi atrakcyjną opcję dla u pacjentów z supresją wiremii • Jednakże w poprzednich badaniach stwierdzono znaczne ryzyko niepowodzenia wirusologicznego • PI/r mogą być dobrą opcją: ↑ potencjał, ↓ryzykooporności • 20/24 miało wiremię nieoznaczalną 48 tygodniupozmianie LPV/r + 2 NRTIs to LPV/r monoterapię[1] • Niepowodzenie wirusologiczne nie powodowało rozwoju mutacji , a dodaniem NRTIs uzyskano supresję 1. Arribas JR, et al. IAS 2005. Abstract WePe12.3C05. 2. Vernazza P, et al. IAS 2005. Abstract WeOa0204.

  19. Pharmakokinetyka of Double-Boosted zestawów z ATV • Pharmacokinetics of double-boosted PI therapy assessed in observational Frankfurt HIV cohort • Compared to each single-boosted PI + NRTIs • ATV also reduces RTV levels when combined with LPV/r • Secondary boosting effect of ATV on LPV P values for PI/r + ATV vs PI/r alone. 1. von Hentig N, et al. EACS 2005. Abstract PS6/5. 2. von Hentig N, et al. EACS 2005. Abstract PS6/6.

  20. By Week 24 after switch 26 (14%) had increases in VL 114 (60%) maintained VL 49 (26%) had decreases in VL 189 suppressed patients switched from ZDV/3TC to TDF/FTC Primary reason for switch: simplification (86%) All had BL VL < 400 copies/mL Small, but significant improvement in lipids TC ↓ 13 mg/dL at Week 12 TG ↓ 12.5 mg/dL at Week 12 Hb increased 0.6 g/dL by Week 24 9 20 94 3 14 COMET: Switch From ZDV/3TC to TDF/FTC 49 Ruane P, et al. EACS 2005. Abstract PE7.3/5.

  21. Rekomendacje europejskie (EACS)Rekomendacje amerykańskie (DHHS)Rekomendacje polskieJak nie zmieniać?

  22. 14% 29% 21% 29% 7% COL40263: Once-Daily ZDV/3TC/ABC + Tenofovir Genotypes of Nonresponders* All patientsBL VL < 100,000 BL VL ≥ 100,000 100 K65R/K (2 of 14 isolates) 80 ≥ 1 TAMs only (3 of 14 isolates) M184V only (1 of 14 isolates) ≥ 1 TAMs + M184V (4 of 14 isolates) 60 Wild type (4 of 14 isolates) Patients With HIV-1 RNA < 50 copies/mL (ITT: M=F) (%) 40 20 0 0 4 4 8 16 24 32 40 48 Study Week *≥ 400 copies/mL at ≥ 24 weeks Cohen C, et al. ICAAC 2005. Abstract H-521.Elion R, et al. ICAAC 2005. Abstract H-1068.

  23. Problemy z Didanosine + Tenofovir + Efavirenz • Badanie TEDDI potwierdziło poprzednie doniesieniaowiększym odsetku pacjentów z niepowodzeniem wirusologicznym przyjmujących ddI + TDF + EFV [1] • VF: 25% po 12 tygodniach of TDF + ddI + EFV • Badanie EFADITE pts ze stabilną supresją, którzy przestawieni zostali na TDF + ddI + EFV albo zostali na dotychczasowym leczeniu[2] • Utrzymano stłumienie wiremii u większości pts • Jednak, CD4+ ↓ na TDF + ddI + EFV • Median change in CD4+ at Yr 1, -25 vs +46 in controls (P = .007) • Significantly larger CD4+ declines in pts on high vs low ddI doses 1. van Lunzen J, et al. IAS 2005. Abstract TuPp0306. 2. Barrios A, et al. IAS 2005. Abstract WePe12.3C16.

  24. 3TC TI 3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART Mean VL Increase (ITT) Mean CD4+ Decrease (ITT) Weeks 2.0 3TC TI 4 12 24 36 48 P = .0015 0 1.5 -50 Mean Change in HIV-1 RNA (log10 copies/mL) 1.0 -100 Mean Change in CD4+ Cell Count (cells/mm3) -150 0.5 -200 -250 P = NS 0 4 12 24 36 48 -300 Weeks • In contrast to treatment interruption arm, 3TC alone resulted in: • Smaller recovery in replication capacity • No further selection of resistance mutations Castagna A, et al. IAS 2005. Abstract WeFo0204.

  25. Lower Incidence of M184V/I Following Virologic Failure With FTC vs 3TC • 1363 treatment-naive patients experiencing virologic failure in 1 of 3 phase III studies • FTC-301A: FTC QD + ddI + EFV vs d4T + ddI + EFV • GS-903: 3TC BID + TDF + EFV vs 3TC BID + d4T + EFV • GS-934: FTC QD + TDF + EFV vs 3TC BID + ZDV + EFV • Significantly ↓ rate of M184V/I emergence with FTC QD vs 3TC BID (both in combination with another NRTI and EFV) 3.0 P = .015 2.4 2.5 2.0 Incidence of M184V/I in 3 Pooled Phase III Trials (%) 1.5 1.0 0.6 0.5 0 FTC (n = 522) 3TC (n = 841) McColl D, et al. EACS 2005. Abstract PE7.3/17.

  26. Intrapartum Postpartum Mother Mother Mother sdNVP Baby Baby Baby sdNVP Arm 1 sdNVP ZDV/3TC x 4d Arm 2 sdNVP ZDV/3TC x 4d sdNVP ZDV/3TC x 7d Arm 3 sdNVP ZDV/3TC x 7d TOPS: Reducing Emergence of Resistance After Single-Dose NVP McIntyre JA, et al. IAS 2005. Abstract TuFo0204.

  27. TOPS Update on NVP Resistance • Coadministration of 4-7 days of ZDV/3TC with single-dose NVP reduced incidence of NVP resistance • 41/68 (60%) vs 15/135 (11%); P = .0001 * Incidence determined by standard genotyping, which is not sensitive to minority variants McIntyre JA, et al. IAS 2005. Abstract TuFo0204.

  28. RESIST-1 i -2: wyniki 48 tygodni 100 100 TPV/r CPI/r TPV/r CPI/r 80 80 52.0 60 60 Patients With HIV-1 RNA < 400 copies/mL (%) Patients With HIV-1 RNA < 50 copies/mL (%) 35.8 40 40 30.4 22.8 19.6 13.8 14.4 10.2 20 20 n = 123 n = 97 n = 123 n = 97 n =746 n = 737 n =746 n = 737 0 0 All Patients First-Time ENF Use All Patients First-Time ENF Use • TPV/r similar toxicity profile to CPI/r, with 2 exceptions • Elevated ALT (9.7% vs 4.2%), AST (6.1% vs 1.8%) • Elevated TGs (24.9% vs 13.0%), TC (2.1% vs 0.4%) Cahn P, et al. EACS 2005. Abstract LBPS3/8.

  29. Niewystępowanie oporności na PI po niepowodzeniu leczenia PI/r • No primary PI resistance mutations in pts with failure of SQV/r regimen • Staccato trial: Of 10 patients failing SQV/r 1600/100 mg QD + d4T/ddI (or TDF/3TC), none had primary PI mutations at failure [1] • Consistent with previous reports on FPV/r, LPV/r • SOLO trial: Of 32 pts failing FPV/r + ABC + 3TC, none developed primary or secondary PI mutations at failure [2] • M98-863 trial: Of 51 pts failing LPV/r + d4T + 3TC, none had primary PI mutations at failure [3] 1. Ananworanich J, et al. IAS 2005. Abstract WePe4.4C12. 2. MacManus S, et al. AIDS. 2004;18:651-655. 3. Kempf DJ, et al. J Infect Dis. 2004;189:51-60.

  30. Pharmacokinetics of Dual-boosted PI Regimens • Substantial reductions in APV and LPV levels previously shown when FPV and LPV/r coadministered [1] • However, new study showed no apparent adverse PK effect with ATV (300 or 400 QD) + LPV/r (400/100 BID) [2] • 20 treatment-experienced pts; 3 PI naive; 14 LPV/r naive • Median ATV and LPV Cmin in target range • 69% < 400 copies/mL at Week 24 • Further formal drug interaction studies and clinical trials are warranted 1. Kashuba A, et al. AIDS. 2005;19:145-152. 2. Duvivier C, et al. IAS 2005. Abstract WePe3.2C10.

  31. Nowe leki • NRTIs/NtRTIs • SPD 754 (DOTC) • Amdoxovir (DAPD) • D-d4FC • Racivir (± FTC) • SN1212 • Compound X • Entry inhibitors • Aplaviroc • Maraviroc • Vicriviroc • BMS-488043 • TNX-355 • NB-2, NB-64 • NNRTIs • TMC125 • GW678248 (prodrug = GW695634) • TMC278 • BILR 355 BS • CSIC • DAPY/DATA • UC781 • TMC120 (as microbicide) • Protease inhibitors • TMC114 • GW0385

  32. Enfuvirtide CCR5 inhibitors Tipranavir TMC114 MK-0518 GS-9137 D-d4FC (NRTI) TMC125 (NNRTI) PA-457 Antiretrovirals Potentially Active in Treatment-Experienced Patients

  33. 0-3 TAMs 4-6 TAMs M41L+ L210W M184V alone M184V+ TAMs L74V/I K65R -0.00 -0.25 Change in HIV-1 RNA at Wk 2 (log10 copies/mL) -0.50 Response to D-d4FC (200 mg QD) during initial 2-wk add-on phase -0.75 -1.00 Virologic Response to D-d4FC • Randomized, dose-ranging trial of D-d4FC vs placebo in 199 experienced pts with VL > 2000 copies/mL • D-d4FC active against NRTI-resistant viruses Cohen C, et al. IAS 2005. Abstract WeOaLB0103.

  34. Placebo 100 mg 200 mg 300 mg 400 mg 0.8 0.4 0.0 -0.4 Change in Plasma HIV-1 RNA (log10 copies/mL) -0.8 -1.2 -1.6 -2.0 5 7 1 3 4 2 6 8 Study Day Activity of Novel NNRTI GW695634 • Multicenter, double blind, randomized 7-day add-on study • N = 44 NNRTI-exp pts • 27 ≥ 1 NNRTI mutation at BL • Remaining 17 had history of NNRTI mutations • Most common NNRTI mut: K103N, V108I, Y181C • BL VL, 4.4-4.6 log • BL CD4+, 230-345 Becker S, et al. IAS 2005. Abstract WePe6.2C03.

  35. 8 1 2 4 12 16 20 24 0 TMC125-C223: Virologic Response in Pts With NNRTI and PI Resistance • TMC125 active in patients with no other active drugs • -0.59 log10 reduction in HIV-1 RNA with 800 mg BID dose Control(n = 40) 400 mg BID(n = 80) 800 mg BID(n = 79) 0.4 0 –0.19 -0.4 Mean (± SE) Change in HIV-1 RNA (log10 copies/mL) -0.8 –1.04* -1.2 –1.18* -1.6 *P < .05 Nadler JP, et al. EACS 2005. Abstract LBPS3/7a

  36. Ongoing 96-week randomized trials of 3-class experienced patients  1 primary PI mutation BL HIV-1 RNA: 4.6-4.7 log10 c/mL BL CD4+: 99-113 cells/mm3 24-week data previously reported from POWER-1 cohort[1] Current analysis presented 24-week data from POWER-2 cohort[2] Same arms and entry criteria in POWER-1 and POWER-2 POWER-2: Darunavir/r (TMC114/r) in PI-Experienced Patients POWER-2 Treatment Arms Darunavir 400 mg QD + Ritonavir 100 mg QD + OBR (n = 57) Darunavir 800 mg QD + Ritonavir 100 mg QD + OBR (n = 56) Darunavir 400 mg BID + Ritonavir 100 mg BID + OBR (n = 55) Darunavir 600 mg BID + Ritonavir 100 mg BID + OBR (n = 57) Investigator-selected PI + OBR (n = 53) 1. Katlama C, et al. IAS 2005. Abstract WeOaLB0102. 2. Wilkin T, et al. ICAAC 2005. Abstract H-413.

  37. Brecanavir (GW640385): PI Susceptibility vs Other PIs • Brecanavir retains in vitro susceptibility against virus resistant to commonly used PIs • In vitro study of 55 isolates from PI-experienced patients Viruses selected based on presence of protease mutations at codons 10, 32, 46, 47, 50, 54, 84, and/or 90 (mean: 8; range: 4-14) Reddy S, et al. ICAAC 2003. Abstract A-1800.

  38. Brecanavir (GW640385) Novel PI Active in HIV-Infected Patients • Open-label, single-arm study in HIV-infected subjects • N = 31 naive and experienced • BL VL: 4.7 log10 copies/mL • BL CD4+: 311 cells/mm3 • Brecanavir/r 300/100 BID + 2 NRTIs • 77% achieved VL < 50 copies/mL at Week 24 (ITT: missing = failure) • 81% < 400 copies/mL at Week 24 6 PI sensitive at BL (n = 23) PI resistant at BL (n = 6) 5 4 Median Plasma HIV-1 RNA (log10 copies/mL) 3 2 Median change at Week 24 PI sensitive: -3.3 log10 c/mL PI resistant: -2.2 log10 c/mL 1 0 0 4 8 12 16 20 24 Study Week Ward D, et al. ICAAC 2005. Abstract H-412.

  39. 1 0 -1 -2 -3 Virologic Response to Novel Integrase Inhibitor Monotherapy • MK-0518, novel integrase inhibitor • Active against HIV resistant to current antiretrovirals • Randomized, placebo-controlled 10-day monotherapy trial in treatment-naive patients • BL VL: 4.53-4.97 log10 c/mL • BL CD4: 256-569 cells/mm3 • Good response seen with 10-day monotherapy • No dose response • All doses generally well tolerated MK-0518 100 mg (n = 7) MK-0518 200 mg (n = 7) MK-0518 400 mg (n = 6) MK-0518 600 mg (n = 8) Placebo (n = 7) Change From Baseline in HIV-1 RNA (log10 copies/mL) 1 2 3 4 5 8 10 Day on Therapy Morales-Ramirez JO, et al. EACS 2005. Abstract LBPS1/6.

  40. MK-0518: Adverse Events • Adverse events similar to placebo • Serious drug-related adverse events • Acute pancreatitis, considered secondary to OBT, n = 1 • Lipoatrophy, n = 1 • Anemia, metabolic acidosis, renal insufficiency, death, n=1 • Hepatomegaly, tenderness, fever (600 mg arm), n = 1 • 2 discontinuations • Lack of efficacy (1); death (1) • Most AEs mild to moderate Grinsztejn B, et al. CROI 2006. Abstract 159LB.

  41. Integrase Inhibitor: GS-9137 • 10-day monotherapy study • N = 40, HIV positive, HCV/HBV negative • ARV naive or experienced 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 0.0 -0.5 -1.0 Log10 Change HIV-1 RNA Placebo 800 QD -1.5 200 BID 400 BID 800 BID -2.0 50 + RTV QD Dosing -2.5 BL 1 2 3 4 7 10 11 14 21 Day • No serious adverse events • Once-daily dosing with RTV to be investigated in phase II trial with experienced patients DeJesus E, et al. CROI 2006. Abstract 160LB.

  42. Next-Generation Fusion Inhibitors • In vitro data • High genetic barrier • Active against ENF-resistant virus • Animal data • Enhanced pharmacokinetic properties • Potential with once-weekly dosing Cynomolgus monkeyIV, 1 mg/Kg 1000 100 Clearance (mL/kg/hr)ENF 40 TRI-114411 TRI-999 7 ENF 10 100 Plasma Concentration(mm3/mL) Fold Decrease in Activity TRI-999 TRI-999 1 10 TRI-1144 TRI-1144 ENF 0 0 0 > 4 40 20 2 1 30 3 10 Time (Hours) (7) (6) (8) (9) (n) Number of Mutations Delmedico M, et al. CROI 2006. Abstract 48.

  43. Novel Maturation Inhibitor, PA-457 • Podawany doustnie; 70 godzin okres półtrwania u HIV (+) • Efekt leczenia koreluje z poziomem w surowicy i trough concentration • Liniowafarmakokinetyka prz różnych dawkach • Badania In vitro oporności potwierdzają efekt działania studies confirm mode of action • We wstępnych badaniach nie stwierdzono oporności Smith P, et al. CROI 2006. Abstract 52.

  44. Anti-CD4 monoclonal antibody blocks gp120 attachment to CD4+ receptor Delivered by IV infusion Phase II randomized trial in 823-class–experienced patients[1] TNX-355 + OBR or OBR alone TNX-355 doses: 15 mg/kg IV every 2 weeks 10 mg/kg IV every week x 8 weeks, then 10 mg/kg every 2 weeks Active against R5- and X4-tropic HIV[2] TNX-355: Novel CD4+ Attachment Inhibitor TNX-355 + OBR OBR Alone 15 mg/kg 10 mg/kg 0 -0.20 -0.4 Mean Change in HIV-1 RNA at Week 24 (log10 copies/mL) -0.8 -0.95(P = .003) -1.2 -1.16(P < .001) 1. Norris D, et al. ICAAC 2005. Abstract LB2-26. 2. Godofsky E, et al. ICAAC 2005. Abstract LB26.

  45. PA-457 first in new class called maturation inhibitors Targets late step in HIV life cycle Reduces viral load by disrupting production of HIV capsid protein, necessary for infecting other cells Randomized, phase IIa study of PA-457 10-day monotherapy in 32 HIV-infected patients Median 1 log10 VL reduction with PA-457 200 mg/day Generally well tolerated PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy PA-457 Dose (mg/day) PL(n = 8) 25(n = 6) 50(n = 6) 100(n = 6) 200(n = 6) 0 +0.05 +0.03 -0.17(P = .02) -0.4 Median Change in HIV-1 RNA at Day 10 (log10 copies/mL) -0.48(P = .004) -0.8 -1.03(P < .0001) -1.2 Beatty G, et al. ICAAC 2005. Abstract H-416d.

  46. Zaburzenia metaboliczne i inne objawy uboczne

  47. Prevalence of Metabolic Syndrome in MACS Cohort • HIV-positive men more likely to have metabolic syndrome than HIV-negative men • Low HDL, elevated TGs, elevated glucose more likely in HIV+ • Increased waist circumference less likely in HIV+ Palella F, et al. IAS 2005. Abstract TuPe2.2B18.

  48. Lipid Effects of First-line Regimens • Swiss HIV Cohort Study (N = 1065; FU 17-18 mos) • ↑ cholesterol with either PIs or NNRTIs • ↑ triglycerides with PIs, particularly with RTV regimens • Patients primarily on LPV/r, IDV/r, or NFV • ↑ HDL-C with NNRTIs Young J, et al. IAS 2005. Abstract TuPe2.2B16.

  49. Dyslipidemia: Lipid-Lowering Therapy vs PI to NNRTI Switch EFV NVP Pravastatin Bezafibrate 300 -10% 250 -27% 200 Mean Total Cholesterol (mg/dL) -46% 150 -38% 100 50 0 3 6 9 12 Months Calza L, et al. AIDS. 2005;19:1051-1058. TuFo0105

  50. Suppressed patients with self-defined lipoatrophy on thymidine analogue NRTI 105 patients randomized to replace TA with Tenofovir, or Abacavir Total limb fat increased to similar extent in both arms over 48 weeks RAVE: Switch Thymidine Analogue to ABC or TDF TDF 1200 1061 ABC 1046 1000 791 800 Change in Fat Mass by DEXA at Week 48 (g) 600 522 393 400 316 200 0 Limb Trunk Total Fat Within-group change in limb fat from baseline: TDF (P = .01), ABC (P = .001) Moyle G, et al. CROI 2005. Abstract 44LB.

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