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Prezentacja na temat: "Clinicaloptions.com/hiv HIV/AIDS Update From Rio Co nowego na zjazdach CROI, ICAAC. EACS."— Zapis prezentacji:

1 clinicaloptions.com/hiv HIV/AIDS Update From Rio Co nowego na zjazdach CROI, ICAAC. EACS

2 clinicaloptions.com/hiv HIV/AIDS Update From Rio Leczenie pierwszego rzutu Nowe strategie leczenia Nowe leki Powikłania leczenia Koinfekcje

3 clinicaloptions.com/hiv HIV/AIDS Update From Rio Leczenie pierwszego rzutu& strategie leczenia

4 clinicaloptions.com/hiv HIV/AIDS Update From Rio Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Kiedy zacząć ?

5 clinicaloptions.com/hiv HIV/AIDS Update From Rio HAART and Survival Based on Initial CD4+ Cell Count Modeled data from ART Cohort Collaborative 10,855 patients included 934 progressed to AIDS or died IDUs excluded from model Sterne J, et al. CROI Abstract 525. Progression and Death According to CD4+ Cell Count (cells/mm 3 ) < 200 vs < 350 vs Hazard ratio for AIDS (95% CI) 3.68 ( ) 1.52 ( ) Hazard ratio for AIDS or death (95% CI) 2.93 ( ) 1.26 ( ) Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART Years Since Initiation of HAART Probability of AIDS or Death cells/mm cells/mm cells/mm 3

6 clinicaloptions.com/hiv HIV/AIDS Update From Rio CD4+ Cell Count Response Based on Baseline CD4+ Cell Count Keruly J, et al. CROI Abstract 529. Gras L, et al. CROI Abstract 530. Years on HAART Johns Hopkins HIV Clinical Cohort Mean CD4+ Cell Count (cells/mm 3 ) ATHENA National Cohort Weeks From Starting HAART 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

7 clinicaloptions.com/hiv HIV/AIDS Update From Rio Związek pomiędzy śmiertelnością a supresją wiremii 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 Lohse N, et al. ICAAC Abstract H % (all values VL 400) 1%-99% (of values VL 400) 0% (all values VL < 400) Months After Baseline (baseline = 18 months after HAART initiation) Cumulative Mortality Proportion of Detectable Viral Loads Over 6-18 Months After Initiation of HAART

8 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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 CD kom/mm³ i > 500 kom/mm³ Lichtenstein KA, et al. CROI Abstract 769.

9 clinicaloptions.com/hiv HIV/AIDS Update From Rio Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Czym zacząć ?

10 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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 Malan N, et al. CROI Abstract 107LB. Weeks < 400 c/mL < 50 c/mL BL % 75% 85% 70% Responders (%) HIV RNA < 400 c/mL and < 50 c/mL Through Week 48 (ITT) 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) *Not powered to determine if ATV noninferior to ATV/r

11 clinicaloptions.com/hiv HIV/AIDS Update From Rio ACTG 5095: Założenia badania Antiretroviral-Naive VL 400 copies/mL (N = 82) Gulick RM, et al. ICAAC Abstract H-416a. 3-NRTI arm Zidovudine/lamivudine/abacavir Median follow-up: 144 weeks 3 NRTIs + EFV arm Zidovudine/lamivudine/abacavir + efavirenz 2 NRTIs + EFV arm Zidovudine/lamivudine + efavirenz 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

12 clinicaloptions.com/hiv HIV/AIDS Update From Rio ACTG 5095: EFV + ZDV/3TC vs EFV + ZDV/3TC/ABC jako terapia inicjująca 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 Gulick RM, et al. ICAAC Abstract H-416a. Virologic Failures* (%) ZDV/3TC + EFV (n = 382) ZDV/3TC/ABC + EFV (n = 383) * Virologic failure defined as 2 consecutive VL 200 copies/mL at Week 16.

13 clinicaloptions.com/hiv HIV/AIDS Update From Rio NRTI-Sparing Initial Therapy: LPV/r + SQV Compared With LPV/r + NRTIs Otwarte, randomizowane, pilotażowe badanie –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 postaci LPV/r and SQV Potrzeba więcej badań nad efektywnością dual-PI Cameron DW, et al. ICAAC Abstract H-523. Week Patients With HIV-1 RNA < 50 copies/mL (Observed Data) (%) % 77% LPV/r + SQV LPV/r + ZDV/3TC n =13 n =10 9

14 clinicaloptions.com/hiv HIV/AIDS Update From Rio Odpowiedź na NNRTIs vs PIs u pacjentów z zaawansowanym AIDS Poprzednie badania sugerowały różnice w efektywności pomiędzy NNRTIs a PIs u pacjentów z zaawansowaną chorobą –Jednak oparte na badaniach obserwacyjnych i porównaniu różnych badań Randomizowane badanie porównujące EFV vs IDV/r u nieleczonych z CD4+ < 100 kom/mm 3 –Nie ma statystycznych różnic w odpowiedzi wirusologicznej –Nie ma statystycznych różnic w odpowiedzi CD4+ w 24 miesiącu Miro JM, et al. EACS Abstract PS1/4.

15 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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/mm 3 –BL median VL, 279,910 copies/mL % 65% 62% 74% % of Subjects < 50 at Wk 48 < 400 at Wk 48 ITT M=FOT Mean log drop: n = Kaleebu P, et al. IAS Abstract WeOaLB0203.

16 clinicaloptions.com/hiv HIV/AIDS Update From Rio Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Jak zmieniać? ?

17 clinicaloptions.com/hiv HIV/AIDS Update From Rio Zmiana na prostszy schemat SWAN study: efektywność i bezpieczeństwo zmiany z reżimu PI BID i/lub 3 tabl/dizennie na ATV (n = 253) lub ATV/r, jeśli z TDF (n = 25) –Kryteria wejścia: na stabilnym HAART z PI-, na 1 st lub 2 nd zestawie, 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 Abstract WePe6.3C15.

18 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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, ryzyko oporności 20/24 miało wiremię nieoznaczalną 48 tygodniu po zmianie 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 Abstract WePe12.3C Vernazza P, et al. IAS Abstract WeOa0204.

19 clinicaloptions.com/hiv HIV/AIDS Update From Rio 1. von Hentig N, et al. EACS Abstract PS6/5. 2. von Hentig N, et al. EACS Abstract PS6/6. 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 Pharmakokinetyka of Double-Boosted zestawów z ATV AUCss After 3 Days of Treatment (ng·hr/mL) Effect on Concomitant Drug [1] Effect on ATV [2] Recommendation Lopinavir/ritonavir (400/100 BID) 16% (P =.21) 22% (P =.077) Use with TDM Saquinavir/ritonavir (1000 BID/100 QD) 40% (P =.001) 16% (P =.11) Use with low-dose ritonavir (100 mg QD) Fosamprenavir/ritonavir (700/100 BID) neutral 31% (P =.003) Further investigation required P values for PI/r + ATV vs PI/r alone.

20 clinicaloptions.com/hiv HIV/AIDS Update From Rio Week 24 copies/mL (n) BL VL copies/mL > 40050–400< 50 50–400 (n = 78) < 50 (n = 111) By Week 24 after switch –26 (14%) had increases in VL –114 (60%) maintained VL –49 (26%) had decreases in VL COMET: Switch From ZDV/3TC to TDF/FTC 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 Ruane P, et al. EACS Abstract PE7.3/

21 clinicaloptions.com/hiv HIV/AIDS Update From Rio Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Jak nie zmieniać?

22 clinicaloptions.com/hiv HIV/AIDS Update From Rio COL40263: Once-Daily ZDV/3TC/ABC + Tenofovir Cohen C, et al. ICAAC Abstract H-521. Elion R, et al. ICAAC Abstract H * 400 copies/mL at 24 weeks 14% 21% 7% 29% Patients With HIV-1 RNA < 50 copies/mL (ITT: M=F) (%) Study Week All patients BL VL < 100,000 BL VL 100,000 K65R/K (2 of 14 isolates) 1 TAMs only (3 of 14 isolates) M184V only (1 of 14 isolates) 1 TAMs + M184V (4 of 14 isolates) Wild type (4 of 14 isolates) Genotypes of Nonresponders*

23 clinicaloptions.com/hiv HIV/AIDS Update From Rio Problemy z Didanosine + Tenofovir + Efavirenz 1. van Lunzen J, et al. IAS Abstract TuPp Barrios A, et al. IAS Abstract WePe12.3C16. Badanie TEDDI potwierdziło poprzednie doniesienia o większym 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

24 clinicaloptions.com/hiv HIV/AIDS Update From Rio 3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART Castagna A, et al. IAS Abstract WeFo Mean Change in HIV-1 RNA (log 10 copies/mL) Weeks Mean Change in CD4+ Cell Count (cells/mm 3 ) Weeks P = NS Mean CD4+ Decrease (ITT)Mean VL Increase (ITT) P = TCTI In contrast to treatment interruption arm, 3TC alone resulted in: –Smaller recovery in replication capacity –No further selection of resistance mutations 3TCTI

25 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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) McColl D, et al. EACS Abstract PE7.3/ Incidence of M184V/I in 3 Pooled Phase III Trials (%) P =.015 FTC (n = 522) 3TC (n = 841)

26 clinicaloptions.com/hiv HIV/AIDS Update From Rio TOPS: Reducing Emergence of Resistance After Single-Dose NVP Arm 3 Arm 2 Arm 1 sdNVP ZDV/3TC x 4d ZDV/3TC x 7d IntrapartumPostpartum Mother Baby Mother Baby Mother Baby sdNVP McIntyre JA, et al. IAS Abstract TuFo0204.

27 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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 TOPS Update on NVP Resistance Study ArmN Maternal NVP Resistance*, n (%) sdNVP6841 (60%) sdNVP + ZDV/3TC x 4d 678 (12%) sdNVP + ZD/3TC x 7d68 7 (10%) McIntyre JA, et al. IAS Abstract TuFo0204. * Incidence determined by standard genotyping, which is not sensitive to minority variants

28 clinicaloptions.com/hiv HIV/AIDS Update From Rio RESIST-1 i -2: wyniki 48 tygodni Cahn P, et al. EACS Abstract LBPS3/8. 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%) All PatientsFirst-Time ENF Use Patients With HIV-1 RNA < 50 copies/mL (%) TPV/rCPI/r n =746n = 737 n = 123n = All PatientsFirst-Time ENF Use Patients With HIV-1 RNA < 400 copies/mL (%) TPV/rCPI/r n =746n = 737 n = 123n =

29 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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] –M trial: Of 51 pts failing LPV/r + d4T + 3TC, none had primary PI mutations at failure [3] 1. Ananworanich J, et al. IAS Abstract WePe4.4C MacManus S, et al. AIDS. 2004;18: Kempf DJ, et al. J Infect Dis. 2004;189:51-60.

30 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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: Duvivier C, et al. IAS Abstract WePe3.2C10.

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

32 clinicaloptions.com/hiv HIV/AIDS Update From Rio Antiretrovirals Potentially Active in Treatment-Experienced Patients Enfuvirtide CCR5 inhibitors Tipranavir TMC114 D-d4FC (NRTI) TMC125 (NNRTI) PA-457 MK-0518 GS-9137

33 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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 Abstract WeOaLB0103. Response to D-d4FC (200 mg QD) during initial 2-wk add-on phase 0-3 TAMs 4-6 TAMs M41L+ L210W M184V alone M184V+ TAMs L74V/IK65R Change in HIV-1 RNA at Wk 2 (log 10 copies/mL)

34 clinicaloptions.com/hiv HIV/AIDS Update From Rio Activity of Novel NNRTI GW Becker S, et al. IAS Abstract WePe6.2C03. 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, log BL CD4+, Placebo100 mg200 mg 300 mg400 mg Change in Plasma HIV-1 RNA (log 10 copies/mL) Study Day

35 clinicaloptions.com/hiv HIV/AIDS Update From Rio TMC125-C223: Virologic Response in Pts With NNRTI and PI Resistance TMC125 active in patients with no other active drugs – log 10 reduction in HIV-1 RNA with 800 mg BID dose Nadler JP, et al. EACS Abstract LBPS3/7a Mean (± SE) Change in HIV-1 RNA (log 10 copies/mL) Control (n = 40) 400 mg BID (n = 80) 800 mg BID (n = 79) –0.19 –1.04* –1.18* *P <.05

36 clinicaloptions.com/hiv HIV/AIDS Update From Rio POWER-2: Darunavir/r (TMC114/r) in PI-Experienced Patients Ongoing 96-week randomized trials of 3-class experienced patients – 1 primary PI mutation –BL HIV-1 RNA: log 10 c/mL –BL CD4+: cells/mm 3 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 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) POWER-2 Treatment Arms 1. Katlama C, et al. IAS Abstract WeOaLB Wilkin T, et al. ICAAC Abstract H-413.

37 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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 Drug Mean IC 50 (nM)Range (nM) Brecanavir to 14.9 Amprenavir to > 1500 Indinavir to > 1500 Lopinavir to 1455 Nelfinavir to 1309 Reddy S, et al. ICAAC Abstract A 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)

38 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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 log 10 copies/mL –BL CD4+: 311 cells/mm 3 –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 Ward D, et al. ICAAC Abstract H Study Week Median Plasma HIV-1 RNA (log 10 copies/mL) PI sensitive at BL (n = 23) PI resistant at BL (n = 6) Median change at Week 24 PI sensitive: -3.3 log 10 c/mL PI resistant: -2.2 log 10 c/mL

39 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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: log 10 c/mL –BL CD4: cells/mm 3 Good response seen with 10-day monotherapy –No dose response All doses generally well tolerated Morales-Ramirez JO, et al. EACS Abstract LBPS1/6. Day on Therapy Change From Baseline in HIV-1 RNA (log 10 copies/mL) MK mg (n = 7) MK mg (n = 7) MK mg (n = 6) MK mg (n = 8) Placebo (n = 7)

40 clinicaloptions.com/hiv HIV/AIDS Update From Rio 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 Abstract 159LB.

41 clinicaloptions.com/hiv HIV/AIDS Update From Rio Integrase Inhibitor: GS 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 No serious adverse events Once-daily dosing with RTV to be investigated in phase II trial with experienced patients DeJesus E, et al. CROI Abstract 160LB. BL BID 400 BID 800 BID 50 + RTV QD Placebo 800 QD Day Log 10 Change HIV-1 RNA Dosing

42 clinicaloptions.com/hiv HIV/AIDS Update From Rio Next-Generation Fusion Inhibitors Delmedico M, et al. CROI Abstract 48. Animal data Enhanced pharmacokinetic properties Potential with once-weekly dosing In vitro data High genetic barrier Active against ENF-resistant virus Fold Decrease in Activity Number of Mutations Plasma Concentration (mm 3 /mL) Time (Hours) ENF TRI-1144 TRI-999 Cynomolgus monkey IV, 1 mg/Kg Clearance (mL/kg/hr) ENF 40 TRI TRI (6) (7) (8)(9) > TRI-999 ENF TRI (n)

43 clinicaloptions.com/hiv HIV/AIDS Update From Rio Novel Maturation Inhibitor, PA-457 Podawany doustnie; 70 godzin okres półtrwania u HIV (+) Efekt leczenia koreluje z poziomem w surowicy i trough concentration Liniowa farmakokinetyka 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 Abstract 52.

44 clinicaloptions.com/hiv HIV/AIDS Update From Rio TNX-355: Novel CD4+ Attachment Inhibitor Anti-CD4 monoclonal antibody blocks gp120 attachment to CD4+ receptor –Delivered by IV infusion Phase II randomized trial in 82 3-class–experienced patients [1] –TNX 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] Mean Change in HIV-1 RNA at Week 24 (log 10 copies/mL) OBR Alone 15 mg/kg 10 mg/kg 1. Norris D, et al. ICAAC Abstract LB Godofsky E, et al. ICAAC Abstract LB (P =.003) (P <.001) TNX OBR

45 clinicaloptions.com/hiv HIV/AIDS Update From Rio PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy 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 day monotherapy in 32 HIV-infected patients –Median 1 log 10 VL reduction with PA mg/day Generally well tolerated 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) Beatty G, et al. ICAAC Abstract H-416d (P =.02) (P =.004) (P <.0001)

46 clinicaloptions.com/hiv HIV/AIDS Update From Rio Zaburzenia metaboliczne i inne objawy uboczne

47 clinicaloptions.com/hiv HIV/AIDS Update From Rio Prevalence of Metabolic Syndrome in MACS Cohort Palella F, et al. IAS Abstract TuPe2.2B18. Estimated Odds Ratio for HIV+ vs HIV- Pts (95% CI) P Value Metabolic syndrome1.50 ( ).004 Elevated fasting triglycerides2.81 ( )<.001 Elevated fasting glucose1.81 ( )<.001 Increased waist circumference0.38 ( )<.001 Low HDL cholesterol3.15 ( )<.001 High blood pressure1.04 ( ).715 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+

48 clinicaloptions.com/hiv HIV/AIDS Update From Rio Swiss HIV Cohort Study (N = 1065; FU 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 Abstract TuPe2.2B16. Lipid Effects of First-line Regimens

49 clinicaloptions.com/hiv HIV/AIDS Update From Rio Dyslipidemia: Lipid-Lowering Therapy vs PI to NNRTI Switch Calza L, et al. AIDS. 2005;19: TuFo0105 Pravastatin Bezafibrate Mean Total Cholesterol (mg/dL) Months EFV NVP % -27% -46% -38%

50 clinicaloptions.com/hiv HIV/AIDS Update From Rio RAVE: Switch Thymidine Analogue to ABC or TDF 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 Moyle G, et al. CROI Abstract 44LB. Change in Fat Mass by DEXA at Week 48 (g) LimbTrunkTotal Fat TDF ABC Within-group change in limb fat from baseline: TDF (P =.01), ABC (P =.001)

51 clinicaloptions.com/hiv HIV/AIDS Update From Rio Risk of Disease Progression or Death No. of Patients With EventsSubgroupsRelative Risk (95% CI) All Patients Sex Male Female Race Black Nonblack Severe Complications CVD, liver, or renal deaths Nonfatal CVD events Nonfatal hepatic events Nonfatal renal events Favors TIFavors CT El-Sadr W, et al. CROI Abstract 106 LB. Risk of Complications SMART: HIV Progression by Sex and Race; Severe Complications

52 clinicaloptions.com/hiv HIV/AIDS Update From Rio CD4+ Cell Count–Guided TIs: Summary TI may be safe if patient has CD4+ cell count > 350 cells/mm³ and remains above that level In these trials, TI has led to some risk of progression and/or resistance and may potentially lead to increased risk of transmission In the US, if therapy is indicated, the best results are seen in patients who are on continuous therapy In developing countries, further investigation of TI is warranted due to limited ART availability In SMART, increased risk of poor outcome noted unexpectedly early in the interruption period In SMART, presence of viremia at baseline associated with poorer outcomes regardless of arm –In viremic patients, no increased risk with CD4+-guided TI (RR 1.1) –In aviremic patients, risk of progression or death with TI (RR 3.8)

53 clinicaloptions.com/hiv HIV/AIDS Update From Rio Koinfekcje

54 clinicaloptions.com/hiv HIV/AIDS Update From Rio *HCV/HIV coinfection linked to IDU Hepatitis C: A Global Health Problem million carriers worldwide 10 million HIV coinfected* USA USA 3-4 M 30% HIV+* Americas Americas M Africa Africa M W. Europe W. Europe 5 M 30-50% HIV+* E. Europe E. Europe 10 M South East Asia South East Asia M Australia Australia 0.2 M Far East Far East 60 M HBV 350 M HCV M HIV 40 M WHO

55 clinicaloptions.com/hiv HIV/AIDS Update From Rio Increase in Sexual Transmission of HCV Great Britain; 3 cities; [1] 111 HIV-positive MSM with acute HCV Phylogenetic analysis of 91 E1/E2 sequences indicated common source transmission of HCV Risk factors for HCV infection by case-control analysis –Meeting sexual partners in bathhouses or over the Internet –Body piercing or tattooing –Sexual partners and unsafe sex practices, including group sex –Recreational drug use and drug use during sex –STDs 1. Danta M, et al. CROI Abstract Coutinho R, et al. CROI Abstract 87. Amsterdam Cohort Study [2] 10-fold increase in HCV since cases of HIV-positive MSM with acute HCV Phylogenetic analysis (n = 24) identified 2 clusters, which are not related to other Dutch risk groups 18 reported unsafe sex practices or mucosal-damaging STDs Out of 20 surveyed, all denied IDU

56 clinicaloptions.com/hiv HIV/AIDS Update From Rio Increase in HCV RNA Detection After HAART Initiation Analysis of HCV/HIV- coinfected pts in the HOMER cohort 20% of patients who were HCV-Ab (+)/HCV RNA (-) pre-HAART became HCV RNA (+) after HAART Possible explanations –Blips –Laboratory variation, error –Immune restoration Braitstein P, et al. IAS Abstract TuPe1.1C30. Baseline samples tested with unambiguous results (n = 1186) PCR (+): 70% (n = 425) PCR (-): 30% (n = 179) HCV Ab (+) and PCR (+) after 6-12 mos of HAART: 20% (n = 24 of 118 evaluable samples) HCV-Ab (+): 51% (n = 606) HCV-Ab (-): 49% (n = 580)

57 clinicaloptions.com/hiv HIV/AIDS Update From Rio Complications in HCV/HIV-Coinfected vs HCV-Monoinfected Patients Miro J. IAS Abstract TuFo0303; Pineda JA et al, Hepatology. 2005, 41: Encepha- lopathy Variceal bleeding HCV/HIV coinfected HCV monoinfected Frequency as First Hepatic Decompensation (%) % 8% 4% 27% 66% 38% 11% 2% 3% 2% 17% 1% 4% AscitesJaundiceSBPHCC Hepatorenal syndrome P =.01 P <.001 P = NS P <.001 P =.02

58 clinicaloptions.com/hiv HIV/AIDS Update From Rio HCV-3 Coinfection Associated With Greater Risk of Hepatotoxicity N = 388 HIV/HCV-coinfected patients in Italian cohort – 132 had HCV genotype 3 Factors associated with risk of grade 3 hepatotoxicity – Male sex – HBsAg positivity – Baseline ALT – HCV genotype Time Since Entry (Years) Cumulative Proportion of Patients Free of Grade 3 Hepatotoxicity P <.001 HCV 3 HCV-3 Torti C, et al. ICAAC Abstract H-1484.

59 clinicaloptions.com/hiv HIV/AIDS Update From Rio Rapid Fibrosis Progression in HCV/HIV-Coinfected Patients Bonnard P, et al. EACS Abstract PE13.2/ F0/1F2F3F4 Patients (%) First biopsySecond biopsy Fibrosis Stage * Mean time between biopsies: 50 months *All patients were F1 at second biopsy. 9/32 (28%) of HCV/HIV-coinfected patients progressed 2 fibrosis points between biopsies

60 clinicaloptions.com/hiv HIV/AIDS Update From Rio HAART and Liver Enzyme Elevations Meta-analysis of 20 publications of HIV-infected patients ± HCV coinfection Grade 2 or higher liver elevations noted Drug Class Patients With LEE,% NNRTI PIMixedBPI NRTI Overall P =.004 P =.025 P =.009 % LEE in HCV-Coinfected Patients by Drug Class Benhamou Y, et al. CROI Abstract 88.

61 clinicaloptions.com/hiv HIV/AIDS Update From Rio Response to Treatment During Acute HCV in HIV-Coinfected Patients 59% SVR among pts with acute HCV treated with 24 wks Peg-IFN alfa 2b + RBV –Similar to overall rate in treatment of chronic HCV in coinfected pts –Better for genotype 1 coinfected pts vs treatment during chronic infection –Lower than that with treatment of acute HCV in monoinfected pts High rate of spontaneous clearance w/o therapy (24%) Nelson M, et al. IAS Abstract TuPe1.1C All Patients (n = 27) Genotype 1 (n = 20) Genotype non-1 (n = 4) 67% 65% 100% 59% 55% SVR ETR Virologic Response (%) Peg-IFN (1.5 g/kg/wk) + RBV ( mg/day) for 24 weeks

62 clinicaloptions.com/hiv HIV/AIDS Update From Rio Low Numbers of HCV/HIV Patients Achieve SVR in an Urban HIV Clinic Retrospective analysis of Johns Hopkins HIV Clinic n = 6 (21%) of these attained SVR This represents 2.1% of those referred, or 0.7% of those with HCV Mehta S, et al. CROI Abstract 884. n = 125 entered evaluation for treatment n = 277 referred (33%) n = 29 initiated treatment n = 845 with HCV

63 clinicaloptions.com/hiv HIV/AIDS Update From Rio Use of QuantiFERON-TB Gold in HIV-Infected Patients QuantiFERON-TB Gold, new blood- based diagnostic test for TB infection –Uses peptides absent from BCG and common non-tuberculous mycobacteria –CDC recommends that QFT-G be used in all circumstances in which the TB skin test is currently used [1] –Sensitivity unknown in HIV population Evaluated in 590 HIV-infected pts [2] –27 QFT-G positive Limitations –No comparison with skin testing –No means of assessing true TB infection rate 1. Mazurek GH, et al. MMWR Morb Mortal Wkly Rep. 2005;54(RR- 15): Brock I, et al. ICAAC Abstract H Patients (%) > QTF-G(-) (n = 543) QTF-G(+) (n = 27) Mean CD4+ Cell Count (cells/mm 3 )

64 clinicaloptions.com/hiv HIV/AIDS Update From Rio Hepatotoxicity with Rifampin + SQV/r 2/05 FDA letter warning of risk of hepatotoxicity when hard-gel SQV/r taken with rifampin in healthy volunteers Confirmed by data in TB/HIV-coinfected patients –Prospective study of 20 coinfected patients who began SQV/RTV (400/400 BID) 30 days into TB treatment [1] –14 pts discontinued during TB-HIV therapy phase due to ARV intolerance (mostly hepatic and gastrointestinal events) –Chart review of 12 coinfected pts on rifampin who began SQV/r (1000/100 BID) + 2 NRTIs during induction phase [2] –6 experienced hepatotoxicity –3 cases moderate to severe; all had HCV –1 pt permanently discontinued antiretroviral treatment 1. Rolla V, et al. IAS Abstract WePe3.3C Duran A, et al. IAS Abstract TuPe7.1C22.

65 clinicaloptions.com/hiv HIV/AIDS Update From Rio EuroSIDA: Liver-Related Deaths in HIV-Infected Patients Death rates from liver-related disease appear to have decreased in Europe ( /5) –After adjusting for CD4+ cell count, small in liver disease–related deaths noted HAART exposure associated with liver disease– related death after adjusting for CD4+ cell count –May be due to ARV-induced liver toxicity, progression of liver disease in HBV- or HCV-coinfected patients as patients survive longer, or other factors Lundgren J, et al. EACS Abstract PS7/2.

66 clinicaloptions.com/hiv HIV/AIDS Update From Rio Predictors of Anal Dysplasia in HIV-Positive and HIV-Negative MSM UCSD anal dysplasia screening clinic [1] –Pap screening not associated with decreased prevalence of invasive anal cancer, although earlier stage at detection suggested –Pap correlated with biopsy (increasingly so with increased operator experience) Anal dysplasia referral population study [2] –36% of HIV-positive men and 30% of HIV-negative men had high-grade anal dysplasia –Pap results did not correlate with biopsy –ARV use and duration not predictive of high-grade anal dysplasia 1. Press N, et al. CROI Abstract Montaner J, et al. CROI Abstract 807.


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