New Antiretroviral Therapies and Classes. Douglas G. Fish, MD Albany Medical College Albany, NY Cali,, Colombia March 29, 2007

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1 New Antiretroviral Therapies and Classes Douglas G. Fish, MD Albany Medical College Albany, NY Cali,, Colombia March 29, 27

2 Overview New therapies existing classes Investigational antiretrovirals Monoclonal antibody Maturation inhibitor Integrase inhibitors CCR5 inhibitors CXCR4 inhibition HBV: Entecavir HIV activity?

3 Credit Clinical Care Options, LLC and Medical Education Collaborative Website:

4 The 14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California February 25-28, 27 Slides with this color scheme were downloaded from: 4

5 Targets of HIV Therapy Entry Inhibitors: Fusion Inhibition Nucleus Integrase Inhibitors Entry Inhibitors: CCR5 & CXCR4 blockers HIV RNA Reverse transcriptase DNA Protease CD4+ T-Cell Reverse transcriptase inhibitors: NRTIs (nucleosides, nucleotides) NNRTIs Protease inhibitors

6 RESIST 1 and 2: Week 96 Data From Phase III Studies of TPV/RTV Patients failing PI-containing HAART; VL > 1; any CD4+ Baseline genotypic resistance testing* Best PI choice HIV resistance expert panel Preselection of regimen by investigator: CPI + OBR (± ENF) Computerized randomization to OBR plus TPV/RTV arm CPI arm LPV/RTV, IDV/RTV, SQV/RTV, APV/RTV Failures in CPI arm after Week 8 eligible for TPV/RTV in rollover study *Entry criteria: 3-class experienced; 1 primary PI mutation: 3N, 46I/L, 48V, 5V, 82A/F/L/T, 84V, or 9M; 2 mutations: 33, 82, 84, or 9. Gazzard B, et al. Glasgow 26. Abstract P23. Hicks CB, et al. Lancet. 26;368:

7 CD4 Cell Responses at Week 48 (LOCF) p<.1 13 th CROI, Denver, CO 26 Hicks CB et al. Lancet 26;368:

8 Intracranial Hemorrhage (ICH) Incidence in tipranavir trials.26/1 person-years of exposure (95% CI.9,.82) Review of U.S. Veterans Healthcare System & Medi-Cal between October 1997 and December 23 VA:.7 Med-Cal.23.7 (.5,.1).23 (.2,.25) Similar rates to TPV pre-approval trials More common in age > 4 and persons with AIDS Fultz S et al. 14 th CROI, Los Angeles, 27; Abstract 819.

9 POWER 1 and 2: Study Design PI-, NRTI- and NNRTIexperienced 1 PI mutation (IAS-USA) PI-based regimen VL > 1 copies/ml Investigatorselected CPI(s) + OBR (without NNRTIs) Investigator-selected CPI(s) + OBR DRV/RTV 4/1 mg QD + OBR DRV/RTV 8/1 mg QD + OBR DRV/RTV 4/1 mg BID + OBR DRV/RTV 6/1 mg BID + OBR DRV/RTV 6/1 mg BID provided greatest virologic response in Wk 24 analysis; FDA-approved dose for treatment-experienced experienced pts VL, viral load; OBR, optimized background regimen (NRTIs ± enfuvirtide) Lazzarin A, et al. IAC 26. Abstract TUAB14.

10 Patients with VL <5 Copies/mL Over Time to Week 48 (ITT-TLOVR) Lazzarin A, et al. XVI IAC Toronto, Canada, Aug , 26; Abst. TUAB14.

11 POWER 1 and 2: % of Pts Achieving VL < 5 at Wk 24 on DRV/RTV* vs CPIs* Patients With VL < 5 copies/ml at Week 24 (%) % DRV/RTV 16% 12% FPV/RTV LPV/RTV 7% ATV/RTV 4% SQV/RTV n = * + Optimized background regimen = 2 NRTIs ± ENF Lefebvre E, et al. Glasgow 26. Poster P29.

12 POWER: Subgroup Analyses of Response to Darunavir/r 6/1 BID Overall ENF Used (Naive) ENF Not Used 3 Primary PI Mut No Sensitive ARVs in OBR POWER-1 Cohort [1] 22% (n = 18) 19% (n = 36) 9% (n = 35) % (n = 9) 17% (n = 12) Darunavir/r 6/1 BID 53% (n = 6) 18% (n = 6) 63% (n = 19) 56% (n = 34) 59% (n = 29) Control POWER-2 Cohort [2] 39% (n = 57) 7% (n = 53) 7% (n = 14) 3% (n = 2) 4% (n = 24) 35% (n = 23) 7% (n = 28) % (n = 7) 18% (n = 11) 64% (n = 14) Patients With HIV-1 RNA < 5 copies/ml at Wk 24 (%) (ITT NC=F) 1. Katlama C, et al. IAS 25. Abstract WeOaLB Wilkin T, et al. ICAAC 25. Abstract H Patients With HIV-1 RNA < 5 copies/ml at Week 24 (%) 1

13 Brecanavir (BCV, GW64385): Open-label, Phase II Study Investigational PI with activity in vitro vs. many PI- resistant viruses Open-label, single-arm study; n=31 BCV/RTV 3/1 mg BID for 48 weeks plus 2 NRTIs; 8- and 24-week interim analysis Entry criteria: ART-na naïve or - experienced HIV RNA >1 c/ml CD4+ >2 cells/mm 3 Virologic response ITT (MD=F) x <4 c/ml <5 c/ml Ward D, et al. 45 th ICAAC, Washington DC 25, #H-412

14 Brecanavir (BCV, GW64385): Open-label, Phase II Study At baseline: Median (IQR) HIV RNA: 4.71 ( ) log 1 c/ml; PI resistant group with HIV RNA 3.98 log Median (IQR) CD4+: 311 (26 46) cells/mm 3 6/31 patients PI resistant: median primary PI mutations 2, LPV fold-change of 8.31 Results ITT (MD-F) <4 and <5 c/ml: : 81% and 77%, respectively Larger phase II/III study in patients with higher-level PI resistance is ongoing Ward D, et al. 45 th ICAAC, Washington DC 25, #H-412

15 Brecanavir Resistance Brecanavir is chemically related to amprenavir and darunavir Similar resistance profiles to amprenavir and darunavir Tipranavir mutation V82L/T had limited effect on susceptibility to darunavir and brecanavir Elston R et al. 14 th CROI Los Angeles, 27; Abstract 62.

16 TMC125 - Etravirine Diaryl pyrimidine derivative an NNRTI In vitro characteristics Potent activity against HIV EC 5 WT HIV-1: 1.4 nmol/l < 5-fold 5 reduction in susceptibility against K13N, Y181C, Y188L, and L1I Phase 1 pharmacokinetics Elimination half-life: life: 3-4 hours Steady state attained within 5 days Metabolized by cytochrome P45 CYP3A Protein binding de Bethune MP, et al. ICAAC 2. Abstract Piscitelli S, et al. IWCPHIVT 22. Abstract 5.3.

17 Response to Etravirine in Patients With NNRTI and PI Resistance (ITT:NC=F) N = 199 HIV-infected patients with NNRTI resistance and 3 primary PI mutations Median fold NNRTI-R Nevirapine: 61 Efavirenz: 41 Etravirine: 1.7 Mean (± SE) Change in VL (log 1 c/ml) Weeks *P =.18 P = * -1.1 OBR alone (n = 4) Etravirine 4 mg BID (n = 8) Etravirine 8 mg BID (n = 79) Cohen C. British HIV Association, 26. Abstract 2.

18 Effect of Baseline Resistance on Response to Etravirine Number of Baseline NNRTI Mutations (Number of Patients) (n = 15) 1 (n = 18) 2 (n = 17) 3 (n = 29) Viral Load Reduction at Week 24 (log 1 copies/ml) Each of the following mutations, always in combination with up to 4 other mutations, was associated with a mean FC > 1 K11P, V179E, V179F, Y181I, Y181V, G19S, M23L For V179E, V179F, G19S, or M23L, the additional mutations always included Y181C when the FC > 1 No single NNRTI drug resistance mutation was associated with FC > 1 Required multiple mutations ( ( 4) Vingerhoets J, et al. Resistance Workshop, 26. Abstract 52.

19 PA-457: Investigational Maturation Inhibitor Disrupts a late step in gag processing involving conversion of the capsid precursor (p25) to a mature capsid protein (p24) Orally-bioavailable bioavailable, T ½ = 6 h 1-day dose-ranging study 25, 5, 1, 2 mg QD (n=6/arm)( vs placebo (n=8)( Entry criteria: CD4+ >2 cells/mm 3, HIV RNA 5 25, c/ml,, ART-na naïve or off >12 wks Beatty G, et al. 45 th ICAAC, Washington DC 25, #H-416d

20 PA-457: Investigational Maturation Inhibitor Results At BL: Median CD cells/mm 3 ; HIV RNA 4.73 log 1 c/ml VL with 2-day 2 delay after first dose, with peak VL 2 3 days after last dose Plasma concentration best predictor of response One outlier at 2 mg dose with good levels and no response No new resistance mutations or drug-specific AEs Phase II/III study to start in 26 Change from BL (log 1 ) DOSE (mg) PBO * Median Mean p=.2 p=.4 Beatty G, et al. 45 th ICAAC, Washington DC 25, #H-416d p<.1

21 TNX-355 Humanized murine mab 5A8 IgG subtype 4 Recognizes unique epitope in domain 2 of CD4 Inhibits post-binding entry of HIV-1

22 TNX-355.1: Virologic and Immunologic Effects of TNX mg/kg 25. mg/kg Mean Change in HIV-1 RNA (log 1 copies/ml) Mean Change in CD4+ Cell Count (cells/mm 3 ) Days Days Kuritzkes D, et al. J Infect Dis. 24;189(2):

23 Absorption, Metabolism and Excretion of MK Raltegravir MK-518: HIV-1 1 integrase strand transferase inhibitor 8 HIV males: Oral dose of 2 mg [14C]MK-518, in vitro studies used microsomes Results: Excreted in both urine (32%) and feces (51%) Eliminated principally via glucuronidation Main mechanism of clearance: UDP-UGT1A1 UGT1A1- mediated glucuronidation MK-518 is not expected to exhibit drug interactions with P45 enzymes Kassahun K, et al. 46th ICAAC, San Francisco, CA, Sept. 27-3, 26; Abst. A-372.

24 BENCHMRK 1 and 2: Trial Design 2 identical ongoing Phase III studies (in different countries) Randomized (2:1), double-blind, placebo controlled ART-Experienced adult patients Documented genotypic/phenotypic resistance to 1 drug in each of 3 classes (NNRTI + NRTI + PI) HIV RNA > 1 copies/ml Raltegravir (4 mg BID) + OBT (n=462) Placebo + OBT (n=237) Primary Endpoints (Week 16): HIV RNA and CD4 counts Adverse experiences Patients virologically failing after 16 weeks could enter open-label RAL arm Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 24

25 Baseline Patient Characteristics BENCHMRK 1 & 2 BENCHMRK-1 BENCHMRK-2 RAL (n = 232) Placebo (n = 118) RAL (n = 23) Placebo (n = 119) Mean Age, yrs (SD) % Male % Caucasian 46 (9) (8) (9) (8) 9 65 Mean CD4 Count, cells/mm 3 GM Viral Load, copies/ml (log 1 HIV RNA) % AIDS Median Yrs of Prior ARTs (median # ART) % Hep B+/% Hep C (4.6) (12) 8/ (4.5) 9 1 (12) 4/ (4.7) 91 1 (12) 1/ (4.7) 92 1 (12) 3/4 % GSS /1 % PSS /1 % new enfuvirtide in OBT % new darunavir in OBT 3/33 19/ /41 18/ /44 1/ /4 19/ GSS/PSS = total ART in OBT to which pt s virus showed geno/phenotypic sensitivity by Phenosense GT assay. Enfuvirtide and darunavir use in naïve patients were each counted as + 1 active agent and added to GSS/PSS Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 25

26 Percent <4 and <5 Copies/mL (ITT, NC=F) BENCHMRK 1 & 2 1 RAL <4 RAL <5 BENCHMRK 1 Placebo <4 Placebo <5 1 BENCHMRK 2 % of Patients <4 Copies/mL Weeks (P<.1 at Week 16 for all parameters) Weeks Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 26

27 BENCHMRK 1 & 2 Combined Efficacy (1) % Patients with HIV RNA <4 copies/ml at Week 16 by Selected ARTs in OBT* Subgroup n % of Patients Overall Efficacy Data Efficacy by ARTs in OBT Enfuvirtide Darunavir : First Use in OBT - : No Use in OBT * BENCHMRK 1 & 2 with virologic failures carried forward RAL Placebo Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 27

28 BENCHMRK 1 & 2 Combined Efficacy (2) % Patients with HIV RNA <4 copies/ml at Week 16 by PSS/GSS of OBT* Subgroup n % of Patients Overall Efficacy Data (PSS) 1 2 or more (GSS) 1 2 or more : First Use in OBT - : No Use in OBT * BENCHMRK 1 & 2 with virologic failures carried forward RAL Placebo Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 28

29 BENCHMRK 1 & 2 Combined Efficacy (3) % Patients with HIV RNA <4 copies/ml at Week 16 by Baseline HIV RNA and CD4 Cell Count* Subgroup n % of Patients Overall Efficacy Data Baseline Plasma HIV RNA (copies/ml) < 1, > 1, Baseline CD4 Cell Counts (cells/mm3) 5 > 5 and 2 > * BENCHMRK 1 & 2 with virologic failures carried forward RAL Placebo Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 29

30 Clinical Adverse Events (%) BENCHMRK 1 & 2 BENCHMRK-1 BENCHMRK-2 Adverse Experiences RAL (n = 232) Placebo (n = 118) RAL (n = 23) Placebo (n = 119) Mean Exposure (weeks) Any AE Drug-related* AE Serious AE Serious drug-related* AE Death AE leading to discontinuation *Drug-related = any grade; relationship to drug by investigator to RAL/placebo ± OBT or to OBT alone; No significant differences between arms for any AE Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 3

31 Drug Related Clinical Adverse Events (%) (3% - mild, moderate and severe) BENCHMRK 1 & 2 BENCHMRK-1 BENCHMRK-2 RAL (n = 232) Placebo (n = 118) RAL (n = 23) Placebo (n = 119) Mean Exposure (Wks) Abdominal Distension Abdominal Pain Diarrhea Nausea Headache Fatigue Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 31

32 Laboratory Abnormalities (%) ( 1 % in at least one treatment group) BENCHMRK 1 & 2 BENCHMRK-1 BENCHMRK-2 Test Toxicity Criteria* RAL (n = 232) Placebo (n = 118) RAL (n = 23) Placebo (n = 119) ANC Hgb <75 c/ul <7.5 gm/dl LDL-C** Chol** TG** 19 mg/dl >3 mg/dl >75 mg/dl Creatinine Panc. Amylase 1.9 x ULN 2.1 x ULN AST x ULN (Gr 2) 5.1 x ULN ALT x ULN (Gr 2) 5.1 x ULN *Grade 3 or 4 per DAIDS toxicity criteria for all tests except grade 2-4 for AST and ALT **Fasting Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 32

33 Elvitegravir (GS 9137) Study Design Phase II study Randomized, partially-blinded (EVG dose) 278 ARV-experienced patients HIV RNA 1 copies/ml; Any CD4 cell count; 1 protease resistance mutation All patients received OBT* Stratified by T-2 use in OBT CPI** (n=63) EVG (2mg) (n=71) EVG (5mg) (n=71) EVG (125mg) (n=73) Primary endpoint: time-weighted average change from baseline in HIV RNA through 24 weeks (DAVG 24 ) *OBT = NRTIs +/- T-2; NNRTIs not allowed in OBT; PIs initially barred in EVG arms **CPI included 49% darunavir, 27% tipranavir Zolopa A, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst. 143LB. 33

34 EVG: Phase II Study Outcomes EVG (2 mg) stopped due to inferior outcomes EVG (5 and 125mg) superior to a boosted PI at week 16 ITT CPI/r 5 mg 125 mg DAVG 16 mean log drop (P=.9) (P=.1) All patients allowed to add a boosted PI as drug-drug interaction data available DAVG: Time-weighted average change from baseline in HIV RNA Zolopa A, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst. 143LB. 34

35 Adverse Events and Laboratory Abnormalities EVG: Phase II Week 24 CPI (n = 63) EVG 2 mg (n = 71) EVG 5 mg (n = 71) EVG 125 mg (n = 73) AEs leading to Drug D/C 2 (3%) 1 (1%) 2 (3%) 1 (1%) Grade 3/4 AEs 9 (14%) 13 (18%) 9 (13%) 1 (14%) Grade 3/4 lab abnormalities 2 (32%) 21 (3%) 15 (21%) 15 (21%) Zolopa A, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst. 143LB. 35

36 Integrase Resistance Mutations Data from Merck Phase III studies 1 : Virologic rebound in 16% RAL versus 51% on control arm Two pathways to resistance: Primary N155H Q148K/R/H Secondary E92Q, V151I, T97A, G163K, L74M G14S/A, E138K Elvitegravir resistance mutations in vitro 2 Two pathways to resistance: Primary T66I E92Q Secondary F121Y, S153Y, R263K S147G, H51Y, E157Q Concern for cross resistance between these by in vitro fold change 1. Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 15aLB and 15bLB. 2. Jones G, et al. Ibid. Abst

37 MOTIVATE 1 & 2: Trial Design MOTIVATE 1& 2 2 identical ongoing Phase IIb/III studies Randomized (1:2:2), double-blind, placebo controlled 176 ARV-experienced patients R5 HIV-1 infection (44% screen failures) HIV-1-RNA 5, copies/ml Stable pre-study ARV regimen, or no ARVs for 4 weeks Resistance to and/or 6 months experience with 1 ARV from 3 classes ( 2 for PIs) All received OBT* Stratified by ENF use and HIV-1 RNA < and 1, copies/ml Placebo (n=29) MVC 15mg QD (n=414) MVC 15mg BID (n=426) Primary endpoint at 24 weeks: Mean change from baseline in HIV-1 RNA *OBT = optimized background therapy of 3 6 ARVs (PK boosting doses of RTV not counted as an ARV) Pts receiving a PI (except TPV) and/or delavirdine in their OBT received 15 mg of MVC, all others received 3 mg of MVC Nelson M and Lalezari J, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 14aLB and 14bLB. 37

38 Demographics and Baseline Characteristics MOTIVATE 1 Treated N = 585 Placebo (n = 118) MVC QD (n = 232) MVC BID (n = 235) Mean age, yrs (range) 46 (31 71) 46 (19 75) 46 (25 69) Male, n (%) 16 (9) 21 (91) 212 (9) White, n (%) 99 (84) 187 (81) 197 (84) Median CD4 count*, cells/mm 3 (range) Mean HIV-1 RNA*, log 1 copies/ml (range) 163 (1 675) 4.84 ( ) 168 (1 812) 4.85 ( ) 15 (2 678) 4.86 ( ) Enfuvirtide in OBT, % active drugs in OBT, % Two patients (1 MVC QD, 1 placebo) were assigned to the wrong treatment group due to a transcription error * Calculated for each patient as the mean of up to three pre-dose assessments (screening, randomization, and baseline) According to overall susceptibility score Nelson M, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst. 14aLB. 38

39 39

40 MOTIVATE 1& 2 Percentage of Patients with HIV-1 RNA < 5 copies/ml by Number of Active Drugs in OBT* Patients (%) N= Placebo + OBT MVC QD + OBT MVC BID + OBT Number of active drugs in OBT* * Based on overall susceptibility score (LOCF) Nelson M and Lalezari J, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 14aLB and 14bLB. 4

41 Safety Analyses Unadjusted for Duration of Exposure MOTIVATE 1 All causalities and severities Placebo + OBT N = 118 MVC QD + OBT N = 232 MVC BID + OBT N = 235 Total exposure, patient-years Patients with AEs 84% 88% 91% Patients discontinuing due to AEs 5% 5% 4% Patients with grade 3 AEs 24% 16% 21% Patients with grade 4 AEs 7% 8% 9% Patients with SAEs 17% 13% 16% Patients with Category C events 4% 4% 3% Deaths*.9%.9%.4% Nelson M, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst. 14aLB. 41

42 Number of Category C Events MOTIVATE 2 Event, n Placebo (n = 91) MVC QD (n = 182) MVC BID (n =+ OBT N = 191 Total exposure, patient-years Herpes virus infection Esophageal candidiasis Cytomegalovirus (CMV) infection* 1 Mycobacterium avium 2 1 Recurrent bacterial pneumonia 3 Pneumocystis jiroveci pneumonia 1 Mycobacterial infection 1 Cryptosporidium enteritis 1 Kaposi s sarcoma Lymphoma 1 1 Total number of events Patients (% of patients) 9 patients (9.9%) 16 patients(8.8%) 11 patients(5.8%) * Includes CMV infection, CMV gastrointestinal infection, and CMV retinitis Lalezari J, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst. 14bLB. 42

43 MOTIVATE 1& 2 Change in CD4 Cell Count from Baseline to Time of Treatment Failure Tropism result, Baseline Treatment Failure All treatment failures R5 R5 R5 D/M or X4 Mean change in CD4 count from baseline, cells/mm 3 in patients with treatment failure Placebo (n = 29) +14 (n = 97) +15 (n = 8) +67 (n = 4) MVC QD (n = 414) +49 (n = 68) +61 (n = 18) +37 (n = 31) MVC BID (n = 426) +71 (n = 77) +138 (n = 17) +56 (n = 32) Approximately 8% of patients had a change in tropism result between screening and baseline, demonstrating the change in background tropism over a 4 6 week period in this population Response to maraviroc treatment in these patients was consistent with the results of study A4129 in patients with D/M-tropic virus 2 Data excludes patients who had no tropism result at time of failure and patients with non-r5 virus at baseline 1. Nelson M and Lalezari J, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Absts. 14aLB and 14bLB. 2. Mayer H, et al. XVI IAC, Toronto, Canada, Aug , 26, Abst. THLB

44 XACT Study CXCR4 inhibitor AMD117 Design: AMD117 dose finding study Results: AMD117 monotherapy x 1 days in 1 pts with CXCR4 (X4) virus AMD117 dose: 2mg BID (n=8) or 1mg BID (n=2) 4 of 9 pts achieved 1 log 1 c/ml reduction in X4 rlu* after 1 days of Tx Responders achieved a median 1.5 log 1 c/ml reduction in X4 rlu (Range: -.72 to -1.9) No significant changes in CD4, CD34, HIV viral load, WBC and R5 rlu* were observed Well tolerated with no drug-related serious adverse events (AEs) or > grade 2 drugrelated AEs observed AMD117 was recently placed on clinical hold by the FDA: liver histology changes observed in animal toxicology *relative luminescence units Moyle G, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst

45 Entecavir: HIV Activity? Entecavir (ETV) previously thought to have no HIV activity Study evaluating ETV in HIV ETV potently inhibits HIV in vitro at an IC5 between.1 and 1 nm 3 HIV/HBV pts Tx d with ETV had significant decline in HIV RNA of ~1-3 log 1 copies/ml 1 pt had emergence of M184V mutation while samples for other 2 pts not available At start of ETV, and at 4 and 6 months following start, %, 61% and 1% of HIV clones harbored M184V ETV may have some anti-hiv activity and use of it in HIV/HBV coinfected patients not on HAART may lead to HIV resistance ETV package insert has been modified to reflect this concern McMahon M, et al. 14th CROI, Los Angeles, CA, February 25-28, 27. Abst. 136LB. 45

46 Conclusions New protease inhibitors potent and durable New NNRTI potent if < 3 NNRTI mutations New classes of integrase inhibitors and CCR5 antagonists will likely change treatment paradigms over the next 5 years.