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44th ICAAC. ANTIRETROVIRAL TREATMENT HIGHLIGHTS. An HIV/AIDS Overview from the 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy October 30 - November 2, 2004; Washington, DC. Summarized by Douglas J. Ward, MD, FACP Dupont Circle Physicians Group, Washington, DC.

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  1. 44th ICAAC ANTIRETROVIRAL TREATMENT HIGHLIGHTS An HIV/AIDS Overview from the 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy October 30 - November 2, 2004; Washington, DC Summarized by Douglas J. Ward, MD, FACP Dupont Circle Physicians Group, Washington, DC Supported by an unrestricted educational grant from

  2. 44thICAAC ANTIRETROVIRAL TREATMENT HIGHLIGHTS • New Findings on: • Virologic Monitoring and Drug Resistance • Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Options and Regimens for First- and Second-line Therapy • Simplification/Switch Strategies for Patients With Virologic Suppression • Current and Investigational Protease Inhibitors in First- and Second-line Therapy • CCR5 Antagonists and Viral Tropism

  3. Virologic Monitoring and Drug Resistance

  4. Intermittent Low-Level HIV-1 Viremia (“Blips”) in Virologically Controlled Patients Viremic “blips” during antiretroviral therapy do not appear to result in evolution of resistant virus or virologic failure. • 10 patients with HIV-1 RNA < 50 copies/mL for 11-79 months • Viral loads measured 3 times weekly for 3-4 months • Each test read by 2 independent labs • 18 blips detected in 9 patients • Only 1 confirmed by both labs • No significant genotypic changes detected • No correlation found with any demographic, clinical, or treatment-related factor Viremic blips are common, do not predict treatment failure or development of resistance, and likely represent laboratory variation in the majority of cases. Nettles RE, et al. 44th ICAAC, 2004. Abstract H-1134.

  5. Frequency and Characteristics of the NRTI-Associated K65R and L74V/I RT Mutations M184V/I T215Y/F M41L D67N K219Q/E/N/R K70R L210W L74V/I K65R Y115F Q151M T69ins Frequency of NRTI-Associated Mutations in 2003 (ViroLogic Database) 44% 31% 25% 20% 20% 16% 15% 12% 4% 2% 1% 1% 0 5 10 15 20 25 30 35 40 45 50 % Genotypes (n > 16,000) McColl DJ, et al. 44th ICAAC, 2004. Poster H-178.

  6. Frequency and Characteristics of the NRTI-Associated K65R and L74V/I RT Mutations K65R + M184V K65R + NAMs K65R alone 100 99 97 96 96 100 85 83 80 71 62 60 % Above Cut-off 40 29 22 20 13 13 6 0 2 1 0 0 ZDV(1.9) d4T(1.7) TDF(1.4) ABC(4.5) ddl(1.7) 3TC(3.5) NRTIs (PhenoSense cut-off) Phenotypic NRTI Resistance of HIV-1 Variants With K65R McColl DJ, et al. 44th ICAAC, 2004. Poster H-178.

  7. Frequency and Characteristics of the NRTI-Associated K65R and L74V/I RT Mutations 100 100 92 85 85 79 80 63 57 60 55 % Above Cut-off 36 40 29 20 0 0 0 0 3 0 0 0 0 ZDV(1.9) 3TC(3.5) d4T(1.7) TDF(1.4) ABC(4.5) ddl(1.7) NRTIs (PhenoSense cut-off) L74V/I alone L74V/I + M184V L74V/I + NAMs Phenotypic NRTI Resistance of HIV-1 Variants With L74V/I McColl DJ, et al. 44th ICAAC, 2004. Poster H-178.

  8. Predictors of K65R With Tenofovir in Antiretroviral Therapy (ART)-Experienced and -Naive Patients In patients taking tenofovir, emergence of the K65R drug resistance mutation was associated with the absence or presence of other specific regimen components. • 258 ART-experienced and 37 ART-naive patients • median follow-up, 67 weeks • K65R developed in 29 (11%) ART-experienced persons • 28 had virologic failure • No K65R in ART-naive persons • Taking triple-NRTI regimens including tenofovir increased risk of K65R • Tenofovir/didanosine + lamivudine or emtricitabine • Tenofovir/abacavir + lamivudine or emtricitabine • Taking tenofovir with zidovudine or lamivudinereduced risk of K65R Staszewski S, et al. 44th ICAAC, 2004. Poster H-177.

  9. Prevalence of Transmitted HIV Drug Resistance in ART-Naive Individuals in the United States in 2003 Proportion of Patients With Reduced Susceptibility to > 1 Drug (N = 317) 23% Any ARV 0.9% > 1 NRTI 18% > 1 NNRTI 10% 1 NNRTI 3% NRTI mutations: 15% • V118I (4%), D67N (1%), M41L (or mix, 1%) NNRTI mutations: 6% • K103N (3%), G190A (or mix, 1%), V108I (or mix, 1%) Primary PI mutations: 4% • None > 1% 2 NNRTI 6% 3 NNRTI 6% > 1 PI 4% 1 PI 0.9% 2 PI 0.3% 3 PI 0 5 10 15 20 25 % Subjects Ross LL, et al. 44th ICAAC, 2004. Poster H-173.

  10. Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Options and Regimens for First- and Second-line Therapy

  11. A single-class, quadruple-NRTI regimen was shown to be equivalent to a standard, 2-class efavirenz-based regimen for first-line therapy. Moyle G, et al. 44th ICAAC, 2004. Abstract H-1131. Trizivir + Tenofovir vs Combivir + Efavirenz in ART-Naive Patients TIMS: 48-week randomized, open-label trial • 113 ART-naive subjects were randomized to receive: or • Baseline characteristics were comparable, including:

  12. Trizivir + Tenofovir vs Combivir + Efavirenz in ART-Naive Patients Moyle G, et al. 44th ICAAC, 2004. Abstract H-1131. Proportion of Subjects With HIV-1 RNA <50 Copies/mL Through Week 48 (ITT, M=F) 100 80 68 % 67 % 60 % Subjects 40 EFV+ZDV/3TC 20 Quad-NRTI 0 0 4 8 12 24 36 48 Treatment Time (Weeks) • Total cholesterol decreased significantly in Quad-NRTI arm: -0.2 mmol/L vs +0.8 mmol/L (P <.001) • 1 virologic failure (Quad-NRTI) ITT , intention-to-treat analysis; M=F, missing equals failure

  13. 100 85 80 71 65 61 54 60 46 40 20 0 Overall BL VL <100,000 BL VL > 100,000 ITT M=F AT DeJesus E, et al. 44th ICAAC, 2004. Poster H-564. Trizivir + Tenofovir in ART-Naive Subjects: COL40263 Proportion of Subjects With HIV-1 RNA <50 Copies/mL at Week 24 • 27 subjects (22%) discontinued study • 12 (9.8%) due to adverse events • 9 (8%) had grade 3/4 lab abnormalities • 8 (7%) had suspected ABC hypersensitivity • Reductions in lipids were observed • 8 virologic nonresponders • >1 TAMs only, 3 • >1 TAMs+M184V, 3 • Wild-type, 2 % Subjects ITT, intention-to-treat analysis; M=F, missing equals failure; AT, as treated

  14. Rodriguez AE, et al. 44th ICAAC, 2004. Poster H-563. Trizivir + Tenofovirin Patients With Early Virologic Failure on Initial Regimen: ESS30005 Zidovudine/lamivudine/abacavir (Trizivir) + tenofovir may be a viable rescue option for patients with early virologic failure on a standard initial regimen. ESS30005: Open-label study • 51 patients with early virologic failure (VL >400 but <10,000 copies/mL) • Failing regimens: zidovudine (or stavudine)/lamivudine + PI or NNRTI • Baseline characteristics: • Median HIV-1 RNA: 3.3 log10 copies/mL (68% <5000 copies/mL) • Median CD4+ cell count: 436 cells/mcL (37% > 350 cells/mcL) • < 2 NRTI mutations: M184V (82%), TAMs (24%), no K65R • 43 patients (84%) completed > 24 weeks of follow-up

  15. 93% 80% 75% 65% Obs <400 Obs <50 ITT M=F <400 ITT M=F <50 Rodriguez AE, et al. 44th ICAAC, 2004. Poster H-563. Trizivir + Tenofovirin Patients With Early Virologic Failure on Initial Regimen: ESS30005 Proportion of Subjects With HIV-1 RNA <50 Copies/mL Through Week 24 100 80 60 % Subjects 40 20 0 0 4 8 12 16 20 24 Treatment Time (Weeks) ITT, intention-to-treat analysis; M=F, missing equals failure; Obs, observed analysis

  16. Gazzard B, et al. 44th ICAAC, 2004. Abstract H-1137c. Tenofovir/Emtricitabine + Efavirenz vs Combivir + Efavirenz in ART-Naive Patients Better overall responses were seen with tenofovir/emtricitabine than with zidovudine/lamivudine (Combivir) in the preliminary analysis of this head-to-head study. Study 934: Open-label, randomized, noninferiority study • Planned 24-week analysis (96-week study) • ART-naive patients were randomized to receive: or • Baseline characteristics were comparable, including:

  17. Tenofovir/Emtricitabine + Efavirenz vs Combivir + Efavirenz in ART-Naive Patients Gazzard B, et al. 44th ICAAC, 2004. Abstract H-1137c. Time to Loss of Virologic Response (TLOVR) <50 Copies/mL (ITT) 100 P = .038 80 73% 65% 60 % Subjects 40 20 0 0 4 8 16 24 Treatment Time (Weeks) TDF/FTC ZDV/3TC ITT, intention-to-treat analysis

  18. Gazzard B, et al. 44th ICAAC, 2004. Abstract H-1137c. Tenofovir/Emtricitabine + Efavirenz vs Combivir + Efavirenz in ART-Naive Patients Patient Disposition Through Week 24 * P = .003 † P = .008 • 5% (vs 0% ) discontinued due to anemia in the Combivir arm Significantly better overall response with tenofovir/emtricitabine due to fewer adverse events leading to fewer discontinuations in that arm

  19. 100 80 % Subjects 69% 60 ABC/3TC+EFV 40 Terminated ABC/3TC+TDF 20 0 0 4 8 12 16 20 24 Efficacy of Fixed-Dose Abacavir/Lamivudine + Efavirenz: ESS30009 Proportion of Subjects With HIV-1 RNA <50 Through Week 24 (ITT, M=F) Treatment Time (Weeks) • Abacavir/lamivudine + tenofovir stopped due to a 49% failure rate • Patients in that arm were assigned new regimens and followed • ABC/3TC/EFV (35%), ABC/3TC/TDF/ZDV (15%), ZDV/3TC/EFV (11%), • ABC/3TC/ZDV/EFV (9%), TDF/3TC/ZDV/EFV (5%) ITT, intention-to-treat analysis; M=F, missing equals failure Gallant JE, et al. 44th ICAAC, 2004. Poster H-567.

  20. 100 80 60 % Subjects 40 Obs <400 Obs <50 ITT M=F <400 ITT M=F <50 20 0 2 4 8 12 Treatment Time Post Switch (Weeks) Virologic Response Following Switch to Second-line Regimens up to 12 Weeks Efficacy of Subsequent Treatment of Tenofovir + Abacavir/Lamivudine Nonresponders: ESS30009 • Predictors of a 12-week post-switch viral load < 50 copies/mL: • Baseline viral load: OR, 0.163; P = .001 • Abacavir use: OR, 7.731; P = .009 • Efavirenz use: OR, 5.797; P = .015 • Zidovudine use: OR, 5.032; P = .022 ITT, intention-to-treat analysis; M=F, missing equals failure; Obs, observed Gallant JE, et al. 44th ICAAC, 2004. Poster H-567.

  21. Early Virologic Failure With Once-Daily Didanosine/Tenofovir/Efavirenz in ART-Naive Patients Didanosine/tenofovir/efavirenz, but not didanosine/lamivudine/efavirenz, was associated with poor virologic responses in patients with high viral loads and low CD4+ cell counts. • In an open-label trial, ART-naive individuals were randomized to receive: • QD didanosine/tenofovir/efavirenz (n=41) • QD didanosine/lamivudine/efavirenz(n=36) • The study was terminated after an unplanned analysis at week 12 *P < .05 • Drug-resistant virus emerged rapidly in first 4 virologic failures • All 5 subjects with virologic failure had baseline VL >100,000 copies/mL and CD4+ cell count < 200 cells/mcL Moyle G, et al. 44th ICAAC, 2004. Poster H-566.

  22. Barrios A, et al. 44th ICAAC, 2004. Abstract H-1132. Tenofovir/Didanosine: Paradoxical CD4+ Cell Declines Despite Good Virologic Control The combined use of tenofovir + didanosine can cause CD4+ cell counts to fall, even as viral load goes down or remains undetectable. Retrospective assessment: 570 patients were taking TDF/ddI, TDF, ddI, or neither agent • All subjects had HIV RNA <400 copies/mL for >1 year (N=570) • Paradoxical CD4+ cell decreases seen only with TDF/ddI • not observed with TDF or ddI individually or with other NRTI • CD4+ cell decreases were more common in patients: • who switched to TDF/ddI to simplify regimen • on NRTI-only regimens that included TDF/ddI • with longer exposure to higher doses of ddI • Median CD4+ cell decline of 385 cells/mcL among subjects who switched to a triple-NRTI regimen containing TDF/ddI • CD4+ cell decreases appeared after ~6 months of TDF/ddI and then increased in magnitude

  23. Simplification/Switch Strategies for Patients With Virologic Suppression

  24. Switching From a PI- to a Once-Daily Efavirenz-Based Regimen: VEST-QD Once-daily efavirenz + didanosine/lamivudine appears to be a safe and effective option for virologically suppressed patients switching from a PI-based regimen. • VEST-QD: Interim results of an ongoing 48-week open-label trial • Patients with VL <50 copies/mL on PI regimens were randomized to: • Efavirenz + didanosine/lamivudine (all QD) • Efavirenz + current NRTIs (ZDV/3TC, 51%; d4T/3TC, 30%; other, 19%) Virologic Response at Week 24 (ITT NC=F): • 1 virologic failure (current-NRTI arm) • HDL-C levels increased in both arms (P < .0001) • Adherence improved in both arms (P < .05) • No difference between arms ITT, intention-to-treat analysis; NC=F, noncompletion equals failure Cohen C, et al. 44th ICAAC, 2004. Poster H-577.

  25. Trizivir vs Combivir + Nevirapine in Patients With Virologic Suppression: SimplifiHAART Two PI-sparing simplification strategies for patients with virologic suppression appear to be comparably safe and effective, and associated with improvements in cholesterol levels. • SimplifiHAART: 48-week randomized, open-label switch study • 134 patients with undetectable VL (not defined) for > 24 months were randomized to: • zidovudine/lamivudine/abacavir • zidovudine/lamivudine + nevirapine • ~90% were taking a PI-based regimen at baseline • Results through week 48 • 13 (19%) and 14 (21%) subjects discontinued due to side effects • 1 virologic failure in each arm ITT, intention-to-treat analysis; NC=F, noncompletion equals failure Bonjoch A, et al. 44th ICAAC, 2004. Poster H-562.

  26. Trizivir vs Combivir + Nevirapine in Patients With Virologic Suppression: SimplifiHAART Proportion of Patients with Elevated TC and LDL-C Levels at Baseline and Week 48 Bonjoch A, et al. 44th ICAAC, 2004. Poster H-562.

  27. Favorable Lipid Changes With Switch From Stavudine to Tenofovir: GS903E LDL-C HDL-C LDL-C/HDL-C TG TC 0 -0.2 -0.2 -4* -10 -6* -20 -17* Week 12 (n=85) -23* -30 Mean Change (mg/dL) *P < .001 Week 24 (n=83) -40 -38* -40* -44* -50 -60 -62* -70 Mean Changes in Fasting Lipid Parameters After d4T to TDF Switch • 85 patients substituted tenofovir for stavudine in rollover phase of GS903 • No patient lost viral suppression (<50 copies/mL) through 24 weeks post-switch • No patient discontinued due to adverse events Suleiman JMAH, et al. 44th ICAAC, 2004. Poster H-158.

  28. Current and Investigational Protease Inhibitors

  29. Favorable Increases in HDL-Cholesterol With Fosamprenavir in ART-Naive Patients: NEAT In the NEAT study, treatment with unboosted fosamprenavir + abacavir/lamivudine was associated with increases in high-density lipoprotein cholesterol (HDL-C) levels. • Secondary analysis of the 48-week NEAT study • Randomized, open-label study in ART-naive patients, comparing: • fosamprenavir 1400 mg + abacavir 300 mg/lamivudine 150 mg (n=166) • nelfinavir 1250 mg + abacavir 300 mg/lamivudine 150 mg (n=83) • Baseline lipids were similar, with relatively low HDL-C, in both arms • HDL-C and other lipid changes were observed through week 48: Nadler JP, et al. 44th ICAAC, 2004. Poster H-156.

  30. Fosamprenavir (n=148) Nelfinavir (n=72) 100% 10 27 21 27 80% 43 60% 49 40% 76 69 47 20% 24 0% BL Max. post- BL Max. post- BL BL <40 mg/dL >40 to <60 mg/dL >60 mg/dL Favorable Increases in HDL-Cholesterol With Fosamprenavir in ART-Naive Patients in the NEAT Study Increases in HDL-C to Maximum Post Baseline by NCEP Lipid Category % Subjects Nadler JP, et al. 44th ICAAC, 2004. Poster H-156.

  31. Tipranavir/Ritonavir vs Other Boosted PIs in ART- Experienced Patients: RESIST-1 Following 24 weeks of treatment, tipranavir/ritonavir appeared to be superior to other boosted PIs in patients with PI-resistant virus. RESIST-1: Randomized, controlled, open-label, phase 3 trial • Study participants had multiple PI experience and PI-resistant virus • failing a PI-containing regimen at entry •  1 primary PI mutation •  2 mutations at codon 33, 82, 84, or 90 • 620 patients were randomized to receive: or • 36.1% of subjects received enfuvirtide Hicks C, et al. 44th ICAAC, 2004. Abstract H-1137a.

  32. Tipranavir/Ritonavir vs Other Boosted PIs in ART- Experienced Patients: RESIST-1 Discontinuations and Adverse Events • More people discontinued a control PI than tipranavir, usually because of virologic failure: • Rates of grade 3/4 side effects were similar overall (22.8% and 18.1%) but differed significantly for certain parameters: * P < .001 † P < .01 Hicks C, et al. 44th ICAAC, 2004. Abstract H-1137a.

  33. 60 *P < .001 * 40 34.7 *P < .001 * % Subjects 25.1 * 16.5 20 * 10 0 Comparator PI Tipranavir < 50 copies/mL < 400 copies/mL Tipranavir/Ritonavir vs Other Boosted PIs in ART- Experienced Patients: RESIST-1 Virologic Responses at 24 Weeks (ITT, LOCF) ITT, intention-to-treat analysis; LOCF, last observation carried forward Hicks C, et al. 44th ICAAC, 2004. Abstract H-1137a.

  34. < 400 copies/mL < 50 copies/mL 60 47.1* *P < .001 32.8* 34.7 40 21.9* 25.1 % Subjects 14.3* 16.5 20 10.0 0 All +ENF All +ENF All +ENF All +ENF Comparator PI Tipranavir/r Tipranavir/Ritonavir vs Other Boosted PIs in ART- Experienced Patients: RESIST-1 Impact of Enfuvirtide (ENF) on Virologic Responses (ITT, LOCF) ITT, intention-to-treat analysis; LOCF, last observation carried forward Hicks C, et al. 44th ICAAC, 2004. Abstract H-1137a.

  35. CCR5 Antagonists and Viral Tropism

  36. 873140, a Novel CCR5 Antagonist: 10-Day Responses to Monotherapy Placebo (n=9) 200 QD 200 BID 400 QD 600 BID (n=7) (n=8) (n=8) (n=8) 0 -0.2 -0.12 -0.4 -0.46 -0.6 HIV-1 RNA (log10 copies/mL) -0.8 -1 -1.03 -1.2 -1.23 -1.4 -1.6 -1.66 -1.8 Median Change in Viral Load at Day 10 by Dose Group • 21 ART-experienced, 19 ART-naive subjects • HIV RNA >5000 copies/mL, CD4+ >200 cells/mcL, CCR5-tropic virus at baseline • No serious adverse events in any treatment group Lalezari J, et al. 44th ICAAC, 2004. Abstract H-1137b.

  37. 100 88 82 80 Total 67 ART-Naive 60 ART-Experienced 40 % Samples 28 16 20 12 5 2 0 0 R5 R5/X4 X4 n = 339 263 76 36 67 31 6 6 Tropism Distribution of Coreceptor Tropism According to Treatment Status Relative Distribution of HIV-1 Tropism Among ART-Naive and -Experienced Patients* * Source = 442 stored samples from GlaxoSmithKline clinical trials; 412 were successfully typed Demarest J, et al. 44th ICAAC, 2004. Abstract H-1136.

  38. 80 60 41.9 40 % X4 or R5/X4 40 16 16 14.8 20 0 > 300(n=248) > 201-300(n=104) > 101-200(n=81) > 51-100 (n=31) < 50 (n=50) CD4+ cell count (cells/mcL) Moyle G, et al. 44th ICAAC, 2004. Abstract H-1135. Distribution of Coreceptor Tropism According to CD4+ Cell Count Prevalence of R4- or R5/X4-Tropic Isolates by Absolute CD4+ Cell Count* * Source = 865 stored samples from Chelsea and Westminster Hospital, London; 616 were successfully typed

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