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Selected and summarized by Jeffrey P. Nadler, MD, FACP USF College of Medicine Tampa, Florida

Antiretroviral Treatment Highlights of the 11th Conference on Retroviruses and Opportunistic Infections (CROI) February 8-11, 2004; San Francisco, California. Selected and summarized by Jeffrey P. Nadler, MD, FACP USF College of Medicine Tampa, Florida.

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Selected and summarized by Jeffrey P. Nadler, MD, FACP USF College of Medicine Tampa, Florida

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  1. Antiretroviral Treatment Highlights of the 11th Conference on Retroviruses and Opportunistic Infections (CROI)February 8-11, 2004; San Francisco, California Selected and summarized byJeffrey P. Nadler, MD, FACP USF College of Medicine Tampa, Florida Supported by an unrestricted educational grant from

  2. Antiretroviral Treatment Highlights of the 11th Conference on Retroviruses and Opportunistic Infections New Data On: • Initial antiretroviral therapy • Treatment failure and second-line therapy • New and investigational agents • Complications of HIV infection and its therapy

  3. Initial Antiretroviral Therapy (1)Lopinavir/Ritonavir (LPV/RTV) Once Daily (QD) vs Twice Daily (BID):48-Week Data • LPV/RTV 800/200 mg QD+ QD emtricitabine/tenofovir DF (n = 115) • LPV/RTV 400/100 mg BID+ QD emtricitabine/tenofovir DF(n = 75) • Efficacy • Patients with HIV-1 RNA < 50 copies/mL (ITT): 70% vs 64% • Mean increase in CD4+ cell count (cells/mcL): 185 vs 188 Prospective, randomized, comparative study of 2 initial antiretroviral regimens • Adverse Events/Lipid Effects • Moderate-to-severe diarrhea: 16%vs 4%(P = .04) • Resulted in discontinuation of treatment: 12%vs 5% • Lipid elevations were common, but equivalent in study arms • Similar virologic and immunologic responses with QD andBID regimens; more adverse GI effects in QD arm Abstract 570

  4. Initial Antiretroviral Therapy (2)Once-Daily (QD) Didanosine (ddI) + Lamivudine (3TC) + Tenofovir DF (TDF) • 22 treatment-naive patients enrolled • 20 discontinued prematurely due to early virologic failure • Patients with resistance-associated mutations post-therapy (n = 20) • M184V/I: 20 (100%) • K65R: 10 (50%); 7 mixed with wild-type • Decrease in HIV-1 RNA at week 24 • 0.49 log10 copies/mL (median), despite absence of phenotypic TDF resistance • QD ddI+3TC+TDFproduced suboptimal responses and rapid emergence of resistance-associated mutations 24-week pilot study evaluating potency and safety of ddI+3TC+TDF Abstract 51

  5. Initial Antiretroviral Therapy (3)Once-Daily (QD) Abacavir (ABC) + Lamivudine (3TC) + Tenofovir (TDF): Tonus Study • Efficacy • Virologic failures (any timepoint):12/36 • 4 patients had early viral rebound > 0.7 log10 copies/mL • 8 patients never achieved HIV-1 RNA < 400 copies/mL • Virologic responders (HIV-1 RNA < 50 copies/mL at 24 weeks): 17/26 • All (8) patients who entered study with HIV-1 RNA < 10,000 copies/mL • 9 of 18 patients with baseline HIV-1 RNA > 10,000 copies/mL • High rate of early virologic failure similar to those observed in other recent studies of ABC+3TC+TDF Pilot study of 38 antiretroviral-naive patients treated with QD ABC+3TC+TDF Abstract 52

  6. Initial Antiretroviral Therapy (3) ContinuedOnce-Daily (QD) Abacavir (ABC) + Lamivudine (3TC) + Tenofovir (TDF): Tonus Study • Rapid selection of resistance-associated mutations • Virologic failure: HIV RT mutations in patients with virologic failure at 3-6 months (n = 12) • M184V + K65R: 11/12 • M184Vonly: 1/12 • No virologic failure: HIV RT mutations in patients with HIV-1 RNA < 400 copies/mL (n = 10) • M184V + K65R: 7/10 • M184Vonly: 2/10 • Plasma and intracellular drug levels • adequate plasma trough concentrations (Cmin), all drugs (week 4): 32/37 • detectable intracellular metabolites, all drugs: 8/14 • Results support a low genetic barrier to resistance as the major cause of virologic failure Abstract 52

  7. Initial Antiretroviral Therapy (4)Once-Daily (QD) Trizivir (TZV) + Tenofovir DF (TDF): COL40263 Early, interim analysis of a pilot study of QD quadruple-NRTI/NtRTI regimen in antiretroviral-naive subjects • 54/88 completed > 24 weeks’ follow-up at interim analysis • Median baseline HIV-1 RNA: 5.1 log10 copies/mL (52% ≥ 100,000 copies/mL) • Median baseline CD4+ cell count: 226 cells/mcL (37% < 200 cells/mcL) • Efficacy (24 weeks) • HIV genotypes in nonresponders: 2 WT, 1 K65R, 3 M184V + TAMS, 2 TAMS • Although preliminary, once-daily TZV+TDF may prove useful in patients with lower viral loads Abstract 53

  8. Treatment Failure and Second-line Therapy (1) Atazanavir (ATV)/Ritonavir (RTV) vs ATV/Saquinavir (SQV) vs Lopinavir (LPV)/RTV: BMS 045 (48-Week Results) • Patients randomized to receive: • ATV/RTV QD+ tenofovir DF + 1 NRTI (n = 120 ) • ATV/SQV QD+ tenofovir DF + 1 NRTI (n = 115 ) • LPV/RTV BID+ tenofovir DF + 1 NRTI (n = 123 ) • Efficacy • Overall,ATV/RTV was comparable in efficacy toLPV/RTV Ongoing, prospective study in patients with ≥ 2 prior HAART failures Abstract 547

  9. Treatment Failure and Second-line Therapy (1) Continued Atazanavir (ATV)/Ritonavir (RTV) vs ATV/Saquinavir (SQV) vs Lopinavir (LPV)/RTV: BMS 045 (48-Week Results) • Lipid effects (mean % change from baseline at week 48) • ATV regimens were generally associated with favorable lipid effects compared with LPV/RTV • Safety • Frequency of adverse events and discontinuations was similar across treatment arms • ATV/RTV wasassociated with hyperbilirubinemia (and some cases of jaundice) • Diarrhea was observed to occur with greater frequency in the LPV/RTVarm HDL-C = high-density lipoprotein cholesterol; LDC-C = low-density lipoprotein cholesterol. *P< .005 (ATV regimens vs LPV/RTV) Abstract 547

  10. New and Investigational Agents (1)Binding/Fusion Inhibitors

  11. New and Investigational Agents (2)Binding/Fusion Inhibitors

  12. New and Investigational Agents (3)Nucleoside/Nucleotide Analogs

  13. New and Investigational Agents (4)Additional Developmental Agents

  14. Complications of HIV Infection and Its Therapy (1)Hyperglycemia and Diabetes • This cohort study shows increased incidence and prevalence in prediabetes and diabetes in HIV-infected men exposed to HAART Prevalence of hyperglycemia examined in cohort of men enrolled in the Multicenter AIDS Cohort Study (MACS) • Analysis • data on 1107 men from April 1999 – September 2002 • 563 HIV-negative, 544 HIV-infected, 423 on HAART • Results • HIV-infected men on HAART had a 5-fold increased likelihood of hyperglycemia or diabetes • Incident risk was 2-fold compared with HIV-negative men • 1.8-fold risk increase with HIV infection alone, 3.1-fold with HAART • Drugs associated with increased risk (hazard ratio [95% CI]) • Protease inhibitors (1.9 [1.1-1.3]), stavudine (2.1 [1.1- 3.9]), and efavirenz (3.9 [1.6-9.5]) Abstract 73

  15. Complications of HIV Infection and Its Therapy (2)Predictors of Hypertension in HIV-Infected Patients in the D:A:D Study • Longitudinal assessment of potential patient- and treatment-related factors associated with differences in blood pressure (BP) and hypertension among HIV-infected adults • Results • 487 of 8341 patients with normal baseline BP developed hypertension • Incidence = 35.8/1000 person-years • Factors associated with increased risk for hypertension included the usual suspects: older age, male sex, higher body mass index, and higher baseline BP measurements • Predictors of hypertension subsequent to enrollment in the D:A:D cohort were assessed for 16,002 patients followed for a median of 1.5 years (range, 0.8-1.7) • 8341patients with normal BP at baseline were included in the primary analysis • Antiretroviral therapy was not a predictor of hypertension • By cumulative duration of exposure to each class of antiretroviral • By type of regimen at baseline • Antiretroviral therapy was not an independent prognostic factor of blood pressure changes or hypertension in this study Abstract 75

  16. Complications of HIV Infection and Its Therapy (3)Rosiglitazone (RSG) Therapy for Lipoatrophy • Double-blind, placebo-controlled 48-week trial of 108 HIV+ patients with lipoatrophy • Key findings (48 weeks; ITT) • RSG had no effect on mean limb fat changes (vs placebo): 0.14 kg vs 0.18 kg • No differences according to PI or thymidine analog use • Lipoatrophic patients (limb fat mass < 20%) randomized to • RSG 4 mg bid (max dose) (n = 53) or placebo(n = 55) • All patients were on stable antiretroviral therapy (≥ 3 months) including a PI and/or thymidine analog (zidovudine or stavudine) • RSG associated with significant adverse lipid effects • Mean increase in total cholesterol: 16% vs 0% (P = .0001) • Mean increase in triglycerides: 40% vs 7% (P = .007) • RSG associated with improvements in insulin sensitivity • Rosiglitazone not effective for the treatment of HIV/antiretroviral therapy-associated lipoatrophy Abstract 79

  17. Complications of HIV Infection and Its Therapy (4)Effects of Switching PI to NNRTI or Abacavir to Treat Lipodystrophy:NEFA Substudy • Metabolic outcomes at 24 months (% change from baseline) • Analysis from a randomized study of patients who substituted abacavir (ABC), efavirenz (EFV), or nevirapine (NVP) for PI LDL-C = low-density lipoprotein cholesterol; TC:HDL-C = Total cholesterol:high-density lipoprotein cholesterol ratio • Switch to any of the 3 treatments improved insulin resistance, total cholesterol (TC), LDL-C, and TC:HDL-C ratio • Slightly better changes in TC:HDL-C were seen with switch to either NNRTI vs ABC • Marked metabolic improvements were seen with switch to PI-sparing therapy Abstract 78

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