Selected and summarized by Joseph J. Eron, Jr, MD

1. Highlights of the42nd Interscience Conference onAntimicrobial Agents and ChemotherapySeptember 27-30, 2002; San Diego, California Selected and summarized byJoseph J. Eron, Jr, MD Associate Professor of MedicineUniversity of North Carolina at Chapel Hill Supported by an unrestricted educational grant from

2. Atazanavir vs Efavirenz: 48-Week Data in Naive Patients Study Outline • BMS AI424-034: randomized, double-blind, phase 3 trial of atazanavir vs efavirenz, each combined with zidovudine/lamivudine • Atazanavir: protease inhibitor; once-daily dosing; minimal effects on lipids in phase 2 studies; frequent increases in indirect bilirubin • Treatment-naive subjects (N = 810): • Baseline HIV-1 RNA  2000 copies/mL (median = 4.87-4.91 log10) • Baseline CD4+ cell count  100 cells/mm3 (median = 280-286) • 91 sites on 5 continents • Approximately one third female, two thirds nonwhite • Primary end point: % with HIV-1 RNA < 400 copies/mL during 48 weeks of follow-up, by intention-to-treat analysis Abstract: H-1076

3. Atazanavir vs Efavirenz: 48-Week Data in Naive Patients (2) Results at Week 48 • Key finding: atazanavir and efavirenz had equivalent antiviral efficacy: • At 48 weeks, 70% and 64%, respectively, had < 400 copies/mL • Surprisingly, only 32% and 37%, respectively, had < 50 copies/mL • Possible explanations for the low response to < 50 copies/mL: • Subjects who altered their NRTI treatment were counted as treatment failures • Subjects who achieved < 50 copies/mL but then experienced 2 subsequent consecutive values > 50 copies/mL were counted as treatment failures even if HIV RNA subsequently returned to < 50 copies/mL • Version 1.5 of the ultrasensitive assay was used outside of North and South America, and may give slightly higher results than version 1.0 of the assay • Larger CD4+ cell count increases with atazanavir (176 vs 160 cells/mm3) • I50I/L mutation emerged in 4 of 25 subjects with HIV-1 RNA > 400 copies/mL after week 24 whose virus was genotyped

4. Atazanavir vs Efavirenz: 48-Week Data in Naive Patients (3) Mean Change in Lipid Levels at Week 48 * P < .0001

5. Equivalence of Once-Daily and Twice-Daily Lamivudine Study Outline • Pivotalstudy that led to approval of once-daily dosing • Intracellular half-life of 3TC-triphosphate = approx. 16 hours • Treatment-naive subjects (N = 554): • Plasma HIV-1 RNA > 400 copies/mL (median = 4.65 log10) • CD4+ cell count > 100 cells/mm3 (median = 360) • Randomized to initiate therapy with either: • Once-daily lamivudine and twice-daily lamivudine placebo • Twice-daily lamivudine and once-daily lamivudine placebo …each combined with open-label efavirenz (QD) + zidovudine (BID) Abstract: H-161

6. Equivalence of Once-Daily and Twice-Daily Lamivudine (2) Results at Week 48 • Equivalent antiviral activity of once-daily and twice-daily dosing • No difference in adverse events • No difference in incidence of M184V among patients with virologic failure Abstract: H-161

7. Lipid and Toxicity Profile of Tenofovir DF vs Stavudine Study Outline • Gilead 903 study: previously reported equivalent efficacy of first-line therapy with either: • Tenofovir DF (QD) and stavudine placebo (BID), or • Stavudine (BID) and tenofovir DF placebo (QD) …each combined with open-label efavirenz (QD) + lamivudine (BID) • New 48-week analyses of: • Changes in lipid levels • Changes in lactate and mitochondrial DNA levels • Adverse events possibly related to mitochondrial toxicity Abstract: LB-2

8. Lipid and Toxicity Profile of Tenofovir DF vs Stavudine (2) Results at Week 48 • Significantly greater increases in fasting triglycerides, total cholesterol, and LDL cholesterol observed with stavudine • Significantly higher mean venous lactate levels with stavudine: • 1.9 vs 1.2 mmol/L • More peripheral neuropathy and investigator-determined lipodystrophy and lactic acidosis among stavudine recipients • Smaller increases in mitochondrial DNA levels in PBMCs with stavudine: • +28 vs +82 DNA copies/mL • possible marker of impact of therapy on mitochondrial function

9. Emtricitabine vs Stavudine in First-line Therapy Study Outline • FTC 301: randomized, double-blind, phase 3 trial of emtricitabine vs stavudine, each combined with enteric-coated didanosine + efavirenz • Emtricitabine: similar to lamivudine; once-daily dosing; long intracellular half-life; M184V leads to high-level resistance • Treatment-naive subjects (N = 571): • Median baseline HIV-1 RNA = 4.9 log10 copies/mL • Median baseline CD4+ cell count = 288 cells/mm3 • Study stopped by DSMB after mean of 42 weeks of follow-up: • All subjects had been enrolled > 24 weeks earlier • 52-week combined primary end point of virologic failure, AIDS diagnosis, death, or loss to follow-up was estimated by Kaplan-Meier analysis Abstracts: LB-1

10. Emtricitabine vs Stavudine in First-line Therapy (2) Results • Estimated 52-week combined primary end point was significantly greater with stavudine therapy • Fewer confirmed virologic failures with emtricitabine: • 4.7% vs 14.1% (P < .001) • More toxicity failures in the stavudine arm (P = .03) • Larger CD4+ cell count increase with emtricitabine: • 152 vs 117 cells/mm3 (P = .003) • Similar rates of adverse events: • Except efavirenz-related CNS symptoms significantly more frequent with stavudine

11. Fosamprenavir vs Nelfinavir in Initial Therapy Study Outline • Fosamprenavir (aka GW433908): • Amprenavir prodrug: efficiently converted to amprenavir in gut and liver • 2 pills twice daily: similar PK profile to AgeneraseTM (8 capsules twice daily) • Well tolerated with no food restrictions • Increased adverse events when given with zidovudine (?) • NEAT Study: randomized, double-blind, phase 3 trial of fosamprenavir vs nelfinavir, each combined with lamivudine + abacavir • Treatment-naive subjects (N = 251): • Median baseline HIV-1 RNA > 4.8 log10 copies/mL • Median baseline CD4+ cell count = approx. 210cells/mm3 • Preliminary, 24-week data presented Abstracts: H-166

12. Fosamprenavir vs Nelfinavir in Initial Therapy (2) Key Results • Higher rates of < 400 and < 50 copies/mL at week 24 with fosamprenavir • Difference betweenarms was more pronounced amongsubjects with viral load> 100,000 copies/mLat baseline • Modest increases in total cholesterol and LDL cholesterol in both arms • No change in triglyceride levels with fosamprenavir Proportion < 400 copies/mL over time

13. 4-Year Durability of First-line Lopinavir/Ritonavir Study Outline • Longest prospectively studied group of lopinavir/ritonavir recipients: • 100 antiretroviral-naive patients initially treated with 1 of 3 doses of lopinavir/ritonavir, plus stavudine and lamivudine • At week 48, all switched to open-label lopinavir/ritonavir (400 mg/100 mg) • Continued follow-up every 3 months Results at Week 204 • 28 discontinuations, 21 with viral load < 400 copies/mL • 72 remained on the original regimen with viral load < 50 copies/mL: • 65 had never experienced virologic failure (defined as failing to reach < 400 copies/mL, or 2 consecutive values > 400 copies/mL) • 7 had transient viremia to > 400 copies/mL that was resuppressed to < 50 copies/mL without changing therapy • CD4+ cell counts increased throughout study (mean = +400 cells/mm3) Abstract: H-165

14. Importance of Background Regimen in Response to T-20 Study Outline • TORO 1 study: • Highly treatment-experienced patients (N = 491) • All received optimized background (OB) regimen (3-5 drugs), chosen based on treatment history and genotypic and phenotypic resistance testing • Results of randomized comparison reported in Barcelona: • T-20 plus OB regimen, vs OB regimen alone • Viral load reduction at week 24: -1.70 vs -0.74 log10 copies/mL (P < .001) • Planned subgroup analyses presented at ICAAC: • Male vs female, white vs nonwhite; age < 40 vs ≥ 40 years • Baseline viral load and CD4+ cell count strata • Number of drugs in OB regimen to which patient’s HIV was sensitive by genotypic or phenotypic testing Abstract: H-1074

15. Importance of Background Regimen in Response to T-20 (2) Key Results • T-20 had similar efficacy regardless of sex, ethnicity, or age • Better efficacy of T-20 at higher CD4+ cell count levels • Baseline viral load did not predict response when evaluated as change in viral load from baseline • Importance of OB regimen: • Activity of T-20 observed even if no active drugs in OB regimen • Magnitude of viral suppression depended on the number of active drugs in OB regimen • Inclusion of lopinavir/ritonavir in OB regimen predicted better response • Prior lopinavir/ritonavir experience predicted poorer response

16. Dose-Dependent Efficacy of T-1249 Study Outline • T-1249: peptide molecule that inhibits HIV fusion; more potent than T-20; active against T-20-resistant variants in vitro. • Open-label, 14-day, dose-escalation, monotherapy study (N = 115) Results • Clear dose response up to 200 mg once daily • PK support once-daily dosing • Few adverse effects: • At higher doses, similar injection- site reactions to T-20 • In vivo activity in T-20-experienced patients now being tested. Abstract: H-1075

17. Lipoatrophy: Switch From Stavudine to Zidovudine or Abacavir Study Outline • 48-week results from the TARHEEL study • Eligibility: • Subjects on a stavudine-containing regimen for ≥ 6 months • HIV-1 RNA < 400 copies/mL • Presence of either: • lipoatrophy (by physical exam or self-report)  lactate levels  2.2 mmol/L • symptomatic hyperlactatemia and lactate levels  2.2 mmol/L • lactate levels > 3.2 mmol/L • Stavudine replaced with either zidovudine (n = 32) or abacavir (n = 86) • Changes in fat distribution assessed by DEXA, CT, anthropometric measurements, and patient self-report Abstract: H-1074

18. Lipoatrophy: Switch From Stavudine to Zidovudine or Abacavir (2) Key Results • Significant increases in regional fat by DEXA: • Overall: arms +35%; legs +12%; trunk +18% (median percent increases) • Benefits also independently observed in abacavir and zidovudine groups, though typically greater with switch to abacavir • CT results consistent with DEXA: • 87% of all subjects had increased subcutaneous abdominal fat • Approximately half of all subjects had decreased visceral abdominal fat, while half gained visceral abdominal fat • Proportions of subjects with self-reported improvements in lipoatrophy: • 27% for face, 20% for legs, 22% for arms, 19% for buttocks • Overall lactate levels decreased; hyperlactatemia did not recur in those with high levels or symptomatic elevations • No change in median HIV-1 RNA (except during therapy interruption for hyperlactatemia) Abstract: H-1929

19. Prevalence of Primary HIV Infection in Malawi Study Outline • HIV screening of male attendees at STD or dermatology outpatient clinics (N = 1361) • Enrolled if presence of acute urethritis (n = 396), symptomatic genital ulcer disease (n = 399), both (n = 134), or dermatologic complaints (n = 432) • HIV antibody testing performed (rapid latex agglutination, confirmed by ELISA) • HIV-1 RNA screening of patients with negative antibody tests • samples pooled in a 1:10:50 pyramid scheme • Primary infection defined as RNA-positive but antibody-negative or indeterminate Key Results • 28% and 47% of men in dermatology and STD clinics, respectively, had established HIV infection • 4.8% of antibody-negative men in STD clinics had primary HIV infection • Primary infection was associated with active genital ulceration and inguinal adenopathy • Viral load ranged from 10,000 to 2 billion copies/mL; median was significantly higher than among HIV-positive controls without an STD (6.1 vs 4.4 log10 copies/mL) Abstract: LB-19

20. Go Online for Additional ICAAC Coverage… http://www.medscape.com/conference/icaac2002 • Next-day news reports of the major studies • HIV • Other infectious diseases • Postmeeting review articles, certified for CME, including: • First-line antiretroviral therapy • Management of treatment-experienced patients • Metabolic complications and lipodystrophy • Other adverse events • Opportunistic infections and coinfections