Supported by an unrestricted educational grant from

1. TREATMENT HIGHLIGHTS OF THE XV International AIDS Conference July 11-16, 2004, Bangkok, Thailand Selected and summarized by Douglas J. Ward, MD, FACP Dupont Circle Physicians Group, Washington, DC Supported by an unrestricted educational grant from

2. CONTENTS XV International AIDS Conference New Agents New Data on Current Drugs New and Novel Approaches to Therapy Complications of HIV Infection and Therapy HIV Prevention Other Studies

3. Conference Facts Theme of the XV International AIDS Conference: 19,843 participants from 152 countries 8,641 acceptedabstracts 5 Program Tracks Oral presentation: 445 Late breakers: 40 Poster presentation: 1110 Poster exhibition: 5086 CD-ROM: 2960 A. Basic Science B. Clinical Care C. Epidemiology and Prevention D. Social and Economic Issues E: Policy and Program Implementation The abstracts of the XV International AIDS Conferenceare available online in eJIAS: eJournal of the International AIDS Society Medscape is the official provider of online conference coverage (HIV science and medicine) and continuing medical education activities based on the XV International AIDS Conference. www.ejias.org www.medscape.com/hiv-aidshome

4. New Agents: Tipranavir www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Walmsley et al, WeOrB1236 Tipranavir in Patients With Highly PI-Resistant HIV (BI1182.51) Design • 296 patients with highly PI-resistantHIV • >/= 3 protease mutations at codons 33, 82, 84, 90 • Patients randomized to receive • tipranavir (TPV)/r + optimized background regimen (OBR) • amprenavir (APV)/r, saquinavir SQV/r, or lopinavir (LPV)/r + OBR • TPVadded to other PI regimens after 2 weeks Results • HIV RNA changes at 2 weeks (log10 copies/mL) • TPV: -1.15 • Other arms: -0.2 to - 0.4 • Decreases in plasma concentrations ofPIswith addition ofTPV • Cmin: SQV: 84%, APV: 51%, LPV: 45%

5. New Agents: NRTIs 1Murphy et al, MoOrB1056 2Bethell et al, WePeA5642 www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] 3Holdich et al, TuPeB4625 Reverset (d4FC) in Treatment-Experienced Patients1 • Background • Cytidine analog with potent in vitro activity against wild-type and resistant viruses • Half life: ~17 hours • No mitochondrial activity in vitro • In treatment-naive patients, 10-day monotherapy associated with mean HIV RNA reductions of >1.5 log10 copies/mL (previously reported) • 10-day results were reported for 8 patients on failing regimens • Treatment-experienced patients • D-d4FC 200 mg was added to patients’ current regimen • 4 patients had > 3 TAMs • 5 patients’ failing regimens included tenofovir, 5 included lamivudine • Mean HIV RNA reduction: 0.8 log10 copies/mL SPD7542,3 • In vitro activity and PK data • Cytidine analog with good activity against wild-type and resistant viruses • Additive or synergistic with most antivirals, antagonistic with 3TC • No plasma interaction with lamivudine • Intracellular SPD-triphosphate levels reduced 6-fold by lamivudine • No effect on 3TC-triphosphate by SPD NRTIs = nucleoside reverse transcriptase inhibitors

6. New Data on Current Drugs Abacavir Safety and Efficacy: ZODIAC ZODIAC: Safety1 • Subset of 200 subjects (out of 770) genotyped at baseline • 13 had single mutation • 2 had double mutations • None of 17 virologic failures at week 48 had baseline resistance • 6 K103N and 1 M184V mutations at baseline: none failed • 13 patients with non-clade B virus • None with virologic failure • Abacavir once-daily vs twice-daily + once-daily EFV and 3TC • Previously reported equivalent efficacy • Safety analysis: • No difference in adverse events • Abacavir hypersensitivity: 7% twice daily vs 9% once daily (NS) ZODIAC: Baseline Resistance and Efficacy2 1Hernandez et al, TuPeB4521 www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] 2Moyle et al, WePeB5698

7. New Data on Current Drugs Tenofovir (TDF): Renal Toxicity Gilead 903 -- 3-Year Data1 • TDF vs stavudine (d4T) + EFV/3TC • No difference between groups in creatinine, phosphorus, proteinuria, glycosuria Kaiser Permanente2 • 199 patients on TDF >/= 3 months at 5 medical centers • Subtle increase in mean creatinine • No increase in proteinuria or hypophosphatemia Mild Renal Dysfunction and TDF3 • Cross-sectional study of patients treated with (n = 74) or without (n = 84) TDF • Other factors associated with renal dysfunction (diabetes mellitus, hypertension) excluded • 34% vs 21% had decreased glomerular filtration rate (by cystatin C clearance) • 36% vs 16% had proteinuria • Renal toxicity of TDF is still ill-defined, but probably does exist 1Stazweski et al, WePeB5917 2Horberg et al, WePpB2066 www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] 3Mauss et al, WePeB5941

8. New Data on Current Drugs CONTEXT: FosAPV/r vs LPV/r in PI-Experienced Patients Fosamprenavir/Ritonavir (fosAPV/r) vs Lopinavir/Ritonavir (LPV/r) • Open label, randomized study of fosAPV/r vs LPV/r • Patients had failed 1-2 PI-based regimens • fosAPV/r: 700 mg/100 mg twice daily or 1400 mg/200 mg once daily + 2 NRTIs • Once-daily arm performed less well and not included in analysis • Once-daily dosing not recommended in experienced patients • Viable NRTI backbone based on genotype Results (48 Weeks) www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Elston et al, MoOrB1055

9. New Data on Current Drugs www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Elston: MoOrB1055 CONTEXT (Continued) Resistance Analysis • Virologic failures: LPV/r: 29, fosAPV/r: 28 Response rate (% of patients) by baseline mutation: • In presence of 46 or 90, virologic failure predicted by number of PI mutations or phenotype of randomized PI • Insufficient virologic failures to determine phenotypic clinical cut-off PI = protease inhibitor

10. New and Novel Approaches to Therapy www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] J C Gathe et al, MoOrB1057 Lopinavir/Ritonavir Monotherapy: IMANI-1 Baseline Characteristics and Treatment Schedule 1 • 30 treatment-naive patients enrolled in this open label pilot study • Mean HIV RNA: 262,000 copies/mL (17/30 had VL > 100,000 copies/mL) • Mean CD4+ count: 170 cells/mcL (13/30 had CD4+ counts < 50 cells/mL ) • No primary drug resistance • Patients < 70 kg and > 70 kg received 3 and 4 LPV/r capsules twice daily • Intensification with SQV or TDF/3TC was allowed at any point 48-Week Results • 20 of 30 patients completed 48 weeks of LPV/r monotherapy • Mean CD4+ cell increase = 317 cells/mcL • No significant toxicity • No protease resistance identified

11. New and Novel Approaches to Therapy Lopinavir/Ritonavir Monotherapy: The “OK” Study LPV/r Monotherapy Simplification (The “OK” Study) • 42 patients on LPV/r + 2 NRTIs; viral load < 50 copies/mL for > 6 months • Randomized to continue current regimen or switch to LPV/r monotherapy • Preliminary 24-week results: • All triple-therapy patients < 50 copies/mL • 3 virologic failures in monotherapy group • Virologic failures had shortest period undetectable (all < 9 months) www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Arribaset al,TuPeB4486

12. New and Novel Approaches to Therapy New and Novel Approaches to Therapy Continuous vs Intermittent Therapy (HIV-NAT 0014) 74 Thai patients on SQV/r-based therapy • Viral load < 50 copies/mL; CD4+ cell count > 350 cells/mcL • Substantial previous NRTI therapy Randomized to • Continuous therapy or • “One week on/One week off” • CD4-guided therapy: stop therapy until CD4+ cell count < 350 cells/mcL, then resume until > 500 • At 96 weeks, resume continuous therapy for 12 weeks Results (108 Weeks) • “One week on/One week off” arm prematurely discontinued due to high virologic failure rate (35%) • Differs from other trials of similar regimen - ? because of previous NRTI treatment • All resuppressed to < 50 copies/mL after resumption of same regimen continuously www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Ananworanich et al, WeOrB1283

13. New and Novel Approaches to Therapy www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Ananworanich et al, WeOrB1283 Continuous vs Intermittent Therapy: HIV-NAT 0014 (Continued) Results (108 Weeks) • All patients in CD4-guided group resuppressed to < 50 copies/mL with an additional 12 weeks of therapy • No differences in adverse events, lipodystrophy, quality of life • CD4-guided intermittent therapy may be a viable strategy, particularly in resource-limited areas

14. New and Novel Approaches to Therapy www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Intermittent Therapy: FOTO Trial Design and Patients • “Five Days On, Two Days Off” therapy design parallels work week • 26 patients on various PI- or NNRTI-based regimens • CD4+ cell count > 200 cells/mcL • HIV RNA < 75 copies/mL for 3 months Results (24 Weeks) • Median follow-up: 42 weeks (range, 8-48) • Patients with HIV RNA < 400 copies/mL: 24 • 17/17on NNRTI-based regimens (10 EFV, 7 NVP) • 7/9on PI-based regimens • Patients with virologic failure (> 400 copies/ML): 2 • Both on LPV/r-based regimens Advantages of FOTO Patients reported strong preference for intermittent therapy 28% reduction in medication use Cohen et al, TuPeB4575

15. New and Novel Approaches to Therapy www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Markowitz et al, LbOrB14 Induction/Maintenance Therapy: ESS40013 448 treatment-naive patients initially treated with AZT/3TC/ABC + EFV • If viral load < 50 copies/mL at weeks 36 and 48, randomized to continue all 4 drugs or discontinue EFV • Only 63% of patients were eligible for randomization 96-week (end of maintenance phase) results • Maintenance with AZT/3TC/ABC may be better tolerated and less toxic than continued 4-drug therapy, but may be at the expense of potency.

16. New and Novel Approaches to Therapy www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Castagna et al, WeOrB1286 3TC Monotherapy After Treatment Interruption Concept • The M184V mutation associated with 3TC resistance causes a decreased viral fitness and may be beneficial to maintain after treatment interruption 50 patients • Failing therapy (viral load > 1000 copies/mL) with known M184V mutation • CD4+ cell count > 500 cells/mcL • Randomized to stopall medication or to continue 3TC monotherapy (300 mg/day) to maintain M184V Preliminary Results (24 Weeks) • Lower replication capacity in 3TC group • Slower reversion to wild-type virus in 3TC group

17. New and Novel Approaches to Therapy www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Ulmer et al,TuPeB4582 Improved CD4 Counts with Prednisolone • Uncontrolled observational trial of prednisolone 5 mg/day • 56 treatment-naive patients • 0.5-11.5 years prednisolone treatment • CD4+ >/= 300 cells/mcL (mean, 565 cells/mcL) • Compared with 135 untreated patients in same clinic • Mean CD4+, 612 cells/mcL Results • CD4+ increased 44.4 cells/mcL per year in first 6 years • Compared with 49.7 cells/mcL decrease in untreated patients • Significant decrease in number on therapy over time Prednisolone During STI • 86 patients with prednisolone during STI vs 41 without • CD4+ decrease of 0.47 cell/mcL per day with prednisolone vs 0.77 without • Nonsignificant trend toward lower viral load with prednisolone • Mechanism of benefit not investigated • Related to decreased immune activation

18. www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Pierone et al, ThOrB1365 Complications of HIV Infection and Therapy Cardiovascular Risk of HAART Study Summary • 3-year prospective analysis of cardiovascular risk in patients on PI-, NVP-, or EFV-based HAART • Evaluated carotid intima-media thickness (CIMT) by ultrasound, coronary artery calcium (CAC) by CT, and brachial artery reactivity (BAR) • Complete lipid profile, C-reactive protein, homocysteine; social and HIV factors also evaluated • PI group had more advanced HIV disease • No difference at baseline in CIMT or BAR • Significant increase in baseline CAC in PI group (controlled for other risk factors for coronary artery disease) • No difference between groups in preliminary 1-year follow-up • Significant increase in all groups in CIMT, compared with expected increase in general population

19. Complications of HIV Infection and Therapy NRTI Substitution With Tenofovir (TDF) for Toxicity Prospective Study of Causes of NRTI Drug Switch • 902 patients switched to TDF; 771 with 24-week follow-up • Patients switched from: • 68% stavudine • 13% didanosine • 12% zidovudine • Lipoatrophy improved in 16% (no change in 84%) • Neuropathy resolved in 29%, improved in additional 33% • Improvement also seen in anemia, liver function elevations, and hypertriglyceridemia • No data provided on antiviral efficacy Miralles Alvarez et al, WePeB5880 www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)]

20. Complications of HIV Infection and Therapy Miscellaneous Complications Osteonecrosis (Mary-Krause et al, ThOrB1358): • Survey of the French Hospital Database on HIV • 122 cases of osteonecrosis among > 56,000 patients • Only associated factor in multivariate analysis was time on antiretroviral therapy Gynecomastia (Biglia et al, ThOrB1357): • True gynecomastia in 1.8% of 2275 males in Barcelona, Spain, database • Slightly more than expected in population • In multivariate analysis associated with: • Lipoatrophy, hepatitis C, low free testosterone • Zidovudine, stavudine, or efavirenz use (but not time on therapy) Pregnancy complications (Suy et al, ThOrB1359): • 472 pregnancies evaluated 1985-2003 • Dramatic increase in preeclampsia (0.4% to 6.4%) and fetal death (0% to 4.2%) in 2001-2003 period • Only associated HIV factor was time on antiretroviral therapy • However, no mother-to-child transmission during this period Emtricitabine (FTC) hyperpigmentation (Mondou et al, WePeB5916) 2% to 4% in clinical trials Most commonly on palms/soles; also nails, tongue

21. HIV Prevention: MTCT www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] McIntyre et al, LbOrB09 Prevention of Mother-to-Child HIV Transmission (MTCT) Single-Dose Nevirapine (sdNVP) “Plus” • sdNVP at delivery has been shown to reduce MTCT, but frequently results in NVP resistance in mothers • In this trial from South Africa, mothers and infants were randomized to: • sdNVP or • sdNVP plus Combivir (zidovudine/lamivudine) for 4 days (CBV4) or • sdNVP plus Combivir for 7 days (CBV7) Preliminary Results (First 61 Patients) Median HIV RNA: 32,600 copies/mL Median CD4+ cell count: 318 cells/mcL Various NNRTI mutations; no NRTI mutations seen 4/68 (6%) of infants infected Addition of Combivir to sdNVP reduces the development of resistance, but optimal duration of therapy remains uncertain

22. Other Studies www.medscape.com MedGenMed. 2004 Jul 11;6(3) [eJIAS. 2004 Jul 11;1(1)] Moyle et al, WePeB5725 Prevalence and Predictive Factors of Coreceptor Tropism • Phenosense assay for tropism in 861 patient • 265 assay failures • 80% CCR5 (R5); 20% CXCR4 (X4) or dual tropic • Viral load significantly higher in X4/dual tropic • CD4+ cell count lower in X4/dual tropic • R5 predicted by viral load < 5000 copies/mL and CD4+ cell count > 300 cells/mcL (89%) • X4 poorly predicted by viral load > 100,000 copies/mL and CD4+ cell count < 50 cells/mcL (55%) Coreceptor tropism is associated with disease progression and will be an important consideration in use of coreceptor antagonists