1. Highlights of the 43rd Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC) September 14-17, 2003; Chicago, Illinois Selected and summarized by Douglas J. Ward, MD Dupont Circle Physicians Group Washington, DC Supported by an unrestricted educational grant from

2. HIV Highlights of the 43rd ICAAC New Data on: Predictors of HIV disease progression Drug resistance and HIV transmission Treatment interruption Clinical trials data on nucleoside reverse transcriptase inhibitors (NRTIs) Clinical trials data on protease inhibitors (PIs) Clinical trials data on entry inhibitors

3. Predictors of HIV Progression Effect of Replication Capacity (RC) and Coreceptor Tropism (CRT) Cohort of 207 hemophiliac pediatric patients minimally treated or untreated, followed 1989-90 to 1997 Evaluated for HIV-1 RNA, CD4+ cell count, RC, and CRT Presence of X4 (vs R5) virus strongly associated with lower CD4+ cell count (450 vs 158), higher viral load (4.1 vs 3.6 log), and higher RC (109 vs 83%) In multivariate analysis, increased RC and presence of X4 virus were independently associated with more rapid decline in CD4 + cell counts and progression to AIDS Abstract H-1772c

4. Reduced Transmission of HIV Containing M184V or Protease Inhibitor Mutations Retrospective review of 163 newly infected patients compared with 552 chronically infected (the “transmitting” population) Genotypic analysis of M184V, TAMs, NNRTI, and PI mutations, or combinations in each group Prevalence of mutations: M184V TAMSNNRTI New0.6% 3%3.6% Chronic7.7% 3%4.8% Relative risk.08 1.75 Relative risk of transmission of PI mutation-containing virus also lower Median viral load: TAM/NNRTI > PI > M184V Decreased relative risk of transmission may be related to lower viral loads, decreased fitness, or other factors Abstract H-815

5. Treatment Interruptions “BASTA” Treatment discontinuation for patients with CD4+ cell count > 800 cells/mcL – Restart for decrease to < 400 114 patients: CD4+ cell count > 800 cells/mcL, HIV RNA < 50 (on treatment) – Randomized 2:1 to stop treatment or continue – 18-month follow-up 21% of patients in STI arm restarted meds (1 patient twice) – All had rapid increase in CD4+ cell counts on restart – STI patients spent 12.1% of time on meds Nadir CD4+ cell count only predictor of rate of decline of CD4 cells – Nadir T-cell countTime to restart < 200 6.9 mo 200-350 14.1 mo 350-500 17.8 mo > 500 No restarts Abstract H-448

6. Tenofovir/Lamivudine/Abacavir (1) ESS30009 360 treatment-naive patients – Median baseline HIV RNA: 4.6 log 10 copies/mL – Median baseline CD4+ cell count: 266 cells/mcL Treatment: Abacavir (ABC) 300 mg /lamivudine (3TC) 300 mg fixed-dose combination qd plus either: – Tenofovir (TDF) 300 mg qd or – Efavirenz (EFV) 600 mg qd Unplanned interim analysis – In response to investigator observations of poor response – 194 patients were included who had completed at least 8 weeks Abstract H-1722a

7. EFV/ABC/3TC TDF/ABC/3TC < 2-log decrease in PCR3%31% 1-log increase in PCR after nadir0% 8% Both above2%10% Total failures5.4%49% % < 50 HIV RNA cells/mcL (16 wk)95% (n = 20)23% (n = 17)  Genotypes on evaluable TDF/ABC/3TC failures (n = 36): all had M184V, 64% also with K65R  Outcome: ABC/3TC + TDF arm of trial terminated This regimen is not recommended for treatment of naive or experienced patients, and should be reevaluated in those already on it. Tenofovir/Lamivudine/Abacavir (2) ESS30009 Abstract H-1722a

8. Outcome similar to that reported with this regimen by Farthing and colleagues at 2nd International AIDS Society Conference in July 2003 Baseline viral load? – Although failure rates higher in those with > 100,000, still significant in lower viral loads [1] PK interaction? – No serum interaction between ABC and TDF [2] – Possible intracellular interaction(s) being investigated QD abacavir? – Serum t 1/2 of ABC ~ 1.5 hr [3] – Intracellular t 1/2 of carbovir triphosphate = 20.5 hr [4] Tenofovir/Lamivudine/Abacavir (3) ESS30009 [1] Abstract H-1722a [2] Abstract H-1615 [3] Kumar et al. Antimicrob Agents Chemother. 1999;43:603-608. [4] Abstract H-1797

9. Double-blind, placebo controlled 770 treatment-naive patients – Median baseline CD4+ cell count: 262 cells/mcL – Median baseline HIV RNA: 4.9 log 10 copies/mL Treatment: – EFV 600 mg qd + 3TC 300 mg qd – Plus ABC randomized to either 300 mg bid OR 600 mg qd Results (48 weeks): ABC qdABC bid Viral load < 50 cells/mcL (ITT)65%67% Viral load < 50 cells/mcL (OT)87%86% CD4+ cell count increase 188 cells/mcL200 cells/mcL No significant clinical difference between once- and twice-daily ABC ITT, intent-to-treat; OT, on-treatment Once-daily vs Twice-daily Abacavir (ABC) CNA30021 (ZODIAC) Abstract H-1722b

10. 649 treatment-naive patients – Median baseline CD4+ cell count: 264 cells/mcL – Median baseline HIV RNA: 4.7 log 10 copies/mL Treatment: – EFV 600 mg qd + 3TC 150 mg bid – Plus ABC 300 mg bid OR AZT 300 mg bid – Double-blind, placebo controlled Results (48 weeks): ABC AZTP Viral load < 50 cells/mcL (ITT) 70% 69%NS Viral load < 50 cells/mcL (OT) 88% 95%NS CD4 cell increase 209 cells/mcL 155 cells/mcL.0039 Increased anemia, nausea, fatigue in AZT group 7% ABC hypersensitivity reactions Conclusion: ABC is “not inferior” to AZT in this regimen ITT, intent-to-treat; OT, on-treatment Abacavir (ABC) vs Zidovudine (AZT) CNA30024 Abstract H-446

11. Long-term efficacy [1] – 5-year follow-up of clinical trial: LPV/r plus d4T/3TC – 67/68 patients continue to have HIV RNA < 400 copies/mL (OT) – 67/100 patients continue to have HIV RNA < 400 copies/mL (ITT) Potency [2] – Pilot trial of LPV/r monotherapy > 30 treatment-naive patients > Mean HIV RNA: 262,020 copies/mL > Mean CD4+ cell count: 169 cells/mcL > 4 capsules bid for > 70 kg body weight – 24-week results: > 8 dropouts (1 because of virologic failure) > 21/22 patients with viral load < 400 copies/mL > Mean CD4+ cell count increase: 220 cells/mcL Lopinavir/Ritonavir (LPV/r) Efficacy Durability & Potency [ 1] Abstract H-844 [2] Abstract H-845

12. CCR5 antagonist Potent in vitro activity [1] – Not active against X4 or X4/R5 strains Good PK, safety in 28-day dose-ranging trial [2] 10-day monotherapy trial [3] – 24 patients, HIV RNA > 5000 copies/mL, CD4+ cell count > 250 cells/mcL, CCR5 tropic virus – 100 mg bid: > 1.42 log 10 copies/mL decrease in HIV RNA > > 90% CCR5 saturation > No significant side effects > Maximum HIV RNA suppression 7 days after last dose of drug New Agents: Entry Inhibitors UK-427,857 [1] Abstract H-875 [2] Abstract H-874 [3] Abstract H-443

13. Fusion inhibitor – Similar to enfuvirtide (T-20) 53 patients failing on T-20 protocols – HIV RNA 5000 to 500,000 copies/mL; median 4.97 log 10 copies/mL – Median 66 weeks on T-20 since “failing” (HIV RNA > 5000 copies/mL) 10-day replacement of T-20 with T-1249 – 192 mg qd (subcutaneous) – Patients continued background antivirals Median decrease in HIV RNA:1.26 log 10 copies/mL at day 11 Injection-site reactions: 64% (usually mild) T-1249 shows significant activity in patients with HIV resistant to T-20 New Agents: Entry Inhibitors T-1249 Abstract H-444

14. ACTG 5143: LPV/r plus 908 [1] – LPV/r vs 908 vs both drugs in treatment-experienced patients (plus TDF and 1-2 other NRTIs) – Formal PK analysis after 8 patients enrolled in each arm – Significant reduction in both PIs with coadministration >Greater and more consistent than with LPV/r and amprenavir (APV) >Not reversible with additional RTV >Combination not recommended for clinical use New Agents: Protease Inhibitors (1) Fosamprenavir (908) Pharmacokinetics [1] Abstract H-855

15. 908 and atorvastatin [1] – Significant increase in atorvastatin levels > Recommended maximum dosage 20 mg/day > Effect seen with RTV-boosted or unboosted 908 > No effect on levels of 908 908 and stomach acid [2] – No significant change in levels seen with antacids (Maalox) or ranitidine New Agents: Protease Inhibitors (2) Fosamprenavir (908) Pharmacokinetics [1] Abstract A-1622 [2] Abstract A-1606

16. No significant interaction between emtricitabine (FTC) and: – AZT [1] – TDF [2] No significant interaction between TDF and: – LPV/2 [3] > Modest increase in TDF levels: Significance unclear – Oral contraceptives (Ortho Tri-Cyclen) [4] Pharmacokinetic Studies (1) Miscellaneous Drugs [1] Abstract A-1620 [2] Abstract A-1621 [3] Abstract A-1617 [4] Abstract A-1618

17. Saquinavir (SQV)/RTV – 2000/100 mg vs 1000/100 bid vs 1600/100 qd – C min of 2000/100 mg qd: 59% lower than 1000/100 bid > Significant increase in C max and AUC – C min, C max, and AUC of 2000/100 qd all significantly higher than 1600/100 qd Pharmacokinetic Studies (2) Miscellaneous Drugs Abstract A-1612

18. Significant reduction in indinavir (IDV) levels with: – Vitamin C (1 g/day) [1] – Omeprazole [2] Capravirine (CPV) and LPV/r – CPV 700 mg decreases LPV/r levels [3] > Increase LPV/r to 4 caps bid > No significant effect with 200- or 400-mg doses – LPV/r significantly increases CPV levels > Appropriate dosing being investigated – Similar PK in presence of tenofovir [4] Pharmacokinetic Studies (3) Miscellaneous Drugs [1] Abstract A-1610 [2] Abstract A-1611 [3] Abstract A-1608 [4] Abstract A-1609

19. Once-daily regimen: atazanavir (ATV), didanosine (ddI) (enteric coated), and tenofovir (TDF) TDF increases ddI levels > 250 mg yields levels similar to 400 mg without TDF TDF decreases ATV levels > Boost with ritonavir 100 mg (this decreases ATV to 300 mg) Pharmacokinetic Studies (4) Miscellaneous Drugs Abstract A-1616