Highlights of the

43rd Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC)

September 14-17, 2003; Chicago, Illinois

Selected and summarized by

Douglas J. Ward, MDDupont Circle Physicians Group

Washington, DC

Supported by an unrestricted educational grant from

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

Predictors of HIV ProgressionEffect 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

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 TAMS NNRTINew 0.6% 3% 3.6%Chronic 7.7% 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

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 count Time to restart < 200 6.9 mo 200-350 14.1 mo 350-500 17.8 mo > 500 No restarts

Abstract H-448

Tenofovir/Lamivudine/Abacavir (1)ESS30009

• 360 treatment-naive patients– Median baseline HIV RNA: 4.6 log10 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

EFV/ABC/3TC TDF/ABC/3TC

< 2-log decrease in PCR 3% 31%1-log increase in PCR after nadir 0% 8%Both above 2% 10%Total failures 5.4% 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

• 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 t1/2 of ABC ~ 1.5 hr[3]

– Intracellular t1/2 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

• Double-blind, placebo controlled• 770 treatment-naive patients

– Median baseline CD4+ cell count: 262 cells/mcL– Median baseline HIV RNA: 4.9 log10 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 qd ABC bidViral load < 50 cells/mcL (ITT) 65% 67%Viral load < 50 cells/mcL (OT) 87% 86%CD4+ cell count increase 188 cells/mcL 200

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

• 649 treatment-naive patients– Median baseline CD4+ cell count: 264 cells/mcL– Median baseline HIV RNA: 4.7 log10 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 AZT PViral load < 50 cells/mcL (ITT) 70% 69% NSViral load < 50 cells/mcL (OT) 88% 95% NSCD4 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

• 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) EfficacyDurability & Potency

[1]Abstract H-844[2]Abstract H-845

• 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 log10 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 InhibitorsUK-427,857

[1]Abstract H-875[2]Abstract H-874[3]Abstract H-443

• 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 log10 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 log10 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 InhibitorsT-1249

Abstract H-444

• 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

• 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

• 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

• Saquinavir (SQV)/RTV– 2000/100 mg vs 1000/100 bid vs 1600/100 qd

– Cmin of 2000/100 mg qd: 59% lower than 1000/100 bid

> Significant increase in Cmax and AUC

– Cmin, Cmax, and AUC of 2000/100 qd all significantly higher than 1600/100 qd

Pharmacokinetic Studies (2)Miscellaneous Drugs

Abstract A-1612

• 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

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