Antiretroviral Treatment Highlights of the 11th Conference on Retroviruses and Opportunistic Infections (CROI) February 8-11, 2004; San Francisco, California

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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
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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

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Initial Antiretroviral Therapy (1)Lopinavir/Riton
avir (LPV/RTV) Once Daily (QD) vs Twice Daily
(BID)48-Week Data
Prospective, randomized, comparative study of 2
initial antiretroviral regimens

• LPV/RTV 800/200 mg QD QD emtricitabine/tenofovir
  DF (n 115)
• LPV/RTV 400/100 mg BID QD emtricitabine/tenofovi
  r DF (n 75)
• Efficacy
• Patients with HIV-1 RNA lt 50 copies/mL (ITT) 70
  vs 64
• Mean increase in CD4 cell count (cells/mcL) 185
  vs 188

• 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 and BID regimens more adverse GI effects in
  QD arm

Abstract 570
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Initial Antiretroviral Therapy (2)Once-Daily
(QD) Didanosine (ddI) Lamivudine (3TC)
Tenofovir DF (TDF)
24-week pilot study evaluating potency and safety
of ddI3TCTDF

• 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 ddI3TCTDF produced suboptimal responses and
  rapid emergence of resistance-associated
  mutations

Abstract 51
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Initial Antiretroviral Therapy (3)Once-Daily
(QD) Abacavir (ABC) Lamivudine (3TC)
Tenofovir (TDF) Tonus Study
Pilot study of 38 antiretroviral-naive patients
treated with QD ABC3TCTDF

• Efficacy
• Virologic failures (any timepoint) 12/36
• 4 patients had early viral rebound gt 0.7 log10
  copies/mL
• 8 patients never achieved HIV-1 RNA lt 400
  copies/mL
• Virologic responders (HIV-1 RNA lt 50 copies/mL at
  24 weeks) 17/26
• All (8) patients who entered study with HIV-1 RNA
  lt 10,000 copies/mL
• 9 of 18 patients with baseline HIV-1 RNA gt 10,000
  copies/mL
• High rate of early virologic failure similar to
  those observed in other recent studies of
  ABC3TCTDF

Abstract 52
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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
• M184V only 1/12
• No virologic failure HIV RT mutations in
  patients with HIV-1 RNA lt 400 copies/mL (n 10)
• M184V K65R 7/10
• M184V only 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
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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 gt 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 lt 200 cells/mcL)
• Efficacy (24 weeks)
• HIV genotypes in nonresponders 2 WT, 1 K65R, 3
  M184V TAMS, 2 TAMS
• Although preliminary, once-daily TZVTDF may
  prove useful in patients with lower viral loads

Outcome All subjects Baseline VL lt105 copies/mL Baseline VL 105 copies/mL
HIV-1 RNA lt400 copies/mL 42/54 (78) 16/19 (84) 26/35 (74)
HIV-1 RNA lt50 copies/mL 36/54 (67) 15/19 (79) 21/35 (60)
Nonresponse 8/54 (15) 1/19 (5) 7/35 (20)
Abstract 53
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Treatment Failure and Second-line Therapy (1)
Atazanavir (ATV)/Ritonavir (RTV) vs
ATV/Saquinavir (SQV) vs Lopinavir (LPV)/RTV BMS
045 (48-Week Results)
Ongoing, prospective study in patients with 2
prior HAART failures

• 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 to
  LPV/RTV

Regimen Mean change in HIV-1 RNA (log10 copies/mL) Mean change in CD4 counts (cells/mcL)
ATV/RTV -1.93 110
ATV/SQV -1.55 72
LPV/RTV -1.87 121
Abstract 547
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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)

• Safety
• Frequency of adverse events and discontinuations
  was similar across treatment arms
• ATV/RTV was associated with hyperbilirubinemia
  (and some cases of jaundice)
• Diarrhea was observed to occur with greater
  frequency in the LPV/RTV arm

• Lipid effects (mean change from baseline at
  week 48)

Total Cholesterol HDL-C Fasting LDL-C Fasting Triglycerides
ATV/RTV -8 -7 -10 -4
ATV/SQV -4 4 -3 -14
LPV/RTV 6 2 1 30
HDL-C high-density lipoprotein cholesterol
LDC-C low-density lipoprotein cholesterol. P
lt .005 (ATV regimens vs LPV/RTV)
Abstract 547
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New and Investigational Agents (1)Binding/Fusion
Inhibitors
Agent/Description Comment
BMS-488043 In this dose-finding monotherapy study, untreated, HIV-infected patients received doses of 800 mg (n 12) or 1800 mg (n 12) bid with a high-fat meal for 8 days. Mean maximal reductions in HIV-1 RNA (log10 copies/mL) were 1.01 and 1.23, respectively max reductions were gt1.5 in 25 and 42 of subjects. No serious adverse events or grade 3/4 lab abnormalities were noted.
Binding/entry inhibitor Phase 1 Binds to gp120, blocks CD4 ligation Orally available, small-molecule In this dose-finding monotherapy study, untreated, HIV-infected patients received doses of 800 mg (n 12) or 1800 mg (n 12) bid with a high-fat meal for 8 days. Mean maximal reductions in HIV-1 RNA (log10 copies/mL) were 1.01 and 1.23, respectively max reductions were gt1.5 in 25 and 42 of subjects. No serious adverse events or grade 3/4 lab abnormalities were noted.
Abstract 141 In this dose-finding monotherapy study, untreated, HIV-infected patients received doses of 800 mg (n 12) or 1800 mg (n 12) bid with a high-fat meal for 8 days. Mean maximal reductions in HIV-1 RNA (log10 copies/mL) were 1.01 and 1.23, respectively max reductions were gt1.5 in 25 and 42 of subjects. No serious adverse events or grade 3/4 lab abnormalities were noted.
TNX-355 Among patients treated with 3 different dose regimens (10 mg/kg weekly 10 mg/kg load, then 6 mg/kg q2 weeks 25 mg/kg q2 weeks), approximately two-thirds of patients had reductions in HIV-1 RNA 1 log10 copies/mL (which were transient at all but highest dose). Treatment was generally well tolerated, although 4 serious adverse events. CD4 cell counts remained stable (ie, there was no T-cell depletion).
Binding/entry inhibitor Phase 1b Humanized anti-CD4 monoclonal antibody Administered intravenously Among patients treated with 3 different dose regimens (10 mg/kg weekly 10 mg/kg load, then 6 mg/kg q2 weeks 25 mg/kg q2 weeks), approximately two-thirds of patients had reductions in HIV-1 RNA 1 log10 copies/mL (which were transient at all but highest dose). Treatment was generally well tolerated, although 4 serious adverse events. CD4 cell counts remained stable (ie, there was no T-cell depletion).
Abstract 536 Among patients treated with 3 different dose regimens (10 mg/kg weekly 10 mg/kg load, then 6 mg/kg q2 weeks 25 mg/kg q2 weeks), approximately two-thirds of patients had reductions in HIV-1 RNA 1 log10 copies/mL (which were transient at all but highest dose). Treatment was generally well tolerated, although 4 serious adverse events. CD4 cell counts remained stable (ie, there was no T-cell depletion).
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New and Investigational Agents (2)Binding/Fusion
Inhibitors
Agent/Description Comment
SCH D In this 14-day, prospective, randomized, phase 1/2 study in 48 antiretroviral-naive patients, 27, 46, and 45 of patients who received 10, 25, and 50 mg SCH D bid, respectively, experienced HIV-1 RNA reductions gt 1.5 log10 copies/mL. The drug appeared to be safe.
Binding/entry inhibitor CCR5 coreceptor antagonist Phase 1/2 Orally available, small-molecule In this 14-day, prospective, randomized, phase 1/2 study in 48 antiretroviral-naive patients, 27, 46, and 45 of patients who received 10, 25, and 50 mg SCH D bid, respectively, experienced HIV-1 RNA reductions gt 1.5 log10 copies/mL. The drug appeared to be safe.
Abstract 140LB In this 14-day, prospective, randomized, phase 1/2 study in 48 antiretroviral-naive patients, 27, 46, and 45 of patients who received 10, 25, and 50 mg SCH D bid, respectively, experienced HIV-1 RNA reductions gt 1.5 log10 copies/mL. The drug appeared to be safe.
GW873140 Double-blind, randomized, dose-escalation study in healthy volunteers, up to 7-day dosing, showed only mild adverse effects (mild diarrhea, cramping, loose stools some modest, reversible amylase elevations).
Binding/entry inhibitor CCR5 coreceptor antagonist Phase 1/2 Orally available, small-molecule Double-blind, randomized, dose-escalation study in healthy volunteers, up to 7-day dosing, showed only mild adverse effects (mild diarrhea, cramping, loose stools some modest, reversible amylase elevations).
Abstract 139 Double-blind, randomized, dose-escalation study in healthy volunteers, up to 7-day dosing, showed only mild adverse effects (mild diarrhea, cramping, loose stools some modest, reversible amylase elevations).
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New and Investigational Agents (3)Nucleoside/Nucl
eotide Analogs
Agent/Description Comment
Reverset, D-D4FC 10-day dosing with 50, 100, or 200 mg qd in 30 antiretroviral-naive subjects was associated with a mean reduction in HIV-1 RNA of 1.7 log10 copies/mL. No serious adverse events were reported. A 3.2-fold reduction in activity against K65R mutants was detected, although the Cmax following the 200-mg dose is above the EC90 for such isolates. 69S and Q151M mutations were also associated with reduced susceptibility to D-D4FC.
Novel cytidine analog RTI Phase 1/2 In vitro activity against NRTI-resistant HIV 10-day dosing with 50, 100, or 200 mg qd in 30 antiretroviral-naive subjects was associated with a mean reduction in HIV-1 RNA of 1.7 log10 copies/mL. No serious adverse events were reported. A 3.2-fold reduction in activity against K65R mutants was detected, although the Cmax following the 200-mg dose is above the EC90 for such isolates. 69S and Q151M mutations were also associated with reduced susceptibility to D-D4FC.
Abstract 137 10-day dosing with 50, 100, or 200 mg qd in 30 antiretroviral-naive subjects was associated with a mean reduction in HIV-1 RNA of 1.7 log10 copies/mL. No serious adverse events were reported. A 3.2-fold reduction in activity against K65R mutants was detected, although the Cmax following the 200-mg dose is above the EC90 for such isolates. 69S and Q151M mutations were also associated with reduced susceptibility to D-D4FC.
SPD754 In a pharmacologic study, HIV-negative volunteers received SPD754 600 mg bid and lamivudine 300 mg qd to explore potential interactions between these similar drugs (lamivudine is also a deoxycytidine analog). Lamivudine plasma and intracellular tri-phosphate levels were unaffected by SPD754, but intracellular 754 tri-phosphate levels were markedly decreased (though plasma levels were unaffected) to levels 2- to 3-fold less than would likely be active against M184V mutants a likely target use of SPD754.
Deoxycytidine analog RTI Phase 1 In vitro activity against NRTI-resistant HIV In a pharmacologic study, HIV-negative volunteers received SPD754 600 mg bid and lamivudine 300 mg qd to explore potential interactions between these similar drugs (lamivudine is also a deoxycytidine analog). Lamivudine plasma and intracellular tri-phosphate levels were unaffected by SPD754, but intracellular 754 tri-phosphate levels were markedly decreased (though plasma levels were unaffected) to levels 2- to 3-fold less than would likely be active against M184V mutants a likely target use of SPD754.
Abstract 138 In a pharmacologic study, HIV-negative volunteers received SPD754 600 mg bid and lamivudine 300 mg qd to explore potential interactions between these similar drugs (lamivudine is also a deoxycytidine analog). Lamivudine plasma and intracellular tri-phosphate levels were unaffected by SPD754, but intracellular 754 tri-phosphate levels were markedly decreased (though plasma levels were unaffected) to levels 2- to 3-fold less than would likely be active against M184V mutants a likely target use of SPD754.
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New and Investigational Agents (4)Additional
Developmental Agents
Agent/Description Comment
TMC114 2 weeks administration (at several doses) of RTV-boosted TMC114 to 35 patients on virologically failing regimens effected a median reduction in HIV-1 RNA of 1.4 log10 copies/mL at day 14 (range, 0.5-2.5).
HIV-1 protease inhibitor In vitro activity against PI-resistant HIV Phase 2 development 2 weeks administration (at several doses) of RTV-boosted TMC114 to 35 patients on virologically failing regimens effected a median reduction in HIV-1 RNA of 1.4 log10 copies/mL at day 14 (range, 0.5-2.5).
Abstract 533 2 weeks administration (at several doses) of RTV-boosted TMC114 to 35 patients on virologically failing regimens effected a median reduction in HIV-1 RNA of 1.4 log10 copies/mL at day 14 (range, 0.5-2.5).
PA-457 The lead candidate of a new potential class of antiretroviral agents (viral maturation disruptors), this compound inhibits conversion of the Gag p25 capsid precursor to the p24 capsid protein, which is required for viral assembly.
Maturation inhibitor Prevents release of infectious virus from infected cells Preclinical testing The lead candidate of a new potential class of antiretroviral agents (viral maturation disruptors), this compound inhibits conversion of the Gag p25 capsid precursor to the p24 capsid protein, which is required for viral assembly.
Abstract 545 The lead candidate of a new potential class of antiretroviral agents (viral maturation disruptors), this compound inhibits conversion of the Gag p25 capsid precursor to the p24 capsid protein, which is required for viral assembly.
New NNRTIs Several posters were presented on new NNRTIs in early, preclinical development, which may have high potency against NNRTI-resistant HIV. New data were not presented on capravirine and TMC125, which are in phase 2 clinical studies.
Include GW678248, GW695634, and novel, NVP-like compounds Preclinical testing Several posters were presented on new NNRTIs in early, preclinical development, which may have high potency against NNRTI-resistant HIV. New data were not presented on capravirine and TMC125, which are in phase 2 clinical studies.
Abstracts 529, 530, 531 Several posters were presented on new NNRTIs in early, preclinical development, which may have high potency against NNRTI-resistant HIV. New data were not presented on capravirine and TMC125, which are in phase 2 clinical studies.
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Complications of HIV Infection and Its Therapy
(1)Hyperglycemia and Diabetes
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)

• This cohort study shows increased incidence and
  prevalence in prediabetes and diabetes in
  HIV-infected men exposed to HAART

Abstract 73
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Complications of HIV Infection and Its Therapy
(2)Predictors of Hypertension in HIV-Infected
Patients in the DAD Study

• Longitudinal assessment of potential patient- and
  treatment-related factors associated with
  differences in blood pressure (BP) and
  hypertension among HIV-infected adults

• Predictors of hypertension subsequent to
  enrollment in the DAD 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

• 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

• 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
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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

• Lipoatrophic patients (limb fat mass lt 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)

• 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

• 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
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Complications of HIV Infection and Its Therapy
(4)Effects of Switching PI to NNRTI or Abacavir
to Treat LipodystrophyNEFA Substudy

• Analysis from a randomized study of patients who
  substituted abacavir (ABC), efavirenz (EFV), or
  nevirapine (NVP) for PI

• Metabolic outcomes at 24 months ( change from
  baseline)

Total Cholesterol LDL-C TCHDL-C
ABC (n 22) -13 -15 5
EFV (n 21) -6 -10 15
NVP (n 26) 2 -17 16
LDL-C low-density lipoprotein cholesterol
TCHDL-C Total cholesterolhigh-density
lipoprotein cholesterol ratio

• Switch to any of the 3 treatments improved
  insulin resistance, total cholesterol (TC),
  LDL-C, and TCHDL-C ratio
• Slightly better changes in TCHDL-C were seen
  with switch to either NNRTI vs ABC

• Marked metabolic improvements were seen with
  switch to PI-sparing therapy

Abstract 78