Transcript 11th CROI: Antiretroviral Therapy Highlights

Antiretroviral Treatment Highlights of the 11th Conference on
Retroviruses and Opportunistic Infections (CROI)
February 8-11, 2004; San Francisco, California
Selected and summarized by
Jeffrey P. Nadler, MD, FACP
USF College of Medicine
Tampa, Florida
Supported by an unrestricted educational grant from
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
Initial Antiretroviral Therapy (1)
Lopinavir/Ritonavir (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/tenofovir DF (n = 75)
• Efficacy
– Patients with HIV-1 RNA < 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
Initial Antiretroviral Therapy (2)
Once-Daily (QD) Didanosine (ddI) + Lamivudine (3TC) + Tenofovir DF (TDF)
24-week pilot study evaluating potency and safety of ddI+3TC+TDF
–
–
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 ddI+3TC+TDF produced suboptimal responses and rapid emergence of
resistance-associated mutations
Abstract 51
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 ABC+3TC+TDF
• Efficacy
– Virologic failures (any timepoint): 12/36
• 4 patients had early viral rebound > 0.7 log10 copies/mL
• 8 patients never achieved HIV-1 RNA < 400 copies/mL
– Virologic responders (HIV-1 RNA < 50 copies/mL at 24 weeks): 17/26
• All (8) patients who entered study with HIV-1 RNA < 10,000 copies/mL
• 9 of 18 patients with baseline HIV-1 RNA > 10,000 copies/mL
• High rate of early virologic failure similar to those observed in other recent
studies of ABC+3TC+TDF
Abstract 52
Initial Antiretroviral Therapy (3) Continued
Once-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 < 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
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 > 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% < 200 cells/mcL)
• Efficacy (24 weeks)
Outcome
All subjects
Baseline VL <105 copies/mL
Baseline VL ≥ 105 copies/mL
HIV-1 RNA <400
copies/mL
42/54 (78%)
16/19 (84%)
26/35 (74%)
HIV-1 RNA <50
copies/mL
36/54 (67%)
15/19 (79%)
21/35 (60%)
Nonresponse
8/54 (15%)
1/19 (5%)
7/35 (20%)
– HIV genotypes in nonresponders: 2 WT, 1 K65R, 3 M184V + TAMS, 2 TAMS
• Although preliminary, once-daily TZV+TDF may prove useful in patients with
lower viral loads
Abstract 53
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
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
• Overall, ATV/RTV was comparable in efficacy to LPV/RTV
Abstract 547
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 < .005 (ATV regimens vs LPV/RTV)
• ATV regimens were generally associated with favorable lipid effects compared
with LPV/RTV
Abstract 547
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 >1.5 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
Abstract 141
TNX-355
•Binding/entry inhibitor
•Phase 1b
•Humanized anti-CD4
monoclonal antibody
•Administered intravenously
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).
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 HIV1 RNA reductions > 1.5 log10 copies/mL. The drug appeared to be
safe.
•Binding/entry inhibitor
•CCR5 coreceptor antagonist
•Phase 1/2
•Orally available, small-molecule
Abstract 140LB
GW873140
•Binding/entry inhibitor
•CCR5 coreceptor antagonist
•Phase 1/2
•Orally available, small-molecule
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).
New and Investigational Agents (3)
Nucleoside/Nucleotide 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 NRTIresistant HIV
Abstract 137
SPD754
•Deoxycytidine analog RTI
•Phase 1
•In vitro activity against NRTIresistant HIV
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.
New and Investigational Agents (4)
Additional Developmental Agents
Agent/Description
TMC114
• HIV-1 protease inhibitor
• In vitro activity against PI•
resistant HIV
Phase 2 development
Comment
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, 0.52.5).
Abstract 533
PA-457
• Maturation inhibitor
• Prevents release of infectious
•
virus from infected cells
Preclinical testing
Abstract 545
New NNRTIs
• Include GW678248,
GW695634, and novel, NVPlike compounds
Preclinical testing
•
Abstracts 529, 530, 531
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.
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.
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
Complications of HIV Infection and Its Therapy (2)
Predictors of Hypertension in HIV-Infected Patients in the D:A:D 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 D:A:D 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
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 < 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 therapyassociated lipoatrophy
Abstract 79
Complications of HIV Infection and Its Therapy (4)
Effects of Switching PI to NNRTI or Abacavir to Treat Lipodystrophy:
NEFA 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
TC:HDL-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; TC:HDL-C = Total cholesterol:high-density lipoprotein cholesterol ratio
– Switch to any of the 3 treatments improved insulin resistance, total cholesterol (TC), LDL-C,
and TC:HDL-C ratio
– Slightly better changes in TC:HDL-C were seen with switch to either NNRTI vs ABC
• Marked metabolic improvements were seen with switch to PI-sparing
therapy
Abstract 78