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, FACPUSF 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

– 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

Abstract 570

Prospective, randomized, comparative study of 2 initial antiretroviral regimens

• 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

Initial Antiretroviral Therapy (2)

Once-Daily (QD) Didanosine (ddI) + Lamivudine (3TC) + Tenofovir DF (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

24-week pilot study evaluating potency and safety of ddI+3TC+TDF

Initial Antiretroviral Therapy (3)Once-Daily (QD) Abacavir (ABC) + Lamivudine (3TC) + Tenofovir (TDF):

Tonus Study

• 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

Pilot study of 38 antiretroviral-naive patients treated with QD ABC+3TC+TDF

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 < 400 copies/mL (n = 10)

• M184V + K65R: 7/10

• M184V only: 2/10

Abstract 52

• 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

Initial Antiretroviral Therapy (4)Once-Daily (QD) Trizivir (TZV) + Tenofovir DF (TDF): COL40263

– 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)

– 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

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%)

Abstract 53

Early, interim analysis of a pilot study of QD quadruple-NRTI/NtRTI regimen in antiretroviral-naive subjects

Treatment Failure and Second-line Therapy (1) Atazanavir (ATV)/Ritonavir (RTV) vs ATV/Saquinavir (SQV) vs Lopinavir (LPV)/RTV: BMS 045 (48-Week Results)

– 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/RTVAbstract 547

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

Ongoing, prospective study in patients with ≥ 2 prior HAART failures

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

• ATV regimens were generally associated with favorable lipid effects compared with LPV/RTV

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)

Abstract 547

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)

• 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

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 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

Abstract 536

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 > 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 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

Abstract 139

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 NRTI-resistant HIV

Abstract 137

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

Abstract 138

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

Abstract 533

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

Abstract 545

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

Abstracts 529, 530, 531

Complications of HIV Infection and Its Therapy (1)Hyperglycemia and Diabetes

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

Abstract 73

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])

• 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

Complications of HIV Infection and Its Therapy (2)Predictors of Hypertension in HIV-Infected Patients in the D:A:D Study

Abstract 75

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

• Antiretroviral therapy was not an independent prognostic factor of blood pressure changes or hypertension in this study

• Antiretroviral therapy was not a predictor of hypertension– By cumulative duration of exposure to each class of antiretroviral– By type of regimen at baseline

• 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

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)

Abstract 79

• Rosiglitazone not effective for the treatment of HIV/antiretroviral therapy-associated lipoatrophy

– 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

• Metabolic outcomes at 24 months (% change from baseline)

Complications of HIV Infection and Its Therapy (4)Effects of Switching PI to NNRTI or Abacavir to Treat Lipodystrophy:NEFA SubstudyAnalysis from a randomized study of patients who substituted abacavir (ABC), efavirenz (EFV), or nevirapine (NVP) for PI

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