Louiza Patsis, MS June 1, 2005
TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial

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Summary of Key Conclusions
• TMC114/RTV showed a potent antiretroviral effect over 14 days in multiple protein inhibitor (PI)-experienced patients
• TMC114/RTV significantly reduced plasma HIV-1 RNA
• TMC114/RTV was well-tolerated.

Background
• PIs have reduced morbidity and mortality in HIV patients
o But resistance has created the need for new PIs
• TMC114/RTV is a new PI with 3(R), 3a(S), 6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere, and occupies a volume within the substrate envelope
o Most PI’s occupy areas that extend beyond the substrate envelope
o TMC114/RTVforms strong hydrogen bonds with residues in the main chains of the protease active site
o TMC114/RTV had individual 50% effective concentration (EC50) against wild-type HIV-1 of 4.6 nmol/1 and little or no loss of activity against highly PI-cross-resistant clinical isolates
• TMC114/RTV pharmacokinetics are enhanced by co-administration of low-dose ritonavir (RTV)

Summary of Study Design

• Randomized, multicenter, controlled, open label design at 15 centers in Europe
• March to August 2002
• N=50
• Approved by local, independent ethics committees
• Written, informed consent of patients obtained
• Screening process four weeks before randomization included:
o Medical history
o Plasma HIV-1 RNA measurement
o Genotype and phenotype resistance analysis at screening, baseline, end of treatment/withdrawal, and at 3-week follow-up visits
• Patients were randomized to TMC114/RTV 300/100 mg twice daily, 900/100 mg daily or 600/100 mg twice daily as substitution for existing PIs, or remained on current regimen
• Each study lasted 14 days
• TMC114/RTV was formulated as an oral solution in polyethylene glycol 400 (PEG400)
• Patient ART and nucleoside reverse transcriptase inhibitors (RTIs) remained the same throughout treatment
• The following assessments were made: time-averaged difference (DAVG) in HIV-1 RNA form baseline, change in HIV-1 RNA form baseline, proportions achieving plasma HIV-1 RNA form baseline, change in HIV-1 RNA from baseline, and proportions achieving plasma HIV-1 RNA < 400 copies/ml and = .5 and = log10 copies/ml reductions in HIV-1 RNA
• Adverse effects (AEs) were graded using a modified version of the Adult AIDS Clinical Trial Group (AACTG) Table for Grading Severity of Adult Adverse Experiences
• Efficacy parameters:
o Primary: time-averaged difference of plasma HIV-1 RNA
o Secondary: Change form baseline in HIV-1 RNA at all time points, nadir and nadir of change, and change in CD4 cell count
o Proportions of patients with = 0.5 and = 1.0 log10 copies/ml decreases from baseline
o HIV-1 RNA < 400 and < 50 copies, ml
o Effects of lopinavir/RTV in non-suppressive regimen
o Number of baseline primary PI mutations

Baseline Characteristics

• Lack of virological suppression (plasma HIV-1 RNA > 2000 copies/ml) on their current ART with nucleoside RTIs and at least one PI

Eligibility

• Inclusion Criteria
o HIV-infected patients =18 years with = 2 months’ prior exposure to 2 to 4 PI drugs

• Exclusion Criteria
o Non-nucleoside RTI in the non-suppressive regimen
o Receipt of investigational drug within 30 days
o CD4 cell count < 50 X 106 cells/l at screening
o Life expectancy of < 6 months
o Acute hepatitis A or acute or chronic hepatitis B or C
o Prior exposure to TMC114
o Serum creatinine > 2 X upper limit of normal (ULN)
o Pancreatic amylase or lipase > 1.5 X ULN
o Haemoglobin < 5.7 mmol/l (men) or < 5.6 mmol/l (women)
o Platelet < 75 X 109 cells/l
o Absolute neutrophils < 1.0 X 109 cells/l
o Alanine aminotransferase, aspartate aminotransferrase or gammaglutamyl-aminotransferase > 2.5 X ULN
o Total bilirubin > 1.5 X ULN

Main Findings

TMC114/RTV Groups Control Group
DAVG responses (P<.001) Range -.56 to -.81 log10 copies/ml -.03 log10 copies/ml
Median change at day 14 -1.38 and +.02 log10 copies/ml -1.38 and +.02 log10 copies/ml
Reduction of = .5 and = 1.0 log10 copies/ml 97% and 76% (respectively) 25% and 17% (respectively)
HIV-1 RNA < 400 copies/ml at any time during treatment 40% 8%

• Most common reported AEs were gastrointestinal and central nervous system disorders (mild to moderate severity)
• No dose relationship was observed
• No significant changes in liver function tests and biochemical, haemotological and electrocardiographic parameters
• No differences in type or frequency of AEs were noted among the three TMC114/RTV groups

Reference

Arastéh K, Clumeck N, Pozniak A, et al. TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial. AIDS 2005;19:943-947.