12th CROI Abstract #164LB

Session 37 Oral Abstracts
Antiretroviral Therapy: New Agents, New Combinations, and Virologic Responses
Friday, 10 am - 12:30 pm
Presentation Time: 12:00 pm
Auditorium

164LB
Efficacy of TMC114/r in 3-Class Experienced Patients with Limited Treatment Options: 24-Week Planned Interim Analysis of 2 96-week Multinational Dose-finding Trials
C Katlama¹, D Berger², N Bellos³, B Grinsztejn⁴, Richard Haubrich*⁵, T Wilkin⁶, J M Molina⁷, C Steinhart^8,9, R Pedro¹⁰, M P de Béthune¹¹, S De Meyer¹¹, R Hoetelmans¹¹, W Parys¹², T Vangeneuden¹¹, and E Lefebvre¹²
¹Hosp Pitie-Salpetriere, Paris, France; ²Univ of Illinois, Chicago, USA; ³Southwest Infectious Disease Associates, Dallas, TX, USA; ⁴Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz, Rio de Janeiro, Brasil; ⁵Univ of California, San Diego, USA; ⁶Weill Med Coll, Cornell Univ, New York, NY, USA; ⁷Hosp St-Louis, Paris, France; ⁸Steinhart Medical Associates, Miami, FL, USA ; ⁹Mercy Hospital, Miami, FL, USA; ¹⁰UNICAMP, Campinas, Brazil; ¹¹Tibotec, Mechelen, Belgium; and ¹²Tibotec, Yardley, PA, USA

Background: Achieving virologic suppression in highly treatment experienced HIV patients has been challenging. TMC114 is a novel protease inhibitor (PI) that previously has shown potent activity in PI-resistant patients in a 14-day trial.

Methods: Patients were ³ 3-class experienced with prior use of ³ 1 PI, ³ 1 primary PI mutation and HIV RNA (viral load) ³ 1000 copies/mL. They were randomized to receive OBR (at least 2 NRTI with or without T-20) and 1 of 4 doses of TMC114/r or CPI of choice. Patients were stratified by use of T-20, number of primary PI mutations, and baseline viral load. A combined interim analysis was performed when at least 150 patients in each trial had been treated for at least 24 weeks or had discontinued earlier. The primary endpoint was thedecrease in viral load from baseline at week 24 and 1 secondary endpoint was proportion of patients with ³ 1 log₁₀ viral load decrease. Data were analyzed by intent to treat (for non-completers, week 24 viral load imputed as baseline viral load). Most discontinuations in the control group were due to virologic failure.

Results: Included in this analysis were 497 HIV-1-infected patients. Baseline median values were HIV RNA 4.6 log₁₀copies/mL, CD4 count 141 cells/µL, PI-resistance-associated mutations 8, PI primary mutations 3, phenotypic resistance (Antivirogram) to all approved PI 66%, fold change for TMC114 4.3. Overall, 47% of patients used T-20 in their OBR, evenly balanced across all treatment groups. In the CPI group, 71% of patients used single, 27% double boosted PI, and 2% used dual unboosted PI. Week 24 interim results (intent to treat) were:

TMC114/r	400/100 once daily	800/100 once daily	400/100 twice daily	600/100 twice daily	CPI
	n =100	n = 100	n = 98	n = 99	n = 100
Mean HIV RNA change	–1.28	–1.43	–1.47	–1.85	–0.27
% ³ 1 log reduction	55	56	58	72	16
% < 400 copies/mL	46	48	55	59	16
% < 50 copies/mL	30	31	38	47	10
% grade 3 and 4 adverse events	23	26	26	26	23
% severe adverse events	10	17	16	9	11

The mean CD4 change was +75 cells/µL for TMC114/r 600/100 twice daily vs +15 cells/µL for CPI (week 24 intent to treat). No differences between all TMC114/r dose groups were observed with regard to the number of overall adverse events, grade 3 or 4 adverse events, severe adverse events, adverse events leading to discontinuation or laboratory abnormalities and no differences found vs CPI.

Conclusions: TMC114/r demonstrated unprecedented efficacy in three class-experienced patients with limited treatment options. All TMC114/r doses were generally safe and well tolerated. The recommended dose for further clinical development in treatment-experienced patients is 600/100 mg twice daily.

Keywords: TMC114; Efficacy; Resistance