Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials

Clinical Infectious Diseases, Feb 2010

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.

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Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials

0 Received 12 June 2009; accepted 2 October 2009; electronically published 19 January 2010 1 Members of the study group are listed at the end of the text. 1000, UG3D-56, North Wales, PA 19454-1099 BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone. - tidrug-resistant HIV-1 in vitro [1, 2]. In phase II clinical trials, raltegravir demonstrated potent and durable antiretroviral activity for up to 96 weeks when given with optimized background therapy (OBT) in treatment-experienced patients [3] or with tenofovir and lamivudine in treatment-naive patients [4]. Week 48 results of the BENCHMRK phase III studies confirmed the efficacy of raltegravir in treatment-experienced patients infected with multidrug-resistant HIV-1 [5, 6]. This report presents follow-up results through week 96 of the ongoing BENCHMRK studies. Methods. BENCHMRK-1 (protocol 018; NCT 00293267) and BENCHMRK-2 (protocol 019; NCT 00293254) are doubleblind, randomized, phase III studies with identical study designs, as described elsewhere [5]. This report presents efficacy results through study week 96 and all available safety data from the double-blind phase through 29 August 2008 (week 96 database lock). From study weeks 1648, virologic failure was defined as !1 log10 decrease in HIV RNA levels from baseline, confirmed 11 log10 increase in HIV RNA level from the nadir, or 2 consecutive HIV RNA level measurements 400 copies/ mL after a prior result of !400 copies/mL. To be consistent with the recently updated recommended target for viral suppression [7], virologic failure after week 48 was defined as confirmed HIV RNA level 50 copies/mL (2 consecutive measurements at least 1 week apart). Patients with virologic failure at any time after week 16 could (1) exit the double-blind study and enter an open-label phase to receive raltegravir as part of a new regimen, (2) remain in the blinded study, or (3) withdraw from the study. The potential emergence of resistance to raltegravir was investigated in patients with virologic failure by genotyping the integrase coding sequence according to standard methods [6] and by comparison with pretreatment genotypes. The following predefined end points were examined at week 96: proportion of patients with HIV RNA levels !50 copies/ mL, proportion of patients with HIV RNA levels !400 copies/ mL, change from baseline in log10 HIV RNA level (copies/mL), and change from baseline in CD4 cell count (cells/mm3). For the proportions over time analysis, a worst-case approach as used that counted all patients who did not complete the study as treatment failures; missing HIV RNA level measurements were imputed as failures unless the values flanking the missing value were both successes, in which case the absent value was left as missing. For the change from baseline analyses, an observed failure approach was used: patients who discontinued treatment for lack of efficacy were assumed to have returned to their baseline value at subsequent times, but no other missing values were imputed. Data from patients who discontinued Table 1. Patient Disposition Variable Treated No. (%) of patients Raltegravir and OBT Placebo and OBT NOTE. OBT, optimized background therapy; OLPVF, open-label postvirologic failure. a Patients completed original 48-week protocol but did not continue into extension. b Including patients who moved or relocated, or the clinical trial was terminated at the site. treatment for other reasons were censored at discontinuation. The observed failure approach was also used for exploratory subgroup analyses by potential prognostic factors and for the assessment of treatment effect homogeneity across subpopulations. Suspected AIDS-defining events were reviewed by an independent adjudicator, and blinded safety and efficacy results were periodically reviewed by an independent Data and Safety Monitoring Board. Additional details of the statistical analyses and the adjudication of AIDS-defining events are described elsewhere [5]. Results. Baseline characteristics were generally balanced between treatment groups [5]. Most enrolled patients were highly treatment-experienced white male individuals with AIDS. Duration of double-blind follow-up was longer in the raltegravir group (median, 110.4 weeks; range, 3.0127.4 weeks) than in the placebo group (median, 37.6 weeks; range, 5.6126.4 weeks) because of more frequent discontinuations for virologic failure among placebo recipients (Table 1). Virologic and immunologic responses were consistent be Variable Death No. of patients/PYR at risk (rate, cases per 100 PYR) Raltegravir (...truncated)


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Roy T. Steigbigel, David A. Cooper, Hedy Teppler, Joseph J. Eron, Jose M. Gatell, Princy N. Kumar, Jurgen K. Rockstroh, Mauro Schechter, Christine Katlama, Martin Markowitz, Patrick Yeni, Mona R. Loutfy, Adriano Lazzarin, Jeffrey L. Lennox, Bonaventura Clotet, Jing Zhao, Hong Wan, Rand R. Rhodes, Kim M. Strohmaier, Richard J. Barnard, Robin D. Isaacs, Bach-Yen T. Nguyen, BENCHMRK Study Teams. Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials, Clinical Infectious Diseases, 2010, pp. 605-612, 50/4, DOI: 10.1086/650002