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Long term Ambrisentan Therapy in Patients with HIV Infection: A Meta-analysis from the Ambrisentan Studies

Harrison Farber

H. Gillies

M. Allard

C. Blair


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Farber HW1; Gillies H2; Allard M2; Blair C2

1. Boston University School of Medicine, Boston, MA, USA
2. Gilead Sciences Inc., Foster City, CA, USA

BACKGROUNDAmbrisentan (ABS) is an oral, once-daily ETA-selective endothelin receptor antagonist approved for treatment of Group 1 pulmonary arterial hypertension (PAH). Presented here is an exploratory post-hoc meta-analysis examining for the first time long-term (48 weeks) efficacy and safety of ABS in patients with PAH associated with HIV infection.

METHODSSeventeen patients with PAH associated with HIV infection were enrolled in ABS clinical studies and received ABS therapy: AMB-220 then AMB220/E (n=2/54 patients), ARIES-1 and ARIES-2 then ARIES-E (n=11/383 patients), and ARIES-3 (n=4/224 patients). AMB-220/E was the open label long term extension of AMB-220, a phase 2, 12-week double-blind, dose-ranging study. ARIES-E was the open label long term extension of two Phase 3, 12-week, placebo-controlled studies (ARIES-1 and ARIES-2). ARIES-3 was an open-label study that evaluated efficacy and safety of ABS in Group 1, 3, 4, and 5 pulmonary hypertension. Patients received ABS doses of 1mg (n=1), 2.5 mg (n=3), 5 mg (n=11), or 10 mg (n=2). Most patients (94%) were receiving antiretroviral therapy. The 48-week endpoints from AMB-220/E, ARIES-E and ARIES-3 include: change in 6-minute walk distance (6MWD), Borg Dyspnea Index (BDI), and WHO functional class (FC); survival; and time to clinical worsening. Change at week 48 from baseline is represented by descriptive statistics and last observation carried forward imputation for missing data.

RESULTSIncluded are 10 males and 7 females: mean age of 459 years; WHO FC II (65%) and FC III (35%). Pulmonary vascular resistance (PVR) was 759±365 dyne.sec/cm5, mean pulmonary arterial pressure (mPAP) was 49±11 mmHg, cardiac index was 2.9±0.9 L/min/m2, mean right atrial pressure (mRAP) was 8.5±4.3 mmHg. At baseline, 6MWD was 364±6m and BDI was 3.1±2.4. At week 48, improvements were observed in 6MWD (+63m, 95% CI: +34 to +93) and BDI (-1.5, 95% CI: -2.94 to -0.02). All patients remaining on ABS improved or maintained their WHO FC and no patient died or experienced clinical worsening events. The most frequent adverse events were peripheral edema (29%), arthralgias (18%), and sinusitis (18%). Two subjects discontinued ABS due to adverse events: One patient due to headache and nasal congestion and 1 patient with a history of hepatitis C discontinued due to moderate transient elevations in serum aminotransferase.

CONCLUSIONSLong term ABS therapy in patients with PAH associated with HIV infection was well tolerated and provided clinically relevant improvements in exercise ability, dyspnea, and WHO functional class.