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Long-term Safety Profile of Bosentan in Patients with Pulmonary Arterial Hypertension Associated with HIV: Results from the Tracleer PMS Database
M Humbert1, M Hoeper2, D Kiely3, Eleanor Segal*4, and J Carlsen5
1Hosp Antoine Beclere, Clamart, France; 2Hannover Med Sch, Germany; 3Royal Hallamshire Hosp, Sheffield, UK; 4Actelion Pharma, Allschwil, Switzerland; and 5Rigshospitalet, Copenhagen, Denmark
Background. Pulmonary
arterial hypertension (PAH) is a devastating complication of HIV, which occurs
in 0.2 to 0.5% of patients irrespective of the severity of immunodeficiency.
The oral dual endothelin (ETA/ETB) antagonist bosentan is
used in first-line therapy of PAH according to recent guidelines. In order to
obtain long-term safety data in particular on the incidence of liver function
test (ALT/AST) elevations on bosentan, a novel postmarketing surveillance
program (PMS) was established to monitor patients with PAH under clinical
practice conditions.
Methods: Web-based non-interventional prospective
database, which provided treatment and drug monitoring algorithms and collected
potential signals, categorized as either safety or non-safety. Potential safety
signals included adverse events with focus on elevations of ALT/AST. Non-safety
signals included reasons for discontinuation such as patient request,
non-medical reason, or lost to follow up. As both accurate numbers of signals
(numerators) and numbers of exposed individuals (denominator) were known, the
true rate of signal frequency could be calculated.
Results: From May 2002 until Nov 2004, a total of 102
patients with PAH-HIV (61% males; 30-40 yrs: 47.1%, 41-50 yrs: 46.1%) were
included. 3.9% of patients were in NYHA class I, 14.7% in class II, 66.7% in
class III and 7.8% in class IV. Concomitant medications at baseline included
anticoagulants in 57.8%, prostanoids in 22.5% (epoprostenol
12.7%, iloprost 4.9%, beraprost 4.9%), and sildenafil in 5.9%. Mean exposure to
bosentan was 38.8 (± 30.7) weeks. 30 patients (29.4%) were treated with
bosentan for at least 1 year. Potential signals were recorded in 34.3 %, which
was lower compared to the rates in idiopathic PAH (IPAH: 44.0 %). Elevated
ALT/AST values after bosentan initiation were recorded in 8.8% (IPAH: 8.4%),
with the following breakdown: < 3 x upper limit of normal (ULN):
1.0%; >3 x to ≤ 5 x ULN: 3.9%; > 5 x to ≤ 8 x ULN: 2.0%; >
8 x ULN: 1.0%; unknown values: 1.0%. Median time to onset of ALT/AST elevations
was 43 days. There were no cases of fatal or permanent liver injury associated
with bosentan.
Conclusions: Long-term bosentan treatment was well
tolerated in patients with PAH-HIV. The incidence of ALT/AST elevations was
similar to that in the IPAH group.
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