Pulmonary hypertension: finally a treatment trial!
Judith Aberg MD, for NATAP.org
There is little data regarding the true incidence of primary pulmonary hypertension (PPH) among HIV-positive patients. Autopsy series prior to the introduction of HAART suggested that PPH was significantly more common among HIV-positive people (incidence of 0.5%) compared to the “general population” (incidence 0.01-01%). Prognosis is extremely poor among persons with PPH and it is estimated that the survival rate among HIV-positive patients with PPH at two years is between 32-46%.
The pathogenesis of PPH is not completely understood. There is limited evidence to suggest that endothelin-1 over expression may be the primary cause of PPH. Endothelin-1 is a potent vasoconstrictor (narrows the pulmonary blood vessels). Bosentan (trade name Tracleer) is an orally administered dual endothelin-receptor antagonist that has been shown to improve exercise capacity and cardiopulmonary haemodynamics in HIV-negative patients with pulmonary arterial hypertension. This is the first study I am aware of studying its effects in HIV-associated PPH.
This is an open-label, non-comparative, multi-centre trial evaluating the efficacy and safety of bosentan in HIV-positive patients with PPH. Patients with HIV-associated PPH and NYHA functional class III received bosentan for 16 weeks (62.5 mg bid for four weeks; thereafter 125 mg bid) with either >3 months antiretroviral therapy (ART) or not on ART and CD4 count >100 cells/mm3. Patients with portal hypertension, cirrhosis or liver enzymes >3 x upper limit of normal were excluded.
Safety was assessed by CD4 cell count, viral load, liver function and adverse events. Efficacy was assessed by exercise capacity, NYHA class and haemodynamics (right heart catheterisation). The study was to enrol 30 patients; however an interim analysis of the first 10 subjects revealed significant results and enrolment was closed at 17 subjects. Results were reported on 16 subjects who completed 16 weeks of study.
Baseline characteristics of the 16 subjects are as follows: nine male, age 39 + 8 years, one HBV co-infected, three HCV co-infected, median CD4 count 333 cells/mm3, and seven subjects with HIV VL <400 copies/ml.
After eight weeks, there were no significant changes in CD4 count or the number of patients with suppression of HIV-1 RNA, suggesting no significant effect of bosentan on control of HIV infection. Adverse events included cramps (n=2), headaches (n=4), ALT/AST >3 x ULN (n=2), leg edema and/or weight gain (n=6), which improved with diuretics.
At 16 weeks, subjects improved their six-minute walk distance from 333±20 to 424±14 m (P<0.001), NYHA class (14 improved to Class I or II; two remained in Class III) and cardiac index (2. ± 0.2 to 3.4 ± 0.2l/min/m2; P<0.001). Significant decreases in pulmonary vascular resistance (781±64 to 476±64 dyn.sec/cm5; P<0.001), and mean pulmonary arterial pressure (51.7±3.4 to 43.3±3.8 mm Hg;P=0.051) were also observed. No patient died, required epoprostenol therapy or hospitalisation for pulmonary arterial hypertension during the study. One patient subsequently died although the cause of death was unknown but did involve illicit drug use. These preliminary results suggest that bosentan significantly improves PPH symptoms, functional status, exercise capacity and haemodynamics similar to those reported in the HIV seronegative population.
Bosentan appears safe when given concomitantly with antiretroviral therapy and is well-tolerated. One has to be cautious about this as the actual ART regimens were not discussed and there may be significant drug interactions as discussed below.
Nevertheless, this is extremely welcome news. I have had several patients die in the past from PPH. I have one woman who is now on bosentan for over one year and is clinically doing well. Her exercise capacity and functional status have improved remarkably. So, it is nice to see a study that supports its use. I have had concerns of potential drug interactions with bosentan. The package insert states it is a substrate of CYP2C8/9, 3A4 and induces CYP2C8/9, 3A4.
There is a large list of potential interactions as follows:
Cyclosporine: Bosentan may enhance the metabolism of cyclosporine, decreasing its serum concentrations by 50%; effect on sirolimus and/or tacrolimus has not been specifically evaluated, but may be similar. Cyclosporine increases serum concentrations of bosentan (approximately 3-4 times baseline). Concurrent use of cyclosporine is contraindicated.
Glyburide: An increased risk of serum transaminase elevations was observed during concurrent therapy with bosentan. Concurrent use is contraindicated.
HMG-CoA reductase inhibitors: Agents metabolised via CYP3A4 may be decreased by bosentan; includes atorvastatin, lovastatin, and simvastatin.
Ketoconazole: May increase the serum concentrations of bosentan; concentrations are increased approximately two-fold; monitor for increased effects. Many interactions have not been specifically evaluated, but may be extrapolated from similar interactions with inducers/inhibitors of CYP3A4 and CYP2C8/9 isoenzymes.
Key potential interactions are summarised as follows:
Anticonvulsants: Bosentan may increase the metabolism of selected anticonvulsants; includes ethosuximide, phenytoin, tiagabine, and zonisamide. The effect of concurrent therapy with enzyme-inducing anticonvulsants on bosentan concentrations has not been established.
Antipsychotics: Bosentan may enhance the metabolism (decrease the efficacy) of antipsychotics; monitor for altered response; dosage adjustment may be needed.
Calcium channel blockers: Bosentan may enhance the metabolism of calcium channel blockers, decreasing their clinical effect.
Corticosteroids: Bosentan may enhance the metabolism of corticosteroids, decreasing their clinical effect.
CYP2C9 inhibitors: May increase the serum concentrations of bosentan; includes amiodarone, fluoxetine, sulfonamides, ritonavir, zafirlukast.
CYP3A4 inhibitors: May increase the serum concentrations of bosentan; includes amiodarone, cimetidine, clarithromycin, erythromycin, delavirdine, diltiazem, dirithromycin, disulfiram, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nevirapine, propoxyphene, quinupristin-dalfopristin, ritonavir, saquinavir, verapamil, zafirlukast, zileuton.
Doxycycline: Bosentan may enhance the metabolism of doxycycline, decreasing its clinical effect; higher dosages may be required.
Oestrogens: Bosentan may increase the metabolism of oestrogens and reduce their efficacy.
Hormonal contraceptives: Bosentan may enhance the metabolism of hormonal contraceptives, decreasing their clinical effect; an alternative method of contraception should be considered.
Methadone: Bosentan may enhance the metabolism of methadone resulting in methadone withdrawal.
Protease inhibitors: Serum concentrations may be decreased by bosentan. Avoid concurrent use of agents metabolised by CYP3A4 or CYP2C8/9.
Warfarin: Bosentan may increase the metabolism of oral anticoagulants; monitor for changes in INR. Significant changes in INR not observed in clinical trials. In addition, the manufacturer recommends avoiding bosentan in moderate to severe hepatic impairment.
Bosentan is associated with a high incidence (11%) of significant transaminase elevations, indicating a potential for serious hepatic injury. Based on animal studies, bosentan is likely to produce major birth defects if used by pregnant women. Ideally, one would like to have pharmacokinetic studies with protease inhibitors and the NNRTIs but it is doubtful these will be done. Usually these patients are on multiple other medications, so it may be difficult to predict the various interactions and one will need to monitor these patients closely for side effects and efficacy. The real test will be whether one can show a survival benefit over time which preliminary data fortunately suggests.
Opravil M, Sitbon O, Gressin V et al. Safety and efficacy of bosentan in pulmonary arterial hypertension associated with HIV infection. Abstract 1007.