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Pulmonary Hypertension: Another Look
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Written for NATAP by Judith Aberg, MD, Bellevue Hospital, New York University Medical Center
Pulmonary hypertension is an uncommon blood vessel disorder of the lung that causes the pressure in the pulmonary artery to increase. The pulmonary artery is the blood vessel from the heart to the lung. When the pressures get too high, it becomes life threatening. The most common symptoms are shortness of breath which worsens when one becomes active, fatigue and sometimes dizzy spells and chest pain. Initially the symptoms may be mild and sometimes people mistake the shortness of breath for "being out of shape". It is called primary pulmonary hypertension (PPH) when the cause is unknown. It is referred to as secondary when there are known contributors such as connective tissue disorders, blood clots to the long, recurrent pneumonias or bronchitis or other known lung disorders. It is often mis-diagnosed at early stages. The mortality remains high but some people with PH are now living with their disease up to 20 years thanks to new medications such as bosentan.
Every few years, a group of investigators will explore the incidence or prevalence of HIV-associated pulmonary arterial hypertension (PAH). There is little data regarding the true incidence of primary pulmonary hypertension (PPH) among HIV-infected patients. Autopsy series prior to the introduction of HAART suggested that PPH was significantly more common among people infected with HIV (incidence of 0.5%) compared to the "general population" (incidence 0.01-01%). It remains unclear whether it is associated with HIV itself or whether it is that those infected with HIV are more at risk of developing secondary pulmonary hypertension (SPH) due to recurrent pneumonias, pulmonary emboli (blood clots) or mitral valve disease. Regardless of the cause, the prognosis remains extremely poor among persons with pulmonary hypertension from any cause and it is estimated that the survival rate among HIV-infected patients with PPH at 2 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 hemodynamics in non-HIV infected patients with pulmonary arterial hypertension. There have also been case reports of using sildenafil (Viagra) but its use remains investigational. At CROI this year, there were three posters regarding PAH; 2 looking at the prevalence and one reporting on the long-term safety of bosentan.
Poster 743: HIV is Associated with Pulmonary Hypertension Independent of Known Risk Factors
Background: Previous data have suggested a high prevalence of elevated pulmonary artery pressures (PAP) in HIV-infected patients, but this work has been limited by the lack of a well-characterized HIV-uninfected comparison group. In patients without HIV, human herpesvirus 8 (HHV-8) infection has been recently linked to pulmonary hypertension. Because HIV-infected patients have a high prevalence of HHV-8 infection, we hypothesized that, when compared to carefully characterized HIV-uninfected individuals, HIV-infected persons would have a higher prevalence of elevated PAP and that this would be related to HHV-8 infection.
Methods: Among a clinic-based cohort of HIV-infected adults (the SCOPE cohort in San Francisco) and community-based HIV-uninfected volunteers, we calculated PAP echocardiographically by measuring the velocity of tricuspid regurgitation to obtain right ventricular (RV) systolic pressure. Mean right atrial (RA) pressure was estimated by assessing inferior vena cava size and collapse. PAP was the sum of estimated RV and RA pressures. HHV-8 antibodies were detected using two enzyme-linked immunoassays and one immunofluorescence assay.
Results: We examined 186 HIV-infected and 36 HIV-uninfected adults. HIV-infected subjects had a median PAP of 26mm Hg [interquartile range (IQR): 19 to 31] compared to 21mm Hg (IQR: 17 to 26) among HIV-uninfected subjects (p=0.001). PAP > 30mm Hg was found in 30% of HIV patients compared to 6% of controls (p=0.003). After adjustment for age, gender, smoking, and intravenous drug use, HIV-infected subjects had 5.5 fold greater odds of having a PAP > 30mm Hg (p=0.02). PAP > 40mm Hg was found in 6% of HIV patients compared to 0% of controls (p=0.28). Of HIV-infected subjects, 56% were HHV-8 antibody positive, but we found no evidence of an association between HHV-8 seropositivity and PAP > 30mm Hg (OR =1.4, p=0.38), even after adjustment for confounding factors.
Conclusions: HIV-infected patients have higher PA systolic pressures independent of age, gender, smoking, and injection drug use history. In contrast, we found no evidence to support an association between HHV-8 infection and elevated PAP. The mechanisms for the higher prevalence of elevated PAP in HIV-infected subjects as well as the natural history of elevated PAP in this group merit further study.
Comment: This study supports the findings of D.Montani and colleagues (AIDS 2005;19:1239-40). In this French study, they looked for HHV-8 antibodies in 93 subjects with PAH; 47 with idiopathic or familial PAH, 34 with PAH related to HIV infection, and 12 with PAH associated with other conditions. They found positive HHV-8antibodies in 1, 8 and 2 of the subjects respectively, suggesting that HHV-8 is unlikely to be the cause.
Poster 744: Prevalence of Pulmonary Arterial Hypertension in HIV Positive Outpatients in the HAART Era (Bold print in abstract reflects revised data in poster presentation)
Background: Pulmonary Arterial Hypertension (PAH) is a rare but severe complication of HIV infection. When early studies in the 90s reported a prevalence of 0.50% [95% CI: 0.10-0.90%], recent reports are controversial with regards to impact of HAART. The objective of our study was to assess the prevalence of PAH in a large population of patients followed for HIV infection according to current medical management.
Methods: This prospective nationwide study was conducted in 15 HIV centers in France. Consecutive HIV patients attending the clinic for their regular follow-up were assessed for dyspnea based on a questionnaire. Unless another cause was diagnosed, patients with dyspnea (NYHA functional class ≥ 2) were screened for PAH according to a pre-defined algorithm based on transthoracic Doppler echocardiography (TTE): PAH was suspected if the peak velocity of tricuspid regurgitation was > 2.5 m/s, or, when not measurable, if the peak velocity of pulmonary regurgitation was > 2.0 m/s (proto diastolic) or > 1.2 m/s (end diastolic). Right heart catheterization (RHC) was then warranted: PAH was confirmed if mean pulmonary artery pressure was ≥ 25 mmHg at rest with pulmonary capillary wedge pressure < 15 mmHg. Patients with a known PAH previously diagnosed on RHC were also enrolled but did not have to undergo any study procedure.
Results: 7648 patients were seen by the investigational centers during the recruitment period (March 04 to March 05). Among them, 30 patients had a known PAH, and 247 patients were identified as having dyspnea not explained by another cause and underwent all study procedures. TTE results suggested PAH in 18/247 patients (7%). These 18 patients underwent RHC which confirmed PAH in 5. Overall, 35 patients out of 7648 (0.46%; [95% CI: 0.32-0.64%]) presented with PAH.
Conclusion: The low estimate for prevalence of PAH in our study was 0.46%, similar to that previously reported in the 90s. Given the good long term prognosis of HIV patients in the HAART era and the severity of PAH in HIV infected patients, screening for PAH according to a precise algorithm is warranted in patients presenting with dyspnea not explained by another cause.
Comment: Although they found a low rate of PAH among those infected with HIV, the rate remains constant and it is higher than the general population without HIV infection. They also found that there was no significant difference in ART use, HIV VL and CD4 count among those with and without PAH. This is an important observation as previously it was postulated that ART via reduction of HIV VL may reduce the incidence of PAH and also may improve the severity of PAH. They discovered that almost 10% of their clinic population had dyspnea on exertion based upon a dyspnea questionnaire, which lead to patients being offered TEE and heart catheterization. It is important for providers to consider PAH in the differential diagnosis among patients who complain of shortness of breath and also to ask patients if they are having shortness of breath.
Poster 745: Long-term Safety Profile of Bosentan in Patients with Pulmonary Arterial Hypertension Associated with HIV: Results from the Tracleer PMS Database
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.
Comments: This post marketing surveillance was re-assuring that there were no striking adverse events among HIV-infected patients with PAH taking bosentan. Potential safety signals were noted in 36.7% (iPAH) and 28.4% (PAH/HIV). Discontinuations occured in 28.8% (iPAH) and 17.6 (PAH/HIV), mainly due to death (9.2% / 5.9%), hospitalisation (3.3% / 2.0%), or ALT/AST increases (3.2% / 2.0%). There have been concerns regarding potential drug interactions between bosentan and antiretroviral therapy. Unfortunately, this database did not include a list of specific HIV medications nor did they report the dose the HIV infected patients were taking.
Potential safety and non-safety signals
_ Potential safety signals (see figure below) were noted in 36.7% (iPAH) and 28.4% (PAH/HIV).
_ Discontinuations occured in 28.8% (iPAH) and 17.6 (PAH/HIV), mainly due to death (9.2% / 5.9%), hospitalisation (3.3% / 2.0%), or ALT/AST increases (3.2% / 2.0%).
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