Download 24. HIV-associated Pulmonary Hypertension

Etiology, pathogenesis, classification
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24. HIV-associated Pulmonary
Hypertension
Georg Friese, Mirko Steinmüller and Ardeschir Ghofrani
Pulmonary hypertension is a severe life-limiting disease, often affecting younger
patients. The connection between HIV infection and the development of pulmonary
hypertension is well documented (Mette 1992, Simonneau 2004). However, the
underlying pathobiology still remains unclear. Given that the prognosis of HIV infection has been improved by HAART, severe pulmonary hypertension is becoming
a life-limiting factor (Nunes 2002).
Etiology, pathogenesis, classification
Pulmonary hypertension can be caused by vasoconstriction, reduction of arterial
elasticity by structural remodeling of the vessel wall, obstruction of the vessel, and
vessel rarification. All forms show the development of functional alterations (reversible vasoconstriction) and structural changes (vascular remodeling), and often
occur in combination with intravasal thrombosis. The increase in right ventricular
afterload induces right ventricular hypertrophy and/or dilatation.
Chronic pulmonary hypertension is classified using five groups according to the
classification developed at the World Symposium on Primary Pulmonary Hypertension 1998 in Evian (modified in Venice 2003). HIV-associated pulmonary hypertension belongs to group number one (PAH):
Pulmonary arterial hypertension (PAH)
1.1 Primary pulmonary hypertension
a) Sporadic disorder
b) Familial disorder
1.2 Associated with
a) Collagen vascular disease
b) Congenital (right-left) systemic-pulmonary shunt
c) Portal hypertension
d) HIV-associated pulmonary hypertension
e) Drugs
f) Persisting PAH of the newborn
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Pulmonary hypertension is classified into three clinical stages:
Latent pulmonary hypertension is characterized when mean pulmonary arterial
pressures (PAP) are below 21 mmHg with an exercise-induced increase to values
above 30 mmHg. The patients suffer from dyspnea upon exercise. In manifested
pulmonary hypertension, the mean PAP exceeds 25 mmHg at rest. Patients already suffer from dyspnea on light exercise. Severe pulmonary hypertension is
characterized by a severely reduced cardiac output at rest, which cannot be increased upon exercise, due to the increase in right ventricular afterload. Thus, patients are unable to perform any physical activity without distress.
Diagnosis
Right heart catheterization
For diagnosis of chronic pulmonary hypertension, right heart catheterization is still
considered to be the gold standard. It allows the essential parameters of pulmonary
hemodynamics to be evaluated. The main parameter is pulmonary resistance, which
can be abnormal even without affecting pulmonary arterial pressure. A test for reversibility of vasoconstriction should be performed at the stage of manifested pulmonary hypertension, to identify patients responding to vasodilative therapy. These
“responders” are identified using oxygen insufflation or vasodilators during right
heart catheterization. For example, during inhalation of nitric oxide, these patients
show a decrease in pulmonary arterial pressure of 30 % and a simultaneous normalization of cardiac output.
ECG
ECG alterations induced by pulmonary hypertension are present after a two-fold
increase in right heart musculature. Typical signs are:
right axis deviation (mean QRS-axis > + 110°)
RS-ratio in lead V6 < 1
S wave in lead I and Q wave in lead III
S waves in lead I, II and III
increased P-wave amplitude (not obligatory).
Chest radiography
Pulmonary hypertension can be inferred by chest radiography observations:
Enlarged right descending pulmonary artery (diameter > 20 mm)
Central pulmonary arterial dilatation in contrast to narrowed segmental arteries
Pruning of peripheral pulmonary blood vessels
Enlargement of transverse heart diameter and increase of retrosternal contact
area of the right ventricle
Therapy
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Echocardiography
Echocardiography allows recognition of right ventricular dilatation and estimation
of systolic pulmonary arterial pressure. Typical signs are:
right ventricular myocardial hypertrophy
abnormal septum movements
abnormal systolic intervals
abnormal movement patterns of the pulmonary valve
altered ejection flow profile of the right ventricle (transthoracic Doppler echocardiography).
Ventilation-perfusion scan, pulmonary angiography and
CT scan
These radiological techniques are used to identify or exclude chronic thromboembolic pulmonary hypertension (CTEPH) and may guide operative treatment.
CTEPH is an important differential diagnosis in intravenous drug abusing HIVpatients suffering from recurring thromboembolisms (Figure 1).
Therapy
General treatment
Various modalities of general treatment have been established for the therapy of
pulmonary hypertension on the basis of empirical data. These are:
1. Diuretics
In the later stages of pulmonary hypertension, volume retention may cause an
enormous increase in the right ventricular preload followed by congestive hepatomegaly, edema and ascites formation. Volume retention is not only caused by
chronic right heart failure but also by stimulation of the renin-angiotensin system
followed by elevated aldosterone levels. For this reason, a combination of loop diuretics (e.g. furosemide 20-80 mg per day) and aldosterone antagonists (e.g. aldactone 50-200 mg per day) has proved to be successful. The usual contraindications,
as well as the risk of dehydration followed by a critical decrease of right ventricular
preload, have to be considered. A preload of about 6-10 mmHg is needed for optimal right ventricular performance.
2. Digitalis
The use of digitalis is still much debated. According to a randomized placebocontrolled double-blinded trial, only patients simultaneously suffering from Cor
pulmonalis and decreased left ventricular function benefit from digitalis medication.
However, digitalis medication is always justified in the case of tachycardic atrial
arrhythmias. It has to be considered that digitalis has a high arrhythmogenic potential in combination with hypoxemia, which might lead to severe complications.
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accidental diagnosis
symptoms
patient history, examination
cardio-pulmonary
exercise testing
ECG
chest X-ray
echocardiography
unclear
no
suspicion of PH?
Doppler-Echo
end
yes
no
end
screening
further
pathol.
LUFU+ABG+DLCO
PVH?
result?
V/Q-lung scan/CT/PAangiography
lung disease?
yes
diagnostic
and therapy
of
underlying
disease
CTEPH?
no
reevaluation 1 year
later
moderate PH?
yes
no
complete diagnostic
work-up
treatable
derlying
ease?
no
follow-up
•right heart catheterization with
sufficient
success?
pharmacological test
•start of specific therapy
undis-
no
yes
(echocardiography,
6-min.
walk, NYHA,
cardio- pulmonary
exercise
testing)
FIGURE 1. Diagnostic and therapeutic algorithm: suggestion for diagnostic procedures on
suspicion of pulmonary hypertension (adapted from Arbeitsgemeinschaft Pulmonale Hypertonie). LUFU: lung function test; ABG: arterial blood gases; DLCO: CO diffusion capacity.
3. Anticoagulation
After considering the contraindications, the application of heparin or oral anticoagulants such as phenprocoumon and warfarin, are an established treatment for
chronic pulmonary hypertension. Long-term anticoagulation therapy addresses the
following aspects of the pathophysiology of PAH:
increased risk of in-situ thrombosis caused by altered blood flow in narrowed
and deformed pulmonary vessels
increased risk of thrombosis caused by peripheral venous stasis, right ventricular dilatation and reduced physical exercise
decreased levels of circulating thrombin and fibrinogen degradation products,
which are supposed to act as growth factors in vascular remodeling processes.
Therapy
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The dose of anticoagulants should be adjusted to maintain the prothrombin time at
an international normalized ratio (INR) of 2.5.
4. HAART
HAART is considered as a general treatment for HIV-associated pulmonary hypertension. According to the CDC classification, pulmonary hypertension is a symptomatic complication and therefore classified as category B. This is independent of
CD4 cell numbers and virus load, indicating an obligation for antiretroviral treatment. Evidence shows that the prognosis of HIV-associated pulmonary hypertension is improved upon effective antiretroviral therapy (Zuber 2004). Furthermore,
the immune status of this high-risk group has to be stabilized to prevent systemic
infection, especially pneumonia.
Specific treatment
The aim of specific therapy is to decrease pulmonary arterial pressure, thereby reducing the right ventricular afterload. Substances that currently used for the treatment of pulmonary hypertension or tested in clinical studies are:
Calcium channel blockers
Prostanoids (intravenous, inhalative, oral, subcutaneous)
Endothelin receptor antagonists (selective, none-selective)
Phosphodiesterase-5 inhibitors
In addition to the immediate effect of muscle relaxation, some vasodilators (especially prostanoids and phosphodiesterase-5 inhibitors) seem to have a sustained
antiproliferative effect.
1. Calcium channel blockers
Currently nifedipine and diltiazem are the most commonly used calcium channel
blockers. Around 5-10 % of primary pulmonary hypertension patients are so-called
responders. The response to calcium channel blockers should be evaluated during
right heart catheterization.
The major disadvantage of oral calcium channel blockers is their effects on the
systemic circulation. Peripheral vasorelaxation causes hypotension and the negative
inotropic effect of calcium channel blockers leads to a reduction in cardiac output.
Furthermore, non-selective vasodilation in the pulmonary circulation may have disadvantageous effects on gas exchange by increasing ventilation-perfusion mismatches. For long-term therapy, up to 250 mg nifedipine or 720 mg diltiazem is
used. The dose must be increased slowly over weeks to the correct treatment dosage.
2. Intravenous prostacyclin
Reduction of endothelial prostacyclin synthesis in lung tissue has been described in
patients suffering from pulmonary hypertension (Christman 1992, Tuder 1999).
Therefore, substitution of exogenous synthetic prostacyclin is an obvious therapeutic option. Due to its short half-life, iloprost is continuously infused intravenously
using a portable pump via a catheter or an implanted port. The intravenous dosage
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of iloprost is slowly increased to a usual dose of between 0.5 and 2.0 ng per kg
bodyweight per minute.
The treatment of outpatients with intravenous prostacyclin is today an established
treatment for long-term therapy of severe pulmonary hypertension (Barst 1996,
Sitbon 2002). Long-term therapy with intravenous prostacyclin induces a sustained
hemodynamic benefit in the treatment of primary pulmonary hypertension (e.g.
HIV-associated pulmonary hypertension).
The disadvantages of intravenous prostacyclin are:
systemic side effects of non-selective vasodilators, e.g. arterial hypotension,
orthostasis, skin hyperemia, diarrhea, jaw- and headache
risk of acute right heart decompensation due to application failures
possible catheter infection
tachyphylaxis
Tachyphylaxis is observed in long-term application of intravenous prostacyclin and
requires increased doses.
Conclusion: experiences with prostacyclin in HIV-associated pulmonary hypertension are based on smaller, uncontrolled trials. However, these studies suggest an
improvement in the prognosis of affected patients (Aguilar 2000, Cea-Calvo 2003).
3. Inhalative prostanoids
Many disadvantages of intravenous application can be avoided by using aerosolized
prostanoids (e.g. the recently approved prostanoid Ventavis™). Alveolar deposition
of prostanoids stimulates a selective intrapulmonary effect. Repeated inhalation of
iloprost has proved to be effective and safe in HIV-negative patients in a recent
multi-centric, randomized placebo-controlled trial (Olschewski 2002). Iloprosttreated patients showed a significant improvement in exercise capacity, as measured
by a six-minute walk test, as well as in NYHA classification.
The effect of this treatment on HIV-associated pulmonary hypertension was demonstrated in a further clinical trial at our center (Ghofrani 2004). Disadvantages of
this form of therapy include the sophisticated aerosolation technology, the short
duration of action after a single application (60-90 min), requiring frequent inhalations (6-9 per day), and the therapy-free interval during the night. Per day, 25-75 µg
iloprost are given in 6-9 inhalations.
4. Endothelin receptor antagonists
Several experimental trials have proved the effectiveness of selective and nonselective endothelin antagonists. A phase III trial on the orally administered endothelin antagonist bosentan showed an improvement in physical exercise capacity
and an increase in complication-free survival time of PPH patients (Rubin 2002).
Applied doses vary between 62.5 and 125 mg twice daily. The major side effect of
this therapy is an elevation of liver enzymes. Therefore, stringent controls of liver
enzymes are necessary. The use of bosentan in patients suffering from HCV/HIV
co-infection has to be considered carefully.
Therapy
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Based on these data, bosentan was approved for the treatment of pulmonary arterial
hypertension in Europe. Due to the potential increase in liver enzymes, frequent
controls of liver enzymes are required. Only physicians registered by the company
Actelion and admitted to the prescription list are able to prescribe bosentan.
An uncontrolled study has reported initial experiences in using bosentan to treat
HIV-associated pulmonary hypertension (Sitbon 2004).
5. Phosphodiesterase-5 (PDE5)-inhibitors
Sildenafil (Revatio™) was the first phosphodiesterase-5 inhibitor to be approved
for the therapy of pulmonary hypertension by the FDA last year, and at the beginning of this year by the EMEA in Europe. Revatio™ is also approved for use in
HIV-associated pulmonary hypertension, although combination with protease inhibitors is not recommended because of possible interactions due to the same metabolic pathway (cytochrome P450 cyp 3A).
Considering the association of the groups of pulmonary arterial hypertension (Venice 2003), a similar therapeutic regime to that used for idiopathic pulmonary hypertension can be applied, depending on the clinical severity of the disease (Figure
2). A daily dose of 25-150 mg sildenafil is usually given in two or three single applications.
636 HIV-associated Pulmonary Hypertension
PAH, Class III/IV
Conventional therapy
( Oral anticoagulation ± diuretics ± O2 )
Vasoreactivity
(ρ Ppa >25% and
ρ PVR >30%)
Yes
No
Oral CCB
Class III
sustainedresponse
Class IV
Epoprostenol
Endothelin R antagonists
Bosentan
Bosentan
Treprostinil
Iloprost iv
or
Prostanoid analogues
yes
No
continue CCB
(< 10%)
Iloprost inh,
Treprostinil,
or
Epoprostenol
PDE 5-inhibitors
Sildenafil
Beraprost
?
No improvement
or deterioration:
(combination
therapy ?)
atrioseptostomy
and/or
lung transplantation
FIGURE 2. Therapeutic algorithm of pulmonary arterial hypertension depending on severity
and vasoreactivity (adapted from World symposium on pulmonary hypertension, Venice 2003).
Class I-IV: NYHA classification; Ppa: Pulmonary arterial pressure; PVR: pulmonary vascular
resistance; CCB: Calcium channel blocker; PDE 5: Phosphodiesterase 5.
Conclusion for clinicians
HIV-patients suffering from exercise-induced dyspnea should be tested for pulmonary hypertension when other pulmonary or cardiac diseases (e.g. restrictive or obstructive ventilation disorders, pneumonia, coronary heart disease) have been excluded. The incidence of pulmonary hypertension is elevated by a factor of 1,000 in
HIV patients compared to the general population, excluding estimated numbers of
unreported cases.
A suspected diagnosis of pulmonary hypertension can be substantiated by noninvasive diagnostic methods (e.g. echocardiography). Since new therapeutic options
have recently become available, correct diagnosis is essential.
Further diagnosis and treatment of patients suffering from every kind of pulmonary
hypertension should be performed in specialized centers with experience in the
treatment of pulmonary hypertension and HIV infection.
References and Internet addresses
1.
Aguilar R, Farber H. Epoprostenol (prostacyclin) therapy in HIV-associated pulmonary hypertension.
Am.J.Respir.Crit Care Med. 2000; 162: 1846-50. http://amedeo.com/lit.php?id=11069824
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Barst R, Rubin L, Long W, McGoon M, et al. A comparison of continuous intravenous epoprostenol
(prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary
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3.
Bower M, Fox P, Fife K, et al. Highly active anti-retroviral therapy (HAART) prolongs time to treatment
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4.
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pulmonary hypertension. AIDS 2002; 16:1568-9. http://amedeo.com/lit.php?id=12131202
5.
Cea-Calvo L, Escribano S, Tello de M, et al. [Treatment of HIV-associated pulmonary hypertension
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6.
Christman B, McPherson C, Newman J, et al. An imbalance between the excretion of thromboxane
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http://amedeo.com/lit.php?id=1603138
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