Because of the recent advances in antiretroviral therapy, patients who are infected with the Human Immune Deficiency Virus (HIV) tend to live longer.₁, ₂ Furthermore, non-infectious complications have become a more frequent cause of morbidity and mortality. Cardiac involvement from non-opportunistic infection in AIDS patients was first reported in 1983 in an autopsy case with myocardial Kaposi's Sarcoma.₃ Approximately 28 to 73% of AIDS patients have been reported to have cardiac involvement, ₄ with the most common form being pericardial effusion, which has been reported to be as frequent as 20 % (range 10-40%). ₅,₆,₇,₈ Pulmonary hypertension in AIDS patients or HIV-associated pulmonary hypertension (PHT), as in our demonstrated case, has been well recognized as a noninfectious complication in these patients.

Since first reported by Kim and Factor in 1987₉, HIV-associated PHT has been increasingly described in the literature. Until October 2000, 131 cases have been reported in the world literature.₁₀ The accurate incidence of HIV-associated PHT is unknown, but estimated to be 1 in 200 HIV cases, according to a study in 1989 by Hilmelman, et al.₁₂Its incidence in the general population averages 1 in 200 000. This incidence should be as high as 7.1-8% among HIV or AIDS patients who presented with cardiopulmonary symptoms and signs.₁₃, ₁₄

The pathogenesis of HIV associated PHT is not yet determined. The hypothesis of direct effect of HIV on pulmonary vascular endothelium or smooth muscle has not been proved in vivo. Mette, et al. failed to demonstrate HIV in pulmonary vascular endothelium in these patients, who have primary pulmonary hypertension, with electron microscopy, immunohistochemistry, DNA in situ hybridization and PCR techniques.₂₇ It has become more evident that HIV may indirectly stimulate the vascular endothelium and smooth muscle cell growth, along with vasoconstriction via some mediators and cytokines. In patients with PHT, the increase in serum interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF- ) concentrations₂₈, supported this hypothesis. Furthermore, serum endothelin-1 also increased in these patients.₂₉ The link to HIV was clearer when the HIV glycoprotein gp 120 was found to stimulate endothelin-1 and TNF- secretion from macrophages in these patients in a concentration-dependent fashion.₃₀ The other possibility is autoimmune phenomenon, since HIV associated PHT patients have been reported to have significantly higher serum anticardiolipin IgM, anti SS-B and neopterin compared with matched control subjects.₂₅ At last, genetic predisposition may play a major role in susceptibility to developing PHT in HIV patients, evidenced by only a small proportion of HIV patients developing this problem. Morse, et al. found the significant increase frequency of HLA-DR6 and of HLA-DR52 in the HIV patients with PHT compared with non-HIV matched subjects and HIV matched subjects who do not have PHT.

The largest collective review to date₁₀ showed that progressive shortness of breath is the most common presentation, along with pedal edema, non-productive cough, fatigue, syncope or near-syncope and chest pain. Physical findings include the common signs of pulmonary hypertension, i.e. jugular venous distension, a loud P2, right-sided S3 gallop, tricuspid and pulmonary regurgitation murmur and peripheral edema. (Table I) There seems to be no correlation between CD4 cell counts (range from 0 to 937 cells/mm³, mean 269) or history of opportunistic infection and the development or progression of HIV associated pulmonary hypertension. ₁₀ But Pellicelli and colleagues did report a statistically significant difference between HIV positive patients with AIDS and those without AIDS with regard to degree of pulmonary hypertension, with AIDS patients having a higher pulmonary artery systolic pressure. ₁₁

Figure 2

Table 1: Clinical Manifestations and Laboratory findings in HIV-associated PHT

As in idiopathic primary pulmonary hypertension, HIV associated pulmonary hypertension is a diagnosis of exclusion. Secondary causes of pulmonary hypertension, i.e. chronic hypoxemia, chronic pulmonary diseases, pulmonary thromboembolism, portal hypertension and talc granuloma (especially in IV drug abusers) must be sought and excluded. Provisional diagnosis is usually made by an echocardiogram. Doppler echo study is widely accepted as a tool to determine the pulmonary artery systolic pressure.₁₅ Right heart catheterization usually confirms the diagnosis, and reveals elevated right-sided filling pressure and high pulmonary artery pressure with essentially normal pulmonary capillary wedge pressure. Mehta et al reported that the average pulmonary artery pressure in HIV associated PHT was (mean ± SD) 67 ± 18 / 40 ± 11 mmHg, with systolic pulmonary pressure range from 33 to 120 mmHg and diastolic pressure ranging from 21 to 70 mmHg.₁₀Lung biopsy is usually performed after workup for secondary pulmonary hypertension, i.e. arterial blood gas, pulmonary function testing and ventilation-perfusion scan, reveals no positive cause. Pulmonary histopathology₁₀ demonstrated plexogenic pulmonary arteriopathy in 78% of the patients, medial hypertrophy and intimal fibrosis without plexiform lesion 11%, pulmonary veno-occlusive disease 7%, and thrombotic pulmonary arteriopathy 4%. Although plexogenic pulmonary arteropathy is the most common histopathological feature in HIV associated PHT, it is not pathognomonic. There are some other medical conditions i.e. portal hypertension, chronic hepatitis with liver cirrhosis, connective tissue diseases, and some type of congenital heart diseases, reported to have pulmonary arteriopathy type pulmonary hypertension.₁₆,₁₇,₁₈,₁₉

To date, there is no known certain therapeutic approach to the patients with HIV associated PHT. Most patients receive supportive treatment for right-sided heart failure and pulmonary hypertension, such as oxygen supplement and diuretics. Oral anticoagulation have shown to significantly improve survival in patients with non-HIV related primary PHT ₁₅,20 but results in HIV associated PHT has not been conclusive enough to encourage the use in this group of patients. ₁₂, ₂₁,₂₂,₂₃ Treatment with oral calcium channel blockers, which have shown to improve survival in subgroups of non-HIV related primary PHT patients, have discouraging data in HIV associated PHT.₂₄, ₂₅ Only Epoprostenol, an intravenous prostacycline, has been reported to improve hemodynamic and functional status acutely ₂₄, ₂₆ and in the long run (12-40 months). ₂₆Also, there is no difference in response to epoprostenol therapy between HIV associated PHT compared with primary pulmonary hypertension patients.₂₄Epoprostenol therapy is generally limited to seriously ill patients₂₆ because of its cost and the need for continuous intravenous infusion. The role of antiretroviral agents in HIV associated PHT have been disappointing. Some data showed to decrease right heart pressure with antiretroviral medications ₂₅ but some study showed no clinical benefit, but rapid deterioration of clinical course in some patients.₁₄

Compared with primary pulmonary hypertension, the patients with HIV associated PHT present at a younger age, at a lower mean pulmonary artery pressure and at the lesser degree of disability, classified by NYHA.₂₄Nevertheless, PHT in HIV patients run a more aggressive course, shown by having the same survival rate at two year follow up (46% and 53%). ₂₄In the same study, most of the HIV patients (80%) died from pulmonary hypertension at one year.₂₄A second study of HIV associated PHT reported a survival rate of 58% at one year with a median survival of 1.3 years, compared to 2.6 years in matched controls HIV patients without PHT (P<0.05).₂₅ In other words, the presence of pulmonary hypertension in HIV patients reduces the probability of survival by 50%.