HIV-Associated Pulmonary Arterial Hypertension

Data from the Centers for Disease Control and Prevention indicate that approximately 1 million persons in the United States are living with HIV and more than 18,000 persons with AIDS die each year. Pulmonary diseases account for a large percentage of HIV-related complications and pulmonary arterial hypertension (PAH) is a noninfectious complication of HIV infection (Morris et al. Proc Am Thorac Soc. 2011;8[1]:17). PAH is reported to occur at an increased frequency in HIV-infected individuals compared with uninfected individuals.

HIV-associated PAH (HAPAH) is more prevalent in men and IV drug users. Though the prevalence of HAPAH has remained at 0.5% before and after the introduction of antiretroviral therapy (Sitbon et al. Am J Respir Crit Care Med. 2008;177[1]:108), the incidence of HAPAH appears to be increasing as antiretroviral therapy prolongs survival in patients with HIV. Speculation that preclinical HAPAH may be more common than recognized is supported by the finding that 35% of HIV-infected individuals had pulmonary artery systolic pressures over 30 mm Hg on screening echocardiography (Hsue et al. AIDS. 2008;22[7]:825). Identifying and treating persons with HAPAH is important because the mortality is higher compared with normotensive patients with HIV (Almodovar et al. Chest. 2010;137[6]:6S).

The clinical and pathologic features of PAH are identical in HIV-infected patients and noninfected individuals. The presentation includes nonspecific symptoms of dyspnea, fatigue, nonproductive cough, chest pain, and syncope. Patients with HAPAH have increased proliferation of endothelial and smooth muscle cells with medial hypertrophy and obliteration of the pulmonary vessels (Petitpretz et al. Circulation. 1994;89[6]:2722). Plexiform lesions are seen in 78% of patients with HAPAH (Mehta et al. Chest. 2000;118[4]: 1133). The pathogenesis of HAPAH is poorly understood. It is uncertain whether the virus has a direct effect on endothelial cells, as there is no evidence that HIV directly infects pulmonary vascular endothelial cells. However, HIV viral antigens are seen in the pulmonary endothelium and may be responsible for stimulating abnormal apoptosis, growth, and proliferation of cells. HIV viral antigens under investigation include glycoprotein 120, negative factor (Nef ) antigen, and HIV-1 tat (transcriptional transactivator). Human herpes virus-8 (HHV-8) has also been investigated but has not been conclusively demonstrated to play a role in the development of HAPAH. In an animal model of simian immunodeficiency virus, primates expressing HIV Nef are noted to develop lesions similar to the plexiform lesions seen in PAH (Marecki et al. Am J Respir Crit Care Med. 2006;174[4]:437). In vitro, Nef antigen causes increased apoptosis followed by proliferation of human endothelial cells (Marecki et al. Proc Am Thorac Soc. 2006;3:A476).

Other pathways by which HIV may play a role in the pathogenesis of PAH include mechanisms related to the chronic inflammation associated with HIV. Lung tissue from patients with HAPAH has been noted to show an increase in the expression of platelet-derived growth factor, a potent stimulus of growth and migration in fibroblasts and smooth muscle cells (Humbert et al. Eur Respir J. 1998;11[3]:554). There is no correlation between HAPAH and CD4 cell count or viral load (Nunes et al. Am J Respir Crit Care Med. 2003;167[10]:1433; Humbert et al. Am J Respir Crit Care Med. 2006;173[9]:1023).

Few studies have investigated therapeutic options for HAPAH. The role of antiretroviral therapy in the development and progression of HAPAH is controversial. Although some studies demonstrate a benefit for highly active antiretroviral therapy (HAART) in HAPAH, other studies show no benefit. Zuber and colleagues (Zuber et al. Clin Infect Dis. 2004; 38[8]:1178) demonstrated an improvement in hemodynamics and survival in patients with HAPAH treated with antiretrovirals, but their findings were limited in that the diagnosis of PAH was made by echocardiography rather than right-sided heart catheterization. Speich and coworkers (Speich et al. Swiss Med Wkly. 2001;131[45-46]:663) reported a case where the subject, who had a history of cocaine use, was noted to have regression of PAH while receiving antiretroviral therapy with an increase in survival to 6 years compared with the then-typical 3-year survival following diagnosis of HAPAH. In a case-control study where Opravil and colleagues (Opravil et al. Am J Respir Crit Care Med. 1997;155[3]:990) compared HIV patients with PAH to those without PAH, a statistically significant decrease of 3.2 mm Hg in the right ventricular systolic pressure–right atrial pressure (RVSP-RAP) gradient was noted in the six patients receiving antiretroviral therapy, while this gradient increased by 19 mm Hg in untreated patients. In contrast, a study published by Reinsch and colleagues (Reinsch et al. HIV Medicine. 2008;9[7]:550) showed that patients with HIV receiving HAART had a slight increase in systolic pulmonary arterial pressure. Comparatively, Pugliese and colleagues (Pugliese et al. J Infect. 2000;40[3]:282) reported that the incidence of PAH was increased in HIV-infected patients receiving HAART compared with those receiving nucleoside reverse transcriptase inhibitors.

Treatment options for HAPAH are limited. Calcium channel blockers, effective in treating PAH in patients who are responsive to vasodilator challenge, tend to be ineffective in HAPAH. Epoprostenol has been shown to improve hemodynamics and functional status in patients with HAPAH. Acute infusion of epoprostenol reduces mean pulmonary artery pressure (PAP).

Long-term changes noted with epoprostenol therapy include a fall in PAP and peripheral vascular resistance with an increase in cardiac output and cardiac index. The NYHA functional class of patients with HAPAH was noted to improve significantly in patients receiving long-term epoprostenol (Aguilar and Farber. Am J Respir Crit Care Med. 2000;162[5]:1846). Side effects of epoprostenol were similar to those seen in non-HIV-infected patients undergoing treatment for PAH, including jaw pain, headache, and flushing.

A small study suggests that inhaled iloprost reduces pulmonary vascular resistance, increases cardiac output, and improves exercise capacity in patients with HAPAH (Ghofrani et al. Eur Respir J. 2004;23[2]:321).

Bosentan therapy has been shown to improve 6-min walk distance, hemodynamics, and quality of life in patients with HAPAH without having a negative impact on the control of HIV infection, as CD4 cell count and viral load were not affected (Sitbon et al. Am J Respir Crit Care Med. 2004;170[11]:1212; Degano et al. Eur Respir J. 2009;33[1]:92). Barbaro and colleagues (Barbaro et al. Heart. 2006; 92[8]:1164) reported that HAART combined with bosentan, compared with HAART alone, reduced PAP by 21% and reduced pulmonary capillary wedge pressure by 12%. The combination of HAART and bosentan appeared to be safe, without negatively impacting the control of the HIV infection.

Sildenafil was noted to cause a rapid improvement in the patient’s dyspnea and symptoms of right-sided heart failure in a case report published by Alp and coworkers (Alp et al. AIDS. 2003;17[11]:1714). Schumacher and colleagues (Schumacher et al. AIDS. 2001;15[11]:1747) reported a similar case in which a patient, after 3 months of follow-up, was observed to have a decrease in PAP estimated from echocardiography with an associated improvement in dyspnea and exercise capacity.

With regards to prognostic indicators, multivariate analysis of patients with HAPAH in NYHA functional class III-IV showed that the CD4 lymphocyte count was the only independent predictor of survival. Univariate analysis of the same study population revealed that a CD4 lymphocyte count over 212 cells/mm³, use of combination antiretroviral therapy, and epoprostenol therapy were significantly associated with a decreased risk of death (Nunes et al. Am J Respir Crit Care Med. 2003;167[10]:1433).

Screening for HAPAH is important to ensure early intervention. Additional studies are needed to further elucidate the pathogenesis of PAH in patients with HIV so that potential treatment targets may be identified.

Dr. Marshaleen Henriques-Forsythe
Assistant Professor of Clinical Medicine
Pulmonary and Critical Care Division
Morehouse School of Medicine
Atlanta, GA

Editor’s Insight
Recent innovations and advances in medical care that have prolonged the survival of individuals with HIV infection has led to an expectation that these individuals will lead longer and fuller lives. Concurrently, significant progress has also been made in the treatment of pulmonary arterial hypertension. This update of HIV-associated PAH should lead us to consider a diagnosis of PAH in HIV-infected individuals with, among other symptoms, unexplained dyspnea.
Dr. Marilyn G. Foreman, FCCP