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Medical > Therapy > Special indications

HIV related PAH

Human immunodeficiency virus (HIV) infection is associated with numerous infectious and non-infectious complications (1). Whereas during the first years of the HIV epidemic opportunistic infections and malignancies dominated the clinical course in these patients, later it became evident that non-infectious conditions such as cardiovascular diseases including dilated cardiomyopathy, pericardial effusion, non-bacterial thrombotic endocarditis and accelerated atherosclerosis may play a significant role.

In 1987, pulmonary hypertension was reported for the first time in a 40-year-old homosexual white man with AIDS and membranoproliferative glomerulonephritis by Kim and Factor (2). Autopsy of the lungs revealed plexiform lesions. An immune-mediated pathogenesis was postulated, but in contrast to the findings of the glomerular immunohistochemistry no IgG deposits were found in the pulmonary vessels. One year later, Goldsmith and coworkers described "primary" pulmonary hypertension in five HIV-infected hemophiliacs and suggested a possible pathogenetic role of treatment with low-purity factor VIII (3). Subsequently, two groups reported 6 cases each with pulmonary hypertension clinically and pathologically resembling primary pulmonary hypertension (PPH) out of a cohort of 1200 HIV-infected patients, thus both estimating a cumulative incidence of 0.5 % (4, 5). Considering the annual incidence of PPH of 1 to 2 per 1 million in the general population these findings strongly suggested an association between HIV infection and pulmonary hypertension. Thus, in accordance with these two and further case series (6), the executive summary of the Second World Symposium on Primary Pulmonary Hypertension in Evian concluded that HIV infection is a definite risk factor for the development of PAH, and subsumed the entity among category 1 in the revised Venice classification (7, 8).

Epidemiology
In large case control study of the Swiss HIV Cohort involving more than 3’000 patients over a period of 5.5 years demonstrated a cumulative incidence of PAH associated with HIV (HIV-APAH) of 0.57 %, resulting in an annual incidence of about 0.1 %. Compared with the annual incidence of PPH in the general population of 2 per million, HIV infection thus carries a relative risk of pulmonary hypertension of about 500. Based on the same cohort, the annual incidence of HIV-APAH remained almost constant through the past decade with a median value of 0.1 % (range 0.04 % to 0.20 %), with only a trend towards a lower incidence during recent years.

Etiology
HIV-APAH is characterized clinically and pathologically by the typical features of IPAH (4). As in the latter disorder, the etiology of HIV-APAH is largely unknown. Even though intravenous drug use is frequently associated with HIV-APAH, according to the second WHO conference only the use of amphetamines is a very likely secondary cause of PAH (7). In contrast, cocaine is just regarded as a possible risk factor for PAH by these experts. The occurrence of pulmonary hypertension in HIV negative cocaine users is highly unusual. There are only nine case reports in literature, in which the hemodynamic changes usually were mild and transient. Injection of small particles containing talc may cause granulomas within small pulmonary arteries and lead to increased pulmonary vascular resistance. However, histologic specimens of patients with HIV-APAH showed only occasional birefringent talc particles that usually were located adjacent to and not within the plexiform lesions. Additionally, in more than one third of the cases described in literature, HIV infection was the sole potential risk factor for PAH. Therefore, it was hypothesized that HIV itself could play a direct role in the pathogenesis of HIV-APAH. The development of pulmonary hypertension not attributable to chronic hypoxia has been demonstrated in a murine model of AIDS (9). So far, however, neither HIV-1 p24 antigen, tat protein nor gag RNA were found in the affected pulmonary vessels of patients with HIV-APAH.

Another possibility is that HIV-APAH results from the production of growth factors, either directly related to HIV or mediated through infected T cells, which may cause pulmonary arteriolar endothelial cell proliferation. A regulatory gene from the HIV-1 triggering the growth of dermal lesions resembling Kaposi's sarcoma in transgenic mice (10), and a growth factor elaborated by HIV-infected T cells that stimulates Kaposi's sarcoma cells in culture (11) have been described. The French group of Humbert et al. has found an increased expression of platelet-derived growth factor (PDGF) in perivascular cells of two patients with HIV-APAH (12). PDGF has the ability to induce the proliferation and migration of smooth muscle cells and fibroblasts, and it has been proposed to be a key mediator in several fibroproliferative disorders including hypoxic pulmonary vasoconstriction.

Endothelin-1 may play an important role in the pathogenesis of HIV-APAH. The HIV-1 envelope glycoprotein gp120 stimulates the secretion of endothelin-1 from macrophages in a concentration-dependent manner (13). Furthermore, they found that in HIV-infected individuals circulating monocytes show a distinct expression of the endothelin-1 gene which is not detectable in healthy controls, indicating chronic activation of this gene in HIV-infection. Further evidence for a pathogenetic role of endogenous vasoactive substances stems from a recent study, which showed a marked reduction in the expression of prostacyclin synthase in two patients with HIV-APAH, comparable to the findings in IPAH (14).

Clinical presentation and diagnosis
The clinical presentation and diagnostic work-up resembles that of other forms of PAH (4). Progressive shortness of breath was the presenting symptom in more than 90% of the patients. Less common symptoms were peripheral edema or syncope in about 30%, and non-productive cough, chest pain or Raynaud phenomenon in about 15 %. All three CDC HIV categories can be involved, and the mean value was 265/µL. More than half of the patients have CD4 cell counts above 200/µL, and only in about one third AIDS-indicator conditions are present.

Diagnosis of HIV-APAH is usually made by Doppler echocardiography. The level of suspicion of PAH in HIV-infected patients should be very low. Because of the relatively low incidence of HIV-APAH, general Echo screening is not recommended.

With respect to modern vasodilator therapy, right heart catheterization should be performed in all patients.

Management
The medical therapy of HIV-APAH is comparable to that of IPAH. Oral anticoagulation is recommended in compliant patients without contraindications. Acute vasoreactivity is very rare, and thus calcium channel blockers are almost never useful. Until recently, continuous intravenous prostacyclin has been the mainstay of treatment in HIV-APAH. In the large French series, its beneficial effect has been clearly demonstrated . However, although having been performed in an open fashion, the recent BREATHE-4 trial convincingly demonstrated the beneficial effect of bosentan in these patients (15). All parameters including 6-minute walking distance, functional class and quality of life improved significantly. There was an impressive improvement in hemodynamic parameters with single patients almost normalizing their pulmonary vascular resistance. Thus, bosentan seems to be the treatment of choice in HIV-APAH, and in fact, most of the patients of the French group have now been converted from continuous intravenous prostacyclin to oral bosentan (Simonneau G. Personal communication).

Antiretroviral treatment most probably has an important effect in HIV-APAH and should be established in all patients. In the first study of the Swiss cohort, patients who received either zidovudine or didanosine had a decrease in RVSP by 3.2 mmHg compared with an increase by 19 mmHg among those not receiving antiretroviral therapy (16). After some case reports of impressive improvements during highly active antiretroviral therapy (17, 18), the recent findings from the Swiss Cohort nicely demonstrated the improved survival of patients receiving HAART (19). The effect of single drug therapy was only modest, but still superior compared with no antiretroviral treatment.


References:

1. Speich R. HIV, AIDS, and the lung. In: Torres A, Ewig S, Mandell L, Woodhead M, eds. Respiratory Infections. London, England: Hodder Arnold, 2006: 719-38.

2. Kim KK, Factor SM. Menbranoproliferative glomerulonephritis and plexogenic pulmonary arteriopathy in a homosexual man with acquired immunodeficiency syndrome. Hum Pathol 1987;18:1293-1296.

3. Goldsmith GJ, Baily RG, Brettler DB, Davidson WJ, Ballard JO, Driscol TE, Greenberg JM, Kasper CK, Levine PH, Ratnoff OD. Primary pulmonary hypertension in patients with classic hemophilia. Ann Intern Med 1988;108:797-799.

4. Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest 1991;100:1268-1271.

5. Himelman RB, Dohrmann M, Goodman P, Schiller NB, Starksen NF, Warnock M, Cheitlin MD. Severe pulmonary hypertension and cor pulmonale in the acquired immunodeficiency syndrome. Am J Cardiol 1989;64:1396-1399.

6. Mehta NJ, Khan IA, Mehta RN, Sepkowitz DA. HIV-Related pulmonary hypertension: analytic review of 131 cases. Chest 2000;118:1133-1141.

7. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S.

8. Speich R. Pulmonary hypertension related to HIV infection. In: Peacock AJ, Rubin LJ, eds. Pulmonary circulation. 2nd ed. London, England: Edward Arnold (Publishers) Ltd, 2004: 204-211.

 

9. Gillespie MN, Hartsfield CL, O'Connor WN, Cohen DA. Pulmonary hypertension in a murine model of the acquired immunodeficiency syndrome. Am J Respir Crit Care Med 1994;150:194-199.

10. Vogel J, Hinrichs SH, Reynolds RK, Luciw PA, Jay G. The HIV tat gene induces dermal lesions resembling Kaposi's sarcoma in transgenic mice. Nature 1988;335:606-611.

11. Nakamura S, Salahuddin SZ, Biberfeld P, Ensoli B, Markham PD, Wong-Staal F, Gallo RC. Kaposi's sarcoma cells: long-term culture with growth factor from retrovirus-infected CD4+ T cells. Science 1988;242:426-430.

12. Humbert M, Monti G, Fartoukh M, Magnan A, Brenot F, Rain B, Capron F, Galanaud P, Duroux P, Simonneau G, Emilie D. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J 1998;11:554-559.

13. Ehrenreich H, Rieckmann P, Sinowatz F, Weih KA, Arthur LO, Goebel FD, Burd PR, Coligan JE, Clouse KA. Potent stimulation of monocytic endothelin-1 production by HIV-1 glycoprotein 120. J Immunol 1993;150:4601-4609.

14. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925-1932.

15. Sitbon O, Gressin V, Speich R, Macdonald PS, Opravil M, Cooper DA, Fourme T, Humbert M, Delfraissy JF, Simonneau G. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;170:1212-1217.

16. Opravil M, Pechère M, Speich R, Joller HI, Jenni R, Russi EW, Hirschel B, Lüthy R. HIV-associated primary pulmonary hypertension: a case control study. Swiss HIV Cohort Study. Am J Respir Crit Care Med 1997;155:990-995.

17. Speich R, Jenni R, Opravil M, Jaccard R. Regression of HIV-associated pulmonary arterial hypertension and long-term survival during antiretroviral therapy. Swiss Med Wkly 2001;131:663-665.

18. Zinkernagel AS, von Overbeck J, Opravil M, Jenni R, Speich R, Mueller NJ. Long-term survival and interruption of HAART in HIV-related pulmonary hypertension. Eur J Clin Microbiol Infect Dis 2005;24:153-155.

19. Zuber JP, Calmy A, Evison JM, Hasse B, Schiffer V, Wagels T, Nuesch R, Magenta L, Ledergerber B, Jenni R, Speich R, Opravil M, Swiss HIVCSG. Pulmonary arterial hypertension related to HIV infection: improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis 2004;38:1178-1185.

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