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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 9  |  Issue : 1  |  Page : 1-6

Pulmonary hypertension in people living with HIV/AIDS


Department of Cardiology, Fortis Escorts Heart Institute, New Delhi, India

Date of Web Publication10-May-2019

Correspondence Address:
Dr. Shailesh Singh
Fortis Escorts Heart Institute, Okhla Road, New Delhi - 110 025
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JICC.JICC_6_19

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  Abstract 


Pulmonary hypertension (PH) can be defined as a group of disorders characterized by an elevated mean pulmonary arterial pressure (≥25 mmHg) at rest. The exact pathophysiologic mechanism underlying the development of PH in HIV/AIDS patient is unknown. Various hypotheses have been proposed to explain the genesis of PAH in HIV/AIDS patients. These theories have talked about the role of HIV itself, opportunistic infections, inflammation, and endothelial cell dysfunction. The role of highly active antiretroviral therapy (HAART) on the outcome of PH secondary to HIV is still controversial. Various guidelines and bodies have suggested that HIV–PAH, because of the similar disease process as idiopathic PAH, may require the same treatment as PAH in the general population.

Keywords: HIV/AIDS, highly active antiretroviral therapy, pulmonary hypertension


How to cite this article:
Singh S. Pulmonary hypertension in people living with HIV/AIDS. J Indian coll cardiol 2019;9:1-6

How to cite this URL:
Singh S. Pulmonary hypertension in people living with HIV/AIDS. J Indian coll cardiol [serial online] 2019 [cited 2019 Sep 17];9:1-6. Available from: http://www.joicc.org/text.asp?2019/9/1/1/257962




  Introduction Top


Pulmonary hypertension (PH) can be defined as a group of disorders characterized by an elevated mean pulmonary arterial pressure (≥25 mmHg) at rest. The most recent PH classification, proposed at the Fifth World Symposium on pulmonary arterial hypertension (PAH) in 2013 (Nice, France), includes five main groups: Group 1 – PH is called PAH; Group 2 – PH is due to left heart disease; Group 3 – PH is due to lung diseases and/or hypoxia; Group 4 is chronic thromboembolic PH; and Group 5 is called as PH with unclear multifactorial mechanisms. PAH associated with HIV has been classified under Group 1.

The first case of HIV-associated PH was reported in 1987 by Kim and Factor in a middle-aged man presenting with breathlessness and renal failure.[1] About 150 cases have been reported since then.[2] The incidence of HIV–PAH is much more than PH in the general population (1 in 200 vs. 1 in 200,000).[3] HIV-associated PH has been described as a cause of precapillary PH.[3] The clinical, histologic, and hemodynamic features do not differ between patients with HIV–PAH and primary PH in noninfected patients, suggesting similar etiopathogenesis in both the subsets of patients.


  Pathogenesis of HIV-Associated Pulmonary Hypertension Top


The exact pathophysiologic mechanism underlying the development of PH is unknown. Various hypotheses have been proposed to explain the genesis of PAH in HIV/AIDS patients. The various theories talk about the role of HIV itself, opportunistic infections, inflammation, and endothelial cell dysfunction. Broadly considered, for PH to develop, there has to be a misbalance between vasoconstriction and vasodilation. This usually results from endothelial dysfunction leading to decreased production of vasodilators such as nitric oxide and prostacyclin and increased production of endothelin-1, a potent vasoconstrictor. Feijoo et al. in their study involving 23 HIV patients with PAH found that endothelin-1 levels were higher in those HIV patients who had PAH compared to seronegative population, and levels of endothelin-1 increased with the increasing severity of PH.[4]

Literature suggests that drugs such as indinavir and zidovudine combination lead to the enhanced synthesis of endothelin-1.[5]

Results of other studies have resonated the idea of endothelium being dysfunctional in HIV/AIDS.[6],[7] What causes such endothelial dysfunction in HIV/AIDS patients has been a matter of considerable debate and research. The direct and indirect role of HIV itself in causing PH by itself has been explored. Studies have not been able to isolate the virus from pulmonary vasculature thus ruling out the role of direct viral invasion.[8],[9]

The role of HHV-8 virus in causing primary PH has been studied, and it postulated that the virus, as an opportunist in patients with HIV/AIDS infection, may have a role in leading to endothelial dysfunction.[10]

A study has shown the role of previous pneumocystis infection leading to PH.[11]

The available evidence in literature has shown the role of HIV viral proteins, namely, negative factor (Nef), transcription proteins (Tat), and glycoprotein 120 (gp-120).[12],[13],[14],[15],[16],[17] These proteins probably induce vascular oxidative stress, smooth myocyte proliferation and migration, and endothelial injury leading to HIV-related PAH. Nef, an extracellular protein, is necessary for the replication of the virus and is essential for maintaining high viral load.[18] Nef targets the C-X-C chemokine receptor type 4 receptors on pulmonary endothelial cells thereby entering into it,[19] and thereafter, they induce the apoptosis of pulmonary endothelial cells and lead to the formation of a complex plexiform lesion in the pulmonary vasculature.[12]

Tat is another HIV-related protein that has been shown to enhance the activity of vascular endothelial cells via interleukin-6 (IL).[20] More recently, the Tat protein was shown to repress the transcription of bone morphogenic protein receptor 2 (BMPR2) and led to abnormal pulmonary vascular function with exuberant cellular proliferation.[21] It is relevant to mention that BMPR2 is among the most studied factors implicated in the pathogenesis of PAH.[22]

Gp-120 is a crucial protein responsible for HIV entry into the target cells, such as macrophages and CD4 T-lymphocytes.[23] It was shown that Gp-120 induces vascular smooth cell proliferation and endothelial cell apoptosis as well as increases the production of endothelin-1, which is a well-established culprit molecule in the pathogenesis of PAH.[24],[25]

The role of systemic inflammation in the causation of PH cannot be undermined.[26]

It has been found that PH patients have higher levels of pro-inflammatory cytokines like IL-1 and IL-6, which ultimately lead to the proliferation of smooth muscle cells and fibroblasts in the pulmonary vasculature, leading to vascular remodeling.[26]

A recent study confirmed the role of IL-1 in the pathogenesis of PH by showing that the blockades of IL-1 reduce inflammation in PAH and right ventricular failure.[27] These pro-inflammatory cytokines are released by the dysfunctional endothelium.

HIV has been described as a state of chronic inflammation with persistently high levels of pro-inflammatory cytokines by many authors.[28],[29],[30]

It is believed that HIV-related inflammation is among the key factors responsible for a higher burden of cardiovascular disease among HIV-infected patients.[31] HIV-related systemic inflammation may activate platelet-derived growth factor[32] and vascular endothelial growth factor pathway,[33] with resultant aberrant pulmonary vascular activity.

Frustaci et al. studied 15 patients with HIV with PAH with right ventricular dysfunction using cardiac magnetic resonance (CMR), cardiac catheterization, coronary angiography, and endomyocardial biopsy. The authors found the evidence of heightened inflammation in the form of subepicardial/mesocardial edema and delayed enhancement on CMR, lymphocytic myocarditis and microvasculitis in biopsy specimens, and raised levels of endothelial adhesion molecules. The authors concluded that HIV–PAH patients have inflammation of myocardium and intramural vessels, which adversely affect the right ventricular function and pulmonary circulation.[34]

There is little debate on the importance of BMPR2 gene mutation in the pathogenesis of PH. This mutation is commonly seen in patients with familial PAH and a few patients with sporadic PH. This gene is located on the long arm of chromosome 2 and its dysfunctional signaling is responsible for the release of pro-inflammatory cytokines such as IL-6 and growth factors such as granulocyte-macrophage colony-stimulating factor which ultimately lead to remodeling of the pulmonary vasculature.[35],[36],[37],[38],[39]

Nunes et al., however, could not find BMPR2 mutations in their cohort of patients with HIV–PAH.[40]

Pulmonary vascular resistance is also increased by thrombosis. Idiopathic PAH is characterized by a procoagulant state. Arterial thrombosis resulting from this procoagulant state may be responsible for intimal fibrosis, thereby leading to the progression of pulmonary vascular disease.[41],[42],[43],[44]

HIV is a hypercoagulable condition and is characterized by multiple thrombophilic abnormalities such as elevated level, for example, elevated levels of Factor VIII and decreased levels of protein C and protein S.[28],[45] This coagulation abnormality explains the predisposition to accelerated atherosclerosis and also may contribute in the pathogenesis of PH.


  Clinical Manifestations and Diagnosis of HIV-Associated Pulmonary Hypertension Top


PH commonly presents with symptoms such as dyspnea on exertion or fatigue decreased exercise tolerance. Less common presenting complaints include chest pain and presyncope or syncope. History suggestive of right ventricular failure, i.e., pedal edema and distension of the abdomen may be seen in patients with long-standing disease. In the most extensive clinical series of HIV-associated PH, 47%–54% of all the patients were male, and the age at the time of diagnosis ranged from 2 to 56 years (mean: 33 years). Intravenous drug use was the most common risk factor and ranged from 50% to 58%, whereas homosexual behavior was present in 20% of the patients and hemophilia in 9%.[2],[46],[47] The mean CD4+ count was 300/mm3 (range: 0–937/mm3). Currently, no correlation has been found between the CD4+ count and the presence of opportunistic infections and the development of PH. The most common presenting symptom in these patients was dyspnea (from 49% to 85%), whereas pedal edema ranged from 11% to 30% of the patients, nonproductive cough from 7% to 19%, syncope from 8% to 12%, and chest pain was present in 7% of the patients. Raynaud's syndrome, which is more frequently found in patients affected by PH associated with connective tissue disease, was present in only one patient (1%).[2],[47]

Signs of PH on physical examination may include aloud pulmonary component of the second heart sound, left parasternal heave due to right ventricular hypertrophy, early systolic click, and a midsystolic ejection murmur at the pulmonary area. A right ventricular S4 gallop may be heard in approximately one-third of the patients. Patients with right ventricular failure have pedal edema, raised jugular venous pressure, tender hepatomegaly, and a right ventricular S3 gallop.[48]


  Treatment Top


Highly active antiretroviral therapy

The role of highly active antiretroviral therapy (HAART) on the prevalence and outcome of PH secondary to HIV is still controversial. The available data suggest that the use of standard antiretroviral therapy in patients with PH secondary to HIV infection may have a beneficial effect on survival.[48],[49],[50],[51] A prospective French national study concluded that improved survival with HAART was likely related to CD4+ counts and better cardiac function as opposed to a direct effect on PH.[52]

Furthermore, some of the antiviral therapies have been observed to contribute to the development of PAH. The SUN study, which was designed to monitor the incidence of HIV drug therapy-related complications, found that two-thirds of the patients using HAART developed some form of cardiac dysfunction. The use of current ritonavir-boosted protease inhibitors was the only factor significantly associated with PAH.[53]

Pugliese et al.[54] found that PAH occurred in 0.7% of patients treated with nucleoside reverse transcriptase inhibitors, compared with 2% in the group of patients treated with HAART (P = 0.048). This indicated that some standard antiretroviral therapy, in particular, the first-generation HIV protease inhibitors but also some HAART treatment, may facilitate the pulmonary vascular pathophenotype of HIV-associated PAH.[55]

Inhaled oxygen

Inhaled oxygen should be considered for patients presenting with acute decompensation. Hypoxemia worsens pulmonary vascular resistance and should be corrected. The oxygen saturation of the blood should be kept >92% at rest and with exertion. The acute decompensation of PH may mandate the use of supplemental oxygen. Bilevel positive airway pressure may be considered for selected patients.

Anticoagulation

The various coagulation abnormalities in HIV and its established role in causing PH mandate the use of anticoagulation in patients with HIV–PAH. However, in terms of survival benefits, the results of the studies evaluating the role of anticoagulants in idiopathic PAH have been controversial. The potential drug–drug interaction between HAART and anticoagulants should be kept in mind.[56],[57]


  Pulmonary Arterial Hypertension-Specific Therapy Top


Various guidelines and bodies have suggested that HIV–PAH, because of the similar disease process as idiopathic PAH, may require the same treatment as PAH in the general population.[58],[59]

Phosphodiesterase inhibitors

Sildenafil, a phosphodiesterase type-V drug, is one of the first oral therapies used in the treatment of HIV-associated PAH. However, its use has been described only in a few case reports and large-scale data proving its efficacy in this condition are lacking.[60]

In one such case report, Schumacher et al. gave sildenafil to two patients with HIV-associated PAH; in both the patients, pulmonary arterial pressures dropped significantly.[60]

Concerns have been raised regarding the drug interaction between protease inhibitors and sildenafil. Muirhead et al.[61] investigated the effect of the saquinavir and ritonavir on the pharmacokinetics of sildenafil and found that by inhibiting CYP3A4, both of these drugs increased the plasma concentration of sildenafil. Ritonavir was found to have significantly more effect than saquinavir;[61] however, studies have suggested that this does not translate into an increase in rates of side effects.[62] Chinello et al.,[62] however, recommended the therapeutic drug monitoring of sildenafil in such scenarios to avoid overdosage.

The study by Muirhead et al.[61] also revealed that pharmacokinetic profile in both protease inhibitors was not affected by sildenafil.

Endothelin-receptor antagonist

Use of the nonselective endothelin-receptor antagonist (bosentan) has also been reported in many patients with HIV-associated PAH with treated patients demonstrating significant improvement in functional and hemodynamic parameters.[63],[64]

In a prospective study by Sitbon et al.,[63] 16 HIV–PAH patients were given bosentan for 16 weeks. The authors reported an improvement in exercise capacity, Doppler parameters, New York Heart Association functional class, and quality of life, and it was found to be reasonably safe. The authors concluded that bosentan might prove to be beneficial for patients with HIV-associated PAH. Degano et al. studied the long-term effects of bosentan in 59 consecutive patients with HIV–PAH and found that drug was safely tolerated when coadministered with HAART. Only three patients had to be withdrawn for the study because of elevated hepatic enzymes. 10 patients who received the drug had complete normalization of hemodynamic parameters after mean treatment duration of 29 months. The authors concluded that bosentan could provide significant long-term clinical and hemodynamic improvements in patients with HIV–PAH. The authors suggested that bosentan may have a favorable impact on survival in HIV–PAH.[64]

Ambrisentan, a selective endothelin-receptor antagonist, has also been studied for its possible role in HIV–PAH. Concerns were raised if ambrisentan could safely be administered in patients receiving ritonavir, as ritonavir is a potent inhibitor of P-gP, CYP3A, and organic-anion-transporting polypeptide, of which ambrisentan is a substrate. Studies have found that there are no significant drug–drug interactions between the two and ambrisentan can safely be used in these patients.[65],[66]

Patients who have been initiated on this class of drug have to serially follow-up with liver function tests because of their potential hepatotoxicity.

Prostaglandin analogs

Various studies have shown the usefulness of prostaglandin-based therapy in HIV–PAH.

In one small-sized study comprising six patients of HIV–PAH, continuous intravenous infusion of epoprostenol was given. It was found that epoprostenol improved the functional class and hemodynamics in the long term as well as acutely.[67]

In another single-center study, three patients of HIV–PAH were treated with subcutaneous treprostinil, and it was found that the drug was safe and effective in the treatment of HIV–PAH.[68]

The safety and efficacy of inhaled iloprost were assessed in a study comprising eight patients with HIV–PAH, and it was found that not only there was an improvement in the functional capacity of the patients but also there was an improvement in hemodynamic parameters.[69]

Other treatment options

Patients not responding to medical management may be considered for an atrial septostomy. Creation of a Potts shunt can be done for decompressing.

Prognosis

PH carries poor prognosis; however, the survival rates have improved following increased use of PH-specific therapies. 1-year survival was approximately 85%, 2-year survival was approximately 70%, and 3-year survival was found to be approximately 55%.[70] HIV–PAH has a worse prognosis compared to patients with HIV alone.

Nevertheless, it was demonstrated that patients with HIV-related PAH had worse survival (approximately two times) compared to patients without HIV-related PAH.

About two-thirds of the deaths in patients with HIV-related PAH were due to the consequences of PAH, such as right heart failure, cardiogenic shock, and sudden death.[49]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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