HIV Associated Pulmonary Arterial Hypertension

HIV-associated pulmonary arterial hypertension is pre-capillary pulmonary arterial hypertension in a person with HIV infection, without another cause. It behaves like IPAH and develops independently of CD4 count and of viral load.

About 0.5% of people with HIV develop it, which is far higher than the general population rate. Prevalence has not fallen in the era of antiretroviral therapy. Co-factors include injection drug use, hepatitis C, co-infection with schistosomiasis, thrombophilia, and genetic susceptibility.

Untreated survival is poor. Median survival in registries is under 3 years, and with specific treatment 5-year survival approaches that of IPAH. Death is usually from pulmonary hypertension, not from HIV.

Other lung and cardiac causes of pulmonary hypertension are common in HIV, including left heart disease, chronic lung disease, tuberculosis sequelae, thromboembolism and cardiomyopathy.

Pathophysiology.

HIV does not infect the pulmonary endothelium directly. Viral proteins (gp120, Nef and Tat), chronic immune activation, inflammatory cytokines and endothelin-1 promote endothelial dysfunction, smooth muscle proliferation and plexiform lesions.

Antiretroviral therapy controls infection but does not reverse established pulmonary vascular disease.

Drug interactions between antiretroviral and pulmonary hypertension drugs are the main management issue, because boosted protease inhibitors and cobicistat inhibit CYP3A4, and efavirenz and rifampicin induce it.

Exertional dyspnoea, fatigue, syncope, chest pain and oedema, often wrongly attributed to infection or deconditioning. Signs of right ventricular loading and failure include a loud pulmonary second sound, right ventricular heave, raised jugular venous pressure and oedema. Features of HIV disease and opportunistic infections may coexist, and liver disease from hepatitis may complicate assessment.

• HIV test and CD4 count, viral load, hepatitis B and C serology, liver tests, and tuberculosis screening.
• Echocardiography, ventilation perfusion scan, pulmonary function tests, high resolution CT, sleep study if indicated, NT-proBNP.
• Right heart catheterisation: mean pulmonary artery pressure over 20 mmHg, wedge pressure of 15 mmHg or less, pulmonary vascular resistance over 2 Wood units. Acute vasoreactivity is rarely positive.
• Exclude pulmonary hypertension from left heart disease (HIV cardiomyopathy), chronic lung disease, thromboembolism, and other causes.
• Risk stratum: low (functional class I or II, 6-minute walk over 440 m, NT-proBNP under 300 ng/L), intermediate (class III, 165 to 440 m, 300 to 1100 ng/L), high (class IV, under 165 m, over 1100 ng/L, syncope).

Differential diagnosis.

• Idiopathic pulmonary arterial hypertension with coincident HIV.
• Pulmonary hypertension from HIV cardiomyopathy, tuberculosis sequelae, Pneumocystis or other lung disease.
• Portopulmonary hypertension (hepatitis C or B) and schistosomiasis associated disease.
• Chronic thromboembolic pulmonary hypertension and drug induced forms (injection drug use).

Antiretroviral therapy. Start or continue therapy in every patient regardless of CD4 count, because it controls the infection and reduces inflammation. Prefer regimens with little interaction potential, such as integrase inhibitor based regimens (dolutegravir or bictegravir), over ritonavir- or cobicistat boosted regimens.

Specific pulmonary hypertension therapy follows the usual risk based practice, adjusted for interactions. All drugs are continued long term.

• Ambrisentan 5 mg orally once daily, increased to 10 mg after 4 weeks (maximum 10 mg), has few antiretroviral interactions. Haemoglobin and liver tests at baseline and when indicated. Avoid in moderate to severe hepatic impairment (viral hepatitis may limit use).
• Bosentan 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily (maximum 250 mg daily). With ritonavir or cobicistat for at least 10 days, start at 62.5 mg once daily or on alternate days. Stop bosentan 36 hours before starting a booster and restart at 62.5 mg after 10 days. It lowers levels of protease inhibitors. Monthly ALT and AST.
• Macitentan 10 mg once daily: avoid with ritonavir, cobicistat and other strong CYP3A4 inhibitors. Avoid with efavirenz.
• Tadalafil 40 mg orally once daily (start 20 mg once daily in patients taking ritonavir for at least a week and increase to 40 mg if tolerated; avoid when creatinine clearance is under 30 mL/min; contraindicated with nitrates and riociguat). Sildenafil 20 mg three times daily: avoid with ritonavir.
• Riociguat starts at 0.5 mg three times daily with protease inhibitors, titrated by 0.5 mg every 2 weeks to a maximum of 2.5 mg three times daily (no phosphodiesterase-5 inhibitor or nitrate). Monitor blood pressure.
• Selexipag 200 microgram twice daily, increased weekly to a maximum of 1600 microgram twice daily. Exposure rises with ritonavir containing regimens, so titrate slowly.
• High risk: epoprostenol intravenously from 2 ng/kg/min or treprostinil from 1.25 ng/kg/min subcutaneously or intravenously. Central line infection is a particular concern, so use strict aseptic technique and consider the subcutaneous route.
• Calcium channel blockers are not used because vasoreactivity is rare.
• Endothelin receptor antagonists are teratogenic: exclude pregnancy before starting and monthly afterwards.

General measures. Diuretics (furosemide 40 to 120 mg orally daily, spironolactone 25 to 100 mg daily; potassium under 5.0 mmol/L, eGFR over 30), oxygen for PaO2 under 8 kPa, vaccination, correction of iron deficiency, and avoidance of pregnancy. Anticoagulation only for a separate indication, with attention to antiretroviral interactions with warfarin and direct oral anticoagulants. Treat hepatitis B and C. Treat tuberculosis, noting that rifampicin lowers levels of endothelin receptor antagonists and phosphodiesterase-5 inhibitors.

Monitoring. NT-proBNP, 6-minute walk and clinical review every 3 months at first. Echocardiography every 6 to 12 months. Liver tests monthly on bosentan, and viral load and CD4 count every 3 to 6 months. Right heart catheterisation after treatment change or deterioration.

Referral and escalation. Refer to a pulmonary hypertension centre with HIV service input. Urgent referral for syncope, progressive failure or high risk status.

Special groups.

• Pregnancy: pregnancy is advised against in pulmonary hypertension. choose antiretroviral therapy with the obstetric and HIV teams, and avoid teratogenic pulmonary hypertension drugs (endothelin receptor antagonists, riociguat, sotatercept).
• Injection drug use: treat addiction, avoid central lines where possible, and counsel on infection risk.
• Kidney or liver impairment: avoid bosentan and ambrisentan in significant hepatic impairment, and adjust tadalafil as set out.
• Region specific: in sub-Saharan Africa, co-infection with tuberculosis and schistosomiasis is common, and limited drug access means that sildenafil or tadalafil with an integrase based regimen is often the realistic option.