HIV Associated Cardiomyopathy

HIV associated cardiomyopathy is left ventricular dysfunction in a person with HIV infection that is not explained by coronary disease, hypertension, valve disease or another cause.

In untreated adults, reduced ejection fraction is found in about 10 to 20% in some African series. It is linked to low CD4 count and high viral load.

Antiretroviral therapy (ART) has reduced the dilated form. Diastolic dysfunction and heart failure with preserved ejection fraction are now more common in treated patients.

Related cardiac problems in HIV are pericardial effusion (often tuberculous in sub-Saharan Africa), pulmonary hypertension, accelerated coronary disease and myocarditis from opportunistic infection.

Pathophysiology. Direct injury from HIV proteins, chronic immune activation, autoimmunity, and myocarditis from co-infection (coxsackievirus, cytomegalovirus, toxoplasma, Chagas disease reactivation) damage myocytes.

Nutritional deficiency (selenium, thiamine, carnitine) and drugs add to it, notably zidovudine, through mitochondrial toxicity. Microvascular disease and pulmonary hypertension contribute.

• Dyspnoea, orthopnoea, oedema, fatigue, weight loss and cachexia. Fever when infection is present.
• Signs of heart failure with a displaced apex, third heart sound and raised venous pressure.
• Pericardial effusion with tamponade features, often with night sweats and weight loss (tuberculosis).
• Arrhythmia, embolic stroke from ventricular thrombus, and pulmonary hypertension with right heart failure.

Red flags.

• CD4 count under 200 cells/microlitre with new heart failure
• Pericardial effusion with fever, weight loss or hypotension
• Interrupted ART or high viral load
• Ejection fraction under 40%, or ventricular thrombus
• Syncope, ventricular arrhythmia or cardiogenic shock
• Recent zidovudine, ganciclovir, doxorubicin or pentamidine

• HIV status, CD4 count and viral load. Hepatitis B and C serology.
• Echocardiography. Dilated hypokinetic ventricle, diastolic dysfunction, effusion, pulmonary pressure and thrombus. ECG and chest X-ray.
• Natriuretic peptide, troponin, creatinine, liver enzymes, thyroid function, glucose and lipids. Selenium and thiamine levels where available.
• Infection screen. Sputum Xpert MTB/RIF Ultra, urine lipoarabinomannan, pericardial fluid Xpert, adenosine deaminase and cytology in effusion, toxoplasma and cytomegalovirus testing, and Chagas serology in endemic regions.
• Cardiac MRI and endomyocardial biopsy only when the diagnosis is uncertain. Coronary assessment when risk factors are present.
• Diagnosis is by exclusion, and recovery with ART supports it.

Differential diagnosis.

• Dilated cardiomyopathy of other cause, including alcohol and hypertensive heart disease
• Tuberculous pericarditis and myopericarditis
• Opportunistic infection myocarditis
• Peripartum cardiomyopathy
• Ischaemic heart disease accelerated by ART and HIV
• Rheumatic heart disease
• Chemotherapy and drug cardiotoxicity
• HIV-associated pulmonary arterial hypertension
• Infective endocarditis
• Thyroid disease and anaemia

Antiretroviral therapy is the first treatment for every patient.

• Tenofovir disoproxil fumarate 300 mg, lamivudine 300 mg and dolutegravir 50 mg orally once daily as a fixed dose combination. Give dolutegravir 50 mg twice daily with rifampicin. Avoid tenofovir disoproxil at creatinine clearance under 50 mL/min and use abacavir 600 mg with lamivudine 300 mg once daily instead, after HLA-B*5701 testing. Take dolutegravir 2 hours before or 6 hours after iron, calcium and magnesium products.
• Avoid zidovudine, stavudine and didanosine, which are cardiotoxic.
• Boosted regimens (ritonavir, cobicistat) interact with amiodarone, apixaban, statins, digoxin, eplerenone and ivabradine. Check interactions before every cardiac drug.

Prophylaxis. Co-trimoxazole 960 mg orally once daily when CD4 is under 350 cells/microlitre or disease is advanced. Halve at creatinine clearance 15 to 30 mL/min and avoid under 15 mL/min. Check potassium, because it raises potassium with ramipril and spironolactone. Contraindicated in sulphonamide allergy and severe liver impairment.

Tuberculosis.

• Isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 mg/kg, each orally once daily for 2 months, then isoniazid and rifampicin for 4 months, with pyridoxine 25 mg once daily. Check liver enzymes at baseline, 2 weeks and monthly. Adjust pyrazinamide and ethambutol at creatinine clearance under 30 mL/min.
• Start ART within 2 weeks of tuberculosis treatment when CD4 is under 50 cells/microlitre, and within 8 weeks otherwise. Watch for immune reconstitution inflammatory syndrome.
• Pericardiocentesis for tamponade. Adjunctive prednisolone is not used routinely in HIV, because it did not reduce death, tamponade or constriction overall and was linked to excess HIV-related cancers.

Heart failure with reduced ejection fraction.

• Ramipril 2.5 mg orally once daily, increased every 2 to 4 weeks to 10 mg once daily (maximum 10 mg daily, and 5 mg daily at creatinine clearance under 30 mL/min). Check potassium and creatinine 1 to 2 weeks after each change. Contraindicated in pregnancy and bilateral renal artery stenosis.
• Bisoprolol 1.25 mg orally once daily, increased every 1 to 4 weeks to the target 10 mg once daily, maximum 10 mg daily in heart failure. Contraindicated in cardiogenic shock, second degree or third degree atrioventricular block without a pacemaker, sick sinus syndrome and severe asthma.
• Spironolactone 25 mg orally once daily (12.5 mg at eGFR 30 to 49 mL/min/1.73 m2), up to 50 mg daily. Check potassium and creatinine at 1 week and 4 weeks, then every 3 months. Withhold at potassium over 5.5 mmol/L and avoid at eGFR under 30 mL/min/1.73 m2. Avoid eplerenone with ritonavir or cobicistat.
• Furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed (higher doses in renal impairment under specialist care). Monitor sodium, potassium and creatinine.

Deficiency correction. Thiamine 100 mg orally once daily when deficiency is shown or suspected. Selenium 200 microgram orally once daily where deficiency is shown, though evidence is limited.

Anticoagulation for atrial fibrillation or ventricular thrombus: warfarin to an INR of 2.0 to 3.0, with INR every 2 to 3 days at the start, weekly until stable, then every 4 to 12 weeks. Rifampicin and boosted regimens change the INR. Avoid apixaban with rifampicin and with ritonavir or cobicistat.

Lipids. Avoid simvastatin and lovastatin with boosted regimens. Use atorvastatin at the lowest effective dose, not over 20 mg daily with boosted protease inhibitors.

Special groups.

• Pregnancy: continue ART (dolutegravir regimens are used), and stop ramipril and spironolactone.
• Children: weight based ART and heart failure doses under paediatric supervision.

Monitoring. Viral load at 6 and 12 months after starting ART, then yearly, and CD4 count at 6 months. Echocardiography at 3 and 6 months after ART starts, then yearly. Potassium and creatinine 1 to 2 weeks after each change of ramipril and at 1 week and 4 weeks after starting spironolactone, and liver enzymes at baseline, 2 weeks and monthly on antituberculous drugs.

Referral and escalation. Refer to cardiology and an HIV clinic jointly. Urgent for tamponade, cardiogenic shock, ventricular thrombus, or syncope.