Can Apretude (cabotegravir) cause hepatic enzyme elevations or liver injury?

Can Apretude Cause Liver Issues?

Yes, Apretude (cabotegravir) can cause hepatotoxicity, including hepatic enzyme elevations and liver injury, though this occurs in a limited number of patients. 1

Hepatotoxicity Risk Profile

The FDA-approved prescribing information for Apretude explicitly warns that hepatotoxicity has been reported in patients receiving cabotegravir, with or without pre-existing hepatic disease or identifiable risk factors. 1 This represents a documented safety concern that requires clinical vigilance.

Specific Hepatic Manifestations

• Transaminase elevations can occur with cabotegravir use, though the exact incidence is not well-quantified in the FDA labeling. 1
• Hepatotoxicity may develop regardless of whether patients have known pre-existing liver disease or identifiable risk factors. 1
• The severity can range from asymptomatic enzyme elevations to clinically significant hepatitis requiring treatment discontinuation. 1

Clinical Monitoring Requirements

For HIV-1 Treatment Use

• Patients with underlying liver disease or marked baseline transaminase elevations are at increased risk for worsening or development of further transaminase elevations. 1
• Monitoring of liver chemistries is recommended throughout treatment. 1
• Discontinue Apretude immediately if hepatotoxicity is suspected. 1

For HIV-1 Pre-Exposure Prophylaxis (PrEP) Use

• Clinical and laboratory monitoring should be considered during treatment. 1
• Discontinue Apretude if hepatotoxicity is suspected and manage individuals according to clinical presentation. 1

Pharmacokinetic Considerations in Hepatic Impairment

• A phase 1 study demonstrated that cabotegravir can be administered without dose adjustment in patients with mild to moderate hepatic impairment. 2
• In patients with moderate hepatic impairment, total plasma exposure decreased modestly (AUC ratio 0.73), but increased unbound fraction (FU ratio 2.14 at 2 hours) resulted in similar unbound drug concentrations. 2
• This pharmacokinetic profile was not considered clinically relevant, and no dose adjustment is required. 2

Recognition and Management Algorithm

Step 1: Baseline Assessment

• Obtain baseline liver function tests (ALT, AST, alkaline phosphatase, total bilirubin) before initiating Apretude, particularly in patients with known liver disease or risk factors. 1

Step 2: Ongoing Monitoring

• Monitor liver chemistries periodically during treatment, with increased frequency in patients with pre-existing liver disease. 1
• Consider checking transaminases every 2 weeks initially in high-risk patients, then monthly once stable. 3

Step 3: Response to Elevated Enzymes

• If ALT/AST >3× upper limit of normal (ULN): Immediately discontinue Apretude and monitor liver function tests every 1-2 weeks until normalization. 1
• If clinical symptoms of hepatotoxicity develop (jaundice, nausea, vomiting, right upper quadrant pain, fatigue, dark urine): Discontinue immediately regardless of enzyme levels. 1
• Monitor clinical status including liver transaminases and initiate appropriate supportive therapy. 1

Step 4: Evaluation for Alternative Causes

• Rule out viral hepatitis (hepatitis B, C), alcohol use, metabolic dysfunction-associated steatotic liver disease, and concomitant hepatotoxic medications. 3
• Consider that HIV-infected individuals have increased baseline risk of liver disease from multiple etiologies. 3

Critical Pitfalls to Avoid

• Do not continue Apretude if hepatotoxicity is suspected or confirmed. Unlike some mild transaminase elevations with other antiretrovirals that may resolve spontaneously, the FDA labeling specifically mandates discontinuation when hepatotoxicity is suspected with cabotegravir. 1
• Do not overlook hypersensitivity reactions that may present with hepatitis as part of a constellation of symptoms including rash, fever, malaise, or eosinophilia. 1
• Do not rechallenge with Apretude after documented hepatotoxicity, as this may result in more severe or rapid recurrence of liver injury. 1
• Do not assume safety based solely on absence of baseline liver disease, as hepatotoxicity has been reported even in patients without identifiable risk factors. 1

Comparison to Other Antiretrovirals

• The hepatotoxicity profile of cabotegravir appears more favorable than some older antiretrovirals; for example, nevirapine causes clinical hepatitis in 1.1% of patients with an overall hepatotoxicity incidence of 12.5%. 4
• Unlike protease inhibitors where hepatotoxicity can occur at any time during treatment, the temporal pattern of cabotegravir-associated hepatotoxicity is not well-characterized in available evidence. 4
• Coinfection with hepatitis C virus, which is a major risk factor for protease inhibitor-associated hepatotoxicity, should also be considered a risk factor when using cabotegravir. 4, 3