What are the risks and management strategies for creatine kinase (CK) elevation associated with Cabenuva (cabotegravir and rilpivirine)?

Cabenuva and Creatine Kinase Elevation: Risk Assessment and Management

Direct Answer

Cabenuva (cabotegravir/rilpivirine) has not been definitively associated with clinically significant CK elevation in clinical trials or post-marketing surveillance, and any CK elevations observed in HIV patients on this regimen are more likely attributable to patient-specific factors such as body weight and exercise rather than the medication itself. 1

Evidence Base

CK Elevation Risk Profile

The most relevant study directly examining this question found no association between dolutegravir-based antiretroviral therapy (another integrase inhibitor like cabotegravir) and CK elevation. 1 While this study examined dolutegravir rather than cabotegravir specifically, both are integrase strand transfer inhibitors with similar mechanisms of action.

Key findings from HIV patients on integrase inhibitor therapy:

• The incidence of grade 3-4 CK elevation (>10× upper limit of normal) was 2.0 per 100 person-years in the integrase inhibitor group versus 1.3 per 100 person-years in non-integrase inhibitor groups (P = 0.32, not statistically significant). 1
• After adjusting for confounding variables, CK elevation was associated with body weight (adjusted OR 1.03 per 10-kg increase) and duration of exercise (adjusted OR 1.02 per 1-hour increase), but NOT with integrase inhibitor-based therapy (adjusted OR 1.00). 1
• No patients required hospitalization or treatment discontinuation due to CK elevation. 1

Clinical Trial Safety Data

Major clinical trials (ATLAS, FLAIR, ATLAS-2M) evaluating cabotegravir/rilpivirine demonstrated comparable safety profiles to oral antiretroviral therapy, with no specific signals for CK elevation as a notable adverse event. 2, 3

Management Approach When CK Elevation Occurs

Initial Assessment (Any CK Elevation)

Evaluate alternative causes before attributing to Cabenuva:

• Recent vigorous exercise or physical activity (CK typically peaks 24 hours post-exercise and resolves within 1-2 weeks). 4, 1
• Body weight and muscle mass (higher weight correlates with higher baseline CK and greater exercise-induced elevations). 1
• Concomitant medications, particularly statins, which are common culprits for CK elevation. 4
• Intramuscular injections themselves (Cabenuva is administered intramuscularly and can cause local muscle injury). 5

Severity-Based Management Algorithm

For CK <4× ULN without muscle weakness:

• Continue Cabenuva without modification. 4
• Provide symptomatic treatment with acetaminophen or NSAIDs for any muscle discomfort. 4
• Recheck CK in 2-4 weeks. 6
• Assess for muscle pain, weakness, or fatigue at each visit. 6

For CK 4-10× ULN without muscle weakness:

• Continue Cabenuva but increase monitoring frequency. 4
• Discontinue any concomitant statins or other myotoxic medications. 4
• Check complete muscle enzyme panel (aldolase, AST, ALT, LDH). 4
• Recheck CK weekly until trending downward. 4

For CK >10× ULN with muscle symptoms OR any CK elevation with documented muscle weakness:

• Temporarily hold Cabenuva and hospitalize for evaluation. 4
• Check troponin and ECG immediately to exclude myocardial involvement (which would require permanent discontinuation). 4
• Initiate prednisone 0.5-1 mg/kg daily if inflammatory myositis is suspected. 4
• Refer urgently to rheumatology or neurology. 4
• Check urinalysis for myoglobinuria to assess rhabdomyolysis risk. 6

Critical Red Flags Requiring Immediate Action

Permanently discontinue Cabenuva if:

• Any evidence of myocardial involvement (elevated troponin, ECG changes). 4
• Progressive proximal muscle weakness develops. 4
• Dysphagia, dysarthria, dysphonia, or dyspnea occur (suggesting severe myositis). 4

Important Clinical Pitfalls

Do not attribute CK elevation solely to exercise in patients without excluding pathological causes. Even in athletes, persistent CK elevation beyond 1-2 weeks or progressive symptoms warrant full evaluation. 4

The long elimination half-life of intramuscular cabotegravir (5.6-11.5 weeks) and rilpivirine (13-28 weeks) means that if true drug-induced myopathy occurs, symptoms may persist for months after discontinuation. 7 This contrasts sharply with oral formulations and necessitates prolonged monitoring if Cabenuva is implicated.

Injection site reactions are extremely common with Cabenuva (pain in 100% of injections, induration in 54%, swelling in 42%), but these are typically Grade 1-2 and should not be confused with systemic myopathy. 5

Monitoring Strategy for Patients on Cabenuva

Routine CK monitoring is not indicated for asymptomatic patients on Cabenuva, as there is no established association between this medication and CK elevation. 1

Check CK only if:

• Patient develops new muscle pain, weakness, or fatigue. 4, 6
• Patient is on concomitant statin therapy (monitor per statin guidelines, not Cabenuva-specific). 4
• Patient has other risk factors for myopathy (hypothyroidism, renal insufficiency, heavy exercise). 4