What is the recommended use and dosage of Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) for HIV-1 infection treatment?

Symtuza for HIV-1 Treatment

Overview and Indication

Symtuza (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) is a single-tablet protease inhibitor-based regimen recommended as an alternative initial therapy for treatment-naïve HIV-1 infected adults, and is particularly valuable for patients with known or suspected multidrug resistance. 1

This is the only protease inhibitor-based single-tablet regimen currently available for HIV-1 treatment in adults and pediatric patients weighing at least 40 kg. 2

Recommended Dosing

Standard Adult Dosing

• One tablet once daily with food 2, 3
• The fixed-dose combination contains:
  • Darunavir 800 mg
  • Cobicistat 150 mg (pharmacokinetic booster)
  • Emtricitabine 200 mg
  • Tenofovir alafenamide 10 mg 2

Key Dosing Considerations

• Must be taken with food to optimize absorption and drug levels 4
• Darunavir requires boosting with either cobicistat (as in Symtuza) or ritonavir for adequate plasma concentrations 4
• Not recommended in pregnancy due to inadequate plasma levels when cobicistat is used as the boosting agent 1

Clinical Positioning

Primary Indications

Symtuza is specifically positioned for:

• Treatment-naïve patients with known or suspected pretherapy multidrug resistance 1
• Treatment-experienced patients switching from other regimens who are virologically suppressed 3
• Patients requiring a high genetic barrier to resistance 2

Advantages Over Other Regimens

• High genetic barrier to resistance - darunavir maintains this advantage even with intermittent adherence 1, 2
• Single-tablet regimen reduces pill burden compared to multi-tablet protease inhibitor regimens 3, 5
• Effective in patients with history of virological failure on non-darunavir regimens 3

Pre-Treatment Requirements

Mandatory Testing Before Initiation

• HIV-1 genotypic and/or phenotypic resistance testing in treatment-experienced patients to assess drug susceptibility 4
• Baseline liver chemistry tests (AST, ALT, bilirubin) 4
• Estimated creatinine clearance (eCrCl) - do not initiate if <60 mL/min 6
• Hepatitis B surface antigen (HBsAg) 4
• Hepatitis C antibody 4

Critical Contraindications

• Creatinine clearance <70 mL/min when coadministered with tenofovir-containing regimens (dose adjustments for tenofovir have not been established with cobicistat boosting) 6
• Severe hepatic impairment 4
• Concomitant use with drugs highly dependent on CYP3A for clearance with narrow therapeutic index 4

Monitoring During Treatment

Ongoing Laboratory Surveillance

• HIV RNA levels: Within first 6 weeks, then every 3 months until <50 copies/mL for 1 year, then every 6 months 1
• Liver function tests: Monitor regularly, especially in patients with chronic hepatitis B or C, cirrhosis, or baseline transaminase elevations 4
• Renal function: Assess creatinine clearance periodically, particularly when coadministered with tenofovir 6
• CD4 count: Every 6 months until >250/μL for 1 year, then can discontinue if virus remains suppressed 1

Efficacy Data

EMERALD Trial Results

The pivotal EMERALD study demonstrated:

• Non-inferiority for virological rebound at week 48: 2.5% in Symtuza group vs 2.1% in control group (difference 0.4%, 95% CI -1.5 to 2.2) 3
• Study included 1,141 treatment-experienced patients, 58% had received ≥5 prior antiretrovirals, 15% had previous virological failure 3
• No resistance to any study drug was observed at week 48 3
• Discontinuations due to adverse events were minimal (1% in both groups) 3

Real-World Performance

• Maintains virological suppression at 96.6% at week 24 when switching from complex multi-tablet regimens 7
• Demonstrates durable efficacy through week 48 with improved treatment satisfaction scores 7

Safety Profile and Adverse Events

Common Adverse Reactions

• Diarrhea, nausea, rash, headache, abdominal pain, and vomiting (≥5% incidence, Grade ≥2) 4
• Grade 3-4 adverse events occurred in 7% of patients on Symtuza vs 8% on control regimens 3

Serious Warnings

• Drug-induced hepatitis (acute hepatitis, cytolytic hepatitis) has been reported; post-marketing cases include fatalities 4
• Severe skin reactions including Stevens-Johnson Syndrome, toxic epidermal necrolysis, DRESS syndrome, and acute generalized exanthematous pustulosis 4
• Use caution in patients with sulfonamide allergy (darunavir contains a sulfonamide moiety) 4

Metabolic Considerations

• Small but statistically significant increase in total cholesterol to HDL ratio (0.2 vs 0.1, p=0.010) compared to control 3
• Potential for new-onset diabetes mellitus or hyperglycemia 4
• Risk of fat redistribution/lipodystrophy 4

Renal Safety

• Cobicistat raises serum creatinine by 0.1-0.15 mg/dL through inhibition of tubular secretion (not actual kidney damage) 1
• Improved renal safety profile compared to tenofovir disoproxil fumarate-based regimens, with reduced proteinuria 7

Drug-Drug Interactions

Critical Interaction Considerations

• Extensive drug interactions due to cobicistat boosting - cobicistat is a strong CYP3A inhibitor 1
• Review all concomitant medications before initiating therapy 4
• Contraindicated with drugs highly dependent on CYP3A clearance with narrow therapeutic index 4
• Cannot be used with rifampin for tuberculosis co-infection (significant drug-drug interaction) 1

Common Pitfalls to Avoid

• Do not use in patients taking proton pump inhibitors without careful consideration of drug interactions 1
• Avoid in patients requiring multiple interacting medications where alternative regimens with fewer interactions (e.g., raltegravir-based) would be preferable 1

Special Populations

Pregnancy

• Not recommended - cobicistat-boosted darunavir achieves inadequate plasma levels during pregnancy 1
• If darunavir is required during pregnancy, use ritonavir-boosted darunavir 600 mg twice daily instead 4

Pediatric Patients

• Approved for pediatric patients weighing ≥40 kg 2
• A pediatric formulation (675/150/200/10 mg) is bioequivalent to the adult formulation 8
• Not recommended in children <3 years due to toxicity and mortality observed in juvenile rat studies 4

Hepatic Impairment

• Not recommended in severe hepatic impairment 4
• Use with caution and enhanced monitoring in patients with chronic hepatitis or cirrhosis 4

When NOT to Use Symtuza

Avoid Symtuza in favor of alternative regimens when:

• Patient is pregnant or planning pregnancy (use ritonavir-boosted regimen instead) 1, 4
• Creatinine clearance <70 mL/min 6
• Active tuberculosis requiring rifampin treatment (use efavirenz, raltegravir, or dolutegravir-based regimens) 1
• Multiple significant drug-drug interactions present (consider raltegravir or doravirine-based regimens) 1
• Patient has severe hepatic impairment 4
• Integrase inhibitor-based regimens are appropriate and available (these are preferred as first-line) 1

Clinical Context

While integrase strand transfer inhibitor (InSTI)-based regimens remain the preferred initial therapy for most treatment-naïve patients 1, Symtuza fills a critical niche for patients with suspected or confirmed multidrug resistance, those intolerant to InSTIs (particularly neuropsychiatric effects), or those requiring a protease inhibitor backbone for resistance considerations. 1, 2 The single-tablet formulation represents a significant advance in reducing pill burden for protease inhibitor-based therapy, improving from the previous median of 5 tablets daily to just 1 tablet. 3, 7