How should darunavir (with ritonavir or cobicistat) be prescribed for an adult with HIV‑1, including appropriate dosing, booster use, baseline labs, contraindications, common adverse effects, drug interactions, and alternative regimens?

Darunavir Prescribing Guide for HIV-1 in Adults

Direct Recommendation

Darunavir boosted with ritonavir or cobicistat is recommended as an alternative (not first-line) protease inhibitor-based regimen for adults with HIV-1, particularly when integrase inhibitor resistance is suspected or documented, or in patients with known multidrug resistance. 1

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When to Use Darunavir-Based Regimens

Primary Indications

• Suspected or documented multidrug resistance: Darunavir/cobicistat/tenofovir alafenamide/emtricitabine is specifically recommended for patients with known or suspected pretherapy multidrug resistance because darunavir maintains a high genetic barrier to resistance. 1
• Alternative to integrase inhibitors: When integrase strand transfer inhibitors cannot be used due to resistance, intolerance, or drug interactions, darunavir + cobicistat + tenofovir alafenamide + emtricitabine serves as the preferred protease inhibitor option. 2, 3
• Treatment-experienced patients: Darunavir is particularly valuable in heavily pretreated adults with limited therapeutic options and multiple protease inhibitor resistance-associated mutations. 4, 5

Specific Clinical Scenarios

• Poor adherence risk: Darunavir/cobicistat plus tenofovir disoproxil fumarate/lamivudine may be used for patients at high risk of poor adherence. 1
• Advanced immunosuppression (CD4 ≤35 cells/µL): Darunavir + cobicistat + tenofovir alafenamide + emtricitabine is an acceptable alternative when integrase inhibitors cannot be used. 2

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Standard Dosing Regimens

Treatment-Naïve or Treatment-Experienced Without Resistance

• Darunavir 800 mg once daily + ritonavir 100 mg once daily with food, combined with two NRTIs. 5, 6
• Darunavir/cobicistat 800/150 mg once daily (single-tablet option) with food, combined with two NRTIs. 1

Treatment-Experienced With Resistance Mutations

• Darunavir 600 mg twice daily + ritonavir 100 mg twice daily with food, combined with optimized background regimen. 4, 5, 6
• This twice-daily dosing is required when darunavir resistance-associated mutations are present (≥3 mutations: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V). 6

Critical Dosing Requirements

• Must be taken with food: Bioavailability increases by 30% when administered with meals. 4, 7
• Always requires pharmacologic boosting: Ritonavir or cobicistat is mandatory to achieve therapeutic darunavir levels by inhibiting CYP3A4 metabolism. 7, 6

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Baseline Laboratory Testing (Do Not Delay ART Initiation)

Mandatory Pre-Treatment Labs

• Genotypic resistance testing (reverse transcriptase, protease, and integrase genes) to identify darunavir resistance-associated mutations and guide regimen selection. 2, 3
• HIV-1 RNA viral load and CD4 cell count to establish baseline disease severity. 2, 3
• HLA-B*5701 testing if considering abacavir-containing alternatives (not applicable to darunavir regimens but required for comprehensive ART planning). 2, 3
• Hepatitis B surface antigen and hepatitis C antibody to identify co-infections requiring specific NRTI selection. 2, 3
• Serum creatinine/eGFR to assess renal function and guide tenofovir formulation choice. 3
• AST/ALT baseline liver function tests, especially critical for darunavir due to hepatotoxicity risk. 8
• Fasting lipid panel because protease inhibitors commonly cause dyslipidemia. 5, 6
• Pregnancy test for individuals of childbearing potential. 3

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Absolute Contraindications

Drug-Specific Contraindications

• Severe hepatic impairment (Child-Pugh Class C): No pharmacokinetic data exist; darunavir is not recommended. 8
• Concurrent use of CYP3A4 substrates with narrow therapeutic index: Including alfuzosin, rifampin, lovastatin, simvastatin, pimozide, ergot derivatives, triazolam, and oral midazolam due to life-threatening interactions. 7, 6
• Sulfonamide allergy: Darunavir contains a sulfonamide moiety; use with extreme caution or avoid in patients with severe sulfa allergies. 5

Clinical Contraindications

• Documented darunavir resistance: Presence of ≥3 darunavir resistance-associated mutations significantly reduces efficacy. 6

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Common Adverse Effects

Most Frequent (>10% incidence)

• Diarrhea: Most common gastrointestinal adverse effect, though less frequent than with lopinavir/ritonavir. 5, 6
• Nausea: Common but usually mild to moderate. 6
• Headache: Frequently reported but rarely leads to discontinuation. 6

Metabolic Complications

• Dyslipidemia: Grade 2-4 elevations in triglycerides and total cholesterol are common, though less severe than with lopinavir/ritonavir. 5, 6
• Hyperglycemia: Monitor glucose in patients with diabetes or metabolic syndrome. 5

Serious Adverse Effects

• Hepatotoxicity: Drug-induced hepatitis occurs in 0.5% of patients; increased risk in hepatitis B or C co-infection requires AST/ALT monitoring. 8
• Rash: Occurs in approximately 10% of patients; severe reactions (Stevens-Johnson syndrome) are rare but possible. 5

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Critical Drug Interactions

CYP3A4-Mediated Interactions

• Darunavir is both a substrate and inhibitor of CYP3A4: Coadministration with other CYP3A4 substrates, inducers, or inhibitors requires dose adjustments or is contraindicated. 7, 6
• Ritonavir and cobicistat are potent CYP3A4 inhibitors: They increase darunavir bioavailability from 37% to 82% but also amplify drug interaction risks. 7

Specific High-Risk Interactions

• Rifampin: Contraindicated; significantly reduces darunavir levels. 3
• Statins: Avoid lovastatin and simvastatin; use atorvastatin (lowest dose) or rosuvastatin with caution. 6
• Proton pump inhibitors and H2 antagonists: No significant interaction with darunavir (unlike rilpivirine). 6
• Hormonal contraceptives: Boosted protease inhibitors may alter estrogen/progestin levels; use additional barrier methods. 5

Cobicistat-Specific Considerations

• More drug interactions than ritonavir: Cobicistat inhibits renal tubular secretion of creatinine, causing falsely elevated serum creatinine without affecting actual GFR. 3
• Cannot be used with certain anticonvulsants, antimycobacterials, or herbal products (e.g., St. John's wort). 3

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Renal and Hepatic Dosing Adjustments

Renal Impairment

• No dose adjustment required for mild to moderate renal dysfunction (CrCl >30 mL/min). 4
• Tenofovir alafenamide preferred over tenofovir disoproxil fumarate in patients with renal impairment or osteoporosis due to superior renal and bone safety. 2, 3
• Fixed-dose combinations containing tenofovir disoproxil fumarate should not be used if CrCl <50 mL/min. 1

Hepatic Impairment

• No dose adjustment for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. 8
• Not recommended in severe hepatic impairment (Child-Pugh C) due to lack of data. 8
• Enhanced monitoring of AST/ALT required in hepatitis B or C co-infection. 8

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Monitoring After Initiation

Viral Load Monitoring

• HIV-1 RNA at 4–6 weeks after starting darunavir to assess initial virologic response. 2, 3
• Continue every 4–6 weeks until viral load is <50 copies/mL (target by 24 weeks). 2, 3
• Once suppressed: Monitor every 3 months during the first year, then every 6 months after sustained suppression. 2, 3

CD4 Monitoring

• Every 3–6 months during the first year, then every 6 months until CD4 >250 cells/µL for at least one year. 2, 3

Safety Monitoring

• AST/ALT every 3–6 months, especially in hepatitis co-infection. 8
• Fasting lipid panel every 3–6 months to detect dyslipidemia. 5, 6
• Serum creatinine/eGFR if using tenofovir-containing regimens. 3
• Fasting glucose in patients at risk for diabetes. 5

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Preferred Alternative Regimens (First-Line Options)

Integrase Inhibitor-Based Regimens (Preferred Over Darunavir)

• Bictegravir/tenofovir alafenamide/emtricitabine: Single-tablet regimen with highest efficacy, best tolerability, and strongest resistance barrier. 2, 3
• Dolutegravir + tenofovir alafenamide + emtricitabine: Equally effective with extensive long-term safety data. 2, 3
• Dolutegravir/abacavir/lamivudine: Requires negative HLA-B*5701 testing. 2, 3

When to Choose Darunavir Over Integrase Inhibitors

• Documented integrase inhibitor resistance (e.g., after long-acting cabotegravir PrEP exposure). 3
• Known or suspected multidrug resistance requiring a high genetic barrier protease inhibitor. 1
• Intolerance to all available integrase inhibitors. 2

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Common Pitfalls to Avoid

• Prescribing darunavir without pharmacologic boosting: Unboosted darunavir has inadequate bioavailability and will fail. 7, 6
• Using once-daily dosing in treatment-experienced patients with resistance: Twice-daily dosing is required when ≥3 darunavir resistance-associated mutations are present. 6
• Failing to take with food: Bioavailability drops by 30% when taken on an empty stomach. 4, 7
• Overlooking CYP3A4 drug interactions: Particularly with statins, rifampin, and narrow therapeutic index drugs. 7, 6
• Not monitoring liver function in hepatitis co-infection: Increased hepatotoxicity risk requires regular AST/ALT checks. 8
• Using tenofovir disoproxil fumarate in renal impairment: Switch to tenofovir alafenamide for better renal safety. 2, 3
• Choosing darunavir as first-line therapy: Integrase inhibitor-based regimens are preferred for treatment-naïve patients unless specific contraindications exist. 2, 3