Should the dolutegravir dose be increased to 50 mg twice daily in a patient previously exposed to raltegravir?

Dolutegravir Dosing with Prior Raltegravir Exposure

No, you do not need to increase dolutegravir to 50 mg twice daily based solely on prior raltegravir exposure. Dose adjustment to 50 mg twice daily is only required when dolutegravir is co-administered with specific enzyme-inducing agents, particularly rifamycins used in tuberculosis treatment—not because of previous exposure to another integrase inhibitor like raltegravir.

Key Principle: Drug Interactions vs. Prior Drug Exposure

The critical distinction is between concurrent drug-drug interactions and historical antiretroviral exposure. 1

• Dolutegravir requires dose escalation to 50 mg twice daily when given concurrently with rifampin (rifampicin) for active tuberculosis treatment, as rifampin significantly reduces dolutegravir trough concentrations through UGT1A1 and CYP3A4 induction 1

• The 2025 International Antiviral Society-USA guidelines confirm that for active tuberculosis with rifamycin-containing regimens, dolutegravir should be dosed at 50 mg twice daily 1

• Prior exposure to raltegravir does not create a pharmacokinetic interaction requiring dolutegravir dose adjustment, as these are separate medications with no ongoing metabolic interference once raltegravir is discontinued 2

When Dolutegravir Dose Adjustment IS Required

Increase dolutegravir to 50 mg twice daily only in these specific scenarios: 1, 3

• Active tuberculosis treatment with rifampin (most common indication) 1
• Co-administration with efavirenz, nevirapine, fosamprenavir/ritonavir, or tipranavir/ritonavir 3
• Co-administration with carbamazepine, phenytoin, or phenobarbital 3
• Integrase inhibitor-experienced patients with specific INSTI resistance mutations (Q148 plus ≥2 additional INSTI mutations) 1, 4

Integrase Inhibitor Cross-Resistance Context

The question of prior raltegravir exposure becomes relevant only if there is documented integrase resistance, not simply because the patient previously took raltegravir. 4, 5, 6

• Dolutegravir has a higher genetic barrier to resistance than raltegravir and maintains activity against many raltegravir-resistant viruses 4, 5

• In the VIKING-3 study of INSTI-experienced patients, dolutegravir 50 mg twice daily was used specifically for those with documented integrase resistance mutations, achieving 66% virologic suppression at week 48 4

• Standard 50 mg once-daily dosing is appropriate for INSTI-naive patients or those without documented resistance mutations, even if they previously received raltegravir 1, 4

• The twice-daily dosing recommendation applies when Q148H/R/K mutations are present with ≥2 additional INSTI resistance substitutions (such as T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R) 4

Clinical Decision Algorithm

Follow this approach for patients with prior raltegravir exposure: 1, 4

1. Determine if patient is currently on rifampin or other enzyme inducers → If yes, use dolutegravir 50 mg twice daily 1

2. If no concurrent enzyme inducers, assess for documented integrase resistance:

   • Review historical genotypic resistance testing from the time of raltegravir failure
   • If Q148 mutations plus ≥2 additional INSTI mutations are documented → use dolutegravir 50 mg twice daily 4
   • If no resistance testing available or no significant INSTI mutations → use standard dolutegravir 50 mg once daily 1, 4

3. For virologically suppressed patients switching from raltegravir to dolutegravir → standard 50 mg once daily is appropriate 1

Common Pitfall to Avoid

Do not confuse the need for dose adjustment based on drug-drug interactions with dose adjustment based on prior treatment history alone. 1, 2

• The twice-daily dosing requirement stems from pharmacokinetic interactions that reduce dolutegravir exposure, not from the patient's antiretroviral treatment history 1

• Raltegravir and dolutegravir have no clinically significant pharmacokinetic interaction when used sequentially (one stopped before the other started) 2

• The metabolic pathways are similar (both primarily metabolized via UGT1A1), but this does not create an interaction when drugs are not given concurrently 1, 3