When is a four‑drug antiretroviral regimen indicated in HIV‑1 infection?

When to Use a Four-Drug Antiretroviral Regimen in HIV-1 Infection

A four-drug antiretroviral regimen is indicated primarily for patients with known or suspected pre-therapy multidrug resistance, specifically using darunavir/cobicistat/tenofovir alafenamide/emtricitabine as the recommended four-drug combination. 1

Primary Indication: Multidrug Resistance

The most clear-cut indication for a four-drug regimen is when you suspect or have documented multidrug resistance before starting therapy. 1 This scenario typically arises in:

• Treatment-experienced patients who have failed multiple prior regimens and harbor archived resistance mutations across drug classes 1
• Patients with documented resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or protease inhibitors (PIs) on genotypic testing 2
• Individuals with transmitted drug resistance involving multiple drug classes 3

The specific four-drug regimen recommended is darunavir/cobicistat/tenofovir alafenamide/emtricitabine, which combines a boosted protease inhibitor with high barrier to resistance (darunavir) plus two NRTIs. 1 Darunavir's high barrier to resistance makes it particularly valuable in this setting. 1

Treatment-Experienced Patients with Archived Resistance

For virologically suppressed patients with archived two-class drug resistance (≤3 thymidine analogue-associated resistance mutations but no Q151 mutation complex, T69 insertion complex, or darunavir resistance mutations), a four-drug regimen combining elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide plus darunavir once daily effectively maintained viral suppression at rates higher than continuing baseline therapy (90% vs 72%). 1

Similarly, darunavir/cobicistat/emtricitabine/tenofovir alafenamide maintained viral suppression to 96 weeks in individuals without darunavir treatment failure history or resistance mutations who switched from a boosted PI plus emtricitabine/tenofovir disoproxil fumarate. 1

Important Caveats and Pitfalls

Standard initial therapy should always be three drugs, not four. 4, 5 The recommended initial regimens consist of an integrase strand transfer inhibitor (INSTI) plus two NRTIs, with evidence rating AIa. 4, 6 Using four drugs as initial therapy in treatment-naïve patients without resistance is not supported by guidelines and exposes patients to unnecessary toxicity and drug interactions. 4

Do not confuse four-drug regimens with treatment intensification for adherence concerns. While darunavir/cobicistat plus tenofovir disoproxil fumarate/lamivudine is listed as having potential use for patients at high risk of poor adherence, this is actually a three-drug regimen, not four. 1

Avoid pharmacological boosters when possible (ritonavir and cobicistat), as they cause significant drug-drug interactions. 4 However, in the context of multidrug resistance where a four-drug regimen is needed, the benefits of darunavir's high barrier to resistance outweigh the interaction risks. 1

When Four Drugs Are NOT Indicated

Four-drug regimens are not recommended for:

• Treatment-naïve patients without documented resistance—use standard three-drug INSTI-based regimens instead 4, 6
• Virologically suppressed patients on stable therapy—switching to add a fourth drug provides no benefit 6
• Acute HIV infection—three-drug regimens with high barrier to resistance (dolutegravir or bictegravir-based) are sufficient 4
• Pregnancy—dolutegravir plus tenofovir/emtricitabine or lamivudine (three drugs) is the recommended regimen 4, 6

Algorithm for Decision-Making

1. Is the patient treatment-naïve? → Use three-drug INSTI-based regimen 4, 6
2. Does resistance testing show multidrug resistance across ≥2 classes? → Consider darunavir/cobicistat/tenofovir alafenamide/emtricitabine 1
3. Is the patient virologically suppressed with archived resistance? → Consider four-drug regimen only if switching from boosted PI and archived resistance involves ≤3 TAMs without Q151M complex or T69 insertion 1
4. Is this for salvage therapy after multiple failures? → Four-drug regimen with darunavir may be appropriate if at least three (or two) drugs are fully active 5, 2

The key principle: four-drug regimens are reserved for complex resistance scenarios, not routine care. 1 Standard HIV treatment remains three drugs for initial therapy and maintenance of suppression. 4, 6