What are dolutegravir, darunavir, ritonavir, and etravirine?

Antiretroviral Drug Classes for HIV Treatment

These are four distinct antiretroviral medications used in combination therapy for HIV-1 infection, representing different drug classes that target various stages of the viral life cycle.

Drug Classifications

Dolutegravir: Integrase Strand Transfer Inhibitor (InSTI)

• Dolutegravir is an integrase inhibitor that blocks HIV integration into host cell DNA, approved by the FDA in 2013 1
• It is metabolized primarily by UGT1A1 with some contribution from CYP3A 2
• Available as a single agent or coformulated with abacavir/lamivudine 1
• Demonstrates superior efficacy compared to efavirenz and ritonavir-boosted darunavir in comparative clinical trials 1
• Has the lowest risk of resistance development with virologic failure among antiretroviral agents 1
• Can be dosed once daily (50 mg) or twice daily (50 mg) depending on drug interactions and resistance patterns 1, 2

Darunavir: Protease Inhibitor (PI)

• Darunavir is a nonpeptidic HIV-1 protease inhibitor that prevents viral maturation by blocking cleavage of HIV gag and gag-pol polyproteins 3, 4
• Requires pharmacokinetic boosting with either ritonavir or cobicistat for once-daily dosing 1
• Demonstrates low risk of resistance with virologic failure, even with intermittent adherence 1
• Has a high genetic barrier to resistance and remains active against multidrug-resistant HIV isolates 4
• Ritonavir-boosted darunavir was inferior to raltegravir and dolutegravir in comparative clinical trials, largely due to lower tolerability 1

Ritonavir: Protease Inhibitor Used as Pharmacokinetic Booster

• Ritonavir is a protease inhibitor primarily used at low doses (100 mg) to boost other protease inhibitors by inhibiting CYP3A metabolism 1, 4
• When used as a booster, it increases darunavir bioavailability by approximately 30% and extends its elimination half-life to approximately 15 hours 4
• Causes many drug-drug interactions due to CYP3A inhibition 1
• Can be used during pregnancy, unlike cobicistat which should be avoided due to inadequate plasma drug levels 1

Etravirine: Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)

• Etravirine is a second-generation NNRTI that inhibits HIV reverse transcriptase, preventing viral RNA conversion to DNA 5
• It is a substrate of CYP3A, CYP2C9, and CYP2C19, and also acts as an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19, and P-glycoprotein 5
• Has the lowest risk of rash among NNRTI-based therapies 1
• Should not be used with rifampin due to significant drug-drug interactions 1

Critical Drug Interactions

Etravirine and Dolutegravir Interaction

• Etravirine significantly reduces dolutegravir plasma concentrations by approximately 71% (based on AUC reduction to 0.294), which can lead to loss of therapeutic effect 2, 5, 6
• The combination of dolutegravir and etravirine should be avoided unless coadministered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir 2, 5
• When etravirine is combined with darunavir/ritonavir or lopinavir/ritonavir, the negative effect on dolutegravir levels is mitigated 2, 5, 6
• Etravirine/darunavir/ritonavir modestly decreases dolutegravir AUC by 25%, C_max by 12%, and C_τ by 37%, which is not considered clinically relevant 6

Clinical Use Considerations

Current Treatment Recommendations

• Integrase inhibitor-based regimens (including dolutegravir) are generally recommended as first-line therapy due to high efficacy and favorable side effect profiles 3
• Darunavir boosted with ritonavir is recommended as an alternative when InSTI-based regimens are not an option 1
• Etravirine-based regimens should not be used without baseline resistance data due to possible transmitted NNRTI-resistant virus 1

Special Populations

• During pregnancy, dolutegravir and darunavir/ritonavir are both recommended options 1
• Cobicistat-containing regimens (including darunavir/cobicistat) should not be used during pregnancy due to inadequate drug levels 1
• For tuberculosis treatment with rifampin, dolutegravir (50 mg twice daily) is recommended, while darunavir and etravirine are not recommended due to drug interactions 1

Dual Therapy Regimens

• Dolutegravir plus darunavir/ritonavir as a dual regimen has demonstrated efficacy in salvage therapy and simplification strategies, with 76.2% achieving undetectable viral load at week 48 7
• This combination provides the best genetic barrier to HIV-1 resistance and may be suitable for heavily treatment-experienced patients 7