First-Line Boosted Protease Inhibitor-Based Regimens in Treatment-Naive HIV-1-Infected Patients – Making a Good Thing Better

Lopinavir/ritonavir has been the recommended boosted protease inhibitor for treatment-naive individualsin all guidelines since its approval in the year 2000. More recently, the rest of ritonavir-boostedprotease inhibitors (namely lopinavir once-daily, fosamprenavir, saquinavir, atazanavir, and darunavir)have demonstrated non-inferior antiviral efficacy at 48 weeks than lopinavir twice-daily. Overall, allritonavir-boosted protease inhibitors display a high genetic and pharmacological barrier to resistancedevelopment and protect the rest of the drugs on board in the regimen, achieving similar CD4 countgains among them. During the last year, studies conducted with atazanavir and darunavir havedemonstrated superior virologic efficacy against lopinavir at 96 weeks in their pivotal trials. Thesetwo protease inhibitors provide significant improvements in triglycerides and gastrointestinal toxicity,together with simpler once-daily formulations, compared to lopinavir. In the case of atazanavir, thisis mainly driven by a lower rate of discontinuations due to drug-related side effects, as pure antiviralefficacy is essentially similar to lopinavir. Furthermore, the gastrointestinal intolerance of lopinaviris actually compensated by an increased risk of hyperbilirubinemia and jaundice with atazanavir, butthis is more a cosmetic problem and rarely a cause of drug withdrawal. Darunavir has been licensedto be taken once-daily in treatment-naive patients, and shows significantly better lipid and gastrointestinaltolerance than lopinavir. Robust sensitivity analysis with darunavir prove superior antiviralefficacy than lopinavir at 96 weeks also when non-virologic failures (toxicity and discontinuations)are censored, or when only patients receiving lopinavir twice-daily are included in the estimation.Moreover, darunavir has shown superior antiviral efficacy than lopinavir, particularly in three situationsof particular clinical concern: high baseline viral load, low baseline CD4 counts, and suboptimal drugadherence. Over the last years, the treatment landscape with ritonavir-boosted protease inhibitors asinitial HIV therapy has accomplished significant advances, with improved degrees of efficacy, tolerability,and convenience, that should be used to guide treatment choice in first-line antiretroviral therapy.