Boosting HIV treatment options: good news, new challenges.

For >15 years, ritonavir (RTV) has been the only pharmacokinetic enhancer (ie, booster) for human immunodeficiency virus (HIV) protease inhibitors. The development of cobicistat (COBI) promises to provide an alternative to RTV without direct antiviral effects of its own. COBI, a potent cytochrome P450 3A (CYP3A) inhibitor recently approved by the Food and Drug Administration (FDA) for use in a single-tablet regimen of elvitegravir/ COBI/emtricitabine(FTC)/tenofovir disoproxil fumarate (TDF), is currently being studied in phase 3 trials as booster of other antiretroviral drugs. In vitro studies demonstrate that COBI, unlike RTV, is a weak inhibitor for CYP2D6 and does not have inhibitory effects on other CYP isoforms (ie, CYP1A2, CYP2C09, and CYP2c19), making pharmacologic interactions more predictable [1]. COBI also seems to have less impact than RTV on normal adipocyte functions, such as lipid accumulation and/or response to insulin, which may offer the potential for fewer adverse biochemical effects relative to RTV [2]. In addition, the better solubility of COBI allows creation of a tablet formulation and coformulations that might foster the availability of other single-tablet regimens. In this issue of the Journal, Gallant et al report the 48-week results of a study comparing COBI with RTV as a pharmacoenhancer for atazanavir (ATV) plus FTC/TDF in 698 treatment-naive HIV type 1 (HIV-1)–infected patients. Study subjects were recruited in the United States, the Dominican Republic, Mexico, Thailand, Portugal, Germany, the United Kingdom, Italy, and Switzerland and were randomly assigned in a 1:1 ratio to receive COBI or RTV. Most of the participants (60%) were white, and similar to other large trials, the proportion of women (17%) was low. Twenty-four percent reported Hispanic/Latino ethnicity. The study allowed the inclusion of individuals with active hepatitis, with hepatitis B present in 3.6% of patients and hepatitis C in 5.3%. The immunologic status of the patients was relatively good, with 48% having CD4 T-cell count of >350 cells/mL, reflecting the latest recommendations for treatment initiation [3]. Randomization was stratified by viral load, with 39.7% of patients having >100 000 HIV RNA copies/mL at baseline. Of the 692 patients who initiated treatment with the study medication, 344 were in the COBI arm and 348 were in the RTV arm. At 48 weeks, COBI-boosted ATV was shown to be virologically noninferior to RTVboosted ATV, with 293 patients (85.2%) and 304 patients (87.4%) in the COBI and RTV arms, respectively, achieving an HIV-1 RNA load of <50 copies/mL, in accordance with the FDA snapshot intention-to-treat analysis (observed difference, −2.2% [95% confidence interval, −7.4% to 3.0%]). Mean increases in CD4 T-cell counts were also similar in the COBI and RTV groups (+213 cells/ mm and +219 cells/mm, respectively at week 48). Favorable responses were comparable in patients with a high viral load (86.4% in the COBI group vs 86.0% in the RTV group). Of the 95 subjects who were not reported as having achieved virologic success, treatment in 34 was defined as virologic failure (5.8% and 4% in the COBI and RTV arms, respectively), but this small difference was not statistically significant. The remaining 61 patients discontinued the protocol because of adverse events or other reasons, despite having undetectable viral loads. No major tolerability issues were reported. Gastrointestinal adverse events were not statistically different between the COBI and RTV groups, with similar rates of nausea (17.7% and 16.4%, respectively), vomiting (7.3% and 4.6%, respectively), or diarrhea (15.4% and Received 6 February 2013; accepted 7 February 2013; electronically published 26 March 2013. Correspondence: Pedro Cahn, MD, PhD, Fundacion Huesped, Angel Peluffo 3932, Buenos Aires, Argentina (pcahn@huesped. org.ar). The Journal of Infectious Diseases 2013;208:4–6 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit124