First, the study was only powered to demonstrate noninferiority with respect to changes in TC, and was not necessarily adequately powered for
the other parameters described. Secondly, the study was not blinded, and therefore pill burden was higher in the SQV/r arm than in the ATV/r arm, which could JQ1 have resulted in differential issues with adherence. Given the similar virological and immunological efficacies, this seems unlikely to have had a major effect. Thirdly, unlike the ATV/r dose, the once-daily dose of SQV/r used in this trial has not been formally approved, and is generally not recommended in current treatment guidelines. Although the study was only powered to demonstrate noninferiority with respect to changes in TC, the observed virological and immunological responses were consistent with those observed in several trials of first-line therapy [11,13,42,44]. Fourthly, objective assessment of body composition was only available in a subset of patients, which may have affected our power to observe differences between treatments. Fifthly, our study was of limited duration, which precludes any conclusions hypoxia-inducible factor pathway regarding longer term safety and efficacy. Finally, whereas the observed reduction in eGFR of up to 10% over 48 weeks in
patients with a generally normal eGFR at baseline may not be of major clinical concern, it could be an issue in patients with compromised renal function at the initiation of treatment. In summary, when combined with TDF/FTC, once-daily SQV/r was noninferior to ATV/r with respect to changes in TC, and the two regimens had similar modest effects on lipids. Neither regimen seemed to affect insulin sensitivity or resulted in lipoatrophy. Whether ATV/r when combined with TDF/FTC truly results in a larger overall increase in adipose tissue than SQV/r
will need to be confirmed in a larger study. Once-daily SQV/r plus TDF/FTC may be considered as an alternative in particular circumstances which preclude the use of ATV/r or other recommended treatment options. The long-term effects of both regimens on renal and bone health as well as their potential effects on cardiac conductivity  warrant further investigation. We would like to thank D. Prelutsky, all substudy investigators and staff, and especially the DNA ligase participants for their time. We are indebted to Hans Hoogeveen, Margot Meijer, Engelien Septer-Bijleveld, Gerrit-Jan Ilbrink, Dianne Ekkel, Sundhiya Mandalia and Veronique Passot for the project management and data collection. We would like to thank Elly Hassink for help with the concept and design of the protocol, Medpace Reference Laboratories for central lipid and glucose/insulin assessments and Tufts for central reading of CT and DXA scans. We would also like to thank Frans Hoek and Jan van Straalen from the Department of Clinical Chemistry for analytical assistance with cystatin C.