Tenofovir alafenamide for HIV infection: is less more?

www.thelancet.com Vol 385 June 27, 2015 2559 Since the late 1980s, progressive development of antiretroviral drugs has revolutionised care for people with HIV infection. Early generation antiretrovirals saved the lives of patients dying from AIDS, in exchange for a high pill burden and substantial morbidity. However, such treatment was susceptible to treatment failure, especially before the introduction of combination antiretroviral therapy in the mid-1990s, but also later because of poor tolerability and adherence challenges. More recently, antiretroviral drug development has evolved towards drugs that are easier to take, resulting in improved adherence and clinical benefi ts. The welltolerated, once a day, mostly single-pill regimens available for the past decade have transformed HIV into largely a chronic disease, allowing for earlier treatment initiation and expected near-normal lifespans. In The Lancet, Paul Sax and colleagues report the combined results of two phase 3, non-inferiority studies comparing the safety and eff ectiveness of the new antiretroviral agent tenofovir alafenamide with the approved tenofovir disoproxil fumarate, both coformulated into one, once a day pill with elvitegravir, cobicistat, and emtricitabine. In the combined analysis of 866 patients randomly assigned to the regimen containing tenofovir alafenamide and 867 patients to that containing tenofovir disoproxil fumarate, noninferiority was established in terms of the proportion of patients achieving the primary endpoint of HIV-1 RNA less than 50 copies per mL at week 48 (800 [92%] patients vs 784 [90%] patients, respectively, adjusted diff erence 2·0% [95% CI –0·7 to 4·7], within the prespecifi ed noninferiority margin of 12%). In addition to addressing the effi cacy of the tenofovir alafenamide-containing regimen, the data suggested an improved safety profi le, with smaller decreases in creatinine clearance and bone mineral density, and smaller increases in proteinuria. Despite substantial progress in the development of new drugs during the past decade, antiretroviral treatment remains associated with important morbidity risks. Although highly potent, safe, and widely used, tenofovir disoproxil fumarate causes proximal tubular injury in a small but clinically relevant minority of patients, and long-term use has been associated with small risks of decreased kidney function, chronic kidney disease, and decreased bone mineral density. Both tenofovir alafenamide and tenofovir disoproxil fumarate are prodrugs of tenofovir, which is phosphorylated intracellularly into its active antiretroviral form. Tenofovir alafenamide has been hypothesised to reduce important risks of toxic eff ects because it achieves high concentrations of tenofovir in HIV-relevant immune cells with substantially lower plasma concentrations than tenofovir disoproxil fumarate, and consequently lower accumulation in tubular epithelial cells because tenofovir is cleared by glomerular fi ltration and tubular secretion. The small but signifi cant diff erence in creatinine clearance decline recorded with tenofovir alafenamide versus tenofovir disoproxil fumarate is reminiscent of the small diff erences recorded when tenofovir disoproxil fumarate was compared with alternative antiretrovirals. In premarketing studies of tenofovir disoproxil fumarate, these small diff erences in creatinine clearance were the only signal that the drug might share the nephrotoxic potential of related agents like cidofovir; it was not until tenofovir disoproxil fumarate was used widely that cases of overt kidney injury were reported. 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