Reply to Brainard and McCallister

Brainard and McCallister assert that emtricitabine/tenofovir alafenamide (TAF-FTC) has clinically meaningful renal and bone safety benefits over emtricitabine/tenofovir disoproxil fumarate (TDF-FTC) for PrEP. They cite a meta-analysis confirming increased risk of renal adverse events (AEs) with TDF-FTC PrEP versus placebo or no PrEP (1), an open-label study of TDF-FTC PrEP for young men that found incomplete recovery of bone mineral density after PrEP discontinuation (2), and a pooled analysis of HIV treatment studies identifying higher rates of discontinuation after renal AEs with TDF versus TAF (3). We disagree that these studies demonstrate clinically meaningful benefits of TAF-FTC versus TDF-FTC for PrEP.

First, the meta-analysis description of increased risk of renal AEs included ≥ grade 1 serum creatinine elevations (1). When focusing on serious renal AEs or withdrawals due to renal AEs, there were no significant differences between TDF-FTC and placebo or no PrEP. In addition, renal abnormalities generally resolved after PrEP cessation.

Second, incomplete bone recovery after discontinuation of TDF-FTC PrEP among young men is not clinically meaningful unless it presages osteoporosis or fractures, which has not been observed (2). Moreover, studies of TDF-FTC PrEP in adults found full recovery of bone mineral density by 12–18 months after discontinuation, including among individuals ≤25 years old.

Third, the cited pooled analysis compared TDF versus TAF for HIV treatment, not HIV prevention. The risk of renal AEs is greater when TDF is used as part of combination antiretroviral treatment, which can increase TDF concentrations (e.g., with boosting agents). Nonetheless, discontinuation due to renal AEs was less than 0.5% for both TDF and TAF (3).

The strongest evidence against clinically meaningful renal and bone benefits for TAF-FTC versus TDF-FTC for PrEP is the absence of such benefits in DISCOVER, the only head-to-head comparison. Moreover, TAF-FTC resulted in weight gain and less favorable lipid levels, with twice as many participants starting lipid-modifying agents with TAF-FTC versus TDF-FTC (1.6% versus 0.8%, P=0.008) (4).

We agree that TAF-FTC may be preferable for individuals with underlying renal or bone disease, a small fraction of PrEP users. Conversely, TDF-FTC may be preferable for people with excess weight or dyslipidemia, which are common. With the impending availability of generic TDF-FTC, which will be substantially more cost-effective than TAF-FTC (5), keeping TDF-FTC as first-line for PrEP will maximize access and impact across all populations at risk of HIV.