Regulatory approvals of tenofovir alafenamide (TAF)-containing tablets for HIV treatment, HIV preexposure prophylaxis (PrEP), and hepatitis B virus (HBV) treatment stemmed from randomized controlled trials (RCTs) that demonstrated noninferior efficacy as compared with equivalent formulations containing tenofovir disoproxil fumarate (TDF) [1–4]. Non-inferior efficacy seems difficult to dispute. Safety comparisons, on the other hand, generate controversy. Trial results suggested reduced renal and bone adverse effects with TAF. However, renal and bone side effects were primarily assessed using various biomarkers (not clinically significant adverse events) and absolute differences were small, calling the clinical significance into question. In practice, most HIV-treating clinicians have seen handfuls of cases of mild renal proximal tubulopathy secondary to TDF, as well as the occasional profound case, and some national guidelines favor TAF over TDF for antiretroviral therapy (ART) [5,6]. Now, adding to this convoluted picture, a systematic review with meta-analysis in this edition of AIDS finds that TDF and TAF are similarly effective and, more remarkably, equally well tolerated. How can clinicians and policy makers juxtapose such mixed experience and findings? Before incorporating the conclusions into practice and protocols, let us examine some details.
Pilkington et al. performed a robust systematic review and meta-analysis, which is an update to previous work . The update adds new data from three recent RCTs with continued follow-up from three prior trials. The revised analysis examines pooled data from nearly 15 000 participants and an impressive 24 000 cumulative patient-years of follow-up. Importantly, the investigators only included data from high-quality HIV or HBV RCTs that followed enrollees for at least 24 weeks. On one hand, this provides considerable data for comparing TDF versus TAF. On the other hand, a cautious lens must be applied when interpreting the results because of limitations based on the patient population and follow-up of the individual trials.
Notably, despite the sizeable pool of patients and addition of data from the ADVANCE trial (enrollees were primarily black African individuals), the predominance of data still comes from young, white, cisgender men with few comorbidities (overall mean age under 40 years, 61% white, 17% women, normal average baseline creatinine clearance) . Given the generally young, healthy population, significant follow-up time would be necessary to observe major renal and bone adverse events, especially renal tubular toxicity and osteoporotic or fragility fractures. Despite ample pooled patient-years of follow-up, the individual RCTs each had more limited observation time (eight trials reported data from 48 weeks of follow-up, four from 96 weeks, and only two from 144 weeks). As a case-in-point, despite the hefty pooled years of follow-up, Pilkinton et al. cite that only three renal tubular adverse events occurred. Not surprisingly, no fragility or osteoporosis-related fracture occurred. So, comparisons of safety must acknowledge the population studied and individual RCT follow-up time, which likely was too short to reach safety endpoints of greatest interest. Therefore, while Pilkinton et al. state, ‘These findings assuage pervasive concerns around the safety of TDF and can reassure clinicians and policy makers that TDF is a safe, well tolerated and affordable antiretroviral component to consider,’ I would add, ‘for young, otherwise healthy individuals’.
The results are most relevant to groups of patients who tend to be younger with few medical comorbidities, such as a majority of persons needing HIV PrEP or perhaps younger individuals newly diagnosed with HIV. It is more difficult to extrapolate findings to all individuals who need HIV or HBV treatment. The findings support HIV treatment guidelines that offer clinicians leeway in choosing TAF or TDF for individual patients based on an assessment of short and long-term toxicity risk [10,11]. They also reinforce recommendations to avoid the boosting agents ritonavir or cobicistat (the only signals for improved efficacy and renal tolerability with TAF occurred when comparing regimens that included boosting agents, though, as Pilkinton et al. point out, absolute differences were small). Unfortunately, the analysis could not compare other outcomes relevant to an aging patient population (weight change, metabolic complications, or cardiovascular risk, e.g.) nor costs. Price differences may favor TDF in some parts of the world and TAF in others; TDF may incur greater laboratory-monitoring burdens.
In sum, participants in antiretroviral RCTs (and therefore, systematic reviews) do not thoroughly reflect current clinic populations, especially clinics treating a preponderance of individuals over age 50 years, persons of color, individuals with multiple comorbidities, or persons of a gender that is not cisgender male. Additionally, follow-up does not extend long enough to exclude safety differences. Although the results of the systematic review by Pilkinton et al. impart reassurance that TDF appears well tolerated from a population perspective, individuals at higher risk of TDF toxicity may develop serious and sometimes irreversible side effects, so careful consideration of risk factors for TDF side effects remains important.
Comparisons between TDF and TAF remain highly relevant, as policy makers work to expand access to ART and PrEP around the world. In regions where TAF and TDF combinations are both available, price differences unfortunately influence coverage and policy must balance systematic review findings with individual safety, provider clinical discretion, and long-term ancillary medical costs. In the USA, for example, impending availability of lower cost TDF combinations has re-ignited debate about clinical indications for TAF and whether TDF can be considered a generic equivalent to TAF. Are the two drugs equivalent? Weigh the evidence, but the details matter.
Conflicts of interest
There are no conflicts of interest.
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