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With great interest, we read the review by Shafran et al. 1 on the advantages of tenofovir alafenamide (TAF) over tenofovir disoproxil fumarate (TDF) in clinical practice. Based on the pharmacological profile of TAF, similar or even superior virological efficacy is considered to be an intrinsic feature of TAF, whereas the overall favourable effects on kidney and bone are attributable to the absence of TDF rather than the use of TAF per se and have been reproduced in other TDF-free antiretroviral therapy (ART) regimens 2-5. However, as the article by Shafran et al. focuses on possible advantages for prevention of comorbidities in an aging population of people living with HIV (PLWH), as stated in both the title and the main text of the paper, we feel it is lacking a critical discussion about the increasing evidence of TAF promoting relevant weight gain, at least in a subset of patients with a potentially unidentified predisposition. This was first reported by Gomez et al. 6, in a study that was limited by the retrospective character of the cohort data, but recent findings from randomized controlled trials support the observation of TAF use being associated with excess weight gain when compared to TAF-free regimens. In the Gilead 380-4030 trial, 565 patients were randomized to switch from dolutegravir (DTG) and TDF/emtricitabine (FTC) or TAF/FTC to either bictegravir (BIC) or DTG in combination with TAF/FTC. Those switching from TDF/FTC to TAF/FTC experienced a higher weight gain compared to patients who were already on TAF/FTC at baseline (median 2.2 versus 0.6 kg, respectively; P-value not reported), while the weight gains in the DTG and BIC groups were comparable (median 1.1 versus 1.3 kg, respectively; P = 0.46) 7. Similarly, in another trial in which patients without ART for at least 6 months were randomized to receive efavirenz (EFV)/TDF/FTC or DTG/TDF/FTC or DTG/TAF/FTC, again the highest increase in body weight was found in the DTG + TAF/FTC group (mean increase 6.4 kg), followed by DTG + TDF/FTC (mean increase 3.2 kg) and the EFV/TDF/FTC group (mean 1.7 kg) 8. Moreover, in HIV-negative individuals taking TAF or TDF for pre-exposure prophylaxis, weight gain was again more pronounced in the TAF group (median 1.0 versus 0.0 kg, respectively; P < 0.05), although the difference was smaller than in PLWH 9. The more pronounced weight gains in clinical trials with PLWH may be attributed to an additive or synergistic effect of TAF in combination with other currently used third agents with potentially obesogenic properties. And even more evidence might have arisen between submission and publication of this comment due to the high interest on this phenomenon. As weight gain – unless occurring in underweight and potentially low-normal weight people – might contribute to cardiovascular risk in a population that is already at higher risk than uninfected controls, even after adjustment for traditional risk factors 10, we need a deeper understanding of the underlying pathomechanisms and clinical implications before we can postulate that TAF use will generally prevent comorbidities.