Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety?

Background: Higher plasma tenofovir concentrations are associated with higher risks of renal and bone adverse events. The pharmacokinetic boosters ritonavir (RTV) and cobicistat (COBI) significantly increase plasma area under the curve (AUC) concentrations of tenofovir disoproxil fumarate (TDF), by 25-37%. When combined with RTV or COBI, the dose of tenofovir alafenamide (TAF) is lowered from 25 mg to 10 mg daily, but the TDF dose is maintained at 300 mg daily. Objective: To assess the differences in safety and efficacy between tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) in regimens with and without the pharmacokinetic boosters RTV and COBI. Methods: A PubMed/Embase search inclusive of dates up to 17 July 2017 identified 11 randomised head-to-head trials (8111 patients) of TDF versus TAF. The Mantel-Haenszel method was used to calculate pooled risk differences and 95% confidence intervals using random-effects models. A pre-defined sub-group analysis compared TAF with TDF, either when boosted with RTV or COBI, or when unboosted. Results: Nine clinical trials compared TAF and TDF for treatment of HIV-1 and two were for hepatitis B treatment. The eleven clinical trials documented 4574 patients with boosting RTV or COBI in both arms, covering 7198 patient-years of follow-up. Some 3537 patients received unboosted regimens, totalling 3595 patient-years of follow-up. Boosted TDF-treated patients showed borderline lower HIV RNA suppression <50 copies/mL (P=0.05), more bone fractures (P=0.04), larger decreases in bone mineral density (P<0.001), and more discontinuations for bone (P=0.03) or renal (P=0.002) adverse events. By contrast, there were no significant differences in HIV RNA suppression rates or clinical safety endpoints between unboosted TAF and unboosted TDF. Conclusions: TDF boosted with RTV or COBI was associated with higher risks of bone and renal adverse events, and lower HIV RNA suppression rates, compared with TAF. By contrast, when ritonavir and cobicistat were not used, there were no efficacy differences between TAF and TDF, and marginal differences in safety. The health economic value of TAF versus low-cost generic TDF may be limited when these drugs are used without cobicistat or ritonavir.