Are the Safety Benefits of Tenofovir Alafenamide Overstated?

Tenofovir alafenamide (TAF) has been heralded as a version of tenofovir that is comparatively free of the adverse renal and bone effects associated with tenofovir disoproxil fumarate (TDF). Pharmacokinetic studies have demonstrated a higher intracellular concentration of the active moiety tenofovir diphosphate when TAF is used as an alternative tenofovir prodrug.¹ This potentially allows the same therapeutic effect at much lower doses and a 90% lower serum concentration, leading to fewer off-target bone and renal side effects.

A recent meta-analysis published in the Journal of Virus Eradication looked at the differences in safety and efficacy between TAF and TDF.² In contrast to previous studies, the researchers additionally assessed the effects of the pharmacokinetic boosters cobicistat and ritonavir. Cobicistat and ritonavir are known to increase the serum level of tenofovir.

Eleven clinical trials were included in the analysis (9 in patients living with HIV, 2 in patients with hepatitis B). Boosted TDF/TAF regimens were given to 4574 participants in both arms and 3537 patients received either unboosted TDF/TAF in both arms or mixed. The analysis included a total of 10,791 patient-years of follow-up.

Clinical efficacy endpoints were significant only for marginally lower rates of HIV suppression (viral load <50 copies/mL) by trial end in the boosted TDF treatment group (2%; 95% CI, 0%-4%; P =.05). No significant difference in emergence of primary genotypic resistance was found between the groups.

The safety profile was significantly different between the boosted and unboosted subgroups. The risk for fracture was 1% lower (95% CI, -2% to 0%, P =.04) in the boosted TAF group compared with the boosted TDF group. This difference was not present in the unboosted groups (0%, 95% CI, 0%-1%).

There was a commensurate decrease in the rate of discontinuation for bone-related adverse events for the boosted TAF group against the boosted TDF group, with no difference between the unboosted groups. Bone mineral density was significantly reduced for TDF compared with TAF in both boosted and unboosted subgroups.

For renal parameters, a difference was found between rates of discontinuation for renal adverse events. The boosted TAF group compared with boosted TDF group had a 1% lower rate of discontinuation (95% CI, -1% to 0%, P =.002), with no difference between the unboosted groups (0%, 95% CI, 0%).

Infectious Disease Advisor interviewed Andrew Hill, PhD, a senior visiting research fellow in the Department of Molecular and Clinical Pharmacology at Liverpool University, United Kingdom, regarding these findings.

Infectious Disease Advisor: Based on this meta-analysis, do think it is valid to consider a switch from a boosted to an unboosted TDF regimen equally beneficial to the use of TAF for patients at risk for renal or bone toxicities?

Dr Hill: There is no evidence for a safety benefit of TAF over TDF when the drugs are used unboosted. For people with preexisting renal impairment or bone toxicities, the use of tenofovir-sparing treatments could be considered, such as dolutegravir with lamivudine, which has shown promising results in the GEMINI trials (ClinicalTrials.gov identifiers: NCT02831673, NCT02831764).

Infectious Disease Advisor: Do you think TDF dose-finding studies should be conducted to establish a safe and efficacious dose reduction for pharmacokinetic booster combinations?

Dr Hill: Yes, these studies could evaluate a lower dose of 150 to 200 mg daily in combination with pharmacokinetic boosters.

Infectious Disease Advisor: Given the uncertain safety profile of TAF in pregnancy and tuberculosis co-infection, do you think the current balance of evidence favors sticking to regimens with TDF in these groups?

Dr Hill: There are very few data available on birth outcomes and abnormalities for pregnant women treated with TAF, whereas there is a comprehensive database for TDF. The concentrations of tenofovir diphosphate are 4 to 6 times higher for TAF compared with TDF. It is not known whether this could affect the risk for adverse birth outcomes. Results on this issue may be available in late 2019. 

Until that time, TAF should be used with caution in pregnant women. Additionally, there are no data available from HIV-tuberculosis coinfected patients treated with TAF and rifampicin-based treatment. Pharmacokinetic data in healthy volunteers suggest that TAF and rifampicin could be used in combination, but these preliminary findings have not been validated in patients.   

Therefore, for both pregnant women and people coinfected with tuberculosis, TDF is the preferred option to TAF.

Conclusion

The benefit of TAF may be limited to situations where it is used as an alternative to boosted TDF regimens.

References

1. Callebaut C, Stepan G, Tian Y, Miller MD. In vitro virology profile of tenofovir alafenamide, a novel oral prodrug of tenofovir with improved antiviral activity compared to that of tenofovir disoproxil fumarate. Antimicrob Agents Chemother. 2015;59(10):5909-5916.
2. Hill A, Hughes SL, Gotham D, Pozniak AL. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad. 2018;4(2):72-79.