HTB

Twice-daily tenofovir alafenamide dose might overcome interaction with rifampicin

Polly Clayden, HIV i-Base

Twice-daily tenofovir alafenamide (TAF) plus rifampicin (RIF) provided similar exposures to once-daily TAF in pharmacokinetic (PK) study. This strategy might be a suitable option for people with HIV/TB coinfection.

TAF and tenofovir disoproxil fumarate (TDF) are prodrugs of tenofovir (TFV). TAF is more stable in plasma compared with TDF and gives about 90% lower plasma TFV exposures.

TAF is a substrate of drug transporters and RIF is a potent inducer and associated with drug-drug interactions and in turn lower drug exposures. The interaction between TAF and RIF has not previously been evaluated. Currently TDF is indicated for use with RIF but once-daily TAF is not.

Gilead Sciences, the originator company of TDF and TAF, conducted a PK study to look at twice-daily TAF co-administered with once-daily RIF. [1] The results were presented at EACS 2017.

The study aims were to evaluate the steady state PK of TAF, the active intracellular moiety tenofovir-diphosphate (TFV-DP), and the TAF major metabolite TFV, after co-administration of twice-daily TAF with once-daily RIF 600 mg, compared with once-daily TAF. It was a phase 1, open label, parallel design, multiple dose, single centre study in HIV/TB negative volunteers.

Participants were enrolled into two cohorts (26 in each cohort). TAF was given in the fixed dose combination (FDC) tablet bictegravir/emtricitabine/TAF (B/F/TAF 50/200/25 mg).

Cohort 1 received B/F/TAF once daily and cohort 2 B/F/TAF twice daily plus RIF 600 mg once daily, both two hours after food, for 28 days. Plasma and intracellular peripheral blood mononuclear cell (PBMC) PK was assessed on days 1 and 28.

Statistical comparisons used geometric least-square mean (GLSM) ratios and 90% confidence intervals (CI).  Cohort 2 was the test regimen and cohort 1 was reference.

The evaluation revealed that with twice-daily administration of TAF plus RIF, exposures over 24 hours of TAF total plasma, overall systemic plasma TFV and intracellular PBMC-associated TFV-DP are expected to be reduced by <15%, about 20%, and about 24%, respectively, compared with once-daily TAF. See results table 1.

Table 1: TAF twice daily + RIF vs TAF once daily PK

Mean (%CV) TAF once daily TAF twice daily + RIF GLSM ratio (90% CI)
Plasma TAF PK                     AUC 0–24 (ng*h/mL) 345 (52) 290 (48) 85.8 (69.7 to 106)
Plasma TFV PK                     AUC 0–24 (ng*h/mL) 348 (20) 277 (19) 79.9 (73.1 to 87.3)
Intracellular TFV-DP                       AUC 0–24 (fmol*h/106 cells) 76.3 (58.7 to 99.2)

Notably, after twice-daily administration of TAF plus RIF, the mean (%CV) steady-state trough concentration of TFV-DP was 359 (58) fmol/106 cells, which is above the historical steady state TFV-DP concentrations achieved with TDF 300 mg.

comment

TAF has the potential to replace TDF as part of an optimised generic first-line regimen for low- and middle-income countries (LMICs).

Due to TAF’s low milligram dose (and lower amounts of active product ingredients) compared with TDF, this could reduce the annual cost per person from the recently agreed US $75 (for a fixed dose combination of TDF/lamivudine [3TC]/ dolutegravir [DTG]/ or TLD) further still. [2] Approval of two generic FDCs of TAF/3TC/DTG is expected by mid-2019.

TAF is not yet recommended in WHO or any national guidelines in LMICs as there are insufficient data on its use in pregnancy and in people with HIV/TB coinfection.  

Previous investigations by Gilead showed co-administration with carbamazepine leads to a 55% decrease in TAF in plasma and results from modelling to predict the interaction with RIF suggested this reduction would be 73% in plasma. [3]

Results from the PK study described above are welcome and provide preliminary evidence for adjusting the TAF dose to twice daily with RIF. But the parallel design is a limitation, and there is no concurrent TDF comparison.

Further evidence will be available early 2018 from the RIFT study that is currently evaluating the effect of RIF on plasma PK of emtricitabine (FTC) and TAF and TFV-DP and FTC-triphosphate (FTC-TP). [4]

If, as the results above suggest, dosing TAF twice daily is the solution to co-administration with RIF this will potentially make HIV/TB co-treatment easier in for programmes in LMICs as twice-daily DTG also looks promising. Botswana is already using this strategy and results from INSPIRING [5] – looking at DTG and efavirenz-containing ART regimens in people with HIV/TB co-infection – will also be available early next year.

The TAF/3TC/DTG could be given twice daily – which is not possible with the TDF-containing FDC that requires giving the extra DTG as a single tablet. 

References

  1. Custodio JM et al. Twice daily administration of tenofovir alafenamide in combination with rifampin: potential for tenofovir alafenamide use in HIV-TB coinfection. 16th European AIDS Conference (EACS). October 25–27 2017. Milan.  Oral abstract PS13/4.
  2. CHAI. ARV market report. Issue 8. 28 September 2017.
    https://clintonhealthaccess.org/content/uploads/2017/09/2017-ARV-Market-Report_Final.pdf (PDF)
  3. Gilead Sciences personal communication.
  4. National Institutes of Health. RIFT: Effect of rifampicin on plasma PK of FTC, TAF and intracellular TFV-DP and FTC-TP.
    https://clinicaltrials.gov/ct2/show/NCT03186482
  5. National Institutes of Health. Open-label study of dolutegravir (DTG) or efavirenz (EFV) for human immunodeficiency virus (HIV) – tuberculosis (TB) co-infection.
    https://clinicaltrials.gov/ct2/show/NCT02178592

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