Tenofovir alafenamide (TAF) approved – but only as part of a fixed dose combination

1 December 2015. Related: Antiretrovirals.

Genvoya: elvitegravir/cobicistat/ FTC/TAF (E/C/F/TAF).

Simon Collins, HIV i-Base

Within the last two weeks, a fixed-dose combination (FDC) containing a new formulation of tenofovir DF called tenofovir alafenamide (TAF) has been approved in both Europe and the US. [1, 2]

This is the first time that a new antiretroviral HIV drug has been approved that is only available in a coformulation, limiting use for people who want or need the single new drug.

The combination (E/C/F/TAF) is a single pill contains elvitegravir (150 mg), cobicistat (150 mg), emtricitabine/FTC (200 mg) and TAF (10 mg). Although cobicistat is included to boost drug levels of the integrase inhibitor elvitegravir, the combination still needs to be taken with food to achieve optimum drug levels.

The license is for treating HIV-1 in adults and children older than 12 years (who weigh >35 kg).

EMA approval in the EU was on 23 November 2015 and FDA approval in the US was three weeks earlier on 5 November.

The European indication is broader, based on an absence of drug resistance mutations associated with the integrase inhibitor class, emtricitabine or tenofovir.

The US indication is:

As initial ART in treatment naive patients; or
As switch option in patients who have had:
1. An undetectable viral load for >6 months on their current ART, and
2. No history of virological treatment failure on previous combinations.

Safety concerns highlighted in the prescribing information include:

E/C/F/TAF should not be co-administered with other antiretrovirals (ARVs).
E/C/F/TAF is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious adverse events.
Patients with chronic hepatitis B/C treated with ARVs are at an increased risk for severe and potentially fatal hepatic adverse reactions.
•The safety and efficacy of E/C/F/TAF in patients co-infected with HIV & HCV/HBV has not been established. It should not be co-administered with medicines containing tenofovir DF, lamivudine (3TCV) or adefovir for treatment of HBV infection.
Discontinuation of E/C/F/TAF in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
E/C/F/TAF should not be used in patients with creatinine clearance (CrCL) < 30 mL/min as no data is available. It should be discontinued in patients with CrCL that declines <30 mL/min during treatment.

For full details please see the full product characteristics. [3]

The combination is manufactured by Gilead and marketed with the tradename Genvoya.

Comment

This new version of Stribild – with TAF replacing TDF – results in a combination that has reduced impact on laboratory markers of renal and bone toxicity. The better lab results probably also have clinical significance, at least for patients who are already at greatest risk. These people are likely to be older patients or those with reduced renal and bone function.

It is unclear whether the differences between TAF and TDF have clinical significance for people without these risks.

The regulatory decision to approve TAF within a combination but without a stand-alone version has been criticised for two reasons.

Firstly, that this ignores the clinical need for some people, especially those with extensive treatment experience, who would benefit from TAF by who are not able to use – or who do not want to – the other components of the FDC.

Secondly, that this might limit the ability of generic companies to coformulate TAF with other ARVs for use in low- and middle-income countries.

A dual formulation of TAF/FTC was submitted to the EMA for regulatory assessment in May 2015. [4]

References:

Gilead press statement. European Commission grant marketing authorisation for Gilead’s single tablet regimen Genvoya (elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide) for the treatment of HIV-1 infection. (23 November 2015).
http://www.gilead.com/news/press-releases
Gilead press statement. U.S. Food and Drug Administration approves Gilead’s single tablet regimen Genvoya (elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide) for treatment of HIV-1 infection. (05 November 2015)
http://www.gilead.com/news/press-releases
Gilead Sciences. Genvoya: full prescribing information and highlights of full prescribing information. (US
http://www.gilead.com/~/media/files/pdfs/medicines/hiv/genvoya/genvoya_pi.pdf (PDF)
Dual F/TAF formulation under evaluation. HTB May/June 2015.
https://i-base.info/htb/28289