New HIV Treatment Genvoya Is Really All About the TAF Part

November 10, 2015

Paul E. Sax, M.D.

Paul E. Sax, M.D., is director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital in Boston.

HIV providers and patients recently got this news from the FDA:

The U.S. Food and Drug Administration today approved Genvoya (a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

(Disclosure: I have been involved with the clinical trials; you can read my full disclosures here. That involvement notwithstanding, some sort of comment seems appropriate -- this is an HIV/ID blog, after all.)

The availability of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide -- hereafter abbreviated "ECF-TAF" -- brings us the fifth one-pill-a-day treatment for HIV. Of course we already have something very similar, which is ECF-TDF, and hence the only thing new here is the TAF component.

So what does ECF-TAF bring us that we didn't already have with ECF-TDF?

Based on multiple clinical studies, here are what I think are the proven differences between the two:

  • Less effect on bone density. As initial therapy, TAF induces less bone loss than TDF -- the former is comparable to NRTI-sparing strategies. Furthermore, in multiple clinical studies, switching from TDF to TAF improves bone density.
  • Decreased renal toxicity. In several trials involving over 3000 patients, no case of tenofovir-related renal toxicity has occurred in an ECF-TAF-treated patient. TAF's effect on urinary proteins (a surrogate marker for renal effects) is also significantly less than TDF. One unknown is whether it can be safely given to a patient with a history of tenofovir-related renal toxicity; that question is under study. The regimen is approved for use in patients with estimated GFR down to 30 ml/min.
  • A lower milligram dose. As part of ECF-TAF, the dose of TAF is only 10 mg, vs 300 mg for TDF. (When not given with cobicistat or ritonavir, the dose will be 25 mg.) A lower milligram dose means smaller pills and easier coformulations.
  • A novel way to simplify complex regimens. As noted here, ECF-TAF can be combined with 800 mg of darunavir to make a two-pill treatment for some patients with multi-drug resistant virus. You couldn't do this with ECF-TDF, at least not with confidence -- it hadn't been studied, and the three-way drug-drug interaction between cobicistat, darunavir, and elvitegravir gave me pause.
  • Less lipid-lowering effect. Tenofovir lowers lipid levels (mechanism still unclear), and since TAF delivers 90% lower blood levels of tenofovir than TDF, there is less of this effect. This lower tenofovir exposure is mostly a good thing (see renal and bone above), but not here. I suspect this won't be clinically relevant, but of course we don't have enough follow-up data since the incidence of cardiovascular events in short-term clinical trials is so low.

And here's what's not different:

  • Antiviral activity. Though in phase I studies TAF induced greater declines in HIV RNA than TDF, virologic outcomes (meaning failures and incident resistance) in studies comparing ECF-TAF with ECF-TDF have been similar.
  • Drug-drug interactions. The "C" in both ECF-TAF and ECF-TDF stands for cobicistat, the ritonavir-like PK "booster" that is necessary for elivitegravir's once-daily dosing. A cytochrome p450 inhibitor, cobicistat has numerous drug-drug interactions -- watch those medication lists carefully! Note that a combination of TAF/FTC and 9883 -- an unboosted integrase inhibitor, no cobicistat required -- is in development.
  • Subjective side effects. There's no significant difference in the incidence of patient-reported side effects. In other words, if your patient didn't tolerate ECF-TDF, there is little point in trying ECF-TAF. Good news is that both are very well tolerated, with extremely low discontinuation rates for adverse events.
  • The price. Encouragingly, ECF-TAF is priced the same as ECF-TDF, a decision lauded by this group. However, integrase-inhibitor based regimens remain relatively expensive (average wholesale price around $30,000/year) compared to NNRTI-based therapies, though cheaper than those that include a boosted PI.

Overall, ECF-TAF is welcome new option for treatment, and to emphasize again it's the TAF part that makes the (only) difference. Future TAF formulations will include TAF-FTC-rilpivirine and TAF-FTC (which will need at least one other active drug) -- these are expected some time next year. TAF-FTC-9883 is further away.

Meanwhile, we can continue to ponder the mysteries of choosing a brand name for a drug -- "Genvoya" sounds to me like a high-end coffee maker.

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This article was provided by NEJM Journal Watch. NEJM Journal Watch is a publication of the Massachusetts Medical Society.
See Also
Genvoya, New Single-Tablet HIV Regimen Containing Tenofovir Alafenamide, Approved By FDA


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