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.
Comment by: Sarah
Fri., May. 27, 2016 at 2:48 am UTC
I have been testing Genvoya.. I start testing 2013 finish 2016.05.i start from 4 tablets daily.and yes there was alot side effects over a year I live with yellow eyes,hits my liver.. After over a year was changed to 1 tablet . And in less the a week,my eyes back to normal,all side effects just gone..that was a 510 and today got the name. Genvoya.its approved, and I am very happy with this treatment.and cary on taking them.My count: undetectable and CD4.1000+.where we go.Thank you so much to research clinic for giving me a chance..feeling lucky..