The Once and Future King: What Will Replace Atripla Atop the First-Line HIV Treatment Realm?
A Blog Entry From CROI 2010
Atripla (which is a combination of efavirenz + tenofovir + emtricitabine) is the acknowledged king in the realm of first-line antiretroviral therapy. Le Roi est mort, vive le Roi! Not so fast: The king still breathes. But his time is growing short.
Atripla is vulnerable primarily because of the efavirenz (Sustiva, Stocrin) component of the regimen. Efavirenz comes with its baggage of neurocognitive side effects, teratogenicity and the exacerbation of hyperlipidemia.
The competition is shaping up in the quest to stake a claim in the coveted "preferred" position for front-line antiretroviral therapy. So who are the contenders for the crown?
If lineage means anything, then the heir apparent is the "quad" pill from Gilead Sciences Inc. It is an amalgamation of GS 9350 (which now has a name: cobicistat), elvitegravir (GS 9137, JTK-303), tenofovir (Viread) and emtricitabine (FTC, Emtriva). A phase 2 study of the drug was presented at CROI, and the results were reported upon by Myles Helfand. The quad tablet showed high levels of efficacy -- similar to the Atripla comparator -- and, as expected, had fewer central nervous system side effects. This integrase inhibitor + boosting agent + nucleoside co-formulated tablet is poised to enter phase 3 trials in the very near future.
Despite being groomed for its role as new monarch, however, the young quad prince has some behavioral issues that have led to hushed discussions in the royal court. The concerns center around potential nephrotoxicity, with modest creatinine increases noted in the phase 2 trials. There is a known congenital kidney infirmity in this bloodline (from the tenofovir side of family), and the worry is that the intermarriage with GS 9350 may have exacerbated this latent tendency. The upcoming phase 3 trials will test the mettle of this aspiring prince and determine the outcome of its planned ascendency to the throne.
Next in line for the title is the co-formulation of rilpivirine (TMC278) and Truvada (which is itself a combination of tenofovir + emtricitabine). Although no new data were presented on rilpivirine at this conference, the phase 3 results are expected to be available in several months. Hereafter, this intermarriage of the second-generation NNRTI (non-nucleoside reverse transcriptase inhibitor) and the fixed-dose NRTI (nucleoside reverse transcriptase inhibitor) will be referred to as Newtripla (at least until the formal name is announced). Newtripla promises to solve the most nettlesome issues associated with efavirenz by hopefully demonstrating a better lipid profile, fewer central nervous system side effects and a lack of teratogenicity.
The only murmurs emanating from the royal court regarding Newtripla have to do with potency concerns about the 25-mg rilpivirine dose and the reduction in plasma levels induced by co-administration with omeprazole (Prilosec, Zegerid). Nonetheless, Newtripla may well represent a solution to the problems clinicians and patients can experience with Atripla -- and if it does, it would also serve to cement the alliance between the realms of Gilead and Tibotec Therapeutics.
Raltegravir (Isentress) deserves mention, but it is a decided outsider in the race for the crown. The dark-horse contender would have to overcome its greater pill burden and twice-daily dosing, but since it is already approved and gaining a following, it has some potential as a spoiler. The royal court is feverishly awaiting once-daily data on raltegravir, but the empire of Merck & Co. Inc., not known for the swiftness of their steeds, plods forward towards Camelot with stolid intent.
The final choice is the integrase inhibitor S/GSK1349572. This young prince, from the once-shining fiefdom of GlaxoSmithKline, has barely graduated from short pants. Despite the immaturity of the data supporting its cause, this agent comes with impressive credentials. Data were presented at CROI detailing the meticulous care that went into the creation of this compound. S/GSK1349572 also pledges to slay virus that eludes elvitegravir and raltegravir, and requires only once-daily unboosted dosing to be effective.
A mark against this young prince is its orphan status. With no natural allies outside of its own distant realm, it will require a long, solitary and arduous journey to even reach the kingdom.
The contest to decide the next king has been enjoined. Stay tuned for the next installment of the tale.