HIV treatment in the coming years will include novel antiretroviral agents and new formulations such as long-acting injectables, as well as new strategies aimed at improving adherence and minimising side-effects.
Two new pro-drugs of tenofovir that look very promising are tenofovir alafenamide (TAF) and CMX157. Tenofovir, a component of widely used co-formulations Truvada, Atripla and Eviplera is highly effective but can cause kidney and bone toxicity in rare cases. Now in phase 3 testing, TAF produces higher drug levels in cells but allows for lower dosing with less effect on the kidneys and bones.
CMX157 also potentially carries less risk of kidney toxicity and its long half-life in a phase 1 trial suggests once-weekly dosing may be possible.
Another NRTI in the pipeline, EFdA claims to be "the most potent antiretroviral reported to date in laboratory studies".
Turning to NNRTIs, and MK-1439 has several attractive properties, including activity against HIV that has developed resistance to older NNRTIs (efavirenz and nevirapine, for example).
Novel agents include Cenicriviroc, which works as a CCR5 entry inhibitor (like maraviroc) but also blocks the CCR2 receptor.
Another, BMS-663068, interacts with HIV's gp120 envelope protein and interferes with binding to CD4 cells. Its mechanism of action resembles that of enfuvirtide (T- 20, Fuzeon) but it is an oral pill rather than a daily injection.
Researchers are also working on a new type of integrase inhibitor, known as lens epithelium-derived growth factor inhibitor or LEDGIN, that interferes with a protein that HIV uses to integrate its genetic material into host cell chromosomes.
While daily injections are clearly problematic, many people would be willing to take a single monthly or quarterly shot for HIV maintenance therapy or perhaps for pre-exposure prophylaxis (PrEP). Two such injectables are proceeding through the development pipeline: TMC278-LA, a long-acting form of rilpivirine (Edurant), and GSK1265744, a new integrase inhibitor that is also being tested as an oral medication.
In the near future we will see more fixed-dose combinations and single-tablet regimens, including the first co-formulations containing HIV protease inhibitors and the first to incorporate abacavir/3TC (rather than tenofovir/emtricitabine) as the NRTI components.