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New Antiretrovirals in development



Beginning with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), two new pro-drugs of tenofovir are being evaluated, tenofovir alafenamide (TAF) and CMX157. Tenofovir, a component of widely used co-formulations including Truvada, Eviplera and Atripla, is highly effective but can cause kidney and bone toxicity. TAF now in phase 3 testing produces higher drug levels in cells but allows for lower dosing with less effect on the kidneys and bones.

CMX157 also carries less risk of kidney toxicity and its long half-life in a phase 1 trial suggests once-weekly dosing may be possible.

Similarly, BMS-986001 is a new analogue of d4T (stavudine, Zerit). This drug is no longer used due to toxicities, with the exception of in some resource-limited settings, where it is a cheap option. BMS-986001 now in phase 2b development causes less mitochondrial toxicity, according to early studies.

Another NRTI in the pipeline, EFdA, is "the most potent antiretroviral reported to date" in laboratory studies, Raffi said. He also mentioned two other drugs in this class, elvucitabine and apricitabine, that have languished in the pipeline since the early 2000s.

Turning to non-nucleoside reverse transcriptase inhibitors (NNRTIs), MK-1439 "is the most promising candidate," according to Raffi. MK-1493 has several attractive properties, including activity against HIV that has developed resistance to older NNRTIs, and it has demonstrated good antiviral activity and tolerability in a phase 1b monotherapy study. Another novel NNRTI, AIC292, has also shown good activity against drug-resistant HIV.

Researchers are working on a new type of non-catalytic site integrase inhibitors, also known as lens epithelium-derived growth factor inhibitors or LEDGINs, that interfere with a protein (LEDGF/p75) that HIV uses to integrate its genetic material into host cell chromosomes.

Leaving the currently approved antiretroviral classes, Raffi reviewed some agents now in development that target other steps of the viral lifecycle. Cenicriviroc works as a CCR5 entry inhibitor (like maraviroc, Celsentri) but also blocks the CCR2 receptor. Data presented at this meeting demonstrated good antiviral activity and tolerability in a phase 2 clinical trial.

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.

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, Raffi predicted, 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.

Miss Philicia:
Lots of great news in that article for everyone, though the one thing I find odd is the development of a pro-drug related to Zerit.


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