described some of the antiretrovirals currently in development, noting that it
is not yet known what role they will play in clinical practice.
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
also carries less risk of kidney toxicity and its long half-life in a phase 1
trial suggests once-weekly dosing may be possible.
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
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.
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.
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
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.
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.
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.