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  20th Conference on Retroviruses and
Opportunistic Infections
Atlanta, GA March 3 - 6, 2013
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Seven-Day Monotherapy With New NNRTI Yields Sharp Viral Load Drop
  20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
Either 25 or 200 mg of MK-1439, a nonnucleoside reverse transcriptase inhibitor (NNRTI), lowered viral load more than 10-fold during 7 days of monotherapy, with no viral breakthroughs and no concerning drug-related adverse events.
In previous cells studies, MK-1439 showed similar strong activity against 93 clinical isolates representing 10 HIV-1 subtypes [2]. In another analysis, MK-1439 had less than a 3-fold loss in susceptibility to each of the three most frequently transmitted NNRTI mutations, K103N, Y181C, and G190A [2]. Tested against a panel of resistant isolates, MK-1439 showed stronger activity than efavirenz and activity comparable to etravirine and rilpivirine [2].
The new double-blind, placebo-controlled trial enrolled 18 antiretroviral-naive people at a single site in Germany and randomized them to 25 or 200 mg of MK-1439 once daily or to placebo for 7 days. (The two MK-1439 doses span the range of doses being studied in a phase 2b trial--25, 50, 100, and 200 mg once daily [3].) After this 7-day treatment phase, all study participants agreed to switch to a local standard-of-care regimen for 10 days to prevent emergence of NNRTI-resistant virus as MK-1439 concentrations fell after dosing stopped.
The monotherapy trial was open to men and women, but only men enrolled. Participants had to be 23 to 45 years old and to have a body mass index between 20.6 and 35 kg/m(2). No one could be taking other medications.
Compared with placebo, 25 mg of MK-1439 suppressed plasma HIV RNA 1.37 log10 copies/mL through 7 days, and 200 mg of MK-1439 induced a 1.26-log drop in viral load.
Thirteen of 16 study participants reported 21 nonserious adverse events, usually headache (in 5), diarrhea (in 3), and nausea, common cold, sore throat, or night sweats (in 2 each). The investigators considered two adverse events possibly or probably related to MK-1439--night sweats and headache. All clinical adverse events were mild or moderate and limited in duration. One serious adverse event arose, a jump in liver enzymes caused by acute HCV infection (judged probably not related to study drug).
Pharmacokinetic profiles in trial participants proved comparable to those recorded earlier in healthy volunteers. Steady-state 24-hour concentrations exceeded serum-adjusted 95% inhibitory concentrations needed to suppress wild-type (nonmutant) virus by 14-fold with 25 mg and by 87-fold with 200 mg.
Steady-state concentrations were achieved in 3 to 5 days. At steady state, accumulation ratios (day 7/day 1) of MK-1439 lay between 1.55 and 1.6 for 24-hour area under the concentration-time curve, maximum concentration, and 24-hour concentration. Mean apparent terminal half-life ranged from 31 to 41 hours; the effective terminal half-life range of 10 to 16 hours was similar to the 9 to 12 hours recorded in healthy volunteers.
The phase 2b dose-ranging trial will compare MK-1439 plus tenofovir/emtricitabine with efavirenz plus tenofovir/emtricitabine in 200 antiretroviral-naive people [3].
1. Anderson M, Gilmartin J, Robberechts M, et al. Safety and antiviral activity of MK-1439, a novel NNRTI, in treatment-naive HIV+ patients. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 100.
2. Lai M, Feng M, Lu M, et al. Antiviral activity and in vitro mutation development pathways of MK-1439: a novel non-nucleoside reverse transcriptase inhibitor. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-551. http://www.natap.org/2012/ICAAC/ICAAC_23.htm.
3. ClinicalTrials.gov. A dose-ranging study to compare MK-1439 plus Ttuvada versus efavirenz plus Truvada in human immunodeficiency virus (HIV)-1 infected participants (MK-1439-007 AM9). http://www.clinicaltrials.gov/ct2/show/NCT0163234.