Background: KP-1461 is a prodrug to KP-1212. KP-1212 is a viral mutagen designed to increase viral error rate. Methods: We describe 2 phase I studies: KP1461-101 (double-blind, placebo-controlled, single, escalating doses, 100 to 1600 mg study in 42 non-HIV-infected participants) and KP-1461-102 (double-blind placebo-controlled dose escalation 14-day study in HIV-infected participants, 400-3200 mg). Primary objectives were safety/tolerability. Secondary objectives included pharmacokinetic analysis with exploratory objective to characterize KP-1212 effects on viral load. Results: KP-1461 was well tolerated. Majority of adverse events were grade 1 (neurological, gastrointestinal, cardiovascular). Four participants experienced grade 3 and 1 experienced a grade 4 event. Analysis demonstrated no difference in pharmacokinetic parameters at day 1 or 14. Linear pharmacokinetics found in 1600 mg arm. Compared to placebo, only at the 3200 mg dose demonstrated a marginally statistically significant virologic response. Conclusions: These studies provide safety/tolerability information and suggest virologic efficacy. KP-1212, a first-in-class antiretroviral, demonstrates the ability to induce viral eradication in vitro. Viral reduction in vivo may foretell a paradigm shift in HIV pharmacotherapy.
ChenRYokoyamaMSatoHReillyCManskyLM. Human immunodeficiency virus mutagenesis during antiviral therapy: impact of drug-resistant reverse transcriptase and nucleoside and nonnucleoside reverse transcriptase inhibitors on human immunodeficiency virus type 1 mutation frequencies. J Virol. 2005;79(18):12045–12057.
2.
Ferrer-OrtaCAriasAPerez-LuqueREscarmisCDomingoEVerdaguerN. Sequential structures provide insights into the fidelity of RNA replication. Proc Natl Acad Sci U S A. 2007;104(22):9463–9468.
3.
OverbaughJBanghamCR. Selection forces and constraints on retroviral sequence variation. Science. 2001;292(5519):1106–1109.
4.
AndersonJPDaifukuRLoebLA. Viral error catastrophe by mutagenic nucleosides. Annu Rev Microbiol. 2004;58:183–205.
5.
AndersonPLKakudaTNLichtensteinKA. The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities. Clin Infect Dis. 2004;38(5):743–753.
6.
DaifukuR. Stealth nucleosides: mode of action and potential use in the treatment of viral diseases. BioDrugs. 2003;17(3):169–177.
7.
EigenM. Error catastrophe and antiviral strategy. Proc Natl Acad Sci U S A. 2002;99(21):13374–13376.
8.
SivapalasingamSEssajeeSNyambiPN. Human immunodeficiency virus (HIV) reverse transcriptase activity correlates with HIV RNA load: implications for resource-limited settings. J Clin Microbiol. 2005;43(8):3793–3796.
9.
HarrisKSBrabantWStyrchakSGallADaifukuR. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res. 2005;67(1):1–9.
10.
HarrisKSSergueevDRenoJ. The chemistry and biology of KP-1461, a selective nucleoside mutagen for HIV therapy. Retrovirology. 2006;3(suppl 1):S13.
11.
LoebLAEssigmannJMKazaziFZhangJRoseKDMullinsJ. Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proc Natl Acad Sci U S A. 1999;96(4):1492–1497.
12.
LoebLAMullinsJI. Lethal mutagenesis of HIV by mutagenic ribonucleoside analogs. AIDS Res Hum Retroviruses. 2000;16(1):1–3.
13.
MurakamiEBasavapathruniABradleyWDAndersonKS. Mechanism of action of a novel viral mutagenic covert nucleotide: molecular interactions with HIV-1 reverse transcriptase and host cell DNA polymerases. Antiviral Res. 2005;67(1):10–17.
14.
McRaeMRezkNLBridgesAS. Plasma bile acid concentrations in patients with human immunodeficiency virus infection receiving protease inhibitor therapy: possible implications for hepatotoxicity. Pharmacotherapy. 2010;30(1):17–24.
Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January10, 2011; 1 -166. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed April 19, 2011.
