Safety, tolerability, and efficacy of KP-1461 as monotherapy for 124 days in antiretroviral-experienced, HIV type 1-infected subjects.
Treatment of HIV infection with conventional antiretroviral therapy (ART) is a lifelong challenge with significant long-term risks of adverse events and treatment failure-induced HIV resistance being major concerns. One potential alternative to standard treatment is the use of viral decay accelerators, antiviral agents that theoretically can drive the rate of viral mutation beyond the compensatory capacity of the virus, thereby inducing viral extinction. One such drug, KP-1461, was tested in a population of HIV-infected persons not receiving ART to assess the safety, tolerability, and efficacy of the strategy in vivo. Of 24 highly treatment-experienced HIV-infected patients who received at least one dose of KP-1461, 13 completed the planned 4 months of monotherapy. The drug was generally well tolerated; it did not significantly affect either HIV viral load or CD4 lymphocyte count over the period of dosing. Pharmacokinetic sampling suggested adequate drug exposure was achieved. There were no new mutations induced by KP-1461 that changed viral susceptibility to standard antiretroviral agents. After the study was completed, analysis of more than 7 million base pairs of HIV samples from study patients and controls demonstrated changes in the pattern of viral mutations that differed significantly from what would be encountered naturally. The identified alterations were consistent with an effect resulting from KP-1461's proposed mechanism of action. These findings suggest that the novel antiretroviral approach illustrated by this study should be further investigated, particularly given the relatively good tolerability and the demonstrated excellent safety in this limited cohort study.
Duke University Medical Center, Durham, North Carolina 27710, USA. charles.hicks@duke.edu
Charles
C
Hicks
Patrick
P
Clay
Robert
R
Redfield
Jay
J
Lalezari
Ralph
R
Liporace
Stefan
S
Schneider
Michael
M
Sension
MaryPeace
M
McRae
Jean-Pierre
JP
Laurent
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D018791:CD4 Lymphocyte Count; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009705:Nucleosides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D019562:Viral Load
D019380:Anti-HIV Agents; C522536:KP 1461; D009705:Nucleosides; D012367:RNA, Viral