9-[2-(Phosphonomethoxy)propyl]adenine therapy of established simian immunodeficiency virus infection in infant rhesus macaques.
The long-term therapeutic and toxic effects of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) were evaluated in simian immunodeficiency virus (SIV)-infected newborn rhesus macaques. Four untreated SIV-infected newborn macaques developed persistently high levels of viremia, and three of the four animals had rapidly fatal disease within 3 months. In contrast, long-term PMPA treatment of four newborn macaques starting 3 weeks after virus inoculation resulted in a rapid, pronounced, and persistent reduction of viremia in three of the four animals. Emergence of virus with fivefold-decreased susceptibility to PMPA occurred in all four PMPA-treated animals and was associated with the development of a lysine-to-arginine substitution at amino acid 65 (K65R mutation) and additional mutations in the reverse transcriptase; however, the clinical implications of this low-level drug resistance are nuclear. No toxic side effects have been seen, and all PMPA-treated animals have remained disease-free for more than 13 months. Our data suggest that PMPA holds much promise for the treatment of human immunodeficiency virus-infected human infants and adults.
Van Rompay
K K
KK
California Regional Primate Research Center, University of California, Davis 95616, USA. kkvanrompay@ucdavis.edu
Cherrington
J M
JM
Marthas
M L
ML
Berardi
C J
CJ
Mulato
A S
AS
Spinner
A
A
Tarara
R P
RP
Canfield
D R
DR
Telm
S
S
Bischofberger
N
N
Pedersen
N C
NC
D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000032:analysis; D004351:Drug Resistance; D007074:Immunoglobulin G / Q000032:analysis; D008253:Macaca mulatta; D008826:Microbial Sensitivity Tests; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D010641:Phenotype; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D015302:Simian Immunodeficiency Virus; D013601:T-Lymphocytes / Q000821:virology; D000068698:Tenofovir
D019380:Anti-HIV Agents; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D000068698:Tenofovir; D000225:Adenine