Important note: Information in this article was accurate in May 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, May 10, 1999
Daniel J. DeNoon, Senior Editor
New in vitro studies show that HIV resistant to nelfinavir is weaker than virus resistant to other HIV protease inhibitors (PIs). They may explain clinical observations that patients failing first-line highly active antiretroviral therapy (HAART) regimens including nelfinavir are more likely than those failing other regimens to respond well to salvage therapy.
"Hypotheses based on the greater fitness impairment of the nelfinavir-selected D30N mutant are suggested to explain observations that prolonged responses to delayed salvage regimens, including alternate PIs, may be relatively common after nelfinavir failure," suggested Javier Martinez-Picado and colleagues of Harvard Medical School, Boston, Massachusetts.
Martinez-Picado et al. reported their findings in the Journal of Virology ("Replicative Fitness of Protease-Inhibitor-Resistant Mutants of Human Immunodeficiency Virus Type 1," J Virol 1999 May;73(5):3744-52.
The researchers tested the relative fitness of HIV mutants selected by various PIs in a series of in vitro experiments, including competitive co-culture.
They found that the D30N mutation that confers resistance to nelfinavir (Viracept, Agouron) substantially reduced ability of the virus to replicate. They also found that the L90M mutation that confers resistance to saquinavir (Fortovase, Roche) moderately impairs viral fitness. Even when multiply substituted (M46I/L63P/V82T/I84V or L10R/M46I/L63P/V82T/I84V), mutants resistant to indinavir (Crixivan, Merck) were just as fit as wild-type HIV.
Reduced susceptibility of PI-resistant HIV to subsequent treatment with other PIs previously was believed due to cross-resistance. The new data suggest that viral fitness may be a more important factor.
"The biology of different drug-selected mutants of HIV-1 can only be fully understood by characterizing their replicative capacities and the likelihood of acquiring additional compensatory mutations, in addition to drug susceptibilities," Martinez-Picado et al. wrote. "The possibility of compensatory mutations suggests that it would be best to change antiretroviral drugs before such mutants evolve."
The authors warned, however, that the clinical implications of their work can be known only when relevant experiments are performed on clinical isolates.
"In order to determine if the observations in this study are relevant to this clinical issue, it will be necessary to compare the relative fitness of mutant viruses from patients for whom therapy with nelfinavir and other PIs has failed, both in the presence and absence of drugs," they warned.
Newer PIs such as Vertex/Glaxo's recently approved amprenavir were not included among the drugs tested in the Martinez-Picado et al. study. HIV isolates from amprenavir-treated patients mainly have the M46I/L, I47V, I50V, I54L/V, and I84V mutations as well as mutations in the viral protease p1/p6 cleavage site.
This work was supported by National Institutes of Health grants and by a postdoctoral fellowship from the Spanish Ministry of Education.
The corresponding author for this study is Richard T. D'Aquila, Infectious Disease Unit and AIDS Research Center, Massachusetts General Hospital, 149 13th St., Charlestown, Massachusetts 02129. Phone: (617) 726-5776. Fax: (617) 726-5411. Email: <daquila@helix.mgh.harvard.edu>.
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