AIDSWEEKLY Plus; Monday, October 5, 1998
Daniel J. DeNoon, Senior Editor
The gag mutations permit the virus to remain viable despite the mutations it must adopt in its protease gene to withstand the powerful new drug, Abbott's ABT-378. Despite these changes, the virus remained sensitive to saquinavir (Roche).
"Mutation of these gag proteolytic cleavage sites is required for the growth of highly resistant HIV-1 selected by ABT-378 and supports recent work demonstrating that mutations in the p7/p1/p6 region [of gag] play an important role in conferring resistance to protease inhibitors," wrote Abbott Laboratories researchers Alejandro Carrillo and colleagues
Carrillo et al. reported the findings in the Journal of Virology ("In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 1 Variants with Increased Resistance to ABT-378, a Novel Protease Inhibitor," J Virol, 1998;72(9):7532-41.)
The researchers serially passaged HIV-1 in the presence of ABT- 378. Selection of increasingly fit viral variants occurred via a sequence of mutations in the viral protease gene: I84V-L10F-M46I- T91S-V32I-I47V.
When virus that had acquired these mutations was further passaged in higher (3.0 (micro)M) concentrations of ABT-378, new mutations occurred: there was a new change at amino-acid position 47 (V47A) and the residue 32 change reverted to its original sequence. These latter changes had a dramatic effect.
"The 50 percent effective concentration of ABT-378 against passaged virus containing these additional changes was 338-fold higher than that against wild-type virus," Carrillo et al. found.
But the high-resistance mutations didn't happen all by themselves. They were accompanied by mutations in the p1/p6 and p7/p1 gag gene proteolytic processing sites.
When the researchers constructed molecular clones of HIV-1 incorporating the highly resistant genotype, the mutant viruses remained viable only if they had the corresponding gag mutations.
"The p7/p1/p6 region may be an important determinant of viral resistance that should be examined in patient populations receiving therapy with other protease inhibitors," Carrillo et al. concluded.
Virus resistant to ABT-378 was cross-resistant to ritonavir but only four-fold less susceptible to saquinavir.
ABT-378 is a non-peptidic drug with a chemical structure based on that of ritonavir but with 10-fold greater in vitro potency, better pharmacokinetics, and a different resistance profile than its parent compound. Early animal studies showed that the drug had pharmacokinetic synergy with ritonavir.
In a clinical study reported by Abbott researcher Eugene Sun, subjects who received 200 to 600 mg ABT-378 twice daily in combination with low-dose ritonavir - 50 or 100 mg twice daily, versus the usual 600 mg twice daily - had steady-state ABT-378 levels well in excess of the drug's effective anti-HIV concentration.
Only one subject had an elevated LFT value. Self-limited loose stools or mild diarrhea were the most common adverse events.
"ABT-378 is an okay drug by itself but when given with ritonavir it becomes a very impressive drug," Sun said. "It is so uniquely enhanced by ritonavir that you can use a very small dose [of ritonavir] - as little as 50 mg."
The corresponding author for the Carrillo et al. study is Alejandro Carillo, D-78P, Strategic Technical Product Development, Building AP8B, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, Illinois 60064. Phone: (847) 937-3179. Fax: (847) 938-3721. Email: <alex.carrillo@add.ssw.abbott.com>.
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