In vitro susceptibility of clinical isolates of HIV-1 to XM323, a non-peptidyl HIV protease inhibitor.

OBJECTIVE: To determine the in vitro susceptibility of primary clinical isolates and laboratory strains of HIV-1 to XM323. METHODS: The AIDS Clinical Trials Group/US Department of Defense p24 antigen-based consensus assay was used to determine in vitro susceptibility of 57 primary clinical isolates and three laboratory strains of HIV-1 to XM323, zidovudine, zalcitabine (ddC), and didanosine (ddI). RESULTS: The concentrations of compound required to inhibit viral p24 antigen production by 50% [median inhibitory concentration (IC50)] for nucleosides were as follows: zidovudine, 0.001-->5 microM; ddC, < 0.01-0.23 microM; ddI, 0.2-->25 microM). Against both nucleoside susceptible and resistant isolates XM323 exhibited potent inhibition with IC50 values of < 0.02-0.27 microM and IC90 values of 0.03-1.17 microM. CONCLUSIONS: XM323 is a potent inhibitor of diverse clinical isolates of HIV-1 in vitro and represents a novel class of non-peptidyl inhibitors of HIV-1 protease.

Limited sequence diversity of the HIV type 1 protease gene from clinical isolates and in vitro susceptibility to HIV protease inhibitors.

Proviral DNAs from 3 laboratory strains and 21 clinical isolates of HIV-1 were extracted from infected cells after proteinase K digestion and the protease gene was PCR amplified and sequenced directly by the Sanger method. In vitro susceptibilities of the virus isolates to protease inhibitors were determined by the ACTG/DoD consensus assay. Four different HIV protease inhibitors were tested including P9941, a C2 symmetrical diol (Du Pont-Merck); A80987, an asymmetric mono-ol (Abbott); XM323, a cyclic urea (Du Pont-Merck); and Ro31-8959, an asymmetric hydroxyethylene isostere (Roche). Maximum sequence variation was 10% at both the nucleic and amino acid levels. Purine-purine substitutions were most common. Five noncontiguous regions were conserved across all isolates and corresponded to amino acids 1-9 (amino terminal), 21-32 (catalytic site), 47-56 ("flap" region), 78-88 (substrate-binding region), and 94-99 (carboxy terminal). All clinical isolates demonstrated in vitro susceptibility to the protease inhibitors. There was no significant difference between the susceptibility of the reference strains and the clinical isolates. These data suggest that the variable regions of protease do not contain sites that are important for interactions with the inhibitors tested.

Recurrent ingrown toenails secondary to indinavir/ritonavir combination therapy.

OBJECTIVE: To report five cases of ingrown toenails (IGTN) associated with indinavir/ritonavir (IDV/RTV) combination therapy. CASE SUMMARY: The median onset of IGTN from initiation of IDV/RTV therapy was 18.4 weeks. Four patients previously received IDV, with one of these experiencing prior IGTN. All patients required surgical management of IGTN. All patients received virologic benefit from ongoing antiretroviral therapy, and the majority of patients elected to maintain IDV/RTV combination therapy. Two patients experienced recurrent IGTN while receiving ongoing IDV/RTV combination therapy. DISCUSSION: IGTN and paronychia have previously been reported with IDV and lamivudine. IGTN in patients with HIV infection is more likely to present acutely, involve more digits, and require surgical management IDV increases retinoic acid signaling and, based on elevated IDV concentrations from concomitant RTV therapy, the risk of IGTN may be increased in patients receiving IDV/RTV combination therapy. CONCLUSIONS: With the increasing popularity of IDV/RTV combination therapy, clinicians should be aware of the potential increase in frequency of dose-related toxicities including IGTN. Evaluation of hands and feet on physical examination should be recommended for all patients being treated with lamivudine and IDV, especially when used in combination with RTV.