A Preliminary Evaluation of Nelfinavir Mesylate, an Inhibitor of Human Immunodeficiency Virus (HIV)‐1 Protease, to Treat HIV Infection

Markowitz, Martin; Conant, Marcus A.; Hurley, Arlene; Schluger, Rosemary; Durán, Margarita; Peterkin, Joanna; Chapman, Sharon; Patick, Amy K.; Hendricks, Amy; Yuen, Geoffrey J.; Hoskins, William J.; Clendeninn, Neil J.; Ho, David D.

doi:10.1086/515312

Cited by 142 publications

(92 citation statements)

References 12 publications

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“…Therefore, the patient's viral subtype is an important factor to be considered when selecting an initial PI regimen. The susceptibility testing results from these clinical samples confirmed the drug-specific nature of the resistance associated with the mutation D30N in HIV subtype C, which is consistent with what was found in subtype B (19,22). Similarly, the cross-resistance conferred by L90M or multiple other PI mutations was also confirmed.…”

Section: Discussionsupporting

confidence: 82%

“…Although these potential pitfalls must be kept in mind, our preliminary studies and those of others (1, Resistance is one of several factors to consider in selecting the optimal drug regimen for an individual patient. Mutation D30N is a primary nelfinavir resistance mutation and appears to be specific to this inhibitor (19). In contrast, L90M, like other major protease mutations (e.g., V82A and I84V) is a primary mutation involved in resistance to several PIs including nelfinavir, indinavir, and saquinavir (3,11,19,27).…”

Section: Discussionmentioning

confidence: 99%

“…Mutation D30N is a primary nelfinavir resistance mutation and appears to be specific to this inhibitor (19). In contrast, L90M, like other major protease mutations (e.g., V82A and I84V) is a primary mutation involved in resistance to several PIs including nelfinavir, indinavir, and saquinavir (3,11,19,27). These two mutations rarely appear together on the same isolate (26).…”

Section: Discussionmentioning

confidence: 99%

“…These two mutations rarely appear together on the same isolate (26). In the majority of subtype-B-infected patients developing resistance after failing nelfinavir as their first PI, mutation D30N is selected, while mutation L90M or other primary mutations are selected in a significantly smaller proportion (7,19). Since mutation D30N does not engender resistance to PIs other than nelfinavir, patients failing nelfinavir will commonly retain susceptibility to other drugs of this class.…”

Section: Discussionmentioning

confidence: 99%

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Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Grossman

Paxinos

Averbuch

et al. 2004

Antimicrob Agents Chemother

109

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Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C-and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P ‫؍‬ 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC 50 ) change in susceptibility to nelfinavir only. Other mutations increased IC 50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ؎ 22% to 22% ؎ 15% (P ‫؍‬ 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Grossman

Paxinos

Averbuch

et al. 2004

Antimicrob Agents Chemother

109

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“…Protein synthesis was evaluated by biosynthetic labeling with 35 S-labeled methionine and cysteine. 35 …”

mentioning

confidence: 99%

Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss

Phenix

Lum

Nie

et al. 2001

Blood

108

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Treatment of cells with the HIV drugs ritonavir, saquinavir, or nelfinavir (Nfv) inhibits apoptosis induced by a variety of stimuli. Because these drugs are protease inhibitors, they have been postulated to inhibit apoptosis by blocking caspase activity. This study shows that Nfv has no effect on caspase activity or on the transcription or synthesis of a variety of apoptosis regulatory molecules. Instead, Nfv inhibits mitochondrial transmembrane potential loss (⌬ m ) and the subsequent release of apoptotic mediators. Consequently, the antiapoptotic ef- IntroductionCurrent therapies used in the treatment of HIV-infected patients include combinations of inhibitors of reverse transcriptase and HIV protease. Multidrug therapy has reduced morbidity and mortality among patients infected with HIV 1-3 and has led to quantitative and qualitative improvements in host immune function. [4][5][6][7][8] Although increases in CD4 T-cell counts typically occur in parallel with a reduction in viral replication, these effects may be seen before significant changes in plasma RNA levels 9 or in the absence of antiviral effect. [10][11][12][13] These and other findings suggest that the protease inhibitor (PI) class of drugs may influence T-cell turnover in a manner that is independent of their role in viral suppression.Nonviral effects of HIV PIs have been evaluated recently. PIs influence proteasome activity, antigen presentation, cytotoxic Tlymphocyte activity, 14 lipoprotein metabolism, 15 adipocyte differentiation, 16,17 cytochrome P450 activity, 18 and adenosine triphosphate (ATP)-dependent drug export mechanisms. 19 Furthermore, PIs may affect the ability of cells to undergo both spontaneous apoptosis and apoptosis induced by a variety of stimuli. 9,[20][21][22][23] These data are consistent with the in vivo observation that apoptosis in both peripheral blood 24 and in lymphatic tissues 25 is rapidly decreased following initiation of PI-based therapy. In this study, we have evaluated the mechanism by which PIs inhibit apoptosis. Materials and methods CellsJurkat T cells and H9 cells (American Type Culture Collection, Rockville, MD) were cultured in RPMI 1640 medium (Gibco, Burlington, ON, Canada) supplemented with 10% or 20% fetal calf serum (Gibco), respectively, together with penicillin, streptomycin, and glutamine (SigmaAldrich, Oakville, ON, Canada), and were incubated at 37°C in a 5% CO 2 humidified environment. Cells were seeded in media supplemented with drugs as indicated at 0.3 ϫ 10 6 /mL and passaged every 2 days. DrugsAzidothymidine (AZT) was purchased from Sigma (Oakville, ON, Canada) and resuspended in water. Nelfinavir (Nfv), ritonavir, and saquinavir were generous gifts from Agouron Pharmaceuticals (La Jolla, CA), Abbott Laboratories (Abbott Park, IL), and Roche Laboratories (Nutley, NJ), respectively, and were resuspended in methanol. Induction and measurement of apoptosis and mitochondrial membrane permeability changesJurkat or H9 cells were cultured in the presence of AZT, Nfv, or diluent at indicated concen...

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Hepatotoxicity Associated With Antiretroviral Therapy in Adults Infected With Human Immunodeficiency Virus and the Role of Hepatitis C or B Virus Infection

Sulkowski¹

2000

JAMA

868

570

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A Preliminary Evaluation of Nelfinavir Mesylate, an Inhibitor of Human Immunodeficiency Virus (HIV)‐1 Protease, to Treat HIV Infection

Cited by 142 publications

References 12 publications

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss

Hepatotoxicity Associated With Antiretroviral Therapy in Adults Infected With Human Immunodeficiency Virus and the Role of Hepatitis C or B Virus Infection

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