Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir

Doyon, Louise; Tremblay, Sonia; Bourgon, Lise; Wardrop, Elizabeth; Cordingley, Michael G.

doi:10.1016/j.antiviral.2005.07.003

Cited by 92 publications

(75 citation statements)

References 43 publications

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“…Indeed, when cHIV NL4-3 was used as a starting HIV-1 strain in the present study, cHIV NL4-3 failed to start replicating in the presence of TPV (Fig. 2), which is in line with the data presented by Doyon et al (9). However, as shown in Fig.…”

Section: Discussionsupporting

confidence: 78%

“…Of note, all the clinical strains employed as a source of the mixed HIV-1 population in the pres- ent study were as sensitive to TPV as the wild-type clinical HIV-1 isolate (HIV 104pre ) (Table 1), although they were moderately to highly resistant to 5 other approved PIs, including SQV, IDV, APV, LPV, and ATV (Table 1). However, the TPV-selected HIV-1 variants became highly resistant to TPV and were much more resistant to all 5 PIs without specific resistance mutations to each PI, as previously reported (9). It is noteworthy that HIV 11MIX P10 remained relatively susceptible to DRV with an IC 50 of 0.034 M ( Table 2).…”

Section: Discussionsupporting

confidence: 54%

“…Doyon and her colleagues have reported that the development of HIV-1 resistance to TPV is slow and requires 9 months of sequential passage as well as multiple amino acid substitutions in culture (9). Indeed, when cHIV NL4-3 was used as a starting HIV-1 strain in the present study, cHIV NL4-3 failed to start replicating in the presence of TPV (Fig.…”

Section: Discussionmentioning

confidence: 56%

“…TPV has been shown to inhibit the replication of HIV-1 variants that are resistant to other PIs and is recommended for patients who harbor multi-PI-resistant HIV-1 variants and do not respond to therapeutic regimens, including PIs (34). HIV-1 resistance to TPV has been reported to require multiple amino acid substitutions in protease (9); however, we have witnessed that HIV-1 often acquires significant levels of resistance to TPV among HIV-1-infected individuals receiving long-term combination chemotherapy (4,17,31). TPV is currently not recommended in the initial therapy mainly because of the higher rate at which patients previously experienced hepatic abnormalities (5,29,37).…”

Section: T Ipranavir (Tpv) Is a Nonpeptidyl Protease (Pr) Inhibitor (Pi)mentioning

confidence: 99%

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Loss of the Protease Dimerization Inhibition Activity of Tipranavir (TPV) and Its Association with the Acquisition of Resistance to TPV by HIV-1

Aoki

Danish

Aoki-Ogata

et al. 2012

J Virol

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I54V/V82T most readily developed TPV resistance and acquired E34D, which compromised TPV's dimerization inhibition with the HIV NL4-3 genetic background. The present data demonstrate that certain amino acid substitutions compromise TPV's dimerization inhibition and confer TPV resistance, although the loss of TPV's dimerization inhibition is not always associated with significantly increased TPV resistance. The findings that TPV's dimerization inhibition is compromised with one or two amino acid substitutions may explain at least in part why the genetic barrier of TPV against HIV-1's development of TPV resistance is relatively low compared to that of darunavir.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 56%

Section: T Ipranavir (Tpv) Is a Nonpeptidyl Protease (Pr) Inhibitor (Pi)mentioning

confidence: 99%

See 2 more Smart Citations

Loss of the Protease Dimerization Inhibition Activity of Tipranavir (TPV) and Its Association with the Acquisition of Resistance to TPV by HIV-1

Aoki

Danish

Aoki-Ogata

et al. 2012

J Virol

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“…In vitro data have shown that resistance to TPV develops slowly (5). When TPV is coadministered with ritonavir (RTV) as a booster, TPV has been shown to have potent antiviral activity in multidrug-experienced patients (3,6,9,12).…”

mentioning

confidence: 99%

Tipranavir (TPV) Genotypic Inhibitory Quotient Predicts Virological Response at 48 Weeks to TPV-Based Salvage Regimens

Requena

Bonora

Calcagno

et al. 2008

Antimicrob Agents Chemother

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The virological response (VR) to a tipranavir-ritonavir (TPV-RTV)-based regimen had been shown to be associated with a number of mutations in the protease gene, the use of enfuvirtide (T20), and the TPV phenotypic inhibitory quotient (IQ). The role of the TPV genotypic IQ (gIQ) has not yet been fully investigated. The aim of our study was to evaluate the relationship between the TPV gIQ and the VR at 48 weeks to TPV-based salvage regimens. Patients placed on regimens containing two nucleoside reverse transcriptase inhibitors plus TPV-RTV 500/200 mg twice a day with or without T20 were prospectively studied. Regular follow-up was performed over the study period. VR, considered a viral load (VL) decrease of >1 log unit and/or the achievement of <50 copies/ml with no VL rebound of >0.5 log unit compared to the maximal VL decrease at week 48, was assessed. Thirty-eight patients who had received multiple drugs were included. At week 48 the VL decrease was ؊1.48 (interquartile range [IQR], ؊2.88 to ؊0.48), 15 patients (39.5%) had VLs of <50 copies/ml, and the CD4 ؉ cell count increase was 37 cells/mm 3 (IQR, ؊30 to ؉175). Twenty subjects (52.6%) achieved VRs. The TPV gIQ and optimized background score (OBS) were independently associated with higher VL decreases. The TPV gIQ and OBS were also independent predictors of a VR at week 48. TPV gIQ and OBS cutoff values of 14,500 and 2, respectively, were associated with a higher rate of VR. The TPV gIQ was shown to be able to predict the VR at 48 weeks to TPV-containing salvage regimens better than the TPV trough concentration or TPV-associated mutations alone. A possible TPV gIQ cutoff value of 14,500 for reaching a VR at week 48 was suggested. Further studies are needed in order to evaluate the calculation of TPV gIQ as a new tool for the optimization of TPV-based salvage therapy.Tipranavir (TPV) is a nonpeptidic protease inhibitor with potent in vitro activity against most human immunodeficiency virus (HIV) type 1 (HIV-1) strains resistant to other protease inhibitors (PIs) (1,14,15). In vitro data have shown that resistance to TPV develops slowly (5). When TPV is coadministered with ritonavir (RTV) as a booster, TPV has been shown to have potent antiviral activity in multidrug-experienced patients (3,6,9,12). In the RESIST-1 and the RESIST-2 studies, the efficacy and safety of TPV-RTV (500 mg/200 mg twice daily) in 1,509 highly treatment-experienced HIV-1-positive patients were assessed. Analysis at 48 weeks showed that the TPV-RTV-containing regimens significantly improved the immune and virological responses (VRs) compared to the responses to an RTV-boosted comparator PI plus an optimized background (OB) regimen (3,6,8).Different factors have been found to be associated with the virological and immunological responses: a lower viral load (VL) at the baseline, the use of enfuvirtide (T20) as a part of the OB regimen, the presence of two or more active drugs in the OB regimen (OB score [OBS], Ն2) (3,6,8), and the baseline numbers of specific TPV-associated resistance mu...

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Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir

Cited by 92 publications

References 43 publications

Loss of the Protease Dimerization Inhibition Activity of Tipranavir (TPV) and Its Association with the Acquisition of Resistance to TPV by HIV-1

Loss of the Protease Dimerization Inhibition Activity of Tipranavir (TPV) and Its Association with the Acquisition of Resistance to TPV by HIV-1

Tipranavir (TPV) Genotypic Inhibitory Quotient Predicts Virological Response at 48 Weeks to TPV-Based Salvage Regimens

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