Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

Lambert-Niclot, Sidonie; Flandre, Philippe; Canestri, Ana; Peytavin, Gilles; Blanc, C.; Agher, Rachid; Soulié, Cathia; Wirden, Marc; Katlama, Christine; Cálvez, Vincent; Marcelin, Anne–Geneviève

doi:10.1128/aac.00909-07

Cited by 33 publications

(31 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data strengthen the observations of Lambert-Niclot et al (5), suggesting the noninvalidation of TPV susceptibility by DRV-associated mutations; in our experience, virological response to TPV benefited from the presence of L76V. In this respect, we agree with Lambert-Niclot et al, who stated that TPV may remain active after DRV use and that its presence could be useful to construct an optimal salvage regimen in multiexperienced patients.…”

supporting

confidence: 79%

“…Lambert-Niclot et al (5) suggested that the virological failure of a DRV/r-based regimen was due to the selection of mutations which, although increasing the level of DRV/r, did not affect tipranavir (TPV) susceptibility; moreover, L76V was found to be protective for the development of additional DRV-associated mutations. L76V has also been reported to increase TPV susceptibility (8,9); nevertheless, the real clinical implication of this mutation in response to TPV-containing regimens is still unknown.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Both a Protective and a Deleterious Role for the L76V Mutation

Tartaglia

Saracino

Monno

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The L76V mutation, unknown in clinical isolates before 2001, has been described as associated with lopinavir resistance (LPV/r) (2, 6, 7), appearing to confer high levels of resistance to LPV and amprenavir; subsequently, it has also been included among darunavir resistance (DRV/r)-associated mutations (3).Lambert-Niclot et al. (5) suggested that the virological failure of a DRV/r-based regimen was due to the selection of mutations which, although increasing the level of DRV/r, did not affect tipranavir (TPV) susceptibility; moreover, L76V was found to be protective for the development of additional DRV-associated mutations. L76V has also been reported to increase TPV susceptibility (8, 9); nevertheless, the real clinical implication of this mutation in response to TPV-containing regimens is still unknown.We studied 176 human immunodeficiency virus type 1 (HIV-1)-infected multiexperienced patients previously exposed to a median of four protease inhibitors, who were administered a TPV resistance-based regimen. The impact on the TPV virological responses of both mutations included in the TPV mutation score (1, 4) and other protease mutations detected in Ͼ10% of the study population was evaluated. Virological success was defined as achieving a plasma viral load (pVL) of Ͻ50 cp/ml and a pVL decrease of Ͼ1 log after 12 and 24 weeks of a TPV-based regimen. While no association between L76V and the virological outcome was observed using the pVL level of Ͻ50 cp/ml as the primary end point (unpublished data), when considering a pVL decrease of at least 1 log cp/ml, L76V correlated with virological response at week 12 (0.19 odds ratio [OR]; 0.04 to 0.86 95% confidence interval [CI]; P ϭ 0.031) with univariate analysis. In the multivariate analysis, in which a stepwise estimation model with a backward procedure was used to select the set of mutations most strongly associated with virological response, three mutations (E34Q, I72VTL, and Q92K) were correlated with treatment failure, while L76V was still associated with virological success (0.04 OR, 0.01 to 0.31 95% CI, and P of 0.002 at week 12 and 0.18 OR, 0.036 to 0.088 95% CI, and P of 0.034 at week 24). Mutation I50LV, also associated with TPV hypersusceptibility, was detected in 7% of the patients and therefore was not included in the analysis. Furthermore, the CD4 nadir, the number of previous protease inhibitors, and CDC stage C classification were also significantly (P Ͻ 0.05) associated with virological failure.Therefore, the L76V mutation seemed to have a beneficial impact on virological response to TPV in our population with both analyses, thus extending the results of previous studies supporting the ability of L76V to resensitize HIV isolates to atazanavir and saquinavir (6).The molecular basis for this ambivalent behavior (which renders L76V either deleterious or protective) might depend on the particular location of residue 76 within the HIV protease. Because of its position in a secondary protein shell, residue 76 is directly in contact with the residues of th...

show abstract

supporting

confidence: 79%

mentioning

confidence: 99%

Both a Protective and a Deleterious Role for the L76V Mutation

Tartaglia

Saracino

Monno

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The most common mutations identified were V32I, L33F, I54M/L, I84V, and L89V (17,21). In the present study, HIV-1 variants resistant to DRV, which replicated in the presence of 1 and 5 M DRV, emerged by passages 39 and 51, respectively.…”

Section: Discussionmentioning

confidence: 68%

In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors

Koh

Amano

Towata

et al. 2010

J Virol

180

View full text Add to dashboard Cite

We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1MIX) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1MIX became highly resistant to DRV, with a 50% effective concentration (EC50) ∼333-fold greater than that against HIV-1NL4-3. HIV-1MIX at passage 51 (HIV-1MIXP51 ) replicated well in the presence of 5 μM DRV and contained 14 mutations. HIV-1MIXP51 was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1MIXP51 had a resemblance with HIV-1C of the HIV-1MIX population, and selection using HIV-1C was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1CP51 , likely contributed to conferring a replication advantage on HIV-1MIXP51 by reducing intravirion cyclophilin A content. HIV-1MIXP51 apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1MIX through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1MIXP51 should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents.

show abstract

“…The use of inconsistent methods between studies associating PR genotype with clinical response or in vitro susceptibility can result in confusing or even misleading interpretation guidelines. Treatment with lopinavir (1,11,12,23,26,27), darunavir (19), or other PIs (5,7,29) can lead to selection of the L76V mutation. L76V is associated with reduced response to darunavir (13).…”

mentioning

confidence: 99%

Prevalence, Mutation Patterns, and Effects on Protease Inhibitor Susceptibility of the L76V Mutation in HIV-1 Protease

Young

Parkin

Stawiski³

et al. 2010

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Patterns of HIV-1 protease inhibitor (PI) resistance-associated mutations (RAMs) and effects on PI susceptibility associated with the L76V mutation were studied in a large database. Of 20,501 sequences with >1 PI RAM, 3.2% contained L76V; L76V was alone in 0.04%. Common partner mutations included M46I, I54V, V82A, I84V, and L90M. L76V was associated with a 2-to 6-fold decrease in susceptibility to lopinavir, darunavir, amprenavir, and indinavir and a 7-to 8-fold increase in susceptibility to atazanavir and saquinavir.Combination chemotherapy for treatment of HIV-1 infection is often composed of 2 nucleoside reverse transcriptase inhibitors (RTI) and a nonnucleoside RTI or PR inhibitor (PI) (28). The plasma concentration of most PIs is increased by coadministration of a low dose of ritonavir. Ritonavir-boosted PI-based (PI/r) regimens are very potent and are recommended for use in patients with or without prior antiretroviral treatment (ART) experience (28). In ART-naive individuals, the use of PI/r regimens raises the genetic barrier to resistance by increasing the inhibitory quotient such that multiple mutations are almost always required in order to confer a large enough decrease in susceptibility to allow the virus to replicate in the presence of drug. Remarkably, the majority of viruses present following failure of a PI/r-based, first-line regimen remain sensitive to all PIs (9, 21

show abstract

Factors Associated with the Selection of Mutations Conferring Resistance to Protease Inhibitors (PIs) in PI-Experienced Patients Displaying Treatment Failure on Darunavir

Cited by 33 publications

References 28 publications

Both a Protective and a Deleterious Role for the L76V Mutation

Both a Protective and a Deleterious Role for the L76V Mutation

In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors

Prevalence, Mutation Patterns, and Effects on Protease Inhibitor Susceptibility of the L76V Mutation in HIV-1 Protease

Contact Info

Product

Resources

About