HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance

Rhee, Soo-Yon; Taylor, Jonathan; Fessel, W. Jeffrey; Kaufman, David R.; Towner, William; Troia, Paolo; Ruane, Peter; Hellinger, James; Shirvani, Vivian; Zolopa, Andrew; Shafer, Robert W.

doi:10.1128/aac.00574-10

Cited by 186 publications

(221 citation statements)

References 45 publications

(46 reference statements)

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“…All single mutations studied exhibited the same pattern, however, showing modest change in IC 50 but decreased slope. The comparatively small fold change in IC 50 caused by protease mutations has been observed previously (55). We hypothesize that the reduction in m may reflect the fact that PIs block a cooperative process in which multiple copies of protease participate in virion maturation (33).…”

Section: Analysis Of Resistance Mutations Using Primary Cells Vs Trasupporting

confidence: 50%

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Sampah¹,

Shen

Jilek³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

129

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HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC 50 caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC 50 , however, and inhibition at clinical concentrations can only be predicted from IC 50 if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC 50 . For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC 50 is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC 50 , and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC 50 , does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.HIV/AIDS | pharmacology | virology | highly active antiretroviral therapy | evolution

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Section: Analysis Of Resistance Mutations Using Primary Cells Vs Trasupporting

confidence: 50%

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Sampah¹,

Shen

Jilek³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

129

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“…Both molecules, (fos) amprenavir and darunavir, are structurally related and hence, share some specific resistance mutations [17]. In our study sample, this effect of (fos) amprenavir might be mediated through the selection of mutations I50V and I54M which were more common in individuals who had received these agents versus other PI.…”

Section: Discussionmentioning

confidence: 77%

Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients

Agudelo¹,

Soto-Ramírez²,

Katime-Zúñiga³

et al. 2013

WJA

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Background: Darunavir (DRV) is a useful antiretroviral treatment in the salvage therapy of multiclass-resistant HIVinfected patients. This study's aim was to determine the frequency and risk factors for DRV resistance-associated mutations (DRV-RAM) among DRV-naïve Mexican patients with virologic failure after extensive antiretroviral treatment and exposure to at least one protease inhibitor (PI). Methods: HIV-infected patients with a history of at least 2 failed regimes were included and their clinical histories and genotype resistance tests were analyzed. Major PI resistance-associated mutations (PI-RAM), DRV-RAM and resistance to DRV were defined according to the IAS-USA criteria. Previous exposure to PI was compared between patients with DRV-resistant HIV and DRV-susceptible HIV-infected controls. Results: The median number of major PI-RAM was 2 (IQR = 0 -3). In 54.7% (95% CI = 50.0% -59.4%) of 631 subjects, no DRV-RAM were found on viral genotyping and 6.7% (95% CI = 4.8% -8.6%) had 3 or more DRV-RAM. The two most frequently found DRV-RAM were in codons I84V (in 22.7% of cases) and L33F (in 20% of cases) in the viral protease gene. The number of major PI-RAM (as a surrogate marker of duration and number of PI used) and previous exposure to (fos) amprenavir or tipranavir were independently associated with DRV-resistant HIV infection. Conclusions: In this Mexican population, despite a high prior PI exposure, HIV-DRV resistance rate is relatively low and successful viral control with DRV-containing combined salvage therapy is expected in most patients.

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“…7 Moreover, the regression coefficients of the mutations associated with decreased susceptibility to DRV and fosamprenavir are strongly correlated. 11 DRV is a…”

Section: Resultsmentioning

confidence: 99%

Prevalence and factors associated with darunavir resistance mutations in multi-experienced HIV-1-infected patients failing other protease inhibitors in a referral teaching center in Brazil

Vidal¹,

Freitas²,

Song³

et al. 2011

Braz J Infect Dis

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Information about resistance profile of darunavir (DRV) is scarce in Brazil. Our objectives were to estimate the prevalence of DRV resistance mutations in patients failing protease inhibitors (PI) and to identify factors associated with having more DRV resistance mutations. All HIV-infected patients failing PI-based regimens with genotyping performed between 2007 and 2008 in a referral teaching center in São Paulo, Brazil, were included. DRV-specific resistance mutations listed by December 2008 IAS-USA panel update were considered. Two Poisson regression models were constructed to assess factors related to the presence of more DRV resistance mutations. A total of 171 HIV-infected patients with available genotyping were included. The number of patients with lopinavir, saquinavir, and amprenavir used in previous regimen were 130 (76%), 83 (49%), and 35 (20%), respectively. The prevalence of major DRV resistance mutations was 50V: 5%; 54M: 1%; 76V: 4%; 84V: 15%. For minor mutations, the rates were 11I: 3%; 32I: 7%; 33F: 23%; 47V: 6%; 54L: 6%; 74P: 3%; 89V: 6%. Only 11 (6%) of the genotypes had ≥ 3 DRV resistance mutations. In the clinical model, time of HIV infection of > 10 years and use of amprenavir were independently associated with having more DRV resistance mutations. In the genotyping-based model, only total number of PI resistance mutations was associated with our outcome. In conclusion, the prevalence of DRV mutations was low. Time of HIV infection, use of amprenavir and total number of PI resistance mutations were associated with having more DRV mutations.

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HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance

Cited by 186 publications

References 45 publications

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients

Prevalence and factors associated with darunavir resistance mutations in multi-experienced HIV-1-infected patients failing other protease inhibitors in a referral teaching center in Brazil

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