Genotypic Susceptibility Scores and HIV Type 1 RNA Responses in Treatment-Experienced Subjects with HIV Type 1 Infection

Anderson, Jeffrey A.; Jiang, Hongyu; Ding, Xiao; Petch, Leslie; Journigan, Terri; Fiscus, Susan A.; Haubrich, Richard; Katzenstein, David; Swanstrom, Ronald; Gulick, Roy M.

doi:10.1089/aid.2007.0127

Cited by 25 publications

(24 citation statements)

References 52 publications

(35 reference statements)

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“…Although some studies reported that GSS had no impact on viral responses [Cingolani et al, 2002;De Luca et al, 2003;Mazzotta et al, 2003], most investigations support genotypic or phenotypic summary measures of regimen potency as independent predictors of viral response [DeGruttola et al, 2000;Haupts et al, 2003;Jiang et al, 2003;Loutfy et al, 2004;Badri et al, 2007;Anderson et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, none of the summary measures of ARV regimen potency have been fully standardized or validated. The genotypic sensitivity score (GSS), partly because of its more consistent associations with virologic benefit, its preservation of future treatment options, and the intuitive nature of the metric, has been used more commonly [DeGruttola et al, 2000;Haupts et al, 2003;Torti et al, 2003;Ziermann et al, 2004;Badri et al, 2007;King et al, 2007;Anderson et al, 2008]. Few investigations of the immune or clinical disease benefits of GSS in HAART-treated patients have been conducted.…”

Section: Introductionmentioning

confidence: 99%

“…Adherence to HAART has been the key confounding variable in explaining sub-optimal virus control, however, the design or analysis of GSS effects did not address this key issue often [DeGruttola et al, 2000;Badri et al, 2007;Anderson et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The relationship between genotypic sensitivity score and treatment outcomes in late stage HIV disease after supervised HAART

Castor

Vlahov

Hoover

et al. 2009

Journal of Medical Virology

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This study investigated the effect of resistance testing quantified through a genotypic sensitivity score (GSS) on virologic, immunologic, and clinical responses among patients with late stage HIV-1 disease receiving supervised highly active antiretroviral therapy (HAART). Newly admitted patients received drug resistance testing (n = 198) and then HAART supervised by residential health-care facilities nurses. After initiating a resistance testing-informed HAART regimen, patients were followed for HIV-1 RNA suppression (<50 copies/ml), mean change in CD4(+) T-cells, new AIDS defining category C opportunistic conditions and death. GSS was constructed using the HAART regimen prescribed after resistance testing and data derived from IAS-USA consensus mutations table with modification. Regressions with generalized estimating equations for robust estimation of standard errors and Cox proportional hazards regression estimated independent associations between GSS and treatment responses. After adjusting for adherence, initial log(10) HIV-1 RNA levels, and other covariates, patients with a GSS > or =3 had significantly greater HIV-1 RNA suppression (adjusted odds ratio (AOR) 2.32; 95% CI 1.14, 4.75). HIV-1 RNA levels were lower among patients with > or =95% adherence, but the effect of GSS on viral suppression was not modified by adherence. Self-rated health status, and baseline CD4(+) T-cell counts independently predicted HIV-1 RNA suppression. GSS did not predict mean change in CD4(+) cells/mm(3) (236 vs. 233, P = 0.92), occurrence of new AIDS defining category C conditions or death. These data support resistance testing-guided therapy as an independent predictive factor to improve virologic responses in treatment-experienced patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The relationship between genotypic sensitivity score and treatment outcomes in late stage HIV disease after supervised HAART

Castor

Vlahov

Hoover

et al. 2009

Journal of Medical Virology

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“…1). The genotypic susceptibility score (GSS) and phenotypic susceptibility score (PSS) of the background antiretroviral regimen after optimization at week 2 were 0.37 and 1.17, respectively (2,55). VCV was discontinued due to a lack of virologic response 2 days after the week 28 blood draw (defined as 28 weeks from the start of VCV therapy), a time point notable for maximal VCV resistance and a maximal percent inhibition (MPI) of 0%.…”

Section: Clonal Envelope Analysis During Sequential Vicriviroc and Enmentioning

confidence: 99%

Vicriviroc Resistance Decay and Relative Replicative Fitness in HIV-1 Clinical Isolates under Sequential Drug Selection Pressures

Tsibris

Paredes

et al. 2012

J Virol

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We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol. 82: 8210–8214, 2008). To investigate the decay of VCV resistance mutations, a standard clonal analysis of full-length env (gp160) was performed on plasma HIV-1 samples obtained at week 28 (the time of VCV discontinuation) and at three subsequent time points (weeks 30, 42, and 48). During 132 days, VCV-resistant HIV-1 was replaced by VCV-sensitive viruses whose V3 loop sequences differed from the dominant pretreatment forms. A deep-sequencing analysis showed that the week 48 VCV-sensitive V3 loop form emerged from a preexisting viral variant. Enfuvirtide was added to the antiretroviral regimen at week 30; by week 48, enfuvirtide treatment selected for either the G36D or N43D HR-1 mutation. Growth competition experiments demonstrated that viruses incorporating the dominant week 28 VCV-resistant env were less fit than week 0 viruses in the absence of VCV but more fit than week 48 viruses. This week 48 fitness deficit persisted when G36D was corrected by either site-directed mutagenesis or week 48 gp41 domain swapping. The correction of N43D, in contrast, restored fitness relative to that of week 28, but not week 0, viruses. Virus entry kinetics correlated with observed fitness differences; the slower entry of enfuvirtide-resistant viruses corrected to wild-type rates in the presence of enfuvirtide. These findings suggest that while VCV and enfuvirtide select for resistance mutations in only one env subunit, gp120 and gp41 coevolve to maximize viral fitness under sequential drug selection pressures.

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“…stanford.edu). Genotypic susceptibility scores (GSS) were calculated based on mutation scores obtained from this database with modifications described by Anderson et al [2008]. HIV-1 subtypes were characterized using the phylogenetic method using reference sequences from the HIV Sequence Compendium 2009 as described previously [Parczewski et al, 2010].…”

Section: Genotyping Procedures and Data Interpretationmentioning

confidence: 99%

Genotypic tropism of antiretroviral‐treated patients with drug resistant HIV‐1

Parczewski¹,

Leszczyszyn-Pynka²,

Urbańska³

et al. 2011

Journal of Medical Virology

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CCR5 inhibitors remain an attractive antiretroviral treatment option for HIV-infected patients; however, tropism testing should be utilized prior their introduction. This study analyzed genotypic HIV-1 tropisms in patients with evidence of genotypic drug resistance to antiretroviral therapies in Northwest Poland. V3 loop sequences were analyzed from plasma samples obtained from patients presenting with virologic treatment failure while on combined antiretroviral treatment and with evidence of genotypic drug resistance. Genotypic X4 and R5 tropisms were identified using the geno2pheno algorithm with a false positive rate threshold set at 10%. Clinical data for all patients examined was collected, in addition to determining the CCR5 Δ32 genotype and calculating the genotypic susceptibility score (GSS). Virologic treatment failure and the presence of drug resistant mutations were observed in 37/450 (8.4%) patients on cART (combination antiretroviral therapy) with successful tropism analysis carried out on 35 (95%) cases. In 22 (62.9%) and 13 (37.1%) cases the R5 and X4 tropisms were predicted, respectively. An association between viral X4 tropism and the M41L (P = 0.04) resistance mutation and R5 tropism and the K103N (P = 0.07) resistance mutation were observed. GSS values were lower in the group with NRTI (P = 0.01) and NNRTI resistance (P = 0.048). In the majority of the drug resistant patients, R5 tropic viruses were found. As genotypic tropism testing is easy to carry out and interpret, its use in clinical practice would be highly useful in determining the use of appropriate drug therapies.

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Genotypic Susceptibility Scores and HIV Type 1 RNA Responses in Treatment-Experienced Subjects with HIV Type 1 Infection

Cited by 25 publications

References 52 publications

The relationship between genotypic sensitivity score and treatment outcomes in late stage HIV disease after supervised HAART

The relationship between genotypic sensitivity score and treatment outcomes in late stage HIV disease after supervised HAART

Vicriviroc Resistance Decay and Relative Replicative Fitness in HIV-1 Clinical Isolates under Sequential Drug Selection Pressures

Genotypic tropism of antiretroviral‐treated patients with drug resistant HIV‐1

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