Genotypic Sensitivity Score Research Articles

Virological Response to Darunavir/Ritonavir-Based Regimens in Antiretroviral-Experienced Patients (PREDIZISTA Study)

We assessed the association of baseline HIV-1 mutations, phenotypic sensitivity and pharmacokinetics with virological failure (VF) at week 12 (W12) after onset of a darunavir/ritonavir (DRV/r)-based regimen in a cohort of 67 antiretroviral-experienced HIV-patients failing on highly active antiretroviral therapy (HAART). VF was defined as HIV RNA >2.3 log10copies/ml at W12. HIV reverse transcriptase and protease sequencing was performed at WO; mutations with a P-value <0.25 in univariable analyses were used for a backward selection to find the best mutation set for VF prediction. Genotypic and phenotypic sensitivity scores were calculated and virtual phenotype predicted fold change (FC) assessed. DRV Cmin, Cmax, AUC(0-->12 h) and genotypic inhibitory quotient (GIQ) were determined. Patients had a median of 15 previous treatments for 10 years. Median W0 values included a T-cell count of 129 cells/microl, 4.7 log10 HIV RNA copies/ml, four major protease and six nucleoside reverse transcriptase inhibitor resistance mutations. At W12, median HIV RNA decrease was -2.1 log10 copies/ml with a gain of +67 CD4+ T-cells/microl; 40% of patients failed. We determined the genotypic score I13V+V32I+L33F/I/V+E35D+ M361/L/V+I47V+F53L+I62V. According to <4, 4-5 and >5 mutations, failure occurred in 11%, 48% and 100% of patients. Failure was associated with CDC stage, baseline CD4+ T-cell count, number of major protease inhibitor resistance mutations, FC and DRV/r score. Pharmacokinetics were not associated with failure, but GIQ was. At W12, 60% of heavily pretreated patients responded on DRV/r-based HAART. Genotypic and phenotypic information constituted the main virological response determinant in patients with optimal drug concentrations.

Response to “Key amprenavir resistance mutations counteract dramatic efficacy of darunavir in highly experienced patients”

Response to “Key amprenavir resistance mutations counteract dramatic efficacy of darunavir in highly experienced patients”

Is HAART based on newest active antiretroviral drugs influenced by GSS?

Methods Major enrollment criterion was the administration of maraviroc, enfuvirtide, raltegravir, etravirine, darunavir/r or tipranavir/r, alone or in combination, in the latest antiretroviral regimen, decided upon the last genotypic RNA resistance test. This allowed us to assess the genotypic sensitivity score (GSS) at the same time. We also recorded previous presence of specific mutations in all available genotypic resistance tests, their persistence in time and their correlation to the last GSS.

Prediction of Virologic Outcome of Salvage Antiretroviral Treatment by Different Systems for Interpreting Genotypic HIV Drug Resistance

The authors assessed the predictive capacity of 3 rule-based algorithms (Bergamo, Stanford University, Rega Institute) for HIV genotypic interpretation. A total of 1132 postgenotypic regimens in 533 patients were considered. The genotypic sensitivity score (GSS) was strongly associated (P < .0001) with the virologic outcome (1 log HIV-RNA reduction). The 3 algorithms had a highly significant prediction efficiency. The Bergamo algorithm receiver-operating characteristic curve area under the curve (AUC) for the prediction of >/=1 log HIV-RNA reduction was 0.753 (95% confidence interval, 0.725-0.781), testifying that the prediction was significantly different (P < .0001) from simple chance. The AUCs obtained by the 2 other systems were similar (0.752 Stanford; 0.741 Rega). The predictive capacity of the algorithms was not influenced by the type of antiviral drugs used. The 3 considered rule-based algorithms for the interpretation of HIV genotypic resistance yield congruent results and may effectively predict the virologic outcome of rescue therapy. Their use may help clinicians in interpreting mutational patterns and in making therapeutic choices.

Repeated Measures Longitudinal Analyses of HIV Virologic Response as a Function of Percent Adherence, Dose Timing, Genotypic Sensitivity, and Other Factors

Adherence to antiretroviral medications is critical to achieving HIV viral suppression. Studies have been limited to cross-sectional analyses using measures that reflect only the percentage of prescribed doses taken (percent adherence), however. The contribution of dose timing and other factors to achieving virologic suppression has received less scrutiny. In a longitudinal study, we collected detailed adherence information using multiple tools along with demographic, clinical, social-behavioral, and virologic measures. Subjects were followed for 48 weeks. Percent adherence, dose-timing, genotypic sensitivity, and virologic outcomes were collected every 4 weeks. Repeated measures mixed effects models (RMMEMs) were used to model the relation between virologic outcomes and adherence as well as genotypic sensitivity and others. Of the 141 subjects, mean percent adherence was 73% with a downward trend. Viral load (VL) dropped significantly (P = 0.01) over time. RMMEMs revealed that higher genotypic sensitivity, higher percent adherence, lower baseline VL, longer inclusion in the study, earlier HIV stage, and smaller dose-timing error were significantly associated with lower VL. In multivariate modeling, a 0.50 increase in the genotypic sensitivity score, a 10% increase in adherence, and a decrease of 3 hours of dose-timing error were associated with a decrease in log10 HIV RNA at 48 weeks of 0.69, 0.54, and 0.48, respectively (P < 0.05 for each). Long-term viral suppression requires consistent and high percent adherence accompanied by optimal interdose intervals. Efforts to improve viral outcomes should address not only missed doses but excessive variation in dose timing and prevention of adherence decline over time. Preventing the development and transmission of resistant variants is also critically important.

Response to ‘Limited benefit of antiretroviral resistance testing in treatment-experienced patients: a meta-analysis’

We read with interest about the meta-analysis performed by Panidou et al. [1] in a previous issue of AIDS, which appeared to demonstrate the limited utility of antiretroviral resistance testing and expert advice. We believe that this meta-analysis has several limitations, and that the conclusions reached by the authors cannot be generalized to all clinical situations. First, the analysis was not controlled for the number of active drugs available to the patients. More recent studies have documented this variable as a genotypic or phenotypic sensitivity score, which is unmeasured in the standard of care arms. In addition, studies included in the meta-analysis had a high proportion of patients who had failed several regimens and had very few active agents available to them, especially in the era studied 1997–1998 [2–4]. We have experience reviewing over 1000 genotypes for a large urban public HIV clinic in the United States. In our clinic, approximately one patient in four tested by genotypic resistance testing (GRT) has complete resistance to two or more classes of medications. The lack of useful agents would dampen the ability of any resistance testing method to affect virological outcome as we recently demonstrated [5]. Our experience suggests that patients who have failed one or two regimens benefit more from GRT than patients with a greater number of previous regimens, which logically correlates with a decreasing number of available antiretroviral agents. Similarly, there appears to be a range of the number of previous regimen failures in which expert advice contributes more and more as medication choices diminish, and then decreases again as the number of fully active choices dwindles towards zero. In our study, we demonstrated a highly statistically significant benefit for GRT plus expert advice versus GRT alone [6]. The study was not reviewed for meta-analysis, as it was a retrospective study. However, the study represents real world outcomes in our clinic. We agree with Panidou et al. [1] that phenotypic antiretroviral resistance testing (PART) is not very useful, and suspect that this is due to the tendency of PART and virtual PART to overestimate the activity of some nucleosides, as demonstrated by Haubrich et al. [7]. In conclusion, our experience suggests that GRT and expert advice are most useful for patients with limited antiretroviral exposure and fewer resistance mutations in choosing antiretroviral regimens for patients failing virologically on highly active antiretroviral therapy. Further studies are needed better to define the utility of GRT in patients who are highly drug experienced.

Enfuvirtide in HIV-1-Infected Individuals Changing Therapy to A Nucleoside Reverse Transcriptase Inhibitor Sparing Regimen: The Alliance Study

The role of the fusion inhibitor enfuvirtide in nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens was assessed in an open-label study of fifty-nine highly antiretroviral drug exposed HIV-1-infected individuals. There was a reduction in plasma HIV-1 RNA of 1.43 (95% confidence interval [Cl]: -2.06, -1.22) log10 copies/ml plasma over 96 weeks, and 44% (95% CI: 31, 58) of individuals had a viral load less than 400 copies/ml. A viral load below detection at 96 weeks was predicted by a baseline genotypic sensitivity score greater than 1. There was an average increase of 67 cells/microl (95% Cl: 15, 120) from baseline CD4+ T-cell count to week 96, and the percentage of patients with CD4+ T-cell counts above 100 and 200 cells/microl increased over the trial. Injection site reactions (ISRs) were less common in people with CD4+ T-cell counts >250 cells/microl at any time during follow-up, and were more severe in patients with lower baseline peripheral fat. Adherence over 48 weeks to enfuvirtide injections ranged from 96.3-99.5%. During the 96 week trial there were two discontinuations due to ISRs and two discontinuations following hypersensitivity reactions. Over the 96 weeks of study lean body mass increased by an average 2.7 kg (95% Cl; 1.7, 3.6 kg). Mean peripheral fat increased by 0.2 kg (95% Cl; -0.2, 0.6 kg). Baseline NRTI-associated toxicities resolved in 17% of participants during follow-up. Enfuvirtide is an important component of antiretroviral therapy in highly treatment-experienced individuals where NRTI sparing may be desirable.

A Randomized Trial of Nelfinavir and Abacavir in Combination with Efavirenz and Adefovir Dipivoxil in HIV-1-Infected Persons with Virological Failure Receiving Indinavir

Objectives (1) To determine the efficacy and safety of nelfinavir versus placebo and abacavir versus other approved nucleoside reverse transcriptase inhibitors (NRTIs), in combination with efavirenz and adefovir dipovoxil, in subjects experiencing virological failure on an indinavir-containing regimen. (2) To determine the relationship of baseline viral drug resistance genotype and phenotype to virological outcome. Design and methods A prospective, randomized, controlled, multicentre study in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive subjects conducted by the Adult AIDS Clinical Trials Group (ACTG 372B) and an open-label, single-arm, multicentre study in NNRTI-experienced subjects (ACTG 372D). Ninety-four subjects were randomized in ACTG 372B, which used a factorial design. All subjects received efavirenz and adefovir dipivoxil, and were randomly assigned to nelfinavir versus nelfinavir placebo and abacavir versus previously FDA-approved NRTIs. Twenty subjects received abacavir, efavirenz, adefovir dipivoxil and nelfinavir in ACTG 372D. Primary analysis time-point was at 16 weeks with follow-up through 48 weeks. Measures of efficacy were plasma HIV-1 RNA levels and CD4 cell counts. Adverse events were recorded according to ACTG criteria. Baseline reverse transcriptase and protease genotype, and drug susceptibility phenotype were determined. Resistance analyses were combined for ACTG 372B and D. Results At 16 weeks in ACTG 372B, 67% of subjects reached a primary study treatment failure end-point. In factorial analyses, nelfinavir was superior to nelfinavir placebo in rate of this failure end-point (56 vs 78%, P=0.02), but abacavir was not different from other NRTIs. No differences by nelfinavir or abacavir factor were noted at week 48. The failure end-point rate was significantly lower in those with baseline RNA levels ≤15000 copies/ml versus those with &gt;15000 copies/ml (42 vs 79%, P&lt;0.001). Higher genotypic and phenotypic sensitivity scores were significantly correlated with better virological responses ( P=0.003 and 0.030, respectively). Conclusions: (1) Treatment responses were low in this trial of nelfinavir, abacavir, efavirenz and adefovir dipivoxil for subjects experiencing virological failure on an indinavir-containing regimen. (2) Subjects with plasma HIV-1 RNA levels ≤15000 copies/ml had a significantly better virological response than those with &gt;15000 copies/ml at baseline. Switching at lower, rather than higher, viral load levels improved response rates in treatment-experienced subjects. (3) Summary measures of regimen sensitivity (such as, genotypic and phenotypic sensitivity scores) are useful in the evaluation of multidrug combination regimens.