Selection of Antiretroviral Therapy Guided by Genotypic or
The phenotype/genotype (PhenGen) open-label, randomized, multicenter study evaluated the genotype/virtual phenotype (vPt) and real phenotype (rPt) for choosing a new highly active antiretroviral therapy regimen at failure. Patients with a plasma viral load (pVL) between 2000 and 200,000 copies/mL and a CD4 cell count >200/µL, failing ≥2 regimens (<6 drugs), were randomized for vPt or rPt. Three hundred three patients were enrolled: 111 and 108 patients received a new treatment in the vPt and rPt arms, respectively. The 2 groups were comparable for baseline patient characteristics and treatment history. The new therapy was in agreement with expert advice in 58.5% of cases. After 6 months, no statistical differences were found in the mean absolute change from baseline CD4 cells (+55 and +46 cells/µL; P = 0.7), mean pVL log decrease (-1.35 and -1.37; P = 0.8), or proportion of patients with a pVL <400 copies/mL (54.8% in vPt arm and 52.6% in rPt arm; P = 0.9). At multivariate analysis, variables independently associated with failure of the new regimen were: pVL at baseline (odds ratio [OR] = 1.81; P < 0.021), number of nucleoside reverse transcriptase inhibitor-associated mutations (OR = 1.21; P = 0.001), number of protease mutations (OR = 1.15; P < 0.001), and recycling of indinavir (OR = 4.63; P = 0.019). Patients' adherence to the prescribed regimen (OR = 0.23; P < 0.001), number of active drugs in the new regimen (OR = 0.55; P = 0.001), and adherence to expert advice (OR = 0.37; P < 0.001) predicted virologic response. The vPt is as predictive of treatment outcome as the rPT. Use of expert advice significantly improved the response to therapy.
Despite its potency, highly active antiretroviral therapy (HAART) does not control HIV-1 replication in some patients. Viral resistance to antiretroviral drugs represents the principal cause for this failure and often forces the clinician to withdraw current therapy and prescribe alternative medications. Because of the wide cross-resistance within each antiretroviral class, however, the sequential use of drugs is frequently problematic, and the most effective combination cannot be predicted solely on the basis of the treatment history. Testing viral susceptibility is now within clinicians' reach and has been encouraged by international guidelines. In fact, several trials, both retrospective and perspective, have demonstrated that genotypic or phenotypic assays for the evaluation of HIV-1 drug resistance are better predictors of virologic outcome than the standard of care. In general, genotypic testing is faster, more accessible, and less costly than phenotypic testing; however, the interpretation of mutation patterns is complex and requires expert advice. As an alternative approach for resolving mutation patterns, Virco (Virco NV, Mechelen, Belgium) has developed the genotype/virtual phenotype (vPt), which uses a large genotypic-phenotypic database based on sequence data to deduct the viral phenotype. Clinical trials are ongoing to validate the correlation between vPt and real phenotype (rPt) prospectively with regard to the virologic and immunologic outcome. By intuition, phenotypic assays, which provide direct quantitative measures of drug susceptibility, would be a better instrument than genotyping, but whether phenotype is actually more advantageous than genotype is still debatable, and clinicians are perplexed about the relative utility of each type of assay and undecided on the choice when requiring resistance testing.
The Narval study, which evaluated genotyping and phenotyping side by side, found no significant difference in the virologic response to treatment modifications based on genotyping, phenotyping, or standard of care. In a subgroup of patients with limited protease inhibitor (PI) experience, however, a significant benefit was observed in the genotyping arm. Whether or not the results of this trial can be regarded as definite, there is undoubtedly a need to evaluate the validity of genotyping or phenotyping in various clinical settings thoroughly, with particular attention to the extent of previous exposure to antiretroviral drugs.
In the context of the MaSTeR (Management Standardizzato di Terapia AntiRetrovirale) Italian Study Group, 2 randomized multicenter studies were designed with the aim of establishing the relative strengths and weaknesses of genotypic and phenotypic HIV-1 resistance assays to select a new antiretroviral regimen. Between May and July 2000, the Genotipo-Fenotipo di Resistenza (GenPheRex) study enrolled a "multifailure" patient population (with exposure to >6 drugs and at least 2 years of exposure to antiretrovirals), but no significant difference was demonstrated between the 2 approaches. As a logical completion of the GenPheRex study, the present article reports the final results of the 6-month follow-up of the phenotype/genotype (PhenGen) study in which the clinical usefulness of vPt versus rPt was evaluated for choosing a new regimen after HAART failure in a population of anti-HIV-positive subjects with limited antiretroviral experience.
The phenotype/genotype (PhenGen) open-label, randomized, multicenter study evaluated the genotype/virtual phenotype (vPt) and real phenotype (rPt) for choosing a new highly active antiretroviral therapy regimen at failure. Patients with a plasma viral load (pVL) between 2000 and 200,000 copies/mL and a CD4 cell count >200/µL, failing ≥2 regimens (<6 drugs), were randomized for vPt or rPt. Three hundred three patients were enrolled: 111 and 108 patients received a new treatment in the vPt and rPt arms, respectively. The 2 groups were comparable for baseline patient characteristics and treatment history. The new therapy was in agreement with expert advice in 58.5% of cases. After 6 months, no statistical differences were found in the mean absolute change from baseline CD4 cells (+55 and +46 cells/µL; P = 0.7), mean pVL log decrease (-1.35 and -1.37; P = 0.8), or proportion of patients with a pVL <400 copies/mL (54.8% in vPt arm and 52.6% in rPt arm; P = 0.9). At multivariate analysis, variables independently associated with failure of the new regimen were: pVL at baseline (odds ratio [OR] = 1.81; P < 0.021), number of nucleoside reverse transcriptase inhibitor-associated mutations (OR = 1.21; P = 0.001), number of protease mutations (OR = 1.15; P < 0.001), and recycling of indinavir (OR = 4.63; P = 0.019). Patients' adherence to the prescribed regimen (OR = 0.23; P < 0.001), number of active drugs in the new regimen (OR = 0.55; P = 0.001), and adherence to expert advice (OR = 0.37; P < 0.001) predicted virologic response. The vPt is as predictive of treatment outcome as the rPT. Use of expert advice significantly improved the response to therapy.
Despite its potency, highly active antiretroviral therapy (HAART) does not control HIV-1 replication in some patients. Viral resistance to antiretroviral drugs represents the principal cause for this failure and often forces the clinician to withdraw current therapy and prescribe alternative medications. Because of the wide cross-resistance within each antiretroviral class, however, the sequential use of drugs is frequently problematic, and the most effective combination cannot be predicted solely on the basis of the treatment history. Testing viral susceptibility is now within clinicians' reach and has been encouraged by international guidelines. In fact, several trials, both retrospective and perspective, have demonstrated that genotypic or phenotypic assays for the evaluation of HIV-1 drug resistance are better predictors of virologic outcome than the standard of care. In general, genotypic testing is faster, more accessible, and less costly than phenotypic testing; however, the interpretation of mutation patterns is complex and requires expert advice. As an alternative approach for resolving mutation patterns, Virco (Virco NV, Mechelen, Belgium) has developed the genotype/virtual phenotype (vPt), which uses a large genotypic-phenotypic database based on sequence data to deduct the viral phenotype. Clinical trials are ongoing to validate the correlation between vPt and real phenotype (rPt) prospectively with regard to the virologic and immunologic outcome. By intuition, phenotypic assays, which provide direct quantitative measures of drug susceptibility, would be a better instrument than genotyping, but whether phenotype is actually more advantageous than genotype is still debatable, and clinicians are perplexed about the relative utility of each type of assay and undecided on the choice when requiring resistance testing.
The Narval study, which evaluated genotyping and phenotyping side by side, found no significant difference in the virologic response to treatment modifications based on genotyping, phenotyping, or standard of care. In a subgroup of patients with limited protease inhibitor (PI) experience, however, a significant benefit was observed in the genotyping arm. Whether or not the results of this trial can be regarded as definite, there is undoubtedly a need to evaluate the validity of genotyping or phenotyping in various clinical settings thoroughly, with particular attention to the extent of previous exposure to antiretroviral drugs.
In the context of the MaSTeR (Management Standardizzato di Terapia AntiRetrovirale) Italian Study Group, 2 randomized multicenter studies were designed with the aim of establishing the relative strengths and weaknesses of genotypic and phenotypic HIV-1 resistance assays to select a new antiretroviral regimen. Between May and July 2000, the Genotipo-Fenotipo di Resistenza (GenPheRex) study enrolled a "multifailure" patient population (with exposure to >6 drugs and at least 2 years of exposure to antiretrovirals), but no significant difference was demonstrated between the 2 approaches. As a logical completion of the GenPheRex study, the present article reports the final results of the 6-month follow-up of the phenotype/genotype (PhenGen) study in which the clinical usefulness of vPt versus rPt was evaluated for choosing a new regimen after HAART failure in a population of anti-HIV-positive subjects with limited antiretroviral experience.
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