Best of AIDS 2003: Clinical - A Randomized Trial Assessing the
Best of AIDS 2003: Clinical - A Randomized Trial Assessing the
Objective: To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response.
Design: A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States.
Participants: A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor.
Interventions: Randomization was to antiretroviral therapy guided by PRT or SOC.
Main outcome measures: The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of active (less than fourfold resistance) antiretroviral agents used (secondary).
Results: At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed; P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml; P = 0.049 for 50 copies/ml assay detection limit). significantly more subjects in the PRT arm were treated with two or more active antiretroviral agents than in the SOC arm (P = 0.003).
Conclusion: Antiretroviral treatment guided prospectively by PRT led to the increased use of active antiretroviral agents and was associated with a significantly better virological response.
Recent studies continue to demonstrate the need to utilize all clinically validated tools when changing regimens after virologic rebound. In the TORO studies of enfuvirtide, only 15% of these heavily treatment experienced patients re-established suppression in the control arm. As new agents and new classes are only slowly reaching the clinic, it is important to understand the contribution of resistance testing to improving outcomes. The TORO study results validated that genotype and phenotype testing will identify active drugs, as each active agent contributed to viral suppression.
Resistance testing has been shown to increase response rates in treatment-experienced patients. The beneficial role of phenotypic resistance testing was first demonstrated in this randomized study. The design compared the viral load reduction at week 16 in 272 patients who had virologic rebound on the first protease inhibitor-based regimen. The Virco phenotypic test results were given to clinicians without additional 'expert' guidance to maximize the generalizability of the results.
The main results showed the benefit of resistance testing versus without resistance testing on viral load reduction: 1.72 log10 versus 1.21 log10 change; P = 0.047. Clinicians indicated their planned regimen in both arms of the study during the screening period, and this was compared to what was prescribed at baseline, allowing the study to assess the contribution of the phenotype results on regimen choice. Twice as many changes were made to the regimen in the phenotype arm versus control (P = 0.001), documenting that phenotyping provided insight towards constructing a new regimen. Testing was particularly useful for those who entered the study with baseline resistance to indinavir, as 55% using phenotype versus 28% without testing achieved viral suppression ( 400 HIV RNA copies/ml plasma). This demonstrates the impact of resistance testing given more difficult resistance patterns. Further, when regimens did not contain a new class of agents (e.g., non-nucleoside reverse transcriptase inhibitors), phenotypic testing doubled the suppression rates (49% versus 23%; P = 0.015), demonstrating the utility of defining activity despite cross-resistance within classes. These data reinforce the role of resistance testing in the current management era.
-- C. Cohen et al.
To quote the authors: "Recent studies continue to demonstrate the need to utilize all clinically validated tools when changing regimens after virologic re-bound". Are resistance tests, in particular phenotypic resistance tests, 'clinically validated'?
The Vira 3001 was an impressive effort to establish validation for the test developed by Virco (VirtualPhenotype). Figure 1 shows a significantly greater decrease in viral load in patients whose physicians were given the results of the phenotypic test.
(Enlarge Image)
(a) HIV-1-RNA response (intent-to-treat observed analysis). —— Standard of care (SOC; < 400 copies/ml); —— phenotypic resistance testing (PRT, < 400 copies/ml); — — SOC (< 50 copies/ml); —— PRT (< 50 copies/ml). (b) Proportion of subjects with plasma HIV-1-RNA levels of 400 copies/ml or less at week 16. ITT, M = F, Intent-to-treat, missing equals failure; phenotypic resistance testing; standard of care.
(Enlarge Image)
(a) HIV-1-RNA response (intent-to-treat observed analysis). —— Standard of care (SOC; < 400 copies/ml); —— phenotypic resistance testing (PRT, < 400 copies/ml); — — SOC (< 50 copies/ml); —— PRT (< 50 copies/ml). (b) Proportion of subjects with plasma HIV-1-RNA levels of 400 copies/ml or less at week 16. ITT, M = F, Intent-to-treat, missing equals failure; phenotypic resistance testing; standard of care.
Unfortunately, this is a far cry from constituting 'clinical validation'. First, 16 weeks is a short follow-up. How long will the viral load benefits persist? Unfortunately for science, but appropriately for the patients involved in the study, patients in the control arm were given the results of resistance testing at week 16, and treatment was adjusted, precluding further analysis of the difference between the two arms. In the Viradapt study, viral load decreases persisted in the arm with genotypic testing after a further follow-up of 24 weeks.
Second, other large and well-designed studies have found less favourable results for resistance testing. The Narval study compared genotypic and phenotypic resistance testing with standard care, and found no significant differences in the percentage of patients with a viral load of less than 200 HIV RNA copies/ml plasma after 12 weeks (35% in the phenotypic arm, 44% in the genotypic arm, and 36% in the control arm).
Third, phenotypic testing is approximately twice as expensive and takes longer than genotypic testing. However, to my knowledge, nobody has shown that phenotypic is better; indeed, the Narval study provided evidence to the contrary.
Fourth, 'clinical validation' would usually mean 'effect on morbidity and mortality'. The gap is wide between surrogate markers such as viral load and the clinical endpoints that matter most to patients. If such a difference were to become apparent, CD4 cell counts would be expected to differ between the study arms. However, in the Vira3001 study, CD4 cell counts increased by a median of 40 x 10 cells/l in the arm without resistance testing, and by 27 x 10 cells/l (a non-significant difference) in the arm with resistance testing.
Nonetheless, resistance testing has been widely adopted. It may be of value in patients who differ from those who enrolled in Vira 3001; for instance, in drug-naive patients infected with resistant viruses. It may be cost-effective by suggesting discontinuation of ineffective drugs. But most
importantly, in a situation where physicians and patients face anxiety and insecurity, it provides both with a sense of direction. The evidence at hand does not prove that the direction is better than the one taken without resistance testing - only that it is no worse.
-- Bernard Hirschel, Editor
Objective: To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response.
Design: A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States.
Participants: A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor.
Interventions: Randomization was to antiretroviral therapy guided by PRT or SOC.
Main outcome measures: The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of active (less than fourfold resistance) antiretroviral agents used (secondary).
Results: At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed; P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml; P = 0.049 for 50 copies/ml assay detection limit). significantly more subjects in the PRT arm were treated with two or more active antiretroviral agents than in the SOC arm (P = 0.003).
Conclusion: Antiretroviral treatment guided prospectively by PRT led to the increased use of active antiretroviral agents and was associated with a significantly better virological response.
Recent studies continue to demonstrate the need to utilize all clinically validated tools when changing regimens after virologic rebound. In the TORO studies of enfuvirtide, only 15% of these heavily treatment experienced patients re-established suppression in the control arm. As new agents and new classes are only slowly reaching the clinic, it is important to understand the contribution of resistance testing to improving outcomes. The TORO study results validated that genotype and phenotype testing will identify active drugs, as each active agent contributed to viral suppression.
Resistance testing has been shown to increase response rates in treatment-experienced patients. The beneficial role of phenotypic resistance testing was first demonstrated in this randomized study. The design compared the viral load reduction at week 16 in 272 patients who had virologic rebound on the first protease inhibitor-based regimen. The Virco phenotypic test results were given to clinicians without additional 'expert' guidance to maximize the generalizability of the results.
The main results showed the benefit of resistance testing versus without resistance testing on viral load reduction: 1.72 log10 versus 1.21 log10 change; P = 0.047. Clinicians indicated their planned regimen in both arms of the study during the screening period, and this was compared to what was prescribed at baseline, allowing the study to assess the contribution of the phenotype results on regimen choice. Twice as many changes were made to the regimen in the phenotype arm versus control (P = 0.001), documenting that phenotyping provided insight towards constructing a new regimen. Testing was particularly useful for those who entered the study with baseline resistance to indinavir, as 55% using phenotype versus 28% without testing achieved viral suppression ( 400 HIV RNA copies/ml plasma). This demonstrates the impact of resistance testing given more difficult resistance patterns. Further, when regimens did not contain a new class of agents (e.g., non-nucleoside reverse transcriptase inhibitors), phenotypic testing doubled the suppression rates (49% versus 23%; P = 0.015), demonstrating the utility of defining activity despite cross-resistance within classes. These data reinforce the role of resistance testing in the current management era.
-- C. Cohen et al.
To quote the authors: "Recent studies continue to demonstrate the need to utilize all clinically validated tools when changing regimens after virologic re-bound". Are resistance tests, in particular phenotypic resistance tests, 'clinically validated'?
The Vira 3001 was an impressive effort to establish validation for the test developed by Virco (VirtualPhenotype). Figure 1 shows a significantly greater decrease in viral load in patients whose physicians were given the results of the phenotypic test.
(Enlarge Image)
(a) HIV-1-RNA response (intent-to-treat observed analysis). —— Standard of care (SOC; < 400 copies/ml); —— phenotypic resistance testing (PRT, < 400 copies/ml); — — SOC (< 50 copies/ml); —— PRT (< 50 copies/ml). (b) Proportion of subjects with plasma HIV-1-RNA levels of 400 copies/ml or less at week 16. ITT, M = F, Intent-to-treat, missing equals failure; phenotypic resistance testing; standard of care.
(Enlarge Image)
(a) HIV-1-RNA response (intent-to-treat observed analysis). —— Standard of care (SOC; < 400 copies/ml); —— phenotypic resistance testing (PRT, < 400 copies/ml); — — SOC (< 50 copies/ml); —— PRT (< 50 copies/ml). (b) Proportion of subjects with plasma HIV-1-RNA levels of 400 copies/ml or less at week 16. ITT, M = F, Intent-to-treat, missing equals failure; phenotypic resistance testing; standard of care.
Unfortunately, this is a far cry from constituting 'clinical validation'. First, 16 weeks is a short follow-up. How long will the viral load benefits persist? Unfortunately for science, but appropriately for the patients involved in the study, patients in the control arm were given the results of resistance testing at week 16, and treatment was adjusted, precluding further analysis of the difference between the two arms. In the Viradapt study, viral load decreases persisted in the arm with genotypic testing after a further follow-up of 24 weeks.
Second, other large and well-designed studies have found less favourable results for resistance testing. The Narval study compared genotypic and phenotypic resistance testing with standard care, and found no significant differences in the percentage of patients with a viral load of less than 200 HIV RNA copies/ml plasma after 12 weeks (35% in the phenotypic arm, 44% in the genotypic arm, and 36% in the control arm).
Third, phenotypic testing is approximately twice as expensive and takes longer than genotypic testing. However, to my knowledge, nobody has shown that phenotypic is better; indeed, the Narval study provided evidence to the contrary.
Fourth, 'clinical validation' would usually mean 'effect on morbidity and mortality'. The gap is wide between surrogate markers such as viral load and the clinical endpoints that matter most to patients. If such a difference were to become apparent, CD4 cell counts would be expected to differ between the study arms. However, in the Vira3001 study, CD4 cell counts increased by a median of 40 x 10 cells/l in the arm without resistance testing, and by 27 x 10 cells/l (a non-significant difference) in the arm with resistance testing.
Nonetheless, resistance testing has been widely adopted. It may be of value in patients who differ from those who enrolled in Vira 3001; for instance, in drug-naive patients infected with resistant viruses. It may be cost-effective by suggesting discontinuation of ineffective drugs. But most
importantly, in a situation where physicians and patients face anxiety and insecurity, it provides both with a sense of direction. The evidence at hand does not prove that the direction is better than the one taken without resistance testing - only that it is no worse.
-- Bernard Hirschel, Editor
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