Efficacy of DRV/r Monotherapy Versus DRV/r Triple Therapy
PROTEA was a 96-week, randomized, open-label phase 3b study, with study centers in 13 European countries and Israel. The trial recruited patients who had HIV-1 RNA suppression below 50 copies/ml on their first-line antiretroviral regimen for the 48 weeks prior to screening. Key exclusion criteria included patients with a CD4 count 100 cells/μl or less at the start of antiretroviral therapy (nadir) and 200 cells/μl or less at screening, history of virological failure or prior protease inhibitor mutations.
During the study, the protocol was amended to allow intensification with nucleoside analogues for any patient in the monotherapy arm who had entered the trial with a CD4 nadir below 100 cells/μl. This amendment was introduced because patients with CD4 nadir below 100 cells/μl were protocol violators and should not be receiving protease inhibitor monotherapy.
Subsequent to screening, patients entered a 4-week run-in period (baseline 1) in which all patients received DRV/r 800/100 mg once daily with their current two NRTIs. Patients were then randomized (baseline 2) 1 : 1 to receive either DRV/r 800/100 mg once daily as monotherapy (monotherapy arm) or in combination with two NRTIs (triple therapy arm). The investigator-selected nucleoside analogues were either tenofovir, abacavir or zidovudine in combination with either lamivudine or emtricitabine. Randomization was stratified by HCV antibody status (anti-HCV negative or positive).
Patients attended study visits at screening, baselines 1 and 2 and then at weeks 4, 24 and thereafter every 24 weeks until the end of treatment (week 96). Evaluations for efficacy and safety were carried out at every study visit according to local standard-of-care; neurocognitive function was also assessed. Evaluation of plasma HIV-1 RNA levels was determined using the Abbott RealTime HIV-1 assay (lower quantification limit 40 copies/ml). Additionally, genotyping was carried out for all patients with two consecutive HIV-1 RNA levels more than 400 copies/ml. In a subgroup of patients, lumbar punctures were performed at baseline and again at week 48 to assess HIV-1 RNA levels in the CSF.
Switch of nucleoside analogues in the triple therapy arm was allowed at any visit in the event of suspected toxicity. Any subject in the monotherapy arm with virologic failure could have their treatment intensified with two nucleoside analogues, provided that major protease inhibitor mutations had not developed.
The Division of AIDS (DAIDS) grading tables were used to define clinical and laboratory abnormalities. An independent Data and Safety Monitoring Board (DSMB) was established to monitor data on an ongoing basis to ensure the continuing safety of the patients enrolled into the study.
Neurocognitive function was assessed using a series of neuropsychological tests: the revised Hopkins Verbal Learning Test (HVLT-r), excluding the retention and recognition tests, the Color Trail Test and the Grooved Pegboard Test. The most common neurocognitive impairments seen in HIV-infected individuals are those that affect frontal subcortical functions, and as such, these tests were chosen to detect such changes.
Patients participating in the study provided informed consent prior to any study procedures. Approval from independent ethics committees and health authorities was obtained before initiating the study.
The primary endpoint for the study was confirmed plasma HIV-1 RNA below 50 copies/ml at week 48 (FDA snapshot algorithm). All patients who discontinued or switched randomized study medication were considered nonresponders, inclusive of patients intensifying treatment with NRTIs in the monotherapy arm. Patients with missing HIV-1 RNA results at the 48-week visit were classified as having HIV-1 RNA more than 50 copies/ml.
Assuming a response rate of 90%, 130 patients were targeted for recruitment in each arm to establish noninferiority a one-sided significance level of 2.5%, 80% power, a noninferiority margin of -12%, and allowing for a maximum of 10% of patients to be excluded from the Per Protocol population. The primary population was the intention-to-treat (ITT) population; the Per Protocol population was analyzed to investigate the impact of exclusion of major protocol violations.
For the primary analysis, a logistic regression model including treatment arm and the stratification factor (anti-HCV positive or negative at screening) was used to estimate the difference in virologic response rate between treatment arms, with corresponding 95% confidence interval (CI). Sensitivity analyses incorporating additional covariates were conducted to examine the impact of differences in baseline factors.
In the secondary, switch-included analysis, all patients who discontinued randomized medications were followed up and their HIV-1 RNA levels at week 48 were included in the analysis, even if they had changed their antiretroviral treatment.
For the neurocognitive assessment, a total of five scores were determined and each standardized to give a normalized z score using the manufacturers' normative data. An overall score (NPZ-5) was derived by averaging the scores. The NPZ-5 score was dichotomized and considered abnormal if the standardized score was less than -1, indicating below-average performance. Analysis of covariance (ANCOVA) was used to identify potential covariates affecting neurocognitive function and to provide an adjusted estimate for the NPZ-5 score at week 48 for each treatment group. The difference between arms was calculated and considered statistically significant if P < 0.05.
A subgroup of subjects participated in the CNS substudy. These subjects underwent a lumbar puncture prior to baseline and again after 48 weeks of randomized treatment to assess CSF HIV-1 RNA levels. Lumbar puncture samples were sent to a central laboratory and CSF HIV-1 viral load was determined using the Abbott RealTime HIV-1 assay.
Patients were considered virologically suppressed in the CSF if HIV-1 RNA was below 50 copies/ml. In cases wherein CSF HIV-1 RNA elevations were observed, other indicators were investigated, including plasma HIV-1 RNA, other disease markers and presentation of clinical symptoms. In addition, all CSF samples were assessed for other key disease markers, including albumin, neopterin and lymphocyte counts.
Methods
PROTEA was a 96-week, randomized, open-label phase 3b study, with study centers in 13 European countries and Israel. The trial recruited patients who had HIV-1 RNA suppression below 50 copies/ml on their first-line antiretroviral regimen for the 48 weeks prior to screening. Key exclusion criteria included patients with a CD4 count 100 cells/μl or less at the start of antiretroviral therapy (nadir) and 200 cells/μl or less at screening, history of virological failure or prior protease inhibitor mutations.
During the study, the protocol was amended to allow intensification with nucleoside analogues for any patient in the monotherapy arm who had entered the trial with a CD4 nadir below 100 cells/μl. This amendment was introduced because patients with CD4 nadir below 100 cells/μl were protocol violators and should not be receiving protease inhibitor monotherapy.
Subsequent to screening, patients entered a 4-week run-in period (baseline 1) in which all patients received DRV/r 800/100 mg once daily with their current two NRTIs. Patients were then randomized (baseline 2) 1 : 1 to receive either DRV/r 800/100 mg once daily as monotherapy (monotherapy arm) or in combination with two NRTIs (triple therapy arm). The investigator-selected nucleoside analogues were either tenofovir, abacavir or zidovudine in combination with either lamivudine or emtricitabine. Randomization was stratified by HCV antibody status (anti-HCV negative or positive).
Efficacy and Safety Assessments
Patients attended study visits at screening, baselines 1 and 2 and then at weeks 4, 24 and thereafter every 24 weeks until the end of treatment (week 96). Evaluations for efficacy and safety were carried out at every study visit according to local standard-of-care; neurocognitive function was also assessed. Evaluation of plasma HIV-1 RNA levels was determined using the Abbott RealTime HIV-1 assay (lower quantification limit 40 copies/ml). Additionally, genotyping was carried out for all patients with two consecutive HIV-1 RNA levels more than 400 copies/ml. In a subgroup of patients, lumbar punctures were performed at baseline and again at week 48 to assess HIV-1 RNA levels in the CSF.
Switch of nucleoside analogues in the triple therapy arm was allowed at any visit in the event of suspected toxicity. Any subject in the monotherapy arm with virologic failure could have their treatment intensified with two nucleoside analogues, provided that major protease inhibitor mutations had not developed.
The Division of AIDS (DAIDS) grading tables were used to define clinical and laboratory abnormalities. An independent Data and Safety Monitoring Board (DSMB) was established to monitor data on an ongoing basis to ensure the continuing safety of the patients enrolled into the study.
Neurocognitive function was assessed using a series of neuropsychological tests: the revised Hopkins Verbal Learning Test (HVLT-r), excluding the retention and recognition tests, the Color Trail Test and the Grooved Pegboard Test. The most common neurocognitive impairments seen in HIV-infected individuals are those that affect frontal subcortical functions, and as such, these tests were chosen to detect such changes.
Patients participating in the study provided informed consent prior to any study procedures. Approval from independent ethics committees and health authorities was obtained before initiating the study.
Statistical Methods
The primary endpoint for the study was confirmed plasma HIV-1 RNA below 50 copies/ml at week 48 (FDA snapshot algorithm). All patients who discontinued or switched randomized study medication were considered nonresponders, inclusive of patients intensifying treatment with NRTIs in the monotherapy arm. Patients with missing HIV-1 RNA results at the 48-week visit were classified as having HIV-1 RNA more than 50 copies/ml.
Assuming a response rate of 90%, 130 patients were targeted for recruitment in each arm to establish noninferiority a one-sided significance level of 2.5%, 80% power, a noninferiority margin of -12%, and allowing for a maximum of 10% of patients to be excluded from the Per Protocol population. The primary population was the intention-to-treat (ITT) population; the Per Protocol population was analyzed to investigate the impact of exclusion of major protocol violations.
For the primary analysis, a logistic regression model including treatment arm and the stratification factor (anti-HCV positive or negative at screening) was used to estimate the difference in virologic response rate between treatment arms, with corresponding 95% confidence interval (CI). Sensitivity analyses incorporating additional covariates were conducted to examine the impact of differences in baseline factors.
In the secondary, switch-included analysis, all patients who discontinued randomized medications were followed up and their HIV-1 RNA levels at week 48 were included in the analysis, even if they had changed their antiretroviral treatment.
For the neurocognitive assessment, a total of five scores were determined and each standardized to give a normalized z score using the manufacturers' normative data. An overall score (NPZ-5) was derived by averaging the scores. The NPZ-5 score was dichotomized and considered abnormal if the standardized score was less than -1, indicating below-average performance. Analysis of covariance (ANCOVA) was used to identify potential covariates affecting neurocognitive function and to provide an adjusted estimate for the NPZ-5 score at week 48 for each treatment group. The difference between arms was calculated and considered statistically significant if P < 0.05.
Central Nervous System Substudy
A subgroup of subjects participated in the CNS substudy. These subjects underwent a lumbar puncture prior to baseline and again after 48 weeks of randomized treatment to assess CSF HIV-1 RNA levels. Lumbar puncture samples were sent to a central laboratory and CSF HIV-1 viral load was determined using the Abbott RealTime HIV-1 assay.
Patients were considered virologically suppressed in the CSF if HIV-1 RNA was below 50 copies/ml. In cases wherein CSF HIV-1 RNA elevations were observed, other indicators were investigated, including plasma HIV-1 RNA, other disease markers and presentation of clinical symptoms. In addition, all CSF samples were assessed for other key disease markers, including albumin, neopterin and lymphocyte counts.
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