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High Viral Load & Low CD4 Predicts Failure to Nefinavir but not to Kaletra
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"Baseline HIV-1 RNA Level and CD4 Cell Count Predict Time to Loss of
Virologic Response to Nelfinavir, but Not Lopinavir/Ritonavir, in Antiretroviral
Therapy--Naive Patients"
The Journal of Infectious Diseases July 15, 2004
"Baseline HIV-1 RNA Level and CD4 Cell Count Predict Time to Loss of Virologic Response to Nelfinavir, but Not Lopinavir/Ritonavir, in Antiretroviral Therapy--Naive Patients"
Martin S. King,1 Barry M. Bernstein,1 Sharon L. Walmsley,4 Renslow Sherer,2 Judith Feinberg,3 Ian Sanne,6 Paul Cernohous,1 Julio S. G. Montaner,5 Scott C. Brun,1 and Eugene Sun1
1Abbott Laboratories, Abbott Park, and 2Section of Infectious Diseases, University of Chicago Hospitals, Chicago, Illinois; 3Department of Medicine, University of Cincinnati, Cincinnati, Ohio; 4Toronto Hospital, University Health Network, University of Toronto, Ontario, and 5St. Paul's Hospital/University of British Columbia, Vancouver, British Columbia, Canada; 6Department of Infectious Diseases and Clinical Microbiology, University of Witwatersrand, Johannesburg, South Africa
Our objective was to assess, in that study, the effect of baseline HIV-1 RNA levels and CD4 cell counts on virologic response for up to 96 weeks.
For nelfinavir-treated patients, baseline HIV-1 RNA level (P < .001) and baseline CD4 cell count (P < .001) were statistically significantly associated with virologic response, whereas, for lopinavir/ritonavir-treated patients, neither variable was associated with loss of virologic response (P > .05 for each)
Treatment with nelfinavir (P < .001), higher baseline HIV-1 RNA level (P < .001), lower baseline CD4 cell count (P < .001), adherence below the median (P < .001) ……were each significantly associated with shorter time to loss of virologic response, whereas race and sex were not.
In each treatment group, lower adherence was associated with loss of virologic response. For nelfinavir-treated patients, the hazard ratio (HR) was 2.5 for adherence below versus above the median (95% confidence interval [CI], 1.7--3.6; P < .001), and, for lopinavir/ritonavir-treated patients, the HR was 2.4 (95% CI, 1.3--4.4; P = .003)
The authors concluded: The results of the present study confirm the prognostic value of baseline CD4 cell counts and plasma HIV-1 RNA levels in predicting virologic response among patients treated with a nelfinavir-based regimen. In contrast, our results demonstrate that lopinavir/ritonavir-based treatment did not lead to significantly decreased virologic response in patients with lower baseline CD4 cell counts and higher baseline HIV-1 RNA levels. Our findings are consistent with the concept that the predictive value of CD4 cell count and HIV-1 RNA level is dependent on the potency of the regimen used, and these results continue to suggest an important role for lopinavir/ritonavir as the initial protease inhibitor--based treatment for HIV infection.
KAPLAN-MEIER ANALYSIS TO TIME TO LOSS OF VIROLOGIC RESPONSE THROUGH WEEK 96 BY BASELINE VIRAL LOAD & CD4 COUNT
VL <20,000 c/ml: 87% undetectable on NFV; 90% undetectable on LPV/r
VL 20,000-65,000 c/ml: 68% on NFV; 80% LPV/r
VL 65,000-150,000 c/ml: 54% NFV; 74% LPV/r
VL 150,000-350,000: 53% NFV; 74% LPV/r
>350,000: 33% NFV; 85% LPV/r
HR 2.00 NFV; HR LPV/r 1.36
CD4 COUNT
<50: 23% NFV; 67% LPV/r
50-199: 55% NFV; 80% LPV/r
200-349: 68% NFV; 80%
350-499: 60% NFV; 82% LPV/r
<500: 81% NFV; 85% LPV/r
HR NFV 1.29; HR LPV/r 1.10
Treatment with nelfinavir (P < .001), higher baseline HIV-1 RNA level (P < .001), lower baseline CD4 cell count (P < .001), adherence below the median (P < .001), lower weight (P < .05), younger age (P < .05), and longer time since diagnosis (P < .05) were each significantly associated with shorter time to loss of virologic response, whereas race and sex were not.
The primary end point was the time to loss of virologic response through week 96. Loss of virologic response was defined by 2 consecutive HIV-1 RNA rebound levels >400 copies/mL following any HIV-1 RNA level <400 copies/mL or by a single HIV-1 RNA rebound level >400 copies/mL followed by study discontinuation. Patients who never achieved HIV-1 RNA levels <400 copies/mL were considered to have a loss of virologic response on day 0. Patients who discontinued or completed the study without demonstrating a loss of virologic response were censored as of their final virus load measurement while receiving randomized treatment.
No significant differences between treatment groups were observed for any baseline characteristics. Patients were primarily men (80%) and white (57%), and the overall mean (median) baseline HIV-1 RNA level and CD4 cell count were 4.90 (4.99) log10 copies/mL and 259 (232) cells/mm3, respectively.
A total of 189 patients met the criteria for loss of virologic response (63 receiving lopinavir/ritonavir and 126 receiving nelfinavir), including 61 who never achieved HIV-1 RNA levels <400 copies/mL (22 receiving lopinavir/ritonavir and 39 receiving nelfinavir) and 128 with confirmed viral rebound after suppression to <400 copies/mL (41 receiving lopinavir/ritonavir and 87 receiving nelfinavir). Of these 189 patients, only 2 demonstrated loss of virologic response after unblinding. Of the 128 patients with viral rebound, 107 had at least 1 follow-up HIV-1 RNA value without a change in regimen, and resuppression of HIV-1 RNA level to <400 copies/mL was more common in lopinavir/ritonavir-treated (22/32; 69%) than in nelfinavir-treated (17/75; 23%) patients (P < .001, Fisher's exact test); for 3 lopinavir/ritonavir-treated patients, virus resuppression occurred after unblinding.
Overall, 77% of patients (80% receiving lopinavir/ritonavir and 74% receiving nelfinavir) completed at least 60 weeks of treatment. The median durations of blinded treatment were 84 weeks (lopinavir/ritonavir) and 81 weeks (nelfinavir), with median durations of overall treatment of 92 weeks (lopinavir/ritonavir) and 87 weeks (nelfinavir) and the maximum duration of treatment of 114 weeks in each group. Premature discontinuations after unblinding were infrequent, occurring in only 2% (lopinavir/ritonavir) and 5% (nelfinavir) of enrolled patients. Discontinuations due to study drug--related adverse events were uncommon, occurring in 6% of patients in each treatment group through the end of the study. Pill count--based adherence was similar between treatment groups, with mean (median) overall adherence levels of 92% (95%) for lopinavir/ritonavir-treated patients and 93% (96%) for nelfinavir-treated patients.
ABSTRACT
Baseline CD4 cell counts and human immunodeficiency virus (HIV)--1 RNA levels have been shown to predict immunologic and virologic responses in HIV-infected patients receiving antiretroviral therapy.
In our randomized, double-blind, comparative trial, 653 antiretroviral therapy--naive patients received lopinavir/ritonavir or nelfinavir, plus stavudine and lamivudine, for up to 96 weeks.
The risk of loss of virologic response was significantly higher for nelfinavir-treated patients than for lopinavir/ritonavir-treated patients (Cox model hazard ratio, 2.2; 95% confidence interval, 1.7--3.0; P < .001).
For nelfinavir-treated patients, but not for lopinavir/ritonavir-treated patients, higher baseline HIV-1 RNA levels and lower baseline CD4 cell counts were associated with a higher risk of loss of virologic response.
Overall, 77% of patients (80% receiving lopinavir/ritonavir and 74% receiving nelfinavir) completed at least 60 weeks of treatment. The median durations of blinded treatment were 84 weeks (lopinavir/ritonavir) and 81 weeks (nelfinavir), with median durations of overall treatment of 92 weeks (lopinavir/ritonavir) and 87 weeks (nelfinavir) and the maximum duration of treatment of 114 weeks in each group. Premature discontinuations after unblinding were infrequent, occurring in only 2% (lopinavir/ritonavir) and 5% (nelfinavir) of enrolled patients. Discontinuations due to study drug--related adverse events were uncommon, occurring in 6% of patients in each treatment group through the end of the study. Pill count--based adherence was similar between treatment groups, with mean (median) overall adherence levels of 92% (95%) for lopinavir/ritonavir-treated patients and 93% (96%) for nelfinavir-treated patients.
AUTHOR DISCUSSION
In the present analysis, the superior virologic response of lopinavir/ritonavir, compared with that of nelfinavir, in antiretroviral therapy--naive patients, previously reported through 48 weeks, was maintained for up to 96 weeks of treatment. The significant effect of baseline HIV-1 RNA level and CD4 cell count on virologic response to a nelfinavir-containing regimen is consistent with previous reports of similar effects with highly active antiretroviral therapy, including protease inhibitor--based, nonnucleoside reverse-transcriptase inhibitor--based, and triple nucleoside reverse-transcriptase inhibitor regimens. In contrast, the absence of a significant effect of baseline HIV-1 RNA level and CD4 cell count on response to a lopinavir/ritonavir-containing regimen in the present study is consistent with results from a phase 2 study of a lopinavir/ritonavir-based regimen in antiretroviral therapy--naive patients who were followed for up to 4 years.
The risk of loss of virologic response was >2-fold higher for nelfinavir-treated patients than for lopinavir/ritonavir-treated patients. In addition, the implications of detectable virus load during therapy with nelfinavir were potentially more serious, in that the greater rates of primary protease inhibitor resistance (0% for lopinavir/ritonavir vs. 45% for nelfinavir) and reverse-transcriptase inhibitor resistance (37% vs. 82%) observed in this study may limit the effectiveness of subsequent treatment options. Among lopinavir/ritonavir-treated patients, the high degree of virus resuppression and the absence of protease inhibitor resistance suggest that the events of loss of virologic response were due to temporary nonadherence or other factors resulting in low drug exposures.
The regimens in the present study demonstrated comparable tolerability and adherence; thus, the differences observed may be attributable to other factors, such as pharmacologic characteristics. Nelfinavir provides mean trough drug levels only 3--4-fold greater than the IC50 for wild-type whereas lopinavir/ritonavir provides trough concentrations about 75-fold greater than the IC50. This margin potentially provides a more forgiving pharmacokinetic profile and a high genetic barrier to resistance, facilitating control of viral replication by a lopinavir/ritonavir-based regimen, even in the presence of high baseline HIV-1 RNA levels and low baseline CD4 cell counts.
There are potential limitations to this analysis. The use of version 1.0 of the HIV-1 Monitor assay instead of version 1.5 may have modestly overestimated the absolute rates of virus suppression, although such an effect would be unlikely to change any conclusions. With a longer duration of follow-up, baseline HIV-1 RNA levels and CD4 cell counts might demonstrate a significant effect on response to lopinavir/ritonavir, as evidenced by a trend toward lowered response in lopinavir/ritonavir-treated patients with baseline CD4 cell counts <50 cells/mm3. Although this result suggests the possibility of lowered response to lopinavir/ritonavir in antiretroviral therapy--naive patients with very advanced HIV disease, its context is difficult to determine, since clinical trials of other antiretroviral therapies often exclude patients with very low CD4 cell counts. In recently reported studies of efavirenz, indinavir, and atazanavir, entry criteria excluded patients with CD4 cell counts <50 or <75 cells/mm3; thus, the efficacy of these agents in patients with low CD4 cell counts may not be well understood. It is unknown whether other ritonavir-boosted protease inhibitor regimens will ultimately demonstrate a similarly robust virologic response in patients with higher HIV-1 RNA levels or lower CD4 cell counts. In a recent study of ritonavir-boosted fosamprenavir, similar response rates at 48 weeks were observed among patients with HIV-1 RNA levels > or <100,000 copies/mL, although the importance of this result is unclear, since, in the overall analysis, the ritonavir-boosted fosamprenavir regimen did not show virologic response superior to that of a nelfinavir-based regimen.
INTRODUCTION
Protease inhibitor--based combination antiretroviral therapy has been associated with dramatic improvements in HIV-associated morbidity and mortality. In several studies, higher baseline HIV-1 RNA levels and/or lower baseline CD4 cell counts have been associated with a reduced probability of the achievement or durability of virus suppression during treatment with a protease inhibitor--based regimen.
Lopinavir, a novel peptidomimetic protease inhibitor with potent in vitro activity against HIV, is coformulated with low-dose ritonavir, a cytochrome p450 3A4 enzyme inhibitor, to enhance its pharmacokinetic profile. Lopinavir/ritonavir-based regimens have demonstrated antiviral activity in antiretroviral therapy--naive and protease inhibitor--experienced patients, and, in a phase 2 study of a lopinavir/ritonavir-based regimen in antiretroviral therapy--naive patients, virologic response through 4 years of treatment was not decreased among patients with lower CD4 cell counts or higher HIV-1 RNA levels at baseline.
In a randomized, double-blind clinical trial conducted in antiretroviral therapy--naive patients, a lopinavir/ritonavir-based regimen demonstrated virologic response superior to that of a nelfinavir-based regimen, through 48 weeks of treatment. Our objective was to assess, in that study, the effect of baseline HIV-1 RNA levels and CD4 cell counts on virologic response for up to 96 weeks.
PATIENTS
Antiretroviral therapy--naive patients were enrolled in a randomized, double-blind phase 3 clinical trial comparing lopinavir/ritonavir to nelfinavir. Details of study design and results through 48 weeks have been reported elsewhere. Patients were enrolled at 93 centers in 13 countries in North and South America, Europe, Africa, and Australia. The study was approved by the institutional review board or ethics committee at each center, and all patients provided written, informed consent. Patients had plasma HIV-1 RNA levels >400 copies/mL with no CD4 cell count restriction. Patients were randomized 1 : 1 to either lopinavir/ritonavir plus nelfinavir placebo or nelfinavir plus lopinavir/ritonavir placebo. All patients received lamivudine and stavudine. After the last active patient completed 60 weeks of treatment, patients and investigators were unblinded to treatment assignment, and, after the last active patient completed 72 weeks of treatment, the study was stopped.
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