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Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
University of Miami, Miami, Florida
Kaiser Permanente, Atlanta, Georgia
Rose Medical Center, Denver, Colorado
Northstar Medical Center, Chicago, Illinois
GlaxoSmithKline, Research Triangle Park, North Carolina
Background.
Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily.
Methods.
This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log10 copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of 1.0 log10 copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions.
Results.
We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log10 copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from 8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P < .001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL.
Conclusion.
The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.
Highly active antiretroviral therapy (HAART) revolutionized the treatment of HIV-1 infection, resulting in dramatic decreases in HIV-associated morbidity and mortality throughout the developed world [1, 2]. However, early regimens, although effective, were often poorly tolerated and complex. With newer agents, HAART has become better tolerated and more convenient, particularly for patients receiving initial therapy. There are now several simple and effective once- and twice-daily regimens with low pill burdens.
All currently recommended initial regimens include a combination of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) [3]. The dual-NRTI combination of abacavir plus lamivudine has been studied in multiple clinical trials, in combination with either a protease inhibitor (PI) [46], a nonnucleoside reverse-transcriptase inhibitor (NNRTI) [68], or other NRTIs [6, 911]. Both drugs have been approved for once-daily administration on the basis of pharmacokinetic studies and randomized clinical trials [8, 1214]. A once-daily fixed-dose combination (FDC) tablet containing abacavir/lamivudine (600/300 mg) was recently approved. When combined with a third once-daily agent, this FDC tablet could allow for effective therapy with a regimen consisting of 2 tablets ingested daily without food restrictions. The present trial was designed to compare 2 such regimens: combinations of either efavirenz or tenofovir disoproxil fumarate (DF) plus the FDC tablet. The combination of efavirenz, abacavir, and lamivudine had been studied previously [68]. The combination of tenofovir DF with abacavir and lamivudine had not been studied but was a promising combination, given the potency of all 3 agents [1517], the absence of in vitro antagonism, and no expectation of negative pharmacokinetic interactions. However, after rapid accrual, several cases of early virologic nonresponse in this arm were spontaneously reported, which led to an urgent interim analysis. We report the results of this unplanned analysis, along with longer term data from the efavirenz arm.
SUBJECTS, MATERIALS, AND METHODS
Study subjects.
Eligible subjects were HIV-1infected adults with a plasma HIV-1 RNA level of 5000 copies/mL who had not received >14 days of ART. Subjects were excluded if they had a history of a Center for Disease Control and Prevention class C event that required treatment within the preceding 45 days; clinically relevant pancreatitis or hepatitis within the preceding 6 months; osteopenia; or conditions deemed by the investigator to compromise safety, predispose toward toxicity, or interfere with adherence or drug absorption. Subjects were also excluded if they had been recently treated with radiation therapy, cytotoxic chemotherapy, immunomodulating agents, agents with anti-HIV activity, or drugs having significant interactions with efavirenz. Laboratory exclusion criteria included a hemoglobin level <10.0 g/dL for men or <9.0 g/dL for women, absolute neutrophil count <1000 cells/mm3, platelet count <75,000 platelets/mm3, transaminase levels >5 times the upper limit of normal (ULN), total bilirubin or serum amylase levels >1.5 times the ULN, or estimated creatinine clearance 60 mL/min. Pregnant or breast-feeding women were excluded, and women of childbearing potential were required to abstain from intercourse or to use double-barrier contraception.
Study design and assessments.
ESS30009 was a randomized, open-label, multicenter trial conducted at 64 sites in the United States. Research was conducted in accordance with good clinical practices and the guiding principles of the Declaration of Helsinki. An institutional review board from each site approved the protocol, and all subjects provided written, informed consent. Subjects were randomized using a centralized telephone-based system with a block size of 4 to receive either 600 mg of efavirenz or 300 mg of tenofovir DF in combination with the abacavir/lamivudine FDC tablet. Subjects with a suspected abacavir hypersensitivity reaction were permitted to switch from the FDC to a twice-daily lamivudine/zidovudine FDC tablet.
Subjects were assessed at screening, baseline, and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48. Laboratory assessments included HIV-1 RNA level, clinical chemical assessments, and hematologic assessment. CD4+/CD8+ lymphocyte subsets were counted at screening, baseline, and weeks 8, 16, 24, 32, 40, and 48. Pregnancy tests were administered to women of childbearing potential at screening, baseline, and weeks 24 and 48. Samples for resistance testing were obtained at baseline, at each visit from week 12 onward, and at suspected and confirmed virologic failure.
Virologic failure before week 24 was defined a priori as 2 consecutive HIV-1 RNA levels of >400 copies/mL obtained at least 24 weeks apart after 2 HIV-1 RNA measurements of <50 copies/mL. At week 24 or later, virologic failure was defined as 2 consecutive HIV-1 RNA levels of >400 copies/mL obtained at least 24 weeks apart.
A planned interim analysis was to be performed after the last enrolled subject completed 24 weeks, followed by a final 48-week analysis. However, after rapid accrual from January through June 2003, several sites reported an inadequate response or rebound within 812 weeks in the tenofovir DF arm. In response to these unsolicited reports, the study team conducted an urgent, unplanned analysis of data from 194 subjects with at least 8 weeks of virologic data as of 7 July 2003. The protocol definition of virologic failure was not applicable, because the majority of subjects had been recently enrolled; therefore, virologic nonresponse was defined before analysis as (1) a <2.0-log10 copies/mL decrease in HIV-1 RNA levels by week 8 (excluding subjects who achieved <50 copies/mL), (2) a rebound of 1.0 log10 copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions.
The results of this unplanned analysis, in addition to summaries of the HIV-1 RNA response of the 194 subjects by treatment arm, were reviewed by members of the GlaxoSmithKline study team and by J.E.G., who recommended termination of the tenofovir DF arm and the rapid dissemination of study results to investigators on 11 July 2003. No concerns were raised with the efavirenz arm, which continued unchanged.
Subjects initially randomized to the tenofovir DF arm were permitted to switch to an investigator-determined second-line regimen and to remain in follow-up. During this observational phase, study drugs and GlaxoSmithKline antiretrovirals were provided; other antiretrovirals were permitted but were not provided through the study.
Statistical analysis.
The primary objective was to compare the efficacy, safety, and tolerability of efavirenz versus tenofovir DF in combination with the abacavir/lamivudine FDC tablet over the course of 48 weeks. When the study was conceived, neither arm was considered to be the standard of care, and no clinical data existed on the tenofovir DF plus abacavir/lamivudine regimen. The study was designed to demonstrate superiority of the efavirenz arm at 48 weeks on the basis of the primary end point: the proportion of subjects with HIV-1 RNA levels <50 copies/mL using the intent-to-treat, exposed population (ITT) and considering all missing data as failure (ITT, M=F). Data from an interim 48-week analysis of a study that had an efavirenz, abacavir, and lamivudine arm and a stavudine, abacavir, and lamivudine arm were extrapolated for sample-size estimation [6]. A sample size of 180 subjects/arm would provide 90% power to detect a 0.17 difference between arms in the proportion of subjects achieving HIV-1 RNA levels <50 copies/mL at 48 weeks, with a type I error rate of 0.05 and inflation adjustment to account for a planned interim analysis.
The Cochran-Mantel-Haenszel test, stratified by screening HIV-1 RNA levels of <100,000 or 100,000 copies/mL, was used to compare virologic nonresponse between the 2 arms. HIV-1 RNA data from a planned ITT, M=F analysis of the complete efavirenz arm population are reported as proportions of subjects with HIV-1 RNA levels <50 and <400 copies/mL up to week 48. The tenofovir DF arm is reported until week 12, because most subjects discontinued or modified therapy by week 16. Changes in CD4+ cell count from baseline were assessed using an as-treated analysis, in which data obtained after a subject discontinued the original study medication were not included.
Observational data from subjects in the tenofovir DF arm who remained in the study are summarized up to 24 weeks after regimen switch using the ITT M=F methodology and allowing for regimen switches. Second-line regimens were defined as the first postswitch regimen that was continued for at least 30 days. Multiple logistic and linear regression analyses were used to explore independent predictors of second-line response, defined as observed HIV-1 RNA levels <50 copies/mL and changes in HIV-1 RNA levels 24 weeks after the switch. The following covariates were examined: age; race; baseline and preswitch HIV-1 RNA levels; baseline CD4+ cell count; the presence or absence of abacavir, tenofovir DF, zidovudine, or efavirenz in the second-line regimen; and days receiving the tenofovir DF regimen before switching. The presence or absence of the K65R mutation was explored in the subset with genotype data available at the time of switching. Stepwise selection was used in the model selection process, and variables with P < .3 were included in the final model.
Grade 2 or higher adverse events were coded on the basis of an adverse-event dictionary (Medical Dictionary for Regulatory Activities; US Food and Drug Administration), and laboratory testing was performed centrally (Quest Laboratories, Van Nuys, CA, and ViroLogic, South San Francisco, CA). Safety data are reported for both groups up to week 48. The majority of subjects in the tenofovir DF arm switched to a second-line regimen during this period, and these subjects are included in summaries of adverse event and laboratory data.
All reported P values are 2-sided; P values and confidence intervals (CIs) are unadjusted for interim analyses. All analyses were performed using SAS (version 8; SAS Institute) on a system of UNIX computers.
Viral resistance analysis.
All baseline and week 12 samples from subjects meeting nonresponse criteria with HIV-1 RNA levels >600 copies/mL were analyzed for genotype and phenotype using the PhenoSense GT assay (ViroLogic). Resistance mutations were those defined by the Drug Resistance Mutations Group of the International AIDS SocietyUSA, with the exception of V118I, which was not included. Phenotypic susceptibility break points are as defined by ViroLogic (4.5-fold for abacavir, 3.5-fold for lamivudine, 1.4-fold for tenofovir DF, and 2.5-fold for efavirenz).
Role of the funding source.
GlaxoSmithKline provided financial support and was involved in the study design, data collection, and analysis. The decision to submit the article for publication was a joint study team decision initiated by J.E.G. and was supported by the study team.
RESULTS
Study subjects.
A total of 460 subjects were screened, and 345 were randomized. The ITT population consisted of 340 randomized subjects who received 1 dose of study drug. The median baseline HIV-1 RNA level was 4.72 log10 copies/mL (range, 2.266.43 log10 copies/mL), and 30% had an HIV-1 RNA level 100,000 copies/mL. The median baseline CD4+ cell count was 251 cells/mm3 (range, 191171 cells/mm3). Baseline demographic characteristics were balanced between arms (table 1). The unplanned interim analysis was performed on a subset of 194 subjects with 8 weeks of virologic data available at the time of analysis.
Study subject disposition.
After 48 weeks, 42 (25%) of 169 subjects in the efavirenz arm had prematurely withdrawn. Those in the tenofovir DF arm were allowed to continue in follow-up on a second-line regimen after the unplanned interim analysis. After 48 weeks, 58 (34%) of 171 subjects in this arm had prematurely withdrawn (figure 1).
HIV-1 RNA level and CD4+ cell count.
In the unplanned interim analysis of 194 subjects, HIV-1 RNA levels declined rapidly in the majority of subjects in the efavirenz arm, whereas many in the tenofovir DF arm had rebound or insufficient response within 812 weeks (figure 2A and 2B). Virologic nonresponse occurred in 49% of subjects in the tenofovir DF arm versus 5% in the efavirenz arm (P < .001) (table 2). On the basis of these findings, investigators and subjects were immediately notified, and a protocol amendment was rapidly implemented. Subjects receiving tenofovir DF were allowed to switch to a second-line regimen at the discretion of the investigator.
Virologic nonresponse was further examined in post hoc subgroup and sensitivity analyses that used the unplanned analysis criteria. In subjects with baseline HIV-1 RNA levels <100,000 copies/mL, 35 (43.8%) of 80 subjects in the tenofovir DF arm met virologic nonresponse criteria, compared with 5 (6.8%) of 73 subjects in the efavirenz arm (P < .001). To explore the effect of the duration of follow-up, nonresponse criteria were applied to 125 subjects with at least 12 weeks of data. With this additional follow-up, nonresponse occurred in 30 (48%) of 63 subjects in the tenofovir DF arm versus 3 (5%) of 62 in the efavirenz arm (P < .001). Finally, in a sensitivity analysis that applied a less-stringent first nonresponse criterion of a 1.5-log10 copies/mL decrease in HIV-1 RNA levels by week 8, virologic nonresponse occurred in 41 (40%) of 102 subjects in the tenofovir DF arm versus 4 (4%) of 92 in the efavirenz arm (P < .001).
Longer term data were available for the efavirenz arm. In a planned ITT, M=F analysis, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL, and 127 (75%) of 169 achieved HIV-1 RNA levels <400 copies/mL after 48 weeks (figure 3A and 3B). The majority of subjects in the tenofovir DF arm switched regimens or withdrew before week 16, and data from after week 12 were censored (figure 3A and 3B). Subjects in the efavirenz arm had median increases in CD4+ cell counts of 111, 126, and 130 cells/mm3 after 8, 16, and 48 weeks, respectively, compared with increases of 62 and 101 cells/mm3 after 8 and 16 weeks in the tenofovir DF arm.
Adverse events and laboratory data.
Grade 2 or higher adverse events were reported in 114 (67%) of 169 subjects in the efavirenz arm and in 102 (60%) of 171 subjects in the tenofovir DF arm. These are summarized, along with grade 3 or higher laboratory abnormalities (table 3).
Resistance.
Baseline resistance was evaluated in 317 subjects. Genotypic mutations associated with NRTI, NNRTI, and primary PI resistance were detected in 3%, 6%, and 2% of subjects, respectively. Decreased phenotypic susceptibility to 1 drug within a class was noted in <1%, 18%, and 6% of subjects for NRTIs, NNRTIs, and PIs, respectively.
Genotypic and phenotypic resistance in the tenofovir DF arm was evaluated at baseline in 100 (98%) of 102 subjects included in the interim analysis and at week 12 in 41 (82%) of 50 subjects with nonresponse at the interim analysis. Week 12 samples from 9 subjects were not analyzed because of withdrawal before week 12, HIV-1 RNA levels that were too low for analysis, or failure to amplify virus.
Baseline genotypic resistance in the tenofovir DF arm was infrequent (table 4). At week 12, NRTI mutations were observed in all but 1 subject; 40 (98%) of 41 subjects had the M184V/I mutation, and 22 (54%) of 41 had both M184V/I and K65K/R. Baseline phenotypic resistance in the tenofovir DF arm was also uncommon; susceptibility to all NRTIs was observed in all 100 subjects. At week 12, phenotypic susceptibility to abacavir, lamivudine, and tenofovir was retained in 80%, 2%, and 95% of nonresponders, respectively.
Observational phase after switching.
After the interim analysis, 131 (77%) of 171 subjects in the tenofovir DF arm remained in follow-up and received a second-line regimen. These subjects were demographically similar to the overall population: 92% were male, the median age was 37.0 years (range, 17.069.0 years), 27% were black, 13% were Hispanic, and 60% were white. The median duration of tenofovir DF therapy before switching was 106.0 days (range, 29.0187.0 days). The median HIV-1 RNA level and CD4+ cell count at the time of switching were 3.26 log10 copies/mL (range, 1.696.28 log10 copies/mL) and 324 cells/mm3 (range, 191052 cells/mm3). At the time of switching, 24% and 41% were virologically suppressed to <50 and <400 HIV-1 RNA copies/mL, respectively. Of the 61 subjects with genotype data available at or before switching, 31 had a detectable K65R mutation.
Thirty unique regimens were used after the switch. Those used in at least 5% of subjects were efavirenz, abacavir, and lamivudine (n = 46); tenofovir DF, zidovudine, lamivudine, and abacavir (n = 18); efavirenz, zidovudine, and lamivudine (n = 13); efavirenz, zidovudine, lamivudine, and abacavir (n = 12); and efavirenz, zidovudine, lamivudine, and tenofovir DF (n = 7). The remaining regimens were classified into 4 exclusive categories: combinations that contained NNRTIs and NRTIs (n = 16); PIs and NRTIs (n = 12); NNRTIs, PIs, and NRTIs (n = 5); and NRTIs only (n = 2).
At 24 weeks after the switch, 101 (77%) of 131 subjects and 108 (82%) of 131 subjects achieved HIV-1 RNA levels of <50 and <400 copies/mL, respectively (ITT, M=F). Exploratory multivariate analyses examined independent predictors of response in the postswitch cohort and in a subset with genotype data. In the postswitch cohort with observed data (n = 113), the only statistically significant predictor of HIV-1 RNA levels <50 copies/mL at 24 weeks after the switch was baseline HIV-1 RNA level (odds ratio, 0.073 [95% CI, 0.0170.303]; P < .001). There were no significant predictors of HIV-1 RNA levels <50 copies/mL at 24 weeks after the switch in the genotyped subset (n = 53), and the K65R mutation was not associated with suppression to <50 copies/mL. In linear regression analyses that explored predictors of changes in HIV-1 RNA levels 24 weeks after switch, significant correlates were HIV-1 RNA level at the switch (parameter estimate [PE], -0.941; SE, 0.047; P < .001) and the use of zidovudine in the second-line regimen (PE, -0.192; SE, 0.094; P = .044), which was correlated with a greater decrease in HIV-1 RNA levels. In the genotyped subset, significant correlates of changes in HIV-1 RNA level were HIV-1 RNA level at the switch (PE, -0.910; SE, 0.093; P < .001) and the use of zidovudine in the second-line regimen (PE, -0.411; SE, 0.191; P = .036). The presence of the K65R mutation was not significantly correlated with decreases in HIV-1 RNA level.
DISCUSSION
In the present trial, treatment with once-daily tenofovir DF and abacavir/lamivudine FDC tablet was associated with an unprecedented rate of early virologic nonresponse accompanied by significant NRTI resistance, with detection of the K65R mutation in the majority of subjects and the M184V/I mutation in all but 1 subject. These findings are consistent with results of 2 small, uncontrolled trials that were concurrently studying the same regimen and reported early virologic failure in 33%58% of patients and similarly high rates of resistance [19, 20].
Several explanations for the poor response have been proposed, including clinical, pharmacokinetic, and virologic hypotheses. Although the dramatic findings of the present trial make it impossible to study this regimen further, some of these hypotheses can be refuted by existing data. Inadequate potency of once-daily abacavir and lamivudine does not explain the poor responsethis combination has demonstrated efficacy and durability when combined with efavirenz, both in the present study and in a large, randomized, double-blind trial [8]. Moreover, pharmacokinetic data support once-daily dosing of abacavir: the mean intracellular half-life of carbovir-triphosphate, abacavir's active metabolite, is >20 h [14].
Pharmacokinetic interactions do not explain these results, either. Tenofovir DF did not adversely affect plasma abacavir concentrations in a study of the single-dose regimen in healthy volunteers [21]. In a clinical trial of tenofovir DF, abacavir, and lamivudine, 32 (86%) of 37 subjects had adequate plasma trough concentrations of all 3 drugs, despite the poor response [20]. Interactions that affect intracellular concentrations of the active phosphorylated metabolites of these drugs also seem to be unlikely. In vitro studies in human peripheral blood mononuclear cells and T lukemic CEM lymphoblast cells found no changes in the phosphorylation of either drug, whether administered alone or in combination [22]. In a study of 15 HIV-infected subjects who received a regimen that included both abacavir and tenofovir DF, there were no changes in carbovir-triphosphate concentrations after the discontinuation of tenofovir DF and no changes in tenofovir-diphosphate concentrations after the discontinuation of abacavir [23].
The most likely explanation is the low genetic barrier to resistance produced by synergistic selection pressure from all 3 drugs for 2 point mutations, M184V and K65R. Both abacavir and tenofovir DF select for the K65R mutation, which reduces susceptibility to both drugs, as well as to lamivudine. M184V is selected for by lamivudine and abacavir, and it decreases susceptibility to both. Thus, the selection of 2 mutations, each of which may preexist as minority species, leads to virologic failure with this regimen. Although K65R was not universally detectable within 12 weeks in all subjects, clonal analysis of samples from selected subjects suggests the early presence of viruses containing mutations at either K65R or M184, followed by selection for viruses containing mutations at both sites [24]. If treatment with this regimen were continued, both mutations would presumably be detected. Further support for this hypothesis comes from a small, uncontrolled pilot trial of the combination of tenofovir DF, didanosine, and lamivudine in which 91% of subjects failed therapy [25]. Resistance issues were similar with this combination, given that didanosine also selects for K65R. Of those subjects for whom genotypic data were available, 100% had the M184V mutation and 50% had the K65R mutation.
While the present study was in progress, the interim results of AIDS Clinical Trial Group (ACTG) 5095 were reported, and they demonstrated that the triple-nucleoside regimen of zidovudine/lamivudine/abacavir was virologically inferior to a regimen that contained efavirenz and 2 or 3 nucleosides [10]. However, our finding of early nonresponse to tenofovir DF and abacavir/lamivudine appears to be a distinct phenomenon, considering the rapid development and high incidence of both virologic nonresponse and resistance. In ACTG 5095, 74% of subjects who received zidovudine/lamivudine/abacavir achieved suppression to <200 HIV RNA copies/mL at 48 weeks, whereas, in the present study, approximately one-half of subjects who received tenofovir and abacavir/lamivudine demonstrated nonresponse as early as 8 weeks into therapy. Futhermore, a combined analysis applied a modified nonresponse criteria to 6 trials that had zidovudine/lamivudine/abacavir arms and found nonresponse rates of 0%, 7%, 12%, 12%, 14%, and 24%, which were strikingly lower than that described with the tenofovir DF regimen studied in ESS30009 [26].
Despite the alarming results observed in the tenofovir DF arm, many subjects were able to achieve or maintain viral suppression in subsequent therapy. These observational data must be viewed with caution, because selection bias, the small sample size, and the short duration of follow-up limit their applicability. These subjects switched therapy early, and approximately one-fourth had HIV-1 RNA levels of <50 copies/mL at the time of switching. Conversely, several subjects who developed resistance, including the K65R mutation, after an early nonresponse did not remain in follow-up, and their outcome is unknown. Subjects in this cohort were also naive to both NNRTIs and PIs, so the availability of treatment options enhanced their likelihood of response. Treatment options for patients in whom the M184V and K65R mutations develop after the failure of regimens currently in use remains an important question that our study could not address.
It is clear from the present study that the 3-drug combination of abacavir, lamivudine, and tenofovir DF should not be used in clinical practice. The early failure of this regimen emphasizes the importance of treating patients on the basis of results of randomized, controlled trials rather than on assumptions about efficacy. This simple, convenient, and well-tolerated regimen was presumed to be effective on the basis of the potency of its component drugs and was already being used by some clinicians in clinical practice. Given the growing number of potent, well-studied combinations now available, there is no longer a rationale for the use of untested regimens outside of clinical trials in the treatment of therapy-naive HIV-infected patients.
ESS30009 INVESTIGATORS
Daniel F. Alvarez, Philadelphia, PA; Stephen L. Becker, San Francisco, CA; Nicholas Bellos, Dallas, TX; Daniel S. Berger, Chicago, IL; Michael J. Borucki, Tyler, TX; Philip Brachman, Atlanta, GA; John Brand, Dallas, TX; Robert O. Brennan, Lynchburg, VA; Alfred F. Burnside, Jr., Columbia, SC; Paul Cimoch, Fountain Valley, CA; Gregg Coodley, Portland, OR; Edwin DeJesus, Altamonte Springs, FL; Joseph DeSimone, Jr., Philadelphia, PA; Robin Dretler, Decatur, GA; Lael Duncan, Tacoma, WA; Victor Fainstein, Houston, TX; Judith Feinberg, Cincinnati, OH; Michael O. Frank, Milwaukee, WI; Gervais Frechette, New York, NY; Joel Gallant, Baltimore, MD; Jose A. Giron, Orlando, FL; Eliot Godofsky, Bradenton, FL; Mitchell Goldman, Indianapolis, IN; Stephen Green, Hampton, VA; Howard Grossman, New York, NY; Ross Hewitt, Buffalo, NY; Michael Hill, New Orleans, LA; Robert S. Jones, West Reading, PA; Francoise Kramer, Los Angeles, CA; Princy Kumar, Washington, DC; Anthony LaMarca, Fort Lauderdale, FL; Joseph Lang, Charlotte, NC; Stanley Lewis, Houston, TX; F. Brobson Lutz, New Orleans, LA; Cheryl McDonald, Fort Worth, TX; Miguel Mogyoros, Denver, CO; Robert A. Myers, Phoenix, AZ; Jeffrey Nadler, Tampa, FL; Ronald G. Nahass, Hillsborough, NJ; David Parks, St. Louis, MO; Robert Peskind, Fort Collins, CO; Gerald Pierone, Vero Beach, FL; Peter Piliero, Albany, NY; Julia Torres, Fort Lauderdale, FL; Bruce Rashbaum, Washington, DC; Frank S. Rhame, Minneapolis, MN; Gary Richmond, Fort Lauderdale, FL; Allan E. Rodriguez, Miami, FL; Jorge Rodriguez, Newport Beach, CA; Michael Sands, Jacksonville, FL; Kunthavi Sathasivam, Washington, DC; Robert Schwartz, Fort Myers, FL; Peter Shalit, Seattle, WA; Gary Simon, Washington, DC; Roy T. Steigbigel, Stony Brook, NY; Corklin Steinhart, Miami, FL; Donna Sweet, Wichita, KS; Karen Tashima, Providence, RI; Winkler Weinberg, Atlanta, GA; Bruce Williams, Albuquerque, NM; Sally Williams, Vancouver, WA; Peter Wolfe, Beverly Hills, CA; Benjamin Young, Denver, CO; and John Zurlo, Hershey, PA.
Acknowledgments
We thank the patients who volunteered to participate in the study and all investigators and study coordinators who conducted the trial; Julie Fleming, Shannon Gooding, Jaime Hernandez, Douglas Manion, Martha Anne A. Moore, Trevor Scott, Jessica Weidner, and Brian Wine (GlaxoSmithKline ESS30009 Study Team), for their contributions; and David Irlbeck, Randall Lanier, Daniel McClernon, and Marty St. Clair (GlaxoSmithKline Virology), for their assistance with genotypic analysis and interpretation.
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