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Induction HIV Therapy: Trizivir/Efavirenz
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"Induction With Abacavir/Lamivudine/Zidovudine Plus Efavirenz for 48 Weeks Followed by 48-Week Maintenance With Abacavir/Lamivudine/Zidovudine Alone in Antiretroviral-Naive HIV-1-Infected Patients"
"..... This study is the first demonstration of success for an induction-maintenance approach to HIV therapy. ABC/3TC/ZDV therapy successfully maintained virologic and immunologic responses in patients treated for 48 weeks with EFV-based quadruple therapy, which establishes induction-maintenance as a viable treatment option for HIV-1 infection....
.....we now ask how to incorporate this treatment strategy into current clinical practice. For the regimen used here, much depends on the results of the ACTG 5095 trial, which compares 3TC/ZDV + EFV with ABC/3TC/ZDV + EFV.4 Should the 4-drug regimen prove superior as initial therapy, it would then follow that simplification would be a reasonable option for patients completing 48 weeks of quadruple therapy. Furthermore, this trial should be the impetus to explore induction-maintenance strategies further in treatment-naive and treatment-experienced patients....."
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 39(3) 1 July 2005
Markowitz, Martin MD*; Hill-Zabala, Christina PharmD; Lang, Joseph MD; DeJesus, Edwin MD; Liao, Qiming PhD; Lanier, E Randall PhD; Davis, E Anne PharmD, MS; Shaefer, Mark PharmD; for the ESS40013 Study Team
From *The Aaron Diamond AIDS Research Center, New York, NY; GlaxoSmithKline, Research Triangle Park, NC; ID Consultants, Charlotte, NC; and Orlando Immunology Center, Orlando, FL.
Received for publication February 17, 2005; accepted May 2, 2005.
Funded by GlaxoSmithKline.
Presented in part at the Second International AIDS Society Conference on Pathogenesis and Treatment, July 13-16, 2003, Paris, France, and at the XV International AIDS Conference, July 11-16, 2004, Bangkok, Thailand.
Abstract
Background: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen.
Methods: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV + EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase.
Results: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56% ≥100,000 copies/mL) and 210 cells/mm3 (48% <200 cells/mm3), respectively. No significant differences were noted between ABC/3TC/ZDV + EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing = failure]; P = 0.697) or time to treatment failure (P = 0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV + EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV + EFV group; P = 0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV + EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P = 0.057).
Conclusions: After induction with ABC/3TC/ZDV + EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.
RESULTS
Patient Disposition
Four hundred forty-eight patients were enrolled in the induction phase. As shown in Table 1, patients were predominantly male, approximately half were nonwhite, 56% had a baseline HIV-1 RNA level ≥100,000 copies/mL, and 48% enrolled with a CD4 count <200 cells/mm3. Thirty-seven percent (166 of 448 patients) discontinued treatment during the induction phase (see Fig. 1), primarily because of adverse events (n = 55 [12.3%]), withdrawn consent (n = 33 [7.4%]), and loss to follow-up (n = 28 [6.3%]). Thirty patients (6.7%) were switched from EFV to nevirapine during the induction phase because of intolerability and were included in the analysis.
A total of 282 patients were randomized to continue quadruple therapy (n = 141) or to discontinue EFV (n = 141). Baseline characteristics for the 2 groups are essentially identical and comparable to those of the original population (see Table 1). Most (87%) patients entering the maintenance phase completed the 96-week trial. Rates of discontinuation during the maintenance phase were similar between treatment groups (ABC/3TC/ZDV + EFV = 15%, ABC/3TC/ZDV = 11%; see Fig. 1). More subjects in the quadruple therapy group discontinued the study because of nonvirologic reasons (eg, adverse events, lost to follow-up), and more subjects in the ABC/3TC/ZDV group discontinued because of virologic failure; however, these differences were not statistically significant (P > 0.05).
Virologic and Immunologic Response
Sixty-one percent of patients who entered the induction phase had HIV-1 RNA levels <50 copies/mL at week 48 (ITT M = F). Ninety percent of patients who completed the induction phase had HIV-1 RNA levels <50 copies/mL at week 48, consistent with the large number of study discontinuations attributable to nonvirologic reasons. No statistically significant differences in proportions reaching undetectable HIV-1 RNA levels were observed at 48 weeks between different baseline HIV-1 RNA strata, suggesting that the induction regimen was equally effective across diverse baseline HIV-1 RNA levels. The median time to reach an HIV-1 RNA level <50 copies/mL was shorter (approximately 16 weeks) in patients with a baseline HIV-1 RNA level <750,000 copies/mL than in patients in the highest HIV-1 RNA strata (35 weeks), however.
At 96 weeks, 79% of patients receiving quadruple therapy and 77% receiving ABC/3TC/ZDV maintenance therapy had HIV-1 RNA levels <50 copies/mL (ITT M = F; P = 0.7). This established ABC/3TC/ZDV as noninferior to continued quadruple therapy (95% confidence interval [CI]: -8.6%, 5.7%). No between-treatment difference was observed in time to treatment failure (log-rank test, P = 0.749). Virologic failure was rare in both groups (16 patients in the ABC/3TC/ZDV group, 8 patients in the quadruple therapy group; P = 0.134).
Patients remaining on therapy during the induction phase experienced a median increase of 179 CD4 T cells/mm3. Virologic response rates were influenced by the magnitude of the baseline CD4 count: at week 48, 97% of patients with baseline CD4 cell counts ≥350 cells/mm3 had HIV-1 RNA levels <50 copies/mL compared with 84% of patients with baseline CD4 cell counts <50 cells/mm3 (P = 0.012). No significant difference in virologic response was observed between groups who had an intermediate baseline CD4 cell count (50-199 cells/mm3 and 200-349 cells/mm3).
Median CD4 T-cell counts at the time of randomization to maintenance were 411 cells/mm3 for the ABC/3TC/ZDV group and 395 cells/mm3 for patients remaining on quadruple therapy. CD4 T-cell counts continued to increase during maintenance to median levels of 453 cells/mm3 and 425 cells/mm3 in the respective treatment groups.
Adverse Events and Adherence
Mild to moderate treatment-related adverse events were common during induction, especially nausea (38%), fatigue (24%), vivid dreams (20%), dizziness (18%), rashes (16%), and sleep disturbances (15%). Adverse events leading to discontinuation in >1% of patients were suspected ABC hypersensitivity reaction (32 patients [7%]) and rash (9 patients [2%]). New adverse events were much less common during the maintenance phase, although they were slightly more common in patients continuing quadruple therapy (15% vs. 6%). Treatment discontinuation was more frequent in the quadruple therapy group for reasons other than virologic failure.
Total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels all increased during the induction phase (median increases: 30 mg/dL, 15 mg/dL, and 11 mg/dL, respectively). During maintenance, total cholesterol, LDL cholesterol, and triglycerides were persistently elevated in the quadruple therapy group but decreased substantially in the ABC/3TC/ZDV group. At week 96, median changes from week 48 were -22 mg/dL and +3 mg/dL for total cholesterol, -16.5 mg/dL and +1 mg/dL for LDL, and -16 and +5 mg/dL for triglycerides for the ABC/3TC/ZDV and quadruple treatment groups, respectively.
Adherence to therapy was excellent in both treatment groups. At week 96, 88.8% of patients on ABC/3TC/ZDV reported perfect adherence on the PMAQ-3W versus 79.6% of patients in the quadruple therapy group (P = 0.057).
Treatment-Emergent Viral Resistance
Eighteen of 22 patients meeting criteria for virologic failure during the induction phase had plasma samples available for genotypic analysis. Of these, 2 had significant baseline mutations associated with study drugs (M184V [n = 1] and K103N [n = 1]). The most common viral resistance pattern at failure (10 of 18 patients) included point mutations associated with resistance to EFV and/or 3TC (M184V alone [n = 1]; K103N alone [n = 4]; M184V and K103N [n = 1]; M184V, K103N, and Y188L [n = 1]; M184V, K103N, and P225H [n = 2]; and M184V and G190S [n = 1]). Two patients had treatment-emergent mutations associated with resistance to EFV, 3TC, and ZDV (M184V, K103N, M41L, D67N, L210W, and T215Y [n = 1] and M184V, K103N, D67D/N, and V118V/I [n = 1]). Two patients had the K65R mutation selected on therapy (K65R, V118I, and G190S [n = 1] and K65R/K, M184V/M, K103N, and Y188H/Y [n = 1]); both had high baseline HIV-1 RNA levels (952,835 copies/mL and 331,154 copies/mL) and low baseline CD4 cell counts (6 cells/mm3 and 8 cells/mm3).
During maintenance, 24 patients (16 in the ABC/3TC/ZDV group and 8 in the quadruple therapy group; P = 0.134) had confirmed HIV-1 RNA levels >500 copies/mL (n = 10) or levels >500 copies/mL at the last study visit (see Table 3B). Of these patients, 19 had paired genotype samples at baseline and virologic failure. One of the 19 had a significant baseline mutation associated with study drugs (K103N). The most common mutation pattern at virologic failure was M184V alone (6 patients receiving the ABC/3TC/ZDV regimen and 2 receiving the quadruple regimen). M184V and thymidine analogue-associated mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) were seen in 4 patients in the ABC/3TC/ZDV group (M184V and D67D/N [n = 1]; M184V, D67D/N, and K70R/K [n = 1]; M184V and T215F [n = 1]; and M184V, D67N, K70R/K, and K219E/K [n = 1]). Three patients (1 receiving ABC/3TC/ZDV therapy and 2 receiving quadruple therapy) had HIV variants with EFV resistance mutations (K103N and M184V [n = 1] in the triple therapy group and K103N [n = 1] and K103N and P225P/H [n = 1] in the quadruple therapy group).
AUTHOR DISCUSSION
This study is the first demonstration of success for an induction-maintenance approach to HIV therapy. ABC/3TC/ZDV therapy successfully maintained virologic and immunologic responses in patients treated for 48 weeks with EFV-based quadruple therapy, which establishes induction-maintenance as a viable treatment option for HIV-1 infection.
We chose a 48-week induction phase for a number of reasons. Given the expectation that patients with high baseline HIV-1 RNA levels would be enrolled, we anticipated that shorter induction periods could limit the number of patients eligible for randomization to maintenance. Furthermore, the induction-maintenance concept is partially predicated on reducing the pool of randomly generated preexisting resistant variants during initial treatment. Given that the half-life of the second phase of HIV-1 RNA decay after HAART initiation is, on average, 2 to 4 weeks,23,24 we hypothesized that treatment of approximately 12 half-lives, or approximately 48 weeks, would result in a substantially reduced residual viral burden at the time of treatment simplification. Additionally, we believe that success in this trial, as compared with previous failures, was achieved by using an effective and well-tolerated triple combination therapy during maintenance.
The large number of treatment discontinuations during induction is problematic. In a recent trial comparing EFV-based HAART with triple-nucleoside therapy for initial treatment of HIV-1, only 7% of patients discontinued therapy by week 32,4 despite one of the treatment groups being ABC/3TC/ZDV plus EFV. A discontinuation rate of 37% in the present study is difficult to explain. That these studies enrolled patients contemporaneously raises the question as to whether there was some selection bias in the selection and referral of patients in these competing trials. The specific 4-drug regimen in this trial failed to improve initial response rates to antiviral therapy, in contrast to established 3-drug regimens.4,6,7 Response rates in patients at all strata of baseline HIV-1 RNA levels were high and demonstrate the potency of this particular combination. We were encouraged by the low rate of virologic failure during induction. Nevertheless, it was surprising that 2 patients experienced failure with viruses that included the K65R mutation despite inclusion of ZDV in the regimen.25 One potential explanation is documented ART nonadherence for both patients, likely resulting in periods of exposure to ABC in the absence of ZDV because of the shorter half-life of ZDV and its anabolites. Additionally, these patients had low baseline CD4 cell counts (<10 cells/mm3) and high HIV-1 RNA levels (>300,000 copies/mL) at treatment initiation, which may increase the risk of K65R emergence.7
In assessing the results of this trial, we must ask what benefits treatment simplification provided. In the short term, a reduction in treatment-related adverse events and improved adherence accompanied triple-nucleoside therapy, as did improvement in fasting lipid profiles. Furthermore, in the face of the emergence of drug-resistant virus, treatment options in all drug classes (NRTI, NNRTI, and PI) remained available for use in most of the ABC/3TC/ZDV-treated patients who experienced virologic failure. It is important to note that during maintenance, treatment-emergent drug resistance was more common in the ABC/3TC/ZDV group than in the quadruple therapy group, although the difference did not reach statistical significance.
Having established the viability of the induction-maintenance approach, we now ask how to incorporate this treatment strategy into current clinical practice. For the regimen used here, much depends on the results of the ACTG 5095 trial, which compares 3TC/ZDV + EFV with ABC/3TC/ZDV + EFV.4 Should the 4-drug regimen prove superior as initial therapy, it would then follow that simplification would be a reasonable option for patients completing 48 weeks of quadruple therapy. Furthermore, this trial should be the impetus to explore induction-maintenance strategies further in treatment-naive and treatment-experienced patients. Within a relatively short time frame, HIV-1 infection has been transformed from a near-uniformly fatal infection to one that is chronic and treatable; thus, it becomes imperative that new and creative ways to manage this condition are explored to optimize therapeutic outcomes.
METHODS
Study Population
HIV-1-infected adults were eligible if they were antiretroviral naive (<2 weeks of prior treatment with NRTIs and/or PIs and no prior exposure to NNRTIs) and had an HIV-1 RNA level ≥5000 copies/mL. Laboratory exclusion criteria included hemoglobin <10 g/dL (male) or <9 g/dL (female), absolute neutrophil count <1000 cells/mm3, platelet count <75,000 cells/mm3, transaminases >5 times the upper limit of normal (ULN), serum pancreatic amylase >1.5 times the ULN, or estimated creatinine clearance <40 mL/min. Female patients were excluded if they were pregnant or breastfeeding.
Study Design TOP
ESS40013 was a randomized, open-label, 96-week study conducted at 40 clinical sites in the United States. The study was conducted in 2 phases: induction and maintenance. Enrollment occurred between March and November 2001.
During the 48-week induction period, all patients were treated with 1 fixed-dose tablet of ABC (300 mg)/3TC (150 mg)/ZDV (300 mg) (Trizivir; GlaxoSmithKline, Research Triangle Park, NC) twice daily and with EFV (600 mg, Sustiva; Bristol-Myers Squibb, New York, NY) once daily. Patients with HIV-1 RNA levels <50 copies/mL at weeks 36 and 44 were eligible for randomization into the 48-week maintenance phase. Randomization was stratified based on an HIV-1 RNA level at study entry (baseline) of <100,000 copies/mL or ≥100,000 copies/mL. Patients were centrally randomized (1:1 ratio) to continue quadruple therapy or to simplify to ABC/3TC/ZDV alone.
Pretreatment evaluations included a clinical assessment and laboratory evaluations (plasma HIV-1 RNA, T-lymphocyte subsets, hematology, clinical chemistries, serum pregnancy test, and collection of a plasma sample later analyzed for viral resistance mutations).
On-study evaluations included clinic visits at baseline and weeks 2, 4, 8, 16, 24, 36, 44, and 48 for the induction phase and at weeks 56, 64, 72, 84, and 96 for the maintenance phase. HIV-1 RNA was assessed at each visit except week 2 using the Roche Amplicor HIV-1 Ultrasensitive Assay, version 1.5 (Roche Diagnostics, Pleasanton, CA). Clinical chemistries, hematology profiles, and T-cell subsets were performed at all visits except weeks 2 and 44. Fasting lipid profiles were measured at baseline and weeks 48 and 96. Serum pregnancy testing was performed at baseline, week 96, and whenever pregnancy was suspected. Samples for possible viral resistance testing were collected at baseline and at confirmation of virologic failure. Safety was assessed through the reporting of adverse clinical events and abnormal laboratory values. The severity of adverse events was assessed by the investigator using the Division of AIDS toxicity grading scale (1992). No substitutions were allowed for ABC/3TC/ZDV. Patients who were intolerant to EFV were able to substitute nevirapine (Viramune; Boehringer Ingelheim, Ridgefield, CT) and remain in the study.
Virologic failure was defined as failure to suppress the HIV-1 RNA level to <50 copies/mL by week 36 or a confirmed HIV-1 RNA level >500 copies/mL after suppression to <50 copies/mL. All patients who met virologic failure criteria were withdrawn from the study. Treatment failure was defined as virologic failure, discontinuation because of toxicity, clinical disease progression, or death.
The protocol and informed consent forms were reviewed and approved by the institutional review boards (IRBs) at each of the participating sites. All patients provided written informed consent.
Analyses
The primary objective was to compare the durability of HIV-1 RNA suppression with ABC/3TC/ZDV compared with ABC/3TC/ZDV + EFV during the 48-week maintenance phase after a 48-week induction phase with a 4-drug regimen composed of ABC/3TC/ZDV + EFV. The primary end points were the proportions of patients with HIV-1 RNA <50 copies/mL at week 96 and time to treatment failure during the maintenance phase. Secondary objectives included safety and tolerability, efficacy, self-reported medication adherence, and development of viral resistance. A sample size of 280 patients randomized to the maintenance phase provided 80% power to demonstrate noninferiority of triple-nucleoside therapy compared with the quadruple regimen based on proportions of patients with an HIV-1 RNA level <50 copies/mL at week 96 using a noninferiority margin of 12% and a type 1 error rate of 0.05, assuming a success rate of 85% for both treatment groups.
The intent-to-treat (ITT) population was used for all analyses. For the induction phase, the ITT population consisted of all patients enrolled in the study. For the maintenance phase, the ITT population included all randomized patients. Analysis methods for the HIV-1 RNA data were (1) missing equals failure (M = F), which considered all missing data as failures, and (2) observed (Obs), which did not include missing data. Adverse events were coded by an adverse event dictionary (MIDAS), and laboratory testing was performed centrally (Covance Laboratories, Indianapolis, IN and Virco, Mechelen, Belgium). Adherence to therapy was measured using the Patient Medication Adherence Questionnaire, version 3W (PMAQ-3W) at weeks 4, 24, 48, 56, and 96. The questionnaire is a self-reported measure of medication adherence with a recall period of the last 3 days and weekend before the visit.21 Viral resistance testing at baseline and at the time of virologic failure was attempted for all patients who met virologic failure criteria and for patients with an HIV-1 RNA level ≥500 copies/mL at their last study visit. Resistance-associated mutations are those defined by the Drug Resistance Mutations Group of the International AIDS Society.22 All analyses were performed using SAS (version 8; SAS Institute, Cary, NC) on UNIX computers.
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