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Abacavir Once or Twice Daily Combined With Once-Daily Lamivudine and Efavirenz for the Treatment of Antiretroviral-Naive HIV-Infected Adults: Results of the Ziagen Once Daily in Antiretroviral Combination Study

Moyle, Graeme J MD, MBBS*; DeJesus, Edwin MD; Cahn, Pedro MD; Castillo, Steve A MSc§; Zhao, Henry PhD§; Gordon, David N MB, ChB; Craig, Charles PhD; Scott, Trevor R PhD§for the Ziagen Once-Daily in Antiretroviral Combination Therapy (CNA30021) Study Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1st, 2005 - Volume 38 - Issue 4 - p 417-425
doi: 10.1097/01.qai.0000147521.34369.c9
Clinical Science
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The long intracellular half-life of abacavir (ABC) supports its once-daily use, and this would be expected to simplify treatment if ABC could be given as part of a complete once-daily regimen. A randomized double-blind clinical trial compared the efficacy and safety of 600 mg of ABC administered once daily (n = 384) versus 300 mg of ABC administered twice daily (n = 386) in combination with 300 mg of lamivudine (3TC) and 600 mg of efavirenz (EFV) administered once daily in antiretroviral-naive patients over 48 weeks. The baseline median plasma HIV-1 RNA level was 4.89 log10 copies/mL (44% with viral load >100,000 copies/mL), and the median CD4+ cell count was 262 cells/mm3. ABC administered once daily was non-inferior to the twice-daily regimen, with 66% and 68% of patients in these respective treatment arms achieving a confirmed plasma HIV-1 RNA level <50 copies/mL (95% confidence interval: −8.4%, 4.9%). The ABC once-daily and twice-daily regimens were similar with respect to infrequency of virologic failure (10% vs. 8%), emergence of resistance mutations, CD4+ cell increases from baseline (median, 188 vs. 200 cells/mm3), safety profile, and incidence of ABC-related hypersensitivity reactions (9% vs. 7%). ABC administered once daily in combination with 3TC and EFV administered once daily was non-inferior to the ABC twice-daily dosing schedule when combined with 3TC and EFV over 48 weeks.

From the *Chelsea and Westminster Hospital, London, United Kingdom; †IDC Research, Altamonte Springs, FL; ‡Fundacion HUESPED, Buenos Aires, Argentina; §GlaxoSmithKline, Research Triangle Park, NC; and ∥GlaxoSmithKline, London, United Kingdom.

Received for publication May 20, 2004; accepted September 28, 2004.

Funded by a grant from GlaxoSmithKline.

The results of this study were presented in part in abstract H-1722b at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 14-17, 2003.

S. Castillo, H. Zhao, C. Craig, D. Gordon, and T. Scott declare their financial conflict of interest as a result of their affiliations with GlaxoSmithKline. G. Moyle has received financial compensation for (inter)national consultancies, grant receipt, and speakers' bureau relations from GlaxoSmithKline, Bristol-Myers Squibb, and Merck. E. DeJesus has received financial compensation for (inter)national consultancies, speakers' bureaus, and research grants from Roche Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck & Co, and Ortho-Biotech. P. Cahn has received financial compensation for (inter)national consultancies and lectures from Abbott, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, and Serono.

G. Moyle, E. DeJesus, and P. Cahn made substantial contributions to the acquisition of the clinical trial data as well as the drafting and revision of the manuscript for important intellectual and medical content. S. Castillo, H. Zhao, C. Craig, D. Gordon, and T. Scott made equal contributions to the clinical trial conception and design, analysis, and interpretation of the data; drafting of the manuscript; and administrative, technical, and material support for the conduct of the clinical trial.

Reprints: Graeme J. Moyle, Chelsea and Westminster Hospital, HIV Clinic, 369 Fulham Road, London SW10 9NH, United Kingdom (e-mail: gm@moyleg.demon.co.uk).

Current clinical management of HIV-1 disease necessitates use of a multidrug regimen generally including 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent.1 Good adherence to potent antiretroviral therapy is critical in achieving a successful outcome. High pill burdens, dosing frequencies, risk of adverse events (AEs), drug interactions, and inconvenient dietary restrictions all potentially affect adherence and, ultimately, treatment efficacy.2,3

Patient preference surveys suggest that persons with HIV may prefer compact once-daily regimens if the efficacy and tolerability of these regimens are similar to those of the twice-daily standard of care regimens.3 Some antiretroviral drugs that have half-lives suitable for administration once a day (OAD) cannot be used together because of drug interactions and dietary restrictions. An expansion in the number of antiretroviral drugs approved for OAD dosing increases the potential for OAD therapy to become the preferred initial therapy.

The NRTI abacavir (ABC) has demonstrated durable efficacy as a component of numerous regimens administered at a dose of 300 mg twice daily.4-6 A multidrug combination of 300 mg of ABC administered twice daily with lamivudine (3TC) and efavirenz (EFV) has been compared with 300 mg of zidovudine (ZDV) administered twice daily with 3TC and EFV and has resulted in similarly potent and durable virologic suppression (<50 copies/mL), superior CD4+ cell recovery, and good tolerability, including an improved hematologic profile over 48 weeks.7 Recent pharmacokinetic studies in HIV-1-infected adults have shown that the active drug moiety of ABC, carbovir triphosphate (CBV-TP), has a long intracellular half-life (>20 hours) that would support OAD dosing of 600 mg of ABC.8-10 A small clinical study in which 600 mg of ABC administered OAD was compared with 300 mg of ABC 300 administered twice daily suggested that ABC could be administered OAD and supported further investigation of this dosing schedule.11 The Ziagen Once Daily in Antiretroviral Combination (ZODIAC) therapy study was a noninferiority clinical trial conducted over 48 weeks that compared the efficacy and safety of triple drug therapy with 600 mg of ABC administered OAD versus 300 mg of ABC administered twice daily, combined with OAD 3TC and EFV, in the treatment of antiretroviral-naive adults.

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METHODS

Patients

Male and female outpatients with HIV-1 infection who were at least 18 years of age were eligible for enrollment. Patients could be antiretroviral-naive or have limited experience (less than 14 days of ZDV monotherapy and naive to all other NRTIs, nonnucleoside reverse transcriptase inhibitors [NNRTIs], and protease inhibitors [PIs]) but were required to have plasma HIV-1 RNA levels >400 copies/mL and CD4+ cell counts of >50 cells/mm3 within 21 days before study enrollment.

Patients were excluded if they had a clinically active diagnosis of AIDS, a malabsorption syndrome that could interfere with drug absorption, or acute or clinically significant chronic active hepatitis; required radiation therapy, cytotoxic agents, or immunomodulating agents within 4 weeks of study entry; received an HIV vaccine within 3 months of study entry; or had a history of allergy or hypersensitivity to any of the study drugs

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Study Design and Treatment

This phase 3 1:1 randomized, double-blind, multicenter, international study was conducted between June 2001 and March 2003 at 120 outpatient sites in the United States (70 sites), Canada (12 sites), Spain (6 sites), Brazil (6 sites), Denmark (5 sites), Germany (5 sites), Poland (5 sites), Argentina (2 sites), Mexico (2 sites), and the United Kingdom (2 sites). Enrollment was stratified at screening by plasma HIV-1 RNA to 1 of 2 strata (≤100,000 and >100,000 copies/mL). Treatment was assigned by a centralized randomization system.

Patients were randomized to receive 1 300-mg ABC tablets administered twice daily plus 2 ABC placebo tablets OAD or 2 300-mg ABC tablets administered OAD plus 1 ABC placebo tablets administered twice daily for at least 48 weeks. Open-label background therapy of 2 150-mg 3TC tablets and 3 200-mg EFV capsules administered OAD was also supplied. Switches to background therapy were allowed to manage drug intolerance. If a patient switched randomized therapy, discontinued randomized therapy (ABC), or added a fourth agent, the patient would be considered have treatment failure in the primary analysis. ABC (Ziagen) 300-mg tablets and matching placebos and 3TC (Epivir) 150-mg tablets were supplied by GlaxoSmithKline (Research Triangle Park, NC). EFV (Sustiva or Stocrin) was supplied by Bristol-Myers Squibb or Merck Research Laboratories depending on the geographic location of the study site.

All patients provided written informed consent, and the protocol was approved by the institutional review boards or ethics committees at each study site.

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Efficacy Assessment

The primary efficacy measure was the comparison of the proportion of patients with plasma HIV-1 RNA <50 copies/mL at week 48 adjusted by randomization strata (screening plasma HIV-1 RNA ≤100,000 copies/mL vs. >100,000 copies/mL). The analysis was based on the intent-to-treat (ITT) exposed population, which included all patients exposed to at least 1 dose of any study drug. A study responder at 48 weeks was defined as a patient who had achieved confirmed plasma HIV-1 RNA <50 copies/mL and had not yet lost virologic response by week 48 as defined by the time to loss of virologic response (TLOVR) algorithm. The TLOVR algorithm is a composite of all available safety and antiviral activity data from all subjects enrolled in the trial through 48 weeks of treatment.

By the TLOVR algorithm, a study responder was defined as a patient who had confirmed viral suppression (2 consecutive plasma HIV-1 RNA measurements <50 copies/mL) and remained suppressed (no confirmed viral rebound measurements) by week 48 of the trial. Any other event occurring at any time during the trial that required a patient to stop randomized treatment or resulted in plasma HIV RNA >50 copies/mL classified the patient as a study nonresponder. Furthermore, the study nonresponders were classified into 2 groups. The virologic failure group consisted of patients with confirmed viral rebound >50 copies/mL and patients who never achieved viral suppression by week 48; these treatment outcomes were solely determined by the plasma HIV RNA assessments. The nonvirologic failure group consisted of any patients who prematurely discontinued randomized treatment because of other reasons, such as AEs, consent withdrawn, protocol violations, clinical progression, or other reasons (eg, nonadherence). Cumulative antiviral efficacy was measured as integrated decrease in plasma HIV-1 RNA, defined as average area under the curve minus baseline (AAUCMB). Immunologic efficacy was measured by absolute change from baseline CD4+ and CD8+ cell counts at 48 weeks and the time-weighted average increase in CD4+ cell counts, defined as the average area under the CD4+ cell count curve minus baseline stratified by time on treatment.

HIV-1 RNA levels were performed at screening; day 1; and weeks 2, 4, 8, 12 and every 12 weeks thereafter until the last patient enrolled reached 48 weeks of treatment as well as at a 4-week posttreatment follow-up visit. Roche Amplicor Standard PCR Assay (version 1.5; Roche Diagnostic Systems, Branchburg, NJ, lower limit of detection, LLOD = 400 copies/mL) plasma HIV-1 RNA measurements reporting less than 50,000 copies/mL were reassayed using the Roche UltraSensitive PCR Assay (version 1.5; LLOD = 50 copies/mL).

Any HIV-1 RNA measurement that exceeded the analysis range of the Roche UltraSensitive PCR Assay was reassayed and reported using the Roche Amplicor Standard PCR Assay.

Virologic failure was defined as patient failure to achieve and maintain confirmed (2 consecutive assessments) plasma HIV-1 RNA <50 copies/mL through 48 weeks of randomized treatment.

CD4+ and CD8+ lymphocyte cell counts were analyzed by flow cytometry and performed at the same study visits as viral load testing.

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Virology Assessments

All genotypic analyses were carried out at GlaxoSmithKline by trained scientific staff using the ViroSeq HIV-1 Genotyping System, version 2.5 (Abbott Laboratories, Abbott Park, IL). The reverse transcriptase (RT) sequence data were presented.

All phenotypic data were generated under contract by ViroLogic (South San Francisco, CA). The susceptibility of the HIV-1 RT coding region to select RT inhibitors was assessed using a recombinant virus assay, PhenoSense HIV (ViroLogic).

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Safety Assessment

Patients were monitored for AEs, laboratory abnormalities, and any HIV-related illnesses at each study visit. AEs were classified as nonserious if they were unfavorable or demonstrated unintended signs or symptoms that were not life threatening and did not incur disability/incapacity, inpatient hospitalization, or prolongation of existing hospitalization. Conversely, AEs were classified as serious if they incurred any of these manifestations or resulted in death. Patients who experienced National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) grade 4 toxicities12 were withdrawn from the study if the event was attributed to study drugs, as were patients who failed to achieve resolution of DAIDS grade 3 toxicities12 after interruption of therapy. A hypersensitivity reaction (HSR) to ABC was considered when the multiorgan signs and symptoms described by Cutrell et al13 were observed. ABC HSR symptoms were solicited to ensure full collection of data. In this study, all suspected HSRs were considered serious adverse events (SAEs) regardless of whether or not they fulfilled the definition of serious. All patients who were diagnosed with ABC HSRs were to discontinue the randomized study drug (ABC once daily or twice daily) permanently and be followed until resolution of HSR symptoms. Patients with ABC HSRs were afforded the option of switching randomized ABC for an alternate drug (eg, ZDV or stavudine [d4T]) or discontinuing from the study. All patients who discontinued randomized treatment for any reason were classified as experiencing study treatment failure at the time of discontinuation.

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Statistical Analysis

A total of 730 patients (365 patients in each treatment group) were planned for enrollment. Seven hundred thirty patients with a 1:1 randomization would provide 90% power to assess the noninferiority of ABC administered OAD compared with ABC administered twice daily at the 0.05 level of significance. This calculation assumed identical 50% success rates in the treatment groups. Noninferiority was defined as a 2-sided 95% confidence interval (CI) that excluded differences as large as 12% in the direction of inferiority of the ABC OAD group.

The noninferiority margin (δ) of 12% was largely based on HIV clinicians' judgment as well as on discussions with independent reviewers. The noninferiority margin represents the maximum effect with respect to the primary clinical outcome that one is willing to give up in return for the other benefits of the new therapy.14 To establish noninferiority, the 2-sided 95% CI should lie entirely to the right of the value of −12%. Establishment of noninferiority confirms that the treatment under study was no less effective in suppressing viral replication than the established comparator treatment.15-17

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RESULTS

Patient Characteristics and Disposition

Seven hundred seventy adult patients were randomized and received 600 mg of ABC administered OAD (n = 384) or 300 mg of ABC administered twice daily (n = 386) in combination with 3TC and EFV. A total of 649 (84%) of 770 patients completed at least 48 weeks on study, with 326 (85%) patients in the ABC OAD group and 323 (84%) patients in the ABC twice-daily group reaching this end point. Randomization and treatment outcomes are presented in Figure 1. Reasons for premature discontinuation were comparable between treatment groups, with most patients (25%) discontinuing from the study because of an AE. Baseline characteristics are presented in Table 1.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

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Virologic Response

For the ITT exposed population, 66% (253 of 384) of patients in the ABC OAD group compared with 68% (261 of 386) of patients in the ABC twice-daily group achieved a virologic response of plasma HIV-1 RNA <50 copies/mL by week 48. Response to treatment was similar within and across baseline HIV-1 RNA strata (Table 2). The stratified 2-sided 95% CI (−8.4%, 4.9%) excludes the predefined noninferiority margin of −12% and thus demonstrates the noninferiority of the ABC OAD treatment group as compared with the ABC twice-daily treatment group.

TABLE 2

TABLE 2

Figure 2 presents the TLOVR based on the proportion of patients achieving plasma HIV-1 RNA <50 copies/mL from baseline through week 48. The number of patients defined as having virologic failure was low and comparable in both groups (10% in ABC OAD group vs. 8% in ABC twice-daily group). Twenty-seven (7%) patients in the ABC OAD group did not achieve virologic suppression RNA <50 copies/mL at week 48 compared with the 21 (5%) patients in the ABC twice-daily group. Twenty-four (89%) of these 27 patients in the ABC OAD group and 19 (90%) of the 21 patients in the ABC twice-daily group did achieve confirmed suppression of plasma HIV-1 RNA <400 copies/mL by week 48.

FIGURE 2

FIGURE 2

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Immunologic Response

Figure 3 presents the median CD4+ cell count change from baseline through week 48. Median CD4+ cell count increases were similar at week 48 in the ABC OAD group (188 cells/μL) and in the ABC twice-daily group (200 cells/μL). Immunologic response was similar in patients who had baseline HIV-1 RNA levels ≥100,000 copies/mL versus <100,000 copies/mL.

FIGURE 3

FIGURE 3

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Genotyping and Phenotyping Analysis

Because of technical limitations of the genotyping and phenotyping assays, only a limited number of samples from patients (31 of 70 patients [44%]) defined as experiencing virologic failure provided genotypic or phenotypic information data. Most patients (56%) defined as experiencing virologic failure maintained plasma HIV-1 RNA levels ≤400 copies/mL but ≥50 copies/mL at the time of failure; therefore, genotyping of these failures was not possible.

In the 31 patients with virologic data, there were more patients with on-therapy resistance mutations in the ABC OAD group compared with the ABC twice-daily group. The numbers of patients with treatment-emergent resistance mutations (ABC OAD group: 13 of 16 patients [81%] vs. ABC twice-daily group: 10 of 15 patients [67%]) was not statistically significant between treatment groups.

The main resistance mutations found to emerge during therapy were M184V/I (ABC OAD group: 10 of 16 patients vs. ABC twice-daily group: 5 of 15 patients; P = 0.1556, 2-sided Fisher exact test) and K103N (ABC OAD group: 6 of 16 patients vs. ABC twice-daily group: 8 of 15 patients; P = 0.4795, 2-sided Fisher exact test). A smaller proportion of patients also selected an additional ABC mutation, L74V (ABC OAD group: 5 of 16 patients vs. ABC twice-daily group: 3 of 15 patients; P = 0.6851, 2-sided Fisher exact test). Only 1 patient in the ABC OAD group selected K65R, and 1 patient from each group selected Y115F.

There was no clear association between baseline mutations detected and virologic failure in either group. In a total sample of 245 baseline sequences that included all 70 patients experiencing virologic failure and 192 subjects selected at random (17 of whom experienced virologic failure), all patients (n = 3 in ABC OAD group vs. n = 1 in ABC twice-daily group) with >2 resistance-associated amino acid substitutions in RT at baseline had virologic failure. Five patients with baseline M184V or K103N (n = 2 in ABC OAD group vs. n = 3 in ABC twice-daily group) responded to therapy, whereas 5 patients with baseline M184V or K103N, Y188L, or Y188C failed virologically (n = 4 in ABC OAD group vs. n = 1 in ABC twice-daily group).

Phenotypic resistance was generally consistent with the genotypes, although treatment-emergent resistance patterns were complex because of preexisting baseline mutations. All patients with assessable virologic failure retained susceptibility to tenofovir, ZDV, and d4T, and most retained susceptibility to ABC.

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SAFETY

A total of 265 (69%) patients in the ABC OAD group and 265 (69%) patients in the ABC twice-daily group had greater than 48 weeks of exposure to the full dose of randomized study drug, 600 mg of ABC administered OAD or 300 mg of ABC administered twice daily. The number of patients who permanently discontinued randomized study drugs during the 48-week treatment phase was similar in both treatment groups (15% in ABC OAD group, 16% in ABC twice-daily group). Of the patients who discontinued study drugs, approximately half switched from a randomized study drug to an alternate drug (8% in ABC OAD group, 6% in ABC twice-daily group) and continued on study for 48 weeks of treatment. These switch subjects were never reclassified as responders, even if they achieved plasma HIV-1 RNA values <50 copies/mL by week 48. Data from these switch patients contributed to the overall safety profile of the study.

The incidence of AEs was similar in the OAD and twice-daily ABC groups (Table 3) including grade 3/4 or SAEs (26% in ABC OAD group, 22% in ABC twice-daily group). Body systems with the highest incidence of events considered by the investigator to be drug related were psychiatric disorders (35% in ABC OAD group, 26% in ABC twice-daily group) and nervous system disorders (32% in ABC OAD group, 28% in ABC twice-daily group). The incidences of other drug-related AEs were generally comparable between treatment groups. The type and frequency of AEs leading to premature discontinuation were also similar: 16% (60 of 384 patients) in the ABC OAD group and 15% (59 of 386 patients) in the ABC twice-daily group.

TABLE 3

TABLE 3

Incidences of SAEs were comparable between the treatment groups, with 17% (67 of 384) of patients in the ABC OAD group experiencing an SAE compared with 16% (62 of 386) of patients in the ABC twice-daily group. There were 5 patient fatalities (2 in the ABC OAD group and 3 in the ABC twice-daily group) and 1 fatality in the offspring of a study patient. None of these was considered to be attributable to a study drug.

A total of 36 (9%) patients in the ABC OAD group and 28 (7%) patients in the ABC twice-daily group reported a suspected ABC HSR. There was no clinically significant difference in the presentation and/or frequency of HSR-associated signs and symptoms reported between the ABC OAD and the ABC twice-daily arms, with most symptoms occurring in the first 6 weeks after initiating ABC treatment.

The number of grade 3 or 4 clinical chemistry and hematology abnormalities was equally distributed across the treatment groups, and no unexpected abnormalities were seen. Similar results were obtained in the analysis of the hematology results, with no differences being seen between the 2 groups.

In this double-blind study, there was no evidence suggesting any change in the safety profile of ABC when administered OAD compared with twice daily. None of the safety parameters indicated any increasing risk with ABC OAD administration, and the profile of ABC HSRs was unchanged.

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DISCUSSION

Data from this study support the clinical utility of OAD ABC dosing in the setting of a fully OAD low pill count regimen. Both ABC treatment groups had rapid and sustained suppression of plasma HIV-1 RNA below the lower limit of detection of the assay (<50 copies/mL), indicating a potent inhibition of viral replication, regardless of baseline plasma HIV-1 RNA levels. Based on the TLOVR algorithm, the proportion of responders was similar between the ABC OAD (66%) and ABC twice-daily (68%) treatment groups, and the incidence of virologic failure was low (10% in ABC OAD group, 8% in ABC twice-daily group) throughout 48 weeks of study treatment. The positive virologic outcomes were accompanied by favorable immunologic responses. Similar improvements in median CD4+ and CD8+ cell counts at week 48 in the ITT exposed population were observed in both treatment groups.

The main genotypic resistance mutations observed were, as expected, M184V or M184I and K103N. The M184V/I mutations are the primary genotypic mutations associated with 3TC and ABC treatment failure,18,19 whereas the K103N mutation is the primary genotypic mutation associated with EFV treatment failure.20 There were numerically more M184V/I resistance mutations observed in the ABC OAD group, but this was not statistically significant, and further analysis indicated that there was an imbalance between the groups in terms of baseline resistance-associated mutations that was contributory. A smaller proportion of patients also selected an additional ABC mutation, L74V, which does not confer resistance to ZDV, d4T, or tenofovir. The patient in the ABC OAD group whose virus selected K65R was found to have resistance to EFV at baseline (K103N and G190A) and selected a mixture at residues 65 (K/R) and 74 (V/I) along with M184V and Y115F. Interestingly, the virus with K65R seemed to retain susceptibility to tenofovir.

The viral load response in this large trial was such that the number of subjects with virus that could be analyzed for genotype at the time of failure was low because of the strict protocol definition used to identify failures (>50 copies/mL). Although additional data are needed, the risk of treatment-emergent resistance or cross-resistance seems to be similar when ABC is administered OAD or twice daily.

The incidences of AEs, treatment-emergent AEs, and SAEs were similar between the ABC OAD and ABC twice-daily treatment groups. The most common AEs were those involving the nervous system, which were expected with EFV therapy.21 The safety results demonstrate that both regimens were generally well tolerated, and safety profiles were comparable over a minimum of 48 weeks of randomized treatment exposure. Suspected ABC HSRs reported by study investigators were similar in incidence and presentation. No unexpected HSR safety concerns were reported. The rates of hypersensitivity reported in this study are consistent with those in other studies in which the symptoms of hypersensitivity were solicited using a specific reporting module.13

Twice-daily ABC has been comprehensively studied as a component of highly active antiretroviral therapy (HAART) in combination with a variety of different NRTIs, NNRTIs, and PIs; has no dietary or fluid restrictions; and has a low potential for drug-drug interactions.4-6 This study has demonstrated that ABC can be dosed OAD, achieving a comparable level of viral suppression as the indicated twice-daily dosing regimen. The ability to dose ABC once or twice daily allows physicians greater flexibility in constructing combination treatment regimens. This could improve adherence, and thus the efficacy and durability of antiretroviral treatment. For these reasons, the ABC OAD dosing regimen provides an important new therapeutic option in the management of HIV disease.

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ACKNOWLEDGMENTS

The authors gratefully acknowledge the study participants and the staff members supporting the study investigators as well as Bristol-Myers Squibb Company, Merck Sharp & Dohme Ltd, and the GlaxoSmithKline CNA30021 study team.

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REFERENCES

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8. Drusano GL, Bilello PA, Symonds WT, et al. Pharmacodynamics of abacavir in an in vitro hollow-fiber model system. Antimicrob Agents Chemother. 2002;46:464-470.
9. Piliero P, Shachoy-Clark A, Para M, et al. A study examining the pharmacokinetics of abacavir and the intracellular carbovir triphosphate (GSK Protocol CNA10905) [presentation A- 1797]. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003; Chicago.
10. Harris M, Back D, Kewn S, et al. Intracellular carbovir triphosphate levels in patients taking abacavir once a day. AIDS. 2002;16:1197-1198.
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12. Table for Grading of Adult Adverse Experience. Washington, DC: National Institute of Allergy and Infectious Diseases, Division of AIDS; 1992.
13. Cutrell A, Hernandez J, Edwards M, et al. Clinical risk factors for hypersensitivity reactions to abacavir: retrospective analysis of over 8,000 subjects receiving abacavir in 34 clinical trials [abstract H-2013]. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003; Chicago.
14. Hauck WW, Anderson S. Some issues in the design and analysis of equivalence trials. Drug Inf J. 1999;33:109-118.
15. Committee for Proprietary Medicinal Products (CPMP). Point to consider on the choice of non-inferiority margin (CPMP/EWP/2158/99 draft guidance document). European Agency for the Evaluation of Medicinal Products (EMEA), London, UK, May 2004. Available at: http://www.emea.eu.int/pdfs/human/ewp/048299en.pdf. Last accessed September 30, 2003.
16. Committee for Proprietary Medicinal Products (CPMP). Point to consider on switching between superiority and non-inferiority (CPMP/EWP/482/99 guidance document). European Agency for the Evaluation of Medicinal Products (EMEA), London, UK, July 2000. Available at: http://www.emea.eu.int/pdfs/human/ewp/215899en.pdf. Last accessed September 30, 2003.
17. Guidance for Industry: Antiretroviral drugs using plasma HIV RNA measurements-clinical considerations for accelerated and traditional approval. FDA Center for Drug Evaluation and Research, October 2002. Available at: http://www.fda.gov/cder/guidance/index.html. Last accessed September 30, 2003.
18. Kuritzkes D, Quinn J, Benoit S, et al. Drug resistance and virologic response in NUCA3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients. AIDS. 1996;10:975-981.
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21. Staszewski S, Morles-Ramirez J, Tashima K, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in treatment of HIV-1 infection in adults. N Engl J Med. 1999;341:1865-1871.
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APPENDIX

Investigators who participated in the CNA30021 study include the following:

United States investigators: B. Akil, MD (Los Angeles, CA); R. Baker, MD (Infectious Disease of Indiana, PSC, Indianapolis, ID); N. Bellos, MD (Dallas, TX); S. Belt, MD (West Orange, NJ); J. Boghossian, MD (St. Michael's Medical Center, Peter Ho Clinic, Newark, NJ); J. Brand, MD, (North Texas Center for AIDS and Clinical Research, Dallas, TX); L. Brown, MD (Addiction Research & Treatment Corporation, Brooklyn, NY); D. Buffington, MD (Clinical Pharmacology Services, Tampa, FL); J. Cade, MD (Wellness Center, Las Vegas, NV); K. Clanon, MD (Alameda County Medical Center, Oakland, CA); J. Collins, MD (The Physician's Clinic of Spokane, Spokane, WA); P. Daly, MD (Nelson Tebedo Health Resource Center, Dallas, TX); E. DeJesus, MD (IDC Research Initiative, Altemonte Springs, FL); J. DeSimone, MD (Thomas Jefferson University, Philadelphia, PA); D. Donnell, MD (Dallas, TX); R. Dretler, MD (Infectious Disease Specialists of Atlanta, Atlanta, GA); V. Fainstein, MD (ID Associates of Houston, Houston, TX); T. File, MD (Akron Infectious Disease Inc., Akron, OH); M. Fischl, MD (University of Miami School of Medicine, Miami, FL); I. Frank, MD (University of Pennsylvania, Philadelphia, PA); M. Frank, MD (Medical College of Wisconsin, Milwaukee, WI); G. Frechette, MD (New York, NY); J. Gathe, Jr., MD (Houston, TX); J. Giron, MD (Florida Infectious Disease Group, Orlando, FL); E. Godofsky, MD (Bradenton, FL); S. Green, MD (Hampton Roads Medical Specialists, Hampton, VA); P. Greiger-Zanlungo, MD (Mt. Vernon Hospital, Mt. Vernon, NY); H. Grossman, MD (New York, NY); F. Haas, MD (Tulsa, OK); J. Harris, MD (Oyster Point Medical Specialists, P.C., Newport News, VA); T. Hawkins, MD (Southwest C.A.R.E. Center, Sante Fe, NM); R. Hsu, MD (New York, NY); A. Huang, MD (University of Louiville Department of Medicine, Louisville, KY); Robert S. Jones, MD (Berks Infectious Disease Services, West Reading, PA); P. Juba, MD (University of Florida Health Science Center, Jacksonville, FL); W. Khayr, MD (N Chicago VA Medical Center, Chicago, IL); F. Kramer, MD (LAC + USC Medical Center, Los Angeles, CA); A. LaMarca, MD (TheraFirst Medical Center, Ft. Lauderdale, FL); J. Lang, MD (I.D. Consultants, PA, Charlotte, NC); S. Lewis, MD (The University of Texas Houston Health Science Center, Houston, TX); F. Lutz, MD (New Orleans, LA); L. Marton, MD (St. Joseph's Hospital, Paterson, NJ); A. Mestre, MD (Plantation, FL); R. Murayama-Greenbaum, MD (Astor Medical Group, New York, NY); R. Nahass, MD (I.D. Care, Inc., Somerville, NJ); P. Piliero, MD (Albany, NY); A. Quinones, MD (Community Healthcare of Broward, Albany, NY); S. Rauf, MD (The University of Texas Medical Branch, Galveston, TX); A. Rodriguez, MD (Jackson Medical Towers, Miami, FL); P. Salvato, MD (Diversified Medical Practices, PA, Houston, TX); M. Sands, MD (Boulevard Comprehensive Care Center, Duval County Health Department, Jacksonville, FL); K. Sathasivam, MD (Whitman-Walker Clinic, Washington, DC); C. Schleupner, MD (Coastal AHEC, Wilmington, NC); U. Schmidt, MD (Infectious Disease Specialists of NJ, Union, NJ); R. Schwartz, MD (Associates in Research, Ft. Myers, FL); D. Seekins, MD (Tampa, FL); M. Sension, MD (HIV Clinical Research, Ft. Lauderdale, FL); S. Shah, MD (MacGregor Medical Association, Houston, TX); P. Shalit, MD (Swedish Medical Center, Seattle, WA); G. Simon, MD (The George Washington University Medical Center, Washington, DC); C. Smith, MD (North General Hospital, New York, NY); R. Steigbigel, MD (State University of New York at Stony Brook, Stony Brook, NY); C. Steinhart, MD (Steinhart Medical Associates, Miami, FL); K. Summers, MD (S. Texas Veterans Health Care System, San Antonio, TX); D. Sweet, MD (University of Kansas School of Medicine-Wichita, Wichita, KS); K. Tashima, MD (The Miriam Hospital, Providence, RI); M. Thompson, MD (AIDS Research Consortium of Atlanta, Inc., Atlanta, GA); B. Wade, MD (Discovery Alliance, Inc., Pensacola, FL); Charles M. Walworth, MD (Newport Beach, CA); W. Weinberg, MD (Kaiser Permanente Cumberland Medical Office, Atlanta, GA); T. West, MD (Coastal Carolina Research Center, Charleston, SC); M. Witt, MD (Harbor UCLA Medical Center, Torrance, CA); P. Wolfe, MD (Pacific Oaks Research, Beverly Hills, CA); B. Yangco, MD (Infectious Disease Research Institute, Inc., Tampa, FL); V. Yeh, MD (AIDS Healthcare Foundation Research Center, Los Angeles, CA); B. Young, MD (Denver ID Consultants, Denver, CO); N. Zide, MD (Horizon Institute for Clinical Research, Hollywood, FL); C. Zurawski, MD (ID Specialists, Atlanta, GA)

Canada investigators: J. Cohen, MD (Windsor Regional Hospital, Windsor, Ontario); M. Gill, MD (S Alberta HIV Clinic, Calgary, Alberta); K. Gough, MD (St. Michaels Hospital); Patrice Junod, MD (Clinique Medicale due Quartier Latin, Montreal, Quebec); D. Kilby, MD (University of Ottawa Health Services, Ottawa, Ontario); R. O. Brien, MD (Clinique Medicale L. Actuel, Montreal, Quebec); A. Rachlis, MD (Sunnybrook and Women's College Health Science Centre, Toronto, Ontario); B. Romanowski, MD (Edmonton, Alberta); S. Rosser, MD (St. Boniface General Hospital, Winnipeg, Manitoba); W. Schlech, III, MD (Queen Elizabeth II Health Sciences Center, Victoria General Hospital, Halifax, Nova Scotia); M. Silverman, MD (Lakeridge Health Corporation, Whitby, Ontario); F. Smaill, MD (Clinic McMaster University, Hamilton, Ontario); S. Walmsley, MD (The Toronto General Hospital, Toronto, Ontario)

Argentina investigators: J. Benetucci, MD (FUNDAI Hospital Muniz, Buenos Aires); Pedro Cahn, MD (Fundacion HUESPED, Buenos Aires)

Brazil investigators: G. de Castro, MD (Hospital das Clinicas, Sao Paulo); D. Bonfim de Lima, MD (Pedro Ernesto University Hospital, Rio de Janeiro); M. Oliveira, MD (Casa de AIDS, Sao Paulo); R. Pedro, MD (State University of Campinas, Campinas); J. Pilotto, MD (Hospital Evandro Chagas, Rio de Janeiro); M. Schechter, MD (Federal University of Rio de Janeiro, Rio de Janeiro)

Denmark investigators: Dr. med. P. Andersen (Afddeling Q, Ambulatoriet, Arhus); Dr. med. J. Gerstoft (Epidemiafdeling, Rigshospitalet, Copenhagen); Dr. med. J. Lundgren (Hvidovre Hospital, Hvidovre); Dr. med. H. Nielsen (Mikrobiologisk afd., Aalborg); Dr. med. Niels Obel (Afdeling Q, Ambulatoriet, Arhus); Dr. med. C. Pedersen (Medicinsk afd. C sektion for Infektionsmedicin, Odense)

Latvia investigator: Prof. B. Rozentale (Latvian Infectology Center, Riga)

Mexico investigators: L. Casanova Cardiel, MD (Centro Medico Nacional La Raza, IMSS, Mexico City); M. Jauregui Chiu, MD (Hospital Regional Lopez Mateos, Mexico, D.F.); J. Ramos-Jimenez, MD (Hospital universitario de Neuvo Leon, Monterrey); L. Soto, MD (Instituto Nacional de la Nutricion, Mexico, D.F.); Dr. S. Zubiran (Mexico D.F., MX)

Germany investigators: Dr. med. K. Arasteh (Auguste-Viktoria-Krankenhaus Innere Abteilung Tagesklinik, Berlin); Dr. med. S. Fenske (IPM-Study Center, Hamberg); Prof. Dr. med. F. Goebel (Klinikum Innenstadt Medizin Poliklinik Infektionsambulanz, Muenchen); Dr. med. B. Kuhlmann (Hannover, Germany); Dr. med. S. Staszewski (Klinikum d. J. W. Goethe Universitat, Zentrum der Inneren Medizin, Frankfurt)

The Netherlands investigators: Dr. C. Richter (Rijnstate Ziekenhuis, Arnhem); Dr. J. Mulder (Slotervaart Ziekenhuis, Amsterdam)

Poland investigators: Prof. A. Boron-Kaczmarska (Department of Infectious Diseases, Szczecin); Prof. A. Gladysz (Department of Infectious Diseases, Wroclaw); Prof. Waldemar Halota (The L. Rydygier Medical University, Floriana); Dr. Andrzej Horban (Warsaw); Dr. H. Trocha (Department of Infectious Diseases, Gdansk)

Spain investigators: A. de Alarcon, MD (Hospital Universitario Virgen del Rocio, Sevilla); A. Antela, PhD (Hospital Ramon y Cajal, Madrid); J. Berenguer, MD (Hospital General Universitario Gregorio Maranon, Madrid); B. Clotet, MD (Hospital General Germans Trias I Pujol, Barcelona); Dr. P. Domingo, PhD (Hospital de la Santa Creu/Sant Pau, Barcelona); Dr. F. Gutierrez, PhD (Hospital General Universitario de Elche, Aliants); J. Mallolas, MD (Hospital Clinico de Barcelona, Barelona); E. Ribera, MD (Hospital Valle Hebron. Barcelona)

United Kingdom investigators: Dr. A. Bonington (North Manchester General Hospital, Manchesterl); Professor B. Gazzard (Chelsea & Westminister Hospital, London); Dr. G. Moyle (Chelsea & Westminister Hospital, London); Dr. K. Radcliffe (Whittall Street Clinic, Birmingham); Dr. C. Skinner (The Royal London Hospital, London)

Keywords:

abacavir; efavirenz; lamivudine; once daily; HIV infection; triple combination antiretroviral therapy

© 2005 Lippincott Williams & Wilkins, Inc.