Intensification of a triple-nucleoside regimen with tenofovir or efavirenz in HIV-1-infected patients with virological suppression
Gulick, Roy Ma; Lalama, Christina Mb; Ribaudo, Heather Jb; Shikuma, Cecilia Mc; Schackman, Bruce Ra; Schouten, Jeffreyd; Squires, Kathleen Ee,f; Koletar, Susan Lg; Pilcher, Christopher Dh; Reichman, Richard Ci; Klingman, Karin Lj; Kuritzkes, Daniel Rk
From the aWeill Medical College of Cornell University, New York, New York, USA
bStatistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts, USA
cUniversity of Hawaii, Honolulu, Hawaii, USA
dUniversity of Washington, Seattle, Washington, USA
eUniversity of Southern California Medical Center, Los Angeles, California, USA
fJefferson Medical College, Philadelphia, Pennsylvania, USA
gOhio State University, Columbus, Ohio, USA
hUniversity of California, San Francisco, USA
iUniversity of Rochester, Rochester, New York, USA
jDivision of AIDS, National Institute of Allergy and Infectious Disease, Bethesda, Maryland, USA
kBrigham and Womens' Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Received 8 September, 2006
Revised 7 November, 2006
Accepted 14 November, 2006
Correspondence to Roy M. Gulick, MD, MPH, Weill Medical College of Cornell University, Box 566, 525 East 68th Street, New York, NY 10021, USA. Tel: +1 212 746 4177; fax: ++1 212 746 8852; e-mail: firstname.lastname@example.org
Objective: To compare a quadruple-nucleoside with an efavirenz-containing regimen for treatment of HIV-1 infection.
Design: A randomized, open-label study of the AIDS Clinical Trials Group (ACTG).
Methods: Subjects receiving zidovudine/lamivudine/abacavir on ACTG 5095 with HIV-1 RNA less than 200 copies/ml were randomly assigned to intensify either with tenofovir or efavirenz. Subjects were followed for time to treatment failure, defined as either virological failure or treatment discontinuation. Analyses were intent-to-treat.
Results: One hundred and seventy subjects (21% women; 56% non-white) entered the study. At baseline, 95 and 73% had HIV-1-RNA levels less than 200 and 50 copies/ml, respectively; the median CD4 cell count was 453 cells/μl. Over a median 79 weeks follow-up, 165 (97%) completed the study, three (2%) discontinued, and two (1%) died. Treatment failure occurred in 31 subjects: 18 (21%) (quadruple nucleosides) and 13 (15%) (efavirenz-containing regimen); however the failure–time curves crossed and demonstrated a non-constant treatment effect over time, characterized by more early treatment failures on the efavirenz-containing regimen and more late treatment failures on the four-nucleoside regimen. HIV-1 RNA remained suppressed in more than 88% of subjects to less than 200 copies/ml and in more than 78% to less than 50 copies/ml at weeks 24, 48, and 72, without differences by treatment arm. There were no significant differences between the regimens in CD4 cell increases, time to new grade 3/4 adverse events, or adherence.
Conclusion: The safety, tolerability, and efficacy of the four-nucleoside regimen were not significantly different from the efavirenz-containing regimen. These pilot data support further investigation of the quadruple-nucleoside regimen.
Current treatment guidelines for the initial treatment of HIV-1 infection in developed countries recommend two nucleoside reverse transcriptase inhibitors (NRTI) in combination with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) [1–3], whereas in developing countries, two NRTI with an NNRTI is the standard initial regimen . These regimens are associated with substantial virological, immunological, and clinical benefits [5–10]. Although now commonly used worldwide, NNRTI-based regimens are associated with side effects (e.g. rash, central nervous system symptoms, hepatitis [9,11]), drug interactions (e.g. with rifampin  or methadone ) and, in the case of efavirenz, teratogenicity . Furthermore, drug resistance to NNRTI commonly develops after virological failure , and surveillance testing suggests that at least 8% of patients are infected initially with NNRTI-resistant viruses in the United States . Therefore, alternative effective antiretroviral regimens are needed.
Triple-nucleoside regimens compared favorably with older PI-containing regimens and were well tolerated and convenient with fewer drug interactions [17–19]. Quadruple-nucleoside regimens demonstrated virological activity in pilot studies [20–23], but comparative data are limited . In AIDS Clinical Trials Group (ACTG) 5095, the co-formulated triple-nucleoside regimen of zidovudine/lamivudine/abacavir was virologically inferior to a standard NNRTI-containing regimen, and consequently that arm was stopped after review by the data and safety monitoring board . Because a number of subjects on the triple-nucleoside arm had virological suppression at the time the study was stopped, we designed an intensification strategy to improve the antiretroviral activity of the triple-nucleoside regimen in which those subjects were randomly assigned to add to their triple-nucleoside regimens either tenofovir (forming a quadruple-nucleoside regimen) or efavirenz, and to compare the safety, tolerability and efficacy of the four-drug intensified regimens.
This was an open-label, randomized study of the ACTG. Eligible patients were HIV-1-infected adult study subjects on ACTG 5095 who were originally randomly assigned to the triple-nucleoside regimen of zidovudine/lamivudine/abacavir (300/150/300 mg co-formulated as Trizivir, one pill twice a day; GlaxoSmithKline, Research Triangle Park, North Carolina, USA). Study subjects were taking their regimen with a plasma HIV-1- RNA level of less than 200 copies/ml within 8 weeks before intensification. Subjects were excluded for pregnancy or estimated creatinine clearance of less than 50 ml/min (Cockroft–Gault method).
Subjects continued triple-nucleoside therapy and were randomly selected to add the nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (tenofovir, 300 mg a day, Viread; Gilead Sciences, Foster City, California, USA), or the NNRTI, efavirenz (600 mg a day, Sustiva; Bristol-Myers Squibb, Princeton, New Jersey, USA). Subjects were stratified for the length of time on ACTG 5095 before intensification (≤ 52 weeks or > 52 weeks). The study was reviewed by institutional review boards at the participating clinical sites, and all subjects provided written informed consent.
Study visits included a clinical assessment and safety laboratories at weeks 2, 4, 6, 8, and then every 4 weeks to week 24 and every 8 weeks thereafter. Plasma HIV-1 RNA (HIV-1 Monitor Assay, version 1.5; Roche Molecular Systems, Branchburg, New Jersey, USA) and CD4 cell counts were assessed every 8 weeks. An adherence questionnaire  was either self-administered by the subject or completed by the subject with the assistance of the study coordinator every 24 weeks. Hepatitis B surface antigen and hepatitis C antibody serological tests were obtained at entry to ACTG 5095. Adverse events were assessed by the site investigators using the Division of AIDS toxicity grading scale .
In the event of toxicity considered treatment-limiting by the site investigator, substitution of study drugs was permitted: stavudine (Zerit; Bristol-Myers Squibb) for zidovudine; didanosine (Videx EC; Bristol-Myers Squibb) for abacavir or tenofovir; and nevirapine (Viramune; Boehringer-Ingelheim, Connecticut, USA) for efavirenz. In the event of virological failure (confirmed HIV-1 RNA ≥ 200 copies/ml), subjects underwent genotypic drug resistance testing (HIV-1 Trugene; Bayer Healthcare Diagnostics, Berkeley, California, USA) conducted both on the ACTG 5095 baseline sample and the confirmatory virological failure sample. After confirmed virological failure, subjects could continue randomized treatment (provided HIV-1 RNA was not confirmed to be ≥ 10 000 copies/ml), change to other antiretroviral drugs selected with the use of resistance testing, or continue study follow-up off antiretroviral drugs, depending on subject and provider choice. The study was reviewed annually by the data and safety monitoring board of the National Institute of Allergy and Infectious Disease.
The primary objectives were to determine the safety of the intensified antiretroviral regimens and to evaluate the relative efficacy of the regimens for tolerability and maintaining a durable virological response. The primary efficacy endpoint was the time to virological failure, defined as two consecutive HIV-1-RNA levels of 200 copies/ml or greater, or the discontinuation of study treatment, whichever came first. Subjects who missed three consecutive HIV-1-RNA evaluations before reaching a primary study endpoint were considered censored at the date of the HIV-1-RNA evaluation before the first missed evaluation. The power of the study to be able to show a difference between study arms was limited by the pool of eligible subjects. If 150–200 individuals enrolled, we estimated that there would be 79–91% power to detect a difference between 0.9 and 0.75 [hazard ratio (HR) 0.37]. If the proportion of subjects without treatment failure by 48 weeks was 70% or more, the width of the 95% confidence interval (CI) around this estimate would be within ±10%.
All primary efficacy analyses were intent-to-treat and included all randomly assigned subjects. Subjects who made protocol-permitted study drug substitutions for treatment-limiting toxicity were considered to be on the randomized study regimen and were not considered to have reached a primary endpoint. All safety analyses were as-treated, including only subjects who initiated study treatment; follow-up data for up to 8 weeks after treatment discontinuation were included. The baseline HIV-1-RNA level and CD4 cell count were calculated as the geometric and arithmetic mean, respectively, using the pre-entry and entry evaluations determined before intensification. The comparison between the study arms and all secondary comparisons were evaluated at a 5% significance level and with 95% CI.
Failure–time distributions were estimated using the Kaplan–Meier method and were compared with a stratified log-rank test. Cox proportional hazards models stratified by the length of time on ACTG 5095 before intensification were used for the estimation of HR and CI. The validity of the proportional hazards assumption in these models was confirmed using the method of Grambsch and Therneau . All HR were presented with the efavirenz-containing arm as numerator. The proportions of subjects with HIV-1 RNA less than 200 or less than 50 copies/ml were presented by treatment group over time. Chi-square tests were used to compare groups at weeks 24, 48, and 72. CD4 cell counts were presented using estimated mean changes from baseline. t-Tests were used to compare groups at specific weeks. Adherence was assessed as a dichotomous metric defined from a standard ACTG questionnaire , in which subjects were considered adherent if they reported no missed doses over the previous 4 days.
A total of 382 patients were originally randomly assigned to the triple-nucleoside regimen in ACTG 5095  (see Table 1 and Fig. 1). Of these, 237 were taking the triple-nucleoside regimen at the time the intensification strategy study became available. Of these 237, 170 (72%) chose to enter the current study from June 2003 to February 2004. The 170 subjects comprised 35 women (21%), 96 non-whites (56%), 15 (9%) with a history of injection drug use, and 16 (10%) with hepatitis C antibody. Most (142, 84%) had participated in ACTG 5095 for more than 52 weeks. At study entry before intensification, 161 (95%) and 124 (73%) had HIV-1 RNA of less than 200 and less than 50 copies/ml, respectively; the median CD4 cell count was 453 cells/μl. Of note was the fact that each of the nine subjects with HIV-1-RNA levels of 200 copies/ml or greater at study entry (before treatment intensification) had a subsequent HIV-1-RNA level documented at less than 200 copies/ml; thus, none reached protocol-defined virological failure on that basis.
The median study follow-up after randomization was 79 weeks (1.5 years). Of 170 subjects randomly assigned, 165 (97%) completed the study, three (2%) prematurely discontinued study follow-up, and two (1%) died, one with coronary artery disease and one in a motor vehicle accident. There was no difference in time to premature study discontinuation between treatment groups (P = 0.63). All 170 subjects started randomized study treatment and 147 (86%) were taking randomized study treatment at study completion, eight (5%) discontinued study treatment but were taking other study-provided antiretroviral treatment, 11 (6%) discontinued study treatment but continued study follow-up (with or without taking antiretroviral treatment), and four (2%) discontinued both study treatment and follow-up.
Virological and immunological efficacy
A total of 31 study subjects (18%) reached protocol-defined treatment failure: 18 (21%) on the quadruple-nucleoside regimen compared with 13 (15%) on the efavirenz-containing regimen (P = 0.36, HR 0.72, 95% CI 0.35, 1.46; Fig. 2a). There was, however, evidence of non-proportional treatment hazards over time (P = 0.03) characterized by a higher early probability of treatment failure (weeks 0–24, none after week 40) on efavirenz-containing treatment and a greater later probability of treatment failure (after week 48) on the quadruple-nucleoside regimen. A multivariate analysis (stratified by treatment arm) revealed significant associations with treatment failure and female sex (P = 0.013, HR 2.94, 95% CI 1.26, 6.88), pre-intensification HIV-1 RNA of 50 copies/ml or greater (P < 0.001; HR 6.31, 95% CI 2.65, 15.1), and pre-intensification CD4 cell count (per 100 cells/μl higher; P = 0.036, HR 0.81, 95% CI 0.66, 0.99; Table 2).
Of the 31 treatment failure events, 18 (58%) were caused by virological failure and 13 (42%) were caused by study drug discontinuation, six on the efavirenz arm [one each for allergic reaction, disallowed medication (interferon), dysphoria, hyperlipasemia, and two for rash] and seven on the tenofovir arm (one each for fatty liver, hyperlipasemia, symptomatic hyperlactatemia, two for clinician decision, and two deaths). Two subjects who discontinued study treatment were censored for the primary study endpoint because of three consecutive missed study visits; however, follow-up for confirmation of virological failure was conducted. In total, 19 subjects experienced virological failure on the study. There was no significant difference between the study regimens in the time to virological failure (P = 0.45, HR 0.70, 95% CI 0.28, 1.75; Fig. 2b) or in the time to treatment discontinuation (P = 0.88, HR 0.94, 95% CI 0.41, 2.13; Fig. 2c).
Although the failure–time curves crossed for both of these endpoints, neither showed significant departures from non-proportional hazards (P = 0.23 and P = 0.27, respectively); given the low number of endpoints, these tests were not well-powered. Overall, HIV-1 RNA remained suppressed throughout the study in more than 88% of subjects to less than 200 copies/ml and in more than 78% to less than 50 copies/ml (intent-to-treat analyses, in which missing data were ignored; Fig. 3a and b). Intent-to-treat analyses, in which missing data or treatment discontinuation were considered failure demonstrated similar trends (Fig. 3c and d). There were no differences by treatment arm in the proportions of subjects with HIV-1 RNA suppressed to less than 200 or less than 50 copies/ml at weeks 24, 48, or 72 (P > 0.1). The median CD4 cell increase was 55 cells/μl at week 72; there were no significant differences in CD4 cell responses between study arms (P > 0.10).
All 19 subjects who experienced virological failure had wild-type virus documented from specimens collected at the time of entry into the original ACTG 5095 study. Fourteen (74%) did not have a genotype attempted at virological failure because their HIV-1-RNA level was less than 500 copies/ml. Of five subjects with available genotypic results, three were on quadruple nucleosides (two with wild-type virus, one with nucleoside resistance-associated substitutions, M41L, M184V, T215F), and two were on the efavirenz-containing regimens [both with lamivudine (M184V) and NNRTI (K103N) resistance-associated substitutions].
More than 77% of subjects in each arm reported not missing a dose of study drug over the previous 4 days at the week 24, 48, and 72 visits. There were no significant differences between the treatment arms in subject self-reported adherence (based on 4-day recall) at study weeks 24, 48, and 72 (P > 0.10).
A total of 20 subjects (12%) experienced at least one grade 4 event: seven (8%) on quadruple nucleosides and 13 (15%) on the efavirenz-containing regimen. Of the remaining subjects, 52 (31% of total subjects) experienced at least one grade 3 event, 28 (33%) on quadruple nucleosides and 24 (28%) on the efavirenz-containing regimen. There were no significant differences in time to the first grade 3 or 4 toxicity between arms (P = 0.74). By week 72, the change in mean estimated creatinine clearance increased 1.64 ml/min (95% CI −3.74, +7.02) with the efavirenz-containing regimen and decreased by 2.04 ml/min (95% CI −6.90, +2.83) with the tenofovir-containing regimen; there was no difference in the change from baseline to week 72 between arms (P = 0.32). Two of 170 subjects (1%) substituted stavudine for zidovudine and 11 of 85 (13%) substituted nevirapine for efavirenz for toxicity considered treatment limiting by the site investigator. HIV-associated clinical events occurred in three subjects (2%): one with both oropharyngeal candidiasis and oral hairy leukoplakia; one with localized varicella zoster; and one with bacterial pneumonia and pyelonephritis.
In ACTG 5095, we previously found increased virological failure in subjects taking a triple-nucleoside regimen compared with those taking an efavirenz-containing regimen, prompting the early closure of the triple-nucleoside study arm . To improve the antiretroviral activity of the triple-nucleoside regimen in ACTG 5095 subjects with virological suppression, we compared the addition of tenofovir (to form a quadruple-nucleoside regimen) or efavirenz. As a result of the inferiority of the triple-nucleoside regimen, we felt it would have been unethical to randomly assign these patients to continue this regimen, and therefore we lacked a triple-nucleoside control arm in the current study. Although the lack of the control arm prevented us from comparing the two intensified regimens with the triple-nucleoside regimen, we were able to evaluate the safety, tolerability, and efficacy of the intensified regimens as well as to compare them directly with one another.
Overall, we found no differences between the intensified regimens in treatment failure, a composite endpoint that incorporated both virological failure and treatment discontinuation. In addition, we found no differences between the regimens in safety, tolerability, CD4 cell increases, self-reported adherence, or drug resistance mutations at virological failure. We enrolled a diverse patient population and followed them with a very low loss-to-follow-up rate. Although the interpretation of this study is complicated because of the non-constant treatment effect over time, the overall low incidence of virological failure and toxicity observed in the study supports the further investigation of quadruple-nucleoside regimens (e.g. in treatment-naive patients).
Current treatment guidelines in both developed and developing countries recommend two nucleoside analogues in combination with an NNRTI among the preferred choices for the initial treatment of HIV-1 infection [1–4]. The choice of regimens must, however, be individualized on the basis of multiple factors regarding the patient, the viral strain and the antiretroviral drugs. Despite their confirmed efficacy, NNRTI-containing regimens are associated with side effects [9,11], drug–drug interactions [12,13], and teratogenicity , and NNRTI-resistant viral strains are increasingly transmitted in the community . These factors may limit the usefulness of NNRTI-containing regimens in some clinical settings. Additional therapy options for the initial treatment of HIV-1 infection would thus be useful.
Although the triple-nucleoside regimen of zidovudine/lamivudine/abacavir is convenient, well tolerated and demonstrated activity comparable to indinavir or nelfinavir-containing regimens [17–19], it was inferior virologically to an efavirenz-containing regimen on the ACTG 5095 study, and showed a higher rate of virological rebound after suppression, suggesting suboptimal virological potency . Consequently, triple-nucleoside regimens are recommended in treatment guidelines only in clinical situations in which NNRTI or PI-based regimens cannot or should not be used . Our current data suggest that a quadruple-nucleoside regimen offers improved virological potency in addition to convenience and tolerability, and should be explored further as an initial treatment strategy.
Quadruple nucleoside regimens have been assessed previously in a few studies [20–24]. Latham and colleagues  identified 122 patients from their clinical database who had failed previous antiretroviral therapy regimens and were given zidovudine/lamivudine/abacavir and tenofovir. At one year, 34% (intent-to-treat) and 65% (on-treatment) had HIV-1-RNA levels of less than 50 copies/ml and cholesterol levels decreased. In a single-armed pilot study, Rodriguez et al.  reported 51 patients who experienced virological failure on an NNRTI or PI-containing regimen and changed to zidovudine/lamivudine/abacavir and tenofovir and showed at 48 weeks that 59% (intent-to-treat) and 77% (on-treatment) suppressed their HIV-1-RNA levels to less than 50 copies/ml. In a second pilot study, D'Ettorre and colleagues  reported 21 patients with HIV-1-RNA levels suppressed on a PI-containing regimen who changed to zidovudine/lamivudine/abacavir and tenofovir for either lipodystrophy (n = 17) or treatment simplification (n = 4), and found all maintained HIV-1-RNA levels of less than 50 copies/ml with an average of 70 weeks of follow-up.
Elion et al.  reported a third single-arm pilot study of zidovudine/lamivudine/abacavir and tenofovir given once a day in 123 treatment-naive patients with only 41% (intent-to-treat) having HIV-1 RNA levels of less than 50 copies/ml at 48 weeks. This result can probably be explained by suboptimal exposure to zidovudine because of once-daily dosing and by a 42% premature discontinuation rate. Moyle and colleagues  reported a pilot study of 114 treatment-naive patients who were randomly assigned to receive either zidovudine/lamivudine/abacavir and tenofovir or zidovudine/lamivudine and efavirenz. At week 48, 68% (quadruple-nucleoside regimen) versus 67% (efavirenz-containing regimen) had HIV-1 RNA of less than 50 copies/ml in an intent-to-treat analysis. The fact that nearly a third of the patients discontinued study follow-up early complicates the assessment of virological activity because ‘missing-data-equals-failure’ analyses were used. This type of analysis fails to distinguish virological failure from discontinuations for toxicity, adherence, or reasons unrelated to the protocol (e.g. patient moving), because if a patient misses the evaluation for any reason, he or she is considered a failure.
In multivariate analyses, we found independent associations between treatment failure and female sex, pre-intensification HIV-1 RNA of 50 copies/ml or more, and a lower pre-intensification CD4 cell count. Given the small number of failure events and with only 35 women participating, the association with virological failure and sex is questionable, and requires evaluation in future studies. Anderson et al.  noted significantly elevated zidovudine and lamivudine triphosphate levels in women compared with men, and suggested a causal relationship with increased nucleoside-associated toxicities; however, there was no difference in grade 3/4 toxicities by sex in the current study. Interestingly, we found a significantly increased rate of virological failure in non-Hispanic blacks, but not women, on the efavirenz-containing regimens in ACTG 5095 , but no association with race/ethnicity was seen in the current study, although the sample size is smaller. It is not surprising that an HIV-1-RNA level of 50 copies/ml or greater before intensification was associated with treatment failure as ongoing viremia increases the risk of the emergence of drug resistance .
In this study, it is interesting that the failure–time curves crossed and demonstrated a significant non-constant treatment effect over time. This changing treatment effect was characterized by more treatment failures in the efavirenz group over the first 24 weeks of the study (and none after week 40) and more treatment failures in the quadruple-nucleoside group after 48 weeks. We hypothesize that early treatment failures may have been associated with efavirenz-related toxicities (including low-level toxicities) that impacted adherence, and as a result increased treatment failure. In contrast, we speculate that the later treatment failures associated with the quadruple-nucleoside regimen may indicate less inherent ability of the regimen to maintain virological suppression in some patients. The clinical significance of the changing treatment effect over time is, however, not clear because there was a low incidence of both virological failure and toxicity with these regimens in this study. Also, because of the small number of endpoints, the power to make definitive conclusions is limited and these hypotheses will need to be explored in future studies.
One of the important distinctions between an NNRTI-containing regimen and a quadruple-nucleoside regimen is the pattern of resistance mutations that emerges after virological failure and the implications for subsequent antiretroviral therapy. It has been well-described that patients experiencing virological failure on a lamivudine (or emtricitabine) and NNRTI-containing regimen most often select the M184V substitution in reverse transcriptase (associated with lamivudine and emtricitabine resistance) or specific substitutions associated with NNRTI resistance (e.g. K103N), with other nucleoside-associated mutations emerging only rarely [9,30]. One would anticipate that the quadruple-nucleoside regimen would also select the M184V substitution with or without additional nucleoside resistance-associated mutations. In this study, of 19 subjects with virological failure, only five had sufficient HIV-1-RNA levels to allow genotypic resistance testing to be conducted, and only three of the five showed drug-resistance mutations. Predictably, two subjects on the efavirenz-containing regimen had both lamivudine and NNRTI resistance, and one subject on the quadruple-nucleoside regimen had both M184V and two other nucleoside resistance-associated mutations (M41L, T215F). Further investigation of genotypic resistance patterns after virological failure on a quadruple-nucleoside regimen and the impact on subsequent treatment regimens is warranted.
In conclusion, we showed that in patients with virological suppression on a triple-nucleoside regimen, intensification with tenofovir (to a quadruple-nucleoside regimen) was not different from intensification with efavirenz with regard to safety, tolerability, and efficacy. These pilot results support further evaluation of the quadruple-nucleoside regimen of zidovudine/lamivudine/abacavir and tenofovir compared with standard antiretroviral regimens in HIV-infected patients, with the goal of defining additional options for either the initial or suppressive maintenance treatment of HIV infection.
Other authors: Edward P. Acosta, PharmD (University of Alabama, Birmingham); William A. Meyer III, PhD (Quest Diagnostics, Inc., Baltimore); Jorge L. Santana, MD (University of Puerto Rico, San Juan); Valery Hughes, FNP (Weill Medical College of Cornell University, New York); Barbara Bastow, RN, BSN (Social and Scientific Systems, Inc., Silver Spring, Maryland).
Other members of the AIDS Clinical Trials Group A5095 Study Team: Carol Bick PhD (Indiana University School of Medicine) and Alison Boyle MT (University of California, Los Angeles), study laboratory technologists; Anne Kmack BS and Sandra Oyola MT (Frontier Science and Technology Foundation), study data managers; Ana Martinez RPh (Division of AIDS, National Institute of Allergy and Infectious Disease), study pharmacist; Monica Murphy MT and Nancy Webb MS (Frontier Science and Technology Foundation), laboratory data coordinators; Vinny Parillo (AIDS Clinical Trials Group Community Constituency Group), community representative; Sally Snyder BS (Social and Scientific Systems, Inc.), study specialist; Doug Ferriman PharmD, Michael Imperiale MD, Marita McDonough MPA RN, Jerry Stern MD, Stephen Storfer MD (Boehringer-Ingelheim-Roxane Laboratories); Awny Farajallah MD, Michael Giordano MD, Kelly Morrissey RN MSN, Jeffery Olson PharmD, Lynn Rugh, Kirk Ryan PharmD, Michael Soccodato, Mary Swingle RN, Shulin Wang MD (Bristol-Myers Squibb); Richard Fallis BA, James Rooney MD, Stephen Smith (Gilead Sciences); Cindy Brothers MSPH, Christina Hill-Zabala MD, Joe Mrus MD, Keith Pappa PharmD, Trevor Scott PhD, Jerry Tolson PhD, and Amy Van Kempen MEd (GlaxoSmithKline).
Laboratory personnel: Michelle Marcial BS, Daniel Eggers BS (Brigham and Women's Hospital); Richard D'Aquila MD, Lorraine Sutton BA (Vanderbilt University); Russell Young MS (University of Colorado Health Sciences Center); Victoria Johnson MD, Darren Hazelwood BS, Julia Parker BA (University of Alabama at Birmingham); Susan Fiscus PhD, Leslie Petch PhD, Tiffany Tribull MS (University of North Carolina, Chapel Hill).
Participating site staff members (in order of subject accrual at the clinical site): William Maher MD, Diane Gochnour RN, Mark Hite RN (Ohio State University); David Currin RN, Lisa Danoit RN, Kim Epperson RN (University of North Carolina); Carol Greisberger RN, Roberto Corales DO, Christine Hurley RN (University of Rochester Medical Center); Santiago Marrero MD, Olga Mendez MD, Irma Torres RN MSN (University of Puerto Rico); Princy Kumar MD (Georgetown University Medical Center), Deborah McMahon MD, Sharon Riddler MD (University of Pittsburgh); Julie Richardson PharmD, Janet Hernandez RN, Scott Hamilton RN (Indiana University Hospital); Sue Swindells MD (University of Nebraska), Jeffery Meier MD (University of Iowa), Henry Balfour Jr MD (University of Minnesota); Martha Silberman RN, Nathan Thielman MD, Kenneth Shipp RPh (Duke University Medical Center); Jose Castro MD, Hector Bolivar MD, Margaret Fischl MD (University of Miami); James Scott RN BSN, Cathi Basler RN MSN, Steven Johnson MD (University of Colorado Health Sciences Center); Timothy Flanigan MD, Karen Tashima MD, Helen Sousa LPN (The Miriam Hospital); Paula Potter RN BSN, Julie Hoffman RN, Francesca Torriani MD (University of California, San Diego); Donna McGregor NP (Northwestern University), Oluwatoyin Adeyemi MD (Cook County Hospital), Harold Kessler MD (Rush-Presbyterian-St Luke's Medical Center); Margrit Carlson MD (UCLA School of Medicine), Mallory Witt MD, Mario Guerrero MD (Harbor-UCLA Medical Center); Mussolini Africano PA-C, Luis Mendez BS, Connie Funk RN BSN (University of Southern California); David Haas MD, Janet Nicotera RN BSN, Jie Wang RN (Vanderbilt University); Ann Conrad RN, Jane Baum BSN RN (Case Western Reserve University); David Clifford MD, Mark Rodriguez RN BSN, Kimberly Gray RN MSN (Washington University); Todd Stroberg RN (Cornell University), Jolene Noel-Connor RN, Madeline Torres BSN (Columbia University); Joanne Frederick RN, Scott Souza PharmD, Debra Ogata-Arakaki RN (University of Hawaii); Jeffrey Lennox MD (Emory University), Kerry Upton RN BSN, J. Michael Kilby MD (University of Alabama at Birmingham); Judith Feinberg MD, Diane Daria BSN, Carol Colegate RPh (University of Cincinnati); Ann Collier MD, Becky Royer PAC, Laura Olin ARNP (University of Washington); Amy Sbrolla RN BSN, Neah Kim MSN FNP, Jon Gothing RN (Harvard University); Dorcas Baker RN, Aruna Subramanian MD (Johns Hopkins University); Deb Him RPh, Wayne Wagner MSW RN (University of Pennsylvania); William O'Brien MD, William Silkowski RN BSN (University of Texas, Galveston).
Supported by grants (AI 38858 [AIDS Clinical Trials Group Central Grant], AI 01781, AI 25859, AI 25868, AI 25879, AI 25897, AI 25903, AI 25915, AI 25924, AI 27658, AI 27659, AI 27660, AI 27661, AI 27664, AI 27668, AI 27670, AI 27673, AI 27675, AI 27767, AI 28697, AI 32775, AI 32782, AI 34832, AI 38855, AI 39156, AI 42848, AI 42851, AI 46339, AI 46381, AI 46386, AI 50410, AI 51966, RR00044, RR00046, RR00047, RR00052, RR00865, RR02635, and subcontracts from grant AI 38858 with the Virology Support Laboratories at Brigham and Women's Hospital, the University of Alabama, the University of Colorado Health Sciences Center, the University of North Carolina, and Vanderbilt University) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline all generously supplied the study medications.
This paper was presented, in part, at the 13th Conference on Retroviruses and Opportunistic Infections. Denver, Colorado, 5–8 February 2006 [Abstract 519].
Sponsorship: This study was supported by grants from the AIDS Clinical Trials Group, Division of AIDS, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Virology Support Laboratories at Brigham and Women's Hospital, the University of Alabama, the University of Colorado Health Sciences Center, the University of North Carolina, and Vanderbilt University. Bristol-Myers Squibb and GlaxoSmithKline also provided funding for HIV-1-RNA assays for the study.
1. Panel on Clinical Practices for the Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents
. Available at: www.aidsinfo.nih.gov
. Accessed: 10 October 2006.
2. Hammer SM, Saag MS, Schechter M, Montaner JSG, Schooley RT, Jacobsen DM, et al
. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society – USA panel. JAMA 2006; 296:827–843.
3. Gazzard B, on behalf of the BHIVA Writing Committee. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005). HIV Med 2005; 6:1–61.
5. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al
. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337:734–739.
6. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al
. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337:725–733.
7. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al
. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:853–860.
8. Mouton Y, Alfandari S, Valette M, Cartier F, Dellamonica P, Humbert G, et al
. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. AIDS 1997; 11:F101–F105.
9. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al
. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999; 341:1865–1873.
10. Severe P, Leger P, Charles M, Noel F, Bonhomme G, Bois G, et al
. Antiretroviral therapy in a 1000 patients with AIDS in Haiti. N Engl J Med 2005; 353:2325–2334.
11. Van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al
. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263.
12. Autar RS, Wit FW, Sankote J, Mahanontharit A, Anekthananon T, Mootsikapun P, et al
. Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis. Antiviral Ther 2005; 10:937–943.
13. Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001; 51:213–217.
14. Chersich MM, Urban MM, Venter FW, Wessels T, Krause A, Gray GE, et al
. Efavirenz use during pregnancy and for women of child-bearing potential. AIDS Res Ther 2006; 3:11.
15. Hirsch MS, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, D'Aquila RG, et al
. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society – USA Panel. Clin Infect Dis 2003; 37:113–128.
16. Weinstock HS, Zaidi I, Heneine W, Bennett D, Garcia-Lerma JG, Douglas JM, et al
. The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-infected persons in 10 US cities. J Infect Dis 2004; 189:2174–2180.
17. Staszewski S, Keiser P, Montaner J, Raffi F, Gathe J, Brotas V, et al
. Abacavir–lamivudine–zidovudine vs indinavir–lamivudine–zidovudine in antiretroviral-naive HIV-infected adults: a randomized equivalence trial. JAMA 2001; 285:1155–1163.
18. Vibhagool A, Cahn P, Schechter M, Smaill F, Soto-Ramirez L, Carosi G, et al
. Triple nucleoside treatment with abacavir plus the lamivudine/zidovudine combination tablet (COM) compared to indinavir/COM in antiretroviral therapy-naive adults: results of a 48-week open-label, equivalence trial (CNA3014). Curr Med Res Opin 2004; 20:1103–1114.
19. Kumar PN, Rodriguez-French A, Thompson MA, Tashima KT, Averitt D, Wannamaker PG, et al
. A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naive patients: effect of sex and ethnicity. HIV Med 2006; 7:85–98.
20. Latham V, Stebbing J, Mandalia S, Michailidis C, Davies E, Bower M, et al
. Adherence to trizivir and tenofovir as a simplified salvage regimen is associated with suppression of viraemia and a decreased cholesterol. J Antimicrob Chemother 2005; 56:186–189.
21. Rodriguez A, Hill-Zabala C, Sloan L, Jefferson T, Yau L, Watson M, et al
. Patients experiencing early virologic failure on a protease inhibitor- or nonnucleoside reverse transcriptase inhibitor-based initial regimen containing a thymidine analogue and lamivudine can be successfully treated with a quadruple-nucleoside regimen [Letter]. J Acquir Immune Defic Syndr 2006; 41:127–129.
22. D'Ettorre, Mastroianni CM, Massetti AP, Lichtner M, D'Agostino C, Vullo V. Switching from protease inhibitors to a single-class regimen of abacavir/lamivudine/zidovudine plus tenofovir in patients with HIV load suppression [Letter]
23. Elion R, Cohen C, DeJesus E, Redfield R, Gathe J, Hsu R, et al
. Once-daily abacavir/lamivudine/zidovudine plus tenofovir for the treatment of HIV-1 infection in antiretroviral naive subjects: a 48-week pilot study. HIV Clin Trials 2006; 7:324–333.
24. Moyle G, Higgs C, Teague A, Mandalia S, Nelson M, Johnson M, et al
. An open-label, randomized comparative pilot study of a single-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy. Antiviral Ther 2006; 11:73–78.
25. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA III, et al
. Triple-nucleoside regimens vs. efavirenz-containing regimens for the initial treatment of HIV-1 infection: AIDS Clinical Trials Group (ACTG) Study A5095. N Engl J Med 2004; 350:1850–1861.
26. Chesney MA, Ickovics JR, Chambers DB, Gifford AL, Neidig J, Zwickl B, Wu AW. Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. AIDS Care 2000; 12:255–266.
28. Grambsch P, Therneau T. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81:515–526.
29. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS 2003; 17:2159–2168.
30. Gulick RM, Ribaudo HJ, Shikuma CM, Lalama C, Schackman BR, Meyer WA III, et al
. Three- vs. four-drug antiretroviral regimen for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA 2006; 296:769–781.
This article has been cited 11 time(s).
Expert Review of Anti-Infective TherapyAssessing adherence to antiretroviral therapy in randomized HIV clinical trials: a review of currently used methodsExpert Review of Anti-Infective Therapy
Quadruple nucleoside therapy with zidovudine, lamivudine, abacavir and tenofovir in the treatment of HIV
Antiviral Therapy, 12(5):
AIDS Research and Human RetrovirusesModulation of K65R Selection by Zidovudine Inclusion: Analysis of HIV Resistance Selection in Subjects with Virologic Failure Receiving Once-Daily Abacavir/Lamivudine/Zidovudine and Tenofovir DF (Study COL40263)AIDS Research and Human Retroviruses
Journal of Theoretical BiologyModeling HIV persistence, the latent reservoir, and viral blipsJournal of Theoretical Biology
Clinical TrialsMethodological issues in the use of composite endpoints in clinical trials: examples from the HIV fieldClinical Trials
Journal of Infectious DiseasesDrug interactions involving combination antiretroviral therapy and other anti-infective agents: Repercussions for resource-limited countriesJournal of Infectious Diseases
Hiv Clinical TrialsSimplified maintenance therapy with abacavir/lamivudine/zidovudine plus tenofovir after sustained HIV load suppression: Four years of follow-upHiv Clinical Trials
JAIDS Journal of Acquired Immune Deficiency SyndromesExpanding Antiretroviral Options in Resource-Limited Settings-A Cost-Effectiveness AnalysisJAIDS Journal of Acquired Immune Deficiency Syndromes
Abacavir; antiretroviral therapy; efavirenz; lamivudine; non-nucleoside reverse transcriptase inhibitors; nucleoside reverse transcriptase inhibitors; quadruple nucleosides; tenofovir; zidovudine
© 2007 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.