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.
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
Abacavir; antiretroviral therapy; efavirenz; lamivudine; non-nucleoside reverse transcriptase inhibitors; nucleoside reverse transcriptase inhibitors; quadruple nucleosides; tenofovir; zidovudine