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.
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.
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.
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.
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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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)