Efficacy and Safety of a Once-Daily Fixed-Dose Combination of Abacavir/Lamivudine Compared With Abacavir Twice Daily and Lamivudine Once Daily as Separate Entities in Antiretroviral-Experienced HIV-1YInfected Patients (CAL30001 Study) Anthony LaMarca, MD,* Nathan Clumeck, MD, PhD,† Andreas Plettenberg, MD, PhD,‡ Pere Domingo, MD, PhD,§ Kaisong Fu, MD, PhD,Ý Charles Craig, PhD,¶ Henry Zhao, PhD,Ý Maria Watson, PhD,Ý David Gordon, MB, ChB,# and Trevor Scott, PhD,Ý on behalf of the CAL30001 Study Team Background: A one-tablet, once-daily abacavir/lamivudine fixed- dose combination (FDC) has been recently approved to treat HIV-1 infection. Methods: A randomized, open-label, parallel-group, multicenter study to compare the efficacy and safety of the FDC group to the separate entities (SE) group, in combination with tenofovir and a new protease inhibitor or nonnucleoside reverse transcription inhibitor in antiretroviral-experienced adults experiencing virologic failure (VF). Eligible subjects had viral loads 91000 copies/mL with e3 nucleoside reverse transcription inhibitor-associated mutations. The primary efficacy end point was time-average changed from baseline (average area under the curve minus baseline) in plasma HIV-1 RNA over 48 weeks. Results: A total of 186 subjects were enrolled. The average area under the curve minus baseline was j1.65 and j1.83 log 10 copies/ mL in the FDC and SE groups, respectively (intention to treat; 95% confidence interval: j0.13, 0.38). Patients in the FDC (50%) and SE groups (47%) achieved viral loads G50 copies/mL based on the time to loss of virologic response algorithm. VF was low and similar in both groups (FDC, 16%; SE, 18%). Tolerability was similar between the 2 groups. Conclusions: The FDC group had noninferior efficacy over 48 weeks to the SE group in treatment-experienced subjects with VF. Key Words: abacavir, lamivudine, fixed-dose combination, antiretroviral therapy, HIV (J Acquir Immune Defic Syndr 2006;41:598Y606) C ombination antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection. 1 However, current combination therapies have a high rate of failure due to issues involving potency, toxicity, patient adherence, individual pharmacokinetics, and/or viral resistance. 2 Regardless of the cause for failure, emergence of viral resistance to one or more of the antiretroviral agents being taken is a frequent outcome. The anticipated pattern of nucleoside reverse transcription inhibitor (NRTI) resistance in the average subject failing first- or second-line ART therapy is the M184V mutation plus 1Y2 thymidine analogue-associated mutations (TAMs). 3 Cross-resistance among NRTIs is an important consideration in the selection of subsequent regimens. Among the most important mutations to consider are the 6 major TAMs (D67N, K70R, T215Y/F, M41L, L210W, and K219Q/E), as well as the K65R, L74V, and M184V mutations. 4 The multinucleoside-resistant complexes marked by the Q151M or T69S mutations may abolish most of the antiviral activity of the NRTI class. 5,6 Mutations selected by zidovudine (ZDV) or stavudine (d4T) can have a negative effect on the susceptibility of virus to all the NRTIs in vitro, but both abacavir (ABC) and tenofovir (TDF) have been shown to confer clinical benefit in subjects with virus harboring some of these mutations. 7Y9 The K65R mutation decreases susceptibility to ABC, didanosine (ddI), and TDF. 10,11 The L74V mutation decreases susceptibility to ddI and ABC while increasing susceptibility to ZDV and possibly TDF. 12Y14 Lamivudine (3TC) rapidly selects for the M184V mutation upon virologic rebound, leading to a large increase in phenotypic resistance to 3TC. 15 However, HIV-1 with the M184V mutation has a reduced replication rate compared with the wild type, and reverse transcription with this mutation exhibits enzymatic defects such as reduced pyrophosphorolysis and decreased processivity. 16 The muta- tion reverses the effect of the TAMs in vitro and can also delay the emergence of these mutations. 15 Additionally, although the M184V mutation is associated with a small (2- to 3-fold) reduction in susceptibility to ABC, 17,18 it enhances susceptibility to TDF, d4T, and ZDV. 19 CLINICAL SCIENCE 598 J Acquir Immune Defic Syndr & Volume 41, Number 5, April 15, 2006 Received for publication March 22, 2005; accepted February 3, 2006. From the *Therafirst Medical, Fort Lauderdale, FL; †CHU Saint-Pierre, Bruxelles, Belgium; ‡Institut fuer Interdisziplinaere Infektiologie und Immunologie GmbH, Hamburg, Germany; §Hospital Sant Greu y Sant Paublo, Barcelona, Spain; ÝGlaxoSmithKline, Research Triangle Park, NC; ¶GlaxoSmithKline, Stevenage, UK; and #GlaxoSmithKline, Green- ford, UK. Supported by GlaxoSmithKline. Reprints: Trevor Robert Scott, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709. Copyright * 2006 by Lippincott Williams & Wilkins Copyr ight © Lippincott Williams & Wilkins. Unauthor iz ed reproduction of this article is prohibited.