July 14, 2004
Abacavir (ABC, Ziagen) has received considerable recent attention through several large, GlaxoSmithKline (GSK)-sponsored studies. Collectively, these studies evaluate the effectiveness of once-daily abacavir and support the very-likely-to-be-approved abacavir/lamivudine fixed-dose combination tablet.
The ZODIAC study (also called CNA30021) was a double-blind, placebo-controlled study that randomized over 700 therapy-naive persons to receive either twice- or once-daily abacavir, in combination with once-daily lamivudine (3TC, Epivir) and efavirenz (EFV, Sustiva, Stocrin). The study was carried out for 48 weeks; the results were previously presented by distinguished Professor Brian Gazzard (Chelsea and Westminster Hospital, London) at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy.1 Overall results of ZODIAC showed that similar, or non-inferior, proportions of patients in the once- and twice-daily abacavir groups achieved undetectable HIV viral loads. Additional data on ZODIAC were presented at this conference by GSK scientists.
Dr. Jaime Hernandez (GSK, Research Triangle Park, North Carolina) presented an update on the safety profile of once-daily abacavir. Overall, the incidence of side effects and treatment-emergent and/or serious adverse events was similar between the once-daily and twice-daily groups. Importantly, there were no significant differences between suspected abacavir hypersensitivity reactions (HSR) in either group, either by frequency of occurrence or by clinical characteristics. In this study, abacavir HSR was observed in 9% of the once-daily group and 7% of the twice-daily group. The median time to onset of HSR was 9 days, and rash as the only symptom was more common in this study than in others, leading the authors to suggest that this may have contributed to the higher frequency of HSR in this study compared with other clinical trials.
Dr. Graeme Moyle (Chelsea and Westminster Hospital, London) presented an analysis of the effect of baseline resistance mutations and HIV clade on response to treatment in ZODIAC. A subset of about 200 patients in ZODIAC received baseline resistance testing. The rate of pre-existing resistance was 8% overall, with most of these subjects harboring virus with single drug-resistance mutations. Six subjects had the NNRTI resistance mutation K103N at baseline, and one had the M184V mutation. Curiously, the presence of these significant resistance mutations did not seem to affect the likelihood of responding to treatment, as 5 of these 7 patients achieved viral suppression. All of the 13 subjects who were found to have non-B-clade HIV were virological responders.
Dr. Gordon (GSK, Greenford, UK) presented a summary on studies of abacavir/lamivudine when dosed either once or twice daily with efavirenz. This analysis pooled safety data from the ZODIAC study (described above) and 2 other studies (CNA30024 and CLASS, presented by DeJesus2 at ICAAC 2003 and Bartlett at this meeting, respectively). Not unexpectedly, abacavir/lamivudine-containing regimens were shown to be generally well tolerated; side effects (excluding HSR) in patients receiving at least 48 weeks of treatment were infrequent, with discontinuation of treatment due to side effects evident in 17 of the 838 (2%) patients exposed to abacavir/lamivudine.
Taken together, these data extend an important series of studies on the safety and efficacy of abacavir/lamivudine plus efavirenz treatments, and they should have immediate impact for healthcare providers. In our clinic in Denver, abacavir/lamivudine has been used for several years; our clinical experiences mirror these reported in Bangkok. With the exception of abacavir HSR, the combination has been very well tolerated and offers a very low pill count, potentially once-daily option. These data add to an already extensive, though shorter-term (about 1 year), follow-up on patients who have received abacavir/lamivudine in a variety of treatment settings. Echoing this, Dr. Gazzard remarked here that while HSR is the major side effect of abacavir, the reaction is manageable, and that "abacavir/lamivudine NRTI [nucleoside reverse transcriptase inhibitor] backbones should allow for effective NRTI treatment options." I'll be looking forward to the abacavir/lamivudine fixed-dose combination as another important advance in antiretroviral treatment options for my patients.
Abstract: Analysis of the Effect of Baseline Resistance and Clade on 48-Week Efficacy of Once-Daily (OAD) or Twice-Daily (BID) Abacavir (ABC) in Combination With OAD Lamivudine (3TC) and Efavirenz (EFV): A Sub-Analysis of ZODIAC (Poster WePeB5698)
Authored by: G Moyle, D Gordon, J Hernandez, T Bonny, S Castillo, C Brothers, T Scott, D Paes, C Craig
Abstract: Long-Term (>48 Week) Safety of Abacavir (ABC) Once Daily (OAD) or Twice Daily (BID), in Combination With Lamivudine (3TC) OAD OR BID and Efavirenz (EFV) OAD (Poster WePeB5868)
Authored by: D Gordon, J Hernandez, A Cutrell, H Zhao, T Bonny, S Castillo, C Brothers, T Scott, D Paes
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