Abacavir treatment limited by prior NRTI exposure
11 June 2002. Related: Antiretrovirals, Drug resistance.
By Brian Boyle MD, for hivandhepatitis.com
It has long been recognised that some of the characteristics of highly active antiretroviral therapy, including high pill burdens and meal restrictions, affect adherence rates.
One approach to these problems has been to simplify regimens. Trizivir (abacavir, zidovudine and lamivudine) combines three antiretrovirals in one tablet, which can be taken without meal restriction.
However, some reluctance to using this regimen persists due to previous studies that have indicated that this triple nucleoside reverse transcriptase inhibitor (NRTI) combination is not as effective as a protease inhibitor (PI) in patients with high viral loads and that some induction-maintenance strategies involving therapy with two NAs have had high rates of virologic failure associated with zidovudine (ZDV, AZT, Retrovir) resistance at baseline, poor adherence, and low plasma levels of indinavir during maintenance therapy predicted virologic failure.
In a prospective, randomised, controlled, open-label study reported in The Journal of Infectious Diseases, 163 patients treated with PI-containing combination regimens who had maintained virological suppression (<400 copies/mL) for six months and had a viral load at screening <50 copies/mL were randomised either to continue their current therapy or to change to abacavir (ABC, Ziagen) plus Combivir (lamivudine plus zidovudine).
Patients were excluded from the trial if they had a mutation detected at codon 215, suggesting prior zidovudine exposure and resistance. In February 2000, the simplified regimen was modified to Trizivir.
The median study duration was 84 weeks. In the intent-to-treat analysis of the overall population, virologic failure was more frequent in the ABC-Combivir than in the continuation group, with 13 patients (15%) versus five patients (6.0%), respectively, experiencing treatment failure. In addition, time to virologic failure was also shorter in the ABC-Combivir group.
Finally, 12 patients (15.2%) in the continuation and six (7.1%) in the ABC-Combivir group discontinued the study prematurely or were lost to follow-up. Reasons for treatment change because of adverse events in the continuation versus the ABC-Combivir group were gastrointestinal intolerance (6 vs. 1), new occurrence or worsening of lipodystrophy (6 vs. 0), hyperlipidemia (1 vs. 0), nephrolithiasis (1 vs. 0), abacavir hypersensitivity (0 vs. 1), anemia or leukopenia (0 vs. 2), and other (2 vs. 2).
Most of the virologic failures in the ABC-Combivir group (eight [62%] of 13) occurred before week 20, whereas failures in the continuation group occurred between weeks 21 and 49. Resistance data collected indicated that after a switch to ABC-Combivir reemergence of archived resistant virus might be a more important reason for virologic failure than development of new resistance mutations that developed during the simplified therapy.
In particular, a history of previous mono- or dual zidovudine therapy was noted in most patients with virologic failure and was a predictor for virologic failure in the ABC-Combivir group. When patients were stratified by history of mono- or dual zidovudine therapy, the risk of virologic failure among the 31 patients in the simplified group who had a history of zidovudine treatment was 23.5% after 48 weeks and 33.3% after 96 weeks.
The authors conclude: “In the overall population, virologic failure was more frequent (15% vs. 6%; P = .081) and occurred faster in the simplified group (P = .066, log rank test)The virologic failure rate in the simplified group was at least partially driven by a high failure rate (nine [29%] of 31) among patients with a history of zidovudine mono- or dual therapy. This strategy, therefore, is appropriate only for patients with no prior zidovudine mono- or dual therapy and no suggestion or evidence of resistance to NRTIs.”
Given the recent reports of nucleoside associated mutations (NAMS) developing with a number of NRTIs, not just zidovudine, this precaution should probably extended to any patient who has had significant prior NRTI exposure.
Therefore, changing any patient who has had any significant NRTI exposure from a successful PI or non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen to a simplified ABC-Combivir regimen may be more likely to lead to virologic failure and may be an ill-advised therapeutic strategy.
Reference:
M Opravil and others. A Randomized Trial of Simplified Maintenance Therapy with Abacavir, Lamivudine, and Zidovudine in Human Immunodeficiency Virus Infection. The Journal of Infectious Diseases. 2002; 185:1251-1260.
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