A triple NRTI regimen containing abacavir showed a trend to poorer virological control than NNRTI-containing regimens in a study published in the September 11th edition of the New England Journal of Medicine. In the article, Spanish investigators present data from the NEFA study, in which protease inhibitor treated patients with controlled viral load substituted NNRTIs efavirenz or nevirapine, or the NRTI abacavir for their protease inhibitor. After twelve months follow-up abacavir-treated patients showed a trend towards greater likelihood of virologic rebound. However, the investigators believe that this was due to prior suboptimal NRTI therapy in the vast majority of cases, and highlight the better lipid profile for the abacavir-containing regimen.
Between 1999 and 2001 460 patients who had maintained an HIV viral load below 200 copies/mL for at least six months after taking HAART including a protease inhibitor and two NRTIs were randomised on an equal basis to replace their protease inhibitor with either the NNRTIs efavirenz or nevirapine, or the NRTI abacavir. The main reason for patients switching therapy was treatment simplification.
Investigators wished to see how many patients in each of the three arms of the study maintained a viral load below 200 copies/mL at twelve months, progressed to an AIDS-defining condition, or died. Secondary endpoints of the study were changes in CD4 cell count, the incidence of side-effects, alterations in blood lipids, and changes in body shape.
The baseline characteristics of the three arms of the study were comparable. After twelve months, in an intent-to-treat analysis 6% of patients in the efavirenz arm had reached a study endpoint, as had 10% of individuals treated with nevirapine and 13% of those receiving abacavir (p=0.10).
Patients who had received prior suboptimal therapy consisting of either NRTI mono- or dual-therapy were over-represented amongst those reaching a study end-point (62% of the nevirapine arm, 80% in the efavirenz arm and 88% in the abacavir arm (hazard ratio 3.76, 95% CI: 1.53 – 9.23, p=0.004).
There was no statistically significant difference in median changes in CD4 cell count between the three arms of the study, with patients receiving nevirapine experiencing a median increase of 50 cells/mm3 compared to 49 cells/mm3 for individuals treated with efavirenz and 39 cells/mm3 for those taking abacavir.
Virological failure, defined as two consecutive HIV viral loads above 200 copies/mL was observed in 29 patients. It was possible to perform resistance tests on 21 of these individuals, five in the nevirapine arm, two in the efavirenz and 14 in the abacavir. All of these patients had resistance mutations to their study medication and to NRTIs.
The incidence of side-effects was significantly lower in the abacavir arm (41%) than the nevirapine group (54%) and the efavirenz-treated patients (57%, p=0.03). Significantly fewer abacaivr-treated patients also discontinued therapy (6% versus 17% for both nevirapine and efavirenz, p=0.01).
Fasting cholesterol was lower in the abacavir arm at the end of the study than the other two medication groups (p
Median fasting glucose levels were significantly higher in the efavirenz group than in either the nevirapine and abacavir arms (p
Commenting on their findings the investigators say, “there was a trend toward a higher failure rate when abacavir rather than nevirapine or efavirenz replaced the protease inhibitor”. Virological failure occurred, the authors stress, almost exclusively amongst patients who had received prior suboptimal NRTI therapy, with resistance tests finding NRTI resistance “in almost all such patients.” Cross-resistance between abacavir and other NRTIs could be an explanation, the investigators suggest, for the higher rate of virological failure seen in this arm of the study.
On the basis of their data, the investigators do not recommend switching treatment from a protease inhibitor to an NNRTI or abavacir as a “strategy to ameliorate body-fat abnormalities.”
The study concludes that “simplification of HAART in patients with a sustained virological response had a higher probability of maintaining viral suppression if nevirapine or efavirenz was substituted for a protease inhibitor than if abacavir was substituted”, particularly if an individual had received earlier suboptimal anti-HIV treatment. Side-effects were, however, less frequently reported in the abacavir arm of the study, and patients receiving this drug also experienced a greater fall in blood lipids.
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Martinez E et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. New England Journal of Medicine 349: 1036 – 1046, 2003.