The ongoing debate about the relative merits of the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine is likely to be further inflamed by analyses from two of the UK’s largest clinic cohorts, one showing that efavirenz is significantly more durable than nevirapine, the other that long-term efavirenz CNS toxicity is higher than previously detected. The findings were presented at last week’s Ninth Annual Conference of the British HIV Association in Manchester.
Durability
Dr Chloe Orkin, a Clinical Research Fellow at the Chelsea and Westminster Hospital, London, reported on the durability of efavirenz in a cohort of 625 patients who had received a non-nucleoside reverse transcriptase inhibitor as first-line therapy since January 1996.
297 received nevirapine, and 17 of these patients subsequently switched to efavirenz, whilst 32 were lost to follow-up. 328 received efavirenz, of whom 14 subsequently switched to nevirapine, with 14 lost to follow-up. 292 patient years of follow-up were available for analysis.
Twenty-five per cent of patients had experienced failure of the nevirapine-containing regimen by 15 months, but it took 28 months for a quarter of efavirenz recipients to experience failure of their assigned regimen. Failure was defined as either viral rebound above 500 copies/ml or switching from the originally prescribed NNRTI.
Multivariate analysis showed that patients with a baseline CD4 count above 100 cells/mm3 were 53% less likely to experience treatment failure than those with CD4 counts below 100 (HR 0.47), whilst those who received a nucleoside analogue backbone comprising d4T/ddI were almost twice as likely as those receiving AZT/3TC to experience treatment failure (RH 1.93).
Overall, patients who received efavirenz were 40% less likely to fail when compared with nevirapine recipients (HR 0.60).
Year of commencing therapy did not affect outcome, suggesting that improvements in adherence support did not skew the results in favour of efavirenz, which has been the preferred first-line therapy at the Chelsea and Westminster Hospital.
Toxicity
An analysis that included treatment-experienced patients was carried out by Leonie Swaden and Caroline Sabin on the Royal Free Hospital’s HIV cohort. 483 patients had taken a regimen that included efavirenz, of whom 75% achieved a viral load below 500 copies/ml within six months of commencing the NNRTI. The presence of AZT (zidovudine) in the regimen, together with starting efavirenz after 1998, were significant predictors of achieving a viral load below 400 copies. The most commonly prescribed nucleoside analogue backbones were AZT/3TC (32%), d4T/3TC (17%) and ddI/d4T (13%). Older age was also a significant predictor.
Prior NNRTI or protease inhibitor therapy, starting efavirenz prior to 2000 and younger age were associated with virologic rebound (two viral loads above 500 copies/ml).
A median of 23 months’ follow-up was available for efavirenz-treated individuals in this cohort.
Thirty-seven per cent of antiretroviral-naïve individuals had stopped efavirenz treatment within 24 months of starting it (27% after 12 months and 19% by six months).
13% of efavirenz-treated patients who stopped the drug within two years did so due to central nervous system adverse events, a higher rate than reported in clinical trials. The numbers of people stopping efavirenz did not decline as time on therapy increased, indicating that CNS toxicities may emerge, or become increasingly problematic beyond the first few months of therapy (the time when patients are usually counselled to expect such problems).
Risk factors associated with stopping efavirenz due to CNS toxicity were male gender, white race and concomitant treatment with a protease inhibitor.
Dr Caroline Sabin told aidsmap that the results opened up an important new area of investigation.
“We will need to look more carefully at the interaction of the nucleoside analogue backbone with the NNRTI following the results of these studies, to determine which element may be contributing particular benefit.”
Further information on this website
What to start with - an overview of the evidence.
References
Matthews G et al. Durability of efavirenz compared to nevirapine with long-term follow-up of an antiretroviral-naïve patient cohort. Ninth Annual Conference of the British HIV Association, Manchester, abstract 08, 2003.
Swaden L et al. Efavirenz: what happens in the long term? Ninth Annual Conference of the British HIV Association, Manchester, abstract 09, 2003.