A higher frequency of inadequate plasma levels of nevirapine may be a contributing factor to its apparent lack of potency compared with efavirenz, according to data presented today at the 9th European AIDS Conference in Warsaw by Gilles Peytavin, reporting from a substudy of the Narval-ANRS 088 trial, which initially set out to compare differences between genotypic and phenotypic resistance testing.
The study found that after 12 weeks, out of 357 treatment-experienced, but NNRTI-naive, individuals on NNRTI-based HAART, 56% versus 28% of those treated with efavirenz and nevirapine had a viral load
Both arms had similar patient characteristics, with around 290 CD4s at baseline, and plasma viral load of around 4.4 logs, although twice as many people were on an efavirenz-containing combination (n=227) compared with nevirapine (n=130).
Plasma concentrations of the drugs were measured at various time points in the study (weeks two, six and 12) and were considered adequate if they reached 1,100 and 4,000ng/mL, for efavirenz and nevirapine, respectively. Surprisingly - and highly significantly - they found that whilst 91% had adequate levels of efavirenz, only 57% had adequate levels of nevirapine (p
When they looked at drug plasma levels and virological response together, they found that the median log reduction in plasma viral load was -1.92 for those with adequate, and -1.44 for those with inadequate levels of efavirenz. Those with adequate levels of nevirapine had a median -0.86 log reduction compared with a -0.38 log reduction in those with inadequate levels. Again this was found to be highly statistically significant (p
This difference in plasma levels partially explains why efavirenz was associated with virological success in multivariate analysis (OR=4.37; 95% CI 2.76-6.90), while nevirapine was not (OR=1.065; 95% CI 0.59-1.89), and suggests that therapeutic drug level monitoring should be routine when starting on a nevirapine-containing regimen. Additionally, since NNRTI resistance can occur within only a few weeks of suboptimal levels, a rapid response to dealing with suboptimal levels must occur.
Interestingly, a poster presentation in Warsaw from the Liverpool therapeutic drug monitoring (TDM) Service shows that between 1999 and 2003, 32.2 % of nevirapine trough plasma concentrations were found to be below target values compared with 30.4% of efavirenz. Although the difference is not significant and inevitably subject to the selection bias of referral for therapeutic drug monitoring due to inadequate response, the results highlight the need to take NNRTI drug levels seriously, particularly in patients receiving an NNRTI as part of a salvage combination.
Peytavin G. et al. Impact Of non nucleoside reverse transcriptase inhibitors plasma concentrations on virological response to antiretroviral therapy In HIV-1 infected NNRTI naive-patients enrolled In Anrs 088 trial
Ninth European Aids Conference, abstract F2/1, 2003.
Gibbons S.E. et al. Therapeutic Drug Monitoring - Lessons from four years Of running a clinical service in the UK Ninth European Aids Conference, abstract 4.2/7, 2003.