The association between cigarette smoking and efavirenz plasma concentration using the population pharmacokinetic approach

AIMS: Efavirenz is still widely used as the preferred first-line antiretroviral agent in middle- and low-income countries, including Malaysia. The efavirenz population pharmacokinetic profile among HIV-positive smokers is still unknown. We aimed to assess the association of smoking with efavirenz and the differences in HIV clinical outcomes.

METHODS: A total of 154 stable HIV-positive patients on efavirenz in northern Malaysia were recruited with a sparse sampling for this multicentre prospective cohort study. The association between smoking and efavirenz pharmacokinetic parameters was determined using the nonlinear mixed-effect model. A mixture model of clearance was adopted to describe the metaboliser status because genetic data are unavailable. The effect of smoking on HIV clinical markers (CD4, CD4/CD8 ratio and viral blips) for at least 2 years after the antiretroviral initiation was also investigated.

RESULTS: Our data were best fitted with a 1-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (β = 1.39; 95% confidence interval: 1.07 to 1.91), while weight affected both clearance and volume. From the mixture model, 20% of patients were in the slow clearance group, which mimic the genotype distribution of slow metaboliser. An efavirenz dose reduction is not recommended for smokers ≥60 kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4/CD8 ratio.

CONCLUSIONS: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.