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.

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Aim: Efavirenz is still widely used as the preferred first-line antiretroviral agent in the 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 non-linear mixed-effect model (NONMEM). A mixture model of clearance was adopted to describe the metaboliser status because genetic data is unavailable. The effect of smoking on HIV clinical markers (CD4, CD4 / CD8 ratio and viral blips) for at least two years after the antiretroviral initiation was also investigated. Results: Our data were best fitted with a one-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (CL/F) (β = 1.39; 95% confidence interval (CI): 1.07 to 1.91), while weight affected both CL/F and volume (V/F). 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 ≥60kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4 / CD8 ratio. Conclusion: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.

Introduction:Statistics show that prevalence of smokers is higher among human immunodeficiency virus-positive patients. Efavirenz is still widely used in resource-limited setting around the world. In view of overlapping metabolic pathways between cigarette smoking and efavirenz, it is suggested that poorer treatment outcome among smokers with HIV might be in some way associated with abnormal plasma concentration of efavirenz. Material and methods:Comprehensive search of the literature was performed using PubMed Central, PubMed/Medline, Cochrane Review, Science Direct, Springer Link, Oxford Academic, and Lippincott Williams & Wilkins journals.Results: A total of 157 articles were chosen, out of which 8 met eligibility criteria and were reviewed. Lower efavirenz plasma concentration were found in 5 articles, where genetic polymorphism was the major significant co-variate. Only 2 studies described smoking as significantly associated with lower efavirenz plasma concentration.Conclusions: Smoking was found to be associated with a lower efavirenz plasma concentration, especially in population with genetic polymorphism. Future research is required with better methodological design, and subjects with genetic polymorphism need to be excluded, to further investigate the causal relationship of smoking status and efavirenz plasma concentration.

Aim: Efavirenz is still widely used as the preferred first-line antiretroviral agent in the 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 non-linear mixed-effect model (NONMEM). A mixture model of clearance was adopted to describe the metaboliser status because genetic data is unavailable. The effect of smoking on HIV clinical markers (CD4, CD4 / CD8 ratio and viral blips) for at least two years after the antiretroviral initiation was also investigated. Results: Our data were best fitted with a one-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (CL/F) (β = 1.39; 95% confidence interval (CI): 1.07 to 1.91), while weight affected both CL/F and volume (V/F). 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 ≥60kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4 / CD8 ratio. Conclusion: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.