HIV Pharmacology Workshop: Are drug levels affected by racial differences?

Racial differences in therapeutic responses have been reported previously in relation to efavirenz (Sustiva)- containing treatments in African-American patients (Haas D et al 2004) correlated with polymorphic variants in CYP2B6. A collaborative study by Bichat-Claude Bernard Hospital in Paris, the Institut Pasteur and Fann University Hospital in Dakar, Senegal described the plasma concentrations of efavirenz in Senegalese patients. They observed plasma distribution and variability in 80 patients enrolled in two prospective pilot studies, administered 600mg efavirenz once a day (QD) plus two nucleoside reverse transcriptase inhibitors (NRTI) comprising 3TC (lamivudine, Epivir), ddI-EC (VidexEC) or d4T (stavudine, Zerit) to patients with CD4 cell count less than 350 cells/mm³ (baseline 143; range 93-213 cells/mm³) and viral load more than 30,000 copies/ml (5.6 log₁₀ copies/ml; range 5.2-5.8). Monitoring included monthly checks for clinical parameters, drug dispensing and adherence and three-monthly for virological, biological and immunological monitoring. Drug levels were observed at month 1 and again at month 6 using standard HPLC-UV techniques approximately 11.3 hours after the last drug intake.

At month 6, CD4 cell count had increased by 113 (range 62-162) and viral load below 50 copies in 67% of patients. At month 1 and month 6, efavirenz plasma concentrations were below 1,000 ng/ml (12% and 4%) and above 4,000 ng/ml (21% and 23%) respectively – within the usual adequate therapeutic range (1,000-4,000 ng/ml). They reported consistent plasma levels between the first and six months on therapy although a high degree of inter-individual variability was reported at 107%. No significant differences were found between men and women in the studies but a number of discontinuations were reported probably due to toxicities related to ddI and d4T. Reassuringly, these results confirm that around 70% of efavirenz plasma concentrations fall within the adequate range and demonstrate virological and immunological efficacy. 18% of patients however were found to be above the therapeutic plasma concentration range at both month 1 and 6. They speculate whether the polymorphism previously describe (CYP2B6) may explain the difference in over-exposure.

Following straight after Dr Maarten’s presentation, Jonathan Schapiro from Stanford University asked the critical question “what are the appropriate drug levels for different population groups?" The answer is that these have not yet been established. Whilst 70% of the patients in this study achieved adequate plasma levels (and consequently, nearly a third not reaching adequate levels, the comparator reference continues to be therapeutic ranges determined in a very different population. To inform large scale and long-term treatment programmes, we need to define therapeutic drug levels that are better characterised in different population groups.