Transition modeling of neuropsychiatric impairment in HIV

• A continuous time Markov model adequately described efavirenz treatment-associated neuropsychiatric impairment.
• Efavirenz dose reduction from 600 to 400 mg would reduce the duration of neuropsychiatric impairment in HIV patients who get impaired without affecting efficacy.
• Delayed neuropsychiatric symptoms are less likely related to efavirenz exposure.

Few studies have reported analyses of neuropsychiatric impairment (NPI) data from HIV patients, in a real world clinical setting with the aim of establishing association between anti-retroviral drug concentrations and NPI development and resolution. No study has modeled the effect of efavirenz exposure beyond the pre-steady state period on the frequency and duration of NPI. The data used consists of 196 HIV patients whose efavirenz pharmacokinetic parameters were previously determined. Neuropsychiatric evaluation was done at baseline, week 2 and week 12. Patients were classified into NORMAL and NPI states. The duration of NPI was further classified as transient (NPI at week 2 but not at week 12), persistent (NPI at week 2 and 12) and delayed (NPI at week 12 but not at week 2). The proportion of patients in each duration category out of the total NPI patients was calculated. A continuous time Markov model was developed in NONMEM 7.3 and used to describe the relationship between efavirenz exposure and the duration of NPI. Monte Carlo simulations with the model were used to describe the effect of efavirenz dose reduction from 600 mg to 400 mg on the duration of NPI. The model adequately described the data. The influence of efavirenz exposure on the rate of development of NPI decayed with a half-life of 8.4 days. Efavirenz dose reduction to 400 mg significantly reduces the duration of NPI, but has no impact on delayed NPI symptoms or efficacy.