The inclusion of both age and weight to predict accurate EFV CL values for the respective genotype groups within this paediatric population was required, whereas the addition of gender and body surface area did not improve the predictions. The importance of introducing IOV in a PK model for a longitudinal study with sparsely collected data was again highlighted by this investigation.

Efavirenz is a highly effective HIV-1 antiretroviral; however, it is also frequently associated with neuropsychiatric adverse events (NPAE) that include abnormal dreams, sleep disturbances, nervousness, anxiety, depression, and dizziness. The incidence of NPAEs upon initiation of treatment with efavirenz-containing medications is high, exceeding 50% in most studies. Although the NPAEs tend to decrease after the first month in many patients, they persist for long periods of time in others. Efavirenz-based treatment is generally well-tolerated in children, although some experience persistent concentration problems, as well as sleep disturbances, psychotic reactions, and seizures. In an effort to link basic with clinical research, parameters associated with efavirenz brain exposure are discussed, and factors that increase efavirenz levels are explored in depth as they are expected to contribute to NPAE risk. These include the role of modifiable and nonmodifiable risk factors such as diet, weight, and drug-drug interactions and sex, age, and ethnicity/pharmacogenetics. In addition to NPAEs, this review explores what is known about antiretroviral (ARV) drugs being used for recreational purposes. Although multiple ARV drugs are covered, special attention is devoted to efavirenz given that the majority of reports of NPAEs and illicit use of ARV drugs concern efavirenz. The evolving molecular mechanistic basis of NPAEs and abuse of efavirenz point to a complex and polymodal receptor pharmacology. Animal studies to date primarily point to a serotonergic mechanism of action. Recently emerging associations between HIV-associated neurocognitive disorder and efavirenz use, and possible contributions of the mitochondrial-immune-inflammatory-redox cascade are explored in the context of the signaling mechanisms that appear to be involved.

Previous studies of gastric secretory function and serum gastrin levels in patients with chronic renal failure (CRF) have yielded conflicting results. In a study of 30 patients on regular hemodialysis, serum gastrin levels were higher than normal (p < 0.05), and the gastric secretory response to pentagastrin was normal for the group as a whole. There were, however, 8 patients who were hypochlorhydric (4 achlorhydric) and 7 who were hyperchlorhydric. The patients with gastric hyposecretion were older, predominantly male and this group was associated with the highest gastrin levels as well as the highest incidence of gastrointestinal hemorrhage. Chronic gastritis is thus more common in CRF than generally believed and may be responsible for much of the morbidity from gastrointestinal complications during hemodialysis.

The aim of this study was to quantify the plasma efavirenz concentrations over 6 months in black HIV-1-infected South African children (3-14 years), from resource-limited households, attending an outpatient clinic. The children were antiretroviral treatment (ART) naive and received efavirenz in combination with two nucleoside reverse transcriptase inhibitors according to South African national guidelines. Two blood samples were taken between 12 and 20 h after the last efavirenz dose at 1 (n = 58), 3 (n = 54), and 6 (n = 54) months post-ART initiation. A total of 328 efavirenz mid-dose plasma samples from 58 patients was determined with a validated liquid chromatography tandem mass spectrometry method. Viral suppression (<25 copies/ml) was achieved in 95% of the children after 6 months on ART. The median (range) plasma concentration at time points 1 and 2 were 2.06 (0.10-11.14) and 1.80 (0.14-10.70) microg/ml with respective mean (+/-SD) blood sampling times of 15.24 (2.03) and 16.91 (2.03) h post-evening dose. Efavirenz plasma samples within the therapeutic range of 1-4 microg/ml accounted for 58%; 17% were <1 microg/ml and 25% were >4 microg/ml over the 6 months. Efavirenz levels persistently >4 microg/ml were recorded for 13 (23%) children and 3 (5%) children had persistent efavirenz levels <1 microg/ml. Possible reasons for efavirenz plasma levels outside the accepted therapeutic range include genetic variation in drug metabolism, incorrect dosing, drug-drug interactions, and nonadherence. However, these need to be further explored and the importance of sequential plasma levels has been highlighted in this study.