We examined the effects of plasma efavirenz concentrations, rifampicin cotreatment and pharmacogenetic variations in five relevant genes on the incidence of efavirenz related neuropsychiatric symptoms using sleep disorders, hallucinations and cognition as its measure. Our results indicate efavirenz plasma concentration as a main predictor of neuropsychiatric symptoms in Ugandan HIV patients receiving efavirenz based ART, a finding that is consistent with previous reports from other populations [28, 34, 42]. Efavirenz plasma concentrations were predicted by CYP2B6 genotypes at all study time points. Though not statistically significant, we observed a tendency of CYP2B6*6 genotype to be associated with relatively higher incidence of sleep disorder and hallucination by second week of initiation of therapy. The cumulative hazards for the incidence of neuropsychiatric symptoms were relatively higher in CYP2B6*6 genotypes (Figure 1). Our result indicates that neither genetic polymorphism of CYP3A5 and ABCB1 (c.4036 A/G and C3435T), CYP2A6 (*9 and *17) nor rifampicin co-treatment are significantly correlated to efavirenz associated neuropsychiatric symptoms. We observed a tendency of NR1I3 rs3003596CT genotype and sex to be associated with neuropsychiatric symptoms. This study is one of the few that have examined efavirenz related neuropsychiatric toxicity during rifampicin treatment in an African context where HIV/TB co-infection and CYP2B6 genetic variation are most prevalent.
HIV infection is characterized by acquired impairment in cognitive functioning, disturbances in memory, attention and processing speed . It is important to note that HIV/TB co infected patients are usually very ill and hence their performance on cognitive tests may in part be influenced by their physical wellbeing. Interestingly one third of the study participants experienced neuropsychiatric symptoms, mainly cognitive disordered at baseline, which improved later during ART. Our result is supporting the evidence that HAART can improve the cognitive dysfunction [48, 49].
On the other hand other neuropsychiatric symptoms associated with efavirenz therapy are recognized as a major cause of non-adherence . Clinical studies have shown a high incidence of psychiatric effects among HIV patients being treated with efavirenz, ranging from 61% to 90% [10–12]. Similarly in the present study, 73% of the patients experienced neuropsychiatric symptoms during the initial twelve weeks of efavirenz treatment. Sleep disorders 60.5% were commonest followed by hallucination 30.7%.
Notable however, is the lack of any significant differences in the incidence of efavirenz related neuropsychiatric symptoms between the two treatment groups even at week two. Efavirenz product information indicates the possibility of 20% and 26% reduction in Cmax and AUC respectively, upon co-treatment with rifampicin . Therefore rifampicin co-treatment is anticipated to lower plasma efavirenz concentration and hence lower incidence of neuropsychiatric symptoms among patient receiving concomitant therapy. But effect of rifampicin on efavirenz pharmacokinetics varies between populations. In the present study effect of rifampicin cotreatment on plasma efavirenz concentration was observed during the first week of efavirenz initiation. Then after there was no significant difference in the mean plasma efavirenz concentration between patients receiving efavirenz with or without rifampicin (Table 2). Coherent with this, we found comparable efavirenz related neuropsychiatric toxicity profiles among patients treated with or without rifampicin based anti-tuberculosis therapy, which is similar to other studies [51, 52]. This finding is plausibly explained by similar efavirenz concentrations exhibited by patients in the two treatment groups. Similar to our finding, several studies mainly in black and Asian populations, reported insignificant effect of rifampicin on efavirenz plasma concentration or even paradoxically increased efavirenz concentration during rifampicin cotreatment [32, 53–58]. Anti-TB drug adverse drug reactions have previously been reported to have significant psychological effects on patients [36, 37, 59]. This study however demonstrates that even with similar efavirenz plasma concentrations in both treatment groups, neuropsychiatric symptoms did not differ implying that anti-TB treatment related neuropsychiatric effects may not be significant among Ugandan HIV patients treated with efavirenz based regimens.
While this study demonstrates influence of CYP2B6 genotype on efavirenz plasma concentrations which predicted neuropsychiatric toxicity, we did not observe a direct significant relationship between genotypes and neuropsychiatric toxicity but rather a tendency. All patients homozygous for CYP2B6*6 allele, except one experienced neuropsychiatric symptoms. Previous studies demonstrated association of CYP2B6*6 with early discontinuation of efavirenz-containing regimens mainly due to neurotoxicity [41, 60, 61] whereas others failed to demonstrate direct associations between CYP2B6 genotypes. Similar to our finding a recent study in South African population reported a strong association of efavirenz plasma concentration and a tendency of CYP2B6*6 genotype with risk of developing neuropsychiatric symptoms . Our findings reveal indirect association of CYP2B6 genotype with efavirenz related neuropsychiatric disorders, indicating the need for more association studies with larger sample size and power. On the other hand, even with reported involvement of p-glycoprotein in the drugs oral absorption and cerebral spinal fluid concentrations, polymorphism of ABCB1 at neither c.4036 A/G (rs3842) nor c.3435C/T was associated with efavirenz neuropsychiatric toxicity, although a tendency to influence day 3 efavirenz concentrations and significant effect on week-8 by c.4036 A/G (rs3843) was observed. Similarly no effect of CYP2B6*11 genotype on neuropsychiatric symptoms was observed despites its association with efavirenz plasma concentration at day-3, week-2 and week-4. The observed allele frequency of CYP2B6*11 and ABCB1 c.4036G alleles is lower than CYP2B6*6 allele in Ugandan population and hence our study sample size may lack adequate power to determine the actual effect size and hence future studies with larger sample size are required.
Current HIV treatment guidelines recommend immediate initiation of ART in HIV patients diagnosed with TB co-infection. Based on the endemicity of TB-HIV co-infection, there is an anticipated increase in patients concomitantly treated with efavirenz and rifampicin particularly in sub-Saharan Africa. The findings of this study, which on one hand allay concerns of possible pooled neuropsychiatric effects of efavirenz and anti-TB drug related adverse drug reactions [36, 37, 59], are in synchrony with periods of adaption of both CDC and WHO guidelines by Uganda and other countries within the African region. Our study may have important clinical implications indicating no effect of concomitant rifampicin therapy in HIV patients with respect to efavirenz associated CNS toxicity. Ideally, neuropsychiatric toxicity should be assessed against CSF efavirenz concentrations, which was not possible to do in the present study. However, results of this study indicate the relationship between CYP2B6 and ABCB1 genetic polymorphisms with efavirenz plasma concentrations.