Treatment of HIV associated neurocognitive disorders

Abstract

Background Human immunodeficiency virus (HIV) invades the central nervous system (CNS) as early as 8 days after HIV infection, causing a wide spectrum of neuropathological changes including HIV associated neurocognitive disorders (HAND). HAND is a spectrum of cognitive impairment, which in its most severe form cause marked interference with day-to-day functioning (HIV-associated dementia). Antiretroviral therapy (ART) has substantially reduced the incidence of HIV-associated dementia, but has not had an impact on the overall prevalence of HAND. The prevalence of milder stages of HAND in ART experienced individuals varies from 15 - 50%. Transporters expressed in the blood brain barrier and blood cerebrospinal fluid (CSF) barrier affect influx and efflux of drugs including antiretrovirals. Antiretrovirals that have better penetration into the CNS may result in improved cognitive function in patients with HAND, however this has not yet been conclusively shown. On the other hand, prolonged CNS exposure to high antiretroviral concentrations has been proposed as a cause of secondary decline in cognitive function as several antiretrovirals are neurotoxic. Efavirenz in particular, but also tenofovir and emtricitabine, have been shown to have direct neurotoxicity in preclinical models. Polymorphisms in genes that encode these enzymes or transporters may therefore affect antiretroviral CSF concentrations. Africans are the most genetically diverse population worldwide and South Africa has the world’s largest ART programme, with most of patients currently receiving efavirenz-tenofovir-emtricitabine. The impact of pharmacogenetic polymorphisms on the pharmacokinetics of efavirenz-tenofovir-emtricitabine CNS penetration are lacking. A number of adjunctive pharmacotherapies for HAND have been studied, including lithium. Multiple mechanisms have been suggested for the potential beneficial cognitive effect of lithium, including the inhibition of glycogen synthase kinase-3- beta, which mediates inflammation signaling pathways and neuronal apoptosis. Lithium has been used in mood disorders and other neuropsychiatric conditions for more than 40 years. In addition, lithium is a low-cost drug and widely available in public service settings in low and middle-income countries. There is a need for controlled data to evaluate the efficacy of lithium as adjunctive therapy for HAND. Finally, it is unknown whether lithium causes additive nephrotoxicity in combination with tenofovir.

Methods We conducted a 24-week randomised placebo-controlled trial of lithium as adjunctive pharmacotherapy in participants with moderate to severe HAND established on ART for at least 6 months, with suppressed viral loads. We randomised 66 participants to lithium (n=32) or placebo (n= 34). Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, while our secondary endpoint was the change in proton magnetic resonance spectroscopy (1 H-MRS) brain metabolite concentrations. We collected paired plasma-CSF samples in 47 adult participants with and without HAND treated with efavirenz-tenofovir-emtricitabine. We considered 2049 single-nucleotide polymorphisms (SNPs), including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. We investigated genetic polymorphisms associated with CSF exposure of efavirenz and its metabolites, tenofovir and emtricitabine. The secondary objective was to explore the pharmacokineticpharmacodynamic relationships with neurocognitive performance. Finally, we investigated the change in estimated glomerular filtration rate (eGFR) in participants who received concomitant tenofovir and lithium.

Results The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95% CI -0.26, 0.15); p = 0.716. The improvement remained similar when analysed according to age, severity of impairment, CD4+ count, time on ART and ART regimen. Standard 1 H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. There was no statistically significant difference in the reduction in eGFR or in potassium between the two arms during the 24 weeks. A model that included the composite CYP2B6 15582/516/983 genotype in univariate analyses best predicted the log10-transformed concentrations of plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 8-hydroxyefavirenz-to-efavirenz ratio and CSF efavirenz. Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742, ABCB1 rs115780656 and CYP2A6 -48A→C. The CYP2A6 -48A→C polymorphism was independently associated with higher CSF 8-hydroxy-efavirenz-to-efavirenz ratio. The CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenzto-efavirenz ratio in univariate on multivariate analyses adjusting for CYP2B6 516G→T and 983T→C. No polymorphisms were associated with CSF-to-plasma ratios of all 3 drugs, plasma or CSF 8-hydroxy-efavirenz, tenofovir or emtricitabine concentrations, or neurocognitive performance.

Conclusion Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment. We found that 24-week treatment of HIV-infected patients with lithium and tenofovir did not result in increased nephrotoxicity. We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz-to-efavirenz ratio, plasma 8-hydroxy-efavirenz-to-efavirenz ratio, CSF 8-hydroxy-efavirenz-to-efavirenz ratio and CSF efavirenz.