Background:  HIV neurocognitive disorder results in neurodegeneration and rising viral burden in brain and CSF. Clinical studies indicate antiretrovirals improves cognitive impairment, however which agents ameliorate brain damage is not known. Also, at present a number of drug resistant viral strains have emerged. Due to the limited knowledge in this area of research it is important to identify the best available drugs for treating the drug resistant strains existing at present. We assessed the efficacy of four reverse transcriptase (RT) inhibitors to suppress viral replication in an AZT resistant strain in human brain tissue. 

Methods:  We utilised our human brain aggregate model consisting of all the relevant cell types: neurons, astrocytes, oligodendrocytes, and microglia/macrophages. Following 4r weeks establishment, aggregates were infected with the HIV-1 AZT resistant strain (RT mutations of 67N, 70R, 215F, and 219Q) (at 10^-1 multiplicity of infection) to which, efavirenz (Efv, 35nM or 350nM), stavudine (D4T, 0.3mM), didanosine (DDI, 0.1mM) or zidovudine (AZT, 2nM) was added either prior to or simultaneously as infection. Efv was also investigated in combination with D4T or DDI and a combination of D4T with DDI. Viral replication was demonstrated by p24 ELISA. The rate of increase (from day 0 to 6) or decrease (from day six to twelve) in viral replication was observed.

Results:  Efv on its own significantly reduced the rate of increase of viral replication from day zero to six at both concentrations 35 nM and 350 nM (univariate analysis of variance, simple contrast, p = 0.022, p = 0.018, respectively). In addition these 2 doses effectively increased the rate of decline of viral replication from days 6 to 12 (p = 0.016 and p = 0.014 at 35 nM and 350 nM, respectively). D4T, DDI, and AZT on their own were not found to reduce the rate of viral replication in HIV-1 AZT resistant strain. Moreover, the combination of D4T and DDI significantly suppressed the rate of increase and decrease in viral replication (p = 0.025 and p = 0.014, respectively).  

Conclusions:  All 4 RT inhibitors were utilised at levels observed in the CSF and within the IC₅₀ range. Both D4T and DDI in combination were found to be effective in suppressing the rate of viral replication in this AZT resistant viral strain. Importantly, Efv on its own significantly suppressed the rate of replication and can be considered as an effective agent for treating zidovudine resistant strains. 

Keywords: efavirenz; neuroprotection; HIV replication