Background: Highly active antiretroviral therapy, but also simpler anti-HIV treatment regimens, including zidovudine (AZT) monotherapy or dual nucleoside reverse transcriptase inhibitor (NRTI) combinations, have been associated with a reduced prevalence of both HIV-related neurocognitive disorders and HIV encephalitis. Objective of this study was to investigate the impact of HIV reverse transcriptase (RT) resistance on the prevalence of HIV-related brain lesions.

Methods:  We retrospectively studied 23 patients with neurological complications observed between 1995 and 1998 for RT resistance mutations in cerebrospinal fluid (CSF) and presence of HIV-related brain lesions at post-mortem examination. Median distance between CSF sampling and death was 21 days (range 4 to 60). All of the patients had been treated with AZT for a median of 480 days (range 30 to 2567). Other administered NRTI included ddI (n = 13), ddC (n = 4), d4T (n = 2) and 3TC (n = 1); 2 patients had received protease inhibitors. At the time of CSF sampling, only two patients were on antiretroviral treatment (AZT or 3TC monotherapy). The other patients had withdrawn any treatment a median of 100 days (range 25-870) and AZT a median of 180 days (range 25 to 900) before sampling.

Results: Of 23 patients, 11 had RT resistance mutations in CSF, always including 1 to 4 nucleotide excision mutations (NEM), i.e., mutations at codons 41, 67, 70, 210, 215, and 219. Other RT or protease resistance mutations were observed in three and one patient, respectively. HIV-related brain lesions were found in 2 of 11 patients with NEM (18%) and in 8 of 12 patients with wild-type (WT) virus (67%, p = 0.019). No differences in CSF or plasma viral load, or in the duration of anti-HIV treatments, including AZT, were observed between patients with or without NEM.

Conclusions: Development of HIV resistant strains carrying NEM in CSF is associated with a reduced frequency of HIV-related brain lesions. These mutations are known for being primarily selected in patients treated with AZT or d4T and for interfering with the response to these and other NRTIs, but may also be associated with a low viral replicative capacity in vitro compared to WT virus. Their presence in the CNS might in part explain the neuroprotective effect of AZT and other NRTI.

Keywords: HIV encephalitis; RT resistance mutations; cerebrospinal fluid