Background:  In the last decade, combination ART (cART) has greatly improved survival of HIV⁺ patients with progressive multifocal leucoencephalopathy (PML) by restoring specific immune response to JC virus (JCV), the causative agent of PML. Moreover, the HIV Tat protein is suspected to promote JCV replication in glial cells through direct or indirect pathways. We aimed to examine the relationship between survival on antiretroviral drugs (ARV) of HIV⁺ patients with PML and ARV penetration into the central nervous system (CNS).

Methods:  From the French Hospital Database on HIV (FHDH), a large prospective hospital cohort, we assessed the impact of the ARV penetration into the CNS on survival after a PML diagnosis using multivariate Cox proportional hazards models for mortality adjusted on:  age, AIDS stage before diagnosis, CD4 cells count nadir, geographical origin, sex, exposure group, and calendar periods (pre-cART period—1992 to 1995; and 3 cART periods—1996 to 1998, 1999 to 2002, and 2003 to 2004). Each ARV was given a cerebral penetration-effectiveness (CPE) score graded from 0 (low penetration) to 1 (high penetration) according (0: didanosine [ddI], tenofovir [TNF], dideoxycytidine [ddC], amprenavir [APV], nelfinavir [NFV], ritonavir [RTV], saquinavir [SQV], SQV/ritonavir[r], tipranavir [TPV]/r, enfuvirtide [T20]; 0.5:  lamivudine [3TC], stavudine [d4T], elfinavir [EFV], APV/r, FPV/r, atazanavir [ATZ]/r, darunavir [DRV]/r; 1:  abacavir [ABC], FTC, zidovudine [AZT], delavirdine [DLV], nevirapine [NVP], indinavir [IDV], IDV/r, lopinavir [LPV]/r). For each patient, the regimen CPE score was calculated as the sum of the scores of each ARV and considered as a time-dependent covariate with 3 categories: no antiretroviral, ARV regimen with CPE score <1.5 and ARV regimen with CPE score ≥1.5.

Results:  During the study period, 1427 patients diagnosed with PML were included, 923 of them died. During the follow-up, 663 patients received ARV regimen with CPE score ≥1.5. In the pre-cART period, 1-year survival after diagnosis was 19.8% (16.6%, 23.0%); it was 54.1% (50.2%, 58.0%) in 1996 to 2004. Compared with no ARV treatment, adjusted mortality hazards ratio associated to ARV regimen with a CPE score <1.5 during the follow-up was 1.04 (0.87, 1.24) and adjusted mortality HR associated to ARV regimen with a CPE score ≥1.5 was 0.62 (0.49, 0.79).

Conclusions:  Survival after a PML diagnosis improved dramatically in the cART era as compared to the pre-cART era. Moreover, ARV regimen including drugs with high CNS penetration lead to a better survival. These results suggest that the  control of HIV replication in the CNS plays a role in the containment of PML, distinct from JCV-specific cellular immune recovery.