Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy

Abstract

Background: Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery.

Methods and findings: All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008).

Conclusions: The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death.

Trial registration: ClinicalTrials.gov NCT00120367.

Figure 1. Survival of PML patients on five-drug antiretroviral treatment.

Kaplan-Meier estimates and 95% confidence interval of the survival rate during five-drug antiretroviral therapy after PML diagnosis. Baseline is the date of the first dose of enfuvirtide. Follow-up is censored at 12 months. The one-year cumulative probability of survival was 0.75 (95% CI, 0.61–0.93). Seven patients died, all before 4 months.

Figure 2.. Time course of clinical and virological parameters.

Biphasic course of a normalized neurological score from baseline to M6 (panel A) and of the Karnofsky performance score from baseline to M12 (panel B). Early and sustained plasma HIV RNA response from baseline to M12 on early five-drug antiretroviral therapy (panel C). Significant reduction in JCV DNA in CSF at M6 (panel D). Whiskers represent medians and interquartiles. Wilcoxon's signed-rank test : * P<0.05, ** P<0.01, *** P<0.001.

Figure 3. Time course of CD4+ and CD8+ T cell populations from baseline to month 12.

Compared to baseline, significant increases were observed at W6 and at each subsequent time point in: the CD4+ T cell count (panel A); the CD4∶CD8 ratio (panel C); naive CD4+ T cells (panel D); central memory CD4+ T cells (panel E); and effector memory CD4+ T cells (panel F). No significant variation in the CD8+ T cell count (panel B) was noted during follow-up. (naive = CD45RA+CD62L+, central memory = CD45RA−CD62L+), effector memory = CD45RA−CD62L−). Whiskers represent medians and interquartiles. Black lines represent survivors and grey lines patients who died. Wilcoxon's signed-rank test : * P<0.05, ** P<0.01, *** P<0.001.

Figure 4. JCV-specific T-cell responses during follow-up.

Panel A: Analysis of anti-JCV CD4+ T cell responses. Panel B: Analysis of ex-vivo anti-JCV CD8+ T-cell responses. A patient was considered to be a responder if he or she had a positive response to at least one JCV VP1 overlapping peptide pool among the 14 pools tested. Panel C shows the percentage of responding pools among the 14 pools tested in each survivor during follow-up. Five of the 21 survivors who had no responses at any time are not represented.