HIV treatment lowers incidence of PML and improves survival if it develops

The incidence of progressive multifocal leukoencephalopathy (PML) in people with HIV declined significantly after the introduction of effective antiretroviral treatment, Swiss investigators report in the May 15^th edition of Clinical Infectious Diseases. The researchers also found that HIV treatment led to a significant improvement in the duration of survival for patients diagnosed with this condition.

PML is a disease of the central nervous system caused by JC virus. It is very rare, but is often fatal in patients with impaired immunity, including individuals with HIV.

Studies conducted before effective combination antiretroviral therapy became available in the late 1990s reported a prevalence of PML amongst people with HIV of between 0.3 and 0.8%. Less than one tenth of patients survived more than one year.

There are, however, limited data about the incidence of PML and its mortality in the era since effective HIV treatment became available. Investigators from the Swiss HIV Cohort Study therefore undertook research to address these issues.

The research involved all 189 HIV-positive patients diagnosed with PML in Switzerland between 1988 and August 2007. Prevalence of PML was highest in the period 1993-95 (0.9%), just before effective HIV treatment became available in 1996.

An analysis of survival was performed involving 159 patients. Their median age was 39 years, 74% were men and 98% were white. Approximately 50% had developed an AIDS-defining illness before PML was diagnosed. The median CD4 cell count at the time of PML diagnosis was 60 cells/mm³. Amongst the 68 patients for whom information was available, median viral load was approximately 80,000 copies/ml. Although 70% of patients were taking antiretroviral treatment at the time of PML diagnosis, only 31% were taking combination HIV therapy.

Overall, 97 patients died within a year of their PML diagnosis, the median survival time being 90 days. The one-year mortality rate was 119 deaths per 100 person years.

Of these 97 deaths, 51 were directly attributable to PML, providing a PML-attributable mortality rate of 59 deaths per 100 person years. The median time between diagnosis and PML-attributable death was 71 days.

A total of 62 patients survived for a year or more after their diagnosis with the condition. Long-term follow-up data were available for 47 of these patients. Most (83%) had persisting neurological defects and only eight individuals (17%) showed a clinical improvement.

Next the investigators compared the characteristics of PML diagnoses in the eras before and after effective HIV treatment were introduced.

The majority (56%) of PML diagnoses were made before 1996. The incidence rate of PML in the Swiss HIV Cohort was 0.24 per 100 person years before this date. It fell four-fold to 0.06 per 100 person years after effective HIV treatment became available. Furthermore, PML-attributable mortality fell from 92 deaths per 100 person years to 38 deaths per 100 person years, a decrease of approximately 50%.

The investigators’ first set of statistical analysis showed that patients treated with effective combination antiretroviral therapy (p

When the investigators controlled for factors including age and CD4 cell count, the only factor still associated with a lower risk of death was the use of combination HIV therapy (p = 0.01).

Next the investigators looked at the factors associated with all-cause mortality. The first analysis showed that a CD4 cell count above 100 cells/mm³ (p = 0.044), the use of combination treatment (p 3 and use of combination HIV therapy (p = 0.006), remained significant.

“The introduction of combination antiretroviral therapy in Switzerland in 1996 was associated with a 4-fold decrease in PML incidence to 0.06%”, write the investigators, “the decrease in PML incidence from 1996 onwards supports the notion that preservation of overall immune functions by combination antiretroviral therapy is a key factor protecting against the manifestation of PML.” The investigators also comment upon the reduction in PML-attributable mortality since effective HIV treatment was introduced, noting that the one-year mortality rate fell by half.

They conclude, “the results of this study, covering 20 years…demonstrate that the introduction of combination antiretroviral therapy has led to a decrease in the incidence of PML amongst HIV-infected patients and has reduced PML-attributable 1-year mortality, regardless of baseline CD4 T cell count”.