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Reply: Pathological heterogeneity in multiple sclerosis: A reflection of lesion stage?

Controversial results of neuropathological studies assessing the effect of antiretroviral treatment on central nervous system (CNS) diseases have emphasized the need for longitudinal studies. A recent article published by d’Arminio Monforte and colleagues provides evidence of a decreased incidence of acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) and other CNS diseases in a European cohort of human immunodeficiency virus (HIV)–infected individuals between 1994 and 2002. The decrease, similar to that of non-CNS AIDS-defining illnesses, is almost completely explained by improved immunological conditions and inhibition of viral replication. Although the findings are convincing, this study has potential limits and biases, specifically, missing information on CNS diseases diagnosed after first AIDS-defining illnesses, short time of observation before the introduction of combined antiretroviral therapy, and lack of availability of HIV seroconversion dates. To confirm the results of the above-mentioned study, we repeated the analysis using data from the Italian Seroconversion Study, a cohort of individuals with known dates of HIV serconversion. Kaplan–Meier curves were used to estimate the risk of developing ADC and other CNS diseases (ie cerebral toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, primary brain lymphoma) after HIV seroconversion (estimated as the midpoint in time between the last negative and first positive test), before and after the introduction of highly active antiretroviral therapy. Adjusted relative hazards (RHs) and their 95% confidence intervals (CIs) were obtained by multivariate Cox models, with calendar year used as dichotomous time-dependent variable, adjusting for age, sex, and transmission category. Overall, 2,045 individuals were enrolled. The median age was 27 years (range, 14–75); 70% were male subjects. During a median follow-up time of 9 years, 191 participants developed an event (78 ADC, 95 other CNS diseases, and 18 both). The incidence of CNS diseases decreased from 2.3 per 100 person-years in 1996 to 0.3 in 2001–02. The risk of developing any CNS disease at 10 years after HIV seroconversion was 0.15 (95% CI, 0.13–0.19) and 0.05 (95% CI, 0.04–0.07) before and after 1997, respectively. At the multivariate analysis (Table), the risk of developing ADC and/or any CNS disease decreased significantly since 1997 (tripletherapy era), whereas no effect was observed in 1995–96 (double-therapy era). In conclusion, we confirm the decline of the incidence of ADC and other CNS diseases, also when controlling for duration of HIV infection. The decline began after the introduction of triple therapy and has continued over the following years. The study was funded by “Programma Ricerche AIDS, Sottoprogetto Epidemiologia,” Istituto Superiore di Sanità.