Background: Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by JC polyomavirus (JCV), affecting immunocompromised individuals. We describe PML demographic, clinical, radiological, and laboratory characteristics and survival over time and according to underlying condition in a large retrospective patient cohort. Methods: This is a retrospective cohort including Italian PML patients observed between 1987 and 2024, with known year of diagnosis and underlying disease. Results: We included 456 cases with either a definite (n = 376, 82.4%) or clinico-radiological (n = 80, 17.6%) PML diagnosis. The relative frequency of human immunodeficiency virus (HIV)-associated cases decreased through four time periods (1987–1996; 1997–2004; 2005–2012; 2013–2024) from 99% to 43%, in parallel with increasing age (P < .0001), proportion of women (P < .001) and CD4+ counts (P < .001) but not cerebrospinal fluid (CSF) or plasma JCV-DNA levels at diagnosis. One-year survival probability increased from 23.8% in 1987–1996 to 59.2% in 2013–2024, with highest values in natalizumab-treated multiple sclerosis (93.8%), followed by combination antiretroviral treatment (cART)-treated HIV infection (55%), hematological malignancies (50.8%), primary immunodeficiencies (41.3%), and cART-untreated HIV infection (11.9%). At multivariate analysis excluding cART-untreated people with HIV, JCV-DNA levels in both CSF and plasma were independently associated with an increased mortality risk of 2.9% and 7.2%, respectively, for each Log increase in JCV-DNA. Conclusions: This observational study showed a changing epidemiological context over 37 years. Although survival improved over time, it remained poor even in the last decade, with a one-year survival probability of 59.2%.

Lamivudine/dolutegravir (3TC/DTG) is effective and safe for most people with HIV infection (PWH) who are virologically suppressed, but specific individual’s characteristics, such as previous detection of archived resistance-associated mutations (RAMs) to 3TC and prior HBV infection, could represent a risk for virological failure (VF). We conducted a retrospective monocentric cohort study to assess rates and predictors of treatment discontinuation (TD) and VF in PWH switched to 3TC/DTG after reaching virological suppression (HIV-RNA<50 cp/mL). Overall, 188 PWH were included. Over 5145 patient-years follow-up (PYFU), 16 (8.5%) PWH experienced TD (2.87 per 1000 PYFU), whereas over 5082 PYFU, 8 (4.3%) experienced VF (1.45 per 1000 PYFU). Probabilities of TD and VF were 1.3%, 2.8%, 7.5%, 12.9%, 34.5% and 0.6%, 2.7%, 2.7%, 4.2%, 22.3% after 1, 2, 3, 4 and 5 years respectively. Independent predictors of VF were a detectable baseline HIV-RNA of 20-49 copies/ml (versus<20 copies/ml, aHR 9.11, 95 % CI 1.05-79.40; p= 0.046), and a higher GSS-score for 3TC (per 10 points more, aHR 1.57, 95 % CI 1.07-2.29; p= 0.023), with a borderline significance for anti-HBcAg positive serostatus (versus negative, aHR 8.88, 95 % CI 0.89-88.45; p= 0.062). After adjustment for age and gender, those with anti-HBcAg positivity who switched from a tenofovir-containing regimen had the highest risk of VF (versus negative anti-HBcAg and no prior tenofovir use, aHR 15.06, 95% CI 1.40-161.38; p-value= 0.025).

Lamivudine/dolutegravir (3TC/DTG) is an effective and well-tolerated antiretroviral regimen for most people with HIV (PWH) who are virologically suppressed; however, specific clinical characteristics, such as prior hepatitis B virus (HBV) exposure or archived resistance-associated mutations (RAMs), may influence the risk of virological failure (VF). We conducted a retrospective, monocentric cohort study to evaluate the incidence and predictors of VF among PWH who switched to 3TC/DTG after achieving virological suppression (HIV-RNA < 50 copies/mL). A total of 188 PWH were included. Over 5082 patient-years of follow-up (PYFU), 8 individuals (4.3%) experienced VF, corresponding to an incidence rate of 1.45 per 1000 PYFU. The cumulative probabilities of VF at 1, 2, 3, 4, and 5 years were 0.6%, 2.7%, 2.7%, 4.2%, and 22.3%, respectively. In exploratory multivariable analyses, anti-HBc positivity was associated with an increased risk of VF (adjusted hazard ratio [aHR] 4.80, 95% CI 1.03–22.43; p = 0.046). After adjustment for age and sex, individuals with anti-HBc positivity who had switched from a tenofovir-containing regimen showed the highest risk of VF compared with anti-HBc-negative individuals without prior tenofovir exposure (aHR 15.06, 95% CI 1.40–161.38; p = 0.025). Given the limited number of virological events, these findings should be interpreted with caution. Nevertheless, they suggest that prior HBV exposure, particularly in the context of tenofovir discontinuation, may represent a clinically relevant factor when considering simplification to 3TC/DTG.