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Background Transmitted resistance to antiretrovirals (TDR), albeit limited in the current Italian panorama, remains a risk, especially in the PrEP era, and calls for active monitoring. Epidemic diversity is also sustained by HIV-1 non-B subtypes, increasingly established in Italy.Here, we describe a cluster of primary HIV-1 infections caused by multi-drug-resistant CRF19_cpx, occurring among MSM in Milan over a six-month period.Material and Methods Retrospective monocentric observational analysis of HIV cases diagnosed at IRCCS Policlinico, Milan, between 06/2025 and 01/2026, and identified as part of a transmission cluster. DRMs analyzed through Stanford algorithm V 10.1 (Jan 18, 2026). Subtype and transmission cluster (TC) confirmed by IqTree through Maximum Likelihood phylogeny based on the GTR+F+GAMMA model with 1000 replicates fast bootstrapping. A transmission cluster was defined by intra-genetic distance ≤0.015 and bootstrap =100.Results Four MSM diagnosed with HIV infection at our outpatient sexual health clinic over six months were identified as a cluster: two reported a direct epidemiologic link, while all were linked through phylogenetic analysis, which confirmed CRF19_cpx infection and identified the sequences as belonging to the same transmission cluster (TC) (bootstrap = 100; genetic distance = 0.008). Median age was 35 years, all were Italian-born, median time since last HIV negative test was 14 months. One had positive T. pallidum serology, and the others did not have any co-infection.None had prior exposure to PrEP.Two were asymptomatic, two had symptoms compatible with acute antiretroviral syndrome.In all four cases, HIV serology was compatible with primary infection (Fiebig 2/3 in one case, Fiebig 5 in three cases).Median HIV RNA load was 265672 cp/mL. Median CD4 count was 533/mcL (35%).At GRT, the following DRMS in the RT portions were detected: D67N (relative abundance: 98%), T215L(99%), K219E(98%), known to belong to pathway 2 of thymidine analogue mutations (TAM2), and S68G(98%), A98G(90%), V106I(93%), Y181C(99%); G190A(99%), the last three known to affect the NNRTI class. Polymorphic mutations included A71T(99%) in protease and M50I (100%) in integrase.Conclusions We observed a transmission cluster of CRF19_cpx, a recombinant of subtypes D, A and G associated with rapid disease progression, among MSM in Milan, with transmitted resistance to all NNRTIs and legacy NRTIs. Identification of primary infections across the cluster within six months (2025–2026) provides a snapshot of recent local transmission dynamics and suggests ongoing undetected spread. This is concerning as the resistance profile limits access to several first-line regimens, including injectable long-acting CAB+RPV. Together with missed prevention opportunities, these findings support the need for targeted public health interventions to prevent further transmission.