Kaposi sarcoma herpesvirus (KSHV) subtypes and impact on outcomes in KSHV-associated diseases

Kaposi sarcoma-associated herpesvirus (KSHV) causes several diseases among people with HIV (PWH), including Kaposi sarcoma (KS), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV inflammatory cytokine syndrome (KICS), known as KSHV-associated diseases (KAD). Genetic diversity in the viral K1 gene defines KSHV subtypes, but clinical significance remains unclear.

We conducted a retrospective study of 143 PWH with KAD treated between 2004-2024. KSHV-DNA was extracted from various clinical samples and sequenced using next-generation and Sanger methods. Phylogenetic analysis was performed to classify K1 subtypes; associations with KAD presentation and survival were assessed.

Among 143 patients, 40% had KS alone, 12% had MCD and KS, 17% had KICS and KS and 31% had PEL+/-MCD+/-KS. Subtype A was the most prevalent (46%), followed by C (27%); subtypes did not vary by KAD presentations. Patients with concurrent KAD had worse survival than those with KS alone, irrespective of KSHV subtype. Twenty-one patients with PEL and subtype A had poorer survival outcomes as compared with PEL with other subtypes (median overall survival 1.6 vs. 7.2 years, p=0.0041). Apart from a trend towards lower albumin levels, there were no other differences in clinical characteristics in patients with PEL and Subtype A vs other subtypes.

Overall, K1 subtypes did not vary by KAD diagnosis and did not impact survival. Individuals with PEL had poorer outcomes, and subtype A in PEL was associated with worse survival. Further studies are required to investigate the functional impact of KSHV genetic variation on disease pathogenesis.