Early emergence of ganciclovir-resistant human cytomegalovirus strains in children with primary combined immunodeficiency

Children with primary combined immunodeficiency (CID) and human cytomegalovirus (HCMV) infection often deteriorate despite antiviral therapy. In this study, the emergence of ganciclovir-resistant strains was examined in 6 children with CID and HCMV infection, using sequence analysis of the HCMV UL97 gene and virus susceptibility assays. Mutations in the proposed ATP binding site associated with ganciclovir resistance were found in 4 of the 6 children. In 1 patient with B- severe CID, an unusual multiplicity of mutations was found in the UL97 substrate binding domain between aa 590-606, All mutations were detected within 10 days to 3 weeks from initiation of therapy. The emergence of resistant strains in children with CID appears earlier than in other groups of HCMV-infected patients. These findings may have relevance to the cellular pathways involved in viral DNA repair and mutagenesis, and they indicate the need for early and frequent genotypic monitoring and prompt therapeutic modification in this patient population.