Clinical evaluation of herPHEgen®: a herpesvirus genotype-to-phenotype antiviral resistance database and testing service

Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) infections may be life-threatening in immunocompromised patients. Antiviral treatment is available but resistance can develop. The gold standard for resistance testing is cell culture-based phenotyping which is slow (3–4 weeks) and has a high (50 %) failure rate. Faster (<10 working days) genotypic testing of viral thymidine kinase (TK) and DNA polymerase (DNApol) can be used with >95 % success rate. However, a reference database for interpreting drug susceptibility from genetic data is lacking. We developed an HSV genotypic test and genotype-to-phenotype drug resistance database. We evaluated the service using 325 clinical samples, previously characterised by phenotypic susceptibility testing, from 248 treatment-experienced patients. The median age was 42.5 years [IQR30.0–51.0] and 50.8 % (n=126) were female. Clinical details were as follows: 42.3 % (n=105) haemato-oncology patients; 12.1 % (n=30) HIV-infected; 4.4 % (n=11) unspecified immunosuppression; 2.4 % (n=6) congenital infection; 1.2 % (n=3) solid organ transplant; 37.5 % (n=93) unknown. HSV-1 was identified in 58.2 % (n=189) samples. Phenotypic testing identified resistance in 63.7 % (n=207) samples. Genotypic testing identified a resistance-associated mutation (RAM) in TK and/or DNApol in 200/207 samples, a positive percent agreement of 96.6 %, whereas a RAM was detected in 1/118 susceptible samples, a negative percent agreement of 99.2 %. Most RAM occurred in TK (n=195; 97.0 %) with few in DNApol (n=32; 15.9 %). In summary, through herPHEgen we have developed a robust HSV resistance testing service, providing clinicians with timely and accurate results. This will improve clinical decision-making, optimising treatment efficacy and minimising toxicity in immunocompromised patients with HSV.