Predictors and outcomes of acyclovir‐resistant herpes simplex virus infection among hematopoietic cell transplant recipients: case–case–control investigation

Hematopoietic stem-cell transplant (HSCT) recipients are heavily exposed to acyclovir (1). However, acyclovir-resistant herpes simplex virus (HSV) infections are considered rare, although underdiagnosis is highly suspected (1). In addition, the full clinical impact of this event was not yet determined in a controlled trial (1). In the study of antimicrobial resistance, control group selection plays a critical role in the proper investigation of predictors and outcomes of resistant pathogens (2). Controls should reflect the background population from which the patients arose, and the case–case– control study methodology is currently considered the most epidemiologically applicable method to study the significance of resistance, while appropriately controlling for confounders associated with the infection itself, regardless of the pathogen’s susceptibility (2). As far as we know, no epidemiologic analyses using the case–case–control methodology had been conducted in this field. Study aims were to use this study design to investigate predictors and outcomes of acyclovir-resistant HSV infection among HSCT recipients and to determine the population at risk and assess the clinical significance of this event. A nested case–case–control investigation was conducted at Karmanos Cancer Institute (KCI), Detroit, Michigan. The electronic databases of KCI were used to locate HSCT recipients with acyclovir-resistant HSV isolation (MIC > 2 lg/mL) from May 1, 2008 to June 30, 2010. These patients were matched (1:1:1 ratio) to two groups: (i) patients with isolations of acyclovir-susceptible HSV (susceptible cases) and (ii) patients with no HSV isolation (uninfected controls). The local protocol for prophylaxis for every HSCT recipient includes oral acyclovir 400 mg bid from the day of transplant until engraftment. Then, from day 30 until one yr post-transplant or until discontinuation of immunosuppression, oral drug is continued at a dose of 800 mg twice daily for varicella zoster virus (VZV) prophylaxis. Virologic cultures were obtained and processed as recommended (3). Susceptibility testing was conducted by the dye uptake method (4). Breakpoint values of >2 lg/mL (8.8 lM) for acyclovir and of ≥100 lg/mL (333.3 lM) for foscarnet were used, as they were widely accepted at the time of the study (3). Ten patients with acyclovir-resistant HSV infection were recorded at KCI during the study period. Table 1 displays the epidemiological characteristics of resistant cases. As displayed in the Table, two of the patients had died, one improved with valacyclovir/acyclovir alone, and of the remaining seven, all required potentially toxic second line agents, and five of seven required maintenance suppressive anti-viral therapies. Table 2 summarizes the bivariate analyses of the separate investigations conducted: That is, resistant cases vs. uninfected controls, susceptible cases vs. uninfected controls, and resistant cases vs. susceptible cases. Demographics, patient background, acute illness indices, and treatments for the background malignancy – did not differ between groups. Graftversus-host disease (GVHD) was a significant predictor (OR = 13.5, p = 0.05) for acyclovir-resistant HSV infection while compared with controls. The association with recent extensive exposure to acyclovir was evident but did not reach significance. The complexities and severities of acute and chronic conditions were equal among groups, but patients with acyclovir-resistant HSV isolates had significantly worse clinical and virologic outcomes. The overall 90-d mortality was increased among resistant cases (insignificant association). In multivariable analysis of resistant cases vs. un-infected controls, GVHD remained an independent significant predictor for isolation of acyclovir-resistant HSV (OR = 11.5, CI-95% = 1.05–139, p = 0.05). No other significant independent predictors were