Herpes Simplex Virus Resistant to Acyclovir A Study in a Tertiary Care Center Janet A. Englund, MD; Mark E. Zimmerman, BS; Ella M. Swierkosz, PhD; Jesse L. Goodman, MD; David R. Scholl, PhD; and Henry H. Balfour Jr., M D
Study Objective: To determine the sensitivity of herpes simplex virus isolates to acyclovir and the importance of resistant isolates in hospitalized patients. Design: Retrospective incidence cohort study. Setting: All herpes simplex virus isolates cultured over 1 year from patients followed at a tertiary care center. Patients: Consecutive herpes simplex virus isolates were collected from 207 patients, including immunocompetent patients, patients with malignancy, neonates, bone marrow and organ transplant recipients, and patients seropositive for human immunodeficiency virus. Measurements and Main Results: A rapid nucleic acid hybridization method was used to assess susceptibility to acyclovir. Acyclovir-resistant herpes simplex viruses were recovered from 7 of 148 immunocompromised patients (4.7%) but from none of 59 immunocompetent hosts. Clinical disease was found in all 7 patients with resistant herpes simplex virus and was more severe in pediatric patients. All resistant isolates were from acyclovir-treated patients and had absent or altered thymidine kinase activity by plaque autoradiography. Conclusion: Herpes simplex virus resistant to acyclovir arises relatively frequently in immunocompromised patients and may cause serious disease. Rapid detection of resistance permits antiviral therapy to be individualized. Antiviral susceptibility testing to monitor viral resistance should be encouraged, especially in tertiary care settings.
Acyclovir is the drug of choice for treatment of mucocutaneous herpes simplex virus infections ( 1 ) . Herpes simplex viruses resistant to acyclovir are uncommonly recovered from patients but can readily be produced in the laboratory due to alteration in viralspecified thymidine kinase activity or changes in viral D N A polymerase (2, 3). Herpes simplex virus isolates with altered or absent viral thymidine kinase activity have been isolated from patients receiving prolonged or multiple courses of acyclovir therapy (4-7). Clinical isolates of acyclovir-resistant herpes simplex virus due to altered D N A polymerase have also been reported (8, 9). Acyclovir-resistant herpes simplex viruses have generally caused self-limited, prolonged infections rather than severe disease. Recently, chronic and debilitating disease due to acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome ( A I D S ) has been reported (10, 11). The frequency of emergence of acyclovir-resistant herpes simplex viruses in different patient populations and the pathogenicity of such strains in these populations, however, has not been well characterized. To investigate these issues, we tested herpes simplex virus strains isolated by a university tertiary care clinical virology laboratory during a 1-year period for viral resistance. We used nucleic acid hybridization techniques to determine the sensitivity of viral isolates to acyclovir. This method, first described in 1984 (12), actually measures the amount of viral D N A as an assessment of antiviral susceptibility. The hybridization method used in our study was a rapid, reproducible, and labor-saving alternative to the standard plaque reduction assay. The concentration of acyclovir required to reduce viral load by 50% ( E D 5 Q ) determined by this method correlates well with values obtained using a standard plaque reduction assay (13). Results of antiviral susceptibilities were available in time to influence the treatment of five of seven patients with acyclovir-resistant herpes simplex virus. Methods Clinical Virology Procedures
Annals of Internal Medicine. 1990;112:416-422. From the University of Minnesota Health Sciences Center, Minneapolis, Minnesota; the St. Louis University School of Medicine, St. Louis, Missouri; and Diagnostic Hybrids, Inc., Athens, Ohio. For current author addresses, see end of text.
416
Culture specimens were obtained from patients at the University of Minnesota Health Sciences Center and from other Minnesota institutions through a laboratory outreach program. Throat, urine, and blood specimens from bone marrow and organ transplant recipients were submitted weekly; lesion cultures and specimens from biopsy sites were also obtained when clinically indicated. Mucocutaneous lesions
©1990 American College of Physicians
Downloaded From: http://annals.org/ by a University of California San Diego User on 12/10/2016
Table 1. Clinical
Charac'teristics
Patient Group
Immunocompetent Immunocompromised Marrow transplant AIDS or A R C * Heart transplant Renal transplant Pancreas transplant Liver transplant Malignancy Miscellaneous Neonates Total
ofl^atients vvith Herpes
Patients Studied
Mean Age
n
y
59
30.7
56,44
29 14 21 21 13 3 39 6 2 207
30 34 49 41 34 40 50 45 5d 32.8
43,57 7,93 24,76 62,38 62,38 67,33 51,49 83, 17 0, 100 49,51
Simpilex Virus
Female, Male
(HS\f)
HSV Isolates from Oral Site, Genital Tract*
%
Infections Patients Receiving Acyclovir
Patients with Isolates after Exposure to Acyclovir)*
n(%)
< 42,58
17(29)
5(8)
78,25 14,96 100,0 95,5 77,23 100,0 85, 15 83, 17 100,0 73,30
29(100) 9(64) 21(100) 17(81) 13(100) 3(100) 30(77) 4(67) 2(100) 145(70)
19(66) 9(64) 5(24) 10(48) 8(62) 1(33) 6(15) 0 1(50) 64(31)
Patients with Resistant HSV
—
•
0 4(14) 1(7) 0 1(5) 1(8) 0 0 0 0 7(3)
* Some patients had herpes simplex virus isolated fr
Study Objective: To determine the sensitivity of herpes simplex virus isolates to acyclovir and the importance of resistant isolates in hospitalized patients. Design: Retrospective incidence cohort study. Setting: All herpes simplex virus isolates cultured over 1 year from patients followed at a tertiary care center. Patients: Consecutive herpes simplex virus isolates were collected from 207 patients, including immunocompetent patients, patients with malignancy, neonates, bone marrow and organ transplant recipients, and patients seropositive for human immunodeficiency virus. Measurements and Main Results: A rapid nucleic acid hybridization method was used to assess susceptibility to acyclovir. Acyclovir-resistant herpes simplex viruses were recovered from 7 of 148 immunocompromised patients (4.7%) but from none of 59 immunocompetent hosts. Clinical disease was found in all 7 patients with resistant herpes simplex virus and was more severe in pediatric patients. All resistant isolates were from acyclovir-treated patients and had absent or altered thymidine kinase activity by plaque autoradiography. Conclusion: Herpes simplex virus resistant to acyclovir arises relatively frequently in immunocompromised patients and may cause serious disease. Rapid detection of resistance permits antiviral therapy to be individualized. Antiviral susceptibility testing to monitor viral resistance should be encouraged, especially in tertiary care settings.
Acyclovir is the drug of choice for treatment of mucocutaneous herpes simplex virus infections ( 1 ) . Herpes simplex viruses resistant to acyclovir are uncommonly recovered from patients but can readily be produced in the laboratory due to alteration in viralspecified thymidine kinase activity or changes in viral D N A polymerase (2, 3). Herpes simplex virus isolates with altered or absent viral thymidine kinase activity have been isolated from patients receiving prolonged or multiple courses of acyclovir therapy (4-7). Clinical isolates of acyclovir-resistant herpes simplex virus due to altered D N A polymerase have also been reported (8, 9). Acyclovir-resistant herpes simplex viruses have generally caused self-limited, prolonged infections rather than severe disease. Recently, chronic and debilitating disease due to acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome ( A I D S ) has been reported (10, 11). The frequency of emergence of acyclovir-resistant herpes simplex viruses in different patient populations and the pathogenicity of such strains in these populations, however, has not been well characterized. To investigate these issues, we tested herpes simplex virus strains isolated by a university tertiary care clinical virology laboratory during a 1-year period for viral resistance. We used nucleic acid hybridization techniques to determine the sensitivity of viral isolates to acyclovir. This method, first described in 1984 (12), actually measures the amount of viral D N A as an assessment of antiviral susceptibility. The hybridization method used in our study was a rapid, reproducible, and labor-saving alternative to the standard plaque reduction assay. The concentration of acyclovir required to reduce viral load by 50% ( E D 5 Q ) determined by this method correlates well with values obtained using a standard plaque reduction assay (13). Results of antiviral susceptibilities were available in time to influence the treatment of five of seven patients with acyclovir-resistant herpes simplex virus. Methods Clinical Virology Procedures
Annals of Internal Medicine. 1990;112:416-422. From the University of Minnesota Health Sciences Center, Minneapolis, Minnesota; the St. Louis University School of Medicine, St. Louis, Missouri; and Diagnostic Hybrids, Inc., Athens, Ohio. For current author addresses, see end of text.
416
Culture specimens were obtained from patients at the University of Minnesota Health Sciences Center and from other Minnesota institutions through a laboratory outreach program. Throat, urine, and blood specimens from bone marrow and organ transplant recipients were submitted weekly; lesion cultures and specimens from biopsy sites were also obtained when clinically indicated. Mucocutaneous lesions
©1990 American College of Physicians
Downloaded From: http://annals.org/ by a University of California San Diego User on 12/10/2016
Table 1. Clinical
Charac'teristics
Patient Group
Immunocompetent Immunocompromised Marrow transplant AIDS or A R C * Heart transplant Renal transplant Pancreas transplant Liver transplant Malignancy Miscellaneous Neonates Total
ofl^atients vvith Herpes
Patients Studied
Mean Age
n
y
59
30.7
56,44
29 14 21 21 13 3 39 6 2 207
30 34 49 41 34 40 50 45 5d 32.8
43,57 7,93 24,76 62,38 62,38 67,33 51,49 83, 17 0, 100 49,51
Simpilex Virus
Female, Male
(HS\f)
HSV Isolates from Oral Site, Genital Tract*
%
Infections Patients Receiving Acyclovir
Patients with Isolates after Exposure to Acyclovir)*
n(%)
< 42,58
17(29)
5(8)
78,25 14,96 100,0 95,5 77,23 100,0 85, 15 83, 17 100,0 73,30
29(100) 9(64) 21(100) 17(81) 13(100) 3(100) 30(77) 4(67) 2(100) 145(70)
19(66) 9(64) 5(24) 10(48) 8(62) 1(33) 6(15) 0 1(50) 64(31)
Patients with Resistant HSV
—
•
0 4(14) 1(7) 0 1(5) 1(8) 0 0 0 0 7(3)
* Some patients had herpes simplex virus isolated fr
