MAJOR ARTICLE

Antiviral Susceptibility of Herpes Simplex

Viruses and Its Clinical Correlates: A Single
Center’s Experience

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N. Rabella,1 M. Otegui,1 R. Labeaga,1 P. Rodrı́guez,1 N. Margall,1 M. Gurguı́,2 and G. Prats1
1
Servei de Microbiologia and 2Unitat de Malalties Infeccioses, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain

The in vitro susceptibility to acyclovir of 204 herpes simplex virus isolates from 165 immunocompromised
patients treated at our hospital was determined by the cytopathic effect reduction assay. Approximately 95%
of herpes simplex virus 1 and 73% of herpes simplex virus 2 isolates were inhibited by acyclovir at concen-
trations of !2 mg/mL. From 8 patients (5%), an isolate with low susceptibility to acyclovir (50% inhibitory
dose, 13 mg/mL) was recovered. Medical records of 83 patients were reviewed. Lesions resolved in most of the
patients, independent of treatment. Treatment failures were not always associated with isolation of an in
vitro–resistant virus. On the contrary, when a virus with low susceptibility to acyclovir was isolated, resolution
of the lesion was the rule. In 9 of 10 patients with subsequent recurrent episodes of disease, the susceptibility
of the viruses isolated was similar to that of the first episode. Routine susceptibility testing in our geographic
area is not encouraged because of the low incidence of acyclovir-resistant herpes simplex viruses.

Infections caused by herpes simplex virus (HSV) are a prolonged Acv therapy; strains of HSV that are less
major cause of morbidity in immunosuppressed hosts, susceptible or resistant to Acv have occasionally been
such as patients who are positive for HIV or are un- recovered from these patients [3]. Otherwise, in im-
dergoing organ transplantation. Acyclovir (Acv) is the munocompromised patients who receive Acv for the
drug of choice for treatment of these patients. Admin- management of acute HSV disease, the incidence of
istered orally or intravenously, it decreases pain and resistance is extremely low. In addition, Acv-resistant
viral shedding and accelerates healing [1]. Topical ther- strains of HSV have rarely been isolated from immu-
apy can also be useful for these patients, although it is nocompetent patients [4].
not as effective [2]. Mucocutaneous HSV infections are The use of susceptibility testing could help improve
usually self-limited in the immunocompetent host. Be- the management of patients with herpesvirus disease
cause immunosuppressed patients cannot depend on who are unresponsive to standard regimens of Acv. Pa-
their immune system to eliminate the virus, infection tients whose lesions persist or worsen while they are
can result in extensive and persistent ulcerative disease
receiving Acv therapy could benefit from susceptibility
with continuous viral shedding and lack of response to
studies. In such cases, knowledge of a strain’s in vitro
susceptibility to Acv would be useful for the selection
of alternative antiviral therapy [5–7], which might in-
Received 9 July 2001; revised 27 November 2001; electronically published 11
March 2002. volve increasing the dose of oral Acv or changing to
Financial support: Partially support from the Fondo de Investigaciones Sanitarias high-dose continuous infusion of Acv (for those pa-
de la Seguridad Social (FISS), Spain (grant 93/0405). Spanish Ministerio de
Educación y Cultura (grant AP94 35775298 [to M.O.]). tients who do not respond to standard regimens of Acv)
Reprints or correspondence: Dr. Núria Rabella, Av. Sant Antoni Ma Claret 167, [8, 9]. To determine the susceptibility of HSV to Acv,
08025 Barcelona, Spain ([email protected]). various tests have been designed. The most frequently
Clinical Infectious Diseases 2002; 34:1055–60
used tests are the plaque reduction assay (PRA), the
 2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3408-0004$03.00 viral cytopathic effect reduction assay (CRA), the dye-

HSV Antiviral Susceptibility • CID 2002:34 (15 April) • 1055

uptake method (DUA), and the DNA hybridization assay. each strain was recorded and scored as positive or negative.
There is no consensus regarding the level of in vitro suscep- We considered a well result to be positive if there was ⭓1 focal
tibility that indicates a drug-resistant virus, but many different lesion of cytopathic effect. The Kärber method [15] was used
types of assays have shown that Acv-resistant isolates are usually to determine the drug concentration causing a 50% reduction
susceptible to an Acv concentration of 12–3 mg/mL [10–12]. in viral cytopathic effect, or 50% inhibitory dose (ID50) and
Nevertheless, correlation between clinical findings and in vitro the 90% inhibitory dose (ID90) of Acv—that is, the dilution at
susceptibility to Acv has not been definitely established, and which 50% or 90% of the inoculated cultures had negative
further studies are needed. The present article reports the results results. The results are expressed as micrograms per milliliter
of susceptibility testing of HSV isolates from immunocom- [16].
promised patients who attended in a university tertiary-care One resistant strain derived by repeated passage in the pres-
hospital and provides further data on the clinical correlates to ence of Acv was introduced in the study as a control (kindly
the in vitro results. provided by Dr. F. Salmerón, Centro Nacional de Microbio-

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logı́a, Virologı́a e Inmunologı́a Sanitarias de Majadahonda,
Spain). Control wells that exclusively contained either cells with
PATIENTS, MATERIALS, AND METHODS virus or the higher concentration of Acv (50 mg/mL) were
included in each assay. Of the 165 patients, medical records
Patients and virus isolation techniques. A total of 204 iso- were available for 83, who had a total of 96 episodes of HSV
lates (131 HSV-1 isolates and 73 HSV-2 isolates) were recovered disease. Treatment and evolution of the lesions were reviewed.
from 165 immunosuppressed patients (89 patients who had
AIDS, 18 who had hematological malignancies, 20 who had
received heart transplants, 8 who had received bone marrow RESULTS
transplants, 14 who were receiving corticoid therapy, 10 who
had neoplastic disease, 4 who had received kidney transplants, Antiviral susceptibility. The in vitro Acv susceptibilities of
1 who had common variable hypogammaglobulinemia, and 1 204 HSV clinical isolates recovered from 165 patients were
who had diabetes). HSV strains were isolated from 178 mu- determined. The median ID50 of Acv for HSV-1 was 0.615 mg/
cocutaneous lesions (70 oral, 4 pharyngeal, 8 nasal, 16 labial, mL (range, 0.050–4.456 mg/mL). For HSV-2, the median ID50
25 genital, 34 anal, and 21 cutaneous exudates), 19 specimens was 1.698 mg/mL (range, 0.472–5.296 mg/mL).
of bronchoalveolar lavage [BAL] fluid, 4 esophageal biopsy Approximately 86% of HSV-1 isolates were inhibited by Acv
specimens, 1 brain biopsy specimen, 1 rectal biopsy specimen, concentrations of !1 mg/mL, and 195% were inhibited by con-
and 1 urine specimen. For isolation of HSV, specimens for centrations of !2 mg/mL. A total of 73% of HSV-2 isolates were
culture were routinely obtained by swabbing the base of mu- inhibited by Acv concentrations of !2 mg/mL. Of 204 virus
cosal or cutaneous ulcers. The swabs or specimens were placed strains studied, 9 (4%; 1 strain of HSV-1 and 8 strains of HSV-
in transport medium and inoculated on cell monolayers, usu- 2) showed susceptibility to Acv at an ID50 of 13 mg/mL.
ally Vero or HeLa cells. BAL fluid and biopsy specimens were Although a wide spectrum of susceptibilities was found
transported to the laboratory without use of transport medium. among the HSV strains studied, none of the strains had ID50
If 2 specimens were available for the same episode of disease, values of Acv comparable to that of the resistant control strain
both were used. (ID50, 12.559 mg/mL). For 6 patients from whom 2 strains were
Virus isolation, identification, and typing (with use of the recovered from the same episode of disease, the Acv ID50 values
Microtrak HSV-1/HSV-2 culture confirmation/typing test; were very similar (table 1). All the strains isolated from lesions
Syva) were performed by using conventional techniques [13]. other than mucocutaneous lesions had Acv ID50 values of !3
Viruses were then passaged in Vero cells to produce a working mg/mL.
stock with a known titer [14] and were stored at ⫺80C until Clinical response. We recorded data on the treatment and
susceptibility tests were performed. evolution of 96 episodes of HSV disease in 83 patients. Acv
Cytopathic effect reduction assay. In vitro susceptibility therapy was administered for 90 episodes. In 46 cases, the treat-
of HSV isolates to Acv was determined by the cytopathic effect ment was oral; in 15 cases, intravenous; and, in 11 cases, topical.
reduction assay, performed in 96-well plates. In summary, Vero In 18 cases, the route of administration was combined (oral
cells were cultured and maintained in Eagle’s minimum essen- and/or intravenous and/or topical). The lesions resolved in 84
tial medium supplemented with nonessential amino acids, l- cases. For 6 patients, lesions did not resolve, despite antiviral
glutamine, and fetal calf serum. Cell cultures were infected with therapy. Four of these patients had incomplete treatment and
∼100 TCID50 (range, 31.6–316 TCID50) of each virus, and serial died of their disease within a few days (1 had received a bone
2-fold dilutions of Acv (range, 0.02–50 mg/mL) were added to marrow transplant, 2 had lymphoma, and 1 had AIDS); these
the wells. After incubation for 72 h, the cytopathic effect of patients were excluded from the analysis. The other 2 patients

1056 • CID 2002:34 (15 April) • Rabella et al.

 Table 1. Susceptibility values for herpes simplex the evolution of the episodes of disease are shown in table 2.
virus (HSV) isolates recovered during single epi- Available clinical data concerning individual patients from
sodes of HSV disease.
whom isolates were recovered with Acv ID50 values of 12 mg/
Acv ID50
mL are shown in table 3. All these patients’ lesions resolved.
of isolate, Time second Recurrences of disease after therapy. There were 15 re-
a
Patient Isolate mg/mL specimen obtained currences in 10 patients (the episodes of disease were separated
2 HSV-1 0.084 — by 0.5–23 months). Of 27 strains of HSV isolated, only 1 had
0.199 Same day an elevated Acv ID50 (table 4). Patient 41 had 4 episodes during
6 HSV-1 0.334 — the study period; in the third episode, a resistant HSV-2 strain
0.334 2 days later was isolated, and, 50 days after that episode resolved without
12 HSV-2 1.330 — treatment, a susceptible HSV strain was isolated.
0.941 1 day later

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17 HSV-1 0.281 —
0.941 Same day DISCUSSION
31 HSV-1 0.236 —
The clinical development of antiviral drug resistance has been
0.561 Same day
increasingly reported for infections caused by HSV [17]. One
92 HSV-1 0.334 —
of the main problems in testing for in vitro susceptibility is
0.472 1 day later
that antiviral studies are not well standardized. To determine
NOTE. Acv, acyclovir; ID50, drug concentration causing a the Acv susceptibility of HSV, various tests have been designed,
50% reduction in viral cytopathic effect. There were no special
reasons for obtaining 2 samples from the same lesion. such as the PRA, the CRA, the DUA, and the DNA hybridi-
a
Time when the second specimens were obtained relative zation assay.
to when the first specimen was obtained. ID50 values obtained by the hybridization method correlate
well with values obtained by the PRA [18]. The DUA yields
received prolonged treatment, and their lesions improved but ID50 values that are 5–10-fold higher than the values determined
did not heal completely. HSV isolates recovered from these by the PRA [10]. Testing of a single virus strain by these dif-
lesions were susceptible to Acv (ID50, 0.941 and 1.330 mg/mL). ferent assays may produce different results. Variables that affect
Both patients died 1–4 months later, because of the natural the results obtained by each of the assays include the inoculum
progression of their disease (AIDS). effect, the media used, and the conditions of incubation [19].
Six patients received no antiviral treatment and their lesions Even with a single type of assay, results are extremely dependent
resolved spontaneously. Of 79 patients with data available for on the origin of the cell culture used [20]. In the case of Acv,
analysis, 2 (patients 5 and 45) had persistence of lesions and intracellular levels of endogenous thymidine may be responsible
failure to eradicate the virus, and they were followed for 2.5 for such differences [21].
and 1.5 months, respectively. The lesions of patient 5 responded PRA has been considered by some investigators to be the
to Acv when treatment was initiated, and the lesions of patient reference method for in vitro study of susceptibility to anti-
45 responded to Acv when the doses were increased. For these virals, but the fact that HSV is a rapidly growing virus and has
2 patients, the in vitro susceptibility of HSV isolated at different a clear-cut cell-killing effect allows for the use of easier methods
times and from different sites, the treatment administered, and for the study of these viruses. The CRA was introduced by Ho

Table 2. Susceptibility of herpes simplex virus (HSV) isolates recovered from 2 patients with persistent lesions.

Date Acv ID50 Acv ID90 Type and

Underlying CD4 count, Site of specimen of isolate, of isolate, duration of
Patient disease cells/mm3 lesion Isolate obtained mg/mL mg/mL Acv therapya Lesion outcome
5 AIDS !100 Nasal HSV-1 11 Feb 0.397 0.69 None Persistence
12 Mar 0.334 0.60 None Persistence
26 Apr 0.472 0.72 Oral, 14 days; Resolution
topical, 9 days
45 AIDS 70 Perianal HSV-2 25 Jul 0.941 2.40 Oral, 14 days Persistence
23 Aug 0.792 1.38 Oral, 37 daysb Persistence
5 Sep 1.119 2.75 Resolution

NOTE. Acv, acyclovir; ID50, drug concentration causing a 50% reduction in viral cytopathic effect; ID90, drug concentration causing a 90% reduction in viral
cytopathic effect.
a
Duration of therapy is measured from the date the specimen was obtained. The oral dosage of Acv was 200 mg given 5 times per day.
b
Because of the persistence of lesions, the dosage of Acv was increased to 800 mg given 5 times per day until lesions resolved.

HSV Antiviral Susceptibility • CID 2002:34 (15 April) • 1057

Table 3. Clinical features of patients with herpes simplex virus (HSV) infections that had low susceptibility to acyclovir treatment.

Underlying Acv ID50 Acv ID90

CD4 count, disease or of isolate, of isolate, Type of
a
Patient cells/mm3 condition Specimen obtained Isolate mg/mL mg/mL Acv therapy Lesion outcome
51 — Malignancy Cutaneous exudate HSV-1 2.654 4.78 Oral Resolution
100 54 AIDS Esophageal biopsy HSV-1 2.654 4.78 Intravenous Resolution
b
103 !200 AIDS Oral exudate HSV-1 4.456 9.53 Oral Resolution
c
41 67 AIDS Perianal exudate HSV-2 2.654 5.48 Topical Resolution
41c 13 AIDS Perianal exudate HSV-2 3.155 9.53 None Resolution
61 46 AIDS Perianal exudate HSV-2 2.233 4.78 Oral Resolution
62 — Malignancy Perianal exudate HSV-2 2.233 4.78 Topical Resolution
101 45 AIDS Perianal exudate HSV-2 2.654 4.78 Oral Resolution

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102 56 AIDS Perianal exudate HSV-2 2.654 4.78 Oral Resolution
b
107 — Heart TP Genital exudate HSV-2 4.456 5.88 Oral Resolution
126 — Diabetes Cutaneous exudate HSV-2 5.296 19.01 Topical Resolution

NOTE. Acv, acyclovir; ID50, drug concentration causing a 50% reduction in viral cytopathic effect; ID90, drug concentration causing a 90% reduction in viral
cytopathic effect; TP, transplantation.
a
The oral dosage of Acv was 200 mg given 5 times per day for 10 days, and the intravenous dosage of Acv was 400 mg given every 8 h for 10 days.
b
The lesions that yielded these isolates resolved with standard regimens of oral Acv therapy.
c
Two episodes separated by 17 months.

and Enders [22] for the in vitro study of the susceptibility of Acv ID50 values of 12 mg/mL. Swierkosz and Biron [32] pro-
cells to interferon. De Clercq et al. [23] and DeClerq [24] used posed that when the DUA is used to study susceptibility, the
the CRA to study the susceptibility of HSV to antivirals. The ID50 value denoting resistance would be 13 mg/mL. In our study,
addition of the vital dye neutral red to the drug-treated, virus- 9 (4%) of 204 virus strains studied (recovered from 5% of the
infected cultures permits automated reading. This method was patients), were resistant at Acv ID50 values of 3 mg/mL.
named the “dye-uptake method.” McLaren et al. [25] adapted It should be noted that, although a low susceptibility to Acv
the DUA method for the study of HSV susceptibility to acy- in vitro was detected in the HSV strains in our study, resistance
clovir. The DUA is equivalent to the CRA, the only difference did not seem to be the major cause of treatment failure, because
being the reading method, and the ID50 values determined by other factors, such as the patient’s immunologic status, may
the CRA and the DUA are comparable, if the optimal condi- have contributed to the poor clinical response. Medical records
tions for both assays are applied [26]. were available for 10 patients infected with strains of HSV for
In our study, we used the CRA, with Vero cells, to test all which the Acv ID50 was 12 mg/mL at presentation. The lesions
isolates. This assay is based on measurements of the inhibition of all of these 10 patients resolved, with or without Acv treat-
of the cytopathic effect and provides a simple determination ment (table 3).
of Acv susceptibility [27]. Using this assay, we found that re- On the other hand, persistence of lesions in spite of therapy
peated testing of several specimens of the same lesion revealed was unrelated to the Acv ID50 of the infecting strain. Testing
similar susceptibilities (table 1), which indicates that the assay results for the 2 patients (patients 45 and 5) whose lesions
has an acceptable degree of reproducibility. persisted and then finally resolved (table 2) show that all isolates
Our results show that the mean ID50 value for HSV-1 (0.615 were susceptible to Acv. Patient 45 received a standard regimen
mg/mL) is almost 3 times lower than that for HSV-2 (1.698 mg/ of Acv, and the HSV isolate was susceptible in vitro. During
mL). These differences and the overlapping of values for the 2 treatment, a new lesion appeared at another site (probably be-
types of viruses confirm previous observations [27–30]. cause of autoinoculation), and, from this lesion, we were also
There is no consensus of opinion regarding which level of able to isolate a strain of HSV that was susceptible to Acv. The
in vitro susceptibility indicates a resistant virus, but most in- lesions resolved completely after treatment with higher doses
vestigators agree that Acv-resistant isolates are usually suscep- of Acv. In patient 5, the lesion did not resolve until the patient
tible to Acv concentrations of 12 mg/mL. However, Chatis and received Acv (table 2).
Crumpacker [31] pointed out that an Acv ID50 value of 12 mg/ HSV infections are usually mild and self-limited. Cell-me-
mL is unusually high for the definition of resistance to Acv, diated immunity plays a significant role in the eradication of
and use of this value could underestimate the real incidence of HSV disease. The great variability in the abilities of immu-
resistance. We detected 26 HSV strains (6 HSV-1 strains and nosuppressed patients to control viral infections is a major
20 HSV-2 strains)—or 13% of the strains isolated—that had confounding factor in efficacy testing of any antiviral therapy.

1058 • CID 2002:34 (15 April) • Rabella et al.

 Table 4. Susceptibility of herpes simplex virus (HSV) isolates recovered during
recurrences of disease in 10 patients.

Episode
(days since Acv ID50
previous of isolate, Type of
Patient Isolate episode) mg/mL Acv therapya Lesion outcome
1 HSV-1 1 (0) 0.397 Oral Resolution
2 (63) 0.199 Oral Resolution
2 HSV-1 1 (0) 0.167 Intravenous Resolution
2 (43) 0.281 Topical Resolution
3 (350) 0.084 Intravenous, oral Resolution
4b HSV-2 1 (0) 0.941 Topical Resolution
HSV-1 2 (146) 0.792 Topical Resolution

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5c HSV-1 1 (0) 0.397 None Persistence
2 (29) 0.334 None Persistence
3 (74) 0.472 Oral Resolution
4 (116) 0.167 Oral Resolution
6 HSV-1 1 (0) 0.666 Intravenous Resolution
2 (50) 0.334 Intravenous Resolution
3 (96) 0.141 Intravenous Persistenced
8 HSV-1 1 (0) 0.397 Oral Resolution
2 (398) 0.666 None Resolution
10 HSV-1 1 (0) 0.199 Intravenous Resolution
2 (689) 0.397 Oral Resolution
12b HSV-2 1 (0) 1.330 Intravenous, oral Resolution
HSV-1 2 (528) 0.397 Oral Resolution
40 HSV-2 1 (0) 1.581 Oral Resolution
2 (353) 1.581 Intravenous Resolution
3 (479) 0.941 Oral Persistence
41 HSV-2 1 (0) 2.654 Topical Resolution
2 (123) 0.792 Topical Resolution
3 (498) 3.155 None Resolution
3 (548) 0.561 Oral Resolution

NOTE. Acv, acyclovir; ID50, drug concentration causing a 50% reduction in viral cytopathic
effect.
a
The oral dosage of Acv was 200 mg given 5 times per day for 10 days, and the intravenous
dosage of Acv was 400 mg given every 8 h for 10 days.
b
Recurrence with different virus type at another site.
c
For episodes 1, 2, and 3, isolates were recovered from specimens obtained from the same
lesion on different days; episode 4 was a recurrence.
d
Patient died before completion of treatment.

Favorable responses were observed in most of our patients poor absorption of the drug, and interaction between drugs,
regardless of therapy. Six episodes of disease resolved without should be taken into account before resistance to antiviral ther-
treatment. Moreover, in the 3 episodes for which the HSV apy is suspected.
isolates were susceptible at Acv ID50 values of 13 mg/mL and After primary infection, HSV remains latent in the organism
for which the patients were treated with Acv, the lesions re- for life, and, from time to time, the virus reactivates and pro-
solved with the use of standard regimens of the antiviral agent, duces a recurrent disease. Recurrences probably reflect the virus
a result that reinforces the finding that most HSV infections that caused the primary infection [19]. During follow-up, a
are self-limited, independent of therapy. total of 15 recurrences of disease were recorded. All but 1 of
Refractory disease due to HSV in these patients could be the HSV isolates were clearly susceptible to Acv in vitro, a
related to circumstances other than in vitro susceptibility. The finding that shows that the appearance of resistance is very
description of HSV as resistant at Acv ID50 values of 13 mg/ infrequent when Acv is used at standard dosages to manage
mL is probably appropriate, on the basis of multiple studies acute infections.
[32–36], other factors, such as incomplete adherence to therapy, To summarize, in 5% of the patients in our study (4 of 83),

HSV Antiviral Susceptibility • CID 2002:34 (15 April) • 1059

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