Acyclovir for Chronic Mucocutaneous Herpes Simplex Virus Infection in
Immunosuppressed Patients
STEPHEN E. STRAUS, M.D.; HOLLY A. SMITH, B.S.; CHAIM BRICKMAN, M.D.; PAULO de MIRANDA,
Ph.D.; COLIN McLAREN, Ph.D.; and RONALD E. KEENEY, M.D.; Bethesda, Maryland; and Research
Triangle Park, North Carolina
Over 25 episodes of severe chronic and recurrent
mucocutaneous herpes simplex virus infections in five
immunodeficient patients were successfully treated with
intravenous or oral acyclovir treatment. Acyclovir was
shown to inhibit viral shedding rapidly, to be well
tolerated, and to permit the complete healing of lesions.
As expected, a course of acyclovir did not prevent later
recurrences of the herpes virus infections. However,
symptomatic recurrences were successfully suppressed
during long (up to 65-day) courses of oral acyclovir.
S O M E PATIENTS with defective cell-mediated immunity
have primary or recurrent mucocutaneous herpes sim-
plex virus infections that are more severe and longer last-
ing than the corresponding infections in immunologically
competent hosts (1-5). Recently, intravenous acyclovir
has been shown to be the first antiherpetic agent capable
of decreasing the duration and severity of mucocutaneous
herpes simplex virus infections in compromised patients
(6-9). Moreover, herpes simplex virus infections after
bone marrow transplantation can be prevented during
treatment with prophylactic intravenous acyclovir ( 1 0 ) .
We report clinical, virologic, and pharmacologic obser-
vations of over 25 episodes of chronic and recurrent her-
pes simplex virus infections in five immunodeficient pa-
tients. Data are presented that indicate repeated treat-
ments of these infections with intravenous or oral acyclo-
vir are effective and well tolerated. Moreover, prolonged
or individually tailored regimens of oral acyclovir seem
to be capable of preventing expected clinical recurrences.
Methods
All patients (Table 1) were evaluated and treated at the Na-
tional Institutes of Health (NIH) Clinical Center after they
gave fully informed consent. Inpatients with mucocutaneous le-
sions were interviewed and examined daily; the severity of pain,
the stages, and the relative sizes of lesions were recorded. Le-
sions were considered to have healed when symptoms and signs
of inflammation had resolved; complete reepithelialization was
not required.
Virus cultures were done before and frequently during thera-
py. Freshly aspirated vesicle fluid or lesion swabs were trans-
ported to the virology laboratory in veal infusion broth on ice
and inoculated within 24 h into roller tubes, some containing
monolayers of human diploid fibroblasts (WI-38) and others
containing human embryonic kidney cells. Quantitative titra-
tions of virus shedding were done by inoculating serial 10-fold
dilutions of the original specimens into WI-38 culture tubes,
and were calculated as 50% tissue culture infective dose units
per 0.2 mL. The appearance of typical cytopathologic effects of
• From the Laboratory of Clinical Investigation, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and
Burroughs Wellcome Co.; Research Triangle Park, North Carolina.
270 Annals of Internal Medicine. 1982;96:270-277.
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herpes simplex virus infection was recorded ( 1 1 ) . Virus typing
was done by a direct immunofluorescence assay ( 1 2 ) .
Acyclovir capsules, 200 mg, and acyclovir sodium salt for
intravenous administration were provided by Burroughs Well-
come Co. Acyclovir drug levels were measured by radioimmu-
noassay ( 1 3 ) . The sensitivity of herpes simplex virus isolates to
inhibition by acyclovir was measured in a quantitative cyto-
pathic effect-reduction assay in microtiter plates using serial
twofold dilutions of acyclovir. Vero cells were challenged with
approximately 30 infectious units of the test virus, and the cyto-
pathic effect at 72 h was measured by uptake of neutral red dye
( 1 4 ) . The 50% infective dose values measured in this assay are
approximately 10-fold higher that those obtained in a standard
plaque reduction assay (McLaren C. Unpublished observa-
tions).
Case Reports
PATIENT 1
This 3-year-old white boy was first referred to the N I H in
September 1979 for evaluation of chronic mucocutaneous le-
sions and a suspected immune defect that later proved to be
associated with nucleoside phosphorylase deficiency (Winkel-
stein J. Personal communication). At age 2 years, he had had a
severe bout of acute encephalitis of undetermined cause that
had resulted in significant chronic neurologic impairment. The
encephalitis was followed by the appearance for the first time of
vesicular and then chronic ulcerative lesions of the mouth and
face, which spontaneously resolved after a few weeks but re-
curred in July 1979. The lesions progressed prompting his refer-
ral to the N I H Clinical Center.
When first examined, large ulcerative lesions involved the
right cheek, lips, tongue, and the crease of the neck. Viral cul-
tures yielded herpes simplex virus type 1. He was admitted to a
National Institute of Allergy and Infectious Diseases ( N I A I D )
collaborative adenine arabinoside (vidarabine)-placebo cross-
over trial (randomly ordered sequential weeks of vidarabine, 10
mg/kg body weight d intravenously, or placebo infusions). The
clinical course and titers of viral shedding suggested little re-
sponse to that treatment (Figure 1). An open trial of vidarabine
at 20 mg/kg body weight • d was attempted with drying and loss
of crusts from cheek lesions but progression of nose, mouth,
and neck lesions (Figure 2 ) . After more than 4 months of pro-
gressive lesions, acyclovir, 5 mg/kg body weight, was adminis-
tered intravenously every 8 h for 5 days. Quantitative viral ti-
ters and daily observation of lesions showed a prompt and dra-
matic improvement (Figures 1 and 2 ) . By the third day of
treatment the lesions were clearly drier. Healing, but for residu-
al erythema, was complete in about 2 weeks. Subsequent cul-
tures and examinations indicated a clinical and virologic recur-
rence about 3 weeks after the acyclovir course was completed.
Oral, labial, and facial lesions progressed steadily, but retreat-
ment was postponed because other severe medical complica-
tions developed, including Pneumocystis carinii and Legionella
pneumophila pneumonias, from which he died.
PATIENT 2
The early history and responses to treatment of multiple her-
pesvirus infections in this 67-year-old black woman have been
 Table 1 . Immunodeficient Patients Treated with Acyclovir

Patient Age Virus Type Location of Lesions Underlying Disorder

yrs
1 3
2 67
3 27
4 38
5 35
1 Face, neck, mouth
2 Vulva, perineum, buttocks
2 Vulva, perineum, buttocks
2 Face, hands, groin, penis, legs
2 Buttocks, penis
Nucleoside phosphorylase deficiency
Common variable immunodeficiency
Common variable immunodeficiency
Common variable immunodeficiency
Acquired combined immunodeficiency

reported elsewhere ( 7 ) . Early in 1979 she developed Pneumo- frequently achieved. Further, we found that 3-day cycles of acy-
cystis pneumonitis, chronic perineal and vulvar herpes simplex clovir treatment, 200 mg by mouth every 4 h while awake (five
virus type 2 infection, and chronic disseminated varicella zoster times daily), alternated with 5-day cycles off the drug interrupt-
virus infection that failed to respond to intravenous vidarabine ed asymptomatic shedding and delayed the appearance of the
administered at another institution. By June 1979 she developed next clinical recurrence. Subsequent cycles of oral acyclovir giv-
cytomegalovirus pneumonia in addition to her other ongoing en three times daily for 2 consecutive days each week initially
herpesvirus infections. The pneumonia and skin lesions pro- appeared to be suppressive but ultimately permitted break-
gressed but resolved promptly after treatment was started with through of a clinial recurrence.
intravenous acyclovir, 5 mg/kg body weight every 8 h for 5 Her most recent preventive treatment (course 21) followed a
days. Approximately 2 weeks later and again several times dur- standard 5-day treatment (200 mg by mouth 5 times daily) and
ing the autumn of 1979, she had brief recurrences of vesicular consisted of 30 days of oral acyclovir at four capsules daily
eruptions involving the buttocks, perineum, and vulva. followed immediately by 30 days of three capsules daily. This
In November 1979, the perineal herpes simplex virus lesions regimen was well tolerated and seemed to suppress asympto-
reappeared and were soon followed by a second episode of dis- matic shedding and the appearance of lesions until several days
seminated zoster and recurrent pneumonia, possibly due to cy- after its completion.
tomegalovirus. Treatment at another hospital with vidarabine
and trimethoprim-sulfamethoxazole was unsuccessful. In mid-
December she was transferred back to the N I H where a second
course of acyclovir, 7.5 mg/kg body weight intravenously every
8 h for 5 days, was associated with prompt clinical resolution of
pneumonia and the cutaneous herpes simplex virus infections
(Figure 1). Since then, she has had chronic fungal osteomyeli-
tis, diffuse histiocytic lymphoma of the lung, and intermittent
self-limited episodes of herpes simplex virus involving the peri-
neum and buttocks.
PATIENT 3
This 27-year-old white woman had a long history of common
variable immunodeficiency complicated by recurrent severe
bacterial infections and numerous cutaneous papillomata. In
mid-April 1980 she had genital herpes for the first time. Over a
period of 6 weeks the infection progressed to ulcerate much of
the vulva and perineum, prostrated her, and necessitated blad-
der catheterization for urinary retention as well as administra-
tion of high doses of analgesics for severe pain. As with Patient
1, she was randomized to receive consecutive 1-week courses of
vidarabine or placebo infusions (Figures 1 and 3). Because she
failed to respond to that treatment, acyclovir, 250 m g / m 2 body
surface area, was intravenously administered every 8 h for 5
days. She responded promptly with inhibition of virus shedding
and improvement in symptoms so that no analgesia was needed
by the fifth day. The lesions were noticeably drier by day 3 and
completely healed in 2 weeks.
Since that first episode, she has had numerous clinically and
virologically documented recurrences of genital herpes (Figure
4); she repeatedly showed that her lesions would become very
large, exceedingly painful, and would fail to improve spontane-
ously without acyclovir treatment. By both clinical and virolog-
ic criteria, she promptly responded to four courses of intrave-
nous therapy and many courses of oral therapy (200 mg acyclo-
vir every 4 h while awake). The interval between completion of
one course of therapy and the next clinical recurrence estab-
lished a regular pattern of only 6 to 10 days. Moreover, asymp-
tomatic shedding was frequent and could begin as soon as 4 to 5
days after the acyclovir treatment was stopped. The interval to
the next recurrence was not significantly increased by reinstitut- Figure 1 . Responses of four patients to antiviral therapy with vidar-
abine (ARA) and placebo (PLC) and intravenous acyclovir (ACV) or
ing intravenous treatment (course 7 ) , or by 28- or 65-day oral acyclovir (fourth treatment of Patient 3). A. Patient 1 . B. Pa-
courses of oral acyclovir (courses 12 and 21). tient 2. C. Patient 3. D. Patient 5. The shaded areas show the
The absence of herpes lesions during long courses of acyclo- relative extent of lesions and symptoms; the height of the shading
vir treatment suggested that, as in the study of Saral and associ- reflects the severity of pain, the size of lesions, or both; solid black
ates (10), clinical recurrences of herpes simplex virus infections bars indicate the quantity of virus recovered; + = a positive (un-
could be suppressed as long as inhibitory acyclovir levels were quantitated) culture; — = a negative culture.

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 In early 1981 a series of vesicular eruptions on the face and
groin were followed clinically, proved to be caused by herpes
simplex virus type 2, and then successfully treated with intrave-
nous acyclovir, 250 m g / m 2 body surface area every 8 h for 5
days (Figure 5). After that treatment, he was totally free of
lesions for nearly 2 weeks, the first time in over 2 years.
After three more episodes of overlapping recurrences at dif-
ferent sites, he was readmitted and treated successfully with
oral acyclovir, 200 mg every 4 h while awake. After a second
course of oral acyclovir, he was placed on an expectant, inter-
mittent suppressive regimen of oral acyclovir similar to that
used for Patient 3. He remained clinically free of lesions for
about 2 weeks after his last dose of acyclovir. Recurrent groin,
ear, and buttock lesions appeared and were successfully treated
with a 5-day course of acyclovir, 200 mg every 4 h while awake.
Subsequent recurrences have been suppressed by treatment
with 30 days of capsules given 4 times daily followed by 30 days
of three capsules a day (Figure 5). While at home during the
long suppressive regimen, he had two brief episodes of erythe-
ma and pain in the groin and chin area. The symptons lasted as
long as 2 days and resolved spontaneously. Cultures were not
obtained.

Figure 2. Results of antiviral treatment of Patient 1. Photographs
were taken (A) 1 day before the vidarabine and placebo treatment;
(B) 4 days after completing the double-dose open (second) vidara-
bine (ARA-A) trial; and ( Q 3 days after completing acyclovir (ACV)
treatment. Although the cheek lesions lost their crusts during the
second vidarabine trial, the mouth and neck lesions (not shown)
were clinically unchanged, and the nasal lesion was worse.
PATIENT 4
A 38-year-old white man with common variable immunodefi-
ciency developed severe primary genital herpes complicated by
culture-proven herpes simplex virus type 2 meningoencephalitis
in late 1978. The lesions of that primary episode gradually re-
solved spontaneously in 6 to 8 weeks. Over the next 2 years, he
had near continuous lesions appearing on the penis, groin, but-
tocks, thighs, legs, hands, chin, and ears. The lesions would last
2 to 4 weeks and resolve spontaneously, but new lesions would
develop elsewhere before the crusts of the earlier lesions had
fallen off.
272 March 1982 • Annals of Internal Medicine • Volume 96 • Number 3
PATIENT 5
A 35-year-old male homosexual developed a syndrome that
has been recognized only recently in that population (15). In
the winter of 1980-1981 he had had several episodes of rather
mild genital lesions. In March 1981, he became severely ill,
persistently febrile, and began to lose weight rapidly. Between
March and May of 1981, Pneumocystis pneumonia, Candida
esophagitis, Mycobacterium avium-intracellulare infection,
hepatitis, and rising cytomegalovirus serologic titers were
found. In April an enlarging ulcerative lesion was noted in the
crease of the buttocks below the sacrum. A biopsy showed in-
tranuclear inclusions. In May, virus cultures recovered herpes
simplex virus type 2 from the lesions. The patient was trans-
ferred to the NIH Clinical Center for further immunologic eval-
uation.
He was found to be anergic, severely lymphopenic, and de-
void of all lymphocyte functions as assessed in vitro. Cultures of
urine, throat, blood, and bone marrow grew cytomegalovirus.
Retinoscopy showed a progressive acute retinitis. The sacral
ulcer remained culture positive for herpes simplex virus and
enlarged to encompass an area of about 25 cm 2 . Acyclovir infu-
sion was begun at a high dose of 500 m g / m 2 body surface area
intravenously every 8 h for 7 days with the hope of possibly
interrupting the cytomegalovirus infection as well as the herpes
simplex virus infection. The herpes simplex virus infection
cleared rapidly from the skin, and the ulceration healed within
10 to 14 days. New perianal lesions were noted about 3 weeks
after his last dose of acyclovir. Blood cultures positive for cyto-
megalovirus remained positive during acyclovir treatment.
The retinitis progressed further. Vidarabine, 15 mg/kg body
weight • d, was administered for 7 days with minimal effect upon
the perineal lesions, but progression of retinitis appeared to halt
transiently. He was retreated with acyclovir 500 m g / m 2 body
surface area for 7 days in mid-September with rapid clearing of
his perianal lesions, but blood cultures remained positive for
cytomegalovirus. By mid-October 1981 the perianal lesions had
reappeared and enlarged to generate a single ulcer of approxi-
matley 100 cm 2 in area. This lesion benefited from treatment
with oral acyclovir but had not resolved at the time of the
patient's death on 28 October.
Results
VIROLOGIC S T U D I E S
Quantitative viral cultures were d o n e during 12 epi-
sodes of recurrent herpes simplex virus infections in four
patients ( F i g u r e 1 ) . Eight episodes were treated; t w o
with randomly ordered w e e k - l o n g trials of vidarabine al-

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 Figure 3. Results of antiviral treatment of Patient 3. Photographs were taken (A) 1 day before vidarabine and placebo trial; (B) 1 day before
acyclovir treatment after completion of vidarabine (ARA-A) trial; and (C) 3 days after completion of acyclovir (ACV) treatment. Ulcerative
lesions progressed markedly during the vidarabine and placebo trial.

ternating with placebo infusions, five with intravenous PHARMACOLGY

acyclovir, and one with oral acyclovir. The data show
that acyclovir treatment was associated with a prompt
cessation of viral shedding and was followed in each case
by complete healing of lesions. Figures 2 and 3 illustrate
some of these excellent clinical responses. Figures 4 and 5
depict the clinical and qualitative virologic observations
in Patients 3 and 4 before, during, and after repeated
successful therapeutic and suppressive trials.
Serum, urine, and stool specimens were obtained from
Patients 1, 2, 3, and 4 and analyzed for acyclovir content
by radioimmunoassay. The data permit a number of ob-
servations on the metabolic fate and pharmacokinetics of
acyclovir in these patients. All patients had normal renal
function.
A total of 59 timed serum specimens, 35 24-h urine
collections, and three 24-h stool collections were obtained

Figure 4. Results of oral acyclovir treatment regimens for Patient 3. Recurrent herpes simplex virus infection episodes five to 16 were
successfully treated. All were treated {dark boxes) with acyclovir, 2 0 0 mg five times daily, except course 6 that used 4 0 0 mg doses, and
course 7 that was administered intravenously with doses of 5 0 0 m g / m 2 body surface area. Intermittent short courses of preventive
treatment lasted 3 days (May) or 2 days (June, July) at dosages of five or three capsules daily, respectively. Long courses used five, four, or
three capsules daily (March to April, July to August, August to September, respectively). The shaded areas show the relative extent of
lesions and symptoms; the height of the shading reflects the severity of pain, the size of lesions, or both; solid black bars indicate acyclovir
administration; + = a positive (unquantitated) culture; — = a negative culture.
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during and after courses of intravenous acyclovir at dos-
ages of 5 mg/kg body weight, 7.5 mg/kg, and 250 m g / m 2
body surface area, every 8 h infused over 30 min. Peak
serum levels of acyclovir (15 min after infusion) ranged
from 40.9 to 60.4 jmmol, and from 62.6 to 90.1 jmmol after
doses of 5 mg/kg body weight and 7.5 mg/kg, respective-
ly. Trough levels (5 to 10 min before dose) ranged from
3.8 to 12.0 u,mol, and from 9.3 to 17.2 jumol for these
dosages, respectively.
Kinetic studies of serum drug concentrations were
done at the dosages of 5.0 mg/kg body weight (Patient 1,
data not shown) and 7.5 mg/kg body weight (Patient 2,
Figure 6 A ) . After the drug infusion was completed, the
rate of fall in serum acyclovir levels was rapid at first but
then slowed considerably, in accord with a biexponential
model of drug distribution described earlier for acyclovir
(16). Over a 5-day course of two infusions daily, there
was only a slight tendency toward gradual accumulation
of drug. Trough drug levels greater than those needed to
completely inhibit herpes simplex virus replication were
present throughout the 8-h period between doses.
Further detailed analyses of the serum levels and drug
excretion were done in two patients treated with intrave-
nous acyclovir and later with oral acyclovir (Table 2 ) .
The data indicate that after intravenous acyclovir admin-
istration about two thirds of the total dose appears un-
changed in the urine (Figure 6B). In first reporting this
finding, de Miranda and associates (16) observed that
renal acyclovir clearance involves both glomerular filtra-
tion and tubular secretion. Little of the drug is excreted
in the stool.
After oral acyclovir administration, drug absorption is
slow and variable, peaking between 1 and 4 h (de Miran-
da P. Unpublished studies). All our data were collected
60 min after drug administration, and, therefore, proba-
bly underestimated the actual peak serum levels. None-
theless, rather modest yet inhibitory levels were achieved
and sustained for at least as long as the interval between
doses. Gastrointestinal absorption is rather poor with to-
tal bioavailability estimated to be in the range of 15% to
30% (Blum R, de Miranda P. Unpublished studies).
About 10% to 15% of the drug was excreted unchanged
in the urine, whereas 15% to 25% was excreted un-
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Figure 5. Results of acyclovir treat-
ment of Patient 4 . Intravenous
(first trial) and oral (all subsequent
trials) acyclovir treatments were
successfully used to terminate five
culture-proven episodes of recur-
rent herpesvirus infection. The
shaded areas show the relative ex-
tent of lesions and symptoms; the
height of the shading reflects the
severity of pain, the size of lesions,
or both; solid black bars indicate
acyclovir administration; + = a
positive (unquantitated) culture;
— = a negative culture.
changed in the stool specimens analyzed.
TOXICOLOGIC S T U D I E S
The following side effects were found during acyclovir
treatments. Patients 4 and 5 had cutaneous irritation and
erythema from the drug, which was infused through im-
properly situated intravenous catheters. Patient 3 devel-
oped two, day-long episodes of nausea and three bouts of
severe diarrhea while on oral acyclovir. These appeared
to be due to bacteriologically proven recurrences of Sal-
monella enteritis that she had had previously. Patient 1
developed a tremor 1 week after acyclovir therapy. The
analysis of that complication is confounded because he
had recently completed two courses of vidarabine, a drug
known to be associated with tremor, and because his neu-
rologic status before treatment was severely abnormal.
Every 3 to 5 days during all of the acyclovir treatment
regimens and every 1 to 2 weeks during the suppressive
regimens, the patients had full batteries of blood and
urine tests for evidence of drug-related toxicity. Patient 2
developed a transient twofold rise in serum transaminase
levels during her first course of intravenous acyclovir.
The level started decreasing toward normal while the pa-
tient was on acyclovir, and was normal within 1 week
after completion of therapy. Patient 5 developed a tran-
sient leukopenia with a fall in his total leukocyte count
from 8000 to 2900 cells/mm 3 during his first intravenous
acyclovir treatment. Other than these findings, no abnor-
malities of complete blood count, differential count, reti-
culocyte count, SMA-18, or urinalysis were found.
D R U G SENSITIVITY S T U D I E S
Herpes simplex virus isolates recovered before, during,
and after treatment were tested for their sensitivity to
acyclovir (Table 3). Although some differences in drug
sensitivity occurred from specimen to specimen for each
patient, this finding was within the range of experimental
variation. In addition, the herpes simplex virus isolates
from the two specimens of Patient 3 with the greatest
disparity in 50% infective dose (specimens 2 and 4) were
shown to express comparable levels of thymidine kinase
activity (results not shown) (18). Thus, we believe that
the herpes simplex virus that reactivated after treatment
 Figure 6. Pharmacokinetics and urinary excretion of acyclovir after intravenous administration. A. Patient 2. Serum drug levels after the
first three doses of intravenous acyclovir (ACV), 7.5 m g / k g body weight-8 h. B. Patient 3. Percent of daily acyclovir dose recovered in -24-h
urine collections during 7 consecutive days after the initiation of a 5-day course of intravenous acyclovir, 2 5 0 m g / m 2 body surface area-8
h. Data are expressed as ± 1 SD.

was completed did not differ greatly in their sensitivity to
acyclovir from the isolates recovered before antiviral
therapy.
Discussion
In terms of the extent, chronicity, and frequency of
recurrence, the lesions in the five patients reported here
represent the severe end of the spectrum of mucocutane-
ous herpes simplex virus infections that are found in the
compromised host. As such, it is important to recognize
that the challenge to successful therapy was greater than in
most persons. We have shown that challenging infections
such as these can be effectively treated with intravenous or
oral acyclovir. All courses of treatment were associated
with a rapid suppression of virus shedding and permitted
complete healing of lesions. Some of the successfully treat-
ed infections had been present for over 4 months and had
proven to be refractory to vidarabine. In addition, we have
shown that expected clinical recurrences can be prevented
as long as acyclovir treatment is continued.
It is possible that the clinical responses in the five pa-
tients were fortuitous and not related to acyclovir admin-
istration. These patients were not treated with acyclovir
in blinded, controlled trials although two patients failed
to improve markedly during controlled trials of vidara-
bine and placebo. Despite this, however, the objective
and subjective data are sufficiently compelling and consis-
tent with the data of other recent human trials of acyclo-
vir therapy (6-10) as to be entirely reasonable.
The biochemical mechanism that underlies the ability
of acyclovir to inhibit herpes simplex virus replication is
known (17, 18). The drug is converted to the monophos-
phate form by the virally coded pyrimidine deoxynucleo-
side (thymidine) kinase, a reaction that proceeds only
slightly in uninfected cells. Acyclovir monophosphate is
subsequently converted by cellular enzymes to the di-
and ultimately the triphosphate form that selectively in-
hibits herpes simplex virus-encoded D N A polymerase.
The concentration of acyclovir that inhibits cell D N A
synthesis in uninfected cells is at least several hundred
times higher than the concentration needed to inhibit
herpes simplex virus D N A synthesis to an equivalent de-
gree. Acyclovir has the greatest activity against herpes
simplex virus type 1 with a mean 50% plaque-reducing
inhibitory dose between 0.1 and 0.5 jumol and slightly
less activity against herpes simplex virus type 2 (0.5 to 2
jimol) (19, 20). These differences should not be clinically
significant.

Table 2. Distribution and Excretion of Acyclovir During Intravenous <3r Oral Therapy*

Doset Patient Serum Levels* Daily Dose Recovered in

Peak Trough 24-h Urine 24-h Stool

jumoJ %
Intravenous
250 mg/m2 . 8 h 3 29 A ± 10.4 (7) 2.7 ± 1.3 ( 9 ) 64.4 ± 1 5 . 0 ( 1 1 ) 0.7 ± 0.6 ( 2 )
250 mg/m2 . 8 h 4 41.0 ± 5.0 (2) 7.5 ± 0.2 (2) 66.0 ± 15.8 (3) 0.0(1)
Oral
200 m g / 4 h 3 2.3 ± 0.9 (7) 2.3 ± 0.9 (7) 12.3 ± 3.9 (8) 19.5 ± 6.7 ( 5 )
400 m g / 4 h 3 3.5 ± 1.4 ( 4 ) 4.5(1) 11.8 ± 1.1 (2) Not done

* All data are expressed as means ± 1 standard deviation for the number of independent measurements shown in the parentheses.
t Intravenous dose is expressed in mg acyclovir / m 2 body surface area.
% Intravenous courses specimens for peak serum levels were taken 15 min after the end of an infusion whereas trough serum level samples were collected 5 to 10 min
before starting an infusion other than that for the first dose. For oral courses, "peak" levels were estimated with samples taken at 60 min after the dose. "Trough" levels
were taken 4 h after dose administration (5 to 10 min before subsequent doses).

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 Table 3. Sensitivity of Herpes Simplex Virus Isolates to Acyclovir
Patient Test Date
Number
1 1 25 September 1979
2 7 December 1979
2 1 30 May 1979
2 7 July 1979
3 23 December 1979
3 1 27 May 1980
2 1 August 1980
3 24 November 1980
4 27 January 1981
5 24 March 1981
6 4 May 1981
* The mean ± SE concentration of acyclovir needed to produce a 50% inhibition of herpes simplex virus as indicated by dye uptake. These results are approximately 10
times greater than those obtained by the plaque reduction method. For acyclovir, 1 fig/mL is approximately equal to 4.35 umol.
The pharmacologic studies of our patients indicate that
their handling of acyclovir was comparable to that found
previously ( 1 6 ) . With intravenous therapy, mean peak
serum levels of 30 to 40 u-mol were achieved at 15 min
after infusion, and mean trough serum levels were 3 to 8
jutmol. With oral therapy, mean peak and trough serum
drug levels were both about to 2 to 3 umol. Although
oral acyclovir was relatively poorly absorbed from the
gastrointestinal tract, levels exceeding those required to
inhibit the replication of herpes simplex virus types 1 or 2
were readily achieved and sustained for several hours.
There are risks associated with the acyclovir treat-
ments used, particularly those given to Patients 3 and 4.
Repeated courses of acyclovir enhance the likelihood of
drug-related toxicity. It is noteworthy that the acyclovir
treatment regimens for the patients presented here and
for the much larger number of patients reported else-
where (6, 8-10) were infrequently associated with toxici-
ty. When apparent, the side effects were uniformly of a
mild and reversible nature.
More importantly, though, repeated acyclovir treat-
ments would be expected to favor selection of drug-resis-
tant virus strains. Therefore, it is noteworthy that we
failed to find drug-resistance in our patients. Acyclovir-
resistant mutants of herpes simplex virus are readily gen-
erated in the laboratory, and some resistant clinical iso-
lates have been recovered ( 2 1 ) . Theoretically, because
most recurrences of herpes simplex virus infection repre-
sent reactivation of the same latent viral genome ( 2 2 ) ,
drug resistance should not develop while adequate inhibi-
tory levels of acyclovir are maintained. Clinically signifi-
cant drug resistance may be possible, however, if latency
had to be reestablished with each recurrence. Experience
with potent antiherpetic drugs like acyclovir indicates
that this may not occur routinely because recurrences
develop despite rapid virus clearance. A more attractive
hypothesis is that drug resistance in a person already har-
boring herpes simplex virus may occur when latency is
established in a new group of nerve cells by reactivated
virus that mutated during exposure to subinhibitory lev-
els of acyclovir. Persons could endogenously reinfect
themselves and potentially reactivate either of two clones
of virus, one sensitive to and one resistant to acyclovir.
Fortunately, early studies suggest that mutations in the
276 March 1982 • Annals of Internal Medicine • Volume 96 • Number
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Identity 50% Infective
Dose*
jug/mL
Before treatment 1 0.20 ± 0.08
After treatment 1 0.36 ± 0.06
Before treatment 1 0.76 ± 0 . 1 7
During treatment 1 1.29 ± 0 . 2 0
After treatment 1 0.58 ± 0.20
Before treatment 1 0.44 ± 0 . 1 1
After treatment 1 0.23 ± 0.04
After treatment 5 1.03 ± 0 . 0 9
During treatment 9 1.59 ± 0 . 2 2
After treatment 11 0.46 ± 0.07
After treatment 12 0.41 ± 0.07
viral thymidine kinase gene, one mechanism for develop-
ment of acyclovir resistance, are associated with a signifi-
cant diminution or the elimination of the capacity of the
virus to establish neural latency (23). Nonetheless, the
potential risk of emergence of clinically important acy-
clovir-resistant herpes simplex virus exists not only for
the treated patient but also for potential contacts. For
persons who have frequent recurrences, chronic therapy
may be preferable to intermittent expectant therapy.
Then the virus would not have the opportunity to repeat-
edly reactivate and be exposed to suboptimal drug con-
centrations. On the other hand, we believe the develop-
ment and understanding of antiviral drugs and their po-
tential toxicities has not yet grown sufficiently to permit
us to recommend very long-term suppressive regimens.
A C K N O W L E D G M E N T S : The authors thank the Burroughs Wellcome
Co. for providing the acyclovir; J. Owens, E. Keith, D. Page, S. Good, and
G. Hunter for technical help; P. Keller for doing the viral thymidine kinase
assays; T. Creagh-Kirk for additional logistical support; K. Leighty for man-
uscript preparation and editing; S. Bachrach, R.N., and many Clinical Asso-
ciates for assistance in patient care; and Drs. A. S. Fauci, A. Muchmore, and
T. Waldmann for patient referrals.
• Requests for reprints should be addressed to Stephen E. Straus, M.D.;
Medical Virology Section, LCI, NIAID, Building 10, Room ll-N-113,
NIH; Bethesda, M D 20205.
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