Download Foscarnet Therapy for Severe Acyclovir

Foscarnet Therapy for Severe Acyclovir-Resistant
Herpes Simplex Virus Type-2 Infections in Patients
with the Acquired Immunodeficiency Syndrome (AIDS)
An Uncontrolled Trial
Kim S. Erlich, M D ; Mark A. Jacobson, M D ; Jane E. Koehler, M D ; Stephen E. Follansbee, M D ;
David P. Drennan, M D ; Lisa Gooze, M D ; Sharon Safrin, M D ; and John Mills, M D
Study Objective: To determine whether trisodium phosphonoformate (foscarnet) is efficacious in treating severe
mucocutaneous disease due to acyclovir-resistant herpes
simplex virus type-2 (HSV-2) infection in patients with the
acquired immunodeficiency syndrome (AIDS).
Design: Open-labeled drug administration to patients with
AIDS and severe ulcerative disease due to acyclovir-resistant HSV-2 infection.
Setting: Medical floors of acute care hospital.
Patients: Four patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals,
perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2.
Intervention: Foscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days.
Measurement and Main Results: All patients receiving
foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and
eradication of HSV from mucosal surfaces.
Conclusion: Foscarnet may be an effective treatment for
severe mucocutaneous disease due to acyclovir-resistant,
TK-negative strains of HSV-2.
Annals of Internal Medicine. 1989;110:710-713.
From the University of California, and the Davies Medical
Center, San Francisco, California. For current author addresses, see end of text.
antiviral agents that do not require viral thymidine
kinase for activation ( 3 ) . Four of these patients with
severe infection due to herpes simplex virus type-2
(HSV-2) that was acyclovir resistant were successfully treated with trisodium phosphonoformate (foscarnet), a drug being investigated because of its activity
against cytomegalovirus and human immunodeficiency virus infections.
Patients and Methods
Acyclovir resistance was suspected in the four patients because of persistent ulcerative mucocutaneous HSV disease
that did not resolve with systemic acyclovir treatment. The
patients were all homosexual men with chronic, ulcerative
HSV infections who also had AIDS as defined by the Centers for Disease Control surveillance criteria. Virus isolates
recovered from these patients were tested for susceptibility
to antiviral drugs using the plaque reduction assay as previously described (4). Control acyclovir-susceptible and -resistant strains were included in each test. The concentration
of drug that inhibited the plaque number by 50% (ID 50 )
when compared to the wells without drug was calculated by
the method of least mean squares. The biochemical characteristic and animal virulence of the virus strains are reported
separately (2).
Foscarnet (Astra Clinical Research, Westboro, Massachusetts) was administered intravenously through either a
peripheral or central venous catheter. All patients initially
received induction therapy of 60 mg/kg body weight of the
drug every 8 hours for 14-21 days. Two patients also received maintenance foscarnet therapy (42 to 60 mg/kg • d)
5 to 7 d/wk. Each infusion was given over 2 hours.
Results
Patient 1
H e r p e s simplex virus (HSV) infections are frequent
in both normal and immunocompromised persons.
Recurrent HSV infections in the immunocompetent
host are usually self-limiting, but patients with the acquired immunodeficiency syndrome ( A I D S ) often
have persistent ulcerative mucocutaneous lesions due
to this virus ( 1 ) . In patients with AIDS, HSV infections usually heal rapidly with systemic acyclovir therapy. We have identified 12 patients with AIDS in
whom acyclovir therapy failed because of the development of acyclovir-resistant strains ( 2 ) . All of the
strains studied were resistant to acyclovir due to a lack
of viral thymidine kinase activity; however, they have
remained susceptible to foscarnet and vidarabine, two
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©1989 American College of Physicians
A 28-year-old man was diagnosed as having A I D S after developing Kaposi sarcoma on the hard palate in
October 1986. He had had recurrent perianal HSV
infection since 1982 and had been treated with daily
oral acyclovir as suppressive therapy since 1985. H e
self-adjusted his dose of medication during this time
and received between 400 and 4000 mg of acyclovir
per day. In April 1987 he started zidovudine therapy
and discontinued acyclovir therapy. Within 2 weeks of
stopping oral acyclovir, however, he developed ulcerations of both the perianal region and the third finger of
his left hand. Oral acyclovir therapy, 400 mg 5 times
daily, was restarted, and although the hand lesion resolved with therapy the perianal lesions persisted. The
patient was maintained on daily acyclovir, 2.4 g/d, but
Figure 1. Effect of foscamet therapy on
mucocutaneous lesions due to acyclovirresistant herpes simplex virus. Patient 1
before therapy (A); Patient 1 after therapy (B); Patient 4 before therapy (C);
Patient 4 after therapy (£>). Arrow refers to lesion that was cultured for acyclovir-resistant virus.
the hand lesion recurred in October 1987. Therapy
with oral zidovudine and acyclovir was continued
(with the oral acyclovir dosage gradually increased to
4.8 g / d ) , but no further clinical response was noted.
In January 1988 cultures of the ulcerative hand lesion (Figure 1A) yielded HSV-2. In-vitro susceptibility tests showed resistance to acyclovir (ID50 = 54.3
fxg/mL), but the virus remained susceptible to foscarnet (ID50 = 33.3 jixg/mL). Both zidovudine and acyclovir were withdrawn, and the patient was begun on
foscamet 60 mg/kg every 8 hours. After 14 days of
treatment the finger lesion and perianal fissure healed
completely and virus cultures were negative (Figure
IB). The patient was treated with 100 mg of zidovudine and 400 mg of acyclovir every 4 hours. Although
the finger lesion did not recur, a 5-mm perirectal ulcer
developed 7 weeks after discontinuation of foscamet
therapy. Cultures of this ulcer yielded acyclovir-resistant HSV.
Patient 2
A 33-year-old bisexual man presented in June 1987
with a 5- X 3- cm perianal ulceration. Cultures showed
HSV-2, and treatment with 200 mg of acyclovir 5
times daily was begun. The ulceration did not improve
after several months of acyclovir therapy, despite a
gradual increase to 1600 mg of acyclovir per day. In
February 1988 the patient developed Pneumocystis
carinii pneumonia and was treated with trimethoprimsulfamethoxazole. The perirectal lesion persisted, and
a repeat culture in March 1988 yielded HSV-2 that
was resistant to acyclovir (ID50 = 54.0 jug/mL) but
susceptible to foscamet ( I D 5 0 = 14.0 jug/mL). Acyclovir was withdrawn and the patient was treated with
foscamet, 60 mg/kg, every 8 hours. After a 14-day
induction period the lesion was reepithelializing and
cultures were negative. During the initial treatment
course (2 weeks) his 24-hour creatinine clearance fell
from 1.47 to 0.97 mL/s. Foscamet was continued
as maintenance therapy with daily dosages ranging
between 42 and 60 mg/kg . d. Dosage adjustments
were required during this time because his 24-hour
creatinine clearance decreased further to 0.60 mL/s.
The patient received foscamet for a total of 50 days, at
which time his lesion had completely healed. He was
released from the hospital on 400 mg of acyclovir
three times daily. Two weeks after completion of fos-
1 May 1989 • Annals ofInternal Medicine • Volume 110 • Number 9
711
carnet therapy his 24-hour creatinine clearance had
increased to 0.85 m L / s .
decreased in size, and all cultures were negative. Foscarnet therapy was discontinued at this time and the
patient was discharged on acyclovir, 400 mg three
times daily.
Patient 3
One month after successful treatment of P. carinii
pneumonia, a 42-year-old homosexual man developed
ulcerative lesions of his right buccal mucosa and lower
lip. Cultures in January 1987 yielded both herpes simplex virus type-1 (HSV-1) and HSV-2. Topical and
oral acyclovir therapy was started, but the lesions increased in size. In March 1987, 1200 mg of oral zidovudine per day was added to a regimen of 1000 mg of
oral acyclovir per day. The facial lesions persisted, and
by December 1987 extensive mucocutaneous ulcerations extended along the upper lip, lower lip, buccal
mucosa, gingival mucosa, and cheek. The largest single lesion (along the right cheek) was 7.6 cm X 6.3
cm. The patient was hospitalized in December 1987
and received intravenous acyclovir, 15 m g / k g • d, for
14 days. Although some improvement in the appearance of the lesions was noted, they increased in size
once intravenous therapy was discontinued and oral
acyclovir therapy, 2000 m g / d , was restarted. In January 1988 intravenous acyclovir, 15 m g / k g • d, was administered on an outpatient basis, but the lesions continued to increase in size. Cultures yielded HSV-2 that
was resistant to acyclovir ( I D 5 Q = 46.7 juig/mL) but
susceptible to foscarnet ( I D 5 0 = 25.9 jLig/mL). The
patient was rehospitalized and treated with foscarnet,
60 m g / k g every 8 hours for 21 days. The lesions decreased during therapy and repeated cultures were
negative. The patient was released from the hospital
and has been maintained on, 50 m g / k g , foscarnet administered 5 to 7 days per week. The lesions have healed
completely and cultures have remained negative.
Patient 4
A 29-year-old homosexual man with a history of recurrent perianal HSV infection developed P. carinii
pneumonia in February 1987. Before this time his
HSV recurrent infections had responded well to short
treatment courses of oral acyclovir. In November
1987, however, he developed recurrent perianal herpes
infection that did not respond to oral acyclovir. Oral
acyclovir, 400 mg 5 times daily, was administered continually from November 1987 through March 1988,
but the lesions increased in size and number. Cultures
in March 1988 yielded HSV-2, and in-vitro susceptibility testing showed that the isolate was resistant to
acyclovir ( I D 5 Q = 18.3 juig/mL) and susceptible to
foscarnet ( I D 5 Q = 14.8 jmg/mL). Acyclovir therapy
was discontinued, but new herpetic lesions involving
the perirectal area, penis, and scrotum developed during the next 2 months (Figure 1C). The largest perirectal lesion at this time was 5 x 3 cm. In May 1988
cultures were still positive for acyclovir-resistant HSV2, and the patient was treated with foscarnet, 60
m g / k g every 8 hours. After 12 days of therapy the
penile and scrotal lesions had resolved completely
(Figure I D ) , the large perianal lesion was markedly
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Discussion
Four patients with A I D S who developed severe mucocutaneous HSV-2 infections due to acyclovir-resistant
virus responded to intravenous foscarnet therapy. The
virus strains isolated from these patients were shown
to be resistant to acyclovir by in-vitro susceptibility
testing, and the lesions failed to heal with systemic
acyclovir therapy; however, the ID50 values for foscarnet were within the range that was achievable in the
serum of patients receiving the drug (5, 6 ) .
Acyclovir-resistant strains of HSV have been previously reported in both normal (7-9) and immunocompromised patients (2, 10-15). The clinical significance
of recovering drug-resistant virus from patients with
normal immune function is unclear; however, patients
with defects in cellular immunity may develop progressive mucocutaneous disease because of these
strains despite acyclovir therapy (2, 10-15). Although
foscarnet has been shown to have good in-vitro activity against HSV in animal models, clinical experience
with the drug in humans with HSV infection is limited
(16). Vinckier and colleagues (15) have reported a
beneficial clinical response to intravenous foscarnet in
a single immunocompromised patient with severe
HSV infection due to acyclovir-resistant virus.
Although the four patients reported here responded
very well to foscarnet therapy, this was not a controlled trial and a longer period of follow-up will be
necessary to determine the natural history of acyclovir
resistance in patients with A I D S . It is likely that natural selection of acyclovir-resistant HSV variants occurs with acyclovir therapy in the large pool of virus
that is found in extensive mucosal lesions. Because latent virus should remain susceptible to acyclovir, recurrences developing after complete healing of the lesions should be due to acyclovir-susceptible virus. It is
possible, however, that the acyclovir-resistant virus
strains that develop in mucocutaneous lesions are capable of infecting paraspinous ganglia and establishing
latency, possibly resulting in recurrences due to acyclovir-resistant virus. In one of our patients (Patient
1), a recurrence that developed after foscarnet therapy
and complete healing of the lesions was due to acyclovir-resistant virus.
Most clinical isolates of HSV that are acyclovir resistant have markedly decreased thymidine kinase activity (TK- mutants). These virus strains are resistant
to acyclovir because drug phosphorylation by viral
thymidine kinase no longer occurs (3, 17). These T K HSV variants remain susceptible in vitro to antiviral
agents that do not require viral thymidine kinase for
activation. Vidarabine, a nucleoside analog, is phosphorylated by host-cell enzymes. Foscarnet is an active inhibitor of HSV D N A polymerase in its native
form and does not require phosphorylation for antiviral activity (3, 17). Both of these antiviral agents are
not affected by the loss of thymidine kinase ( 3 ) . Thus
1 May 1989 • Annals ofInternal Medicine • Volume 110 • Number 9
far, all acyclovir-resistant HSV strains recovered from
patients with A I D S have been T K - variants and have
remained susceptible to both foscarnet and vidarabine
( 2 ) . Strains of HSV that are resistant to acyclovir by
virtue of alterations in the substrate specificity of the
thymidine kinase or the viral D N A polymerase, however, may develop concurrent resistance to either foscarnet or vidarabine ( 3 ) .
Oral absorption of foscarnet is poor, and intravenous therapy is required to achieve adequate serum
levels ( 5 ) . Intermittent administration of foscarnet, 60
m g / k g body weight every 8 hours (infused over 2
hours) produces peak and trough serum drug concentrations of 530 and 100 JLIM, respectively ( 6 ) . Excretion of the drug occurs solely by renal mechanisms,
with a serum half-life ranging between 0.7 and 4.8
hours (6, 16). Progressive impairment of renal function can occur with prolonged use of the drug, and
dosage adjustments are required in patients with renal
dysfunction (5, 16).
In view of the increasing numbers of patients with
A I D S it is likely that acyclovir-resistant HSV infections will become more prevalent. These case reports,
which show a beneficial effect of foscarnet therapy, are
encouraging but they do not establish efficacy. Further
clinical trials evaluating the use of foscarnet in persons
with A I D S and acyclovir-resistant HSV infection are
warranted, and the in-vitro susceptibility data suggest
that both foscarnet and vidarabine should be studied.
Addendum
Since submission of this manuscript, an additional patient with A I D S and infection due to acyclovir-resistant herpes simplex virus who responded to foscarnet
therapy has been described (18).
Acknowledgments: We thank Ruth Ackerman and Joanne Rush for
technical assistance. Reference HSV strains and acyclovir were provided
by Nick Ellis and Sandra Nusinoff-Lehrman, Burroughs Wellcome
Company. Foscarnet was provided by Astra Pharmaceuticals and Astra
Clinical Research, USA.
Grant Support: Kim S. Erlich was supported by training grant 5-T32AI07234 from the National Institutes of Health.
Requests for Reprints: John Mills, MD, Division of Infectious Diseases,
San Francisco General Hospital, Building 80, Ward 84, 995 Potrero
Avenue, San Francisco, CA 94110.
Current Author Addresses: Drs. Jacobson, Koehler, Gooze, Safrin, and
Mills: Division of Infectious Diseases, San Francisco General Hospital,
San Francisco, CA 94110.
Dr. Erlich: Seton Medical Center, Daly City, CA 94015.
Dr. Follansbee: 3620 Army Street, San Francisco, CA 94110.
Dr. Drennan: Davies Medical Center, San Francisco, CA 94114.
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