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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and
Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

Chapter 65Antiviral therapy of varicella-zoster virus

infections
Authors
John W. Gnann Jr.

Affiliations
Departments of Medicine, Pediatrics and Microbiology, Division of Infectious Diseases,
University of Alabama at Birmingham and the Birmingham VA Medical Center
Birmingham, AL, USA
Introduction
Primary infection caused by varicella-zoster virus (VZV) is manifest by
varicella (chickenpox), while reactivation of latent virus causes herpes zoster
(shingles). In immunocompetent children, varicella is usually not a serious
disease, but can cause severe morbidity and mortality in adults and in
immunocompromised individuals. Similarly, herpes zoster is associated with
much greater morbidity in patients with impaired cell-mediated immune
responses. In addition, herpes zoster can cause prolonged pain (postherpetic
neuralgia) that can be very difficult to manage, particularly in older
individuals. The outcomes of varicella and herpes zoster, especially in
immunocompromised patients, have been dramatically improved by the
development of safe and effective antiviral drugs with potent activity against
VZV. Early drugs with modest efficacy and substantial toxicity (e.g.,
interferon, vidarabine, etc.) have been replaced by antiviral agents with
enhanced in vitro activity, improved pharmacokinetic properties, and
excellent safety profiles.

Diagnosis
Most experienced physicians will be able to make an accurate clinical
diagnosis of chickenpox based on the distinctive appearance of the skin
lesions (Fig. 65.1(a)). The clinical syndrome of a child with mild
constitutional symptoms, the typical diffuse vesicular rash, and no prior
history of chickenpox is strongly suggestive of the diagnosis, especially if
there has been exposure to VZV within the previous two weeks. However, in
countries where the incidence of varicella is dramatically declining (such as
the United States), younger physicians will have fewer opportunities to see
patients with chickenpox and may feel less confident with the clinical
diagnosis. In addition, a variety of atypical presentations may occur in
immunocompromised patients that will require laboratory confirmation. The
classical dermatomal presentation of herpes zoster is also highly distinctive
and readily lends itself to clinical diagnosis, although the diagnosis may be
obscure initially in patients who present with dermatomal neuralgic pain prior
to the onset of skin lesions (Fig. 65.1(b)).
Culture for VZV is performed by inoculating vesicular fluid onto monolayers
of human fetal diploid kidney or lung cells. Unlike HSV, VZV is labile and
every effort should be made to minimize the time spent in specimen transport
and storage. Ideally, fluid should be aspirated from clear vesicles using a
tuberculin syringe containing 0.2 ml of viral transport medium, inoculated
directly into tissue culture at the bedside (or taken immediately to the
laboratory), and then incubated at 36 ℃ in 5% CO2 atmosphere. If no
vesicles or pustules are available for aspiration, the clinician should carefully
remove overlying debris or crusts from the freshest lesions available, swab
the underlying ulcers, and place the swab directly into viral transport medium
for rapid delivery on ice to the laboratory. Characteristic cytopathic effects
are usually evident in tissue culture in 3–7 days, although cultures should be
held for 14 days before they are declared negative. The culture process can be
accelerated by using centrifugation cultures in shell vials. Identification of the
viral isolate is confirmed by staining the monolayer with VZV-specific
monoclonal antibodies. In general, viral culture for VZV is highly specific
but slow, insensitive, and expensive.
Since VZV is not shed asymptomatically, demonstration of VZV virions,
antigens, or nucleic acids in body fluids or tissues (other than sensory
ganglia) is diagnostic of active infection. Visualization of multinucleated
giant cells or herpesvirus virions in tissues by histopathology or electron
microscopy does not distinguish between VZV and herpes simplex virus
(HSV). Immunohistochemical staining of viral antigens can provide a more
specific diagnosis. Direct fluorescent antigen (DFA) staining using
fluorescein-conjugated monoclonal antibodies to detect VZV glycoproteins in
infected epithelial cells is especially helpful for making a rapid diagnosis
when the clinical presentation is atypical. To perform the DFA assay,
epithelial cells are scraped from the base of a vesicle or ulcer with a scalpel
blade, smeared on a glass slide, fixed with cold acetone, stained with
fluoroescein-conjugated monoclonal antibodies, and then examined using a
fluorescence microscope. By using virus-specific monoclonal antibodies,
HSV can be readily distinguished from VZV, making DFA staining a much
more powerful technique then a simple Tzanck preparation. DFA is also
more sensitive than virus culture, especially in later stages of VZV infection
when virus isolation becomes more difficult. In a population of 92 HIV-
infected adults with suspected herpes zoster, DFA and viral culture were
positive in 85 of 92 (92%) and 60 of 92 (65%) patients, respectively (Dahl et
al., 1997).
Using the polymerase chain reaction (PCR) to detect VZV nucleic acids in
clinical specimens is an important diagnostic method (Stranska et al., 2004).
PCR overcomes the difficulties inherent in culturing labile VZV and has been
used successfully to detect viral DNA in cerebrospinal fluid (CSF) from
patients with VZV encephalitis and in ocular fluids and tissues from cases of
VZV retinitis. Diagnosing VZV infection of the central nervous system
(CNS) can be difficult, especially when there are no concomitant cutaneous
lesions. Examination of the CSF usually reveals a moderate lymphocytic
pleocytosis, normal to moderately elevated protein, and normal glucose. The
PCR for VZV DNA in CSF should be positive in more than 75% of cases. In
one series of 34 HIV-infected patients with VZV neurologic complications,
the mean CSF white blood cell count was 126/mm3, the mean protein
concentration was 230 mg/dl, and the PCR was positive for VZV in all cases
(De La Blanchardiere et al., 2000).
Serologic techniques can be used to determine susceptibility to VZV
infection and to document rising antibody titers following varicella. Serum
IgG becomes detectable several days after the onset of varicella and titers
peak after 2 to 3 weeks, so routine serologic testing provides only a
retrospective diagnosis. Acute infection can be confirmed by VZV-specific
serum IgM titers, but antigen detection techniques are usually faster and more
reliable. Patients with herpes zoster are VZV-seropositive at the time of
disease onset, but most show a significant rise in antibody titer during the
convalescent phase. A variety of methods have been used to detect VZV
antibodies, but many laboratories have adopted an enzyme-linked
immunosorbent assay (ELISA) or a latex agglutination (LA) assay for VZV
serodiagnosis. The ELISA is capable of detecting IgG or IgM responses, is a
reliable indicator of immune status following natural infection, and is readily
automated. However, the ELISA may not be sufficiently sensitive to detect
vaccine-induced immunity. The LA assay is rapid, simple, inexpensive and
highly sensitive, but cannot be automated or used to detect IgM.

Drugs with activity against VZV

Acyclovir and valacyclovir
Acyclovir, an acyclic analogue of guanosine, is a selective inhibitor of VZV
and HSV replication (Whitley and Gnann, 1992). The drug is converted to
acyclovir monophosphate by virus-encoded thymidine kinase (TK), a
reaction that does not occur to any significant extent in uninfected cells.
Cellular enzymes catalyze the subsequent diphosphorylation and
triphosphorylation steps which yield high concentrations of acyclovir
triphosphate in VZV-infected cells. Acyclovir triphosphate inhibits viral
DNA synthesis by competing with deoxyguanosine triphosphate as a
substrate for viral DNA polymerase. Incorporation of acyclovir triphosphate
into viral DNA results in obligate chain termination since the molecule lacks
the 3-hydroxyl group required for further DNA chain elongation. Viral DNA
polymerase is tightly associated with the terminated DNA chain and is
functionally inactivated. Viral DNA polymerase has a much higher affinity
for acyclovir triphosphate than does cellular DNA polymerase, resulting in
little incorporation of acyclovir triphosphate into cellular DNA. The median
inhibitory concentration of acyclovir necessary to reduce VZV plaque counts
by 50% (IC50) is approximately 3 µg/ml.
After oral administration, acyclovir is slowly and incompletely absorbed with
bioavailability of about 15–30%. Following oral administration of multiple
doses of 200 mg or 800 mg of acyclovir, mean plasma peak concentrations at
steady state are approximately 0.6 and 1.6 µg/ml, respectively. Plasma
protein binding is less than 20%. Acyclovir penetrates well into most tissues,
including the CNS. About 85% of an administered acyclovir dose is excreted
unchanged in the urine via glomerular filtration and tubular secretion. The
terminal plasma half-life of acyclovir is 2–3 hours in adults and 3–4 hours in
neonates with normal renal function, but is extended to about 20 hours in
anuric patients.
Valacyclovir is an orally administered prodrug of acyclovir that overcomes
the problem of poor oral bioavailability and exhibits improved
pharmacokinetic properties (Acosta and Fletcher, 1997). Valacyclovir, the L-
valine ester of acyclovir, is well absorbed from the gastrointestinal tract via a
stereospecific transporter and undergoes essentially complete first pass
conversion in the gut and liver to yield acyclovir and L-valine. Using this
prodrug formulation, the bioavailability of acyclovir is increased to about
54%, yielding peak plasma acyclovir concentrations that are three- to fivefold
higher than those achieved with oral administration of the parent compound.
Oral valacyclovir doses of 500 mg or 1000 mg produce peak plasma
acyclovir concentrations of 3–4 and 5–6 µg/ml, respectively. Following
administration of valacyclovir at a dose of 2 g orally four times daily, plasma
acyclovir area-under-the-curve (AUC) values approximate those produced by
acyclovir given intravenously at a dose of 10 mg/kg every 8 hours. Acyclovir
AUC values after oral valacyclovir dosing are slightly higher in elderly
individuals when compared with younger control groups, presumably due to
declines in creatinine clearance associated with aging.
Acyclovir is cleared primarily by renal mechanisms so dosage modification
for both acyclovir and valacyclovir are required for patients with significant
renal dysfunction. The mean elimination half-life of acyclovir after a single 1
gram dose of valacyclovir is about 14 hours in patients with end-stage renal
disease. Acyclovir is readily removed by hemodialysis, but not by peritoneal
dialysis. No specific dosage modification for these drugs is required for
patients with hepatic insufficiency. Acyclovir and valacyclovir are not
approved for use in pregnancy, but have been widely use to treat serious HSV
and VZV infections in pregnant women without evidence of maternal or fetal
toxicity (Reiff-Eldridge et al., 2000).
Acyclovir is an extremely safe and well-tolerated drug. Local inflammation
and phlebitis may occur following extravasion of intravenous acyclovir.
Renal dysfunction resulting from accumulation of acyclovir crystals in the
kidney has been observed following rapid intravenous infusion of large doses
of acyclovir, but is uncommon and usually reversible. Acyclovir-related
neurotoxicity (including agitation, hallucinations, disorientation, tremors, and
mild clonous) has been reported, most often in elderly patients with
underlying CNS abnormalities and renal insufficiency (Hellden et al., 2003).
Oral acyclovir therapy is rarely associated with either neurotoxicity or
nephrotoxocity. Studies of patients receiving long-term acyclovir for chronic
suppression of genital herpes have revealed no cumulative toxicity (Tyring et
al., 2002).
At standard doses, valacyclovir is also a very safe and well-tolerated drug
(Acosta and Fletcher 1997). A syndrome of thrombotic microangiopathy
(characterized by fever, microangiopathic hemolytic anemia,
thrombocytopenia, and renal dysfunction) was observed in AIDS patients
receiving high dose valacyclovir (8 grams per day) in a clinical trial.
However, this syndrome has not been observed in immunocompetent patients
receiving valacyclovir at standard doses (up to 3 grams per day). There is no
contraindication to using valacyclovir at approved doses in HIV-infected
patients. Clinically significant interactions between acyclovir or valacyclovir
and other drugs are extremely uncommon.
Acyclovir is available in topical, oral, and intravenous formulations. The
dermatologic preparation consists of 5% acyclovir in a cream or polyethylene
glycol ointment base. Topical acyclovir is intended for treatment of minor
mucocutaneous HSV infections and plays no role in treatment of VZV. Oral
acyclovir preparations include a 200 mg capsule, 400 and 800 mg tablets, and
a liquid suspension (200 mg per 5 ml). Acyclovir sodium for intravenous
infusion is supplied as a sterile water-soluble powder that must be
reconstituted and diluted to a concentration of 50 mg/ml. The approved dose
of oral acyclovir for chickenpox is 200 mg/kg (up to a maximum of 800 mg)
4–5 times daily for 5 days. Adults with herpes zoster can be treated with oral
acyclovir at a dose of 800 mg five times daily. The recommended dose of
intravenous acyclovir for VZV infections is 10 mg/kg every 8 hours,
although higher doses (12–15 mg/kg) are sometimes used for life-threatening
infections, especially in immunocompromised patients. Dosage reduction is
required in patients with renal insufficiency. Valacyclovir is available as 500
mg and 1000 mg tablets. The recommended dose for immunocompetent
adults with varicella or herpes zoster is 1000 mg three times daily for 7 days.
Because a suspension formulation of valacyclovir is not available, clinical
experience with this drug in children with chickenpox is limited.
Penciclovir and famciclovir
Penciclovir is an acyclic guanine derivative that resembles acyclovir in
chemical structure, mechanism of action, and spectrum of antiviral activity
(Perry and Wagstaff, 1995). Like acyclovir, penciclovir is first
monophosphorylated by viral TK, then further modified to the triphosphate
form by cellular enzymes. Penciclovir triphosphate blocks viral DNA
synthesis through competitive inhibition of viral DNA polymerase. Unlike
acyclovir triphosphate, penciclovir triphosphate is not an obligate chain
terminator and can be incorporated into the extending DNA chain.
Intracellular concentrations of penciclovir triphosphate are higher then those
seen with acyclovir triphosphate. In VZV infected cells, the half-life values
for penciclovir triphosphate and acyclovir triphosphate are 7 hours and 1
hour, respectively. However, this potential advantage is offset by the lower
affinity of penciclovir triphosphate for viral DNA polymerase. The median
IC50 of penciclovir for VZV in MRC-5 cells is 4.0 µg/ml. Because
penciclovir is very poorly absorbed, famciclovir (the diacetyl ester of 6-
deoxy-penciclovir) was developed as the oral formulation. The first acetyl
side chain of famciclovir is cleaved by esterases found in the intestinal wall
and the second acetyl group is removed on first pass through the liver.
Oxidation catalyzed by aldehyde oxidase occurs at the six position, yielding
penciclovir.
When administered as the famciclovir prodrug, the bioavailability of
penciclovir is about 77%. Following a single oral dose of 250 mg or 500 mg
of famciclovir, peak plasma penciclovir concentrations of 1.9 and 3.5 µg/ml
are achieved at 1 hour. The pharmacokinetics of penciclovir are linear and
dose dependent over a famciclovir dosing range of 125–750 mg. Penciclovir
is not metabolized, but is eliminated unchanged in urine, with an elimination
half-life of about 2 hours after intravenous administration. Penciclovir for
intravenous administration has not been commercially marketed. Famciclovir
is available as 125 mg, 250 mg, and 500 mg tablets. In the United States, the
recommended dose of famciclovir for uncomplicated herpes zoster is 500 mg
three times daily. Famciclovir doses of 250 mg three times daily and 750 mg
once daily are approved for treatment of shingles in some countries and
appear to be comparable with respect to cutaneous healing of herpes zoster
(Shafran et al., 2004). Adjustment of the famciclovir dose is required in
patients with creatinine clearance of <60 ml/min. The adverse effects most
frequently reported by patients participating in clinical trials of famciclovir
were headache and nausea, although these symptoms did not differ
significantly between famciclovir and placebo recipients.

Other drugs

Brivudin

Brivudin (bromovinyl deoxyuridine) is a highly potent thymidine nucleoside

analogue with selective activity against HSV-1 and VZV (Keam et al., 2004).
The mechanism of action of brivudin appears to be inhibition of the viral
DNA polymerase. The drug is well-absorbed after oral administration and has
a favorable pharmacokinetic profile which permits once-daily dosing.
Brivudin is generally well-tolerated; nausea is the most frequently reported
adverse event. Because of concerns about the safety profile of the drug,
commercial development of brivudin was halted in the United States. The
drug is available in several countries as a 125 mg tablet and as a 0.1%
ointment for ophthalmologic use.

Foscarnet

Foscarnet (phosphonoformic acid) is a pyrophosphate analogue that functions

as an inhibitor of viral DNA polymerase by blocking the pyrophosphate
binding site (Wagstaff and Bryson, 1994). Unlike the nucleoside analogues
discussed above, foscarnet does not require intracellular activation by TK,
therefore, TK-deficient HSV and VZV isolates that are resistant to acyclovir
and related drugs remain susceptible to foscarnet. Foscarnet is administered
only by the intravenous route and 80%–90% of an administrated dose is
excreted unchanged in the urine. The appropriate dose of foscarnet for
treatment of acyclovir-resistant VZV infections has not been assessed
systematically, but doses ranging from 40 mg/kg every 8 hours to 100 mg/kg
every 12 hours have been used successfully. The most important adverse
effect associated with foscarnet therapy is nephrotoxicity. Dose limiting renal
toxicity was noted in 15%–20% of patients treated with foscarnet for CMV
retinitis. Loading the patient with intravenous saline prior to foscarnet
infusion can help reduce the risk of nephrotoxicity. Foscarnet can also induce
a variety of electrolyte and metabolic abnormalities, most notably
hypocalcemia. Foscarnet-induced electrolyte disturbances can predispose the
patient to cardiac arrhythmias, tetany, altered mental status, or seizures. To
avoid serious adverse effects that can result from bolus infusion, foscarnet
must be administered with an infusion pump over a duration of at least one
hour. Serum creatinine levels should be checked at least three times weekly
in patients receiving foscarnet and the dosage adjusted according to the
manufacturer’s guidelines.

Vidarabine

Vidarabine (adenine arabinoside) was the first intravenous antiviral drug

accepted for widespread clinical use and was shown to be effective for VZV
infections in immunocompromised patients. Vidarabine has now been
replaced by more effective and less toxic antiviral drugs.

Interferon

Administration of alpha-interferon to immunocompromised patients with

herpes zoster reduces the risk of viral dissemination, but has little impact on
dermatomal rash healing or pain. Interferon therapy was associated with
significant adverse events and has been supplanted by more specific antiviral
drugs.

Clinical indications for therapy

Varicella

Children

In healthy children, varicella is associated with low rates of morbidity and

mortality. For most children, supportive care alone is sufficient. Astringent
soaks, antipruritics, and antipyretics (preferably acetaminophen) improve
comfort. Trimming the fingernails closely helps prevent bacterial
superinfections caused by scratching. If bacterial cellulitis (especially caused
by group A streptococcus) develops, antibiotics may be required.
Oral acyclovir has been evaluated for treatment of uncomplicated varicella in
immunocompetent children (Balfour et al., 1990; Dunkle et al., 1991).
Acyclovir therapy, initiated within 24 hours of the onset of rash, resulted in
shorter duration of fever, fewer skin lesions, and accelerated lesion healing.
Overall, oral acyclovir was well tolerated and reduced the duration of
symptomatic illness by about 24 hours. The populations studied in these
clinical trials were not significantly large to assess the impact of acyclovir
therapy on the incidence of varicella complications. Unlike acyclovir,
valacyclovir and famciclovir are not available as suspension formulations and
have not been evaluated extensively for treatment of varicella in small
children. Some pediatricians still view antiviral therapy as optional for
otherwise healthy children with chickenpox. Since the introduction of the
varicella vaccine in the United States in 1995, the incidence of chickenpox
has declined dramatically, reducing the need for antiviral options in this
population.

Adults

Immunocompetent adolescents and adults with varicella can be seriously ill,

with high fever, hundreds of cutaneous lesions, incapacitating constitutional
symptoms, and a higher risk of complications (especially pneumonitis). Since
they are likely to miss at least seven days of school or work, interventions
that will reduce the duration of the acute illness are warranted. In a placebo-
controlled trial of therapy for 148 adults with varicella, acyclovir (800 mg
orally five times daily) was shown to reduce the duration of new lesion
formation, reduce the maximum number of lesions, accelerate cutaneous
healing, and shorten the duration of fever (Wallace et al., 1992). Similarly, a
study of acyclovir treatment in otherwise healthy adolescents demonstrated
shorter duration of new lesion formation and of constitutional symptoms,
including fever (Balfour et al., 1992). In these studies, the benefit of
acyclovir therapy was minimal when treatment was initiated later than 24
hours after rash onset. Overall, acyclovir reduced the duration of illness by
about two days. Valacyclovir and famciclovir are also likely to be effective in
this setting, but data from controlled clinical trials are lacking. While antiviral
therapy is considered optional for healthy children with varicella, the higher
potential for morbidity clearly favors treatment in adolescents and adults
(Table 65.1). Available data are insufficient to determine whether acyclovir
therapy reduces the risk of complications such as pneumonitis or encephalitis.
In immunocompetent patients, visceral dissemination of varicella most often
involves the CNS (presenting as cerebellar ataxia, encephalitis, transverse
myelitis, or stroke syndromes) or the lungs (viral pneumonitis)
(Gnann, 2002). No controlled studies of antiviral therapy for these
complications of varicella have been performed. However, information
derived from clinical experience and case reports suggests that intravenous
acyclovir (10–15 mg/kg every 8 hours) may be beneficial (Haake et al., 1990;
Wilkins et al., 1998) (Table 65.1).
The decision whether to initiate antiviral therapy in a patient with chickenpox
will hinge on the patients age, underlying medical conditions, and the risk of
complications (Arvin, 2002). In general, young children (under age 12 years)
are at lower risk for complications than are adolescents or adults. An
exception may be secondary pediatric cases in a household, who tend to have
more severe disease than the index case. Benefits of antiviral therapy are
minimal for healthy children presenting with greater than 24 hours of illness.
Because of the greater risk of complications, antiviral therapy is appropriate
for adolescents and adults with chickenpox, probably even for those
presenting 48–72 hours into the course of illness. Immunocompromised
patients with varicella are at significant risk for viral dissemination and
visceral involvement and should always receive antiviral therapy.

Pregnant women

Although based more on case reports than on prospectively acquired data, the
evidence that varicella in pregnancy is associated with enhanced morbidity is
compelling (Nathwani et al., 1998). Women who contract varicella while
pregnant have an estimated 10% risk for developing severe VZV
pneumonitis. Aggressive antiviral therapy is recommended for a pregnant
woman with varicella who develops any evidence of pulmonary involvement,
including cough, shortness of breath, or abnormal chest radiograph. Data
from clinical trials are lacking, but several case series have reported clinical
improvement in pregnant women with varicella pneumonia who were treated
with intravenous acyclovir. Although acyclovir is not approved for use during
pregnancy for any indication, no fetal toxicity attributable to acyclovir has
been demonstrated and the risk-benefit ratio clearly supports the use of
acyclovir in the setting of maternal varicella pneumonia (Reiff-Eldridge et
al., 2000). Many experts favor antiviral therapy (with acyclovir or
valacyclovir) for all pregnant women with chickenpox in an effort to reduce
maternal morbidity. No data are available to indicate whether treating the
mother will alter the risk of the rare fetal varicella syndrome (Harger et
al., 2002).
Immunocompromised patients

The availability of safe and effective antiviral drugs has greatly reduced the
high mortality rate previously associated with varicella in
immunocompromised patients. Populations at high risk include organ
transplant recipients, patients with cancer (especially hematologic
malignancies), and other patients receiving immunosuppressive medications
(including corticosteroids). Because of the high frequency of visceral
involvement in immunocompromised children (or adults) with chickenpox,
antiviral therapy is mandatory (Nyerges et al., 1988). A small placebo-
controlled trial of intravenous acyclovir in immunocompromised children
with varicella demonstrated a dramatic reduction in the frequency of VZV
pneumonitis from 27% to 0% (Prober et al., 1982). Therapy with intravenous
acyclovir (10 mg/kg or 500 mg/m2 every 8 hours for 7–10 days) should be
initiated at the first sign of infection. A switch to oral antiviral therapy
(acyclovir, valacyclovir, or famciclovir) can be considered when the patient
is afebrile and new lesion formation has ceased. When feasible, the dosage of
immunosuppressive medications should be temporarily reduced in
immunosuppressed patients with varicella. Despite the lack of data from
large-scale controlled trials, the safety and efficacy of intravenous acyclovir
have led to its acceptance as the drug of choice for varicella in severely
immunocompromised patients (Table 65.1). Oral antiviral therapy may be
efficacious in modestly immunocompromised patients (e.g., those with solid
tumor malignancies or a low-dose corticosteroids), but prospectively acquired
data are limited. In a retrospective review of 14 pediatric heart transplant
recipients with varicella, half received intravenous acyclovir and half
received oral valacyclovir; all patients recovered without serious
complications (Dodd et al., 2001).

Patients with HIV infection

Varicella does not appear to be unusually severe in most HIV-seropositive

children, although some investigators have reported a longer duration of new
lesion formation and higher median lesion counts. A variety of varicella
complications in HIV-infected children have been reported (including DIC,
pneumonitis, hepatitis, and encephalitis), although reliable incidence figures
are not available. Deaths attributable to chickenpox in children with HIV
infection are rare and are usually due to pneumonitis. No controlled
prospective studies of antiviral therapy for chickenpox in HIV-infected
children have been reported, so recommendations must be derived from
anecdotal experience. Most clinicians prescribe oral antiviral therapy,
reserving intravenous acyclovir for patients with unusually severe or
complicated infections (Gershon et al., 1997).

Herpes zoster

Immunocompetent adults

The goals of therapy for herpes zoster in immunocompetent adults are to

accelerate the events of cutaneous healing, reduce the severity of acute
neuritis, and most importantly, to reduce the incidence, severity, and duration
of chronic pain (Gnann and Whitley, 2002). Even without antiviral therapy,
the cutaneous lesions of herpes zoster almost always resolve within a month.
However, chronic pain (postherpetic neuralgia) can persist for months or
even years and is the most significant manifestation of herpes zoster in the
normal host (Johnson, 2002). Three oral antiviral drugs are currently
approved in the United States for treatment of herpes zoster. Acyclovir,
valacyclovir, and famciclovir have been demonstrated to reduce the duration
of viral shedding, promote resolution of skin lesions, and limit the duration of
pain when antiviral therapy is initiated within 72 hours of lesion onset
(Table 65.1).
In placebo-controlled trials, oral acyclovir (800 mg five times daily for 7
days) was shown to accelerate cutaneous healing and to reduce the severity of
acute neuritis in immunocompetent adults with herpes zoster (McKendrick et
al., 1986; Huff et al., 1988; Wood et al., 1988; Morton and Thomson, 1989).
Overall, acyclovir therapy reduced the duration of new vesicle formation by
about 1.5 days and the time to 50% lesion healing by about 2.5 days. These
clinical trials with acyclovir showed variable benefit for reduction of the
frequency and duration of postherpetic neuralgia (PHN), partially due to
limitations in study design and population size. Data from these studies were
reexamined in another analysis which demonstrated that acyclovir was
significantly superior to placebo for reducing the duration of “zoster
associated pain,” defined as the continuum of pain measured from initial
onset until final resolution (Wood et al., 1996). Among patients ≥50 years of
age, the median time to resolution of pain was 41 days and 101 days and the
proportion with persistent pain at 6 months was 15% and 35% in the
acyclovir and placebo treatment groups, respectively. Intravenous acyclovir
is also effective in this setting, but is impractical for outpatient management
of most patients with shingles. Extending oral acyclovir therapy beyond 7
days does not produce any additional benefit (Wood et al., 1994).
Valacyclovir (1000 mg three times daily for 7 days) was compared with oral
acyclovir in a study of 1141 immunocompromised patients over 50 years of
age with herpes zoster (Beutner et al., 1995). When initiated within 72 hours
of lesion onset, the two drugs were equivalent for accelerating the events of
cutaneous healing, but valacyclovir was superior to acyclovir in shortening
the median time to resolution of zoster associated pain (38 days vs. 51
days; P = 0.001). The proportion of patients still experiencing pain at six
months was 25.7% in the acyclovir treatment group and 19.3% in the
valacyclovir groups (P = 0.02). Extending valacyclovir therapy to 14 days did
not result in any additional benefit.
In a controlled trial conducted in 419 immunocompetent patients presenting
within 24 hours of lesion onset, famciclovir (500 mg three times daily) was
significantly superior to placebo in reducing the duration of viral shedding,
limiting the duration of lesion formation, and accelerating the events of
cutaenous healing (Tyring et al., 1995). In a subset of shingles patients ≥50
years of age who had persistent pain after skin healing (n = 170), the median
duration of PHN was reduced from 163 days to 63 days (P = 0.004) in the
placebo and famciclovir treatment Groups, respectively. In a study comparing
famciclovir and acyclovir, the two drugs were shown to have similar efficacy
for herpes zoster (Degreef and the Famciclovir Herpes Zoster Study
Group, 1994).
Valacyclovir and famciclovir were compared for treatment of herpes zoster in
immunocompetent patients in a randomized clinical trial. In this population
of 597 patients ≥50 years of age enrolled within 72 hours of rash onset, the
two drugs were shown to be therapeutically equivalent, both in terms of
cutaneous healing and pain resolution (Tyring et al., 2000). At six months
after onset of shingles, 19% of patients in each treatment group still reported
pain. Acyclovir, valacyclovir, and famciclovir are all well tolerated and
appear to be approximately comparable in clinical efficacy for managing
herpes zoster in the immunocompetent host. Because their improved
pharmacokinetic properties allow simpler dosing regimens, valacyclovir and
famciclovir are preferred over acyclovir for this indication. Comparative drug
cost is also a legitimate variable in selecting an antiviral drug for treatment of
herpes zoster.
Brivudin (125 mg once daily × 7 days) was compared with acyclovir (800 mg
5 times daily × 7 days) in a study of 1227 immunocompetent adults with
herpes zoster. Brivudin was judged to be superior to acyclovir for reducing
the time to cessation of new vesicle formation and equivalent to acyclovir in
terms of cutaneous healing and acute pain alleviation (Wassilew and
Wutzler, 2003a,b). In a follow-up survey of subjects ≥50 years old, the
incidence of PHN was lower in brivudin recipients (32.7%) than in acyclovir
recipients (43.5%) (Wassilew and Wutzler, 2003a,b). Brivudin is
commercially available in several European Union countries, but has not
been approved in the United Kingdom or the United States because of
concerns about potential drug-related toxicities (Gross et al., 2003).
Certain characteristics have been defined which identify immunocompetent
patients at highest risk for complications of shingles and thus most likely to
benefit from antiviral therapy. Careful studies have clearly showed that older
age, greater skin surface area involved with herpes zoster, and severity of
pain at time of clinical presentation are all predictors of more severe and long
lasting pain (Wood et al., 1996; Dworkin et al., 1998; Harrison et al., 1999;
Whitley et al., 1999; Nagasako et al., 2002). Patients meeting these criteria
should be targeted for therapy with antiviral drugs and potent analgesics.
Conversely, patients under 50 years of age are at lower risk for severe or
prolonged pain and an argument could be made that antiviral therapy in this
group is optional. Available efficacy data from published studies relate to
patients who present within 72 hours of lesion onset, although patients
frequently present for medical care beyond that window (Wood et al., 1998).
The presence of new vesicles correlates with recent viral replication and may
be a marker for patients who would benefit from antiviral therapy, even
beyond 72 hours. In addition, patients presenting with the high-risk
characteristics cited above should be considered for antiviral treatment, even
when presenting beyond 72 hours after lesion onset. However, patients whose
lesions that have all begun to crust are unlikely to derive benefit from
antiviral therapy.
Adding corticosteroids to antiviral therapy in patients with acute herpes
zoster has been suggested as a way to reduce pain. A study conducted in the
United Kingdom compared acyclovir with and without prednisolone in 400
immunocompetent patients over 18 years of age (Wood et al., 1994). Another
clinical trial, conducted in the United States, enrolled 208 patients over 50
years of age into a four-armed study (acyclovir plus placebo, prednisone plus
placebo, acyclovir plus prednisone, placebo plus placebo) (Whitley et
al., 1996). Both studies targeted patients within 72 hours of the appearance of
lesions. Both of these studies demonstrated that corticosteroid therapy led to
a reduction of pain during the acute phase of herpes zoster, but neither
showed any reduction in the risk of postherpetic neuralgia (Wood et
al., 1994; Whitley et al., 1996). Addition of corticosteroids to antiviral
therapy for treatment of herpes zoster in selected older adults may result in
improvements in quality of life measurements such as reduction in time to
uninterrupted sleep, reduction in time to return to usual activities, and
reduction in analgesic use (Whitley et al., 1996). In the American trial cited
above, prednisone was given for three weeks (60 mg daily for 7 days, 30 mg
daily for 7 days, and 15 mg daily for 7 days), although it is possible that
shorter courses of prednisone are also effective. Corticosteroid therapy can
have significant adverse effects and should not be used in patients at risk for
steroid toxicity (e.g., patients with diabetes mellitus, gastritis, etc.). Although
only the combination of corticosteroids plus acyclovir has been studied,
combination therapy using valacyclovir or famciclovir is assumed to be
equally effective. Use of corticosteroids for herpes zoster without
concomitant antiviral therapy is not recommended. Furthermore, use of
corticosteroids in immunocompromised patients with herpes zoster has not
been evaluated and is not recommended.
Symptomatic measures should be suggested to keep the patient with herpes
zoster more comfortable. Patients should keep the cutaneous lesions clean
and dry to reduce the risk of bacterial superinfection. Patients may wash the
skin lesions with soap and water in the shower and then carefully pat the skin
dry with a clean towel. Some patients find warm or cool astringent soaks
(e.g., Domeboro® solution) to be soothing. A sterile non-occlusive, non-
adherent dressing placed over the involved skin will protect the lesions from
contact with clothing, which may be especially helpful for patients with
increased skin sensitivity (i.e., allodynia). There is no role for topical creams
or ointments (including topical acyclovir or penciclovir) in management of
herpes zoster. The acute pain of shingles can be very severe and should not
be underestimated by the clinician. The pain may be disproportionate to the
rash; that is, patients with limited skin involvement can still have severe
neuralgic pain. Pain is the most important symptom of herpes zoster and
should be aggressively managed. In patients with severe neuralgic pain,
sympathetic nerve blocks can provide rapid, but temporary relief
(Opstelten et al., 2004). Short-acting narcotic analgesics given on a scheduled
(rather than as-needed) basis should be prescribed. Some models used to
explain the pathogenesis of PHN suggests that early attenuation of acute pain
will reduce the degree of nociceptive input that reaches the spinal cord
neurons and prevent the initiation of central mechanisms of chronic pain,
thereby reducing the risk of PHN (Dworkin et al., 2000).
Medical management of established PHN is complex and often requires a
multifaceted approach (Dworkin and Schmader, 2003; Johnson and
Dworkin, 2003). Opioid analgesics are the mainstay of therapy during the
acute phases of neuralgic pain (Table 65.2). A clinical trial with controlled-
release oxycodone for patients with PHN demonstrated a significant level of
pain reduction (67% of those receiving oxycodone versus 11% receiving
placebo) as measured by visual analogue scale (Watson and Babul, 1998).
Long-acting opioid preparations (oral or transdermal) are preferable to short-
acting analgesics for management of chronic PHN. Several randomized,
controlled clinical trials have shown tricyclic antidepressants (including
amitriptyline, nortriptyline and desipramine) to be effective in reducing the
pain of PHN, either as a single agent or in combination with other drugs
(Raja et al., 2002; Bowsher, 2003). Because tricyclic antidepressants are
frequently associated with sedation and anticholinergic side effects, treatment
should begin with a relatively low dose at bedtime, with a gradual increase in
dosage as required and tolerated. Nortriptyline is as efficacious as
amitriptyline for PHN, but nortriptyline is associated with fewer adverse
effects in elderly patients (Watson et al., 1998). In two clinical trial, the
anticonvulsant gabapentin was shown to significantly reduce established
PHN when used alone or in combination with other modalities
(Rowbotham et al., 1998; Rice and Maton, 2001). For treatment of PHN,
physicians should initiate gabapentin at a low dose of 100 mg three times
daily and escalate (in increments of 100 mg t.i.d.) as required, watching for
adverse effects such as somnolence, dizziness, and ataxia. Total daily doses
of 1800–3600 mg may be required (Stacey and Glanzman, 2003). Pregabalin
has also been shown to be effective and well-tolerated in studies of patients
with PHN and is likely to replace gabapentin for this indication (Dworkin et
al., 2003; Sabatowski et al., 2004). The adverse effects of these medications
can be additive (such as sedation due to opioid analgesics, tricyclic
antidepressants, and gabapentin), especially in elderly patients
(Schmader, 2001). Local transdermal administration of lidocaine via patches
has been shown to significantly reduce PHN in two controlled trials (Davies
and Galer, 2004). Topical treatments should only be used on intact healed
skin. Topical application of capsaicin cream can provide relief of PHN for
some patients, but the local stinging and burning associated with capsaicin
may be intolerable for many individuals. In a controlled clinical trial of 277
patients with intractable PHN, intrathecal injection of 60 mg of
methylprednisolone acetate once weekly for 4 weeks resulted in significant
pain reduction, but these results require confirmation (Kotani et al., 2000).
There is no evidence that prolonged administration of antiviral drugs has any
benefit for treatment of established PHN (Acosta and Balfour, 2001).

Herpes zoster ophthalmicus

Special emphasis should be given to patients presenting with herpes zoster

involving the first division of the trigeminal nerve because of the potential for
sight-threatening ocular complications. The ophthalmic division of the
trigeminal nerve is the cranial nerve most frequently affected by herpes
zoster. Without antiviral therapy, 50% of patients with herpes zoster
ophthalmicus (HZO) will develop significant ocular complications (which
can include neurotrophic keratopathy, episcleritis, iritis, epithelial or stromal
keratitis, etc.) (Liesegang, 1999). Controlled prospective clinical trials clearly
demonstrated that oral acyclovir therapy reduced the frequency of serious late
ocular inflammatory complications of HZO from about 50%–60% to 20%–
30% (Cobo et al., 1986; Harding and Porter, 1991; Herbort et al., 1991;
Hoang-Xuan et al., 1992; Beutner et al., 1995). A clinical trial comparing the
efficacy of valacyclovir and acyclovir for HZO demonstrated the two drugs
to be comparable (Colin et al., 2000). Similarly, a controlled study comparing
acyclovir and famciclovir in 454 patients with HZO found that the prevalence
of severe and non-severe ocular manifestations (58%) was the same for both
treatment groups (Tyring et al., 2001a,b). Some experts favor intravenous
acyclovir as initial therapy for patients (especially immunocompromised
patients) with severe HZO. Systemic antiviral therapy has largely replaced
topical antiviral preparations for treatment of the ocular complications of
HZO. Systemic or topical corticosteroids may be indicated for some of the
ocular inflammatory phenomena that accompany HZO (e.g., uveitis), but
should only be administered under the supervision of an experienced
ophthalmologist (Liesegang, 1999). Available data strongly support the
routine and early use of systemic antiviral therapy in all patients with HZO in
an effort to reduce the risk of ocular complications (Severson et al., 2003;
Zaal et al., 2003).

Immunocompromised patients

Patients with disorders of cell-mediated immunity are at increased risk for

development of herpes zoster. In this population, those patients with the
greatest degree of immunosuppression (such as hematopoietic stem-cell
transplant (HSCT) recipients or patients with lymphoproliferative
malignancies) are at highest risk for VZV dissemination and visceral organ
involvement. Clinical trials with intravenous acyclovir for localized or
disseminated herpes zoster in immunocompromised patients clearly
demonstrated that treatment resulted in more rapid virus clearance and halted
disease progression (Serota et al., 1982; Balfour et al., 1983). Subsequent
studies in HSCT recipients have demonstrated that acyclovir, in addition to
promoting faster disease resolution, is highly effective at preventing VZV
dissemination (Meyers et al., 1984; Shepp et al., 1986). Because most VZV-
related fatalities result from disseminated infection, the ability to prevent
dissemination has markedly reduced the herpes zoster mortality rate in
immunocompromised patients. In addition, intravenous acyclovir is
considered the drug of choice for treating dissemination when it occurs,
although efficacy data from prospective studies are limited (Balfour et
al., 1983; Whitley et al., 1992). The recommended dose of intravenous
acyclovir for herpes zoster in severely immunocompromised patients is 10–
15 mg/kg (or 500 mg/m2) every 8 hours (Table 65.1). When the infection is
under control, therapy can be switched from intravenous acyclovir to an oral
antiviral drug for the remainder of the course of treatment. Patients should be
treated until healing is complete or for a minimum of 10–14 days (whichever
is longer) to reduce the risk of relapsing disease.
Treating shingles in immunocompromised patients on an outpatient basis
with oral antiviral drugs is an attractive approach, although supporting data
are limited. One small study randomized 27 allogenic HSCT recipients with
herpes zoster to either oral or intravenous acyclovir. No VZV dissemination
occurred in either group, and no differences in healing or clinical outcome
were apparent (Ljungman et al., 1989). Published data from clinical trials
with famciclovir and valacyclovir for herpes zoster in immunocompromised
patients remain limited, but a growing body of clinical experience suggests
that these drugs are safe and effective in this setting (Tyring et al., 2001a,b).
For less severely immunosuppressed patients, oral therapy with acyclovir
(800 mg five times daily), valacyclovir (1000 mg three times daily), or
famciclovir (500 mg three times daily), coupled with close clinical
observation, is a reasonable option. Because of the risk of ocular
involvement, intravenous acyclovir plus evaluation by an ophthalmologist are
recommended for highly immunocompromised patients who present with
HZO.

HIV-seropositive patients

The incidence of herpes zoster is about 15-fold higher in HIV-seropositive

men than in age-matched controls. Shingles in this population is associated
with higher rates of CNS complications, necrotizing retinitis, and recurrent
episodes. Prospectively acquired data to guide clinicians when selecting
antiviral therapy for herpes zoster in HIV-seropositive patients are currently
limited. Nearly 300 HIV-infected patients with shingles were enrolled in
controlled studies comparing orally administered acyclovir with the
investigational antiviral drug sorivudine. Overall, the time to cessation of
new vesicle formation, total crusting, and resolution of zoster-associated pain
were 3–4 days, 7–8 days, and about 60 days, respectively (Bodsworth et
al., 1997; Gnann et al., 1998). These studies confirm the efficacy and safety
of oral antiviral therapy for herpes zoster in patients with HIV infection.
Valacyclovir and famciclovir have not been systematically evaluated as
treatments for herpes zoster in HIV-infected patients, although anecdotal
clinical experience suggests therapeutic benefit. Long term administration of
antiherpes virus drugs to prevent recurrences of herpes zoster in patients with
AIDS is not routinely recommended. Because of the documented risk of
relapsing infection, VZV disease in HIV-seropositive patients should be
treated until all lesions are completely resolved, which is often longer than
the standard 7–10-day course. What impact anti-VZV therapy may have on
the risk of subsequent complications such as CNS infection or retinitis is
unknown. Adjunctive therapy of herpes zoster with corticosteroids has not
been evaluated in HIV-infected patients and is not currently recommended.
On the basis of clinical experience, most physicians select intravenous
acyclovir as the drug of choice to treat severe or complicated herpes zoster in
HIV-infected patients. The literature contains numerous case reports
documenting successful therapy of neurologic complications with
intravenous acyclovir (Poscher, 1994; Lionnet et al., 1996). Some experts
have recommended intravenous acyclovir for initial therapy of HZO in HIV-
infected patients, although oral therapy appears adequate in most cases.
A syndrome of herpetic retinal necrosis can occur as a late complication of
herpes zoster in either immunocompetent or immunocompromised patients,
but is seen with the greatest frequency in patients with AIDS. Responses to
intravenous acyclovir or ganciclovir have been inconsistent and
disappointing. Several case reports have documented preservation of vision
in patients treated with a combination of intravenous ganciclovir plus
foscarnet, with or without intravitreal ganciclovir (Galindez et al., 1996). The
optimal duration of induction therapy and options for long-term maintenance
therapy for acute retinal necrosis in HIV-seropositive patients have not been
established (Ormerod et al., 1998). When VZV retinitis occurs in
immunocompetent patients, the clinical outcome is clearly improved by
acyclovir therapy and the prognosis is better. In this population, a suggested
treatment regimen based on clinical experience is intravenous acyclovir (10–
15 mg/kg every 8 hours) for 10–14 days, followed by oral valacyclovir 1
gram po three times a day for 4–6 weeks (Palay et al., 1991).

Clinical indications for prophylaxis

Varicella

Immunocompetent patients

Administration of varicella vaccine within the first few days after exposure to
VZV will produce a protective (or partially protective) immune response in
VZV seronegative individuals (Watson et al., 2000). About half of patients
receiving post-exposure immunization may still develop some signs and
symptoms of chickenpox, but the disease manifestations are usually very
mild. Postexposure vaccination appears to be more effective and less
expensive than preemptive therapy with antiviral drugs. This approach may
be useful for managing VZV exposures that occur in a family, in the
workplace, or in a medical care setting.

Pregnant women

Advisory committees have recommended administration of varicella-zoster

immune globulin (VZIG) to VZV-susceptible pregnant women who have
been exposed to varicella (Centers for Disease Control and
Prevention, 1996). For maximal efficacy, VZIG must be administered as soon
as possible after exposure (within 96 hours). VZIG (as available in the United
States) is administered by deep intramuscular injection at a dose of 125
units/10 kg of body weight, to a maximum of 625 units. Intravenous
immunoglobulin also contains substantial titers of VZV-specific IgG and may
be substituted if VZIG is not available. Unfortunately, in this time-critical
scenario, the true VZV serologic status of a pregnant woman with a negative
history of varicella is often not known. The clinician may be faced with a
decision to initiate passive immunoprophylaxis empirically or to wait for the
results of serologic testing. The ideal time to determine VZV serologic status
is before pregnancy, when vaccination can be offered to women who are
confirmed to be seronegative (Glantz and Mushlin, 1998). Varicella
vaccination of pregnant women is not currently recommended because of the
theoretical risk of the live virus vaccine for both the fetus and the mother.
Prophylactic (or pre-emptive) therapy with acyclovir for a pregnant woman
after VZV exposure may be effective, but is an unproven approach.

Immunocompromised (including HIV-seropositive) patients

VZV-seronegative immunocompromised patients with a defined close

exposure to either chickenpox or herpes zoster should receive VZIG to
provide passive immunity (Zaia et al., 1983). In most cases, VZIG
administration will not prevent infection in the susceptible host, but it will
significantly reduce the severity of the resultant illness. Placebo-controlled
trials in immunocompromised children have demonstrated that VZIG
ameliorates the severity of chickenpox and that it significantly reduces the
risk of disseminated infection. A single treatment reduces the risk of
disseminated infection by about 75% and provides four weeks of passive
immunity. VZIG must be administered within 96 hours of exposure at the
dose described above. VZIG is not useful for the treatment of established
varicella or herpes zoster. The efficacy of VZIG prophylaxis in HIV-
seropositive children or adults has not been evaluated prospectively.
Prophylactic administration of acyclovir following VZV exposure has been
studied to a limited extent in susceptible immunocompetent patients, but not
in immunocompromised individuals. In studies of healthy children conducted
in Japan, varicella developed in 16% of the children prophylactically treated
with acyclovir and in 100% of children in the control group (Asano et
al., 1993) About 80% of children prophylactically treated with acyclovir
subsequently seroconverted, indicating VZV infection without significant
disease (Suga et al., 1993). However, additional data are required before this
approach of preemptive antiviral chemotherapy can be routinely
recommended in either immunocompetent or immunocompromised
populations. A suggested (but unvalidated) regimen is acyclovir 200 mg
orally four or five times daily for 21 days beginning five days after VZV
exposure.
Concerns about the use of the live, attenuated VZVoka vaccine in
immunocompromised patients have focused on the potential for the vaccine
virus to cause disease and on the possibility that immunocompromised
patients will fail to mount a protective immune response. Limited experience
with the vaccine in leukemic children and renal transplant recipients have
demonstrated that it can be used safely in highly selected populations
(Arbeter et al., 1990; Furth and Fivush, 2002).

Herpes zoster

Immunocompetent patients

There are no circumstances that warrant antiviral chemotherapy to try to

prevent herpes zoster in immunocompetent individuals. A live-virus vaccine
has proven to be effective for preventing herpes zoster and reducing PHN
(Oxman et al., 2005). A randomized, double-blind, placebo-controlled
clinical trial enrolling 38,546 adults (age 60 and over) was conducted to
evaluate the live attenuated Oka/Merck VZV vaccine. The primary endpoint
was “herpes zoster burden of illness,” a composite score capturing zoster
incidence, duration, and severity of total pain and discomfort. Compared with
placebo, the vaccine reduced the zoster burden of illness by 61.1%, reduced
the incidence of herpes zoster by 51.3%, and reduced the incidence of PHN
by 66.5% (P < 0.001 for all comparisons). The vaccine was associated with
mild reactogenicity (local erythema or tenderness) in 48.3% of recipients, but
was otherwise well tolerated. The herpes zoster vaccine was approved for use
in the United States in 2006 for immunocompetent adults 60 years of age and
over.

Immunocompromised patients

Drug regimens designed to prevent HSV recurrences in

immunocompromised patients undergoing cancer chemotherapy or organ
transplantation will also effectively prevent herpes zoster (Ljungman, 2001).
Combined results from two placebo-controlled trials of long-term (6 months)
acyclovir prophylaxis in HSCT recipients demonstrated herpes zoster in 11
(18%) of 62 placebo recipients and in none of the 62 acyclovir treated
patients (Lundgren et al., 1985; Perren et al., 1988). Interestingly, the
incidence of zoster increased dramatically after the discontinuation of
prophylaxis such that, 12 months after transplantation, the cumulative
number of herpes zoster cases was virtually identical between the acyclovir
and placebo groups. Nonetheless, acyclovir prophylaxis effectively prevents
herpes zoster during the early post-transplant period when patients are most
severely immunosuppressed and thus have the highest risk for VZV-related
complications. Although transplant specialists almost universally recommend
3–6 months of acyclovir prophylaxis, no consensus currently exists regarding
the relative merits of longer term prophylaxis. Development of a heat-
inactivated VZV vaccine for use in immunocompromised patients is an area
of active investigation (Hata et al., 2002).

HIV-seropositive patients

Antiviral chemoprophylaxis for prevention of herpes zoster in patients with

AIDS is not routinely recommended. A significant number of HIV-
seropositive patients take suppressive antiviral drugs to prevent genital HSV
reactivations, which may also prevent herpes zoster. In patients with multiple
recurrent episodes of herpes zoster, chemoprophylaxis could be considered
(e.g., valacyclovir 1 gram orally twice a day or famciclovir 500 mg orally
twice a day), although this approach is unvalidated.

Drug-resistant varicella-zoster virus

Since first reported in 1988, multiple isolates of acyclovir-resistant VZV have
been recovered from immunocompromised patients, usually HIV-infected
individuals with very low CD4+ T-lymphocyte counts. The mechanism of
resistance is based on the deletion or truncation of the gene expressing
thymidine kinase. Most isolates resistant to acyclovir are also resistant to
valacyclovir, famciclovir, penciclovir, and ganciclovir, all of which depend
on viral TK for activation. A strong association exists between acyclovir-
resistant VZV and the presence of atypical skin lesions (Boivin et al., 1994;
Levin et al., 2003a,b). One report described four HIV-seropositive adults
undergoing chronic suppressive acyclovir therapy who developed
disseminated hyperkeratotic papules that failed to respond to acyclovir
(Jacobson et al., 1990). In vitro susceptibility testing confirmed that the VZV
isolates were acyclovir-resistant with a mean IC50 for acyclovir of 20 µg/ml,
compared with 0.75 µg/ml for the reference strain (VZVoka). Although the
mechanisms that lead to the development of acyclovir resistance are
incompletely understood, clinical data indicate that many cases are associated
with inadequate dosing of acyclovir for either acute therapy or long-term
suppression, possibly allowing for selection of TK-deficient mutants.
Clinicians using acyclovir or related drugs for treatment of varicella or herpes
zoster in AIDS patients should utilize the full therapeutic dose and continue
therapy until all VZV lesions have completely resolved (Jacobson et
al., 1990).
The drug of choice for treatment of acyclovir-resistant VZV disease is
foscarnet, an inhibitor of viral DNA polymerase that is not dependent on TK
for activation (Breton et al., 1998) (Table 65.1). In a series of 13 patients
with AIDS and acyclovir-resistant VZV infections treated with intravenous
foscarnet, 10 patients (77%) had complete lesion healing after a mean of 17.8
days of therapy (Breton et al., 1998). Most cases of disease caused by
acyclovir-resistant VZV have been limited to cutaneous involvement,
although a few instances of visceral infection caused by acyclovir-resistant
VZV have been reported, including cases of retinal necrosis and
meningoradiculitis.
Fortunately, VZV isolates resistant to both acyclovir and foscarnet have been
encountered infrequently. The molecular biology of these duly-resistant
isolates has not been fully explored, but a mutation in the viral DNA
polymerase can account for both acyclovir and foscarnet resistance.
Cidofovir would likely retain activity against these isolates and would
become the drug of choice for patients with disease caused by dually-resistant
VZV.

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Figures
Fig. 65.1
Clinical appearance of varicella and herpes zoster. (a) Typical generalized
vesicular rash of chickenpox in an adult. (b) Typical dermatomal papulo-
vesicular rash of shingles in an adult. (See color plate section.)

Tables
Table 65.1Antiviral therapy for VZV infections
Drug Dosea Major toxicities
Immunocompetent patients
Varicella Acyclovir 20 mg/kg (800 mg max.) po 5 None; minor nausea or
times daily × 5 d. In adults, headache
famciclovir and valacyclovir will
also likely be effective.
Herpes zoster Acyclovir 800 mg po 5 times daily × 7–10 d As above
 Drug Dosea Major toxicities
Valacyclovir 1000 mg po every 8 h × 7 d None; minor nausea or
headache
Famciclovir 500 mg po every 8 h × 7 d None; minor nausea or
headache
Brivudinb 125 mg po once daily × 7 d Potentially lethal
interaction with
fluoropyrimidines (e.g., 5-
fluorouracil)
Immunocompromised patients
Varicella Acyclovir 10–15 mg/kg (or 500 mg /m2) Nephrotoxicity (rare);
intravenously every 8 h for ≥7 d CNS disturbances (rare)
Herpes zoster Acyclovir IV therapy (as above). Mild to As above
moderately immunocompromised
patients (including most AIDS
patients) can be treated with oral
therapy.
Disseminated Acyclovir IV therapy (as above) As above
VZV syndromes
(e.g., encephalitis,
pneumonitis)
Infection caused Foscarnet 60–90 mg/kg intravenously every Nephrotoxicity (common):
by acyclovir- 12 h until healed (≥10 d) electrolyte disturbances
resistant VZV (common), seizures,
arrhythmias, anemia,
genital ulcers
a
Doses given are for adults with normal renal function.
b
Not licensed in the United States.
Table 65.2Management of postherpetic neuralgia
Drug Dosing Comments Adverse effects
Opioid Varies with drug Begin with short-acting drug at Sedation, nausea,
analgesics morphine oral equianalgesic constipation, dizziness,
dose of 5–15 mg every 4 hr. dependence, abuse,
After 2 wk, convert to overdose
equianalgesic does of long-
acting druga
 Drug Dosing Comments Adverse effects
Gabapentinb Begin with 100 mg Titrate dose up by 300 mg/d (in Somnolence, dizziness,
po every 8 hr divided doses) to target dose of ataxia, peripheral
1800–3600 mg/d, as tolerated edema
Tricyclic Nortriptyline 25 mg Titrate dose up to 75–150 Sedation, confusion,
antidepressants po at bedtime mg/d, as necessary. anticholinergic effects
Amitriptyline also effective but (dry mouth, blurred
may cause more adverse effects vision, constipation,
in elderly patients. Desipramine urinary retention)
is option if nortriptyline causes
excess sedation
Lidocaine (5%) Apply to painful Apply only to healed, intact Localized skin irritation
patch area; up to 3 patches skin. Patches may be cut to only. Systemic toxicity
can be used at a time size. Especially helpful for from cutaneous
for a maximum of allodynia. Benefit apparent absorption of lidocaine
12 hr daily within 2 weeks. is very rare.
a
Options for long-acting opioid analgesics include: controlled-release morphine,
controlled-release oxycodone, transdermal fentanyl, levorphanol, methadone.
b
Pregabalin is available as an alternative to gabapentin.
c
(Modified with permission from Gnann and Whitley, N. Engl. J. Med., 2002.)
Copyright © Cambridge University Press 2007.

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