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 g/ml.
After oral administration, acyclovir is slowly and incompletely
absorbed with bioavailability of about 1530%. 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 g/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 23 hours in adults and 34 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 five fold 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 34 and 56 g/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) 45 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 (1215 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 g/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 g/ml are achieved at 1 hour. The pharmacokinetics of
penciclovir are linear and dose dependent over a famciclovir dosing
range of 125750 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
manufacturers 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.

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 1015 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 1014
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
34 days, 78 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
710-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 (1015 mg/kg every 8 hours) for 1014 days,
followed by oral valacyclovir 1 gram po three times a day for 46
weeks (Palay et al., 1991).

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 36 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 g/ml, compared with 0.75 g/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.
Valacyclovir adalah prodrug asiklovir yang dikelola secara oral
yang mengatasi masalah bioavailabilitas oral yang buruk dan
menunjukkan sifat farmakokinetik yang lebih baik (Acosta dan
Fletcher, 1997). Valacyclovir, ester L-valina asiklovir, diserap
dengan baik dari saluran gastrointestinal melalui transporter
stereospesifik dan mengalami konversi lintasan pertama yang
lengkap pada usus dan hati untuk menghasilkan asiklovir dan L-
valin. Dengan menggunakan formulasi prodrug ini,
bioavailabilitas asiklovir meningkat menjadi sekitar 54%,
menghasilkan konsentrasi plasma asiklovir puncak yang tiga
sampai lima kali lipat lebih tinggi daripada yang dicapai dengan
pemberian oral senyawa induk. Dosis valacyclovir oral 500 mg
atau 1000 mg menghasilkan konsentrasi plasma asiklovir
puncak 3-4 dan 5-6 g / ml. Setelah pemberian valacyclovir pada
dosis 2 g secara oral empat kali sehari, nilai asiklovir plasma di
bawah kurva (AUC) mendekati perkiraan yang dihasilkan oleh
asiklovir yang diberikan secara intravena pada dosis 10 mg / kg
setiap 8 jam. Nilai AUC asiklovir setelah pemberian valacyclovir
oral sedikit lebih tinggi pada orang tua bila dibandingkan dengan
kelompok kontrol yang lebih muda, mungkin karena penurunan
clearance kreatinin yang terkait dengan penuaan.

Asiklovir dibersihkan terutama oleh mekanisme ginjal sehingga

modifikasi dosis untuk asiklovir dan valasiklovir diperlukan untuk
pasien dengan disfungsi ginjal yang signifikan. Waktu eliminasi
rata-rata asiklovir setelah satu dosis tunggal valacyclovir 1 gram
adalah sekitar 14 jam pada pasien dengan penyakit ginjal
stadium akhir. Asiklovir mudah dikeluarkan dengan
hemodialisis, namun tidak dilakukan dengan dialisis peritoneal.
Tidak ada modifikasi dosis spesifik untuk obat ini yang
diperlukan untuk pasien dengan insufisiensi hati. Asiklovir dan
valasiklovir tidak disetujui untuk digunakan dalam kehamilan,
namun telah banyak digunakan untuk mengobati infeksi HSV
dan VZV yang serius pada wanita hamil tanpa bukti toksisitas
pada ibu atau janin.
Asiklovir adalah obat yang sangat aman dan dapat ditolerir
dengan baik. Peradangan lokal dan flebitis dapat terjadi setelah
ekstravasi asiklovir intravena. Disfungsi ginjal akibat akumulasi
kristal asiklovir di ginjal telah diamati setelah infus intravena
dosis asiklovir yang sangat cepat, namun jarang terjadi dan
biasanya dapat terjadi reversibel. Asotoksir terkait
neurotoksisitas (termasuk agitasi, halusinasi, disorientasi,
tremor, dan klonus ringan) telah dilaporkan, paling sering pada
pasien lanjut usia dengan kelainan SSP yang mendasarinya dan
insufisiensi ginjal (Hellden et al., 2003). Terapi asiklovir oral
jarang dikaitkan dengan neurotoksisitas atau nephrotoxocity.
Studi pasien yang menerima asiklovir jangka panjang untuk
penekanan kronis herpes genital tidak menunjukkan toksisitas
kumulatif.

Pada dosis standar, valacyclovir juga merupakan obat yang

sangat aman dan dapat ditoleransi dengan baik. Sebuah
sindrom microangiopathy trombotik (ditandai dengan demam,
anemia hemolitik mikroangiopati, trombositopenia, dan disfungsi
ginjal) diamati pada pasien AIDS yang menerima valacyclovir
dosis tinggi (8 gram per hari) dalam percobaan klinis. Namun,
sindrom ini belum diamati pada pasien imunokompeten yang
menerima valasiklovir pada dosis standar (sampai 3 gram per
hari). Tidak ada kontraindikasi untuk menggunakan valacyclovir
pada dosis yang disetujui pada pasien terinfeksi HIV. Interaksi
klinis yang signifikan antara asiklovir atau valasiklovir dan obat
lain sangat jarang terjadi.

Asiklovir tersedia dalam formulasi topikal, oral, dan intravena.

Persiapan dermatologis terdiri dari asiklovir 5% dalam dasar
salep krim atau polietilena glikol. Asiklovir topikal ditujukan untuk
pengobatan infeksi HSV mukokutan ringan dan tidak berperan
dalam pengobatan VZV. Persiapan asiklovir oral meliputi kapsul
200 mg, 400 dan 800 mg tablet, dan suspensi cair (200 mg per
5 ml). Asiklovir sodium untuk infus intravena diberikan sebagai
bubuk yang larut dalam air steril yang harus dilarutkan dan
diencerkan dengan konsentrasi 50 mg / ml. Dosis asiklovir oral
yang disetujui untuk cacar air adalah 200 mg / kg (maksimum
800 mg) 4-5 kali sehari selama 5 hari. Orang dewasa dengan
herpes zoster dapat diobati dengan asiklovir oral dengan dosis
800 mg lima kali sehari. Dosis asiklovir intravena yang
dianjurkan untuk infeksi VZV adalah 10 mg / kg setiap 8 jam,
meskipun dosis yang lebih tinggi (12-15 mg / kg) kadang-kadang
digunakan untuk infeksi yang mengancam jiwa, terutama pada
pasien dengan immunocompromised. Dosis perlu dilakukan
pada pasien dengan insufisiensi ginjal.
Valacyclovir tersedia sebagai tablet 500 mg dan 1000 mg. Dosis
yang dianjurkan untuk orang dewasa dengan imunokompeten
dengan varicella atau herpes zoster adalah 1000 mg tiga kali
sehari selama 7 hari. Karena formulasi suspensi valacyclovir
tidak tersedia, pengalaman klinis dengan obat ini pada anak-
anak dengan cacar air terbatas.

Brivudin (bromovinyl deoxyuridine) adalah analog nukleosida

thymidine yang sangat manjur dengan aktivitas selektif melawan
HSV-1 dan VZV (Keam et al., 2004). Mekanisme aksi brivudin
nampaknya merupakan penghambatan DNA polimerase virus.
Obat ini diserap dengan baik setelah pemberian oral dan
memiliki profil farmakokinetik yang menguntungkan yang
memungkinkan pemberian dosis sekali sehari. Brivudin
umumnya dapat ditolerir dengan baik; Mual adalah kejadian
buruk yang paling sering dilaporkan. Karena kekhawatiran
tentang profil keamanan obat tersebut, pengembangan
komersial brivudin dihentikan di Amerika Serikat. Obat ini
tersedia di beberapa negara sebagai tablet 125 mg dan sebagai
salep 0,1% untuk penggunaan oftalmologis.

Immunokompeten
Tujuan terapi herpes zoster pada orang dewasa yang
imunokompeten adalah mempercepat kejadian penyembuhan
kutaneous, mengurangi keparahan neuritis akut, dan yang
terpenting, mengurangi kejadian, tingkat keparahan, dan durasi
rasa sakit kronis (Gnann dan Whitley, 2002). Bahkan tanpa
terapi antiviral, lesi kulit herpes zoster hampir selalu sembuh
dalam waktu satu bulan. Namun, nyeri kronis (postherpetic
neuralgia) dapat bertahan selama berbulan-bulan atau bahkan
bertahun-tahun dan merupakan manifestasi herpes zoster yang
paling signifikan di host normal (Johnson, 2002). Tiga obat
antiviral oral saat ini disetujui di Amerika Serikat untuk
pengobatan herpes zoster. Acyclovir, valacyclovir, dan
famciclovir telah ditunjukkan untuk mengurangi durasi
penumpahan virus, mendorong resolusi lesi kulit, dan
membatasi durasi rasa sakit saat terapi antiviral dimulai dalam
72 jam onset lesi.

Pada percobaan terkontrol plasebo, asiklovir oral (800 mg lima

kali sehari selama 7 hari) ditunjukkan untuk mempercepat
penyembuhan kutaneous dan untuk mengurangi keparahan
neuritis akut pada orang dewasa yang imunokompeten dengan
herpes zoster (McKendrick et al., 1986; Huff et al. , 1988; Wood
et al., 1988; Morton dan Thomson, 1989). Secara keseluruhan,
terapi asiklovir mengurangi durasi pembentukan vesikula baru
sekitar 1,5 hari dan penyembuhan lesi sampai 50% sekitar 2,5
hari. Uji klinis dengan asiklovir menunjukkan manfaat bervariasi
untuk pengurangan frekuensi dan durasi neuralgia postherpetik
(PHN), sebagian karena keterbatasan dalam rancangan
penelitian dan ukuran populasi. Data dari penelitian ini dikaji
ulang dalam analisis lain yang menunjukkan bahwa asiklovir
secara signifikan lebih unggul daripada plasebo untuk
mengurangi durasi "nyeri terkait zoster," yang didefinisikan
sebagai rangkaian nyeri yang diukur dari onset awal sampai
resolusi akhir (Wood et al., 1996) .

Di antara pasien 50 tahun, waktu rata-rata untuk mengatasi

nyeri adalah 41 hari dan 101 hari dan proporsi dengan nyeri
persisten pada 6 bulan adalah 15% dan 35% pada kelompok
perlakuan asiklovir dan plasebo. Asiklovir intravena juga efektif
dalam pengaturan ini, namun tidak praktis untuk penanganan
rawat jalan kebanyakan pasien dengan herpes zoster.
Memperluas terapi asiklovir oral di luar 7 hari tidak menghasilkan
manfaat tambahan.
Valacyclovir (1000 mg tiga kali sehari selama 7 hari)
dibandingkan dengan asiklovir oral dalam sebuah penelitian
terhadap 1141 pasien immunocompromised berusia di atas 50
tahun dengan herpes zoster (Beutner et al., 1995). Ketika
dimulai dalam 72 jam onset lesi, kedua obat itu setara untuk
mempercepat kejadian penyembuhan kutaneous, namun
valasiklovir lebih tinggi dari asiklovir dalam memperpendek
waktu rata-rata untuk mengatasi nyeri terkait zoster (38 hari vs
51 hari; P = 0,001 ). Proporsi pasien yang masih mengalami
nyeri pada enam bulan adalah 25,7% pada kelompok perlakuan
asiklovir dan 19,3% pada kelompok valasiklovir (P = 0,02).
Memperpanjang terapi valacyclovir sampai 14 hari tidak
menghasilkan manfaat tambahan.

Brivudin (125 mg sekali sehari x 7 hari) dibandingkan dengan

asiklovir (800 mg 5 kali sehari x 7 hari) dalam sebuah penelitian
terhadap 1227 orang dewasa dengan herpes zoster
imunokompeten. Brivudin dinilai lebih unggul dari asiklovir
karena mengurangi waktu untuk menghentikan pembentukan
vesikula baru dan setara dengan asiklovir dalam hal
penyembuhan kutaneous dan pengentasan nyeri akut
(Wassilew dan Wutzler, 2003a, b). Dalam survei tindak lanjut
subyek 50 tahun, kejadian PHN lebih rendah pada penerima
brivudin (32,7%) dibandingkan penerima asiklovir (43,5%)
(Wassilew dan Wutzler, 2003a, b). Brivudin tersedia secara
komersial di beberapa negara Uni Eropa, namun belum disetujui
di Inggris atau Amerika Serikat karena kekhawatiran tentang
toksisitas terkait obat-obatan.

Menambahkan kortikosteroid pada terapi antiviral pada pasien

herpes zoster akut telah disarankan sebagai cara untuk
mengurangi rasa sakit. Sebuah penelitian yang dilakukan di
Inggris membandingkan asiklovir dengan dan tanpa prednisolon
pada 400 pasien imunokompeten berusia di atas 18 tahun
(Wood et al., 1994). Uji coba klinis lainnya, yang dilakukan di
Amerika Serikat, mendaftarkan 208 pasien berusia di atas 50
tahun ke dalam studi empat-tangan (asiklovir ditambah plasebo,
prednison plus plasebo, asiklovir plus prednison, plasebo plus
plasebo) (Whitley et al., 1996). Kedua penelitian tersebut
menargetkan pasien dalam 72 jam munculnya lesi. Kedua studi
ini menunjukkan bahwa terapi kortikosteroid menyebabkan
pengurangan rasa sakit selama fase akut herpes zoster, namun
keduanya tidak menunjukkan adanya pengurangan risiko
neuralgia postherpetik.

Penambahan kortikosteroid pada terapi antiviral untuk

pengobatan herpes zoster pada orang dewasa yang berusia
lanjut dapat menyebabkan perbaikan kualitas pengukuran
kehidupan seperti pengurangan waktu tidur tanpa gangguan,
pengurangan waktu untuk kembali ke aktivitas normal, dan
pengurangan penggunaan analgesik (Whitley et Al., 1996).
Dalam percobaan di Amerika yang disebutkan di atas,
prednisone diberikan selama tiga minggu (60 mg setiap hari
selama 7 hari, 30 mg setiap hari selama 7 hari, dan 15 mg setiap
hari selama 7 hari), walaupun mungkin saja kursus prednison
yang lebih pendek juga efektif. Terapi kortikosteroid dapat
memiliki efek samping yang signifikan dan tidak boleh digunakan
pada pasien yang berisiko toksisitas steroid (misalnya, pasien
diabetes mellitus, gastritis, dan lain-lain). Meskipun hanya
kombinasi kortikosteroid ditambah asiklovir yang telah dipelajari,
terapi kombinasi dengan menggunakan valasiklovir atau
famciclovir dianggap sama efektifnya.

Penggunaan kortikosteroid untuk herpes zoster tanpa terapi

antiretroviral bersamaan tidak dianjurkan. Selanjutnya,
penggunaan kortikosteroid pada pasien immunocompromised
dengan herpes zoster belum dievaluasi dan tidak
direkomendasikan.

Pasien dengan gangguan imunitas yang dimediasi sel berisiko

tinggi mengalami perkembangan herpes zoster. Pada populasi
ini, pasien dengan tingkat penekanan imunosupresi terbesar
(seperti penerima transplantasi sel punca hematopoietik (HSCT)
atau pasien dengan keganasan limfoproliferatif) berisiko
tertinggi terserang penyebaran VZV dan keterlibatan organ
viseral. Uji klinis dengan asiklovir intravena untuk herpes zoster
lokal atau disebarluaskan pada pasien dengan
immunocompromised dengan jelas menunjukkan bahwa
pengobatan menghasilkan pembersihan virus yang lebih cepat
dan pengembangan penyakit yang dihentikan (Serota et al.,
1982; Balfour et al., 1983). Studi selanjutnya pada penerima
HSCT telah menunjukkan bahwa asiklovir, selain untuk
mempromosikan resolusi penyakit yang lebih cepat, sangat
efektif untuk mencegah penyebaran VZV (Meyers et al., 1984;
Shepp et al., 1986). Karena sebagian besar kematian akibat
VZV akibat infeksi disebarluaskan, kemampuan untuk
mencegah penyebaran telah secara nyata mengurangi tingkat
kematian herpes zoster pada pasien dengan
immunocompromised. Selain itu, asiklovir intravena dianggap
sebagai obat pilihan untuk mengobati diseminasi saat terjadi,
walaupun data efikasi dari studi prospektif terbatas. Dosis
asiklovir intravena yang dianjurkan untuk herpes zoster pada
pasien dengan immunocompromised berat adalah 10-15 mg / kg
(atau 500 mg / m2) setiap 8 jam (Tabel 65.1). Bila infeksi
terkendali, terapi dapat beralih dari asiklovir intravena ke obat
antiviral oral selama sisa masa pengobatan. Pasien harus
diobati sampai penyembuhan selesai atau minimal 10-14 hari
(mana saja yang lebih lama) untuk mengurangi risiko penyakit
kambuh.

Mengobati herpes zoster pada pasien immunocompromised

pada pasien rawat jalan dengan obat antiviral oral merupakan
pendekatan yang menarik, walaupun data pendukungnya
terbatas. Satu penelitian kecil mengelompokkan 27 penerima
HSCT alogenik dengan herpes zoster ke asiklovir oral atau
intravena. Tidak ada penyebaran VZV pada kedua kelompok,
dan tidak ada perbedaan dalam penyembuhan atau hasil klinis
yang nyata (Ljungman et al., 1989). Data yang dipublikasikan
dari uji klinis dengan famciclovir dan valacyclovir untuk herpes
zoster pada pasien immunocompromised tetap terbatas, namun
semakin banyak pengalaman klinis yang menunjukkan bahwa
obat ini aman dan efektif dalam pengaturan ini (Tyring et al.,
2001a, b). Untuk pasien dengan penekanan immunosuppressed
kurang, terapi oral dengan asiklovir (800 mg lima kali sehari),
valasiklovir (1000 mg tiga kali sehari), atau famciclovir (500 mg
tiga kali sehari), ditambah dengan pengamatan klinis yang ketat,
merupakan pilihan yang masuk akal. Karena risiko keterlibatan
okular, asiklovir intravena ditambah evaluasi oleh dokter mata
disarankan untuk pasien dengan immunocompromised yang
hadir dengan HZO.

Sejak pertama kali dilaporkan pada tahun 1988, beberapa isolat

VZV yang resisten terhadap asiklovir telah ditemukan dari
pasien yang immunocompromised, biasanya orang dengan HIV
yang terinfeksi dengan jumlah CD4-T-limfosit yang sangat
rendah. Mekanisme resistensi didasarkan pada penghapusan
atau pemotongan gen yang mengekspresikan timidin kinase.
Sebagian besar isolat yang resisten terhadap asiklovir juga
resisten terhadap valasiklovir, famciclovir, penciclovir, dan
gansiklovir, yang semuanya bergantung pada virus TK untuk
aktivasi. Hubungan kuat ada antara VZV yang resisten terhadap
asiklovir dan adanya lesi kulit atipikal.

Satu laporan menggambarkan empat orang dewasa dengan

HIV-seropositif menjalani terapi asiklovir supresif kronis yang
mengembangkan papula hiperkeratosis disebarluaskan yang
gagal merespons asiklovir (Jacobson et al., 1990). Uji kepekaan
in vitro memastikan bahwa isolat VZV bersifat asiklovir-resisten
dengan IC50 rata-rata untuk asiklovir 20 g / ml, dibandingkan
dengan 0,75 g / ml untuk strain referensi (VZVoka). Meskipun
mekanisme yang mengarah pada pengembangan resistensi
asiklovir tidak sepenuhnya dipahami, data klinis menunjukkan
bahwa banyak kasus dikaitkan dengan dosis asiklovir yang tidak
adekuat untuk terapi akut atau penekanan jangka panjang, yang
mungkin memungkinkan pemilihan mutan defisien TK. Dokter
yang menggunakan asiklovir atau obat terkait untuk pengobatan
varicella atau herpes zoster pada pasien AIDS harus
menggunakan dosis terapeutik penuh dan melanjutkan terapi
sampai semua lesi VZV benar-benar terselesaikan.

Obat pilihan untuk pengobatan penyakit VZV yang resisten

terhadap asiklovir adalah foscarnet, penghambat DNA
polimerase virus yang tidak bergantung pada TK untuk aktivasi
(Breton et al., 1998) (Tabel 65.1). Dalam rangkaian 13 pasien
dengan infeksi VZV AIDS dan asiklovir yang diobati dengan
foscarnet intravena, 10 pasien (77%) mengalami penyembuhan
lesi lengkap setelah rata-rata 17,8 hari terapi (Breton et al.,
1998). Sebagian besar kasus penyakit yang disebabkan oleh
VZV yang resisten terhadap asiklovir terbatas pada keterlibatan
kutaneous, walaupun beberapa kasus infeksi viseral yang
disebabkan oleh VZV resisten-asiklovir telah dilaporkan,
termasuk kasus nekrosis retina dan meningoradikulitis.

Untungnya, isolat VZV yang resisten terhadap asiklovir dan

foscarnet jarang ditemukan. Biologi molekuler dari isolat yang
tahan uji ini belum sepenuhnya dieksplorasi, namun mutasi pada
DNA polimerase virus dapat menjelaskan resistensi asiklovir
dan foscarnet. Cidofovir kemungkinan akan mempertahankan
aktivitas melawan isolat ini dan akan menjadi obat pilihan untuk
pasien dengan penyakit yang disebabkan oleh VZV yang
resisten.