Varicella-Zoster Virus

Updated September, 2010

Dora Ho, M.D., Ph.D., Jason G Newland, M.D., Ann M Arvin, M.D.

VIROLOGY Guided Medline Search

               Varicella-zoster virus (VZV) is a member of the Herpesviridae family, within the subgroup of alphaherpesvirus. The intact VZV particle is approximately 180 to 200 nm in diameter, and is comprised of an icosahedral nucleocapsid, surrounded by the tegument and a lipid envelope (47). Its linear, double-stranded DNA genome contains approximately 125,000 base pairs and encodes at least 70 distinct gene products. The viral particle is highly temperature sensitive and depends upon the envelope proteins for infectivity. VZV is spread as cell-free virus to susceptible hosts, but within the infected host, it is transmitted by cell-to-cell spread. No distinct subtypes have been identified although epidemiologically unrelated viruses have differences in restriction endonuclease digest patterns.

Klein JO and Hanshaw JB. Thomas H. Weller, 1915-2008: A Remembrance. Clin Infect Dise 2009 April 15; 48:1102-3.

EPIDEMIOLOGY Guided Medline Search   

               VZV causes two distinct clinical diseases, namely varicella (or commonly called chickenpox) and zoster (or referred to as shingles). Humans are the only known reservoir for VZV. Varicella, or primary VZV infection, results when susceptible or sero-negative individuals are exposed to the virus. It is primarily a disease of childhood, with 90% of the cases occur in children under 13 years old. Varicella occurs in a worldwide geographic distribution, but typically during childhood in temperate climates and during adolescence or early adulthood in tropical areas (187). Annual epidemics are more common in temperate climates than in tropical areas. Cases of varicella or herpes zoster are a source of transmission to susceptible close contacts. Unlike other herpesviruses, VZV is transmissible by the respiratory route. Attack rates range from about 30% with classroom exposure to 90% among household contacts.

               In contrast to varicella, zoster results from the reactivation of the virus, which becomes latent in dorsal root ganglia after the primary infection. VZV reactivation in the ganglia leads to its spread along the nerve roots to infect the corresponding dermatomes. Although herpes zoster can occur in any individual who has previously been infected with VZV, it is classically a disease of the elderly or those with depressed cell-mediated immunity because of disease or immunosuppressive drugs. Recent epidemiologic data from the United States (U.S.), Canada and several European countries suggest that overall, there are between 3.2 and 5.3 cases of herpes zoster per 1000 person-years (183). Herpes zoster can occur at any age but the incidence increases dramatically after middle-age. For instance, while the incidence of herpes zoster for all ages in the U.S. is 3.2 cases per 1000 person-years, it increases to 6.9 cases per 1000 person-years for age 60-69 and further to 9.5 cases per 1000 person-years for age 70-79. For those ≥80 years old, an approximate of 1.1% will develop herpes zoster annually (108). It is estimated that about one-fifth of the population of the developed world will develop herpes zoster at some stage during their lifetime, with an annual incidence of 600,000 to 850,000 cases in the U.S. (105,165,182). Children or adolescents who acquired primary VZV infection in utero or in the first year of life have a relative risk up to 20.9 times greater than others of developing herpes zoster before the age of 20 years (14,33,94). Recurrent episodes of zoster occur in ≤5% of individuals (58), but occur more frequently in immunocompromised patients (e.g. up to 19-27% in patients with acquired immune deficiency syndrome or AIDS) (206).

               Patients with lymphoma or leukemia (particularly T-cell dysplasias) have a fivefold greater incidence of herpes zoster than the general adult population (72,150,165). The reported incidence of recurrent VZV infection after hematopoietic cell transplantation (HCT) ranges from 16-63% (120,134). In particular, between 30% and 50% of adults and 25% of children develop herpes zoster in the year following HCT, typically from the third month onwards (120). Herpes zoster occurs in about 10-15% of solid organ transplant (SOT) recipients, usually in the first 6 months after transplantation. For patients with human immunodeficiency virus (HIV) infection, herpes zoster occurs at all stages of HIV, but the incidence of herpes zoster increases with the decrease of CD4+ cell counts and T-cell reactivity (208). Overall, the annual incidence of herpes zoster in HIV-infected individuals is increased 10-20 fold over the rate in the general population (35,208). While most adults with HIV infection have had varicella prior to acquiring HIV, the reverse is true in pediatric patients (82). HIV-infected children who develop varicella when they are severely immunocompromised are at extremely high risk of herpes zoster (83).

CLINICAL MANIFESTATIONS Guided Medline Search

Varicella: Varicella may be associated with a prodrome of fever, malaise, headache and abdominal pain, occurring 24-48 hours (h) before a rash appears (125,222). These symptoms are more common in older children and adults. Varicella is usually diagnosed clinically by the appearance of the rash, which is often initially observed on the face, scalp, or trunk. The cutaneous lesions are pruritic. Each begins as a small erythematous macule that evolves rapidly to a vesicle of 1-4 mm diameter on an irregular erythematous base, referred to as “dewdrop on a rose petal”. Vesicles can also be observed on mucous membranes such as the conjunctiva, the oropharynx, the rectum or the vagina. Without treatment, new vesicle formation typically continues for about 3 days, with a range of 1-7 days. The number of lesions varies from fewer than 10 to more than 1500, with a usual range of 100-300. The rash is more extensive in older children, in secondary household cases, in immunocompromised patients and in patients with skin trauma, such as sunburn. Varicella is usually accompanied by lymphopenia and granulocytopenia in the acute phase. Abnormal liver function tests can be seen in immunocompetent patients with varicella, but hepatic involvement is usually subclinical. In contrast, for immunocompromised patients, fulminant varicella hepatitis can develop. Secondary bacterial infections, usually due to Staphylococcus aureus or Streptococcus pyogenes (group A beta-hemolytic streptococcus) are the most common complication of varicella.

               Varicella pneumonia is almost never observed in healthy children but complicates primary VZV infection in up to 5% of adults, with about 1 in 400 adults requiring hospitalization (70). Fever, cough, dyspnea and hemoptysis develop within a few days of the onset of the rash and chest radiographs usually show ill-defined diffuse infiltrates (70). Untreated there is a mortality of about 10%. Neurologic complications include meningoencephalitis, which is associated with direct infection of the central nervous system (CNS), and cerebellar ataxia, which is probably not (84,114). Encephalitis is usually transient, resolving within 24-72 h and permanent sequelae are rare; cerebellar ataxia often persists for days or weeks but also usually resolves completely (222,225,229). Hemorrhagic complications may occur as a result of hepatitis and thrombocytopenia and may progress to disseminated intravascular coagulopathy.

               Populations at high risk for complications of varicella include patients with hematologic malignancies or solid tumors, recipients of SOT or HCT, patients receiving high-dose or chronic steroid therapy, patients receiving immunomodulating or immunosuppressive drugs, patients with congenital cellular immunodeficiency disorders, and newborn infants whose mothers have varicella just before or after delivery (125). While the clinical manifestations of VZV in immunocompromised patients are similar to normal hosts in some instances the initial presentation or the appearance of lesions may be different. HCT patients often develop cutaneous dissemination (defined as more than five vesicular lesions beyond the primary dermatome) and are also at risk of visceral dissemination, which may lead to pneumonia, hepatitis, encephalitis and disseminated intravascular coagulopathy. Occasionally HCT patients with visceral dissemination may present with severe abdominal pain in the absence of classic cutaneous manifestations, resulting in delayed diagnosis, misdiagnosis as graft-versus-host disease or other disease entities (107,127,197,209). Other signs such as elevated aminotransferases and/or pancreatic enzymes, disseminated intravascular coagulopathy or hyponatremia (due to inappropriate secretion of antidiuretic hormone) may accompany visceral dissemination. HIV patients may have an unusual hyperkeratotic varicella (48,93). Immunosuppressive therapy given during the incubation period and an absolute lymphocyte count of less than 500 cells at the onset of rash are associated with an increased risk of disseminated varicella. Without antiviral therapy, varicella in high-risk populations is associated with prolonged new lesion formation, increased numbers of lesions, and risk of dissemination with pneumonia, hepatitis, encephalitis and disseminated intravascular coagulopathy. Pneumonia frequently occurs within 3 to 7 days and is the primary reason for mortality. Fulminant hepatitis and disseminated intravascular coagulopathy are also associated with high mortality rates.

Herpes Zoster: Herpes zoster is almost always unilateral, affecting one or two adjacent dermatomes. The most frequently affected dermatome is that of the trigeminal nerve, particularly the ophthalmic branch, which is involved in 10-15% of all cases. Otherwise each dermatome is affected at a similar rate of 3-4%. About 50% of herpes zoster involves the trunk as a result of reactivation of one or more of the thoracic dermatomes. The pathologic changes of VZV reactivation start in the relevant sensory ganglion, and pain and paraesthesias within the affected dermatome often precede the rash by several days. Since it can mimic a wide range of other conditions, the cause of the pain is usually not recognized until the rash appears. The rash of herpes zoster begins as erythematous maculopapules, which develop into vesicles, 0.5-2 cm in diameter, within 12 hours or so (153). After 3-4 days, pustules form and gradually dry and crust over the next 7-10 days. New lesions continue to appear for a mean of <2 days and for more than 4 days in only 10-15% of normal individuals. Virus can generally be cultured from the vesicles for three or four days, although in 15% it is recoverable from lesions up to one week (153).

               In immunocompromised individuals herpes zoster infection is often more extensive and may continue to appear for 2 weeks or longer. Scabbing may not occur for as long as 1 month. Lesions can involve the dermis and may be hemorrhagic and necrotic. In 20% to 30% of cases there is viremic spread with widespread cutaneous and visceral dissemination (153). In advanced HIV disease herpes zoster can be severe, disseminated and atypical [reviewed in (206)]. There is a higher risk of multi-dermatomal herpes zoster (60) and/or recurrent episodes and there are many reports of the skin lesions becoming indolent, hyperkeratotic and verrucous (82,93,153). A link between such chronic lesions and in vitro resistance to acyclovir has been observed (106,131,156).

Herpes Zoster: Classic and Unusual Manifestations.  Infections in Medicine 2008;25:506-508.

Scheinfeld, NS. Skin Disorders in Elderly Persons: Identifying Viral Infections. Infect Med. 2007:479-81

Strangfeld A et al. Risk of Herpes Zoster in Patients with Rheumatoid Arthritis Treated with Anti-TNF-Alpha Agents. JAMA. 2009 Feb 18;301(7):737-44.

McDonald, JR, et al. Herpes Zoster Risk Factors in a National Cohort of Veterans with Rheumatoid Arthritis.  Clin Infect Dis 2009;48:1364-1371.

               Although most cases of herpes zoster in the immunocompetent host are self-limiting and resolve completely, 15-20% experience one or more complications. The major complication and cause of morbidity after herpes zoster in an immunocompetent host is postherpetic neuralgia (PHN). The definition of PHN varies from any pain lasting after the resolution of the rash to pain that persists for more than 2 months. Estimates of the incidence of PHN differ, depending on the definition used. In general, PHN is rare in children, even in pediatric HCT recipients, but the risk of developing PHN increases with advanced age. A recent large randomized trial that evaluated a vaccine against herpes zoster noted PHN occurred in 6.9% of the patients 60-69 years old, but in 18.5% of those ≥70 years old (155). In another study, for adults under 60 years old, the risk for developing PHN is less than 2% (103). In 10 to 15% of adult patients with herpes zoster, pain persists for more than 4 weeks after the resolution of the rash, but only 30 to 50% of these patients are still in pain after 3 months, and 25 to 30% after 12 months (36,105,165). Prolonged pain is more common in the elderly. In patients over 60 years of age pain persists for 1, 3 and 6 months after the illness in 50 to 61%, about 25%, and 9 to 13%, respectively (138,160). The pathogenesis of PHN is poorly understood but increased transmission of nociceptive impulses during the period of acute neuronitis may induce central sensitization and hyperexcitability of spinal neurons, which is then maintained by a changed peripheral input and by excitotoxic damage in the dorsal horn of the spinal cord (89,235). On-going viral replication was one of the postulates to explain the persistent pain, but antiviral treatment has not been shown to have any effects on PHN (1).

               When VZV reactivation involves the cranial nerves (CN), complications may include corneal damage, facial scarring, CN VII palsy or hearing loss. Herpes zoster ophthalmicus results when the ophthalmic division of CN V is involved, and accounts for approximately 10% to 20% of cases of herpes zoster. The clinical findings of ocular herpes zoster may include conjunctivitis, anterior uveitis, keratitis or pan-ophthalmitis (43,158,220). VZV reactivation from the geniculate ganglion leads to herpes zoster oticus or the Ramsay Hunt syndrome, which is typically comprised of a triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Subsequent involvement of CN VIII may also lead to unilateral hearing loss, tinnitus and vertigo.

               Other neurologic complications seen with herpes zoster include peripheral motor paralysis, transverse myelitis, ascending paralysis and encephalitis (84). Cerebral angiitis may lead to thrombotic strokes several weeks to a few months after the initial zoster eruption (85). Fortunately, this complication remains rare. A similar wide range of neurologic complications, including myelitis, chronic progressive encephalitis and Guillain-Barré syndrome, have been reported in patients with AIDS (90). Only two-thirds of these patients have had concomitant or previous cutaneous herpes zoster lesions (136). However, the role of VZV in these neurologic complications is confirmed by the presence of VZV antigens and VZV DNA and the ability to culture the virus from cerebrospinal fluid (5). Acute retinal necrosis, both in otherwise healthy and immunocompromised persons, can be caused by VZV (along with other herpesviruses) (81). The syndrome is characterized by retinal vasculitis, confluent retinal necrosis and acute vitritis and produces devastating visual loss. Acute retinal necrosis may occur concurrently or follow herpes zoster but many cases caused by VZV in HIV-positive patients are not accompanied by any cutaneous lesions. Progressive outer retinal necrosis (PORN), a distinct form of VZV necrotizing chorioretinitis is seen almost exclusively in patients with AIDS (13), but few cases after allogeneic HCT have been reported recently (112,116). PORN is characterized by early involvement of the outer retina, but relative absence of intraocular inflammation. Visual loss can occur within weeks despite antiviral therapy and involvement of the fellow eye may progress within weeks to months.

Dworkin RH, et al. A Randomized, Placebo-Controlled Trial of Oxycodone and of Gabapentin for Acute Pain in Herpes Zoster. Pain. 2009 Feb 3. [Epub ahead of print]

Ihekwaba UK et al. Clinical Features of Viral Meningitis in Adults: Significant Differences in Cerebrospinal Fluid Findings Among Herpes Simplex Virus, Varicella Zoster Virus, and Enterovirus Infections. Clin Infect Dis. 2008 Sep 15;47(6):783-9.

Nagel MA, et al. The varicella zoster virus vasculopathies. Neurology 2008;70:853-860

LABORATORY DIAGNOSIS Guided Medline Search

               Diagnosis of varicella does not require laboratory confirmation in healthy children. However, rapid diagnosis may be required to guide decisions about antiviral therapy in immunocompromised hosts. Rapid diagnosis of cutaneous VZV infection can be performed by staining cells from the base of a vesicle with fluorescein-conjugated monoclonal antibodies to VZV antigens. Alternatively, vesicular fluid can be tested for viral antigens with enzyme immunoassay methods (77). VZV can also be isolated in tissue culture cells. In most cases, diagnosis by culture is not rapid enough to influence clinical decisions, but may confirm diagnoses made with rapid antigen detection methods. VZV DNA can also be detected by in situ hybridization or polymerase chain reaction (PCR). PCR assays are commercially available and can be applied to various kinds of tissue samples including blood, cerebrospinal fluid (CSF), broncheoalveolar lavage, etc. Serologic tests can be use to establish immune status before transplantation and are also useful to assess susceptibility of exposed individuals. The most sensitive serologic assay for detection of VZV antibodies is fluorescent-antibody staining of membrane antigen, but this remains a research tool only. Other available serologic tests include enzyme-linked immunosorbent assays, indirect fluorescent antibody tests (including anticomplement immunofluorescence and time-resolved fluoroimmunoassay) and latex agglutination. VZV IgG and IgM antibodies are present at the time of onset of varicella in some individuals and in almost all patients by 3 days; titers increase more than fourfold during convalescence. It should be noted that IgM can be detected also in the majority of patients with recurrent infection and thus, testing for VZV IgM is not useful in clinical practice.

               The diagnosis of herpes zoster is also generally clinical. In the pre-eruptive phase the pain may be confused with that of any localized condition, but once the rash appears the diagnosis is usually obvious. Routine serology alone is not useful in establishing reactivation of VZV. Virologic confirmation can be made by the same methods as for varicella. Neurologic infection with VZV can be confirmed by PCR amplification of VZV DNA extracted from the CSF (173). Evidence of local production of specific antibodies within the CSF might also be obtained. To determine the etiology of acute retinal necrosis or rapidly progressive herpetic retinal necrosis, the causative virus can be detected within the affected eye by culture of the vitreous. Viral DNA may be detected in either vitreous or aqueous fluid by PCR, or intraocular specific antibody production can be detected (52).

Leung J, et al. Evaluation of Laboratory Methods for Diagnosis of Varicella. Clin Infect Dis. 2010 Jul 1;51:23-32.
 

PATHOGENESIS Guided Medline Search

               During primary VZV infection, the virus is inoculated at respiratory mucosal sites. Presumably, it then spreads to regional lymph nodes and cause a primary viremia (47,92). A secondary viremia occurs 4 or 5 days before onset of symptoms and persists for 1-2 days after. VZV is lymphotropic for CD4+ as well as CD8+ T lymphocytes, although the possible infection of other mononuclear cells has not been ruled out definitively. Infected T cells are presumed to transfer the virus to skin cells. VZV replication in epidermal and dermal cells produces the characteristic vesicular rash and further amplifies viremia by transfer of the infectious virus into migrating T lymphocyte populations, leading to secondary “crops” of skin lesions. The virus has the pathogenic potential to cause disseminated infection involving lungs, liver, CNS and other organs if the replication at skin sites and cell-associated viremia are not terminated by the host response and/or by antiviral therapy.

               One property of herpesviruses is the ability to establish latent infection without replication in their hosts. During the primary infection VZV is thought to pass centripetally along the sensory nerve fibers from the skin to the corresponding sensory ganglia. Hematogenous seeding of the ganglia may also occur through cell-associated viremia. Within the ganglia VZV establishes latency in neuronal and/or satellite cells (47,115). The virus then remains quiescent but reactivates sporadically and infrequently to cause herpes zoster (191). The molecular mechanisms that establish and maintain VZV latency are not fully understood but reactivation of the virus is clearly related to declining VZV-specific cell-mediated immunity. Cell-mediated immunity to VZV declines markedly in immunocompromised patients and in the elderly (142). Levels of VZV-specific cell-mediated immunity also correlate with the development of herpes zoster in leukemic children after live varicella vaccine administration (96).

               VZV reactivation within the ganglia results in extensive viral replication, causing severe neuronal necrosis and inflammation. VZV then spreads down the sensory nerve to infect the skin, producing the characteristic dermatomal vesicular rash of herpes zoster.

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

Single Drug

               In vitro, VZV is susceptible to several antiviral drugs. The activity of these drugs depends to some extent on the viral strains and cell types used for testing. Acyclovir and penciclovir are guanine analogues that are phosphorylated by a VZV-encoded thymidine kinase and act as competitive inhibitors of the viral DNA polymerase. The 50% inhibitory concentration (IC50) of acyclovir for VZV is 0.6-1.2 µM and a similar range of values has been determined for penciclovir (6). Ganciclovir, which is licensed for the treatment of cytomegalovirus infection, also has in vitro activity against VZV similar to that of acyclovir. However, clinical studies to evaluate its efficacy for the treatment of VZV infections have not been done because of its greater drug toxicity. Other nucleoside analogues with anti-VZV activities include vadarabine, sorivudine and brivudine. Vadarabine, a nucleoside analogue of adenosine, was the first antiviral agent to be licensed for the treatment of systemic herpesvirus infection. It is less effective than acyclovir and is no longer available (190). Sorivudine and brivudine are nucleoside analogues of thymidine. They are very potent inhibitors of VZV replication in cell culture with inhibitory concentrations several hundred to several thousand times lower than acyclovir (6). Despite their potency and clinical efficacy (211,212), both drugs, when co-administered with 5-fluoro-uracil (5FU) or cepecitabine (which is metabolized to 5FU), may lead to lethal complications (151). For this reason, the development of sorivudine was terminated and brivudine is approved for sale only in some European countries but not licensed in the United States.

               Foscarnet is a pyrophosphate analogue that directly inhibits viral DNA polymerase and has an IC50 for VZV of 50 to 90 µM (6,129). It does not depend upon thymidine kinase for activation and can be used for VZV strains that are resistant to nucleoside analogues (e.g. acyclovir and penciclovir) due to thymidine kinase deficiency. Cidofovir is a nucleotide agent that may also be used for such resistant strains since it is already phosphorylated and its activity is not dependent on virally-encoded enzymes (53). However, toxicity of this drug has limited its use. Resistance of herpesviruses to either foscarnet or cidofovir has been mapped to mutations of the viral DNA polymerase (102).

Combination Drugs

               There are no data on combinations of antiviral drugs against VZV in vitro.

ANTIVIRAL THERAPY Smart search

Drug of Choice Guided Medline Search

               Oral formulations of antivirals for the treatment of VZV infections (varicella and/or zoster) include acyclovir, famciclovir and valacyclovir. Intravenous formulations include acyclovir, foscarnet and cidofovir, but the latter two drugs are not licensed for treating VZV infections (as summarized in Table 1). In otherwise normal hosts, the management of VZV infections is directed toward symptomatic relief (for instance, of constitutional symptoms and rash-associated pruritis) and the reduction of complications; antiviral treatment may not be essential. However, in immunocompromised hosts, prompt diagnosis and initiation of antiviral therapy may be life-saving.

               The plasma concentrations achieved by intravenous administration of acyclovir at doses of 10 mg/kg or 250-500 mg/m2 range from 15-25 μg/ml, which are several folds above the in vitro inhibitory concentrations for most VZV isolates. However, when administered orally, only about 20% of acyclovir is absorbed. The resulting peak plasma concentration achieved by oral acyclovir dosing may be significantly lower then the acyclovir concentrations required to inhibit some VZV isolates. The L-valine ester of acyclovir, valacyclovir, has improved oral bioavailability of approximately 60% and is rapidly converted to acyclovir after oral administration. An oral dose of 1000 mg valacyclovir yields comparable systemic exposures but reduced peak levels of acyclovir as compared to intravenous acyclovir given at 5 mg/kg (104). Similarly, famciclovir, a pro-drug of penciclovir, has been developed to provide therapeutic plasma concentrations and achieved oral bioavailability of 77% (50,192).

Varicella: Despite its poor bioavailability and need of frequent dosing, oral formulation of acyclovir has been proven efficacious for the treatment of primary and recurrent VZV infections. Oral acyclovir is licensed for the treatment of varicella in healthy children and adults, on the basis of clinical efficacy and safety demonstrated in placebo-controlled studies. Antiviral therapy with this agent diminishes the clinical symptoms of varicella in otherwise healthy children, adolescents and adults when given within 24 h after appearance of the initial cutaneous lesions (17,19,56,210,211). Treatment reduces fever, pruritis, the number of days of new lesion formation, and the total number of cutaneous lesions, as compared with placebo (56). Some (but less) clinical benefits are obtained if treatment is started 24 to 48 h after rash onset (17). A Cochrane review of 3 randomized controlled trials performed in children concluded that acyclovir is associated with a reduction of fever by 1.1 days and a reduction of the maximum number of lesions by 76 as compared to placebo (119). There were no clinically important differences between acyclovir and placebo with respect to complications associated with varicella. In healthy adolescents, ages 13 to 18 years, and adults, acyclovir treatment within 24 h of onset also reduces the duration of fever, new lesion formation, and total number of lesions (17,19,211). Since varicella is more severe in older individuals, oral acyclovir should be given if possible within 24 to 48 h. Early antiviral therapy in this age group can potentially reduce the risk of varicella pneumonia.

               Since varicella is a self-limited infection in healthy children and the clinical benefit of acyclovir therapy is only modest, the American Academy of Pediatrics does not recommend the routine treatment of uncomplicated varicella in otherwise healthy children (4). Acyclovir therapy should be initiated in patient groups with increased risk of severe disease or of complications from varicella, including premature infants, adolescents, adults, those with chronic cutaneous or cardiopulmonary diseases, those requiring chronic salicylate therapy (with higher risk for developing Reye’s syndrome) or being treated with short or intermittent courses of steroids or aerosolized corticosteroids. Secondary household cases should also receive antiviral treatment since the illness is likely to be more severe than in primary cases. The dose for children, 2 to 16 years old, is 20 mg/kg 4 times a day for 5 days (maximum 800 mg per dose). No additional benefit is gained treating for 7 days (17). Adolescents and adults can receive up to 800 mg 5 times daily. Intravenous acyclovir is frequently used for those with severe complications and in immunocompromised hosts (see below). Oral acyclovir treatment started after the appearance of the cutaneous lesions of varicella does not block the acquisition of immunity to VZV.

               There are no controlled studies of famciclovir or valacyclovir in varicella but, on the basis of pharmacokinetic data, both are likely to be as effective as acyclovir.

Herpes Zoster: The currently available data suggest that oral acyclovir (800 mg 5 times daily for 7 days), famciclovir [250 mg (Europe) and 500 mg (USA) 3 times daily for 7 days] and valacyclovir (1000 mg 3 times daily for 7 days) have very similar clinical efficacy in herpes zoster in immunocompetent patients if started within 72 h of onset of the rash. A choice between them may depend on costs and convenience of administration (Table 1).

               Randomized placebo-controlled studies have shown that oral acyclovir (800 mg 5 times daily for 7 or 10 days) reduces the duration of new lesion formation and significantly accelerates rash healing in normal hosts with herpes zoster (109,232). In the largest such study the time to full crusting of skin lesions was reduced by more than 36 hours by the use of acyclovir (233). Pain during the acute phase was also improved but conflicting results were obtained in the individual studies regarding the effect of acyclovir on the incidence of postherpetic neuralgia. A meta-analysis of 4 placebo-controlled trials showed that acyclovir, when given within 48 to 72 hours of the onset of rash, accelerates the resolution of pain by all of the measures employed, with benefits more evident in patients of age 50 or older (232). Another meta-analysis that included one additional trial also demonstrated that acyclovir treatment reduced PHN by 46% at 6 months (109). Increasing the duration of acyclovir therapy beyond 7 days provides no additional benefit (231).

               The safety and efficacy of valacyclovir  (1 gm orally 3 times daily for 7 to 14 days) was compared to acyclovir (800 mg orally 5 times daily for 7 days) in a randomized, double-blind study of 1141 immunocompetent adults of age ≥50 years with herpes zoster (23). Valacyclovir given for 7 or 14 days significantly accelerated the resolution of zoster-associated pain as compared to acyclovir (median pain durations were 38 and 44 days, respectively, versus 51 days for acyclovir). Treatment with valacyclovir also significantly reduced the duration of PHN and decreased the proportion of patients with pain persisting for 6 months (19.3 versus 25.7%). However, there were no differences between rates of resolution of cutaneous manifestation or quality-of-life measures. Adverse events were also similar for both the valacyclovir groups and acyclovir group. Subsequent analysis of the trial data showed that the benefits of valacyclovir over acyclovir were maintained whether treatment was commenced within 48 h or between 48 and 72 h after rash onset (234).

               Famciclovir (500 mg or 750 mg orally every 8 h for 7 days) was evaluated in a placebo-controlled trial in 429 immunocompetent adults with herpes zoster (202). When given within 72 h of rash onset, famciclovir accelerated lesion healing and reduced the duration of viral shedding. Famciclovir recipients also had resolution of PHN approximately twofold faster than placebo. The median duration of PHN was reduced by approximately 2 months. The efficacy and tolerability of famciclovir (250 mg, 500 mg and 750 mg 3 times daily) was compared to oral acyclovir (800 mg 5 times daily) in another randomized, double-blind, double-dummy study. A total of 545 immunocompetent adults participated and treatment was initiated within 72 h of the onset of rash. Famciclovir was found to be as effective as acyclovir at all dose levels for cutaneous lesion healing, duration of VZV shedding and the time to loss of acute pain (55). When zoster-associated pain was assessed, famciclovir at all doses resolved pain significantly faster than acyclovir in a subset of patients treated within 48 h of rash onset. In a more recent study, famciclovir (500 mg 3 times daily) was compared with valacyclovir (1 gm 3 times daily) for the treatment of herpes zoster and no differences (either statistical or clinical) were observed with respect to rash healing, the resolution of zoster-associated pain, loss of PHN or safety profiles (205). No comparative studies have been done of valacyclovir and famciclovir in a dosage of 250 mg every 8 h.

               The longer intracellular half-life of penciclovir triphosphate in VZV-infected cells as compared to acyclovir triphosphate (7 h versus 1 h) has prompted a clinical trial to evaluate the efficacy of famciclovir administered with less-frequent dosing (189). Immunocompetent adults presenting with herpes zoster within 72 h of rash onset were randomized to receive famciclovir 750 mg once daily, 500 mg twice daily and 250 mg daily, or acyclovir 800 mg 5 times daily for 7 days. All treatment groups were comparable with respect to the cutaneous healing of herpes zoster and the loss of acute pain. However, the effects of the treatments on PHN were not evaluated. Current guidelines for the treatment of zoster with famciclovir recommend 500 mg 3 times daily. Further trials are needed before daily dosing can be adopted.

               Brivudine is not licensed in the U.S, but several clinical studies showed that a single daily dose of brivudine at 125 mg is effective in the treatment of herpes zoster as compared to acyclovir 800 mg 5 times a day or to famciclovir  250 mg 3 times a day, all given orally (54,212,213).

               Overall, clinical trials with these agents demonstrated that antiviral therapy with acyclovir, famciclovir, valacyclovir and brivudin in patients with zoster reduces the duration of viral shedding and new lesion formation and accelerates rash healing [reviewed in (58)]. Antiviral therapy may also attenuate the development of PHN by inhibiting viral replication and limiting neural damage (58), and thus, should be instituted without delay. It is recommended that systemic antiviral therapy should be administered to all immunocompetent patients with zoster who are ≥50 years of age, have moderate or severe pain, have moderate or severe rash, or have nontruncal involvement. Patients with low risks for complications of zoster may also benefit from antiviral treatment, since they are still at risk of developing PHN. For patients who present >72 h after rash onset, the potential benefits of antiviral therapy are unclear, but treatment should be considered for those of advanced age and with severe pain, those with continued new vesicle formation and those with complications from zoster (58).

(Printable Version of General Antiviral Therapy for Varicella-Zoster Virus )

Special Situations

Varicella

               Otherwise healthy patients who develop varicella pneumonia, hepatitis, thrombocytopenia or encephalitis should be treated with intravenous acyclovir, 10 mg/kg/dose for adults and 500 mg/m2/dose for children every 8 h, for 7-10 days.

Pneumonia: Pneumonia can be a serious and life-threatening complication associated with varicella. It remains uncommon in healthy children, but is more common in adults and in immunocompromised hosts. The incidence in adults is estimated to be approximately 1 in 400 cases (145). The overall mortality for VZV pneumonitis ranges from 10% to 30% (181,200), with a higher rate in pregnant women and those with respiratory failure at the start of therapy (87,95,181,200). Mortality rates from pneumonia has decreased in the last few decades, from an average of 19% in the 1960s and 1970s to about 6% in more recent data (145). The improvement of mortality is likely due to multiple factors, including earlier diagnosis, better supportive care and the availability of antiviral therapy. Risk factors for developing pneumonia include cigarette smoking (previous or current) (63,69), pregnancy (68), immunosuppression (76) and chest symptoms at presentation (146). In pregnant women risk factors for the development of VZV pneumonia are being a current smoker and having greater than 100 skin lesions (76). In adults with pulmonary symptoms such as tachypnea, cough, increasing dyspnea or hemoptysis and with pulmonary infiltrates in the setting of primary VZV, it is prudent to initiate treatment immediately with intravenous acyclovir (181). Steroids have been utilized in some cases and controversy still remains whether this is beneficial. In an uncontrolled study that evaluated 15 adult patients with varicella pneumonia, 6 patients that received steroids in addition to intravenous acyclovir and support measures demonstrated a clinically significant therapeutic response with shorter hospital and ICU stays. There was also no mortality among the patients that received steroids despite their lower median ratios between PaO2 and the fraction of inspired oxygen upon admission to the ICU than those patients (n=9) who did not receive corticosteroid therapy. A more recent case series also examined the outcome and effect of corticosteroid use in varicella pneumonia (2). Among 19 patients with varicella pneumonia, 10 patients received corticosteroids, in addition to antiviral and supportive treatment. The corticosteroid group presented with greater disease severity, but showed a much more rapid improvement in oxygenation and a trend towards shorter duration of mechanical ventilation. However, the durations of ICU and hospital stays were not significantly different. Popara et al. also studied a small group of 7 HIV/AIDS patients with varicella pneumonia and suggested that systemic corticosteroids may improve outcome (161). These studies favor the use of corticosteroids in varicella pneumonia, but further investigations with randomized controlled trials are warranted. Additionally, an immunocompetent patient with VZV pneumonia and adult respiratory distress syndrome was successfully treated with intravenous immunoglobulin (IVIG) and acyclovir (199). However, the role of IVIG in the treatment of varicella, especially in immunocompetent patients, has not been established.

Central Nervous System: Central nervous system complications are rare occurring in less than 1% of children with VZV. The most common neurologic complication is cerebellar ataxia occurring in 1 in 4000 cases in children less than 15 years of age (222). While it is a benign, self-limited complication, experts recommend treating with acyclovir (10 mg/kg every 8 h for adults and 500 mg/m2 every 8 h for children) for 7 days based on anecdotal experience (84).

               VZV encephalitis is a more severe disease than cerebellar ataxia and occurs in 1-2 per 1000 cases in adults (222). Mortality has ranged from 0-35% and up to 20% of patients experience neurologic sequelae (59,163). No control studies exist but due to clinical experience acyclovir is recommended at 10 mg/kg/dose every 8 h for adults and 20 mg/kg/dose every 8 h for children. Duration of therapy is typically 7 days, but immunocompromised patients may require longer treatment.

Pregnancy: Pregnancy is associated with decreased cell mediated immunity, resulting in increased risk for severe varicella (179). The incidence of varicella is estimated to be 1 to 5 cases per 10,000 pregnancies (193), but pregnant women are at greater risk of developing severe or fatal complications than non-pregnant immunocompetent adults. Up to 20% cases of VZV infections in pregnancy can be complicated by pneumonia and the morbidity is highest if infection occurs during the third trimester (51). Mortality with varicella pneumonia may be as high as 45% in untreated pregnant women (99,179), but decreased to 14% with acyclovir treatment, as reported by Broussard and colleagues (32). Due to the risk of mortality, pregnant women with complicated varicella should receive intravenous acyclovir at 10 mg/kg/dose every 8 h for 7 days and potentially longer depending on the clinical course.

Congenital: The risk of congenital varicella syndrome following maternal primary VZV infection is estimated to be 0.4% when maternal infection occurs from conception through the 12th week of gestation and 2% when infection occurs from the 13th to the 20th week of gestation (64,97,147,157). In contrast, herpes zoster occurs during pregnancy does not post any risks to intrauterine infection (64). Most cases of congenital varicella occur in infants whose mothers were infected between 8 and 20 weeks of gestation, but cases of congenital varicella syndrome have been reported as late as the 28th week of gestation (15,177). Mothers who become infected with VZV during their second and third trimesters are recommended to take oral acyclovir 800 mg 5 times daily until all lesions are crusted over. Since acyclovir is a category B drug for pregnancy risk, it is unclear whether a mother who contracts varicella during the first trimester should receive acyclovir treatment for the prevention of congenital varicella. However, antiviral treatment should be initiated for varicella pneumonia or other disseminated infections during pregnancy. Zoster during pregnancy should only be treated with acyclovir in severe disease (179).

Neonatal: Neonatal varicella may occur if a mother contracts chickenpox during the last 3 weeks of pregnancy. The severity of intrauterine acquired neonatal chickenpox is closely associated to the time of onset of maternal infection and can be life threatening with mortality of up to 20-30% [reviewed in (179)]. Approximately 20% of neonates born to mothers who become ill with varicella 5 days before or 2 days after delivery will develop disseminated varicella infection (140,179). Therefore, neonates must receive passive immunization with either varicella zoster immune globulin (VariZIG) or IVIG, if the mother develops varicella 5 days before or 2 days after delivery (179). The dose for VariZIG is 125 IU/10 kg body weight, up to 625 IU total, given intravenously or intramuscularly. The minimum dose is 125 IU. The dose of IVIG is 400 mg/kg. (Also see section on Passive Immunization.) Intravenous acyclovir should be administered only if the neonate develops a varicella rash (500 mg/m2/dose every 8 h or 10 mg/kg/dose every 8 h).

Herpes Zoster

Encephalitis: Although no controlled clinical trials have been performed, a review of case reports suggested a good response of herpes zoster encephalitis to intravenous acyclovir (10 mg/kg or 500 mg/m2 per dose, given 8 hourly for 14-21 days). Additionally, these reports showed a statistical trend towards a lower mortality in patients treated with acyclovir (138).

Ophthalmicus: Herpes zoster ophthalmicus occurs in 10-20% of cases of herpes zoster. Of these, approximately 50% of patients develop ocular involvement without antiviral treatment [reviewed in (128)]. Therefore, all cases of herpes zoster opthalmicus are treated with oral acyclovir (800 mg 5 times daily), valacyclovir (1 gm 3 times daily) or famciclovir (500 mg 3 times daily) for 7 days to reduce the risk of ocular complications. In a double-blind, placebo controlled trial, Cobo and colleagues demonstrated a reduction in ophthalmic complications after the administration of acyclovir (600 mg 5 times daily for 10 days) in patients with herpes zoster ophthalmicus. These benefits were observed even in patients who had a rash present for up to 7 days (44). Topical acyclovir has little proven value in acute keratitis accompanying herpes zoster ophthalmicus. Oral valacyclovir results in acyclovir concentrations in the aqueous humor twice of those after oral acyclovir administration. In a study of 110 immunocompetent patients, valacyclovir (1 gm 3 times daily for 7 days) was as effective as acyclovir (800 mg 5 times daily for 7 days) in preventing complications of herpes zoster ophthalmicus (49). Additionally, the safety and efficacy of famciclovir (500 mg 3 times daily) has also been compared with oral acyclovir and there was no difference in the ocular manifestations in the two groups (204). No data exists to support the use of steroids in these patients and should only be considered with the assistance of an ophthalmologist.

Acute Retinal Necrosis/Progressive Outer Retinal Necrosis: Acute retinal necrosis can occur with varicella or zoster. No randomized trials of therapy have been conducted in acute retinal necrosis. A common treatment regimen administered is intravenous acyclovir (10 mg/kg or 500 mg/m2 per dose) 3 times daily for 7-10 days followed by oral acyclovir 800 mg 5 times daily for 12 weeks. This therapy has been shown to speed the resolution of retinal lesions and decrease the risk of disease in the fellow eye (24). However, it does not prevent the occurrence of retinal detachment and other ocular complications in the initially affected eye. Oral famciclovir or valacyclovir has been successfully used as adjunctive follow-up therapy to intravenous acyclovir or foscarnet (74,144). System steroids administration is also recommended by some experts, but this practice is variable (126,148).

Underlying Diseases

Varicella

Immunocompromised: Intravenous acyclovir is the drug of choice for the treatment of varicella in high-risk patients (164). Acyclovir therapy compensates for impaired host response and terminates viremia and viral replication in skin lesions. Those at risk for progressive varicella include patients receiving immunosuppressive therapy for malignancy, SOT, HCT, autoimmune diseases or other chronic diseases. In children with cancer dissemination occurs in 1/3 of cases (71). Early antiviral therapy reduces the mortality of varicella in immunocompromised patients primarily by reducing the risk or severity of varicella pneumonia. Early placebo-controlled trials of acyclovir showed no effects of the drug on the number of days to defervescence and resolution of cutaneous lesions, but varicella pneumonitis was prevented in the acyclovir recipients (18,164). In a controlled trial of acyclovir and vadarabine in children with cancer and varicella, no evidence of VZV pneumonitis was observed after 2 days of acyclovir therapy whereas 30% of the vadarabine recipients developed pneumonitis (73). The efficacy of acyclovir for the treatment of established VZV pneumonitis or other visceral sites of infection has not been established in controlled trials.

               Prompt diagnosis during the early phase of infection is important to the success of antiviral therapy. In immunocompromised patients, the appearance of the cutaneous lesions may be atypical and the decision to initiate antiviral therapy must be made before progression of the rash becomes obvious, since visceral dissemination may occur at the same time. Intravenous acyclovir therapy should be initiated within the first 24 to72 h after the onset of rash, but importantly, treatment later in the course is also beneficial to inhibit the infection while the host response develops and to treat varicella complications. The dosage of intravenous acyclovir for varicella in high-risk patients is 10 mg/kg/dose (or 500 mg/m2/dose) every 8 h, with administration continuing for 7-10 days or longer, depending on the patient’s clinical response and the degree of his/her immunodeficiency. In milder cases, antiviral therapy can be continued until no new lesions have appeared for 48 h. In immunocompromised patients who fail to clinically respond to 8-hourly doses of intravenous acyclovir, a continuous infusion of a higher dose (2 mg/kg per hour) may be successful (111).

               Although no controlled trials of oral acyclovir, famciclovir or valacyclovir for the treatment of varicella in immunocompromised individuals exist, oral therapy may be sufficient for those taking low-dose cytotoxic chemotherapy or high dose corticosteroids (46). Sequential intravenous and oral acyclovir has been studied in immunocompromised children (38). A switch to oral acyclovir was performed after 48 h providing the child was afebrile, had no new lesions within the past 24 h, and had no visceral involvement; 25 of the 26 children recovered without needing resumption of the intravenous acyclovir (38).

HIV: Varicella infection has been primarily observed in HIV-infected children not adults. Children with HIV are more likely than normal children to develop severe disease and occasional deaths were reported (110). However, in a prospective study of 33 HIV-infected children with varicella, no patients developed disseminated disease even with low CD4 cell counts. HIV-infected children with varicella should be treated with acyclovir, valacyclovir or famciclovir promptly. Oral therapy can be utilized in children with mild disease and high CD4 cell counts providing they are observed carefully. If the child fails to improve then intravenous acyclovir should be implemented. Treatment course is usually 1-2 weeks, depending on the clinical course of the patient (82).

Herpes Zoster

Immunocompromised: Herpes zoster infection in immunocompromised patients has an increased risk for cutaneous and visceral dissemination. Without antiviral treatment, 6-26% of immunocompromised patients would develop cutaneous dissemination and 10-50% of these patients will further develop visceral dissemination (86). Intravenous acyclovir (10 mg/kg every 8 h or 500 mg/m2 every 8 h in children) is the standard therapy for severely immunocompromised patients with localized herpes zoster. Therapy should continue until there have been no fresh cutaneous lesions for 3 days (usually a 7-14 day course). Intravenous acyclovir decreased the risks of cutaneous or visceral dissemination of the disease (16) and a further study (190) conclusively showed acyclovir to be more effective than vadarabine at preventing dissemination of the disease, at 0% versus 50%, respectively. In a study enrolling only HCT patients with localized herpes zoster, Meyers et al. showed that intravenous acyclovir treatment resulted in a shorter time to cessation of new lesion formation, more rapid crusting and healing as well as prevention of cutaneous and visceral dissemination (141). Although early acyclovir treatment is likely to produce the best results, clinical benefit can still occur when therapy is delayed for more than 3 days (16). Relapse of herpes zoster is occasionally observed in HCT patients who are treated with acyclovir (190), but most of them respond to a second course of acyclovir treatment.

               Oral acyclovir may be used in selected patients with minimal degrees of immunosuppression and localized herpes zoster. Ljungman et al. studied 27 HCT patients with localized zoster and reported similar effectiveness of intravenous and oral acyclovir (132). Some experts recommend that patients receiving intermittent or continuous high dose steroids or low dose cytotoxic chemotherapy (daily cyclophosphamide, methotrexate, 6-mercaptopurine and azathioprine) can receive oral therapy. However, no data exists to distinguish the level of immunosuppression that would allow for oral therapy. Given the low bioavailability of oral acyclovir, a dose of 800 mg 5 times a day is required and adherence might be a concern. Patients receiving oral acyclovir should be monitored for signs of progressive VZV infection and should be treated with the intravenous drug promptly if complications arise.

               Tyring and colleagues demonstrated that oral famciclovir is as effective as oral acyclovir in the treatment of localized dermatomal herpes zoster infection in immunocompromised patients (including HCT, SOT, and cancer patients undergoing chemotherapy and/or radiation). Both groups had similar outcomes and progression to disseminated disease occurred in 3% of the famciclovir group and 8% of the acyclovir group (203).

               Valacyclovir has a 3-5 fold increase in bioavailability as compared to oral acyclovir (22). The safety and efficacy of oral dosages of valacyclovir, 1 gm 3 times daily versus 2 gm 3 times daily, for the treatment of herpes zoster in adult immunocompromised patients was studied in a double-blind study (8). Immunocompromised states in this study included congenital immune deficiency, active internal malignancy, collagen vascular diseases, HCT or SOT, HIV infection or therapy with cytotoxic or immunosuppressive drugs in the previous 3 months. Both dosages were safe and effective therapies for cutaneous healing, reduction of zoster-associated pain and zoster-associated abnormal sensations in the immunocompromised patient population. While famciclovir and valacyclovir are safe and effective alternatives to oral acyclovir, there have not been any randomized trials comparing these drugs to intravenous acyclovir for the treatment of VZV infections in immunocompromised patients. Breton et al. reported a case of herpes zoster in an HIV-infected patient who developed neurologic complications while on valacyclovir therapy, but responded favorably to intravenous acyclovir (30). It is conceivable that only intravenous acyclovir administration can achieve sufficient plasma concentrations to inhibit all VZV wild strains (3,221).

               Cases of multifocal leukoencephalitis caused by VZV have been described in immunocompromised patients (with or without recent cutaneous herpes zoster). Several anecdotal reports had success with prolonged (10 weeks or more), high dose (20 mg/kg every 8 h) acyclovir (162,218).

HIV: HIV-infected patients are at greater risk to develop herpes zoster and have recurrent disease than individuals without HIV infection. However, they rarely develop disseminated disease like other immunocompromised patients. For uncomplicated herpes zoster in HIV-infected patients, oral acyclovir 800 mg 5 times daily is sufficient. However, if patients do not improve then prompt initiation of intravenous acyclovir must occur. In AIDS patients, VZV infections refractory to acyclovir treatment have occasionally been reported (39). Resistance to acyclovir may be secondary to prolonged prophylaxis against zoster with low dose acyclovir (39,156,206). Oral sorivudine has been shown to be of value for herpes zoster in patients with HIV infection but is no longer licensed for use (25,223). For otherwise healthy adolescents and adults, famciclovir and valacyclovir are preferred over oral acyclovir because of better bioavailability and less frequent dosing. These drugs have not been studied in the HIV-infected population in controlled trials, and the experience with these drugs in immunocompromised patients (including HIV-infected) is more limited as compared to oral acyclovir (82).

Progressive Outer Retinal Necrosis: PORN is almost exclusively observed in patients with HIV [reviewed in (13)] and is often refractory to acyclovir or ganciclovir monotherapy with disappointing visual prognosis (20,65,152). A case report witnessed a halt in disease progression and improvement in visual acuity with the use of cidofovir (180), but recent experience with combination therapy has provided greater success. Scott and colleagues (184) treated 7 AIDS patients with parenteral ganciclovir and foscarnet as well as intravitreal ganciclovir and/or foscarnet. Only 2 of the 11 treated eyes with PORN progressed to no light perception. Other recent studies also reported successful treatment of PORN with disease remission and preservation of visual acuity out to 1 year with a combination of ganciclovir implant, intravenous acyclovir (10 mg/kg every 8 h), intravitreal foscarnet (2.4 mg), and highly active antiretroviral therapy (118,236). Intravitreal foscarnet combined with intravenous acyclovir and ganciclovir implant may represent another effective alternative (169).

(Printable Version of Antiviral Therapy for Varicella-Zoster Virus in Special Situations/Underlying Diseases )

Alternative Therapy

               Vadarabine and interferon-alpha were used for varicella and herpes zoster in immunocompromised patients in early clinical trials but have been replaced by acyclovir because it is less toxic, more effective and easier to administer (139,224,226).

               Sorivudine (40 mg once daily for 5 days) was statistically superior to placebo at shortening the time to crusting of lesions, new lesion formation and VZV shedding in varicella in otherwise healthy adults (211). Sorivudine, 40 mg, once daily for 7 days was also effective for HIV-infected adults with acute cutaneous herpes zoster (25). In comparison with oral acyclovir, sorivudine significantly shortened the duration of new vesicle formation in HIV patients. There were fewer recurrences of herpes zoster although no differences were seen in the incidence and duration of pain (25). Another study in HIV patients also showed accelerated healing of cutaneous lesions with sorivudine when compared with acyclovir. However, its clinical development in the U.S. has been terminated because of its lethal interactions with 5FU and the concern that it might be inadvertently administered to patients receiving 5FU, or cepecitabine (which is metabolized to 5FU).

               Brivudine is also effective in the treatment of herpes zoster (54). A single daily dose of brivudine at 125mg was found to be more superior to acyclovir 800 mg 5 times a day in shortening the duration of new vesicles formation and was equivalent to famciclovir 250 mg 3 times a day in terms of efficacy (212,213). All three drugs have similar safety profiles, but brivudine provides a more convenient once-daily dose schedule. However, similar to sorivudine, brivudine can also lead to lethal complications when co-administered with 5FU. This drug is not licensed in the U.S., but is approved for sale in some European countries.

               Treatment with intravenous foscarnet (180 mg/kg/day in divided doses every 8 h or every 12 h) is recommended for the thymidine-kinase deficient, acyclovir-resistant strains of VZV that are sometimes cultured from the chronic lesions of herpes zoster in patients with AIDS or from lesions in immunocompromised patients with prior acyclovir exposure (31,101). Foscarnet has been used successfully to treat VZV pneumonitis in AIDS patients with acyclovir-resistant VZV (176). However, its clinical use is complicated by potential nephrotoxicity and the emergence of resistance (75,129). Cidofovir has been used to treat acyclovir or foscarnet resistant mucocutaneous HSV infection or CMV retinitis failing ganciclovir (34,124) or foscarnet (75,129). It may be considered for treatment of VZV strains resistant to acyclovir and/or foscarnet, but clinical experience is limited. The use of this drug is hampered by its serious side effects, including nephrotoxicity, metabolic acidosis, neutropenia and ophthalmic complications.

Dworkin RH, et al. A Randomized, Placebo-Controlled Trial of Oxycodone and of Gabapentin for Acute Pain in Herpes Zoster. Pain. 2009 Feb 3. [Epub ahead of print]

Combination Therapy

               Continued viral replication during primary VZV infection is more frequently due to impaired host responses than to resistance to acyclovir. There is no evidence that combinations of antiviral drugs may improve clinical outcome, but instead, may increase the risks of adverse drug interactions.

VACCINES Guided Medline Search

Vaccination Against Varicella

               In 1995, a live attenuated varicella vaccine, made from the Oka strain of VZV (VZV_Oka) (196), was licensed for clinical use for administration to healthy children in the U.S. (9,10). Various investigations from the last 10-20 years showed that the overall vaccine effectiveness ranges from 71-100% against varicella and 95-100% against moderately severe and severe disease [reviewed in (188)]. By the end of 2005, over 47 million doses of varicella vaccine were distributed (42). The implementation of universal childhood vaccination led to a decline of varicella incidence by 90% and a decline of related mortality by 66% (149). Varicella-related hospitalization across the US has also decreased by 66% (91,167). Two live, attenuated VZV-containing vaccines are now available in the U.S. for the prevention of varicella: a single-antigen varicella vaccine (Varivax®, Merck & Co., Inc.) and a combination vaccine for measles, mumps, rubella and varicella (MMRV, ProQuad®, Merck & Co., Inc.). Varivax® contains a minimum 3.13 log10 PFUs (plaque forming units) of the attenuated virus. Studies with early versions of combination vaccines noted that the immune response to varicella was diminished when given as combined vaccines than when it was given separately, possibly due to interaction between varicella and the MMR components. Thus, the formulation of ProQuad® uses a higher dose of VZV as compared to Varivax® in order to overcome the interaction with MMR. Each dose of ProQuad® contains a minimum of 3.99 log10 PFUs.

               In 1995, the Advisory Committee on Immunization Practices (ACIP) recommended one dose of varicella vaccine for children aged 12 months to 12 years, but two doses, 4-8 weeks apart, for those aged ≥13 years (40). However, despite a vaccine effectiveness of 85% with the 1-dose regimen, varicella outbreaks have been observed in highly vaccinated school populations (201). Moreover, a 2-dose regimen administered 3 months apart was found more effective than a single injection with a 10-year observation period (123). Therefore, in June 2006, ACIP adopted new recommendations to include a routine 2-dose vaccination program for children, and for all susceptible adolescents and adults, with the goal of further reducing varicella disease and its complications in the U.S. (41). Specifically, children should receive the first dose at age 12-15 months and the second dose at age 4-6 years. A second dose catch-up should be given to children, adolescents, and adults who previously have received 1 dose. All healthy persons aged ≥13 years without evidence of varicella immunity should also be vaccinated with 2 doses, 4-8 weeks apart.

               In general, live vaccines (including varicella vaccines) should not be administered to patients with primary or acquired immunodeficiency, including those with HCT, SOT, malignant neoplasms (e.g. leukemia and lymphoma), high-dose systemic immunosuppressive therapy and congenital or hereditary immunodeficiency. Six cases of disseminated VZV_Oka in immunocompromised patients were reported from 10 years of global postmarketing surveillance (79). However, several groups with altered immunity can be candidates for varicella vaccination. Single-antigen varicella vaccine (not MMRV) should be considered for HIV-infected children with age-specific CD4+ T lymphocyte percentages of 15-24% and adolescents and adults with CD4+ T lymphocytes counts ≥200 cells/µL (41). For patients with leukemia, lymphoma or other malignancies, vaccination against varicella can be considered if their disease is in remission and if their chemotherapy has been terminated for at least 3 months (41). However, the immune status of such patients must be carefully evaluated before the decision of vaccination can be made. Guidelines on the use of varicella vaccines were detailed in the ACIP recommendations (41). Alternative regimens recommended in other countries focus on targeted vaccination of high-risk individuals and their contacts (135,175).

Adverse Effects

               The safety profile of the varicella vaccine from 1995-2005 has been recently reported (42,79). The vaccine is generally safe and well tolerated. After immunization, some healthy children and adults may develop vesicular rashes. Vesicular rashes that occurred within the first 2 weeks or >42 days after vaccination were more likely due to breakthrough infection by the wild type virus, while rashes that occurred 15-42 days after vaccination were mostly associated with VZV_Oka (79). Breakthrough varicella is usually mild, with only 1% of 5054 reported cases met the regulatory definition of “serious”. The disease is modified to fewer than 50 cutaneous lesions without associated fever in most cases. Secondary transmission of VZV_Oka from vaccinees with vaccine-associated rashes to susceptible household contacts has been reported (79). As mentioned above, VZV_Oka can also lead to disseminated infection in immunocompromised hosts (79). The vaccine virus is inhibited by acyclovir so that episodes of vaccine-related varicella-like illness or herpes zoster can be treated with antiviral therapy if necessary.

               The live attenuated varicella vaccine retains the ability to establish latency in sensory neurons. Cases of herpes zoster confirmed to be due to the vaccine strain have been reported (42,79). However, the extent to which vaccinated individuals would harbor the latent virus with the vaccine strain and the rate of subsequent development of herpes zoster is unclear. Other concerns about universal immunization against varicella include questions about the persistence of immunity, whether decreasing the frequency of exogenous re-exposures to varicella will affect long-term protection or lead to an increase in herpes zoster, and the possibility that more adolescents and adults will be susceptible to varicella.

Vaccination Against Herpes Zoster

               In an individual previously infected with VZV, development of herpes zoster is related to declining cellular immunity and this might be prevented by boosting this immunity with vaccination. A live attenuated VZV vaccine against zoster (Zostavax®, Merck & Co., Inc.) has been approved by the US Food and Drug Administration in May 2006. This vaccine is also prepared from the VZV_Oka strain, the same strain used in the varicella vaccines Varivax® and ProQuad®. Each dose of Zostavax contains a minimum of 4.29 log10 PFUs, with at least 14 times the potency of Varivax® (but similar to ProQuad®). The efficacy of this vaccine in the prevention of herpes zoster in immunocompetent elderly (≥60 years) individuals was evaluated in a double-blind, placebo-controlled trial (155). The vaccine significantly reduced the incidence of herpes zoster and the incidence of PHN by 51.3% and 66.5%, respectively. The burden of illness caused by herpes zoster was also reduced by 61.1%. Adverse events were similar between the two groups except for an increase in mild injection site reactions in the vaccine group (154,155). ACIP now recommends routine vaccination of all persons aged ≥60 years with 1 dose of this vaccine (98). The risk for zoster and its related complications is much greater among immunocompromised individuals. For immunocompetent patients aged ≥60 years who might be anticipating initiation of immunosuppressive therapy, the zoster vaccine should be administered at least 14 days, but preferably ≥1 month, before the initiation of immunosuppressive therapy (98).

Simberkoff MS, Arbeit RD, et al. Safety of Herpes Zoster Vaccine in the Shingles Prevention Study: A Randomized Trial. Ann Intern Med. 2010 May 4;152:545-54.

               Similar to the varicella vaccines, zoster vaccine should not be administered to persons with primary or acquired immunodeficiency. Patients whose leukemia or lymphoma is in remission and who have not received chemotherapy or radiation for at least 3 months can be considered to receive zoster vaccine (98). In general, physicians should carefully assess the immune status of the recipients on a case-by-case basis. Guidelines on the use of zoster vaccine have been published by ACIP (98).

               Since live varicella or zoster vaccines cannot be administered to immunocompromised patients, inactivated or replication-defective VZV vaccines are currently being developed [reviewed in (45)]. In a randomized control trial involving 119 autologous HCT recipients, a heat-inactivated vaccine based on VZV_Oka was given to the vaccine group within 30 days before and again at 30, 60, 90 days after HCT (100). At 1 year post HCT, there was a significantly lower rate of herpes zoster in the vaccine group (13%) as compared to the placebo group (33%). Protection against zoster was found correlated with the reconstitution of VZV CD4 T cell immunity (100). This vaccine is currently under early phase clinical trials in HCT recipients as well as other immunocompromised populations.

Guidelines:  ACIP: Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine.  MMWR, May 2010.

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

               The efficacy of acyclovir treatment of varicella is assessed by the cessation of new lesion formation and recovery of the function of involved organs when infection is disseminated. Immunocompromised patients may exhibit new lesion formation shortly after antiviral therapy for varicella is stopped. Re-treatment may be required in some cases.

               The efficacy of herpes zoster treatment may be judged by the cessation of new lesion formation, by the speed of healing of cutaneous lesions, and by resolution of pain. Attempts have been made to measure the duration of acute pain and postherpetic neuralgia independently but this can be misleading (228,230). Patients are unable to determine when the acute neuritis stops or when the central pain mechanisms begin and merely recognize that they are in pain. Therefore, it is more appropriate, and probably more clinically relevant to measure in any individual the duration of the painful sensations following initiation of therapy.

ADJUNCTIVE THERAPY Guided Medline Search

Treatment of Acute Pain and PHN

               The optimal approach to the management of herpes zoster includes appropriate analgesics to control the acute pain. Severe acute pain is a risk factor for subsequent development of PHN and thus, effective relief of acute pain may further add to the benefits of antiviral therapy in decreasing the risk of PHN. Agents that can been employed for the management of acute pain or chronic pain (PHN) from zoster include opioid analgesics (166,171), steroids (67,231), tricyclic anti-depressants (137,172,215,217), antiepileptics such as gabapentin (168,170), pregabalin (57,174) and divalproex sodium (121). The dosages of these medications that can be used for patients with herpes zoster in conjunction with antiviral therapy were reviewed by Dworkin et al. (58) and are summarized in Table 2.

               Clinical trials of opioid agonists for the treatment of neuropathic pain have been analyzed in a recent meta-analysis (61,62). While short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain, intermediate-term studies demonstrate significant efficacy of opioids over placebo. The efficacy of opioids in the treatment of neuropathic pain associated with PHN have been demonstrated in two studies, which employed oxycodone and morphine (MS contin or methadone), respectively (166,214).

Dworkin RH, Barbano RL, et al. A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster. Pain. 2009 Apr;142:209-17. Epub 2009 Feb 4.

               Administration of corticosteroids during the acute phase has been shown to have some effects on the acute pain of herpes zoster in large double-blind studies (67,231). Studies that added prednisolone to oral acyclovir showed that pain was reduced during the first few days of the illness but there was no effect on the incidence, duration or severity of PHN (67,231). A placebo-controlled study that independently analyzed the effects of acyclovir and prednisone again showed there was no benefit from steroids on the chronic pain but patients given prednisone had significantly less acute pain and returned to work and normal activity more rapidly (227). The use of corticosteroids should be considered for patients with moderate to severe pain and for those with VZV-associated cranial nerves peripheral nerves or CNS involvement (58). Systemic corticosteroids are usually also prescribed in acute retinal necrosis but their role is unclear. The administration of corticosteroids is not without potential hazards, especially in an elderly population with other chronic disorders and caution should be exercised in their use.

               Topical corticosteroids are helpful in aiding the resolution of episcleritis, scleritis or iritis in herpes zoster ophthalmicus (158); otherwise, the use of topical steroids for the treatment of zoster has no evidence base and is not recommended (58).

               Tricyclic antidepressants for the treatment of neuropathic pain associated with PHN have been evaluated and most studies studied the efficacy of amitriptyline (29,137,172,215). In a randomized double-blind trial, amitriptyline and nortriptyline were found to have a similar analgesic action for the treatment of PHN (217). In a more recent randomized, double-blind trial comparing desipramine, amitriptyline, and fluoxetine, Rowbotham et al. reported the best outcome with desipramine, which provided satisfactory relief in 80% of those treated (172). Since amitriptyline has significant side effects, especially in elderly patients, nortriptyline is preferable. Desipramine can also be considered, but it is more sedative that nortriptyline (58).

               Antiepileptics such as gabapentin (21,168,170) and pregabalin (57,78,174,207) can provide significant relief in neuropathic pain, including that associated PHN. In randomized controlled trials, both drugs were found to reduce severity of pain and sleep interference associated with PHN and improved mood and quality of life (57,78,168,170, 207). A single dose of gabapentin at 900 mg also reduced acute pain and allodynia associated with zoster (21). Both drugs have been approved by the U. S. Food and Drug Administration for the treatment of PHN. Pregabalin might be preferable to gabapentin since it can be titrated to an effective dose more rapidly (58). Divalproex sodium is also effective for the management of various painful neuropathies. A randomized double-blind placebo-controlled trial showed that divalproex sodium provided significant pain relief in patients of PHN with very little incidence of adverse reactions (121). However, clinical experience with this drug for PHN is relatively limited.

               Topical application of lidocaine patches or capsaicin (216) can also provide some relief. Medical interventions are often used in combination, or sequentially, because no single approach is beneficial in most patients. Patients with intractable pain despite the approaches mentioned above may consider intrathecal corticosteroids (117,122). The benefits of some other approaches, such as sympathetic blockade, intravenous lidocaine or cryotherapy have not been convincingly demonstrated.

               While acetaminophen or NSAIDs can be used for symptomatic relief in patients with VZV infections, aspirin is contraindicated in varicella because of the risk of Reye syndrome.

PREVENTION OR INFECTION CONTROL MEASURES Guided Medline Search

               VZV is highly contagious, and the risk is of transmission is highest among pediatric populations. While primary infections (varicella) and reactivation (zoster) are mostly self-limited in immunocompetent patients, severe disease may occur, particularly in immunocompromised patients. Thus, guidelines to minimize the risk for nosocomial transmission of VZV have been established (28,41,80) and are reviewed here.

               Transmission of VZV is primarily airborne through aerosolized droplets from respiratory secretions or by direct contact with skin lesions and respiratory secretions. As an enveloped virus, the VZV virion is very labile and is unlikely to be transmitted by inanimate objects. The incubation period can range from 10 to 21 days, but in most cases, the vesicular rash develops in 14 to 15 days. If an individual has received passive immunization with varicella-zoster immune globulin (VZIG or VariZIG), the incubation period may be prolonged to 28 days. Patients with varicella are infectious up to 2 days prior to and about 5 days after onset of rash. Immunocompromised patients may remain infectious for a longer period of time.

               Sources of nosocomial transmission may include patients, hospital staff and visitors, who have varicella or zoster. Nosocomial transmission of VZV infection by airborne route has been clearly documented when VZV infection occurs in susceptible individuals without any direct contact with the index case (219). To minimize nosocomial spread of VZV, all healthcare workers should have evidence of immunity to VZV, such as documented seropositivity. A history of prior varicella or birth before 1980 is not a reliable indicator of immunity. Many institutions, including ours, test all healthcare workers with serologic screening and vaccinate those with negative VZV serology. However, routine testing for seroconversion after 2 doses of vaccine is not recommended, since available commercial assays for VZV serology may lack sensitivity to detect antibody response after vaccination.

               Any patients with varicella or disseminated zoster, or immunocompromised patients with localized zoster should be placed on respiratory precautions and contact isolation for the duration of illness and until all crops of vesicles or lesions are crusted over. Immunocompetent patients with localized zoster do not required respiratory precautions, but should be placed in private rooms. Any susceptible healthcare workers or patients exposed to varicella or zoster should be monitored daily from day 10-21 after exposure for clinical status. Nosocomial exposure may include sharing the same hospital room with an infectious patient or direct face-to-face contact with an infectious person for >5 minutes while indoor (noted some experts define close contact as >1 hour) (4,41). For healthcare workers, those exposed, but without evidence of immunity should be furloughed during this period and receive postexposure vaccination as soon as possible. Vaccination within 3 days of exposure was ≥90% effective in preventing varicella whereas vaccination within 5 days of exposure was approximately 70% effective in preventing varicella and 100% effective in modifying severe disease (7,11,41). Those who have previously received 1 dose of vaccine should receive the second dose provided 4 weeks have elapsed after the first dose. Healthcare workers who develop any signs and symptoms of infection (e.g. fever, skin lesions or constitutional symptoms) should be placed on sick leave immediately.

               For any patients exposed to varicella or zoster, they are regarded as susceptible if they have not had varicella or zoster in the past or if they have a negative varicella serology. If the immune status is uncertain, a varicella serology should be obtained within 4 days post exposure. Postexposure vaccination should be considered for those without evidence of immunity and without any contraindications for vaccination. For high risk patients who have contraindications for vaccination, passive immunization with VariZIG or IVIG should be given within 96 hours post-exposure (see below) and followed very closely (41). If possible, exposed susceptible patients should be discharged as soon as possible. Those must remain hospitalized should be placed on respiratory precautions and contact isolation for the duration for the incubation period (day 10-21 post exposure, or day 10-28 post exposure if received VariZIG).

               If an ambulatory patient with undiagnosed varicella was admitted to a hospital ward and the diagnosis was made only after discharge, then the Infection Control team must determine if any health workers or patients were in close contact with this patient 2 days prior to and about 5 days after onset of rash. Immunocompromised patients may have atypical rash and can remain infectious for a longer period of time. Health workers and patients considered exposed should be managed as above. If the exposed patients are themselves immunocompromised, passive immunization should be given to those with negative VZV immunity. Post-exposure vaccination against varicella is contraindicated in immunocompromised patients. Acyclovir prophylaxis might be considered in very high risk patients after exposure (12,130), but this approach has not been well studied.

               Susceptible patients with exposure to varicella or zoster in the community should not be admitted to the hospital during the incubation period, unless it is a medical necessity or emergency. If admitted, they should be placed in a private room with respiratory precaution and contact isolation for the duration of incubation. Those who must attend clinic or other outpatient settings must be placed in a private room or private waiting area upon arrival. A surgical mask can be placed on the patient and only immune personnel should have contact with such patients.

Passive Immunization: Passive antibody prophylaxis can prevent or modify clinical disease of varicella if administered within 96 hours after exposure (41). It is indicated following exposure of susceptible high risks patients and those with contraindications for vaccination, such as immunocompromised patients, seronegative pregnant women, newborn infants whose mothers have varicella within 5 days before or 48 h after delivery, and hospitalized premature neonates (41). Patients who receive HCT should be considered non-immune, regardless of pervious history of varicella or varicella vaccination (in themselves or in donors). Patients who receive steroids at doses ≥2 mg/kg or a total of 20 mg/day of prednisone or equivalent should also receive passive immunization (41). Passive immunization should be administered within 96 h, and if possible, within 48 h. In the past, passive immunization was through administration of varicella-zoster immune globulin (VZIG), which is prepared from high titer immune human serum. However, its production has been discontinued by its only US licensed manufacturer (Massachusetts Public Health Biologic Laboratories, Boston, MA) and it is no longer commercially available. An investigational product of varicella-zoster immune globulin (VariZIG ) is available under an investigational New Drug application Expanded Access protocol (Cangene Corp., Winnipeg, Canada) (37), but Investigational Review Board approval is required to obtain this product from its sole authorized distributor FFF Enterprises (Temecula, CA; 1-800-843-7477). The dose is one vial (125units)/10kg body weight given intramuscularly or intravenously, with minimum and maximum doses of 125 units and 625 units, respectively. An alternative to VariZIG is IVIG, administered at a dose of 400 mg/kg intravenously. As mentioned above, passive immunization may extend the incubation period of the virus from 10-21 days to 10-28 days.

               Passive immunization is ineffective if given after the onset of varicella and does not always prevent varicella in high-risk patients. Patients should be followed for breakthrough infection and treated with antiviral therapy if symptoms occur. Oral acyclovir (40 mg/kg/day) has been used as an adjunctive measure to VZIG in a small study of children receiving corticosteroid treatment for chronic renal disease (88). Per ACIP recommendations, varicella vaccination should not be given until 5 months after VZIG administration (41). This guideline should also be applicable to passive immunization with VariZIG or IVIG.

Acyclovir Prophylaxis: Oral acyclovir has been given to immunocompetent children during the incubation period for varicella in some small studies (12,130). However, it is not recommended for routine postexposure prophylaxis because of the limited information about its safety and efficacy as prophylaxis. It is possible that treatment before the appearance of the cutaneous lesions interferes with the development of immunity.

               HCT recipients are at high risk of varicella and herpes zoster irrespective of the serostatus of the donor or recipient. The efficacy of acyclovir prophylaxis for preventing recurrent VZV infection in HCT recipients has been evaluated in several studies. The dose and duration of acyclovir used in these studies varied greatly, ranging from 400 mg per day to 3200 mg per day and for durations of 6 months to 12 months (27,113,133,159,185,186,194,198). Overall, most of these studies reported no breakthrough of VZV infection during acyclovir administration as compared to a 30-60% incidence without prophylaxis. However, regardless of the acyclovir dose or duration employed, acyclovir prophylaxis apparently delays but does not prevent VZV reactivation. Most studies showed no overall reduction in VZV infection rate with acyclovir prophylaxis as compared to control groups. For instance, Boeckh et al. studied the efficacy of long-term acyclovir prophylaxis in a double-blind controlled trial (27). Patients who underwent allogeneic HCT were randomized to receive acyclovir 800 mg twice daily or placebo given from 1 to 2 months until 1 year after transplantation. Again, acyclovir significantly reduced VZV infection at 1 year after transplantation, with a hazard ratio of 0.16. However, the postintervention observation at 2, 3 and 5 years showed no statistical difference in VZV infection between the two groups. More recently in a retrospective study with sequential cohorts, Erard et al. reported that prophylaxis given for one year after HCT significantly reduced VZV disease with no evidence of rebound VZV disease (66), but their observation has not been validated by randomized prospective studies.

               Currently, some institutions elect to use acyclovir or related antiviral drugs as prophylaxis to prevent herpes zoster in HCT recipients (26), but such practice is not recommended as routine practice (195). Rather, antiviral prophylaxis may be considered for selected patients at high risk, such as those with T-cell depletion, antithymocyte globulin therapy, anti-CD3 antibody therapy, unrelated or HLA-mismatch transplantation, graft-versus-host disease, or severe immunodeficiency (178,194). For SOT patients, there have been no randomized clinical trials to study the efficacy of acyclovir prophylaxis to prevent VZV reactivation. Some authors have suggested that prophylaxis may be appropriate in SOT patients at increased risk for zoster or disseminated disease, including those who are older than 60 and are receiving high intensity immunosuppression (e.g. antibody treatment of rejection, multi-drug regimen or prednisone dose >0.3 mg/kg) (143). In general, prolonged administration of acyclovir as routine prophylaxis should be avoided to prevent the emergence of resistant VZV strains. Valaciclovir and famciclovir have the benefit of improved oral bioavailability as compared to acyclovir, but there are no data from controlled trials using these newer drugs for VZV prophylaxis.

               In patients with AIDS, recurrent or relapsing herpes zoster is frequent and after the second or third recurrence (or earlier for severe, relapsing infection) acute therapy could be followed by lifelong oral acyclovir prophylaxis at high dosage. Such long-term prophylaxis with oral acyclovir in an attempt to prevent recrudescence of chronic cutaneous VZV infection in HIV-infected patients has been effective in some, but acyclovir-resistant VZV has emerged in others, resulting in clinical disease while on acyclovir prophylaxis (106,131,156). VZV neurological disease has also been reported in AIDS patients receiving oral acyclovir at lower dosages as prophylaxis for HSV (136). Most acyclovir-resistant strains of VZV are thymidine-kinase negative mutants and are thus also resistant to other nucleosides analogues such as penciclovir, ganciclovir or brivudine. Foscarnet is the treatment of choice for acyclovir-resistant VZV. Given the potential problem of viral drug resistance and lack of placebo-controlled studies demonstrating the efficacy of long-term acyclovir prophylaxis in HIV/AIDS patients, acyclovir prophylaxis should not be routine, but should be decided based on individual cases (82).

(Printable Version of Prevention of Varicella-Zoster Virus)

TABLES

Table 1: Antiviral Drugs Used For VZV Infection.

Table 2: Adjunctive Therapy for Post-Herpetic Neuralgia. [Adapted from Dworkin et al. (58)]

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