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Varicella-Zoster Virus and HIV
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Overview
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Epidemiology
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Pathogenesis
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Clinical Syndromes
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transparent imageVaricella
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transparent imageZoster
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transparent imagePneumonitis
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transparent imageEncephalitis
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transparent imageOphthalmic Zoster
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transparent imagePain
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Diagnosis
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Treatment
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transparent imageAnti-VZV Drug Therapy
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transparent imageIntravenous Acyclovir
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transparent imageOral Acyclovir
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transparent imageFamciclovir and Valacyclovir
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transparent imageAntiviral Resistance
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transparent imageSteroids
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transparent imageSpecific Treatment Recommendations
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transparent imagePost-Herpetic Neuralgia
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VZV Vaccine
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Primary VZV Vaccination
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Zoster Vaccination
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References
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Tables
Table 1.Dosage Adjustment of Intravenous Acyclovir in Patients with Renal Dysfunction
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Overview
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Varicella-zoster virus (VZV), a neurotropic herpesvirus, is the causative agent of both varicella (chickenpox) and zoster (shingles). As with the other herpesviruses, VZV causes both acute illness and lifelong latency. Before vaccination became widespread, acute primary infection (varicella or "chickenpox") was common during childhood--especially in temperate climates. Primary infection is much less common in recent years as a result of childhood vaccination, but still may occur in unvaccinated individuals and in instances of vaccine failure. Varicella usually is a benign and self-limiting illness, but can be more severe in adults and in individuals with cellular immunodeficiency. These individuals are at much higher risk of pneumonia and disseminated disease with visceral involvement.

Recurrent VZV infection (zoster or "shingles") occurs with advancing age in immunocompetent hosts, but may occur earlier in immunocompromised hosts as a result of decreased specific VZV immunity. Zoster typically presents as a painful, localized cutaneous eruption occurring along 1 or more contiguous dermatomes. As with varicella, zoster usually is self-limited in the immunocompetent host, but immunocompromised persons are at risk of more severe illness with cutaneous or visceral dissemination.(1,2) Pain is a frequent complication of zoster, and pain that persists following complete healing of cutaneous lesions, referred to as postherpetic neuralgia, can be debilitating and difficult to control.

Persons with HIV infection are at risk of developing severe illness from either varicella or zoster. HIV-infected patients with active, symptomatic VZV infection usually require specific antiviral chemotherapy; hospitalization may be necessary in some cases. Acyclovir, valacyclovir, and famciclovir are the antiviral therapies of choice for most VZV infections.(3-14) Intravenous foscarnet is effective for patients with acyclovir-resistant VZV infections.(15-18) Administration of the varicella vaccine to prevent primary infection is an important strategy to protect children and adults who have not had prior VZV infection. The vaccine can be given to HIV-infected patients who have CD4 T-lymphocyte counts of >200 cells/µL despite the theoretical risk of live-virus vaccination in this population.(19-23) A high-titered VZV vaccine to prevent reactivated VZV disease also is available for adults, but is not specifically recommended for immunocompromised patients such as those with HIV infection.(24)

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Epidemiology
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Humans are the only known natural hosts of VZV. Transmission of VZV occurs through direct contact with infectious lesions or by inoculation of aerosolized infected droplets onto a susceptible mucosal surface. The virus is transmitted easily; the rate of secondary cases of varicella in susceptible household contacts typically exceeds 90%. Infectivity usually begins 1-2 days before the onset of rash, and patients remain infectious until all vesicular lesions are dried and crusted. In the immunocompetent host, the period of infectiousness is usually 5-7 days after the lesions first appear.(1,2) In immunocompromised patients, however, healing can be slow and patients may remain infectious for up to several weeks. (25-34)

Because varicella is primarily a disease of childhood in temperate climates, most HIV-infected patients born in the United States and Europe either have been infected with VZV already or have been vaccinated, and are not susceptible to primary infection. Individuals born in tropical and subtropical areas often escape primary infection during childhood, however, and HIV-infected patients from Africa, Haiti, and other equatorial areas are more likely to be susceptible to primary VZV infection. (35)

In the immunocompetent host, the risk of recurrent VZV infection (zoster) increases with advancing age, with the highest incidence occurring between the ages of 50 and 80. A person’s lifetime risk of herpes zoster infection is 15-20%, with the highest incidence occurring in the elderly and in immunocompromised persons. HIV-infected patients are at higher risk of developing zoster than age-matched, HIV-uninfected individuals.(36) Zoster may occur at any time in the course of HIV-induced immunosuppression, and may be the first clinical clue to suggest undiagnosed HIV infection. An episode of zoster in a young individual warrants consideration of underlying HIV infection. Recurrent episodes of zoster also may occur in HIV-infected patients, and appear to be more common than in the HIV-uninfected population.(37,38)

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Pathogenesis
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Primary VZV infection occurs following inoculation of infected airborne droplets onto a mucosal surface of a previously uninfected individual. Initial virus replication occurs in tonsillar and lymphoid tissue, and is followed 4-7 days later by primary viremia. Virus spreads to internal organs, and a secondary, more prolonged viremic stage occurs 10-21 days after the initial infection. Virus reaches the skin surface during the secondary viremia, and results in the characteristic vesicular rash of varicella.(1,2)

Successive crops of new vesicles occurring over the course of several days are typical during varicella, attesting to the waves of viremia that occur during the acute illness. New lesion formation ceases with the appearance of circulating serum antibody and a detectable immune response, usually 1-5 days following onset of the illness in the immunocompetent host. In HIV-infected individuals and others with a compromised immune system, prolonged viremia and an extended duration of new lesion formation may occur.(39-41)

During primary infection, VZV enters cutaneous endings of sensory nerves and migrates centripetally along nerve fibers to reach sensory nerve ganglia. Latency is established within these sensory ganglia by incorporation of virus nucleoprotein within ganglionic cells, and latency is maintained through intact cellular immune mechanisms.(42) With the waning of VZV-specific cellular immunity as a result of advancing age or immunosuppression, virus may reactivate and travel peripherally along sensory nerves to reach the mucocutaneous surface that is innervated by the ganglia in which the virus reactivated. Although uncommon, disseminated zoster with viremia and infection of distant cutaneous or visceral sites may occur; this may be more common in patients with cellular immunodeficiency such as those with advanced HIV infection.(25-34) Because several ganglia become latently infected during primary VZV infection, reactivation of more than 1 ganglion can occur, with zoster involving more than 1 noncontiguous dermatome.(42)

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Clinical Syndromes
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Varicella
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The rash of primary VZV infection (varicella) appears at an average of 14 days after infection (range of 10-21 days). Prodromal symptoms often occur in adults 1-2 days before the appearance of the rash, and may include malaise, low-grade fever, and myalgia. Skin lesions begin as small erythematous macules and progress over the course of 12-36 hours to become papules and true vesicles. Lesions typically appear initially and are most numerous on the face, trunk, and neck; fewer lesions appear on the extremities. Vesicles are variable in size and shape. They are filled with straw-colored fluid and rest on an erythematous base. The vesicles ulcerate, dry, and form crusts and scabs. Pruritus is often present and can be severe, resulting in excoriation and a risk of secondary bacterial infection. Lesions in all stages of development (macules, papules, vesicles, ulcers, and crusts) are characteristic of varicella, and they result from the successive waves of viremia occurring during the first few days of illness.

HIV-infected patients with primary varicella are at risk of prolonged new lesion formation and are at increased risk of extensive cutaneous involvement, secondary bacterial infection of skin lesions, and life-threatening visceral dissemination.

Varicella can be confused with other exanthems, but the centripetal distribution of the rash and the presence of lesions in all stages of development are clues that VZV is the etiologic agent. The differential diagnosis in a patient with suspected varicella includes other viral infections (measles, coxsackievirus, rubella, disseminated HSV), rickettsial infections (Rocky Mountain spotted fever, typhus), secondary syphilis, bacterial infections, adverse drug reactions, systemic allergic reactions, and infestations such as scabies.

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Zoster
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Reactivated VZV infection (zoster or shingles) may occur at any stage of HIV infection, and may be the first clinical evidence of HIV infection. Zoster typically begins with local pain and discomfort, and then progresses to a localized or segmented erythematous, maculopapular eruption along a single dermatome. Lesions evolve to vesicles, pustules, and crusts. Vesicles often become confluent, and bullae may form. Although zoster usually remains localized and resolves spontaneously, it can result in significant and persistent pain as well as cutaneous scarring. In immunocompromised hosts, zoster lesions may be particularly bullous, hemorrhagic, necrotic, and painful. Blisters and crusts usually last 2-3 weeks, and necrotic lesions may last for up to 6 weeks and result in significant scarring. HIV-infected persons are at risk of recurrences, which may be more severe with increasing immunosuppression. (32,38)

Diagnostic clues in a patient with suggestive findings include the presence of lesions and sensory symptoms that do not cross the midline, and pain or sensory signs that are characteristic of nerve injury. Dissemination of zoster outside the dermatomal pattern can make the diagnosis of zoster difficult, and cutaneous dissemination may resemble other exanthems.

A less-common manifestation of VZV infection in HIV-infected individuals is persistent, chronic zoster, with lesions that either fail to clear with antiviral therapy or immediately recur after treatment is completed. These patients may develop drug-resistant VZV, with resistance owing to selection of thymidine kinase-deficient or thymidine kinase-altered viral strains under the selective pressure of antiviral drug therapy. (15-18)

Patients with advanced HIV infection may present with prolonged lesion formation, progressive local extension, and viral dissemination.(25-34,41-43) Cutaneous dissemination can result in hundreds of vesicles outside the primary dermatome and may be difficult to distinguish from primary varicella.(25) Disseminated VZV infection may appear as widespread blisters with or without an associated dermatomal eruption, or may present as widespread ecthymatous ulcers or hyperkeratotic verrucous lesions. The verrucous pattern is more often seen with prolonged infection that has been treated with acyclovir. (15-18) VZV strains cultured from verrucous lesions in patients who do not respond to acyclovir therapy are often thymidine kinase-deficient or thymidine kinase-altered mutants of VZV that are resistant to acyclovir and other antiviral agents.

Despite having a severely impaired immune system response, however, the majority of HIV-infected patients with zoster do not develop these life-threatening complications, and most patients have an uncomplicated clinical course.

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Pneumonitis
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All adults with chickenpox, including HIV-infected patients, are at risk of varicella pneumonia; the risk is especially high for pregnant women with varicella. Varicella pneumonia is much less common in children. Although many patients have only mild respiratory symptoms, severe pulmonary involvement (with hypoxemia, cyanosis, and death) can occur. For this reason, all adults with chickenpox should be followed closely for respiratory symptoms. Chest radiography is warranted for patients who experience dyspnea, cough, or other respiratory symptoms. Radiographic abnormalities in VZV pneumonia are more pronounced than are clinical signs and symptoms, and they include diffuse coalescent nodular densities.

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Encephalitis
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Encephalitis is a rare complication of VZV infection. Symptoms usually develop 3-8 days after onset of chickenpox and 1-2 weeks after development of zoster.(29) Encephalitis occurs more frequently with zoster in the ophthalmic distribution, and cerebellar findings are typical, including ataxia, tremors, and dizziness. Corticocerebral involvement may result in headache, vomiting, and lethargy. Cerebrospinal fluid (CSF) findings usually are nonspecific, showing mononuclear pleocytosis, elevated protein concentration, and negative viral cultures. Diagnosis can be made most reliably by demonstration of VZV nucleoprotein in CSF through polymerase chain reaction (PCR) testing.

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Ophthalmic Zoster
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Zoster of the ophthalmic division of the trigeminal nerve can result in permanent visual loss. Pain may precede the development of skin lesions, and may be severe. Skin lesions may be extensive and confined to the affected dermatome with involvement of the conjunctivae, cornea, and other eye structures. Virus infection and inflammation of eye structures can result in anterior uveitis, corneal scarring, acute retinal necrosis, and severe postherpetic neuralgia.(1-25,28) Rapidly progressive outer retinal necrosis and acute retinitis are feared ocular manifestations of VZV disease in patients with HIV infection, and they respond poorly to therapy.(44-46)

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Pain
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Pain, described as burning, stabbing, or aching, is a common complication of zoster. Although acute pain may resolve as the skin lesions heal, pain may persist long after healing has occurred (postherpetic neuralgia). Postherpetic neuralgia can be severe and disabling, and it results in significant long-term morbidity in HIV-infected patients. (47-49) The risk of postherpetic neuralgia increases with age, and is more likely to occur in elderly patients than in younger individuals.

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Diagnosis
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The diagnosis of VZV infection often is suspected on the basis of clinical presentation, but laboratory studies may be required for confirmation. Testing options include virus culture, antigen detection, nucleoprotein detection, and serology. In most instances of cutaneous manifestations, the diagnostic procedure of choice is the demonstration of virus antigens on cells obtained directly from cutaneous lesions. Scrapings obtained from the lesions are stained with specific fluorescein-conjugated monoclonal antibodies. The technique is rapid, relatively inexpensive, and reliable.(1,2)

Virus culture is less sensitive than direct antigen staining in the diagnosis of VZV. Unlike herpes simplex virus (HSV), VZV remains highly cell associated in tissue culture and is not released in high titer into the overlying media. Cytopathic effects develop slowly in tissue culture, and culture results typically are not available soon enough to be clinically useful. A virus culture in a patient with suspected VZV infection often is obtained to exclude the presence of HSV.(1,2)

Staining scrapings to demonstrate multinucleated giant cells (Tzanck preparation) is less sensitive than antigen detection and cannot differentiate VZV from other herpesvirus infections, such as HSV and cytomegalovirus.

Serologic testing can determine whether a patient has prior VZV infection, but it usually is not useful in the evaluation of a patient with an acute illness suspected as attributable to VZV. Serologic testing is indicated when immunity to VZV must be determined, as in an HIV-infected patient without a history of chickenpox. When performed, serologic testing should involve fluorescent-antibody-to-membrane-antigen (FAMA) or enzyme immunoassay (EIA) techniques. Complement fixation is not used, because this assay yields a negative result after resolution of acute infection.(1,2)

Detection of VZV nucleoprotein by PCR is sensitive but more costly than other testing options. This assay is most useful when applied to CSF in patients with suspected VZV central nervous system infection.

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Treatment
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Antiviral treatment for varicella or zoster in the HIV-infected patient should begin as early as possible once the infection is identified. Treatment of severe or disseminated VZV infection usually mandates hospitalization and intravenous acyclovir. Many HIV-infected patients with varicella or zoster do not require hospitalization, however, and outpatient therapy for these individuals may be appropriate. Whether a patient requires inpatient or outpatient therapy should be determined on the basis of the extent and severity of the infection, the immune status of the host, and whether visceral or cutaneous dissemination has occurred.(3-12)

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Anti-VZV Drug Therapy
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Intravenous Acyclovir
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The serum levels of acyclovir necessary to inhibit the replication of VZV are about 10 times greater than those needed to inhibit HSV, so the dosage of acyclovir must be higher than that used for treatment of HSV. The dosage of intravenous acyclovir for the treatment of VZV infection is 10 mg/kg every 8 hours. Because acyclovir is eliminated primarily by glomerular filtration, adequate hydration should be maintained to prevent crystallization of the drug in the renal tubules, and the dosage must be adjusted for renal dysfunction (Table 1).(10) Studies have shown that early administration of acyclovir decreases the duration of viral shedding, the extent of new lesion formation, the incidence of dissemination, and patient mortality in those with VZV infection.(3,7)

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Oral Acyclovir
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Oral acyclovir in the dosage used for HSV infection results in steady-state serum levels that are too low to inhibit VZV. High dosages of oral acyclovir (800 mg 5 times daily) are needed to produce serum levels that are adequate to treat VZV infection in adults.(4-6,8-12)

Oral acyclovir is effective for the treatment of chickenpox in both immunocompetent children and adults, and it reduces the total number of lesions, duration of fever, and duration of illness as compared with placebo treatment. (8,9,11) Treatment should begin within 24 hours of the onset of the skin rash for maximal efficacy, but is likely to be effective even if initiated while new lesions continue to occur.

Treatment of zoster with oral acyclovir (800 mg 5 times daily) is effective in accelerating skin healing and preventing virus dissemination,(3-7,50)and it also may reduce the risk of postherpetic neuralgia.(12) For optimum benefit, treatment should begin as soon as possible (preferably within 72 hours of onset of the skin rash) and continue for at least 7 days or until all lesions have dried and crusted.(51)

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Famciclovir and Valacyclovir
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These oral antiviral drugs have improved bioavailability compared with acyclovir and result in higher antiviral serum levels. Both agents have good in vitro activity against VZV.

Famciclovir 500 mg 3 times daily results in accelerated healing of zoster lesions and faster resolution of acute pain, compared with placebo.(13)

Valacyclovir, a prodrug of acyclovir, achieves serum levels 3-5 times greater than those resulting from administration of oral acyclovir. Compared with oral acyclovir, valacyclovir 1 g 3 times daily significantly accelerated the resolution of "zoster-associated pain," and fewer valacyclovir-treated patients continued to have pain 6 months later.(14) Of note, however, high-dose oral valacyclovir (8 grams per day) has been linked to thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in severely immunocompromised patients. For this reason, valacyclovir dosing should not exceed 1 g 3 times daily.(52)

Both famciclovir and valacyclovir are excreted by renal mechanisms, and dosage adjustment of both medications is required for patients with renal dysfunction.(51)

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Antiviral Resistance
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Persistent disseminated VZV infection that fails to respond to intravenous or oral acyclovir has been described in patients with advanced HIV infection.(15-18) These patients developed disseminated hyperkeratotic papules, often in the setting of chronic or repeated acyclovir therapy. When tested in vitro, virus strains isolated from these lesions have been resistant to acyclovir on the basis of altered or deficient activity of viral thymidine kinase, an enzyme necessary to activate acyclovir by phosphorylation.(15-17) Because cross-resistance to both famciclovir and valacyclovir is to be expected, these agents should not be used in the setting of proven or suspected acyclovir resistance. Intravenous foscarnet should be considered for acyclovir-resistant VZV infection, although careful study has been limited by the rarity of this condition(18)

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Steroids
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Treatment with corticosteroids for patients with zoster to prevent postherpetic neuralgia remains a matter of controversy. One trial demonstrated that administration of corticosteroids in combination with an effective antiviral agent reduces acute pain and improves the quality of life for immunocompetent patients ≥50 years of age, but has no effect on the presence of postherpetic neuralgia 6 months later.(53) In view of the potential risk of virus dissemination while on steroids, HIV-infected patients with zoster should not be treated with steroids alone, but treatment with a combination of tapering steroids and an effective antiviral regimen could be used cautiously for individuals at high risk of postherpetic neuralgia.

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Specific Treatment Recommendations
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Prompt initiation of antiviral therapy is indicated for all HIV-infected patients with varicella or zoster. Treatment should begin as soon as possible to be maximally effective, and it may consist of oral acyclovir, intravenous acyclovir, oral famciclovir, or oral valacyclovir. Intravenous acyclovir (10 mg/kg every 8 hours with dosage adjustment for impaired renal function) is indicated for patients with primary varicella complicated by visceral involvement, ophthalmic zoster, or disseminated recurrent zoster (cutaneous or visceral). Patients with severe localized zoster also may require hospitalization and intravenous acyclovir therapy, especially if parenteral analgesia for pain control is required or if high-dose oral acyclovir is not tolerated.

Patients with localized dermatomal zoster who do not require hospitalization can be treated with oral acyclovir 800 mg 5 times daily, famciclovir 500 mg 3 times daily, or valacyclovir 1 g 3 times daily. Therapy should be initiated within 72 hours of the onset of symptoms, if possible, but can be started any time before all lesions have crusted; it should be continued for 7-10 days or until all external lesions are crusted, whichever is longer.

Steroids should be used cautiously, if at all, for patients with VZV infection and always with an effective antiviral drug for patients with HIV infection who develop zoster, because of the potential for virus dissemination.

For HIV-infected patients who develop recurrent VZV lesions when antiviral therapy is discontinued, chronic suppressive acyclovir 400-800 mg 3-5 times daily, famciclovir 250 mg 3 times daily, or valacyclovir 500 mg 3 times daily may be helpful. For documented acyclovir-resistant VZV infection, intravenous foscarnet 40-60 mg/kg every 8 hours, with adjustments for renal failure, should be prescribed.(54)

Proper local care of cutaneous lesions is important for preventing secondary bacterial or fungal infection in patients with varicella or zoster. Lesions should be kept clean and dry whenever possible. Necrotic areas can be debrided gently with "wet-to-dry" saline dressing changes. Empiric antibacterial or antifungal therapy usually is not indicated, but areas suspected of being secondarily infected should be evaluated by Gram stain and culture for bacteria and fungi. Treatment of secondary bacterial or fungal infection is instituted, if necessary, on the basis of clinical suspicion and identification of the pathogenic organisms.

Proper local care of cutaneous lesions is important to prevent secondary bacterial or fungal infection in patients with varicella or zoster. Lesions should be kept clean and dry whenever possible. Necrotic areas can be gently debrided with "wet-to-dry" saline dressing changes. Empiric antibacterial or antifungal therapy is usually not indicated, but areas suspected of being secondarily infected should be evaluated by Gram stain and culture for bacteria and fungi. Treatment of secondary bacterial or fungal infection is instituted, if necessary, on the basis of the identification of the pathogenic organisms.

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Post-Herpetic Neuralgia
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Postherpetic neuralgia can be severe and incapacitating, and may be a major source of morbidity in some patients with advanced HIV infection. Several types of treatment are available, but no comparative trials have been published to assist in selection of therapy. Most patients with postherpetic neuralgia have gradual improvement in symptoms with time.(47-49)

Treatment options include nonnarcotic analgesics, narcotics, gabapentin, pregabalin, anticonvulsant agents (phenytoin and carbamazepine), tricyclic antidepressants (amitriptyline, desipramine), phenothiazines, cimetidine, and topical capsaicin.(55,56,57)

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VZV Vaccine
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Two attenuated live VZV vaccines currently are licensed for use in the United States. These vaccines contain the identical attenuated strain of VZV in different amounts and have separate clinical indications.

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Primary VZV Vaccination
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The vaccine used to prevent primary VZV infection (Varivax) is given as 2 doses 1-3 months apart. Studies show that this strategy protects against primary VZV infection, but 2 doses are needed. Patients with an uncertain history of prior VZV infection should be screened serologically before vaccination to determine whether immunity is present. Because the vaccine is composed of a live virus, latency occurs after vaccination and recipients are at risk of developing zoster from the vaccine strain.(23) On the basis of safety and immunogenicity data, the Advisory Committee on Immunization Practices recommends that physicians consider vaccinating HIV-infected children ≥12 months of age who are in U.S. Centers for Disease Control and Prevention (CDC) clinical class N, A, or B and have CD4 T-lymphocyte percentages of ≥15% and no evidence of varicella immunity. These HIV-infected children should receive 2 doses of Varivax 3 months apart. The duration of protection afforded by the vaccine remains a matter of investigation, and vaccinated individuals may require additional booster doses later in life. Owing to the theoretical risk of virus dissemination from this live-virus vaccine, patients should be evaluated promptly if a postvaccination, varicella-like rash develops, and initiation of antiviral therapy should then be considered. Data on the use of varicella vaccine in HIV-infected adolescents and adults are lacking, and the immunogenicity may be lower in this group of HIV-infected individuals. However, based on expert opinion, vaccination (2 doses administered 3 months apart) of HIV-infected persons >8 years of age who are in CDC clinical class A or B and have CD4 T-lymphocyte counts of ≥200 cells/µL may be considered. If a vaccinated HIV-infected individual develops clinical disease following vaccination (such as a chickenpox-type rash), systemic antiviral therapy should be used to modify the disease.(19,23,58,59-61)

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Zoster Vaccination
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In immunocompetent hosts who are ≥50 years of age, the vaccine reduces the risk of developing zoster and postherpetic neuralgia. Owing to the theoretical risk of virus dissemination from this live-virus vaccine, zoster vaccine is not routinely recommended for patients with HIV infection (note that the vaccine used to prevent reactivated VZV disease [Zostavax] contains 14 times the amount of virus as the vaccine to prevent primary infection). The safety and efficacy of zoster vaccination in HIV-infected patients with CD4 counts of >200 cells/µL has not been demonstrated,(59,62) though studies are under way. Some clinicians choose to offer the vaccine to HIV-infected persons who are >50 years of age and have good HIV control and CD4 counts of >200 cells/µL; however, zoster vaccination should be avoided in patients with CD4 counts of <200 cells/µL. For HIV-infected patients who do not have a history of primary varicella or evidence of antibody protection, it may be advisable to vaccinate against primary varicella (using the lower dosage of Varivax vaccination; the higher-dose zoster vaccine should be avoided). If an HIV-infected adult receives zoster vaccine and a postvaccination, varicella-like rash occurs, a prompt evaluation should be made and consideration should be given to starting antiviral therapy.

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References

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