THE OI REPORT: A Critical Review of the Treatment & Prophylaxis of AIDS-Related Opportunistic Infections (OIs)

VARICELLA ZOSTER VIRUS (VZV)
by Paul Dietz

INTRODUCTION
Varicella zoster virus (VZV), a member of the human herpesvirus family, is the cause of both chicken pox (varicella) and shingles (herpes zoster). Like other members of the herpesvirus family, VZV is not eliminated from the body after the acute illness but remains in a latent state for the life of the host. While antibodies generally prevent the recurrence of chickenpox, latent VZV can reactivate to cause herpes zoster, a more localized cutaneous (skin) disease which is commonly referred to as shingles. Zoster is a painful blistering skin rash, usually confined to either the trunk, forehead, or scalp. In a minority of zoster patients -- mostly the elderly -- severe pain may persist after resolution of the zoster skin lesions.

VZV reactivation (zoster) is very common in people with AIDS (PWAs), and it is frequently among the first opportunistic infections (OIs) to emerge. Due to the strong correlation between the reactivation of VZV and immunodeficiency, an episode of zoster in an otherwise healthy person provides grounds to suspect an underlying HIV infection (Melbye 1987).

While most PWAs with zoster suffer only one self-limiting course, up to a quarter of PWAs with zoster experience repeated episodes (Colebunders 1988) which may be more severe and resistant to treatment depending on the extent of immunosuppression. Visceral (internal organ) complications of herpes zoster have been reported to occur in 20% of immunocompromised patients, though treatment is believed to reduce the risk of complications considerably (Whitley 1982). In patients with HIV, such complications most often involve the eye or central nervous system (CNS) (Sharon Safrin, personal communication). Patients developing certain ocular complications of VZV are at risk of permanent vision damage (Cole 1984; Pinnolis 1995). Though rare, CNS involvement (i.e., VZV myelitis and encephalitis) represents a potentially fatal condition (Drew 1995).

EPIDEMIOLOGY
VZV seropositivity exceeds 90% for adults living in the United States (Gershon 1981). VZV is spread through oral-nasal absorption of airborne antigens or by direct physical contact with infectious lesions. Exposure can come from someone with chickenpox or shingles. Patients are thought to be infectious from two days preceding the rash up to the point that all lesions have crusted over (Erlich 1995).

A vaccine for chicken pox has been approved by the FDA for immunocompetent patients and for immunosuppressed children with acute lymphocytic leukemia. The vaccine is not currently given to children with HIV because there is concern that the active, attenuated virus contained in the vaccine may cause disease (Drew 1990). However, a clinical trial to test the vaccine in HIV-positive children, ACTG 265, is underway. The Public Health Service recommends that HIV-infected patients with no history of varicella who have recently been exposed at close contact (within 96 hours) to someone with chickenpox or shingles receive varicella zoster immune globulin prophylaxis.

Zoster is not newly acquired, but represents the reactivation of an existing latent infection. Therefore, contact with an actively infected individual (whether the infection is primary or secondary) is not believed to cause another person's dormant VZV infection to reactivate. The incidence of zoster in the general population is moderate (1.3 episodes per 1,000 person years) (Ragozzino 1982), though it occurs more frequently in people with weakened immune systems such as PWAs and cancer patients who have been exposed to immunosuppressive chemotherapeutic agents (Melbye 1987). A high incidence of zoster is also seen in the elderly, presumably as a result of declining immune status (Waldman 1990).

An observational study of 1,246 HIV-infected patients with CD4 counts of less than 300 found that VZV occurred at rates between 2 and 4 episodes per 100 person-years (Moore 1996). Furthermore, a retrospective review of 300 AIDS patients with Kaposi's sarcoma noted that 8% of those patients had at least one prior attack of zoster (Drew 1990). There is no established prophylaxis for herpes zoster.

PATHOGENESIS
Two weeks or so following initial infection, varicella lesions emerge in the form of small red blemishes on the skin, progressing over one to three days while they become fluid-filled vesicles. Lesions can surface anywhere on the body but tend to concentrate on the face, neck, and trunk. The patient may experience fatigue and flu-like symptoms before and during the outbreak. In the majority of HIV-infected patients receiving treatment, new lesion formation ceases within four days (FDA Data 1996).

In the face of an effective immune response, VZV retreats through cutaneous nerve endings to establish latency in the dorsal root or cranial nerve ganglia. Laboratory studies have discovered latent VZV in the thoracic dermatomes, cervical region, trigeminal nerve, and lumbo-sacral region (Waldman 1990). Multiple ganglia can be infected simultaneously (Mahalingam 1990).

Reactivation of zoster is first characterized by specific symptoms, including pain and hypersensitivity near the affected area. After a few days, a rash emerges in the form of a band or patch of raised, fluid-filled reddish-looking vesicles, often around the head or trunk. New vesicle formation ceases in roughly four to five days, and the rash and pain disappear within three to five weeks for most HIV-positive patients receiving proper treatment (FDA Data 1996).

DIAGNOSIS
Cutaneous varicella or zoster is usually simple to diagnose. Zoster lesions demarcate the distribution of the underlying nerve region, and pain and sensory symptoms characterize nerve involvement. In cases of doubt resulting from disseminated VZV, an atypical lesion pattern, or when scalp lesions are difficult to observe, VZV can be isolated from vesicular fluid by culture or stained with a flourescent monoclonal antibody test kit. This may take up to two weeks. Serological testing is not helpful since much of the population has previously been exposed to chickenpox (Erlich 1995).

OTHER CLINICAL MANIFESTATIONS

Post-Herpetic Neuralgia
One of the most troublesome complications of herpes zoster is post-herpetic neuralgia (PHN), a condition characterized by severe, unremitting pain and hypersensitivity remaining for a significant period beyond the resolution of zoster skin lesions. PHN can be debilitating and may cause psychological trauma and depression in its sufferers (Waldman 1990). The risk of PHN is associated more with advanced age than with immune status (Bruxelle 1995). Nevertheless, some researchers believe that prompt (within 48 hours of the first outbreak of rash), effective treatment of an acute zoster outbreak reduces the duration of zoster-associated pain in the normal host (Boon 1995).

The symptoms of post-herpetic neuralgia are often treated with antidepressants (such as amitriptyline), nerve blockers, narcotic analgesics, and/or topical pain relievers (Waldman 1990; Watson 1995). Though such treatments may bring only partial relief, some patients experience gradual resolution of pain over time (Bruxelle 1995).

VZV Infections of the Eye
Primary varicella and herpes zoster involving the ophthalmic division of the trigeminal nerve can affect the eye. The eye infection may or may not occur in conjunction with a cutaneous outbreak. Symptoms include floating spots, loss of vision, and a high incidence of retinal detachment (Neger 1996). VZV-associated progressive outer retinal necrosis is a sight-threatening condition which is difficult to treat (Pinnolis 1995). Patients may also develop keratitis, anterior uveitis, or corneal scarring, which can lead to permanent visual loss.

Limited treatment options include, intravitreal injections (injecting medication directly into the eye) and/or intravenous (IV) ganciclovir or foscarnet (Cochereau 1995). There has also been at least one reported case of success in treating VZV-associated progressive outer retinal necrosis with a combination of IV ganciclovir and oral sorivudine (see investigational treatments below) in a PWA who had failed standard therapy (Pinnolis 1995). However, sorivudine is no longer under development by its licensee Bristol-Myers Squibb.

VZV Encephalitis and Myelitis
These potentially fatal complications of VZV are very rare. It tends to occur in conjunction with ocular or viscerally disseminated VZV. In an observational study of 626 PWAs with central nervous system manifestations, only four (0.5%) resulted from VZV (Bossi 1996). PWAS have reportedly developed VZV-related neurological disease up to three months after the onset of localized zoster (Ryder 1986). Symptoms include headache, vomiting, lethargy, tremors, and dizziness (Drew 1990). Diagnosis is often aided by the presence of cutaneous zoster. With encephalitis, a brain scan often reveals a multifocal infection of white matter or vasculitis. Gershon and colleagues reported success in serological testing for VZV antibody in the cerebrospinal fluid (Gershon 1980), though this is not a universally accepted practice. More recently, positive results in detecting VZV in cerebrospinal fluid (CSF) with polymerase chain reaction (PCR) have been documented (Burke 1996).

VZV Pneumonia
Though not often seen in patients with HIV, pneumonia may result from primary varicella or secondary zoster, and its severity can range from mild respiratory symptoms to potentially life-threatening hypoxemia (low concentration of oxygen in the blood) (Erlich 1995).

TREATMENTS FOR VZV

Acyclovir (Zovirax™, Glaxo Wellcome)
Acyclovir is considered first-line therapy for primary varicella or herpes zoster (Balfour 1994). It has been used by more than 30 million patients to date and has been shown to reduce the mortality and incidence of serious complications resulting from herpes zoster in both normal and immunocompromised patients (Easterbrook 1994). Acyclovir has poor bioavailability and only modest activity against VZV. High and frequent dosing is required to achieve a therapeutic effect. For immunocompromised patients with severe cases, cautious clinicians favor intravenous administration of 10 milligrams per kilogram (mg/kg) of acyclovir every 8 hours for seven to ten days or until all vesicles are crusted over (Fletcher 1992). Treatment outcome improves when therapy is administered within 24 to 48 hours of an outbreak (Balfour 1996).

Patients not ill enough to require hospitalization are often treated with high doses of oral acyclovir. An oral dose of 800 mg 5 times a day has been approved for the treatment of primary varicella and recurrent zoster in otherwise-healthy patients. Though commonly also used in immunocompromised patients, the 4 grams a day oral regimen has been inadequately studied in this population and should therefore be accompanied by careful patient monitoring (Fletcher 1992).

Acyclovir has a good safety profile even at the high doses required for the treatment of VZV. Reported side effects include nausea, diarrhea, headaches, dizziness, and rash ( Huff 1988; McGrath 1994). There have also been reports of nephrotoxicity (kidney damage) in connection with intravenous administration and when administered in conjunction with other nephrotoxic medications. This may be overcome through adequate hydration (Shepp 1988).

Adult Dosage Compendium for Treatment of Adult VZV
Primary Varicella	IV 10 mg/kg thrice daily (for children, IV 500 mg/m2 thrice daily) or 800 mg orally 5 times daily
Localized Zoster	IV 10 mg/kg or 800 mg orally 5 times daily
Severe, recurrent, or when oral absorption dubious; Visceral disseminated VZV	IV 10 mg/kg thrice daily
Acyclovir-resistant VZV	IV Foscarnet 40 mg/kg thrice daily

(Fletcher 1992)

Acyclovir-resistant VZV is rare and appears to be confined to the immunosuppressed patient (Balfour 1994). Resistance usually results from treatment-induced selection for thymidine kinase-deficient VZV strains, which may present distinctly thickened wart-like lesions (Jacobson 1990).

An algorithm for the treatment of acyclovir-resistant VZV was developed by Balfour and colleagues. Practitioners should consider beginning therapy with IV acyclovir (10 mg/kg thrice daily) or foscarnet in the face of a priori evidence of acyclovir resistance. Such evidence may include previous episodes of resistant zoster, recurrence in the same location after treatment with acyclovir, recurrence in the face of ongoing administration of acyclovir or ganciclovir, or the appearance of atypical hyperkeratotic lesions. Patients not responding to seven to ten days of IV acyclovir therapy should be switched to foscarnet (40 mg/kg thrice daily) until all lesions are crusted (Balfour 1994).

In a randomized trial of 22 severely immunocompromised non-AIDS patients presenting within 72 hours of onset of zoster, IV acyclovir was found superior to vidarabine (ara-A, the then-current standard of care) in shortening the period of viral shedding (four versus seven days), the period of new lesion formation (three versus six), time to first lessening of pain (four versus seven), time to crusting of all lesions (seven versus 17), and time to full healing of all lesions (17 versus 28 days) (Shepp 1988). Cutaneous dissemination occurred in 50% of patients receiving vidarabine, but in none receiving acyclovir.

For HIV-positive patients with multiple post-treatment zoster recurrences, maintenance therapy with oral acyclovir 400-600 mg three to five times daily may be justified, though lack of proof of efficacy and the potential for selection of acyclovir-resistant VZV add controversy to this practice (Jacobson 1990).

Foscarnet (Foscavir™, Astra Pharmaceuticals)
Foscarnet has demonstrated in vitro activity against several human herpes viruses including HSV 1 and 2, VZV, cytomegalovirus, Epstein-Barr virus and also HIV. Foscarnet's side effects include severe kidney toxicities -- such as dangerous reductions in phosphate, calcium and magnesium levels -- as well as seizures, anemia, thrombocytopenia, neutropenia, penile ulcers and gastrointestinal intolerance (Sasadeusz 1993; McGrath 1994).

In a very small study in patients with acyclovir-resistant cutaneous VZV, lesions healed completely in 4 of 5 patients treated with foscarnet (Safrin 1991). Though data regarding foscarnet's efficacy against VZV are scant, for lack of alternatives, it has become the second-line therapy for VZV (Balfour 1994).

Famciclovir (Famvir™, SmithKline Beecham)
Famciclovir is a nucleoside analogue which is converted to penciclovir in the body. It was approved for the treatment of zoster in immunocompetent patients, and it is starting to undergo tests in patients with HIV. Famciclovir is similar in nature to acyclovir but is reportedly more bioavailable (77% versus 30% or less) and has a much longer intracellular half-life (Boyd 1988). It is thus administered only three times rather than five times per day as for acyclovir. Famciclovir relies on viral thymidine kinase for phosphorylation, and so is ineffective against most acyclovir-resistant strains of VZV. A trial comparing various dosages of famciclovir to acyclovir in immunocompetent adults with acute zoster found all regimens equally effective (Gheeraert 1992).

Sullivan and colleagues reported interim results from an open-label study of famciclovir in HIV-infected patients at the Fourth Conference on Retroviruses and Opportunistic Infections. Fifteen HIV-infected patients with uncomplicated herpes zoster were treated with a seven day course of famciclovir (500 mg thrice daily). By day seven, blister formation had ceased in all patients, and complete resolution of pain was reported in 6/11 patients by day 28. One patient required hospitalization for the management of zoster pain (Sullivan 1997). Unfortunately, no comparison was made with acyclovir, as the sponsor apparently plans to rely upon famciclovir's favorable dosing advantage to market the drug. SmithKline Beecham plans to file a supplementary new drug application for Famvir for the treatment of acute herpes zoster and recurrent genital herpes in immunocompromised patients.

INVESTIGATIONAL TREATMENTS

Valacyclovir (Valtrex™, Glaxo Welcome)
Valacyclovir, a drug that is converted to acyclovir in vivo, is approved to treat HSV and VZV in immunocompetent patients. An oral dose of 1 gram thrice daily results in roughly the same level of acyclovir in the body as IV acyclovir (Easterbrook 1994). In a Phase II trial comparing 1 gram of valacyclovir per day to the standard acyclovir regimen of 800 mg 5 times daily in immunocompetent adults, the valacyclovir group had a slightly lower median duration of pain (38 for valacyclovir versus 51 days for acyclovir) though no other significant benefits were noted (Beautner 1995).

A Phase I trial conducted in HIV-infected patients with CD4 counts of less than 150 established a generally favorable safety profile for valacyclovir at dosages of 1,000 and 2,000 mg four times a day for 30 days, though a small number of patients developed neutropenia (Jacobson 1994). However, valacyclovir carries a warning against its use in immunocompromised patients because of its association with hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (potentially fatal bleeding in the kidneys) in this population (FDA Data 1996). The warning resulted from the results of ACTG 204, a study comparing valacyclovir to acyclovir for the prevention of CMV retinitis in HIV-positive patients. Ironically, the ACTG has commenced a study, ACTG 253, in HIV-infected children.

Sorivudine (BV-araU/Bravavir™; Bristol Myers Squibb)
Sorivudine is a nucleoside analogue with extremely potent in vitro activity against herpes zoster. In a study comparing the in vitro sensitivity of over twenty antivirals to VZV (including acyclovir, penciclovir, foscarnet, and others) sorivudine was found to be the most potent among 14 acyclovir-sensitive strains (Andrei 1995). It has a bioavailability of 63% versus 30% for acyclovir. Moreover, sorivudine's longer half-life permits once per day dosing as compared to 5 times per day for acyclovir.

While sorivudine is well tolerated when taken alone (Easterbrook 1994), the drug is extremely dangerous when administered along with certain other drugs including the cancer drug fluorouracil and the anti-fungal drug flucytosine. The latter is often used by PWAs in combination with amphotericin as a treatment for cryptococcal meningitis (Whitley 1995). For a brief period, sorivudine was licensed in Japan for the treatment of herpes zoster. It was, however, quickly taken off the market after its concomitant use with fluorouracil derivatives caused 15 deaths in Japan

Comparative clinical trials have found sorivudine to be at least as effective as acyclovir (Whitley 1995). As a result, Bristol-Myers Squibb presented the drug for approval to the FDA on June 6, 1996. Unfortunately, the FDA Antiviral Advisory Committee voted 7 to 2 against approval due to its concerns over the fatal drug interaction. We believe this was an over-reaction based on avoidable deaths in Japan where physician education about the drug's toxic interactions was inadequate. After the FDA rejected Bristol-Myers Squibb's new drug application (NDA) for sorivudine, the sponsor stopped all ongoing clinical trials, canceled a planned open-label study in patients with sight-threatening VZV retinitis and a trial in HIV-positive children with herpes zoster or primary varicella, and the drug's development was halted.

*

Andrei G, Snoeck R, Reymen D, et al.: Comparative activity of selected antiviral compounds against clinical isolates of varicella-zoster virus. Eur J Clin Microbiol Infect Dis 14:318-29, 1995.
Balfour HH Jr., Benson C, Braun J, et al.: Management of acyclovir-resistant herpes simplex and varicella-zoster infections. J Acquir Immune Defic Syndr 7:254-60, 1994.
Beautner KR, Friedman DJ, Forszpaniak C, et al.: Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 39: 1546-53, 1995.
Boon RJ, Griffen DRJ: Efficacy of famciclovir in the treatment of herpes zoster: reduction of pain associated with zoster. Neurology 45:S76-S77, 1995.
Bossi P, Caumes E, Astagneau P, et al.: Survival of 626 AIDS patients with central nervous system manifestations [abstract: I104]. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], New Orleans, 1996.
Boyd MR, Bacon TH, Sutton D: Antiherpes activity of 9-(4-hydroxy-3-hydroxy-methyl-1-butyl)guanine (BRL 39123) in animals. Antimicrobial Agents and Chemotherapy 32:358-63, 1988.
Bruxelle J: Prospective epidemiologic study of painful and neurologic sequelae induced by herpes zoster in patients treated early with oral acyclovir. Neurology 45:S78-S79, 1995.
Burke DG, Kalayjian R, Madreperla S, et al.: The detection of varicella zoster virus in cerebrospinal fluid by polymerase chain reaction, and its clinical significance in HIV-infected patients [abstract: Th.A.4069]. XI Intl Conf AIDS, Vancouver, 1996.
Cochereau I, Lariven S, Matheron S, et al.: VZV Retinitis in AIDS [abstract: I19]. 35th ICAAC, San Francisco, 1995.
Cole EL, Moisler DM, Calabrese LH, et al.: Herpes zoster ophthalmicus and acquired immune deficiency syndrome. Arch Ophthalmol 102:1027-29, 1984.
Colebunders R, Mann JM, Francis H, et al.: Herpes zoster in African patients: a clinical predictor of human immunodeficiency virus infection. J Infect Dis 157:314-18, 1988.
Drew W, Buhles W, Dworkin RJ, et al.: Management of herpes virus infections (CMV, HSV, VZV). In: Sande MA, Volberding PA, eds. The Medical Management of AIDS. Dallas, WB Saunders, 1990:316-38.
Drew W, Buhles W, Erlich KS: Management of herpes virus infections (CMV, HSV, VZV). In: Sande MA, Volberding PA, eds. The Medical Management of AIDS. 1995:511-36.
Easterbrook P, Wood MJ: Successors to acyclovir [review]. J Antimicrob Chemother 34:307-11, 1994.
Erlich K, Mills J: Varicella-Zoster Virus. In: Cohen PT, Sande MA, Volberding PA eds. The AIDS Knowledge Base: A Textbook on HIV Disease from the University of California, San Francisco, and the San Francisco General Hospital. New York, Little Brown, 1995:6:11:1- 9.
FDA Data: Bravavir(r) (sorivudine) NDA No. 20-585: Advisory Committee Background Document: p. 46 (Synopsis of clinical trials - efficacy in HIV-infected adults with zoster (phase III trials)), p. 55 (Pooled analysis of multinational and US NIH trials), p. 64 (risk benefit analysis), 1996 [unpublished].
Fletcher CV: Treatment of herpes virus infections in HIV-infected individuals [review]: Ann Pharmacother 26:955-62, 1992.
Gershon A, Steinberg S, Greenberg S, et al.: Varicella-zoster-associated encephalitis: Detection of specific antibody in cerebrospinal fluid. J Clin Microb 12: 764-67, 1980.
Gheeraert P, et al.: Efficacy and safety of famciclovir in the treatment of uncomplicated herpes zoster [abstract: 1108]. 32nd ICAAC, Anaheim, 1992.
Huff JC, Bean B, Balfour HH, et al.: Therapy of herpes zoster with oral acyclovir. Am J Medicine 85 (suppl2A): 84-89, 1988.
Iten A, Chatellard P, Sahli R, et al. Varicella-zoster virus (VZV) infection of the central nervous system (CNS) in HIV+ patients: VZV PCR in CSF, a useful premortem diagnostic method [Abstract]. Fourth Conference on Retroviruses and Opportunistic Infections, Washington, DC, 1997.
Jacobson MA, Berger TG, Fikrig S, et al.: Acyclovir-resistant varicella-zoster virus infection after chronic acyclovir therapy in patients with the acquired immunodeficiency syndrome. Ann Intern Med 112:187-91, 1990.
Jacobson MA, Gallant J, Wang LH, et al.: Phase I trial of valacyclovir, the L-valyl ester of acyclovir, in patients with advanced human immunodeficiency disease. Antimicrob Agents Chemother 38:1534-40, 1994.
Mahalingam R, Wellish M, Wolf W, et al.: Latent varicella-zoster viral DNA in human trigeminal and thoracic ganglia. N Engl J Med 323:627-31, 1990.
McGrath BJ, Newman CL: Genital herpes simplex infection in patients with the acquired immunodeficiency syndrome [review]. Pharmacotherapy 14:529-42, 1994.
Melbye M, Grossman RJ, Goedert JJ, et al.: Risk of AIDS after herpes zoster. Lancet 725-31, 1987.
Moore RD, Chaisson RE: Natural history of opportunistic disease in HIV-infected urban clinical cohort. Ann Intern Med 124:633-42, 1996.
Neger RE: HIV complications that can affect the eye. Positively Aware 7:10-11, 1996.
Pinnolis MK, Foxworthy D, Kemp B: Treatment of progressive outer retinal necrosis with sorivudine. Am J Ophthalmol 119:516-17, 1995.
Ragozzino MW, Melton LJ III, Kurland LT, et al.: Population-based study of herpes zoster and its sequelae. Medicine 61:310-16, 1982.
Ryder JW, Croen K, Kleinschmidt-DeMasters BK, et al.: Progressive encephalitis three months after resolution of cutaneous zoster in patients with AIDS. Ann Neurol 19:182-88, 1986.
Safrin S, Berger TG, Gilson I, et al.: Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection. Ann Intern Med 115:19-21, 1991.
Sasadeusz JJ, Sacks SL: Systemic antivirals in herpes virus infections [review]. Dermatologic Clinics 11:171-85, 1993.
Shepp DH, Dandlicker PS, Meyers JD: Current therapy of varicella-zoster virus infection in immunocompromised patients, a comparison of acyclovir and vidarabine. Am J Medicine 85(suppl 2a):96-98, 1988.
Sullivan M, Skiest D, Signs D, et al. Famciclovir in the management of acute herpes zoster in HIV+ patients [Abstract]. Fourth Conference on Retroviruses and Opportunistic Infections, Washington DC, 1997.
Waldman SD: Acute Herpes Zoster and Postherpetic Neuralgia. Internal Medicine Specialist 11:33-34 , 1990.
Watson CPN: The treatment of post-herpetic neuralgia. Neurology 45:S58-S60, 1995.
Whitley RJ, Soong SJ, Dolin R, et al.: Early vidarabine therapy to control the complications of herpes-zoster in immunosuppressed patients. N Engl J Med 307:971, 1982.
Whitley RJ: Sorivudine: a promising drug for the treatment of varicella-zoster virus infection. Neurology 45: S73-75, 1995.

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