Treatment of herpes zoster
Treatment of herpes zoster
Author
Mary A Albrecht, MD Section Editor
Martin S Hirsch, MD Deputy Editor
Barbara H McGovern, MD
INTRODUCTION — Varicella-zoster virus (VZV) infection causes two clinically distinct forms of disease [1] . Primary infection with VZV results in varicella, also known as chickenpox, characterized by vesicular lesions in different stages of development on the face, trunk and extremities. Herpes zoster, also known as shingles, results from reactivation of endogenous latent VZV infection within the sensory ganglia. This clinical form of the disease is characterized by a painful, unilateral vesicular eruption, which usually occurs in a restricted dermatomal distribution [2] .
The treatment of herpes zoster will be reviewed here. The prevention, pathogenesis, epidemiology, and sequelae of this infection and manifestations during pregnancy are discussed separately. Routine vaccination of children against primary varicella and the possible impact on herpes zoster is discussed elsewhere. (See “Prevention of varicella-zoster virus infection: Chickenpox” and see “Prevention of varicella-zoster virus infection” and see “Clinical manifestations of varicella-zoster virus infection: Herpes zoster” and see “Postherpetic neuralgia” and see “Varicella-zoster virus infection in pregnancy”).
GENERAL PRINCIPLES — The efficacy of antiviral therapy for the treatment of herpes zoster infection has been demonstrated by multiple randomized controlled clinical trials. There are three related drugs available for treatment including acyclovir, famciclovir, and valacyclovir. These agents share a common mechanism of action: they are phosphorylated by viral thymidine kinase and cellular kinases to a triphosphate form that inhibits viral replication. (See “Acyclovir: an overview”, section on Mechanism of action).
The primary goal of antiviral therapy is to reduce the risk or severity of postherpetic neuralgia (PHN). (See “Clinical manifestations of varicella-zoster virus infection: Herpes zoster” and see “Postherpetic neuralgia”). Other important goals of treatment are to [3,4] :
Promote more rapid healing of skin lesions
Decrease viral shedding
Lessen the severity and duration of pain associated with acute neuritis
ANTIVIRAL THERAPY FOR UNCOMPLICATED INFECTION — Treatment of herpes zoster is associated with earlier healing of lesions and prevention of complications, particularly postherpetic neuralgia (PHN). Most available data regarding treatment of herpes zoster involves patients over 50 years of age.
The three antivirals used for treatment are discussed below. In general, these medications are well tolerated; side effects are discussed elsewhere. (See “Acyclovir: an overview”).
Acyclovir — Acyclovir (ACV) has an excellent safety profile but is only moderately active against VZV in vitro with a median effective concentration (EC50) of 2.3 to 4.0 mcg/mL against clinical viral isolates [5] .
The efficacy of acyclovir for the treatment of herpes zoster was evaluated in several clinical trials, two of which are highlighted below [6,7] :
In a randomized double-blind, placebo-controlled trial of 364 elderly immunocompetent patients, initiation of acyclovir within 48 hours of rash onset led to faster lesion resolution and decreased the number of new lesions [7] . Although there was a significant reduction in pain symptoms in the acyclovir arm, there was no decrease in the incidence or severity of postherpetic neuralgia.
In a similarly designed trial of 205 elderly immunocompetent patients, acyclovir, administered within 48 hours of rash, led to faster resolution and arrest of new lesions compared to placebo [6] . Furthermore, of the patients with severe pain on entry, 40 percent improved in the acyclovir arm while there was no improvement in the placebo arm.
Acyclovir use within 48 to 72 hours of the onset of rash has demonstrated clinical benefit in meta-analyses that addressed different clinical outcomes [8,9] :
In a meta-analysis of four placebo-controlled trials, ACV accelerated resolution of the pain associated with acute neuritis; a more marked benefit was noted in patients over the age of 50 years [8] .
In a second meta-analysis that included one additional trial, treatment with ACV also significantly reduced the incidence of PHN at six months by 46 percent [9] .
Although oral acyclovir (800 mg five times daily) has been the mainstay of herpes zoster treatment, its poor bioavailability and need for frequent daily dosing prompted the development of later generation antiviral agents (valacyclovir and famciclovir) with improved pharmacokinetics and lower dosing frequency [8-11] . The use of acyclovir may still be favored, however, if cost is an issue.
Valacyclovir — Valacyclovir is well absorbed from the gastrointestinal tract and rapidly converted to ACV in vivo, thereby providing a three- to fivefold increase in ACV bioavailability [11,12] . Valacyclovir is approved by the United States Food and Drug Administration (FDA) for the treatment of herpes zoster in immunocompetent adults. (See “Valacyclovir: An overview”).
The efficacy of valacyclovir was demonstrated in a randomized, double-blind study of 1141 immunocompetent adults with herpes zoster older than 50 years; the efficacy and safety of valacyclovir (1000 mg orally three times daily for 7 or 14 days) was compared to acyclovir (800 mg orally five times daily for seven days) [12] . In an intent to treat analysis:
Valacyclovir therapy for 7 or 14 days significantly accelerated the resolution of acute neuritis compared to acyclovir (median duration of pain 38 and 48 days versus 51 days for acyclovir).
Valacyclovir significantly reduced the duration of PHN and decreased the proportion of patients with pain persisting for six months compared to acyclovir (19 versus 26 percent).
Lesions resolved at similar rates in all groups.
Adverse events were similar for both the valacyclovir and acyclovir groups.
Whether these better overall outcomes in association with valacyclovir are related to differences in bioavailability or simply lower pill burden (and improved adherence) is unknown.
Famciclovir — Famciclovir, the prodrug of penciclovir, is well absorbed from the gastrointestinal tract and is rapidly converted in the intestinal wall and liver to the active compound penciclovir that has broad activity against VZV [11,13] . (See “Famciclovir: An overview”).
A randomized, double-blind trial conducted in 419 immunocompetent adults (mean age 50 years) with uncomplicated zoster evaluated oral famciclovir (500 mg or 750 mg, each given three times daily) or placebo given within 72 hours of rash for seven days [13] . Famciclovir recipients at both doses had an approximately twofold faster resolution of PHN than placebo recipients. The median duration of PHN was reduced by approximately two months with famciclovir therapy. Famciclovir was well tolerated with accelerated lesion healing compared to placebo.
The long intracellular half-life of famciclovir provided the rationale for a trial in uncomplicated herpes zoster presenting within 72 hours of symptom onset that showed 750 mg once daily produced equivalent outcomes to multiple daily dosing of acyclovir (800 mg five times daily) [14] . Further trials are needed before this approach should be considered.
Summary — We recommend antiviral therapy for patients >50 years of age with uncomplicated herpes zoster who present within 72 hours of clinical symptoms. The benefit of antiviral therapy in younger patients is not as clear, although the risk of adverse events is low. (See “Treatment of younger patients” below and see “Acyclovir: an overview”, section on Toxicity).
All three antiviral drugs have demonstrated efficacy in the treatment of herpes zoster in immunocompetent patients. However, we prefer valacyclovir (1000 mg three times per day for seven days) based upon the trial data cited above, in which valacyclovir was associated with more rapid resolution of acute neuritis, a shorter duration of PHN, and had a lower pill burden, compared to acyclovir [12] . However, if cost is an issue, then ACV (800 mg every four hours [five times/day] for seven to ten days) may be preferred. Although famciclovir is now available in a generic formulation, its cost is still approximately threefold higher than acyclovir. If famciclovir is used, we recommend standard dosing with 500 or 750 mg three times daily.
OPTIMAL ONSET OF THERAPY — Antiviral therapy should be initiated within 72 hours of clinical presentation in patients greater than 50 years of age to maximize the potential benefits of treatment. The clinical utility of initiating acyclovir therapy more than 72 hours after the onset of lesions has not been definitively established since most treatment studies have enrolled patients within three days of symptoms. However, treatment should be considered if new lesions are still appearing at that time to possibly limit further spread [15] .
The rapid initiation of therapy is particularly critical in the severely immunocompromised, such as the organ transplant recipient [16] . However, antiviral therapy should be initiated in immunocompromised patients, even if they present after 72 hours.
ANALGESIA FOR ACUTE NEURITIS — The pain associated with herpes zoster can be severe and may increase over time. Pain management should include use of standardized pain measures, use of analgesics, and frequent follow-up to assess efficacy in relief of symptoms [4] . (See “Evaluation of chronic pain in adults”).
Antiviral therapy has only a modest benefit in decreasing the pain of acute herpetic neuralgia. As a result, analgesic drugs are often needed at presentation. Nonsteroidal anti-inflammatory drugs and acetaminophen are useful for mild pain, either alone, or in combination with a weak opioid analgesic (eg, codeine or tramadol). For moderate to severe pain that disturbs sleep, stronger opioid analgesis (eg, oxycodone or morphine) may be necessary [4] .
If moderate to severe pain continues despite these interventions, steroids can be considered in patients who have no contraindications to glucocorticoid therapy. (See “Use of glucocorticoids” below).
The management of the pain associated with postherpetic neuralgia is discussed elsewhere. (See “Postherpetic neuralgia”).
USE OF GLUCOCORTICOIDS — Glucocorticoids have been used in combination with acyclovir for the treatment of uncomplicated acute herpes zoster in an attempt to improve the quality of life, the time to healing of lesions, and the incidence of PHN. These early trials suggested only modest benefit on a limited number of clinical outcomes with an increased risk of adverse events [10,17-19] :
One placebo-controlled trial in 201 adults found that the addition of corticosteroids to antiviral therapy led to faster resolution of lesions, decreased the symptoms of acute neuritis, and improved the quality of life [10] . Another trial reported similar findings in association with corticosteroid use [17] . However, the benefits were considered modest and adverse events attributed to study medication were reported more frequently in glucocorticoid recipients compared to those subjects receiving acyclovir alone.
Most importantly, neither of these trials, nor two earlier and smaller trials, found any effect of glucocorticoid therapy on the incidence or duration of PHN [10,17-19] .
A subsequent meta-analysis of five placebo-controlled trials evaluating acyclovir alone compared to antiviral therapy plus glucocorticoids did not demonstrate any benefit of combination therapy on quality of life or the incidence of PHN [20] . Furthermore, corticosteroids could potentially increase the risk of secondary bacterial skin infection. Thus, we do not recommend the routine use of corticosteroids in addition to antiviral therapy. However, an expert panel suggested that corticosteroids may be a useful adjunctive therapy in patients with acute neuritis that is not controlled by opioid analgesics [4] .
VIRAL LOAD AND CLINICAL OUTCOME — During episodes of acute herpes zoster, VZV viremia occurs in some, but not all patients [21] . The following observations have been noted in patients who had evidence of viremia:
One study of 130 patients with acute herpes zoster, who were monitored for 6 to 12 months, found that VZV DNA was detected in peripheral blood mononuclear cells of 78 percent of those with acute zoster and in 9 percent of healthy asymptomatic blood donors [21] . However, the height of the viral load was not associated with the development or persistence of postherpetic neuralgia.
In one study, viral load was increased in patients with multidermatomal involvement [22] .
At present, there is no indication for monitoring viremia in patients with acute VZV.
PREVENTION OF POSTHERPETIC NEURALGIA — One of the goals of antiviral therapy is to reduce the incidence or severity of postherpetic neuralgia (PHN). It is hypothesized that antiviral therapy likely reduces neural damage, which may contribute to the development of PHN [4] . The results of three meta-analyses [8,9,23] and some, but not all, randomized controlled trials have demonstrated that treatment for herpes zoster reduces the duration or incidence of prolonged pain.
Data on individual agents (eg, acyclovir, famciclovir, and valacyclovir) are discussed above. The management of postherpetic neuralgia is discussed elsewhere. (See “Postherpetic neuralgia”, section on Prevention of PHN, and see “Antiviral therapy for uncomplicated infection” above).
TREATMENT OF YOUNGER PATIENTS — Further research is needed to assess the efficacy and cost-effectiveness of antiviral agents in younger patients [24] . In the meta-analysis cited above, the benefit of acyclovir therapy was less marked in patients under the age of 50 years [8] .
Therapy can be considered on an individual basis in younger patients based upon predictors of PHN such as the severity of the acute pain and rash and history of prodromal pain [25-27] . Alternatively, treatment may be considered in all younger patients, regardless of these predictive factors, since therapy is generally well tolerated and the risks of adverse events are minimal. However, antiviral therapy should always be administered to an immunocompromised patient with zoster, regardless of age. (See “Complicated herpes zoster” below). Side effects of antiviral therapy are discussed elsewhere. (See “Acyclovir: an overview”).
HERPES ZOSTER DURING PREGNANCY — Although maternal varicella (chickenpox) infection during pregnancy can lead to neonatal morbidity, congenital varicella has not been documented in association with maternal herpes zoster infection. A consensus panel of experts with clinical and research experience in herpes zoster issued the following guidelines in 2007 for the management of pregnant women with herpes zoster [4] :
Experience with acyclovir therapy in both HSV infection and varicella pneumonia suggests that this drug is safe in pregnancy, including the first trimester; however, data are limited. (See “Genital herpes simplex virus infection and pregnancy”, section on Safety of antiviral drugs in pregnancy).
Thus, the treatment of herpes zoster in a pregnant woman should be undertaken only when the benefits to the mother outweigh the potential risks to the fetus. We recommend initiation of antiviral therapy for zoster in a pregnant woman presenting with herpes zoster opthalmicus, a serious sight-threatening condition, which has been linked to VZV reactivation within the trigeminal ganglion.
We also suggest initiation of antiviral therapy in a pregnant woman with severe rash or dermatomal pain to promote more rapid healing and to lessen the severity and duration of pain associated with acute neuritis.
COMPLICATED HERPES ZOSTER — Complicated herpes zoster includes infections occurring in immunosuppressed patients or manifested by ophthalmic involvement.
HIV-infected and other immunosuppressed patients — All HIV-infected patients should be treated with antiviral therapy for episodes of uncomplicated herpes zoster, regardless of the age of onset. Since corticosteroids have only modest benefit, we do not routinely use them in these patients.
A clinical trial performed prior to the era of HAART showed that intravenous ACV stopped progression of the rash among patients with disseminated cutaneous zoster and enhanced the rate of clearance from vesicles [28] . However, given the increased bioavailability of valacyclovir, intravenous ACV (10 mg/kg three times daily for seven days) is generally limited to the following subgroups:
Patients with disseminated disease or ophthalmic involvement.
Transplant recipients undergoing treatment for graft rejection.
Patients with advanced AIDS who have active opportunistic infections or prominent wasting.
These patients may benefit from intravenous acyclovir as the initial therapy for herpes zoster with a switch to an oral agent, such as valacyclovir or famciclovir, after initial clinical improvement. Dosing information is discussed above. (See “Antiviral therapy for uncomplicated infection” above).
Acyclovir-resistant zoster — Uncommonly, HIV-infected patients have VZV infections that are resistant to acyclovir. Foscarnet, an inhibitor of viral DNA polymerase, has in vitro activity against acyclovir-resistant VZV strains [29] . (See “Foscarnet: An overview”).
Foscarnet has been extensively evaluated in AIDS patients with ACV-resistant herpes simplex virus syndromes [30] . However, its efficacy in treating complicated herpes zoster that has been refractory to prolonged acyclovir therapy has been variable in severely immunosuppressed hosts [31] . Significant disadvantages to foscarnet are the requirement for intravenous administration and significant toxicity.
We recommend foscarnet 40 mg/kg IV every eight hours for 10 days in patients with acyclovir-resistant zoster [32] .
Herpes zoster ophthalmicus — Herpes zoster ophthalmicus occurs when HZ presents in the ophthalmic division of the fifth cranial nerve [33] . In the past, some clinicians treated herpes zoster ophthalmicus with intravenous ACV. However, two trials comparing oral ACV to valacyclovir or famciclovir in patients with ophthalmic involvement showed comparable outcomes with any of the regimens [34,35] . Thus, current treatment for this form of herpes zoster is administered orally [3] . However, intravenous ACV (10 mg/kg three times daily for seven days) should be considered in the rare patient who is extremely ill and requires hospitalization or is immunocompromised.
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See “Patient information: Herpes zoster (Shingles)”). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.
SUMMARY AND RECOMMENDATIONS
Reactivation of latent varicella-zoster virus (VZV) infection within the sensory ganglia results in herpes zoster, or “shingles.” This syndrome is usually characterized by a painful, unilateral vesicular eruption in a dermatomal distribution. (See “Introduction” above).
The goals of antiviral therapy are to promote more rapid healing of skin lesions, to lessen the severity and duration of pain associated with acute neuritis, and to reduce the incidence or severity of postherpetic neuralgia (PHN). (See “General principles” above).
We recommend antiviral therapy for patients >50 years of age with uncomplicated herpes zoster who present within 72 hours of clinical symptoms (Grade 1A). We prefer valacyclovir (1000 mg three times daily for seven days) because of its lower dosing frequency. However, if cost is a major consideration, we prefer acyclovir (800 mg five times/day for seven days). (See “Antiviral therapy for uncomplicated infection” above).
The benefit of antiviral therapy in younger patients is not as clear, although the risk of adverse events is low. As a result, we suggest antiviral therapy for patients <50 years of age with herpes zoster who present within 72 hours of clinical symptoms (Grade 2C).
Analgesic drugs are often needed at presentation to address symptoms of acute neuritis. (See "Analgesia for acute neuritis" above).
Most trials have demonstrated that early antiviral treatment for herpes zoster reduces the duration or incidence of postherpetic neuralgia. (See "Prevention of postherpetic neuralgia" above).
We do NOT recommend the routine use of corticosteroid therapy since glucocorticoids do not decrease the risk of postherpetic neuralgia (Grade 1B). (See "Use of glucocorticoids" above).
All HIV-infected patients should be treated with antiviral therapy for episodes of uncomplicated herpes zoster, regardless of the age of onset. Intravenous acyclovir may be considered for more severe infections, such as disseminated disease or ophthalmic involvement. (See "Complicated herpes zoster" above).
Use of UpToDate is subject to the Subscription and License Agreement .
REFERENCES
1 Lopez, A, Burnett-Hartman, A, Nambiar, R, et al. Transmission of a Newly Characterized Strain of Varicella-Zoster Virus from a Patient with Herpes Zoster in a Long-Term-Care Facility, West Virginia, 2004. J Infect Dis 2008; 197:646.
2 Oxman, MN. Immunization to reduce the frequency and severity of herpes zoster and its complications. Neurology 1995; 45:S41.
3 Gnann, JW Jr, Whitley, RJ. Clinical practice. Herpes zoster. N Engl J Med 2002; 347:340.
4 Dworkin, RH, Johnson, RW, Breuer, J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007; 44 Suppl 1:S1.
5 Biron, KK, Elion, GB. In vitro susceptibility of varicella-zoster to acyclovir. Antimicrob Agents Chemother 1980; 18:443.
6 McKendrick, MW, McGill, JI, White, JE, Wood, MJ. Oral acyclovir in acute herpes zoster. Br Med J (Clin Res Ed) 1986; 293:1529.
7 Wood, MJ, Ogan, PH, McKendrick, MW, et al. Efficacy of oral acyclovir treatment of acute herpes zoster. Am J Med 1988; 85:79.
8 Wood, MJ, Kay, R, Dworkin, RH, et al. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: A meta-analysis of placebo controlled trials. Clin Infect Dis 1996; 22:341.
9 Jackson, JL, Gibbons, R, Meyer, G, Inouye, L. The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia. Arch Intern Med 1997; 157:909.
10 Whitley, RJ, Weiss, H, Gnann, JW, et al. Acyclovir with and without prednisone for the treatment of herpes zoster. Ann Intern Med 1996; 125:376.
11 Gnann, JW Jr. New antivirals with activity against varicella-zoster virus. Ann Neurol 1994; 35 Suppl:S69.
12 Beutner, KR, Friedman, DJ, Forszpaniak, C, et al. Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39:1546.
13 Tyring, S, Barbarash, RA, Nahlik, JE, et al. Famciclovir for the treatment of acute herpes zoster: Effects on acute disease and postherpetic neuralgia. Ann Intern Med 1995; 123:89.
14 Shafran, SD, Tyring, SK, Ashton, R, et al. Once, twice, or three times daily famciclovir compared with aciclovir for the oral treatment of herpes zoster in immunocompetent adults: a randomized, multicenter, double-blind clinical trial. J Clin Virol 2004; 29:248.
15 Cohen, JI, Brunell, PA, Straus, SE, Krause, PR. NIH conference. Recent advances in varicella-zoster virus infection. Ann Intern Med 1999; 130:922.
16 Miller, GG, Dummer, JS. Herpes simplex and varicella zoster viruses: forgotten but not gone. Am J Transplant 2007; 7:741.
17 Wood, MJ, Johnson, RW, McKendrick, MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994; 330:896.
18 Esmann, V, Geil, JP, Kroon, S, et al. Prevention of post-herpetic neuralgia. Evaluation of treatment with oral prednisone, oral acyclovir, and radiotherapy. Lancet 1987; 2:126.
19 Benoldi, D. Mirizzi, S. Zucci A. Allegra, F. Prevention of post-herpetic neuralgia. Evaluation of treatment with oral prednisone, oral acyclovir and radiotherapy. Int J Dermatol 1991; 30:288.
20 He, L. Cochrane Database Sys Rev 2008; CD005582.
21 Quinlivan, ML, Ayres, HR, McElwaine, S et al. Effect of Viral Load on the Outcome of Herpes Zoster. J Clin Microbiol 2007; 45:3909.
22 de Jong, MD, Weel, JF, Schuurman, T, et al. Quantitation of varicella-zoster virus DNA in whole blood, plasma, and serum by PCR and electrochemiluminescence. J Clin Microbiol 2000; 38:2568.
23 Crooks, RJ, Jones, DA, Fiddian, AP. Zoster-associated chronic pain: an overview of clinical trials with acyclovir. Scand J Infect Dis Suppl 1991; 80:62.
24 Moomaw, MD, Cornea, P, Rathbun, RC, Wendel, KA. Review of antiviral therapy for herpes labialis, genital herpes and herpes zoster. Expert Rev Anti Infect Ther 2003; 1:283.
25 Johnson, RW, Whitton, TL. Management of herpes zoster (shingles) and postherpetic neuralgia. Expert Opin Pharmacother 2004; 5:551.
26 Whitley, RJ, Weiss, HL, Soong, SJ, Gnann, JW. Herpes zoster: risk categories for persistent pain. J Infect Dis 1999; 179:9.
27 Dworkin, RH, Boon, RJ, Griffin, DR, Phung, D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 1998; 178 Suppl 1:S76.
28 Balfour, HH Jr, Bean, B, Laskin, OL, et al. Acyclovir halts progression of herpes zoster in immunocompromised patients. N Engl J Med 1983; 308:1448.
29 Baba, M, Konno, K, Shigeta, S, De Clerq, E. Inhibitory effects of selected antiviral compounds on newly isolated clinical varicella-zoster strains. Tohoku J Exp Med 1986; 148:275.
30 Safrin, S, Assaykeen, T, Follansbee, S, Mills, J. Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infections in 26 AIDS patients: Preliminary data. J Infect Dis 1990; 161:1078.
31 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 1991; 115:19.
32 Drugs for non-HIV viral infections. Treat Guidel Med Lett 2005; 3:23.
33 Liesegang, TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology 2008; 115:S3.
34 Colin, J, Prisant, O, Cochener, B, et al. Comparison of the efficacy and safety of valaciclovir and acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology 2000; 107:1507.
35 Tyring, S, Engst, R, Corriveau, C, et al. Famciclovir for ophthalmic zoster: A randomised aciclovir controlled study. Br J Ophthalmol 2001; 85:576.
©2009 UpToDate® • customerservice@uptodate.com
www.uptodate