Current Treatment and Future Strategies for Herpes Zoster and Postherpetic Neuralgia

Prevention of Herpes Zoster in Older Adults: Where Do We Stand with the Herpes Zoster Vaccine? Michael N. Oxman, MD
Why do we need a herpes zoster (HZ) vaccine? First, there are more than 1 million new cases of HZ in the United States each year, and that number will increase as the population ages.^1,2 Second, once HZ develops, no treatment presently available, including early antiviral therapy (with or without corticosteroids) and pain medications, can prevent the most frequent debilitating complication of HZ, postherpetic neuralgia (PHN).^3,4 In 1965, based upon an analysis of all cases of HZ that occurred in his medical practice over a period of 16 years, Dr. R. Edgar Hope-Simpson5 published a series of important observations and a theory of the pathogenesis of HZ and PHN. He observed that the incidence and severity of HZ, as well as the incidence of PHN, increased with increasing age, and he hypothesized that this was because of an age-related decline in the immunity to varicella zoster virus (VZV) that originally developed in response to chickenpox. Hope-Simpson also observed that second episodes of HZ were relatively uncommon in healthy immunocompetent adults (in contrast to herpes simplex, which recurs repeatedly), and he hypothesized that this was because the large amount of viral antigen produced by VZV replicating in the skin and neuraxis during an episode of HZ boosts immunity to VZV, essentially “immunizing” the afflicted individual against another episode of the disease.⁵ During the past 40 years, evidence from many investigators has validated every aspect of Hope-Simpson’s prescient hypothesis, and has demonstrated that the component of the host immune response that determines susceptibility and resistance to HZ is cell-mediated immunity (CMI) rather than humoral immunity.^6,7 In the early 1970s, Dr. Michiaki Takahashi isolated VZV from a child in Japan with chickenpox and attenuated the virus by serial passage in cell culture. The resulting Oka strain of live attenuated VZV induced immune responses in susceptible children and adults that resembled those induced by natural varicella.⁸ Live attenuated Oka/Merck varicella vaccine was licensed in the United States in 1995 for the prevention of varicella in susceptible children and adults. Since then, widespread childhood immunization with varicella vaccine has nearly eliminated varicella and its complications in the United States.⁹ Based upon Hope-Simpson’s observations and hypothesis, my colleagues and I hypothesized that immunization of older adults with a VZV vaccine would boost their waning CMI to VZV and, thereby, provide protection against HZ and PHN.^1,7 However, since older adults already have significant immunity to VZV, as evidenced by their immunity to varicella, a much larger amount of VZV is required to induce a meaningful increase in VZV-specific CMI than is required for primary immunization of a child who has never been exposed to VZV. Consequently, the minimum potency of the investigational zoster vaccine used in the Shingles Prevention Study (see below) was at least 14 times greater than the minimum potency of live attenuated Oka/Merck varicella vaccine.¹

The Shingles Prevention Study
The Shingles Prevention Study (Department of Veterans Affairs [VA] Cooperative Study #403)1 was designed to test the hypothesis that imitating the immune response to VZV induced by an episode of HZ by administering a highpotency VZV vaccine would protect older adults from HZ and PHN. Several problems had to be addressed in order to carry out the study. Important among these is the assessment of outcomes. Pain is the major cause of morbidity in HZ, especially among older adults, and thus pain should be a primary outcome measure. However, pain is subjective. Therefore, essential to this study was the development of an HZ-specific assessment tool that measured not only classical pain, but also other forms of discomfort related to neural damage, such as pruritus, which can be severe enough to disturb sleep, and allodynia, which is pain elicited by normally innocuous stimuli such as the touch of clothing or a breeze on the skin in the area of the HZ rash. The assessment tool that was developed, the Zoster Brief Pain Inventory (ZBPI),¹⁰ was used serially in each suspected case of HZ to measure the severity of pain at predetermined time points over the 6 months following the onset of HZ. These measurements yielded a pain severity-by-time curve, and the area under the curve (AUC) was defined as the HZ severity-of-illness score.^1,10 It was not known whether zoster vaccine, if effective, would reduce the incidence of HZ, or the severity or duration of HZ pain and discomfort, or some combination of these. Consequently, a primary endpoint was needed that would be sensitive to a vaccine-induced reduction in any one or any combination of these parameters. The burden of illness due to HZ (HZ BOI)—defined as the sum of the HZ severity-of-illness scores of all cases of HZ in the study group (ie, vaccine or placebo recipients), with subjects who did not develop HZ during the study assigned a score of zero—was such a composite endpoint, and it was chosen as the primary study endpoint. If zoster vaccine reduced the incidence but not the severity of HZ, there would be fewer cases of HZ in the vaccine group, but these would be, on average, just as severe as those in the placebo group, and the HZ BOI would be reduced. Alternatively, if zoster vaccine reduced the severity but not the incidence of HZ, there would be just as many cases of HZ in the vaccine group as in a placebo group, but their average HZ severity-of-illness score (ie, the average AUC of the zoster pain-by-time curve) would be lower, and thus the HZ BOI would be reduced. Finally, if zoster vaccine reduced both the incidence and the severity of HZ, there would be fewer cases of HZ in the vaccine group and the cases of HZ that did occur would be less severe, again, resulting in a reduced HZ BOI. The secondary study endpoint was the incidence of clinically significant PHN. The definition here is important, because, when queried, many individuals with HZ experience minor sensory abnormalities or occasional brief episodes of mild pain or discomfort that persist after their HZ rash has healed, but that do not adversely affect their quality of life (QOL) or activities of daily living (ADLs), and do not cause them to consult a physician. Hope-Simpson argued that such persons should not be considered to have PHN.¹¹ Thus, for the Shingles Prevention Study, clinically significant PHN was defined as pain scored as 3 or higher on the 0-10 scale of the ZBPI that persists or develops more than 90 days after the onset of the HZ rash. ZBPI pain scores 3 or higher were required because scores lower than 3 are not associated with deficits in the capacity to perform ADLs or in QOL.¹⁰ The Shingles Prevention Study was a randomized, double-blind, placebo-controlled trial that enrolled 38,546 participants 60 years of age or older at 22 sites across the United States. Subjects were stratified into two age groups, those between 60 and 69 years of age and those 70 years of age or older, and randomized to receive either a single dose of investigational zoster vaccine or placebo. All subjects were followed actively by means of an automated telephone response system, and the threshold for suspecting HZ was intentionally set very low so that vaccine-modified cases would not be missed. More than 95% of the enrolled subjects were followed to the end of the study. Most of those who were not followed to the end of the study died of causes typical for their age. There were 1308 suspected cases of HZ, of which 315 were confirmed as evaluable cases of HZ in the vaccine group and 642 in the placebo group. More than 93% of the evaluable cases of HZ in each group were confirmed by the identification of VZV DNA by polymerase chain reaction (PCR) assay.¹

Results
Zoster vaccine reduced the HZ BOI in the entire population of vaccinated subjects by 61.1% (95% confidence interval [CI], 51.1%-69.1%), by 65.5% in the younger (60-69 yr) age group, and by 55.4% in the older (=70 yr) age group (Figure 1).¹ These rates exceeded the pre-specified criteria for success, which were a point estimate reduction of greater than 47% and a lower bound of the 95% CI of greater than 25%. Zoster vaccine also reduced the incidence of HZ in the entire population of vaccinated subjects by 51.3% (95% CI, 44.2%-57.6%), by 63.9% in the younger age group, but by only 37.6% in the older age group (Figure 2).¹ The adverse impact of HZ on ADL was reduced by 66% (Schmader KE, personal communication)—a reduction similar to the reduction in the HZ BOI, providing additional evidence that the HZ BOI is a valid measure of the total impact of HZ. The zoster vaccine reduced the incidence of PHN by two-thirds, even among the subjects in the older age group (Figure 3).1 This is an important outcome because the impact of PHN is much greater among older patients than among those less than 70 years of age.^1,12,13 The Shingles Prevention Study underestimated the severity of HZ, and thus the efficacy of the zoster vaccine. Study investigators made every effort to see subjects with symptoms of HZ early and initiate treatment with famciclovir, one of the two preferred antiviral treatments for HZ. In addition, HZ pain was treated aggressively.¹ Since pain was the primary measure of HZ severity, to the extent that the treatment provided to study subjects reduced the severity of HZ-associated pain, it would have reduced the severity of HZ in the placebo group and minimized the apparent efficacy of the zoster vaccine. Zoster vaccine was well tolerated. Percentages of deaths and of patients with at least one serious adverse event were ascertained actively at the end of the first 42 days after vaccination, and were similar in the placebo and vaccine groups.The occurrence of local injection site reactions was substantially greater in vaccine than in placebo recipients, but these reactions were generally transient and mild. One concern was whether the Oka strain of live attenuated VZV might actually cause HZ itself or by causing reactivation of endogenous latent wild-type VZV. In the first 30 days after vaccination, there were three times as many cases of HZ in the placebo group as in the vaccine group. Although this is not statistically significant, it does suggest that vaccination did not induce reactivation of the latent wild-type VZV in the ganglia. In addition,VZV was detected by PCR assay in 919 cases of HZ, and in every one of these the viral DNA was wild-type VZV DNA; no case of HZ yielded Oka vaccine strain VZV DNA.¹ The relationship between subjects’ age and vaccine efficacy was analyzed. In the group of subjects 70 years of age or older, the efficacy of zoster vaccine was well maintained for the HZ BOI endpoint and was undiminished for the incidence of PHN, but it was reduced for the incidence of HZ compared with vaccine efficacy in the younger age stratum. Only 9 of the 40 subjects whose HZ severity-of illness scores were greater than 600 (ie, the equivalent of more than 60 days of the worst pain imaginable) were from the younger age stratum, and all but one of these were in the placebo group. Among all subjects with HZ severity-of-illness scores greater than 600, the efficacy of the vaccine was 73%, higher than in the overall study population. Among subjects with HZ severity-of-illness scores greater than 800, vaccine efficacy was 83%. Thus, zoster vaccine was most effective in preventing the most severe cases of HZ.^1,12,13

Conclusion
The Shingles Prevention Study demonstrated the efficacy of zoster vaccine in reducing the burden of illness due to HZ, the incidence of PHN, and the incidence of HZ. In subjects less than 70 years of age, vaccine efficacy was due largely to the prevention of HZ, whereas in subjects 70 years of age and older, vaccine efficacy was due largely to the attenuation of the disease. Of the approximately 1 million cases of HZ that occur in the United States each year, more than half, as well as most of the nearly 70,000 cases of clinically significant PHN, occur among people 60 years of age or older who would be eligible for vaccination. If all of these patients were vaccinated, the number of new cases of HZ each year in the United States would be reduced by at least 280,000 and the number of new cases of PHN by at least 46,000. Since some cases of PHN persist for more than a year, the cumulative effect would be even greater. Several questions remain unanswered: How long does the effect of the HZ vaccine last? Will people need boosters and, if so, when? Why is the indication for HZ vaccine different between the Food and Drug Administration approval and the preliminary recommendations of the Advisory Committee on Immunization Practices issued in October 2006? Should patients with histories of HZ be vaccinated, or would this just be “bringing coals to Newcastle”? Should people younger than 60 years of age be vaccinated, even though this would be an off-label use of the vaccine? What about the use of HZ vaccine in immunocompromised patients, in particular, patients with rheumatoid arthritis who are receiving modest doses of steroids or tumor necrosis factor inhibitors, a growing and important population? Finally, who is going to pay for the HZ vaccine?

References
1. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284. 2. Insinga RP, Itzler RF, Pellissier JM, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748-753. 3. Gnann J, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med 2002;347:340-346. 4. Kost RG, Straus SE. Postherpetic neuralgia—Pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32-42. 5. Hope-Simpson RE The nature of herpes zoster: A long-term study and a new hypothesis. Proc R Soc Med 1965;58:9-20. 6. Arvin AM. Cell-mediated immunity to varicella-zoster virus. J Infect Dis 1992;166(suppl 1):S35-S41. 7. Oxman MN. Immunization to reduce the frequency and severity of herpes zoster and its complications. Neurology 1995;45(12 suppl 8):S41-S46. 8. Takahashi M. Clinical overview of varicella vaccine: Development and early studies. Pediatrics 1986;78(4 pt 2):S736-S741. 9. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Eng J Med 2005;352:450-458. 10. Coplan PM, Schmader K, Nikas A, et al. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the brief pain inventory. J Pain 2004;5:344-356. 11. Hope-Simpson RE. Postherpetic neuralgia. J R Coll Gen Pract 1975;25:571-575. 12. Oxman MN, Williams HM, Levin MJ, et al. The impact of age on the efficacy of zoster vaccine. Presented at:The 43rd Annual Meeting of the Infectious Diseases Society of America; October 6-9, 2005; San Francisco, CA. 13. Oxman MN, Weinberg A, Stanley HA, et al.VZV-specific immune responses in older adult recipients of a clinically effective herpes zoster vaccine. J Nutr Health Aging 2006;10:343.

Current Treatment and Future Strategies for Herpes Zoster and Postherpetic Neuralgia CME Assessment Test Answer Sheet Instructions: Release Date: September 15, 2007 • Expiration Date: September 14, 2008
To receive a certificate of completion: 1. Read all articles in the supplement. 2. Circle your answers to the post-test questions in the section below. 3. Complete the program evaluation. 4. Submit the test and evaluation via fax or mail to: American Geriatrics Society Attn:Dennise McAlpin • The Empire State Building • 350 Fifth Ave, Suite 801 • New York, NY 10118 • Fax: (212) 832-8646 Please allow 4 weeks for processing. Please phone (212) 308-1414 with any questions. 1. A B C D 2. A B C D 3. A B C D E 4. A B C D 5. A B 6. A B C D 7. A B C D E 8. A B C D E 9. A B C D 10. A B C D

PARTICIPANT INFORMATION (please print clearly)
Name/Degree: Specialty Title: Affiliation: Mailing Address (including name of business if work address): City: State: ZIP: Daytime Phone: Fax: E-mail: Signature: Date Completed: Hours of CME requested: ______0.5 ______1.0 1. There are approximately_______new cases of HZ in the United States each year. A. 10,000 B. 500,000 C. 1 million D. 5 million 2. The primary goal of treatment for HZ is A. reducing pain. B. reducing the rash. C. preventing further complications. D. None of the above 3. Famciclovir and valacyclovir are preferred over acyclovir for treating HZ because A. they have greater bioavailability. B. the required duration of treatment is shorter. C. they require less-frequent dosing. D. A and C E. B and C 4. Although opioids are considered the gold standard for pain treatment, elderly patients A. are afraid to take them. B. may not tolerate their side effects. C. tend to become addicted too easily. D. All of the above 5. Gabapentin and pregabalin are the only anticonvulsants currently approved by the FDA to treat PHN. A. True B. False 6. Although tricyclic antidepressants are effective in treating PHN, the drug with the highest risk of anticholingeric adverse effects is A. nortriptyline. B. desipramine. C. amitriptyline. D. imipramine. 7. Nonpharmacologic measures that help control chronic pain include A. mental and physical activity. B. psychological counseling. C. trigger point injections. D. acupuncture. E. All of the above 8. The lifetime risk of developing HZ is approximately_____%. A. 5 B. 10 C. 20 D. 30 E. 45 9. In the 10 years since the introduction of the varicella vaccine, the incidence of chickenpox has decreased by about_____%. A. 75 B. 80 C. 90 D. 95 10. In the Shingles Prevention Study, use of the herpes vaccine reduced the incidence of PHN among patients at least 70 years of age by more than_____%. A. 80 B. 70 C. 60 D. 50

CME Evaluation Form
Please indicate the degree to which you believe you are able to achieve the stated learning objectives after completing this program: Explain the rationale for the use of a zoster vaccine to prevent herpes zoster and postherpetic neuralgia in older adults and the pharmacoeconomic implications of the vaccine. Completely Partly Not at All Describe how the zoster vaccine is being used in the United States and around the world. Completely Partly Not at All Discuss the most recent data on the impact of the varicella vaccine on chickenpox and herpes zoster. Completely Partly Not at All Discuss state-of-the-art thinking/practice regarding the treatment of acute herpes zoster pain and postherpetic neuralgia. Completely Partly Not at All Please circle the response below that best describes your experience with this CME activity. Poor Satisfactory Excellent 1 2 3 4 5 1. Program topic and content: 1 2 3 4 5 2. How well program met your expectations: 1 2 3 4 5 3. Level of difficulty of material: 1 2 3 4 5 4. Applicability of program examination questions: 1 2 3 4 5 5. Absence of commercial bias: 1 2 3 4 5 6. Potential impact on your practice: 1 2 3 4 5 7.Overall opinion of the program: 1 2 3 4 5 Additional comments: Suggestions for future CME topics: This activity is sponsored by the American Geriatrics Society, published by HMP Communications, and supported by an educational grant from Merck & Co., Inc. The views expressed in this publication are not necessarily those of the American Geriatrics Society, Merck & Co., Inc., or the publisher. This publication may not be reproduced in whole or in part without the express written permission of HMP Communications. HMP Communications 83 General Warren, Blvd., Suite 100 Malvern, PA 19355 800-237-7285 www.hmpcommunications.com Copyright © 2007 HMP Communications. All rights reserved. Printed in USA. G-230-07-001