ABSTRACT: A varicella-zoster vaccine significantly decreases incidence of herpes zoster and postherpetic neuralgia in immunocompetent individuals aged 60 years and older.

CME OBJECTIVE: The reader will understand the study findings and therapeutic approaches for treatment of herpes zoster and postherpetic neuralgia.
John W. Gnann, Jr, MD, grants and research support Merck, Novartis; consultant GlaxoSmithKline

A nationwide clinical study finds vaccination significantly reduces incidence and severity of herpes zoster, commonly known as shingles. Nearly 1 million Americans are afflicted annually by the disease. Caused by a reactivation of latent varicella-zoster virus within the sensory ganglia, shingles primarily affects older adults who had chickenpox as children. Findings were published in the June 2, 2005 New England Journal of Medicine (352;22:2271-2284).

Infectious diseases experts at 16 Veterans Affairs (VA) medical centers and at six National Institute of Allergy and Infectious Diseases-funded research sites collaborated on the Shingles Prevention study, a double-blind placebo-controlled trial to evaluate a live attenuated Oka/Merck “zoster” vaccine. The investigational vaccine, essentially a larger dose of the chickenpox vaccine routinely used to immunize children since 1995, has a much higher potency with a median 24,600 plaque-forming units (PFU) per dose compared with 1350 PFU in the varicella vaccine.

The study followed 38,546 immunocompetent volunteers, aged 60 years and older, with a history of varicella. Participants received a one-time injection of active vaccine or placebo. More than 95% of participants completed the trial, which was conducted between 1998 and 2001 with 3-year follow ups.

“Because a case of herpes zoster boosts immunity and keeps the virus in check, immunocompetent patients seldom develop shingles more than once. The goal of the study was to increase immunity against the varicella-zoster virus in older healthy adults to determine if doing so improves their immune systems’ ability to control the virus and prevent reactivation as shingles,” says UAB infectious diseases expert John W. Gnann, Jr, MD, principal investigator for the Birmingham VA Medical Center study site.

The painful rash caused by herpes zoster features clusters of vesicles and pustules with surrounding erythema developing unilaterally along dermatomes. Individuals can initially mistake the rash for an outbreak of poison ivy or an allergic reaction.

In the study, the burden of illness associated with herpes zoster was measured by incidence, severity, and duration of pain and discomfort associated with the disease, as well as incidence of postherpetic neuralgia (PHN) — the debilitating complication of shingles that causes persistent pain after the characteristic dermatomal rash heals. About 35% of those who develop herpes zoster after age 60 years develop PHN.

Nationwide, study participants had 957 confirmed cases of herpes zoster: 315 vaccine recipients and 642 placebo recipients developed shingles. In addition, 27 vaccine recipients and 80 placebo recipients developed PHN. In the vaccine group, the incidence of herpes zoster was reduced by 51.3%, the burden of illness by 61.1%, and the incidence of PHN by 66.5%.

“The vaccine not only markedly decreased incidence of shingles, but also substantially diminished severity of symptoms, including postherpetic neuralgia, among individuals who developed shingles,” says Gnann, who considers the study an overwhelming success.

Beyond a prior varicella infection, advancing age and decreasing immunity are the two principal risk factors for herpes zoster. Immunosuppressive drugs, lymphoma, and radiation therapy also can reactivate the virus.

“Cell-mediated immunity declines as we age,” says Gnann. “The incidence of shingles is lower among people younger than 60. The curve becomes steeper when people hit age 55 or 60, and half of all adults who reach age 85 will be afflicted.” The implication for an aging US population is clear: with 35 million Americans older than 65 years (a 12% increase from 1990), the number of shingles cases will increase as baby boomers enter their 60s.

Existing Treatment Options

Once chickenpox has run its course, the varicella-zoster virus persists in a latent state along the entire neuraxis and, once reactivated later in life, can crop up anywhere on the skin. Until adult vaccination is routine, only “early diagnosis and antiviral treatment can slow viral replication and decrease the pain and duration of an attack,” says Gnann.

To be beneficial, antivirals such as acyclovir (Zovirax), valacyclovir (Valtrex), or famciclovir (Famvir) must be administered in high doses as soon as possible after the rash appears. Gnann notes all three drugs are relatively well tolerated, but a dose adjustment is required for patients with renal insufficiency.

“Beyond the first 72 hours, treatment is less likely to be effective,” says Gnann, who regrets that patients — who often do not recognize the relatively unfamiliar symptoms of shingles — are often diagnosed days after symptoms appear, delaying treatment. “As with any infection, prevention rather than treatment is a much better option.”

Following disappearance of lesions, lingering symptoms experienced by nearly 50% of patients 70 years and older include persistent burning pain and hyperesthesia in areas supplied by the involved sensory nerves. PHN may last for months or years, and available therapies offer only limited relief.

Gnann emphasizes that clinicians should not underestimate the severity of neuropathic pain, which although rarely life-threatening, can be prolonged and disabling, leading to significant depression and morbidity. “Because neuropathic pain involves both peripheral and central nervous systems, it has a complex pathogenesis, making treatment challenging,” he says.

Because there is no single effective remedy to alleviate symptoms, pain therapy should be tailored to individual patients. Pain management is particularly complicated when treating elderly patients, who often suffer more than younger individuals from the adverse effects of medications. Administered separately or in combination, numerous topical medications, such as lidocaine patches, and oral medications, including gabapentin, pregabalin, nortriptyline, and opioids, can reduce PHN severity.

Younger, healthier, middle-aged people tolerate shingles better than older patients and have fewer problems with long-term pain. “It is a linear relationship — the older patients are, the higher their risk for shingles. If they develop the condition, they have a significantly higher risk for postherpetic neuralgia and long-term pain,” Gnann says. “Severe pain during acute episodes of herpes zoster predicts patients who are at increased risk for long-term pain.”

Vaccine Shows Promise

From the Shingles Prevention Study, researchers conclude varicella-zoster vaccine markedly reduces risk for developing shingles, as well as incidence of PHN in immunocompetent individuals 60 years and older.

“In fact, the reduction in incidence was more apparent in the slightly younger 60 to 65 age group,” says Gnann. “The reduction in severity was more pronounced among older participants.” Regarding response, there were no upper age limits in the study. Further research will determine if a booster vaccination is needed.

Food and Drug Administration approval is pending on Merck’s live-attenuated varicella-zoster virus vaccine, trademarked Zostavax. Study investigators and the FDA review panel deemed the vaccine safe and well tolerated, with no serious adverse effects clearly attributable to vaccination. Local reactivity, with some redness and soreness at the vaccination site similar to that with a flu vaccination, was the only apparent adverse effect, which occurred with significantly greater frequency in the study’s vaccine group: 35.8% showed redness around the injection site, 34.5% experienced pain or tenderness, 26.2% had swelling, and 7.1% noted itching.

Although well tolerated among older healthy adults, the vaccine is not recommended for immunocompromised patients, including patients with cancer or HIV infection. “The varicella-zoster vaccine is a live-virus vaccine and could pose additional risks for these individuals, because their compromised immune systems might not be able to control the virus,” says Gnann, noting that smaller studies with killed-virus vaccines are underway in this patient population.

For more information
Dr. John Gnann
1.800.UAB.MIST
mist@uabmc.edu