New options for varicella prophylaxis now available

July 2006

Over the past several months, two new agents have become available to aid clinicians in preventing infections due to varicella-zoster virus (VZV).

The first agent is Zostavax (Merck), a new vaccine licensed by the FDA in May that is designed to reduce the risk of shingles, or herpes zoster, in people aged 60 years and older. The second agent is a new formulation of an older product, varicella-zoster immune globulin (VZIG). Although the U.S. production of VZIG was discontinued in 2004, there is a similar product that is not licensed in the United States, but is approved in Canada, VariZIG (Cangene Corp.), which is now available under an investigational new drug (IND) application for appropriate patients.

Varicella-zoster infection

Primary infection with the VZV causes chickenpox in susceptible individuals. Chickenpox is a contagious, usually benign, viral infection that occurs most often in children, infecting more than 90% of the U.S. population before adulthood. When primary infection does occur in adults, the disease tends to be more severe and can be complicated by VZV encephalitis and pneumonia. VZV has the potential to be fatal, particularly in the elderly, neonate and immunocompromised patient populations. After primary infection with VZV, the virus becomes latent and resides in the sensory dorsal root ganglia.

Reactivation of latent VZV infection within the sensory ganglia results in herpes zoster. Unilateral pain and a vesicular rash along the dermatome of a nerve root characterize the syndrome. Shingles can lead to significant complications including postherpetic neuralgia as well as ocular, neurologic and bacterial superinfection of the skin. The complications associated with herpes zoster can be very disabling, have a profound effect on a patient’s quality of life and are difficult to treat effectively.

Herpes zoster cases are reported in up to 600,000 individuals each year, with the highest incidence — five to 10 cases per 1,000 people — occurring after age 60. The occurrence and severity of postherpetic neuralgia also increases as a person ages. Antiviral therapy has been shown to reduce the severity and duration of herpes zoster, but does not prevent the development of postherpetic neuralgia. Antiviral agents that are currently available for the treatment of herpes zoster include acyclovir, famciclovir (Famvir, Novartis) and valacyclovir (Valtrex, GlaxoSmithKline). These drugs mainly shorten the duration of viral shedding, halt the formation of new lesions, accelerate healing and reduce the severity of acute pain. They have little effect on the prevention and duration of postherpetic neuralgia. Of these agents, valacyclovir and famciclovir are preferred due to favorable dosage and pharmacokinetics. If antiviral therapy is initiated, it should be done within the first 72 hours after the onset of lesions. Earlier onset of therapy may provide better response.

If antiviral therapy is delayed, not provided, or ineffective, treatment for patients with postherpetic neuralgias focuses on pain management. Usually, a multi-pharmacologic approach is taken, using agents, such as tricyclic antidepressants, opioid analgesics and gabapentin (Lyrica, Pfizer). When used either alone or in combination, these agents can reduce the severity and duration of postherpetic neuralgia. In addition, the topical application of lidocaine patches or capsaicin cream can provide relief for some patients.

Given the limitations of these treatment strategies, a more desirable approach may be to prevent primary infection with VZV, subsequent reactivation of disease and development of herpes zoster.

Preventing primary infection

Varivax: The varicella zoster virus Oka strain vaccine (Varivax, Merck) is a live-attenuated vaccine that has been available since the early 1990s for prevention of chickenpox in children and at-risk adults. The Advisory Committee on Immunization Practices (ACIP) recommends this vaccine for universal childhood vaccination at any visit at or after 12 months for susceptible children.

The ACIP recommends the vaccine for all adults without evidence of immunity to varicella. Special consideration should be given to those with any of the following criteria:

• Those who have close contact with people at high risk for severe disease, such as health care workers and family contacts of immunocompromised people;
• Those who are at high risk for exposure or transmission, including teachers of young children, child care employees, residents and staff members of institutional settings such as correctional institutions, college students and military personnel;
• Adolescents and adults living in households with children;
• Nonpregnant women of childbearing age;
• International travelers.

For all patients older than age 13, a second booster dose is required within four to eight weeks after the initial immunization.

Routine vaccination is clearly the most effective strategy for preventing complications associated with VZV infection. However, in cases where the live vaccine is contraindicated or for patients without immunity, it is sometimes necessary to provide prophylaxis following a documented varicella exposure. The vaccine can be used as post-exposure prophylaxis and should be offered to any eligible, exposed individual within two to five days after exposure.

If vaccination is not an option, immune globulin preparations made from plasma with high levels of antivaricella antibodies can be administered as post-exposure prophylaxis. The only U.S. company licensed to produce VZIG, Massachusetts Public Health Biologic Laboratories, discontinued the product in October 2004. There are no other licensed products in the United States to meet this need.

In February 2006, the FDA granted an investigational new drug (IND) application to Cangene Corp. in Winnipeg, Canada, to distribute a similar immune globulin product, VariZIG, in the U.S. This lyophilized product can be administered either intravenously (IV) or intramuscularly (IM), although the IV route does result in more rapid peak serum concentrations. As with any other investigational product, patients must qualify to receive the product and provide written, informed consent prior to administration.

When a patient without history of prior immunity is exposed to varicella, the ACIP recommends that VariZIG be considered for the following people:

• Those who are immunocompromised;
• Neonates whose mothers have signs and symptoms of varicella around the time of delivery, five days before to two days after;
• Premature infants born at 28 weeks or less of gestation who are exposed during the neonatal period and whose mothers do not have evidence of immunity;
• Premature infants born at more than 28 weeks of gestation or who weigh <1,000 g at birth and were exposed during the neonatal period, regardless of maternal history of varicella disease or vaccination;
• Pregnant women.

VariZIG should be administered as soon as possible following exposure and no longer than 96 hours following varicella exposure. It is dosed based on body weight in international units (IU). The recommended dose is 125 IU/10 kg, not to exceed 625 IU.

VariZIG can only be obtained on an as needed basis from FFE Enterprises in Temecula, California. Although approval from the central Institutional Review Board (IRB) has been obtained, many institutions may require local IRB approval prior to administration as well. Health care providers who anticipate use of this product may complete the regulatory process and stock small supplies of VariZIG in advance. The available supply does not permit this and drug will only be released for individual patient cases; however, it is anticipated that advance inventories will be allowed in the coming months. There is hope that this product will gain FDA approval and be available commercially by the end of 2007.

More information on how to obtain VariZIG is available at the CDC Web site: www.cdc.gov/mmwr/preview/mmwrhtml/mm5508a5.htm.

Prevention of shingles

Zostavax: Until recently it was unknown whether immunization against VZV for adults aged 60 years or older would boost their immunity enough to prevent the development of herpes zoster and postherpetic neuralgia. The Shingles Prevention Study (SPS), published in the June 2, 2005 issue of The New England Journal of Medicine, was conducted to determine whether the VZV vaccine would decrease the incidence, severity or both of herpes zoster and postherpetic neuralgia in adults aged 60 or older. The vaccine used in the study contains the same live-attenuated virus as in Varivax, Merck’s childhood chickenpox vaccine, but at concentrations about 14 times that found in Varivax. It contains 18,700 to 60,000 plaque-forming units of virus. Median potency in the study was 24,6000, considerably more potent than the approximately 1,350 plaque-forming units found in Varivax.

The randomized, double-blind, placebo-controlled study enrolled eligible immunocompetent adults aged 60 or older who had a history of varicella or who had lived in the United States for at least 30 years. Eligible patients randomly received the VZV vaccine or placebo with follow-ups to determine the burden of illness associated with the development of herpes zoster. The burden of illness was a severity by duration measure of the total pain and discomfort associated with zoster in the population of study patients. A total of 38,546 patients were enrolled in the study with more than 95% continuing to study completion. The results were quite substantial, with a 61% reduction in pain and discomfort due to herpes zoster for the vaccinated group and a 66% reduction of the incidence of postherpetic compared to placebo.

The incidence of zoster in the placebo group was 11.12 per 1,000 person-years, which corresponds to the results of previous epidemiologic surveys. Of note, the incidence in the vaccinated group was only 5.42 per 1,000 person-years. Minor adverse events after vaccination included redness, pain or tenderness, pruritus and swelling, mainly at the injection site. The incidence of these was 48% and 17% for the vaccine and placebo groups, respectively. Serious adverse events were uncommon but statistically higher, 1.9% vs. 1.3%, in the vaccine recipients.

The results of the SPS study were instrumental in the FDA granting approval to Merck to market Zostavax to prevent the development of herpes zoster in people aged 60 and older. It is important to note that this vaccine is not a treatment for shingles in older adults, but only a preventive strategy.

In summary, VZV may affect a wide range of populations from neonates to the elderly. Varivax is a well-established component of the childhood immunization schedule and has proven efficacy for prevention of VZV disease as well as post-exposure prophylaxis. Zostavax now has a role in decreasing the incidence, severity and complications of herpes zoster in older individuals. It is anticipated VariZIG will provide post-exposure prophylaxis for susceptible patients who cannot receive Varivax. Look for U.S. approval in late 2007.

For more information:

• Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-2284.
• Gnann JW Jr, Whitley RJ. Herpes zoster. N Engl J Med. 2002;347:340-346.
• CDC. Prevention of varicella updated recommendations of the ACIP. MMWR. 1999 ; Accessed 5/20/02006 at: www.cdc.gov/mmwr/preview/mmwrhtml/rr4806a1.htm