Herpes Zoster: Counseling Patients About Prevention and Treatment

RELEASE DATE: April 1, 2016

EXPIRATION DATE: April 30, 2018

FACULTY:

Edward M. DeSimone II, RPh, PhD, FAPhA
Professor of Pharmacy Sciences
School of Pharmacy and Health Professions
Creighton University
Omaha, Nebraska

Derek E. Popken, RPh, PharmD
Community Pharmacy Practice Resident
School of Pharmacy and Health Professions
Creighton University
Omaha, Nebraska

FACULTY DISCLOSURE STATEMENTS:

Drs. Popken and DeSimone have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-16-016-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

FEE INFORMATION:

Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
CE Customer Service: (800) 825-4696 or cecustomerservice@jobson.com

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To enhance pharmacists' knowledge of the pathophysiology and clinical presentation of herpes zoster and to provide patient counseling information regarding prevention and treatment.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Understand the pathophysiology and presentation of herpes zoster, as well as its clinical features and complications.
  2. Describe pharmacologic therapies for the treatment of herpes zoster and its complications.
  3. Discuss the features of the vaccine used for the prevention of herpes zoster.
  4. Counsel patients on important information about herpes zoster, including prevention and treatment.

ABSTRACT: Herpes zoster (shingles), which is caused by the same virus as chickenpox, is a painful and debilitating disease that has dermatologic, neurologic, vascular, and ophthalmic consequences and may result in physical, psychological, and financial stresses. Advanced age is the strongest risk factor for a shingles outbreak. Recommendations exist regarding which individuals should be vaccinated, and at what age. Pharmacists have a crucial role in educating patients about herpes zoster and preventive measures, including the appropriateness of vaccination. Pharmacologic management aims to treat the patient’s clinical manifestations of shingles. Drugs used to treat this disease include antivirals, anticonvulsants, tricyclic antidepressants, and opiates. Pharmacists can assist patients by performing drug-utilization reviews and medication therapy management, as well as by providing counseling on treatment.

Herpes zoster (HZ), commonly known as shingles, is a debilitating disease caused by the same virus that is responsible for chickenpox.1 After a patient’s chickenpox clears, the virus remains dormant in the body. As the person ages, the risk of viral reactivation increases, and if reactivation occurs, shingles develops. HZ affects millions of Americans each year, resulting in short-term and long-term physical, psychological, and financial stresses. A variety of drugs are available to treat HZ and the health problems it can cause.

BACKGROUND

Pathogenesis
Chickenpox, a common childhood disease, is caused by the varicella-zoster virus (VZV) and is transmitted by way of an airborne mechanism (e.g., coughing or sneezing). It can also be imparted by inhaling or touching the viral particles that emanate from the vesicles.1 Upon transmission, primarily through the respiratory system, VZV begins local replication in the nasopharyngeal pathway.1,2 The virus then migrates from lymphoid tissues to infiltrate circulating CD4+ T cells, establishing an incubation period of 10 to 21 days.1 Skin manifestations of chickenpox develop once the virus reaches the skin, resulting in a vesicular rash that is accompanied by itching, fatigue, and fever. Most people develop lifelong immunity after the initial varicella infection. This immunity develops through three different mechanisms: innate immune response, humoral immune response, and cell-mediated immunity (CMI). CMI is the most important host response for long-term protection against VZV. Once CMI is established, latency is maintained unless the virus reactivates, manifesting as HZ.1

Latency
During an active varicella infection, cell-free VZV penetrates sensory neurons via epithelial cells, resulting in latency. Once in the neuron, the virus migrates through retrograde axonal transport, ultimately reaching cell bodies located in the dorsal root ganglia (DRGs) and cranial root ganglia (CRGs).1 The DRG is an afferent sensory ganglion located in the spinal cord, whereas the CRG is located in the brain and innervates sensory and motor neurons of the head and neck. It is hypothesized that during VZV’s viremic stage, infected T cells carrying the virus combine with neurons located in the DRGs and/or CRGs. Proliferation begins inside neuronal cell bodies, and latency is established once proliferation ceases.1 Latent cells do not express viral antigens and therefore are protected from CMI responses.

Reactivation
Latency is maintained until a variety of host factors trigger VZV reactivation, leading to a lytic infection. A lytic infection is a consequence of unopposed viral replication inside cells that ultimately leads to cellular rupture and the release of viral progeny capable of infecting other cells. Through a variety of biochemical interactions, the inhibitory effects of genes proposed to prevent viral transcription and replication are interrupted, resulting in the translocation of viral products to neuronal nuclei—most commonly, the trigeminal, cervical, and thoracic sensory nerves.2 Unopposed viral transcription in the affected ganglia progresses to local cellular necrosis and inflammation, ultimately producing the clinical manifestations of HZ.3

Manifestations
With the initiation of the reactivation process, neuronal destruction caused by HZ activity results in clinical manifestations. Frequently, patients experience prodromal sensations in the area of skin innervated by the DRG or dermatome that will eventually become the site of the vesicular rash. Tingling and pain generally develop 2 to 4 days prior to the eruption of lesions. A unilateral rash that initially presents as erythematous, macropapular lesions transforms into vesicles within the first 24 hours. Furthermore, the rash typically does not cross the mid-line (the imaginary line separating the left and right sides of the body). This process continues for 3 to 7 days until the vesicles develop into pustules and ultimately scab over, approximately 10 days later.2,4,5

Differential Diagnosis
The development of a unilateral vesicular rash is the signal necessitating further investigation to differentiate HZ from other pathogenic processes. For example, a patient presenting with herpes simplex virus (HSV) may be inaccurately diagnosed with HZ based on similar features.4 Furthermore, important characteristics are necessary for an observational diagnosis. These may include a past history of chickenpox, possible painful prodromal sensation, dermatomal distribution, papules with or without grouped vesicles, no previous history of similar rash, or a painful rash with surrounding allodynia (pain from a stimulus that normally would not provoke a reaction).2 Generally, diagnosis is made on the basis of the patient’s presenting signs and symptoms. However, for a definitive diagnosis, laboratory tests may be used. Testing may be recommended for patients with HIV/ AIDS, patients undergoing organ transplantation, newborns, or pregnant patients.2

Advances in laboratory testing have decreased false-negatives while increasing VZV specificity. Tzanck smears have been used to identify multinucleated giant cells in lesions, but this inexpensive test fails to differentiate between HSV and VZV. Lesion culture results in delayed identification, as well as false-negatives, because viable specimens are difficult to recover. Compared with culturing, direct fluorescent antibody testing provides faster identification at a lower cost; however, this test has a decreased sensitivity for identifying VZV. Polymerase chain reaction (PCR) provides rapid results with the greatest sensitivity for VZV antigens. Furthermore, a modified PCR test has been used to differentiate between wild-type strains and vaccine strains of VZV (Oka/Merck).3 Unfortunately, this test is expensive, it takes a day to get results, and not all laboratory settings are equipped with the technology necessary to perform the test.2,3

EPIDEMIOLOGY

Incidence
According to epidemiologic data, the incidence of HZ is estimated to occur at a rate of 3.2 cases per 1,000 person-years annually in the United States.3 Furthermore, with approximately 1 million cases occurring each year, studies suggest that the prevalence of HZ is increasing.4 One explanation could be that changing demographics have resulted in a more vulnerable population because of increased risk factors.

Risk Factors
VZV Infection: A previous VZV infection is a prerequisite for reactivation of latent VZV to HZ. Older adults are at greater risk, owing to the high prevalence of a previous wild-type VZV infection in people aged >40 years, as well as diminished immune competency. Two doses of varicella vaccine are highly effective at preventing varicella infections due to wild-type strains of VZV. Consequently, initial infections associated with vaccine-type VZV that may be prevented are not likely to progress to HZ in these individuals.3

Age: After previous infection, age is the most important factor for the evolution of HZ. As a person ages, VZV-specific CMI responses diminish, leaving him or her vulnerable to reactivation.1 Older individuals are more likely to have had chickenpox, and many are unvaccinated. The incidence of HZ approaches 50% in such patients who attain 85 years of age.1 The incidence is 10.9 cases per 1,000 person-years in persons aged ≥80 years.2 Conversely, individuals with immature immune activity—such as infants—who experience an early varicella infection are more susceptible to reactivation in childhood.3

Asthma: As a follow-up to earlier studies suggesting a correlation, a recent study examined the relationship between asthma and HZ in children. This population-based study included a cohort of 459 pediatric and adolescent subjects. It was concluded that the risk of HZ development in children and adolescents was significant in subjects who had a diagnosis of asthma.6

Immune Status: With advancing age, CMI deficiencies in immunocompromised persons are a major risk factor for the development and severity of HZ.1 Immunosuppression can emerge from a variety of etiologies, including medications, which can influence HZ and the ensuing complications. Patients with malignancies have an increased risk of VZV reactivation, not only because of the underlying disease, but also because of the disease-specific treatment regimens. Moreover, rates of HZ in patients who have undergone solid-organ and stem-cell transplantation are greatest in the first year following the procedure—up to 17% and 55%, respectively. HIV-positive patients with declining CD4+ T cells are equally susceptible, with a reported frequency 12 to 17 times greater than in HIV-negative patients.3,5 TABLE 1 provides a summary of risk factors for HZ reactivation.


Inflammatory Disorders: A number of recent studies have investigated the treatment of various inflammatory disorders, especially rheumatoid arthritis (RA) and the incidence of shingles. Research has focused on whether a disorder or its treatment increases the risk of HZ. Two studies have reported that RA patients were at greater risk for HZ and that this risk was increased when certain drug treatments were initiated.7,8 In one study, the risk of HZ was doubled in RA patients and even higher in patients taking disease-modifying antirheumatic drugs (DMARDs).8 See TABLE 2 for a list of DMARDs.


Some concern has been raised about the use of other drugs—especially tumor necrosis factor antagonists—to treat inflammatory disorders other than RA, although data have been inconclusive. A study investigating the use of tumor necrosis factor antagonists (infliximab, adalimumab, and etanercept) to treat ankylosing spondylitis, inflammatory bowel disease, psoriasis, and psoriatic arthritis concluded that there was no increase in HZ in patients who received these agents.9 This study, which also examined corticosteroids (which are used to treat a variety of inflammatory disorders), determined that a mean daily corticosteroid dosage of ≥10 mg (prednisone equivalents) was associated with a significantly higher risk of HZ regardless of which inflammatory disease was being treated.9

COMPLICATIONS

Complications associated with HZ reactivation can be classified according to location. Classifications include cutaneous, neurologic, ocular, vascular, and visceral complications.

Postherpetic Neuralgia
Postherpetic neuralgia (PHN) is an aftereffect of damage to nerve tissues in the skin and spinal cord following latent HZ reactivation. PHN, which is dermatomal pain continuing for more than 90 days following the onset of a herpetic rash, is the most common complication associated with HZ.10 Advanced age, rash severity, and greater initial pain with HZ onset have a strong correlation with the incidence of PHN. Patients who have chronic diseases or are immunocompromised may also be at higher risk. Specifically, the occurrence of PHN has been shown to increase from 8% in persons aged 50 to 54 years to 21% in those aged 80 to 84 years.10 The pain associated with PHN is difficult to treat and may be extremely debilitating. Consequently, quality of life and independence may be diminished, and the patient may simultaneously experience an increased financial burden from unexpected healthcare costs.10

HZ Ophthalmicus
HZ ophthalmicus (HZO) is the second most common complication following HZ reactivation.11 However, the incidence and outcomes can be difficult to determine owing to the lack of a consensus definition in the literature.11 Commonly, HZO is considered to be a relationship between HZ and the ophthalmic branch of the fifth cranial nerve that can manifest with or without direct eye involvement. Severe complications may occur as reactivated HZ migrates to the nasociliary nerve, which innervates many of the surrounding tissues and major structures of the eye. These areas include the ethmoidal sinuses, the skin on the tip of the nose and the eyelids, and the conjunctiva, sclera, cornea, iris, and/or choroid. Consequently, HZO can manifest as a periorbital rash similar to that of HZ, whereas acute optic neuritis (an uncommon complication of HZO) may progress to permanent vision loss.12 Patients may present with varying degrees of involvement, in some cases severe, as depicted in FIGURE 1. An estimated 9% of the 1 million annual HZ infections will involve some form of HZO, which translates to a lifetime risk of 1%.11,12


Vasculopathy
Epidemiologic data have suggested that some acute vascular events may be due to endothelial dysfunction associated with HZ reactivation.13 Recent publications have identified a significant correlation between HZ and an increased risk of stroke within the first 6 months following reactivation.13 Compared with patients without ocular involvement, those with HZO were at greatest risk for an acute vascular event. Furthermore, the highest incidence occurred within the first 4 weeks after HZ reactivation, with the risk gradually decreasing over the subsequent 22 weeks. It has also been suggested that HZ vaccination and early antiviral therapy may reduce the prevalence of vascular events.13 TABLE 3 summarizes the complications associated with HZ reactivation.


HZ MANAGEMENT

The management of modifiable risk factors, such as stress reduction and treatment of coexisting conditions, involves measures that can help prevent VZV reactivation. However, the primary goal of managing HZ is to treat the complications that may develop during the active stage.

Antivirals
Antiviral agents interact with viral kinases during phases of replication in which, upon phosphorylation, DNA polymerase ceases function.2 Consequently, viral shedding is reduced, lesions heal faster, and the acute pain is less severe. Antivirals should be initiated in patients with HZ who are >50 years old, are experiencing moderate-to-severe pain or rash, present with HZO or other severe complications, are immunocompromised, or have nontruncal involvement (i.e., the face).2,4 Ideally, these agents should be initiated within 72 hours of rash formation; however, delayed initiation may still be beneficial, especially in patients with new lesion formation >3 days after a rash is observed.2,4

The antiviral agents most commonly used to treat HZ are acyclovir, valacyclovir, and famciclovir. All antivirals require multiple daily doses, with acyclovir requiring at least five daily doses; therefore, medication adherence could be a barrier to adequate treatment in some patients. Valacyclovir and famciclovir are administered three times daily, which may facilitate adherence; moreover, acyclovir is available in a suspension, which may be beneficial for some patients who have difficulty swallowing. In patients who are immunocompromised, have had organ or bone marrow transplants, or are undergoing chemotherapy, acyclovir may be administered at an IV dosage of 10 mg/kg every 8 hours for 7 days. In HIV-infected patients with visceral involvement or extensive cutaneous lesions, HIV guidelines recommend an IV dosage of 10 to 15 mg/kg every 8 hours until the patient experiences clinical improvement. At this point, oral therapy with one of these three agents may be started so as to complete a total therapy course of 10 to 14 days.14 Nephrotoxicity is a potential problem with systemic acyclovir, especially in patients who are dehydrated, have renal dysfunction, or are taking high doses. Diligent monitoring of renal function and maintenance of adequate hydration are critical.2,4 The manufacturer recommends using ideal body weight in the dosing of obese adults.15

Adverse effects are similar among these agents. Headaches and gastrointestinal complications are the most commonly reported mild adverse effects. See TABLE 4 for a summary of antiviral agents used to treat HZ.


Supplemental Therapy for Acute Pain
Opioid and nonopioid analgesics may be used as adjunctive therapy for acute pain, and nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen may be appropriate for patients experiencing mild-to-moderate pain.4 However, NSAIDs should be used conservatively in patients with underlying cardiovascular disease or those taking certain medications. For instance, ACE inhibitors may exacerbate renal insufficiency when given with antiviral therapy. Oxycodone and tramadol, with or without a nonopioid component, have been useful for managing moderate-to-severe pain.4 Although these analgesics are efficacious, nonanalgesic effects, including self-limiting effects such as nausea, sedation, and sexual dysfunction, may be difficult to manage or overcome in some patients. Furthermore, when needed, a stimulant laxative should be given concurrently with an opioid-based regimen to manage constipation. Although opiates are recommended for short-term use, the major concern with their use is the potential for dependence. Finally, although their use is controversial, oral corticosteroids may improve activities of daily living when used as a part of triple therapy along with antivirals and analgesics for acute HZ pain.4 However, they are not recommended for patients with a severely compromised immune system or those who have uncontrolled diabetes, hypertension, and/or osteoporosis.2,4

Management of PHN
PHN, which occurs in 10% to 15% of patients with shingles, is generally described as neuropathic pain lasting more than 3 months after a bout of HZ.10,16 This condition often requires a patient to continue taking medication long after the lesions have disappeared. Gabapentin and pregabalin are FDA-approved for the treatment of PHN. Tricyclic antidepressants (TCAs) such as amitriptyline, desipramine, and nortriptyline, as well as analgesics, may be effective when used off-label.6,16,17 Gabapentin and pregabalin may cause significant drowsiness during the initial phase of titration, so patients may benefit from bedtime dosing until tolerance develops. Gabapentin and pregabalin are excreted renally, so regimens should be adjusted based on kidney function, which is monitored throughout the duration of therapy. TCAs may be considered for off-label use in patients who have not achieved adequate relief from, or who have a contraindication to, primary therapy with gabapentin or pregabalin. Overall, TCAs have been shown to be effective for PHN. However, they are also less tolerated compared with other agents. Owing to potent anticholinergic adverse effects, TCAs should be titrated slowly and used cautiously, especially in elderly patients. Although a number of TCAs are available for use, nortriptyline may be preferred because it has similar outcomes and decreased adverse effects compared with other agents in the class.2,4,10,18

Both methadone and morphine have been reported to provide better analgesia than the TCAs.16,17 It is recommended that long-acting dosage forms of morphine—extended-release or controlled-release—be used. See TABLE 5 for a summary of agents that are used in the management of PHN.


Management of HZO
Patients with HZO should be referred to an ophthalmologist for proper assessment of any damage that may have occurred. In addition to systemic antiviral therapy, topical agents may be introduced to reduce or prevent ocular complications. Mydriatic drops such as atropine and cyclopentolate reduce the risk of scarring through pupil dilation, topical corticosteroids such as prednisolone reduce local inflammation, and agents for glaucoma can reduce intraocular pressure.4

PREVENTION

The debilitating effects precipitated by HZV reactivation led researchers to develop a preventive mechanism to improve quality of life and decrease healthcare costs. As a result, the HZ vaccine Zostavax was approved by the FDA in 2006 and adopted by the Advisory Committee on Immunization Practices (ACIP) in 2008 for the prevention of HZ and its complications.19 The vaccine, which contains the Oka/Merck strains of VZV, is administered as a single 0.65 mL SC injection after reconstitution with sterile water. Since it is a live, attenuated vaccine, Zostavax is contraindicated in individuals who are immunocompromised or pregnant. Injection-site reactions and headaches are the most common adverse effects following administration. Patients with a hypersensitivity to gelatin or neomycin should not receive the vaccine, since anaphylaxis has occurred. There is some confusion regarding the indicated age of administration. In 2008, the ACIP recommended Zostavax only for persons aged ≥60 years; in 2011, however, the FDA approved its use in persons aged 50 to 59 years.19 Even so, based on data from vaccine-efficacy and duration-of-protection studies, the ACIP did not change its recommendations.

The Shingles Prevention Study (SPS) and the Short-Term Persistence Substudy (STPS), a subanalysis of the SPS, examined the short-term efficacy of HZ vaccine in patients aged >60 years.19 The SPS, which followed 38,546 subjects for 4.9 years following vaccination, showed that the vaccine had an efficacy of 51.3% in preventing overt HZ and effected a 66.5% decrease in PHN events.19 The STPS assessed the same outcomes in a subset of 14,270 subjects from the SPS who were followed 4 to 7 years following vaccination. The STPS demonstrated efficacy for preventing HZ and PHN of 39.6% and 60.1%, respectively.19 Furthermore, point-in-time estimates of vaccine efficacy for the prevention of HZ and PHN identified the greatest protection occurring after year 1 and decreasing in the subsequent 4 years. Protection beyond 5 years could not be determined because of statistically insignificant results.19 Based on this evidence, the ACIP developed recommendations that would have the greatest impact on the patient population at greatest risk: persons aged >60 years.

The ACIP projected that vaccination at age 60 years would prevent HZ reactivation in 26,147 cases per million people, which is more than if vaccination occurred at age 50 or 70 years.19 Conversely, with respect to PHN, patients vaccinated at age 60 years had more than double the incidences compared with the group aged 70 years.19 Consequently, since HZ reactivation and related complications increase with age, the ACIP maintains that vaccination against HZ should be recommended for persons aged ≥60 years.19 Patients aged <60 years should be educated about the risks versus benefits of early vaccination, such as duration of protection related to the ages that are most vulnerable to HZ reactivation and the related complications.19 Finally, the pneumonia and influenza vaccines may be administered concomitantly with varicella-zoster without compromising immunoprotection.20

THE PHARMACIST’S ROLE

Pharmacists’ accessibility allows them to educate their patients about the specific risks and benefits associated with shingles prevention and treatment (SIDEBAR 1). Pharmacists need to understand the recommendations for vaccination and be proactive in advising the appropriate patients to receive Zostavax. The role of pharmacists in preventive healthcare has grown exponentially over the past decade as their immunization privileges have become more commonplace in a variety of practice settings. Community pharmacists are developing collaborative-practice agreements that enable them to administer a vaccine after assessing a patient’s immunization needs in the same visit. With an increasing number of studies determining disease states and drug treatments that put patients at risk for developing HZ, pharmacists can assist in identifying at-risk patients. Moreover, in patients who need management with pharmacologic agents, pharmacists can oversee care by conducting drug-utilization reviews, implementing medication therapy management, and providing patient counseling, thereby helping reduce adverse effects and improve outcomes. A pharmacist’s most important role is to empower patients, through effective counseling, with the skills and knowledge to successfully manage and overcome barriers associated with HZ and related illnesses and with their treatment.


CONCLUSION

VZV remains dormant in the body for many years after the initial infection, only to reactivate as shingles. The most important risk factor is host immune status, which may be altered by increasing age, coexisting conditions, or concurrent medications. Patients with HZ may experience a variety of complications, all of which can impact quality of life and may confer a substantial financial burden. Consequently, preventive measures should be recommended to patients who may receive the most benefit based on available recommendations and data.

REFERENCES

  1. Gershon AA, Gershon MD, Breuer J, et al. Advances in the understanding of the pathogenesis and epidemiology of herpes zoster. J Clin Virol. 2010;48(suppl 1):S2-S7.
  2. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis. 2007;44(suppl 1):S1-S26.
  3. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendation of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57:1-30.
  4. Cohen JI. Herpes zoster. N Engl J Med. 2013;369:255-263.
  5. Weinberg JM. Herpes zoster: epidemiology, natural history, and common complications. J Am Acad Dermatol. 2007;57(suppl 6):S130-S135.
  6. Wi CI, Kim BS, Mehra S, et al. Risk of herpes zoster in children with asthma. Allergy Asthma Proc. 2015;36:372-378.
  7. Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66:2675-2684.
  8. Smitten AL, Choi HK, Hochberg MC, et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 2007;57:4131-4138.
  9. Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. JAMA. 2013;309:887-895.
  10. Johnson RW, Rice AS. Postherpetic neuralgia. N Engl J Med. 2014;371:1526-1533.
  11. Yawn BP, Wollan PC, St Stauver JL, Butterfield LC. Herpes zoster eye complications: rates and trends. Mayo Clin Proc. 2013;88:562-570.
  12. Liesegang TJ. Herpes zoster ophthalmicus: natural history, risk factors, clinical presentation, and morbidity. Ophthalmology. 2008;115(suppl 2):S3-S12.
  13. Langan SM, Minassian C, Smeeth L, Thomas SL. Risk of stroke following herpes zoster: a self-controlled case-series study. Clin Infect Dis. 2014;58:1497-1503.
  14. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed January 27, 2016.
  15. Acyclovir product information. Schaumburg, IL: APP Pharmaceuticals, LLC; March 2008.
  16. Garroway N, Chhabra S, Landis S, Skolnik DC. What measures relieve postherpetic neuralgia? J Fam Pract. 2009;58:584d-584f.
  17. Fashner J, Bell AL. Herpes zoster and postherpetic neuralgia: prevention and management. Am Fam Physician. 2011;83:1432-1437.
  18. Thakur R, Philip AG. Treating herpes zoster and postherpetic neuralgia: an evidence-based approach. J Fam Pract. 2012;61(suppl 9):S9-S15.
  19. Hales CM, Harpaz R, Ortega-Sanchez I, et al; CDC. Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014;63:729-731.
  20. Zostavax (zoster vaccine live) product information. Whitehouse Station, NJ: Merck & Co, Inc; 2014.
  21. Clinical Pharmacology [subscription database]. www.clinicalpharmacology-ip.com/default.aspx. Accessed January 27, 2016.