THE EFFECT OF ANTIVIRALS ON POST-HERPETIC NEURALGIA: CAN THEY HELP US FORGET HERPES ZOSTER?

By Cameron Roessner, BSc. Pharm, PharmD Student

Learning Objectives

Outline the epidemiology, incidence, and impact of post-herpetic neuralgia as a major sequelae of herpes zoster

Review current preventative strategies for herpes zoster and post-herpetic neuralgia

Critically appraise the evidence behind the use of antivirals in acute herpes zoster in order to better understand their role in the prevention of post-herpetic neuralgia

Background, Incidence, and Complications

Herpes Zoster

Herpes Zoster: Background

Herpes zoster (HZ) – the reactivation of dormant varicella-zoster virus (VZV) – manifests as a painful vesicular rash affecting a single dermatome and generally resolves within a few weeks

Increasing age is the greatest risk factor Others at higher risk include organ or

hematopoietic stem-cell transplant recipients, immunocompromised persons, and those with leukemia, lymphoma, or HIV infection N Engl J Med. 2013 Oct

31;369(18):1766N Engl J Med. 2014 Oct 16;371(16):1526-33

Herpes Zoster: Incidence

Roughly 95% of young adults in North America and Europe are seropositive for VZV and therefore at risk of herpes zoster

The overall annual incidence of HZ is 3.4 cases per 1000 persons which increases to 11 cases per 1000 persons in those older than 80 years of age

Each year more than 1,000,000 new cases are diagnosed in the US and 130,000 in Canada N Engl J Med. 2013 Oct

31;369(18):1766N Engl J Med. 2014 Oct 16;371(16):1526-33CMAJ. 2010 Nov 9;182(16):1731-6

Herpes Zoster: Complications Herpes zoster can result in vision and

hearing impairments, various neurological complications, and bacterial superinfection of cutaneous lesions

Immunocompromised persons are at increased risk of varicella-zoster virus dissemination as well as secondary bacterial infection

Post-herpetic neuralgia is the most common chronic complication of herpes zoster Annals of Internal Medicine 154 (5):

ITC3-1N Engl J Med. 2014 Oct 16;371(16):1526-33

Definition, Incidence, and Impact

Post-Herpetic Neuralgia

PHN: Definition

The definition has varied: Traditionally, it was defined as pain persisting at

more than 30 days after rash onset A duration of 90-120 days is now more commonly

used The definition most often used in clinical trials

is: HZ-associated pain persisting at least 90 days after

the appearance of the acute herpes zoster rash Pain must be rated at least a 30/100 (sometimes

40) for it to significantly impact quality of lifeJ Infect Dis. 2008 Mar 1;197 Suppl 2:S207-15N Engl J Med. 2014 Oct 16;371(16):1526-33

PHN: Incidence

Of the 130,000 cases of HZ annually in Canada, approximately 17,000 are complicated by post-herpetic neuralgia

It is estimated that PHN develops in 9-34% of patients with herpes zoster.

It occurs more frequently with increasing age and greater severity of the prodrome, rash, and pain during the acute phase of HZ

CMAJ. 2010 Nov 9;182(16):1731-6Am J Clin Dermatol. 2013 Apr;14(2):77-85

PHN: Incidence

N Engl J Med. 2014 Oct 16;371(16):1526-33

PHN: Impact

Patients tend to experience stimulus-independent pain, stimulus-evoked pain (allodynia), and spontaneous intermittent lancinating pain

Pain intensity can range from trivial to debilitating

Postherpetic neuralgia may impact sleep, mood, and concentration, as well as instrumental and basic activities of daily living(CMAJ/ JID 2008:197)

J Clin Virol. 2010 May;48 Suppl 1:S8-13Annals of Internal Medicine 154 (5): ITC3-1CMAJ. 2010 Nov 9;182(16):1731-6

Current Strategies

Post-Herpetic Neuralgia Prevention

VZV Vaccine

Live, attenuated vaccine available since 2006

Approved for those aged 50 and older and recommended in those aged 60 and older

In a double-blind RCT following (median 3.1 years) 38,546 immunocompetent adults >60 years old with a history of varicella, Oxman et al. found the vaccine to reduce the risk of HZ by 51.3% and the subsequent risk of PHN by 66.5% (SPS)

N Engl J Med. 2005 Sep 29;353(13):1414-5http://www.phac-aspc.gc.ca/naci-ccni/hzv-vcz-eng.phpc

VZV Vaccine

J Clin Virol. 2010 May;48 Suppl 1:S14-9

What about antivirals?

Acyclovir, Valacyclovir, and Famciclovir Evidence exists for the prompt use (< 72

hours of rash onset) of antivirals for relieving acute pain and expediting cutaneous healing (NEJM PHN)

What does this mean for rates of post-herpetic neuralgia?

N Engl J Med. 2014 Oct 16;371(16):1526-33

Clinical Question

In adult patients with acute herpes zoster, is prompt administration of antiviral therapy associated with a reduced risk of developing post-herpetic neuralgia?

Description and Critique

Appraisal

Article

Chen N, Li Q, Yang J, Zhou M, Zhou D, He L. Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD006866. DOI: 10.1002/14651858.CD006866.pub3

Objective: To assess the effectiveness of antiviral

agents in preventing PHN

Study Criteria

Eligibility: RCTs (blind/unblind) of any language Patients: All ages with herpes zoster of all

degrees of severity presenting within 72 hours after the onset of herpes zoster

Intervention: Antiviral agents (acyclovir, famciclovir, valacyclovir, brivudin) given via oral or IV route alone or with another treatment within 72 hours of the onset of herpes zoster

Comparator: No treatment, placebo, or another treatment (when the intervention was an antiviral + the same other treatment)

Outcomes

Primary: Presence of PHN six months after onset of acute

herpetic rash PHN definition: Pain lasting ≥ 120 days from rash onset

Any pain persisting or recurring at the site of shingles Secondary:

1) Pain severity at 3, 6 and 12 months measured by a validated visual analogue scale

2) Quality of life measured with a validated scale after 6 months

3) Adverse events during treatment or within 2 weeks of stopping treatment

Search

All RCTs of antiviral treatment for PHN prevention following acute herpes zoster infection

Online databases (CENTRAL, MEDLINE, EMBASE, LILACS), clinical trial registries, and references of publishes studies up until April 2013

Data Collection

Two authors reviewed articles independently using a data extraction form

A third author was available for arbitration in the case of unresolved disagreement

Randomisation, allocation concealment, blinding of participants, personnel and outcome assessment, completeness of outcome data, selective reporting and any other potential bias were assessed and each study was ranked as having ‘low’, ‘unclear’, or ‘high’ risk of bias

Included Studies

Six RCTs with a total of 1211 participants 48% male 69% > 50 years old 5 of the trials evaluated acyclovir

800mg fives times a day for 7 (2), 10 (2), and 21 days 1 trial evaluated famciclovir

500 or 750mg TID for 7 days Common exclusion criteria:

Immunosuppression/immunosuppressive therapy Pregnant or nursing women Patients on any antiviral therapy

Study Quality

One was rated as low risk of bias and the other 5 as unclear risk of bias

None were rated as high risk

Primary Outcome

Acyclovir vs. Placebo PHN at 6 months: RR 1.05, 95% CI 0.87-

1.27, P=0.62 PHN at 4 months: RR 0.75, 95% CI 0.51-

1.11, P=0.15 Famciclovir vs. Placebo

PHN at 5 months: 500mg: RR 1.15, 95% CI 0.87-1.52 750mg: RR 1.31, 95% CI 1.01-1.71

Primary Outcome

Figure 2. Oral acyclovir versus placebo or no treatment: The presence of PHN 6 months after the onset of acute herpetic rash

Figure 3. Oral acyclovir versus placebo or no treatment: The presence of PHN 4 months after the onset of acute herpetic rash

Secondary Outcomes

Pain Severity Most trials did not measure pain after 3

months and in the two that did, results could not be combined

In one, acyclovir represented an average reduction in pain of -9.1 (100mm scale) at 3 months and -8.3 at 6 months

Quality of life Only one trial assessed this outcome, finding

no significant differences between acyclovir and placebo

Secondary Outcomes

Adverse Events Most commonly nausea, vomiting, diarrhea, and

headache Acyclovir vs. Placebo: RR 1.01 95% CI 0.88-1.15 Famiciclovir also exhibited a safety profile

similar to placebo PHN at 1 month (not in original protocol)

Acyclovir vs. Placebo: RR 0.83 95% CI 0.71-0.96 NNT = 24 Heterogeneity: I2 = 72%

Commentary: Strengths

The rationale, objectives, study eligibility, and search strategy were clearly described

Study selection, evaluation, and data extraction processes were done independently

The included studies were assessed for validity according to each domain (i.e. blinding, allocation concealment, etc.)

The possibility of publication bias, reporting bias, performance bias, and recall bias in included studies was addressed and adequately discussed

Commentary: Strengths

The outcomes considered are patient important

The results were similar across a range of patients, interventions, and outcomes No included study favoured antivirals

across a wide age range of immunocompetent patients

Efficacy and adverse effects were largely the same regardless of treatment duration or antiviral used

Commentary: Weaknesses

Immunocompromised persons were not included

An analysis stratified to baseline pain and rash severity was not possible

Data regarding pain severity, quality of life, and duration of rash at presentation were insufficient to properly evaluate

Valacyclovir, perhaps the most commonly used antiviral for acute herpes zoster, was not included Studies directly comparing it with placebo

are lacking

Commentary: Weaknesses

A small number of trials were eligible Assessment of publication bias was not possible

Trials differed in follow-up, duration of treatment, and site of herpes zoster, making combining results difficult or at risk of heterogeneity

Possible Biases (‘unclear’ risk): Reporting bias Performance bias Recall bias

Conclusion

Authors Conclusion There is high quality evidence that acyclovir does

not reduce the incidence of PHN significantly. In addition, insufficient evidence exists to determine the effects of other/newer antiviral agents such as famciclovir.

My Conclusion/Bottom-Line Current evidence does not support the use of

antiviral agents solely for the prevention of post-herpetic neuralgia. However, they still may be used for the acute treatment of herpes zoster to attenuate pain and speed cutaneous healing.

Questions?

References

1. Cohen, J. I. 0724. Clinical practice: Herpes zoster. N Engl J Med. 2013 Oct 31;369(18):1766

2. FAU, Johnson RW, and A. S. Rice. 1028. Clinical practice. postherpetic neuralgia. N Engl J Med. 2014 Oct 16;371(16):1526-33

3. Gan, E. Y., Tian EA FAU, and H. L. Tey. 1017. Management of herpes zoster and post-herpetic neuralgia. Am J Clin Dermatol. 2013 Apr;14(2):77-85

4. Levin, M. J., Gershon AA FAU, Dworkin RH FAU, M. FAU Brisson, and L. Stanberry. 0907. Prevention strategies for herpes zoster and post-herpetic neuralgia.  J Clin Virol. 2010 May;48 Suppl 1:S14-9

5. Opstelten, W., J. FAU McElhaney, B. FAU Weinberger, Oaklander AL FAU, and R. W. Johnson. 0907. The impact of varicella zoster virus: Chronic pain.  J Clin Virol. 2010 May;48 Suppl 1:S8-13

References

6. Oxman, M. N., Levin MJ FAU, Johnson GR FAU, Schmader KE FAU, Straus SE FAU, Gelb LD FAU, Arbeit RD FAU, et al. 0607. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005 Sep 29;353(13):1414-5

7. Schmader, K., Gnann JW Jr FAU - Watson,,C.Peter, and C. P. Watson. 0521. The epidemiological, clinical, and pathological rationale for the herpes zoster vaccine. J Infect Dis. 2008 Mar 1;197 Suppl 2:S207-15

8. Watson, C. P. 1210. Herpes zoster and postherpetic neuralgia. CMAJ. 2010 Nov 9;182(16):1731-6

9. Whitley, R. J., A. FAU Volpi, M. FAU McKendrick, Wijck Av FAU, and A. L. Oaklander. 0907. Management of herpes zoster and post-herpetic neuralgia now and in the future. J Clin Virol. 2010 May;48 Suppl 1:S20-8

10. Wilson, Jennifer F. 2011. Herpes zoster. Annals of Internal Medicine 154 (5) (03/01): ITC3-1, http://dx.doi.org/10.7326/0003-4819-154-5-201103010-01003.