Managing Herpes spectrum: "Hit early" and "Hit hard" with antiviral acyclovir

Although the acute stage of these conditions is usually short, there may be long-lasting debilitating complications. For example, acute herpetic gingivostomatitis lasts 5-7 days, but the symptoms of pain, myalgia, etc. take almost 2 weeks to subside. (2)

In this scenario, arresting the viral replication in the early phase of the disease has been shown to achieve earlier recovery and prevention from the long-term sequel. (3) One such time-tested agent acyclovir has shown remarkable benefits for the herpes spectrum of diseases over the last seven decades and will be discussed in the following review.

The herpes spectrum: Acute conditions with chronic pain

HSV (types 1 and 2) is a double-stranded DNA virus that specifically targets the human epithelium during the primary infection that manifests as vesicular lesions in mucocutaneous regions. (4)

Retrograde transport through adjacent neural tissue to sensory ganglia leads to lifelong latent infection which manifests as reactivations that are usually mild and are precipitated by local or systemic stimuli such as immunodeficiency, trauma, fever, menstruation, ultraviolet (UV) light, and sexual intercourse. (4)

Herpes zoster, or shingles, is caused by the reactivation of the varicella-zoster virus, which causes chickenpox. Patients may present with constitutional symptoms with abnormal skin sensations for 2-3 days before the classic maculopapular rash appears. The rash is usually unilateral, confined to a single dermatome, and typically progresses to clear vesicles that become cloudy and crust over in seven to 10 days. (5)

Postherpetic neuralgia, the most common complication of herpes zoster, is defined as pain in a dermatomal distribution that is sustained for at least 90 days after the rash. It occurs in approximately 20% of patients with herpes zoster, and 80% of cases occur in patients 50 years or older. (5)

Clinical presentation and diagnostic clues:

Herpes simplex virus infection is common and has multiple clinical manifestations. The classic clinical presentation of vesicles progressing to painful ulcers is unusual; atypical and mild symptoms are common, and most people have the unrecognized disease. (6)

Symptoms of oral herpes (herpes labialis) include tingling and burning followed by the development of vesicular then ulcerative lesions involving the oropharynx and perioral mucosa. (6) (Figure 1)

Symptoms of genital herpes range from asymptomatic to tingling and burning without lesions, to recurrent genital ulcerations. (6)

For both HSV-1 and HSV-2, asymptomatic shedding may occur in the absence of lesions; transmission of the virus may occur during asymptomatic shedding. HSV establishes latency in neuronal ganglia and periodically reactivates. Most reactivations are asymptomatic but can result in the transmission of the virus. (6)

The clinical presentation of a typical sore usually points to the diagnosis but, in the case of genital herpes, it should always be confirmed by laboratory testing. This can be accomplished through the use of direct tests for viral isolation, the detection of antigen, or, more recently, the detection of HSV DNA using molecular diagnostic techniques. (7)

Ideally, the sample should be taken from a vesicular lesion that has been present for less than 24 h because once the lesion has begun to crust, the test sensitivity will decline. If multiple vesicles are present, more than one lesion should be sampled. (8)

Herpes zoster typically presents with pain described as burning or stabbing, followed by a vesicular rash in the affected dermatome; the location of symptoms depends on the affected nerve. (9) (Figure 2)

The signs and symptoms of herpes zoster are usually distinctive enough to make an accurate clinical diagnosis once the rash has appeared. However, diagnosis of herpes zoster might not be possible in the absence of a rash (for example in immunocompromised patients) in which case Polymerase chain reaction (PCR) is the most useful test. (9)

How acyclovir helps in the early resolution of symptoms by reducing viral load?

HSV infection results in life-long morbidity due to recurrent reactivations of latent ganglionic infection. Acyclovir triphosphate inactivates viral DNA polymerase causing its termination. (10) Initiation of acyclovir administration within 24 hours of viral challenge can reduce the establishment of viral latency following primary infection. In another word, if started early, it can prevent the establishment of latency and also promote quicker healing of the primary lesions. (3)

It has been shown that daily suppressive therapy by antivirals reduces recurrences by 80% and decreases transmission risk by approximately 50%. (6)

Trial evidence for acyclovir in early resolution of herpes pain

In Immunocompetent Patients (11-15)

Double-blind placebo-controlled studies in immunocompetent patients have demonstrated the efficacy of oral (200mg 5 times daily) and topical (applied 4 to 6 times daily) acyclovir initiated within 4 days of the first symptoms of HSV perinatal infection. The duration of viral shedding and time to complete healing of lesions are significantly reduced, particularly in the primary episode.

Most well-controlled trials have shown complete suppression of genital herpes recurrence in 71% to 88% of immunocompetent patients, using prophylaxis with oral acyclovir 800 to 1000 mg/day for up to 2 years.

Complete suppression of recurrence for 5 years has been achieved in 20% of patients on acyclovir prophylaxis (800 to 1600 mg/day).

Oral acyclovir therapy causes significant improvements in recurrent orofacial and cutaneous infections if begun as early as possible after reactivation. Prophylaxis with topical, and especially oral acyclovir reduces the severity and frequency of orofacial and cutaneous HSV recurrence during treatment.

Acyclovir 3% ophthalmic ointment 5 times daily eliminates 95 to 100% of herpetic dendritic corneal ulcers in 5 to 9 days. Combination of acyclovir with topical interferon-α shortens the time to healing of superficial herpetic keratitis. Prophylaxis with oral acyclovir 800 to 1000 mg/day for 12 to 15 months completely prevented HSV keratitis recurrence in all patients undergoing penetrating keratoplasty.

Chickenpox (16):

Oral acyclovir initiated within 24 hours of the appearance of the rash associated with varicella (chickenpox) has resulted in decreased numbers of lesions, duration of new lesion formation, severity or duration of pruritus, time to healing, and duration of fever in otherwise healthy children, adolescents, and adults in several well-designed studies.

Shingles: In patients with herpes zoster (shingles), oral (4000 mg/day for 7 days) acyclovir treatment begun within 72 hours of exanthem onset; attenuates the development of rash and pain, offers protection against ocular involvement, and appears to decrease the duration of post-herpetic neuralgia.

Immunocompromised patients (17,18,19):

Oral (2000 mg/day) acyclovir is well established in the treatment of immunocompromised patients with HSV infections. Severe infections refractory to normal dosages of acyclovir (such as HSV hepatitis, or infections caused by viruses deficient in thymidine kinase activity) may respond to higher dosages, as demonstrated in case reports.

Managing post-herpetic neuralgia 

Back in the 1990s, Huff et al found that the median duration of pain in acyclovir recipients was 20 days vs. 62 days for their placebo counterparts (P = 0.02). Thus, acyclovir has been shown to reduce chronic zoster-associated pain. (20)

Later, a meta-analysis of four double-blind, randomized, placebo-controlled trials of oral acyclovir for the treatment of herpes zoster found that acyclovir accelerates pain resolution by all of the measures employed. The time for cessation of pain was shortened by nearly 80% for adult patients. (21)

Tolerability (11): 

Acyclovir is well tolerated whether administered by ocular, topical, oral, or intravenous routes. Adverse reactions to topical preparations have been mainly limited to mild local effects. 

Essential take away messages for clinicians:

1. Herpes and zoster lesions have very characteristic diagnostic features and thus can be diagnosed clinically in most cases. Laboratory investigations are available for less obvious presentations.

2. Acyclovir is a broad-spectrum antiviral with applications ranging from various herpes infections, chickenpox, shingles, etc.

3. The benefit is directly related to the impact on viral load which in turn depends on the timing of initiation of therapy. Earlier initiation leads to better outcomes for primary infection as well as decreases the frequency of recurrences.

4. The drug has proved its effectiveness over the past 7 decades. Being a generic drug, its lower cost, wide availability and highly effective anti-viral properties make it every physician's choice today.

References

1. https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus

2. https://emedicine.medscape.com/article/218580-clinical

3. Blum MR, Liao SHT, de Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. Acyclovir Symposium. American Journal of Medicine 73: 186–192, 1982

4. Emmert DH. Treatment of common cutaneous herpes simplex virus infections. Am Fam Physician. 2000 Mar 15;61(6):1697-706, 1708.

5. Saguil A, Kane S, Mercado M, Lauters R. Herpes Zoster and Postherpetic Neuralgia: Prevention and Management. Am Fam Physician. 2017 Nov 15;96(10):656-663.

6. https://bestpractice.bmj.com/topics/en-us/53

7. Singh A, Preiksaitis J, Ferenczy A, Romanowski B. The laboratory diagnosis of herpes simplex virus infections. Can J Infect Dis Med Microbiol. 2005;16(2):92-98.

8. Lafferty WE, Krofft S, Remington M, et al. Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence population. J Clin Microbiol 1987;25:323-6.

9. https://www.cdc.gov/shingles/hcp/diagnosis-testing.html

10. Schaeffer HJ Acyclovir chemistry and spectrum of activity. Am J Med. 1982; 73: 4-6

11. Wagstaff, A.J., Faulds, D. & Goa, K.L. Aciclovir. Drugs 47, 153–205 (1994).

12. Ashley RL, Corey L. Effect of acyclovir treatment of primary genital herpes on the antibody response to herpes simplex virus. Journal of Clinical Investigation 73: 681–688, 1984

13. Baker DA, Blythe JG, Kaufman R, Hale R, Portnoy J. One-year suppression of frequent recurrences of genital herpes with oral acyclovir. Obstetrics and Gynecology 73: 84–87, 1989

14. Barton IG, Kinghorn GR, Rowland M, Jeavons M, Al-Omer LS, et al. Recurrences after first episodes of genital herpes in patients treated with topical acyclovir cream. Antiviral Research 4: 293–300, 1984

15. Cobo LM, Foulks GN, Liesegang T, Lass J, Sutphin J, et al. Oral acyclovir in the therapy of acute herpes zoster ophthalmicus. Ophthalmology 92: 1574–1583, 1985

16. Balfour Jr HH, Kelly JM, Suarez CS, Heussner RC, Englund JA, et al. Acyclovir treatment of varicella in otherwise healthy children. Journal of Pediatrics 116: 633–639, 1990

17. Balfour Jr HH, Bean B, Laskin OL, Ambinder RF, Meyers JD, et al. Acyclovir halts progression of herpes zoster in immuno-compromised patients. New England Journal of Medicine 308: 1448–1453, 1983

18. Barton IK, Nicholson F. Use of pooled immunoglobulin and acyclovir as prophylaxis against cytomegalovirus disease in recipients of renal allografts. Nephrology Dialysis Transplantation 6: 525–526, 1991

19. Chazotte C, Anderson HF, Cohen WR. Disseminated herpes simplex infection in an immunocompromised pregnancy: treatment with intravenous acyclovir. American Journal of Perinatology 4: 363–364, 198

20. Huff JC, Drucker JL, Clemmer A, Laskin OL, Connor JD, Bryson YJ, Balfour HH Jr. Effect of oral acyclovir on pain resolution in herpes zoster: a reanalysis. J Med Virol. 1993;Suppl 1:93-6. doi: 10.1002/jmv.1890410518.

21. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis. 1996 Feb;22(2):341-7