Role of acyclovir in Management of chickenpox: Analyzing the importance of starting early

Varicella infections, commonly known as chickenpox, are generally a mild, contagious childhood disease, but can affect adults more severely. (1)While the initial (primary) infection caused by the Varicella-Zoster virus (VZV) is manifested as chickenpox, reactivation of the latent virus in later phases of life, is responsible for herpes zoster (shingles). (2)

Most often, the clinical diagnosis of chickenpox is based on the distinctive appearance of the skin lesions-the typical diffuse vesicular rash, though prodromal symptoms of fever, malaise, and headache, appearing 12 -24 hours before, maybe the first warning signs of the disease. (1,3)

Today, the use of potent antiviral agents with enhanced activity, improved pharmacokinetic properties, and excellent safety profiles, has revolutionized the prognosis of Varicella-Zoster infections.

The disease burden: Where do we stand?

WHO estimates show that the global annual disease burden of varicella is estimated to be 140 million cases, 4·2 million severe complications, and 4200 deaths. (4) With research revealing that chickenpox is more rampant in tropical climates (4), the implications of the disease in the Indian scenario appear grim.

Research has consistently highlighted that an unfathomable amount of financial burden is associated with chickenpox, owing to hospitalization costs, physician visits, prescription, and nonprescription medications, and lost income by caregivers who must remain at home during the child's illness. (5)

With 90% of cases occurring in children 1 to 14 years of age, chickenpox can be particularly severe in neonates, adults, and individuals who have impaired immune systems (5 ) 70% of the affected children undergo hospital admissions, while 50% of deaths have been reported. (4) Occurring in 5-10% of all patients, complications of varicella most commonly involve the skin, the central nervous system, and the respiratory system. (5)

Under such scenarios, the benefits of acyclovir in managing chickenpox, its mechanism of action, and supporting studies, need to be re-evaluated.

Mechanism of action of acyclovir: How does the drug act?

Classified as an antiviral drug, acyclovir exerts its action by engaging with the viral DNA. Once attached to the viral DNA, it gets converted to acyclovir triphosphate by enzymatic action, preventing viral replication and halting further DNA synthesis. (3) Being a highly selective inhibitor of VZV, this drug is active only in VZ infected cells in the human body. (2)

Acyclovir has a demonstrated inhibitory efficacy, both in vitro and in vivo, against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus. (3)

Is starting early really helpful?

Starting antiviral therapy early has its benefits.

Assessing the efficacy of Immediate vs. delayed acyclovir therapy, Henry Balfour et al (6) concluded that when initiated within 24 h of onset of rash as compared to the second day or on the third day, acyclovir exhibited a superior potency and shortened the median times to maximum number of lesions. Also, the time from onset of rash to cessation of new lesion formation, 50% healing, defervescence, and cessation of itching were hastened. The team further highlighted that earlier treatment resulted in fewer facial lesions on follow-up visits.

The probable rationale behind starting early lies in the fact that antiviral drugs have a fairly short period during which to perform. Once immune clearance exceeds the rate of viral production, which occurs within a few days in immunocompetent patients, any drug effect becomes negligible. (6)

It has been documented that in immunocompromised children with chickenpox or adults with chickenpox pneumonia, early therapy is life-saving. If viral replication is not controlled at an early stage in such patients, it may produce substantial tissue damage after it outstrips the inhibitory capacity of the antiviral drug. (6)

Clinical indications for early therapy -STUDIES ASSESSING THE ROLE OF EARLY INITIATION OF ACYCLOVIR-

• In Immunocompetent children, adolescents, and adults –Balfour et al and Dunkle et al showed that initiating Acyclovir treatment of varicella in otherwise healthy children was particularly beneficial when started within 24 of rash onset, resulting in a shorter duration of fever, fewer skin lesions, and accelerated lesion healing. Overall, oral acyclovir was well tolerated and reduced the duration of symptomatic illness by about 24 hours. (7,8)
• Yet another study confirmed that if treatment was begun within the first 48 hours of varicella exanthem, then the number of days of fever and number of days to crusting were reduced. If acyclovir was begun within the first 24 hours of varicella exanthem, the rash was dramatically lessened. (1)
• In a placebo-controlled trial of therapy for 148 adults with varicella, acyclovir (800 mg orally five times daily) was shown to reduce the duration of new lesion formation, reduce the maximum number of lesions, accelerate cutaneous healing, and shorten the duration of fever (9)
• Resonating with the above findings, in a review report by D Harris et al, investigating the efficacy of acyclovir in immunocompetent children with chickenpox, Oral acyclovir exhibited a lesser time to fever reduction and time to no new lesions by 1 day. The team further reaffirmed that these reductions were only seen if treatment was initiated within 24 hours of rash onset. (10)

Results from the above studies point out a very important fact– benefits from acyclovir therapy were reduced to a minimum when treatment was initiated later than 24 hours after rash onset.

• In Immunocompromised patients-The high frequency of visceral involvement in immunocompromised children (or adults) with chickenpox mandates the use of effective anti-viral therapy. (3)

Experts suggest that therapy with intravenous acyclovir should be initiated at the first sign of infection. Once the patient is afebrile and new lesion formation has ceased, oral antiviral therapy should be considered. (3)

Managing the complications- Visceral dissemination of varicella most often involves the CNS and is presented as cerebellar ataxia, encephalitis, transverse myelitis, or stroke syndromes. (2)

• Research has highlighted the benefits of acyclovir in treating myelopathy secondary to varicella-zoster infection. In a study with patients suffering from the laboratory-confirmed varicella-zoster virus (VZV) and MRI confirmed myelopathy, marked improvement of symptoms was noted in most patients, within two months. (3)
• Alleviation of all symptoms related to Brachial plexus neuritis secondary to VZV infection and visceral disseminated VZV infection was noted, on treatment with acyclovir. (3)
• A case reported that when a VZ patient presenting with truncal ataxia, was treated with intravenous acyclovir, the patient improved and ultimately was free of neurologic disability and cerebellitis, affirming that the complication burden would decrease if the source infection was urgently treated. (3)

Dose regime –Oral acyclovir preparations include a 200 mg capsule, 400 and 800 mg tablets, and a liquid suspension (200 mg per 5 ml). (2)

The approved dose of oral acyclovir for chickenpox is 200 mg/kg (up to a maximum of 800 mg) 4–5 times daily for 5 days. For the intravenous route, the dose is 10 mg/kg every 8 hours, although higher doses (12–15 mg/kg) are sometimes used for life-threatening infections, especially in immunocompromised patients. (2)

No specific dosage modification for these drugs is required for patients with hepatic insufficiency, though the dose needs to be altered in significant renal dysfunction as this drug is primarily cleared by renal mechanisms. (2)

Acyclovir has also been widely used in serious VZV infections in pregnant women, without evidence of maternal or fetal toxicity. (2) This vouches for the fact that oral acyclovir is an extremely safe and well-tolerated drug.

Key pointers-

• Initiation of antiviral therapy in a patient with chickenpox depends on the patient's age, underlying medical conditions, immune status of the person, and the risk of complications.
• Acyclovir prevents the replication of the VZV and has the potential to eradicate VZV and relieve symptoms more rapidly.
• Since the drug is only absorbed by the cells that are infected with the virus, acyclovir has minimal adverse effects.
• With ample studies supporting the unmatched potency of this drug when initiated at the earliest, physicians are positioned to consider this drug as a key antiviral against chickenpox.

Conclusion- To date, chickenpox exists as a highly contagious and common infection. Though regarded to be self–limiting in nature in most cases, it remains associated with severe complications and economic burden, if not treated appropriately.

The superiority of acyclovir in managing the infection has been proved over and again in studies. As more studies continue to unveil the extreme benefits of this drug when started at the right time, the onus lies on the medical fraternity to keep themselves updated on its recent advances.

References

1. Feder, H. M. (1990). Treatment of adult chickenpox with oral acyclovir. Archives of internal medicine, 150(10), 2061-2065

2. Gnann Jr. JW. Antiviral therapy of varicella-zoster virus infections. In: Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge University Press, Cambridge; 2007. PMID: 21348091.

3. Taylor, M., & Gerriets, V. (2021). Acyclovir. In StatPearls [Internet]. StatPearls Publishing.

4. World Health Organization. (2014). Varicella and herpes zoster vaccines: WHO position paper, June 2014. Weekly Epidemiological Record= Relevé épidémiologique hebdomadaire, 89(25), 265-287.

5. Klassen_TP, Hartling_L.Acyclovir for treating varicella in otherwise healthy children and adolescents.Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD002980.DOI: 10.1002/14651858.CD002980.pub3.

6. Balfour Jr, H. H., Edelman, C. K., Anderson, R. S., Reed, N. V., Slivken, R. M., Marmor, L. H., ... & Talarico, C. L. (2001). Controlled trial of acyclovir for chickenpox evaluating time of initiation and duration of therapy and viral resistance. The Pediatric infectious disease journal, 20(10), 919-926.

7. Balfour HH Jr, Kelly JM, Suarez CS, et al. Acyclovir treatment of varicella in otherwise healthy children. J Paediatr 1990;116:633–9.6

8. Dunkle L. M., Arvin A. M., Whitley R. J., et al. A controlled trial of acyclovir for chickenpox in normal children. N. Engl. J. Med. 1991;325:1539–1544. [PubMed: 1944438]

9. Wallace M. R., Bowler W. A., Murray N. B. Treatment of adult varicella with oral acyclovir. Ann. Intern. Med.1992;117:358–363. [PubMed: 1323943]

10. Harris, D., & Redhead, J. (2005). Should acyclovir be prescribed for immunocompetent children presenting with chickenpox?. Archives of disease in childhood, 90(6), 648-650.4