Acyclovir- Exploring the novelty and versatility of an age-old, time-tested antiviral

Being a generic drug, its lower cost, wide availability and highly effective anti-viral properties make it a popular physician's choice today. The following review aims to explain the indications for this drug through the broad spectrum of herpes infections with an aim to acquaint physicians with the current literature about this drug. This review also touches upon the recently discovered role of this molecule in HIV infected patients.

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 muco-cuatneous regions. Retrograde transport through adjacent neural tissue to sensory ganglia leads to lifelong latent infection which manifests as reactivations that are precipitated by local or systemic stimuli such as immunodeficiency, trauma, fever, menstruation, ultraviolet (UV) light and sexual intercourse.(3)

Acyclovir, an acyclic guanosine analogue, binds viral DNA polymerase, acting as a chain terminator and ending replication. Its mechanism of action necessitates early administration, because replication may end as soon as 48 hours into a recurrence. (4)

An estimated 3.7 billion people under age 50 (67%) have HSV-1 infection globally. An estimated 491 million people aged 15-49 (13%) worldwide have HSV-2 infection. (5)

Acute herpetic gingivostomatitis lasts 5-7 days, but the symptoms of pain, myalgia etc. subside in 2 weeks. (6) Hence an antiviral agent that can cut down the duration of debilitating pain and other symptoms is an obvious choice.

In the treatment of primary orolabial herpes, oral acyclovir, in a dosage of 200 mg five times daily for five days, accelerates the loss of crusts by one day (seven versus eight days) in adults and can reduce the mean duration of pain by 36 percent. (3) In one study involving children up to six years of age, acyclovir, in a dosage of 15 mg per kg five times daily for seven days, decreased the duration of oral lesions in primary infection from 10 days to four days, shortened viral shedding and reduced the duration of eating difficulties from seven days to four days.(7)

Recurrences of herpes are often mild and infrequent, and most patients do not seek treatment. It is noteworthy in this regard that acyclovir therapy to prevent recurrences is easily available and effective in preventing recurrences. (3) Suppressive antiviral therapy in these patients has the following benefits:

1. It reduces the frequency and severity of herpes symptoms,

2. Decreases the transmission of HSV to sexual partners and infants of infected mothers, and

3. Decreases the transmission of associated viral diseases (i.e., HIV).

Acyclovir has been used to suppress recurrences of genital herpes, decreasing the frequency by as much as 80 percent and preventing recurrence by as much as 45 percent of patients. (8) Successful suppression for as long as five years without adverse effects has been reported. (4) The drug is titrated from a starting dose of 400 mg twice daily to achieve maximal efficacy with the lowest, least frequent dose.(9) Therapy should be discontinued once a year to assess whether its continuation is necessary.(3)

The mechanism of acyclovir's antiviral action necessitates early administration, because replication may end as soon as 48 hours into a recurrence. (4) Hence diagnosing the disease at an early stage is directly related to the beneficial impact of acyclovir.

The diagnosis of HSV infection may be made clinically, but laboratory confirmation is recommended in patients presenting with primary or suspected recurrent infection. The gold standard of diagnosis is viral isolation by tissue culture. Polymerase chain reaction enzyme-linked immunosorbent assay (PCR-ELISA) is extremely sensitive (96 percent) and specific (99 percent). (3)

HSV infection results in life-long morbidity due to recurrent reactivations of latent ganglionic infection. Initiation of acyclovir administration within 24 hours of viral challenge can reduce the establishment of viral latency following primary infection. In other words, if started early, it can prevent the establishment of latency and also promote quicker healing of the primary lesions. (10)

Herpes zoster, or shingles, is caused by the reactivation of varicella-zoster virus, which causes chickenpox. Patients with conditions that decrease cell-mediated immunity are 20 to 100 times more likely to develop herpes zoster. Patients may present with malaise, headache, low-grade fever, and abnormal skin sensations for two to three 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. (11)

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. (11)

Acute herpes zoster (chickenpox) is treated with oral guanosine analogues. Acyclovir is the antiviral medication approved for the treatment of herpes zoster in children. (11) The typical adult dose is 800 mg orally five times per day for seven days.(11) Acyclovir decreases the time during which new lesions occur by 12 hours and the time to full crusting by two days while decreasing pain severity. (12)

Back in 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. (13)

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. The benefit was especially evident in patients 50 years of age or older. Fewer acyclovir recipients had postherpetic neuralgia at 3 or 6 months. Overall, the reductions of pain duration and prevalence were approximately twofold. (14) The typical dose used in these trials was 800mg five times a day.

Co-infection with HSV-2 in HIV patients is common. Suppressive therapy of HSV-2 with acyclovir reduces plasma HIV-1 concentrations. Lingappa et al found that acyclovir reduced risk for HIV-1 disease progression by 16% compared with placebo.(1) A second study showed that, in those with HIV and HSV-2 as well as HIV viral loads above 50,000/mL, there was a significant delay in the progression to AIDS-defining illnesses or CD4 T-cell decline in the acyclovir group compared to placebo.(15)

1. Treatment of the often self-limited herpes spectrum diseases is warranted to prevent recurrences (in herpes simplex) and post-herpetic neuralgia (after chickenpox).

2. Acyclovir decreases herpes simplex recurrences by as much as 45% and post-herpetic neuralgia by as much as 80%, hence making it an essential tool in the battle against herpes spectrum disorders.(8,14)

3. Being a widely available and much cheaper alternative to other anti-virals, this drug is relevant in contemporary clinical practice due to its highly efficacious antiviral profile.

4. Acyclovir is well tolerated whether administered by ocular, topical, oral or intravenous routes. The incidence of most adverse events, such as gastrointestinal symptoms, rash and headache, occurring during oral acyclovir therapy is similar to that seen in patients receiving placebo. (2)

References:

1. Lingappa JR, Baeten JM, Wald A, et al Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial. Lancet. 2010 Mar 6;375(9717):824-33. doi: 10.1016/S0140-6736(09)62038-9.

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

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

4. Clark JL, Tatum NO, Noble SL. Management of genital herpes. Am Fam Physician. 1995;51:175–82.

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

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

7. Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double-blind placebo-controlled study. BMJ. 1997;314:1800–3.

8. Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med. 1992;327:782–9

9. Whitley RJ, Kimberlin DW, Roizman B. Herpes simplex viruses. Clin Infect Dis. 1998;26:541–55

10. 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

11. 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.

12. McKendrick MW, McGill JI, White JE, Wood MJ. Oral acyclovir in acute herpes zoster. Br Med J (Clin Res Ed). 1986;293(6561):1529–1532.

13. 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.

14. 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.

15. Ruel TD, Boivin MJ, Boal HE, et al. Neurocognitive and motor deficits in HIV-infected Ugandan children with high CD4 cell counts. Clin Infect Dis. 2012;54(7):1001-1009. doi:10.1093/cid/cir1037