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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 2  |  Issue : 3  |  Page : 74-78

Antiviral therapy for herpes simplex virus encephalitis: Systematic review and meta-analysis of randomized control trials


1 Department of General Medicine, Great Eastern Medical School and Hospital, Srikakulam, Andhra Pradesh, India
2 Central Research Lab, Great Eastern Medical School and Hospital, Srikakulam, Andhra Pradesh, India
3 Dr. NTR University of Health Sciences, Vijayawada, Andhra Pradesh, India

Date of Submission20-May-2021
Date of Acceptance06-Aug-2021
Date of Web Publication25-Sep-2021

Correspondence Address:
Dr. Sridhar Amalakanti
Department of General Medicine, Great Eastern Medical School and Hospital, Srikakulam, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jascp.jascp_13_21

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  Abstract 


Background: Herpes simplex virus (HSV) infection of the brain is treated with antiviral drugs such as acyclovir. A summary of randomized control trials (RCTs) of antiviral drugs against HSV encephalitis has not been put forward yet. We aimed to determine the effect of antiviral agents in treating HSV encephalitis on mortality and neurological sequelae at approximately 2 years. The secondary objective was to assess the adverse effect of antiviral agents on the patients. Materials and Methods: RCTs were identified by searching PUBMED, European Medicines Agency ( EMA ), USFDA, US Clinical trials, Elsevier database, and Cochrane website and the reference lists of published trials. Randomized controlled trials of antiviral therapy in biologically proven HSV infection were included in the study. Results: A total of 5 studies met the criteria. The first study was published in 1980 and the latest was in 2015. All the studies used acyclovir/valacyclovir or vidarabine. Three studies compared acyclovir and vidarabine, one study was placebo-controlled vidarabine trial and another one was a placebo-controlled trial of long-term valacyclovir therapy. Acyclovir improved mortality and lowered the incidence of neurological sequelae. There was no significant reduction in the risk of mortality with vidarabine therapy. Conclusion: Trial evidence suggests that acyclovir decreases mortality and morbidity in acute HSV encephalitis.

Keywords: Acyclovir, herpes encephalitis, herpes meta-analysis, viral encephalitis


How to cite this article:
Amalakanti S, Boppana SH, Sivaraj N, Raman Arepalli KV, Suvvari TK. Antiviral therapy for herpes simplex virus encephalitis: Systematic review and meta-analysis of randomized control trials. J Appl Sci Clin Pract 2021;2:74-8

How to cite this URL:
Amalakanti S, Boppana SH, Sivaraj N, Raman Arepalli KV, Suvvari TK. Antiviral therapy for herpes simplex virus encephalitis: Systematic review and meta-analysis of randomized control trials. J Appl Sci Clin Pract [serial online] 2021 [cited 2021 Oct 28];2:74-8. Available from: http://www.jascp.com/text.asp?2021/2/3/74/326722




  Introduction Top


Herpes simplex encephalitis is a severe rapidly fatal viral infection of the brain. It is the most common cause of sporadic infectious encephalitis. It accounts for up to 20% of all cases of acute encephalitis.[1],[2],[3] A few antiviral drugs have shown definitive recovery in patients afflicted with herpes simplex virus (HSV) encephalitis, but a comprehensive meta-analysis of the trials of antiviral drugs against herpes encephalitis is lacking. We analyzed the published work on antiviral treatment in HSV encephalitis and present the summary.


  Materials and Methods Top


We extracted data from published randomized controlled trials involving HSV patients treated with antiviral drugs following PRISMA guidelines [Figure 1]. Data were retrieved on January 12, 2019, using search terms in PUBMED. The keywords used were described below.
Figure 1: PRISMA diagram for the analysis method

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  1. (“encephalitis, herpes simplex” [MeSH Terms] OR (“encephalitis” [All Fields] AND “herpes” [All Fields] AND “simplex” [All Fields]) OR “herpes simplex encephalitis” [All Fields] OR (“herpes” [All Fields] AND “simplex” [All Fields] AND “encephalitis” [All Fields])) AND (Randomized Controlled Trial [ptyp] OR Controlled Clinical Trial [ptyp] OR Clinical Trial [ptyp] OR systematic [sb] OR Meta-Analysis [ptyp] OR Comparative Study [ptyp]) which yielded 309 studies
  2. (“herpes simplex” [MeSH Terms] OR (“herpes” [All Fields] AND “simplex” [All Fields]) OR “herpes simplex” [All Fields]) AND (Randomized Controlled Trial [ptyp] OR Controlled Clinical Trial [ptyp] OR Clinical Trial [ptyp] OR systematic [sb] OR Meta-Analysis [ptyp] OR Comparative Study [ptyp]) which yielded 5200 studies
  3. (“encephalitis, herpes simplex” [MeSH Terms] OR (“encephalitis” [All Fields] AND “herpes” [All Fields] AND “simplex” [All Fields]) OR “herpes simplex encephalitis” [All Fields] OR (“herpes” [All Fields] AND “simplex” [All Fields] AND “encephalitis” [All Fields])) AND Meta-Analysis [ptyp] which yielded three studies.




We searched the bibliographies of the selected studies and included studies only if they were randomized controlled trials on patients with herpes simplex encephalitis. The outcome measures which we considered were mortality, adverse drug reactions and neurological sequelae. Data were retrieved independently by the two authors and any disagreement was resolved by consensus.

Statistical methods

We compared the outcome measures between the interventions by assessing relative risk (RR) with 95% confidence intervals. All analyses were performed by MS Excel 2007 and RevMan software.


  Results Top


A total of 5 studies met the criteria. The first study was published in 1980[4] and the latest was in 2015.[5] All the studies used acyclovir/valacyclovir or vidarabine. Three studies[6],[7],[8] compared acyclovir and vidarabine, out of which, the 1991 study[8] included only children below 1 month of age. Among the other two, one study[4] was a placebo-controlled vidarabine trial in neonates and another one[5] was a placebo-controlled trial of long-term valacyclovir therapy after IV acyclovir for acute treatment. We found no randomized placebo-controlled trials of acyclovir for HSV encephalitis.

There are minor differences between the three studies comparing acyclovir with vidarabine. In the 1984 study,[6] the dose of acyclovir was lesser when compared to the other two studies 10 mg/kg versus 30 mg/kg thrice daily. The 1986 study[7] was not blinded and the technique of randomization was not mentioned. The 1991 study[8] used a higher dose of vidarabine compared to the other two studies 30 mg/kg versus 15 mg/kg twice daily.

Ninety-four patients had received acyclovir and 99 patients received vidarabine [Table 1]. Acyclovir treatment resulted in lesser mortality RR 0.53, 95% confidence interval (CI) 0.33, 0.85, P = 0.008 [Figure 2] and fewer adverse drug reactions RR 0.56, 95% CI 0.41, 0.78, P = 0.0005 [Figure 3] than vidarabine therapy. Gastrointestinal events were the more common adverse effects with both the drugs [Table 2]. The proportion of postencephalitis neurological sequelae were similar [Figure 4] with both the treatments RR 0.59, 95% CI: 0.59, 1.09, and P = 0.15. A statistically significant difference in mortality [Figure 5], adverse effects [Figure 6], or neurological sequelae did not occur with vidarabine treatment in comparison with placebo. The long-term treatment study[5] concluded that, after standard treatment with intravenous acyclovir, an additional 3-month course of oral 6 g daily of valacyclovir therapy was of little benefit in herpes simplex encephalitis patients.
Table 1: Characteristics of included studies

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Figure 2: Comparison of mortality in patients between acyclovir and vidarabine treatment

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Figure 3: Comparison of adverse effects of drugs in patients between acyclovir and vidarabine treatment

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Table 2: Adverse events noted in the studies

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Figure 4: Comparison of neurological sequelae of disease in patients between acyclovir and vidarabine treatment

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Figure 5: Comparison of mortality in patients between vidarabine and placebo treatment

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Figure 6: Comparison of adverse effects of drugs in patients between vidarabine and placebo treatment

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  Discussion Top


Our review of randomized controlled trials of antiviral drugs against herpes simplex encephalitis showed that acyclovir has a more favorable profile when compared to vidarabine in terms of mortality and adverse effects but not residual neurological sequelae. However, the placebo-controlled vidarabine trial shows no advantage of the drug in herpes simplex encephalitis; also chronic treatment with valacyclovir was not useful. Three studies comparing acyclovir and vidarabine show clear differences in mortality and adverse events with the treatment. The differences in terms of residual neurological sequelae were much more modest. Presumably, other factors such as age and speed of institution of treatment might have affected this outcome. The study comparing vidarabine and placebo included only thirty patients in each arm. The small sample size needs to be borne in mind when considering the equivocal conclusion of the study.

A previous review of antiviral drugs against HSV infection in neonates seconded their efficacy and beneficial effect. However, it could not find any superiority of acyclovir over vidarabine. Our review encompassing all age groups shows that acyclovir is beneficial in herpes simplex encephalitis. Vidarabine has no significant effect on the course of the illness. There is a lack of large-scale randomized controlled trials of the antiviral drugs against HSV encephalitis. Many other drugs have been shown to be successful against herpes simplex in randomized controlled trials. Many other drugs have been shown to be successful against herpes simplex in randomized controlled trials. Examples include Ganciclovir and steroids against keratitis,[9],[10] famciclovir and alpha interferon against genital herpes,[11],[12] foscarnet and ascorbic acid against mucocutaneous lesions.[13],[14] So, there is scope for trials with the above drugs in herpes encephalitis also. These studies showed that gastrointestinal events are the commonest adverse effects. This data also thus suggests a potential arena for fine tuning the drugs like acyclovir and vidarabine.


  Conclusion Top


Evidence from trials suggests that acyclovir decreases mortality and morbidity in acute HSV encephalitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bradshaw MJ, Venkatesan A. herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics 2016;13:493-508.  Back to cited text no. 1
    
2.
Solomon T, Michael BD, Smith PE, Sanderson F, Davies NW, Hart IJ, et al. Management of suspected viral encephalitis in adults-Association of British Neurologists and British Infection Association National Guidelines. J Infect 2012;64:347-73.  Back to cited text no. 2
    
3.
Jørgensen LK, Dalgaard LS, Østergaard LJ, Nørgaard M, Mogensen TH. Incidence and mortality of herpes simplex encephalitis in Denmark: A nationwide registry-based cohort study. J Infect 2017;74:42-9.  Back to cited text no. 3
    
4.
Whitley RJ, Nahmias AJ, Soong SJ, Galasso GG, Fleming CL, Alford CA. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 1980;66:495-501.  Back to cited text no. 4
    
5.
Gnann JW, Sköldenberg B, Hart J, Aurelius E, Schliamser S, Studahl M, et al. Herpes simplex encephalitis: lack of clinical benefit of long-term valacyclovir therapy. Clin Infect Dis 2015;61:683-91.  Back to cited text no. 5
    
6.
Sköldenberg B, Forsgren M, Alestig K, Bergström T, Burman L, Dahlqvist E, et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet Lond Engl 1984;2:707-11.  Back to cited text no. 6
    
7.
Whitley RJ, Alford CA, Hirsch MS, Schooley RT, Luby JP, Aoki FY, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986;314:144-9.  Back to cited text no. 7
    
8.
Whitley R, Arvin A, Prober C, Burchett S, Corey L, Powell D, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med 1991;324:444-9.  Back to cited text no. 8
    
9.
Wang X, Wang L, Wu N, Ma X, Xu J. Clinical efficacy of oral ganciclovir for prophylaxis and treatment of recurrent herpes simplex keratitis. Chin Med J (Engl) 2015;128:46-50.  Back to cited text no. 9
    
10.
Wilhelmus KR, Gee L, Hauck WW, Kurinij N, Dawson CR, Jones DB, et al. Herpetic eye disease study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 1994;101:1883-96.  Back to cited text no. 10
    
11.
Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D, et al. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group. Arch Intern Med 1997;157:343-9.  Back to cited text no. 11
    
12.
Shupack J, Stiller M, Knobler E, Ackerman C, Jondreau L, Kenny C. Topical alpha-interferon in recurrent genital herpes simplex infection. A double-blind, placebo-controlled clinical trial. Dermatologica 1990;181:134-8.  Back to cited text no. 12
    
13.
Safrin S, Crumpacker C, Chatis P, Davis R, Hafner R, Rush J, et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group. N Engl J Med 1991;325:551-5.  Back to cited text no. 13
    
14.
Hovi T, Hirvimies A, Stenvik M, Vuola E, Pippuri R. Topical treatment of recurrent mucocutaneous herpes with ascorbic acid-containing solution. Antiviral Res 1995;27:263-70.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

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