Pediatric Annals

Antiviral Chemotherapy

George A Nankervis, PHD, MD

Abstract

Antiviral chemotherapy has recently assumed an important role in medical therapeutics. From very ineffective agents only a few years ago, several viral illnesses are now amenable to therapy with antiviral compounds. These agents have been particularly important for the therapy of illnesses which have nor been controlled by vaccines. Their development has gone hand-in-hand with the emergence of a number of rapid viral diagnostic techniques. This review will deal only with the antiviral agents which are currently of the most interest.

DNA VIRUSES

Vidarabine was the first nucleoside analogue effective against the herpesviruses to be licensed in the United States. This compound has activity against herpes simplex, varicella-zoster, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). This purine nucleoside analogue probably exerts its antiviral activity via inhibition of virus-specific DNA polymerase, inhibition of virus-specific ribonucleotide reducíase, direct incorporation into viral DNA or a combination of these modalities.1 The data are conflicting but clearly, viral DNA synthesis is inhibited at a much lower drug concentration than is cellular DNA.

A major problem with vidarabine is that the drug is poorly soluble in aqueous solutions. Thus intravenous (IV) administration necessitates the use of large amounts of diluting fluid resulting in the administration of large quantities of fluid. This is a particular disadvantage in the treatment of herpesvirus infections in the neonate and infant and in the treatment of herpes simplex encephalitis.

Vidarabine IV at 10 mg/kg per day for 5 days reduces the rate of new lesion formation and the duration of viral shedding in immunocompromised patients with herpes zoster or chickenpox.2 Vidarabine has also proven to be efficacious in the treatment of herpes simplex encephalitis, a potentially devastating disease. In a controlled study, mortality in a placebo group was 70% while mortality in the treated group was 28% at the end of 1 month.3 Approximately 50% of treated survivors had normal central nervous system (CNS) functions at the end of a year. The outcome of therapy is closely correlated with early intervention. Unfortunately, the early diagnosis of herpes simplex encephalitis is difficult clinically. Brain biopsy can facilitate early diagnosis but there is often great reluctance to undertake this procedure.

Of more interest to pediatricians is the treatment of neonatal herpes simplex. These infections carry a high morbidity and mortality rate. Vidarabine at 15 mg/kg/ day IV reduced mortality from 74% in the placebo group to 38% in the treated group.4 However, only 29% of the latter with CNS or disseminated disease were normal at 1 year of age. Higher doses in subsequent studies did not alter the outcome.

Acyclovir is a recently licensed antiviral compound with specific activity against certain of the herpesviruses and can be administered by the IV, oral, or topical routes. The IV route requires significantly less fluid than does vidarabine. The specificity of this drug is related to its activity being dependent upon a virusinduced thymidine kinase present in some herpesvirus-infected celts. This enzyme phosphorylates acyclovir to acyclovir monophosphate which is subsequently converted to di- and triphosphates by host cell kinases. The triphosphate inhibits herpesvirusinduced DNA polymerase and can also serve as a substrate for the above polymerase resulting in incorporation of acyclovir into viral DNA. Acyclovir is active against herpes simplex types I and II and varicella-zoster viruses but significantly less active against CMV or EBV since these latter viruses do not induce a thymidine kinase. 5 EBV is more sensitive than CMV, perhaps because of the highly sensitive EBV DNA polymerase. Acyclovir- resistant mutants which either do not induce thymidine kinase or inhibit DNA polymerase poorly have been described. Mutants have been less pathogenic in some animal…

Antiviral chemotherapy has recently assumed an important role in medical therapeutics. From very ineffective agents only a few years ago, several viral illnesses are now amenable to therapy with antiviral compounds. These agents have been particularly important for the therapy of illnesses which have nor been controlled by vaccines. Their development has gone hand-in-hand with the emergence of a number of rapid viral diagnostic techniques. This review will deal only with the antiviral agents which are currently of the most interest.

DNA VIRUSES

Vidarabine was the first nucleoside analogue effective against the herpesviruses to be licensed in the United States. This compound has activity against herpes simplex, varicella-zoster, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). This purine nucleoside analogue probably exerts its antiviral activity via inhibition of virus-specific DNA polymerase, inhibition of virus-specific ribonucleotide reducíase, direct incorporation into viral DNA or a combination of these modalities.1 The data are conflicting but clearly, viral DNA synthesis is inhibited at a much lower drug concentration than is cellular DNA.

A major problem with vidarabine is that the drug is poorly soluble in aqueous solutions. Thus intravenous (IV) administration necessitates the use of large amounts of diluting fluid resulting in the administration of large quantities of fluid. This is a particular disadvantage in the treatment of herpesvirus infections in the neonate and infant and in the treatment of herpes simplex encephalitis.

Vidarabine IV at 10 mg/kg per day for 5 days reduces the rate of new lesion formation and the duration of viral shedding in immunocompromised patients with herpes zoster or chickenpox.2 Vidarabine has also proven to be efficacious in the treatment of herpes simplex encephalitis, a potentially devastating disease. In a controlled study, mortality in a placebo group was 70% while mortality in the treated group was 28% at the end of 1 month.3 Approximately 50% of treated survivors had normal central nervous system (CNS) functions at the end of a year. The outcome of therapy is closely correlated with early intervention. Unfortunately, the early diagnosis of herpes simplex encephalitis is difficult clinically. Brain biopsy can facilitate early diagnosis but there is often great reluctance to undertake this procedure.

Of more interest to pediatricians is the treatment of neonatal herpes simplex. These infections carry a high morbidity and mortality rate. Vidarabine at 15 mg/kg/ day IV reduced mortality from 74% in the placebo group to 38% in the treated group.4 However, only 29% of the latter with CNS or disseminated disease were normal at 1 year of age. Higher doses in subsequent studies did not alter the outcome.

Acyclovir is a recently licensed antiviral compound with specific activity against certain of the herpesviruses and can be administered by the IV, oral, or topical routes. The IV route requires significantly less fluid than does vidarabine. The specificity of this drug is related to its activity being dependent upon a virusinduced thymidine kinase present in some herpesvirus-infected celts. This enzyme phosphorylates acyclovir to acyclovir monophosphate which is subsequently converted to di- and triphosphates by host cell kinases. The triphosphate inhibits herpesvirusinduced DNA polymerase and can also serve as a substrate for the above polymerase resulting in incorporation of acyclovir into viral DNA. Acyclovir is active against herpes simplex types I and II and varicella-zoster viruses but significantly less active against CMV or EBV since these latter viruses do not induce a thymidine kinase. 5 EBV is more sensitive than CMV, perhaps because of the highly sensitive EBV DNA polymerase. Acyclovir- resistant mutants which either do not induce thymidine kinase or inhibit DNA polymerase poorly have been described. Mutants have been less pathogenic in some animal models and thus their emergence does not necessarily portend a poor response to therapy. Studies of this phenomenon are in the early stages and, as with bacterial resistance to antibiotics, it may prove to be a significant problem.

Acyclovir is effective against mucocutaneous herpes simplex infections. In immunocompromised patients topical acyclovir treatment results in a modest improvement. ,Intravenous therapy results in marked improvement in these situations.6 Prophylactic oral or IV administration results in the prevention of lesion formation and virus shedding but only as long as the agent is given.

The most extensive use of acyclovir is in the treatment of genital lesions. Topical therapy of primary genital infections exerts a modest beneficial effect, reducing virus shedding and time to crusting of lesions. However, topical therapy is relatively ineffective as a treatment modality for recurrent infections even when applied early in the episode.6 The IV or oral preparations are very effective in the therapy of primary genital herpes simplex infection.7 Oral therapy of recurrent genital infections results in no effect to a minimal effect on the lesions. The earlier the institution of therapy, the more favorable the result. Oral acyclovir prophylaxis for prevention of recurrent herpes simplex genital infections has shown promise.

At least two recent studies8·9 have indicated that acyclovir may be superior to vidarabine with respect to mortality and sequelae in the treatment of herpes simplex encephalitis. In one study9 of brain biopsy proven disease, the mortality in vidarabine treated disease was 54% versus 28% in acyclovir- treated patients. At 6 months post-disease only 14% of vidarabine treated patients versus 38% of acyclovirtreated patients were functioning normally. Currently acyclovir is the treatment of choice for herpes simplex encephalitis.

Although varicella-zoster virus is less sensitive to acyclovir than herpes simplex, IV acyclovir is effective against varice Ila- zoster infections in the immunosuppressed as well as in the normal patient. 10 Therapy in the latter, however, is rarely indicated. Comparative studies of acyclovir versus vidarabine in immunocompromised patients have indicated that acyclovir is superior in controlling dissemination, shortening the period of virus shedding, and inducing lesion healing.11

Recent data indicate that acyclovir may have some efficacy in the treatment of infectious mononucleosis.12 Although there were no significant differences in individual clinical symptoms or laboratory parameters, duration of fever, weight loss, tonsillar swelling, and pharyngitis were significantly less in the acyclovir versus the placebo- treated group.

Acyclovir has been generally very well-tolerated and free of toxicity. The exceptions have been occasional toxicity when the drug was given too rapidly or when patients were significantly dehydrated. Longterm follow-up studies are not currently available.

RNA VIRUSES

Amantadme has been under study for over 20 years with increasing interest over the past 5 years. The activity of this primary symmetrical amine is limited to influenza A although at higher concentrations there is some activity against parainfluenza and rubella viruses. The precise mechanism of action is unclear but inhibition probably occurs in the replication process after it penetrates the cell surface. ' ' Resistant mutants can be readily generated in the laboratory but resistant virus has only rarely been reported in natural infection.

Amantadine is effective in both prophylaxis and therapy in diverse populations and age groups in different epidemiologie settings. l4 Prophylactic protection approaches 80% efficacy and has been evaluated primarily in young adults with uncomplicated influenza A. The therapeutic effect has been modest with recipients experiencing more rapid resolution of symptoms and fever.

Amantadine has been generally well-tolerated. Side effects have been reported in approximately 5% to 10% of patients and have consisted of mild CNS symptomatology such as anxiety, jitteriness, insomnia, decreased attention span, and vertigo.14 These side effects clear rapidly on discontinuation of the drug.

Ribavirin has become an extremely popular antiviral agent over the past 1 to 2 years, particularly during the past winter. Ribavirin is a synthetic nucleoside analogue with in vitro activity against a wide spectrum of DNA as well as RNA viruses. Its mechanism of action is not completely clear and may be different for different groups of viruses. Ribavirin does not interfere with attachment or penetration and does not induce interferon production. Ribavirin is first phosphorylated in the cells and these products become incorporated into messenger RNA preventing its complete formation. In addition the drug inhibits viral nucleic acid polymerases.15

Most of the enthusiasm has centered around the use of ribavirin to treat respiratory syncytial virus (RSV). The efficacy of ribavirin was initially evaluated in Rochester16·17 and Houston18 in infants with lower respiratory tract RSV infections. Infants were randomized in double blind fashion and treated with ribavirin aerosol or water aerosol for 20 hours per day for 5 days. The infants treated with ribavirin showed significant improvement in their illness, degree of hypoxemia, and in decreased viral shedding. This mode of therapy may be particularly important in infants with congenital heart disease, chronic lung disease or severe combined immunodeficiency where RSV infection can be devastating. These initial studies have been corroborated by other groups.

Early studies of ribavirin in the therapy of influenza A & B utilized oral ribavirin and produced conflicting results. Subsequent trials utilizing aerosol administration to college students with acute influenza A and B infections indicated that ribavirin-treated patients had earlier improvement of clinical signs and symptoms as well as decreased viral shedding. l9

In vivo or in vitro activity of ribavirin against parainfluenza 1 and 2, rubella, measles, adenovirus, hepatitis A, and Lassa fever have also been reported. Further studies are needed in these areas to delineate the possible role of ribavirin in the treatment of these diseases.

Ribavirin has been well-tolerated with no evidence of induction of drug resistance thus far. Although the drug has been administered to infants on respirators, there is a tendency for the drug to precipitate and clog the lines if care is not taken. Possible long-term effects of ribavirin on young, developing lungs is currently unknown.

SUMMARY

The above discussion is not intended to be exhaustive but rather to discuss several compounds which are particularly promising at this time. There is no question that great strides have been made in the development of antiviral compounds over the past couple of decades. Many questions remain unanswered such as long-term effects on the host, possible emergence of resistant viruses, optimal routes of administration, and the proper regimens for particular viruses and diseases. In addition, current studies are evaluating combinations of antiviral agents as well as combination therapy involving interferon or antibody or immunity stimulants along with an antiviral agent. Surprising progress has been made to date resulting not only in new therapeutic modalities but promising a new era of progress.

REFERENCES

1. Shannon WM: Mechanisms of act ion and pharmacology: Chemical agents, in Galasso GJ (ed): Antiviral Agents and Viral Diseases of Man. New York, Raven Press, 1984. pp 55-121.

2. Whitley RJ, Soong SJ, Doli n R, et al: Early vidarabine therapy to control he complications of herpes zoster in immunosuppressed patients. N Engl J Med 1982; 307;97l-97S.

3. Whitley RJ. Soong SJ, DoIm R. et al: Adenine arabinoside therapy of biopsy-proved herpex simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N fingi J Mid 1977; 297:289-294.

4. Whitky RJ, Nahmias AJ, Visin t i ne AM. et al: The natural history of herpes simplex virus infection of mother and newborn. Pediatrics 1980; 66:489-494.

5. Darta AK. Colbv BM. Shaw JE. et al: Acyclovir inhibition of Epstein-Barr virus replication. Proc Nad Acad So USA 1980; 77;5163-5I66.

6. Correy L. Nahmias AJ, Guinan ME, et al A trial of topical acyclovir in genital herpes simplex vine infections. N Eng J Med 1982: 306:1313-1319.

7. Meni GJ, Critchlow CW. Benedetti J. et al: Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex vims infection. JAMA 1984; 252:1147-1151.

8. Skoldenberg B, A lest ig K, Burman L. et al: Acvcluvir versus vidarabine m herpes simplex encephalitis. Randomized multkenfre study in consecutive Swedish patients. Lancet 1984; 707-711.

9. Whitley RJ, A ford CA, Hirsch MS, et al: Vidarabine vetsus atycliivir therapy in herpes simplex encephalitis. N Engl J Med 1986;314:144-149.

10. Balfour HH: Intravenous acyclovir therapy for varicella in immunocompmmised children. J Miau 1984; 134-136.

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12. Anderssein J. Britron S. Ernberg I, et al Effect of acyclovir on infectious tnonunucleosis: A double-Mind, placebo-controlled study. ; Infect Da 1986; 153:283-265.

13. Kato N. Eggers HJ: Inhibition of uncoating of fowl plague virus hy l-adamantanamine hydrochloride. Virology 1969; 37:632-641.

14. LaMontagneJR, GalassoGJ: Report of a worfcshopon clinical studies of the efficacy of amantadine and rimanradine against influenza virus. J Infect Du 1978; 138:928-931.

15. Hall CB: Ribavirin; Beginning the blitz on respiratory viruses? Pedian Infect Du 1985: 4:668-671.

16. Hall CB. Wabh EE, Hruska JF et al: Ribavirin treatment of experimental respiratory syncYtial viral infccrion. JAMA 1983; 249:2666-2670.

17. Hall CB, McBndeJT. WalshEE, et al Aerosolized nbavinn treatment of infanti with rejpiraiory syncytial vital infection. N En1I J Med 1983; 308:1443-1447.

18. Taber LH. Knight V, Gilbert BE, et al: Ribavinn aerosol treatment of brunch 10! ins associated with respiratory syncytiii virus infection in infants. Pediatric 1983, 72:0.3-018.

19. Gilben BE, Wilson SZ. Knight V. et al: R iba v inn small-particle aeroso] treatment of infections cased by influenza virus strains A/Victoria/7/8 J (HINI) and B/Trxas/1/84. Antimicrob Agents Chemorter 1985; 27:309-313.

10.3928/0090-4481-19860601-06

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