Antiviral therapy: old and current issues

Many antiviral drugs are currently approved and formally licensed for clinical use in the treatment of viral infections caused by human immunodeficiency virus, herpes simplex viruses, varicella-zoster virus, respiratory syncytial virus, cytomegalovirus, hepatitis B virus, hepatitis C virus or influenza virus. Recent decades have seen major advances in our knowledge of the natural history and pathogenesis of viral diseases as well as ongoing developments and improvements in antiviral therapy. However, research is far from complete and indeed previously unknown and unexpected issues are currently arising. This review aims to discuss some of these issues in the belief that they should be carefully addressed to enhance the management of patients with viral infections.     

Acyclovir: mechanism of action, pharmacokinetics, safety and clinical applications

Acyclovir is a new antiviral drug that acts as a specific inhibitor of herpesvirus DNA polymerase. It shows good in vitro activity against herpes simplex and varicella-zoster viruses. The drug may be administered topically to the skin, intravenously, orally, or topically to the eye (only topical and intravenous preparations are currently available). Acyclovir kinetics are described by a two-compartment open model. The drug and its metabolites are excreted by the kidney via glomerular filtration and tubular secretion. Dosage adjustment is required in patients with renal failure. Safety and tolerance studies in animals and humans have shown acyclovir to be very well tolerated. The most important adverse effect is crystalluria and elevated serum creatinine related to bolus intravenous administration. Other reported adverse effects include infusion site inflammation and rash. Topical acyclovir is effective for treating initial genital herpes and mucocutaneous herpes in the compromised host, but has not been shown to be clinically useful for recurrent labial or genital herpes. Intravenous acyclovir is effective for mucocutaneous herpes infections in the compromised host and initial genital herpes in the normal host; it is being evaluated for the treatment of herpes simplex virus encephalitis and varicella-zoster infections. An investigational oral preparation may prove to be effective therapy for both initial and recurrent genital herpes. Acyclovir therapy does not eliminate latent virus or prevent subsequent recurrences.     

Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy

Acyclovir (aciclovir) is a nucleoside antiviral drug with antiviral activity in vitro against members of the herpes group of DNA viruses. As an established treatment of herpes simplex infection, intravenous, oral and to a lesser extent topical formulations of acyclovir provide significant therapeutic benefit in genital herpes simplex and recurrent orofacial herpes simplex. The effect of acyclovir therapy is maximised by early initiation of treatment, especially in non-primary infection which tends to have a less protracted course than the primary episode. Long term prophylactic oral acyclovir, in patients with frequent episodes of genital herpes simplex, totally suppresses recurrences in the majority of subjects; as with other infections responding to acyclovir, viral latency is not eradicated and pretreatment frequencies of recurrence return after discontinuation of treatment. Caution should accompany the prophylactic use of acyclovir in the general population, due to the theoretical risk of the emergence of viral strains resistant to acyclovir and other agents whose mechanism of action is dependent on viral thymidine kinase. Intravenous acyclovir is the treatment of choice in biopsy-proven herpes simplex encephalitis in adults, and has also been successful in the treatment of disseminated herpes simplex in pregnancy and herpes neonatorium. Intravenous and oral acyclovir protect against dissemination and progression of varicella zoster virus infection, but do not protect against post-herpetic neuralgia. In immunocompromised patients, intravenous, oral and topical acyclovir shorten the clinical course of herpes simplex infections while prophylaxis with oral or intravenous dosage forms suppresses reactivation of infection during the period of drug administration. Ophthalmic application of 3% acyclovir ointment rapidly heals herpetic dendritic corneal ulcers and superficial herpetic keratitis. Thus, despite an inability to eradicate latent virus, acyclovir administered in therapeutic or prophylactic fashion is now the standard antiviral therapy in several manifestations of herpes simplex virus infection, and indeed represents a major advance in this regard. With the exception of varicella zoster virus infections, early optimism concerning the use of the drug in diseases due to other herpes viruses has generally not been supported in clinical investigations.     

Acyclovir: an update of the clinical applications of this antiherpes agent

This paper reviews the clinical evaluation of acyclovir in the treatment of herpes-virus infections, predominantly those due to herpes simplex and varicella-zoster viruses. Intravenous, oral and topical acyclovir have been reported to be effective in the therapy of a wide variety of established herpes simplex virus infections and the systemic drug has been shown to be capable of suppressing reactivation of that virus. Although acyclovir has less activity against varicella-zoster virus, infections caused by this agent are also susceptible to intravenous and possibly oral therapy. Clinical efficacy against Epstein-Barr virus and cytomegalovirus infections has not been demonstrated but several studies are currently in progress. Limited evidence of in vivo activity against hepatitis B virus also requires further evaluation. Continued studies on tolerance of the drug in clinical use has confirmed the early promise of this selective antiviral, whilst initial concern about the development of widespread resistance has not been borne out in practice.     

Orthopoxvirus targets for the development of antiviral therapies

The potential use of smallpox virus as a bioterror agent and the endemic presence of monkeypox virus in Africa underscores the need for better therapies for orthopoxvirus infections. The only existing clinical experience treating vaccinia and smallpox infections has been with Marboran, which suggested that antiviral therapies could be effective in treating and preventing smallpox infections, but this compound has not been pursued. Drugs that have been approved for other indications, like cidofovir, could be approved for the treatment of orthopoxvirus infections in a timely manner, and this compound has already been approved for emergency treatment of smallpox and complications from vaccination. Its lack of activity when given orally, however, limits its use in a major outbreak involving large numbers of people exposed to the virus. The discovery and development of new therapies can be achieved more rapidly by drawing on the experience and successes with other antiviral agents, particularly with the herpesviruses. This review will discuss the orthopoxvirus replication cycle in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug design and development. This discussion is designed to help investigators relate these targets to parallel functions and existing assays in other virus systems that have been used successfully in drug development. The rapid progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new strategies for antiviral therapy with other viruses.     

Genital herpes: antiviral therapy for symptom relief and prevention of transmission

The episodic and daily suppressive treatment of genital herpes is safe and effective with the currently available antiviral agents: acyclovir, valacyclovir and famciclovir. Clinical strategies for the comprehensive management of genital herpes simplex virus infections are recommended. Data from recent clinical trials demonstrating the efficacy of shorter duration of therapy for recurrences and the use of antivirals for the prevention of transmission are reviewed in this article. The factors influencing the choice of therapy, such as cost, ease of dosing and acyclovir resistance are also discussed.     

Genital herpes: antiviral therapy for symptom relief and prevention of transmission

The episodic and daily suppressive treatment of genital herpes is safe and effective with the currently available antiviral agents: acyclovir, valacyclovir and famciclovir. Clinical strategies for the comprehensive management of genital herpes simplex virus infections are recommended. Data from recent clinical trials demonstrating the efficacy of shorter duration of therapy for recurrences and the use of antivirals for the prevention of transmission are reviewed in this article. The factors influencing the choice of therapy, such as cost, ease of dosing and acyclovir resistance are also discussed.     

Current status of anti-HBV chemotherapy

In the past decade, significant progress has been achieved in the battle against hepatitis B virus. In addition to the immunomodulating agents such as interferon-α and thymosin, many novel antiviral agents have been discovered, among which nucleoside analogues are the main-stay. New-generation compounds such as 3TC and famciclovir have shown promise in the treatment of patients chronically infected by this virus, and are on the line for approval. However, viral rebound after cessation of therapy still remains a major problem. Additionally, the reports on the drug resistance to these antiviral agents suggest that combination therapy will be the eventual strategy (Bartholomewet al., 1997; Tippleset al., 1996). Therefore, developments of safe and effective antiviral agents which do not cross-resist with currently available antiviral drugs are still much needed.     

Emerging drugs for varicella-zoster virus infections

INTRODUCTION: Varicella-zoster virus (VZV) is the etiological agent of two distinct diseases, varicella (chickenpox) and shingles (herpes zoster). Chickenpox occurs following primary infection, while herpes zoster (usually associated with ageing and immunosuppression) is the consequence of reactivation of the latent virus. Post-herpetic neuralgia is the major complication of shingles. AREAS COVERED: This review will discuss vaccination strategies and the current status of antivirals against VZV. A live attenuated vaccine, Varivax, is available for pediatric varicella while Zostavax was developed to boost VZV-specific cell-mediated immunity in adults older than 60 years and, via this mechanism, to decrease the burden of herpes zoster and pain associated with post-herpetic neuralgia. Despite the availability of a vaccine, there is a need for new antiviral agents. Current drugs approved for the treatment of VZV infections include nucleoside analogs that target the viral DNA polymerase and depend on the viral thymidine kinase. Novel anti-VZV drugs have recently been evaluated in clinical trials, including the bicyclic nucleoside analog FV-100, the helicase-primase inhibitor ASP2151 and valomaciclovir (prodrug of the acyclic guanosine derivative H2G). EXPERT OPINION: New anti-VZV drugs should be as safe as and more effective than acyclovir and its prodrug valacyclovir (current gold standard for the treatment of VZV).     

Design and development of antivirals and intervention strategies against human herpesviruses using high-throughput approach

Introduction: Although a number of antiviral agents are licensed for treatment of some human herpesvirus (HHV) infections, effective antiviral therapy is not available for all HHVs. Additional complications are associated with approved drugs, such as toxicity and side effects, and rise in drug-resistant strains is a driving force for new drug development. Success in HHV vaccine development is limited with only vaccines against varicella-zoster virus currently in use in the clinic. In vitro, in vivo and in silico high-throughput (HTP) approaches and innovative microfluidic systems will provide novel technologies to efficiently identify and evaluate new targets and antiherpetic compounds. Coupled with HTP strategies for manipulation of herpesvirus viral genomes, these strategies will greatly accelerate the development of future antivirals as well as candidate vaccine intervention strategies.

Areas covered: The authors provide a brief overview of the herpesvirus family and associated diseases. Further, the authors discuss the approved and investigational antiherpetic drugs in the context of current HTP technologies.

Expert opinion: HTP technology such as microfluidic systems is crucial for the identification and validation of novel drug targets and next-generation antivirals. Current drug development is limited by the unavailability of HTP preclinical model systems. Specific advancement in the development of HTP animal-specific technology, applied in parallel, allows a more rapid evaluation of drugs at the preclinical stage. The advancement of HTP combinatorial drug therapy, especially ‘Organ-on-a-Chip’ approaches, will aid in the evaluation of future antiviral compounds and intervention strategies.     

Epidemiology and prevention of viral infections in patients with hematologic malignancies

Viral infections are some of the most frequent complications in patients with hematologic malignancies are viral infections. Infections caused by cytomegalovirus, herpes simplex virus, varicella zoster virus, hepatitis B virus and influenza virus are associated with high morbidity and mortality in this vulnerable population. Fortunately, a growing number of antiviral medications and vaccines are allowing for more effective prophylaxis against these pathogens. This article reviews the epidemiology and prophylactic strategies available for these opportunistic viral pathogens.     

Future prospects in antiviral therapy

Two important stumbling blocks to the development of effective and nontoxic antiviral drugs are the intracellular localization of the virus and the fact that a virus uses host cell functions to multiply. Therefore, new antiviral drugs must act on a virus-specific function. Most currently available useful antiviral drugs are the result of compound screening of large numbers of possible agents. Advances in our understanding of the molecular biology and biochemistry of the viral multiplication cycle and new laboratory techniques for determining the molecular sites of action have now made it possible to develop and screen new antiviral drugs in a more purposeful manner. Another possible option in antiviral therapy is combination therapy using drugs that enhance the therapeutic effect or diminish side-effects. The most promising new antiviral drugs are discussed according to the different steps they affect in the viral multiplication process. Combination therapy is also reviewed.     

Slipping and sliding: Frameshift mutations in herpes simplex virus thymidine kinase and drug-resistance

Some of the most successful antiviral agents currently available are effective against herpes simplex virus. However, resistance to these drugs is frequently associated with significant morbidity, particularly in immunocompromised patients. In addition to the clinical implications of drug resistance, the range of biological processes exploited by the virus to attain resistance while maintaining pathogenicity is proving to be surprising. These mechanisms, which include ribosomal frameshifting, induced infidelity of the DNA polymerase, and internal ribosome entry, are discussed.     

Evaluation of oral acyclovir therapy

Acyclovir is a specific antiviral agent. The triphosphate form inhibits viral DNA replication by competing for incorporation into the replicating DNA chain or by inhibiting viral DNA polymerase. Cells not infected with herpesvirus are generally unaffected. Oral acyclovir inhibits most herpes simplex virus types 1 and 2, and varicella-zoster virus at concentrations used clinically. Oral acyclovir has an average plasma half-life of three hours and is eliminated primarily by renal mechanisms. Peak plasma concentrations occur 1.5 to 2.5 hours after administration and the oral bioavailability is 15 to 30 percent. Acyclovir distributes into most body tissues, including vesicular fluid and the central nervous system. Oral acyclovir is effective treatment of initial and recurrent genital herpes and can suppress frequently recurring genital herpes in both immunocompetent and immunocompromised patients. It is also effective for acute herpes zoster in the immunocompetent and possibly immunocompromised patient. No role is established in either Epstein-Barr virus or cytomegalovirus infections. Oral acyclovir appears to be effective and relatively safe, nontoxic therapy when administered in doses of 1-4 g/d. Oral acyclovir represents a major therapeutic advance in the treatment of herpesvirus infections.     

Viral diseases of the skin: diagnosis and antiviral treatment

Viral diseases in children can present with characteristic mucocutaneous manifestations. This article focuses, from a practical clinical point of view, on the laboratory and clinical diagnoses, and treatment of pediatric dermatological diseases that have specific antiviral therapies: herpes virus infections (including varicella), papillomavirus infections and molluscum contagiosum. Special issues, such as viral infections in pregnancy, therapy of viral infections in immunosuppressed children, as well as special problems associated with the epidemiology of genital herpes and papillomavirus infections in adolescents are discussed. The antivirals discussed in detail include: aciclovir, valaciclovir, famciclovir, penciclovir, cidofovir, foscarnet and the immune response modulator, imiquimod. Since these antiviral drugs generally have not been evaluated in children, caution should be exercised with their usage.     

Strategies in the design of antiviral drugs

A decade ago, just five drugs were licensed for the treatment of viral infections. Since then, greater understanding of viral life cycles, prompted in particular by the need to combat human immunodeficiency virus, has resulted in the discovery and validation of several targets for therapeutic intervention. Consequently, the current antiviral repertoire now includes more than 30 drugs. But we still lack effective therapies for several viral infections, and established treatments are not always effective or well tolerated, highlighting the need for further refinement of antiviral drug design and development. Here, I describe the rationale behind current and future drug-based strategies for combating viral infections.     

Ribavirin

Despite the plethora of antibiotics available for the treatment of bacterial infections, very few agents have been developed to treat viral diseases. Ribavirin (Virazole) is a triazole nucleoside antiviral agent that produces selective antiviral effects against a broad spectrum of RNA and DNA viruses. The drug has been effective in the treatment of naturally occurring influenza A and B infections when administered by aerosol; oral administration has been ineffective. Ribavirin aerosol therapy also has proven effective to reduce symptoms of respiratory syncytial virus infections in young adults and hospitalized neonates. Ribavirin aerosol may be the first antiviral agent to treat these common diseases.     

Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms.

Nucleoside analogues such as acyclovir and ganciclovir have been the mainstay of therapy for alphaherpesviruses (herpes simplex virus (HSV) and varicella-zoster virus (VZV)) and cytomegalovirus (CMV) infections, respectively. Drug-resistant herpesviruses are found relatively frequently in the clinic, almost exclusively among severely immunocompromised patients receiving prolonged antiviral therapy. For instance, close to 10% of patients with AIDS receiving intravenous ganciclovir for 3 months excrete a drug-resistant CMV isolate in their blood or urine and this percentage increases with cumulative drug exposure. Many studies have reported that at least some of the drug-resistant herpesviruses retain their pathogenicity and can be associated with progressive or relapsing disease. Viral mutations conferring resistance to nucleoside analogues have been found in either the drug activating/phosphorylating genes (HSV or VZV thymidine kinase, CMV UL97 kinase) and/or in conserved regions of the viral DNA polymerase. Currently available second line agents for the treatment of herpesvirus infections--the pyrophosphate analogue foscarnet and the acyclic nucleoside phosphonate derivative cidofovir--also inhibit the viral DNA polymerase but are not dependent on prior viral-specific activation. Hence, viral DNA polymerase mutations may lead to a variety of drug resistance patterns which are not totally predictable at the moment due to insufficient information on specific drug binding sites on the polymerase. Although some CMV and HSV DNA polymerase mutants have been found to replicate less efficiently in cell cultures, further research is needed to correlate viral fitness and clinical outcome.