Therapeutic Options for Herpes Simplex Eugene Au and Stephen L. Sacks, MD

Address initiates through direct Department of Pharmacology and Therapeutics, The University of contact with mucosal surfaces or abraded skin. Following British Columbia, Viridae Clinical Sciences Inc.,1134 Burrard Street, infection, the virus is transported to the dorsal root gan- Vancouver, BC, Canada V6Z 1Y8. E-mail: [email protected] glion, where latent infection is established. Stimuli such as stress, fever, and exposure to ultraviolet light can cause Current Infectious Disease Reports 2003, 5:22–27 Current Science Inc. ISSN 1523-3847 reactivation from latency, upon which active infection Copyright © 2003 by Current Science Inc. occurs near the point of entry into the host [5•]. Signs of recurrent infection may include a prodrome of pain, burn- Herpes simplex viruses are responsible for a number of dis- ing, tingling, or discomfort, which precede the develop- ease states in infected individuals. Capable of establishing ment of classic herpes lesions characterized by vesicle latent infection, herpes simplex can reactivate, causing pain, formation on a red patch of skin. Classically, vesicular discomfort, and psychosocial consequences. Because no lesions evolve into erosions, although atypical presenta- cure is available, treatment modalities for herpes simplex tions are common [2]. infection are required, from both personal and public health There is no known cure for herpes simplex infections. standpoints. To date, therapy has centered around the use As the incidence of infection continues to rise, and with of antiviral drugs to control infection and suppress recur- mounting evidence that HSV-2 is a significant cofactor in rences. To expand the scope of available treatments, efforts the transmission of HIV, it may be imperative to develop have focused on the development of against her- new therapeutic options for HSV disease. This review dis- pes simplex virus and new agents such as immune response cusses the use of antiviral drugs currently used in episodic modifiers. Recent data suggest that these new agents are and suppressive therapy. In the immunocompromised promising in their therapeutic potential. host, use of antivirals may play a role in the selection of drug-resistant HSV, and therapies for resistant virus strains are discussed. In addition, vaccines against HSV are consid- ered, as well as topical treatment modalities and other Introduction potential targets for HSV . The family, officially designated as human herpes viruses 1 through 8 (HHV-1 through HHV-8), con- sists of eight viruses capable of producing pathogenic Antivirals in the Treatment of Herpes infection in humans [1]. HHV-1 and HHV-2 are com- Simplex Infections monly referred to as herpes simplex viruses type 1 and type The major treatment modality for HSV infections is the use 2 (HSV-1 and HSV-2), respectively. HSV are enveloped, of antiviral nucleoside analogues. Common across this double-stranded DNA viruses distinguished by differences class of is the requirement of activation by in clinical and virologic characteristics, including differ- viral-encoded thymidine kinase (TK). The first nucleoside ences in glycoproteins expressed on the viral envelope. It is analogue shown to be effective agent in clinical trials was estimated that up to 85% of the population is seropositive acyclovir. In cells infected with HSV, acyclovir is phospho- for HSV-1 [2], and though this virus is most often associ- rylated to acyclovir monophosphate by TK, and subse- ated with herpes labialis (cold sores), the incidence of her- quently converted to its di- and triphosphate forms pes genitalis (genital herpes) caused by HSV-1 is on the rise through the actions of host cellular enzymes. The active [3]. HSV-2 is the major cause genital herpes, one of the form of the drug is acyclovir triphosphate, which inhibits most common sexually transmitted infections (STIs). HSV-encoded DNA polymerase through competition with Despite the efforts aimed at preventing the spread of AIDS deoxyguanosine triphosphate as a substrate for the and other STIs, the prevalence of HSV-2 infection has enzyme. This results in obligate termination of HSV DNA increased, as evidenced by the National Health and Nutri- replication, and thus inhibition of viral growth [6]. Oral tion Examination Surveys (NHANES) II and III, which acyclovir is approved by the US Food and Drug Adminis- showed a 30% increase in HSV-2 seroprevalence [4]. HSV-2 tration (FDA) for the treatment of genital herpes infection. is also associated with neonatal herpes. Primary infection is effectively treated with 200 mg five Therapeutic Options for Herpes Simplex Infections • Au and Sacks 23 times daily for 5 to 10 days, and episodic drug therapy with the presence of a 3' hydroxyl group, whereas acyclovir lacks 200 mg five times daily for 5 days is used for the treatment the 3' hydroxyl group making its chain termination "obli- of recurrent infection [7••]. An alternative regimen recom- gate." It has been shown that the active drug form, penci- mended by the Centers for Disease Control and Prevention clovir triphosphate, is made in excess and has a much (CDC) is 400 mg three times daily for the treatment of longer intracellular half-life (20 hours) than acyclovir both primary and recurrent infections [8]. A 2-day regimen triphosphate (1 hour) in cells infected with HSV-2. How- of acyclovir has also been successfully used for episodic ever, triphosphate is proportionally less potent treatment of recurrent infection [9]. For patients with fre- against viral DNA polymerase [20]. A topical 1% cream quent recurrences, 400 mg twice daily is effective in contin- preparation of penciclovir, applied once every 2 hours for 4 uous suppressive therapy of genital herpes [7], although days, is approved by the FDA for the treatment of recurrent dosages of 200 mg two to five times daily have also been herpes labialis. effectively used [10,11]. Acyclovir may also be of minimal , administered at 125 mg twice daily for 5 benefit in the treatment of herpes labialis. Acyclovir is not days, is approved for the episodic treatment of recurrent FDA-approved for treatment of HSV labialis [12–14]. genital herpes. It is also effective in the suppression of Though acyclovir has been demonstrated to be both effec- recurrent infection, approved at a dose of 250 mg twice tive and safe, its inconvenient dosing schedule, which leads daily [7••]. The dosing of famciclovir is often confusing to to issues in compliance, and low bioavailability (approxi- clinicians, but results from the intracellular pharmacoki- mately 15%) have fostered the development of the nucleo- netic advantage in its conversion to its triphosphate. This side prodrugs and famciclovir, which exhibit provides a dosing advantage during active treatment, but improved absorption characteristics. that advantage disappears between active episodes, when Valaciclovir, the 1-valyl ester prodrug of acyclovir, is viral TK is not expressed. The use of famciclovir in the metabolized to L-valine and acyclovir. Its safety and phar- treatment of primary genital herpes infection has been macokinetics are essentially identical to those of acyclovir investigated in clinical studies. It was determined that as the parent nucleoside, but valaciclovir is much better when administered at 250 mg, 500 mg, and 750 mg three absorbed than acyclovir, with an oral bioavailability of times daily for 5 days, famciclovir was as efficacious as about 55%. The peak plasma concentrations of acyclovir acyclovir at doses approved for the treatment of primary achieved are approximately four times greater when valaci- infection [21], and has the practical advantage of reduced clovir is administered in similar doses to acyclovir [15]. dosing frequency. Oral valaciclovir is efficacious in the treatment of genital In assessing the advantages of the antivirals currently herpes, and is indicated for primary (1000 mg twice daily available for the treatment of HSV infection, acyclovir and for 10 days) and recurrent (500 mg twice daily for 3 days) valaciclovir are favored for the potency of acyclovir triphos- infections [7••]. It is also approved for continuous sup- phate, whereas famciclovir has a dosing advantage only pressive therapy of genital herpes at a dosage of 500 mg during episodic therapy due to its long intracellular half- once daily for patients with 10 or fewer recurrences per life. These differences in drug characteristics may be indi- year, and 1000 mg once daily for patients with greater than vidually optimized to select treatment regimens according 10 recurrences annually [7••]. Doses of 250 to 500 mg to each individual’s needs. twice daily have also been shown to be effective in suppres- sive therapy [16,17]. Recent studies have demonstrated the therapeutic Resistance to Antivirals potential of valaciclovir for the treatment of herpes labia- A concern regarding the use of antiviral for lis. High-dose valaciclovir at the first prodromal symptom the treatment of HSV infections has been the development for 1 day (2000 mg twice) or 2 days (2000 mg twice on of drug resistance. Strains of HSV that are resistant to acy- the first day, followed by 1000 mg twice on the second clovir have been identified, with a far higher rate of occur- day) was effective in reducing episode duration and rence in immunocompromised individuals (4% to 11%) lesion healing time [18]. It has also been recently compared with the general population (0.4%) [2]. Resis- reported that suppressive valaciclovir therapy is effective tance may be conferred by viral mutations resulting in in reducing transmission of genital herpes among hetero- strains of HSV that are deficient in TK [22], or strains that sexual HSV-2 discordant couples, a significant finding in exhibit altered TK activity without loss of virulence [23]. that it is the first controlled trial demonstrating the ability Strains lacking TK are resistant, but also frequently subviru- of antiviral therapy to reduce sexual transmission of viral lent. Mutations in viral DNA polymerase are rare, but may infections [19]. retain virulence. Famciclovir is the oral prodrug of penciclovir, another Drugs that have been developed for the treatment of possessing antiviral activity against acyclovir-resistant HSV include and . HSV. Though penciclovir and acyclovir are both dependent Foscarnet is a non-nucleoside pryophosphate analogue, on viral TK, penciclovir differs from acyclovir in that HSV and therefore does not require conversion by HSV TK. It DNA chain termination is attained with penciclovir despite acts thererfore by inhibiting the cleavage of pyrophosphate 24 Antimicrobial Agents groups from deoxynucleoside triphosphates, thereby inter- Vaccines against HSV currently under development can fering with viral DNA chain elongation [24]. Foscarnet is be classified as either live or inactive vaccines [30••]. The approved by the FDA for the treatment of acyclovir-resis- challenge of the developmental process is to balance the tant HSV infections in immunocompromised patients, advantages and disadvantages of each potential candidate, however, its use is limited to intravenous administration taking into account factors such as immunogenicity and due to poor oral bioavailability. Drug toxicity is a dose- safety profile. Live vaccines include nonpathogenic attenu- dependent concern with foscarnet, as potential adverse ated virus forms, replication-limited mutants, and also effects include renal dysfunction, gastrointestinal distur- replication vectors for the delivery of HSV antigens. Advan- bances, hypocalcemia, and genital ulcers [25]. tages of live vaccines that make them preferable over inac- Another broad-spectrum antiviral agent under investi- tive vaccines include the generation of a broader immunity gation for the treatment of acyclovir-resistant HSV is cido- that would be longer lasting because of replication fovir, an analogue of the nucleotide deoxycytosine in the recipient. However, there are concerns regarding monophosphate. Like foscarnet, the antiviral activity of their safety and stability, especially with nonpathogenic cidofovir bypasses viral-encoded TK. Cidofovir is metabo- strains of HSV derived from cell culture that have been lized to its active diphosphate form through the actions of shown to revert to pathogenic forms [31]. cellular enzymes, and exerts its antiviral activity through Inactive vaccines include killed or inactivated virus interaction with viral DNA polymerase. Incorporation of forms, nucleic acid vaccines, and protein subunit vaccines. one cidofovir molecule causes a decrease in chain elonga- Subunit vaccines, usually based on HSV envelope glyco- tion efficacy, and incorporation of two cidofovir molecules proteins gB and gD, have been developed in an attempt to separated by one nucleotide results in complete termina- increase antigenic concentration, thereby inducing a stron- tion of DNA synthesis [24]. Though limited by intravenous ger immune response while maintaining a good safety pro- adverse effects and a poor oral bioavailability of less than file by not requiring whole live virus and eliminating viral 5% [7••], the use of topical cidofovir gel for the treatment DNA [29]. While the degree of immunogenicity achieved of HSV infections has been shown to have a significant with subunit vaccines may be less than that of live vaccines, antiviral effect. A trial of 1%, 3%, and 5% cidofovir gel for immunogenicity can be improved through the addition of the treatment of genital herpes lesions in immunocompe- adjuvants in the formulation. tent patients showed a dose-dependent decrease in median Various subunit vaccine candidates have been evalu- time to negative virus culture compared with placebo, ated in clinical trials. An early study of an HSV-2 purified however, adverse effects included dose-dependent genital envelope glycoprotein vaccine developed by Merck (Rah- ulcers in men [26]. Cidofovir gel has also been tested in a way, NJ) showed that it was poorly immunogenic and small study in immunocompromised patients, and was failed to provide protection from HSV infection, with shown to possess both antiviral and clinical efficacy [27]. acquisition rates of infection being similar in groups Unfortunately, this gel is not approved and is not available receiving vaccine (10.7%) versus placebo (8%) [32]. Subse- from a commercial source. Some pharmacies have used the quently, clinical trials have been conducted to investigate intravenous preparations to prepare the gel formulation in the efficacy of a vaccine developed by Chiron (Emeryville, critical clinical situations. CA), a gD2- and gB2-based vaccine containing MF59, a squalene oil-in-water emulsion adjuvant. In these studies, a benefit was observed for the initial 5 months of the study, Development of Herpes Simplex as HSV-2 acquisition rates were 50% lower among vaccine Virus Vaccines recipients compared with placebo during this period. Another approach to control HSV infection is the prevention Although high levels of HSV-2 neutralizing antibodies of viral transmission, which can be difficult for two reasons: were induced in patients receiving the vaccine, the overall 1) individuals infected with HSV are often unaware of the efficacy was determined to be 9%. Therefore, the authors fact, and 2) transmission can occur during asymptomatic concluded that high titers of specific neutralizing antibod- shedding, during which infection is active, but unnoticed ies alone were insufficient to provide sustained protection [28]. An ideal vaccine against HSV would be capable of from HSV-2 infection [33]. A recombinant gD2 subunit inducing immune responses in the susceptible partner suffi- vaccine developed by GlaxoSmithKline (Research Triangle cient to prevent infection. It follows, then, that if primary Park, NC) has also been evaluated in clinical trials. This infection could be prevented, there would be no virus avail- vaccine, which is combined with the adjuvant alum plus able to cause recurrent HSV, or, in turn, to be transmitted sec- monophosphoryl lipid A, was shown to be efficacious in ondarily. Clinical endpoints include reduction of the severity protecting HSV double-seronegative women from both of primary episodes, prevention of ganglionic latency or infection (43%) and disease (72%). However, double- reduction of severity or frequency of recurrent disease, or seronegative men and all individuals seropositive for HSV- reduction of asymptomatic sheding [29••]. 1 were not afforded protection [34•]. Therapeutic Options for Herpes Simplex Infections • Au and Sacks 25

Other Treatment Modalities for Herpes than in those given placebo. n-Docosanol was also shown Simplex Virus Infection to be efficacious with respect to other endpoints of clinical Resiquimod significance, as both the time to relief from pain and other Resiquimod belongs to class of therapeutic agents known symptoms and the duration of the most severe stage of the as immune response modifiers (IRMs). Unlike the nucleo- lesion were reduced [42]. Antiviral effects in humans have side antivirals that directly target HSV, IRMs do not possess not been tested. direct antiviral effects. Rather, they exert their actions through modulation of certain immune cells, resulting in Microbicides production of cytokines that regulate the immune An area of recent research interest has been the develop- response against viral infection. In vivo studies on the ment of topical microbicides with broad-spectrum activity mechanism of IRM action suggest that they activate against various sexually transmitted pathogens, including immune cells via the Toll-like receptor 7 (TLR7)-MyD88– HSV. First-generation microbicides, each of which confer dependent signaling pathway [35]. Resiquimod is more protection through a unique mechanism of action, have soluble and potent in stimulating T-helper 1 (Th)-1 cell- been evaluated in animal models of genital herpes [43]. mediated immune responses than , a first-gen- Buffergel, an acidic buffer microbicide that acts by inacti- eration synthetic IRM [36]. Resiquimod has been shown to vating acid-sensitive pathogens, showed protective effects stimulate the production of -α, interferon-γ, and against HSV-2 transmission in a mouse infection model interleukin-12, as well as enhancement of dendritic cell [44]. Protection against genital herpes was also observed antigen presentation [37,38]. with the naphthalene sulphonate polymer PRO 2000, A recent clinical study was conducted to evaluate the which prevents infection by blocking pathogen-target effects of resiquimod applied during a recurrence of genital attachment [45]. These results suggest that the use of herpes. In this study, patients with frequently recurring microbicides in the prevention of herpes is promising, and genital herpes applied topical resiquimod gel (0.01% two further studies designed to study their efficacy are war- or three times weekly, or 0.05% once or twice weekly) or ranted. With the incidence of HSV-2 infection increasing, vehicle gel to lesions for 3 weeks. During the 6-month and because it increases the risk of HIV acquisition, all observation period, resiquimod was shown to decrease attempts to reduce transmission need to be examined. recurrences, with median days to first recurrence of 169 days for the pooled resiquimod group versus 57 days for Potential approaches for antiviral therapy the vehicle group. It was also determined that 32% of Drugs currently available for the treatment of HSV infec- patients receiving resiquimod completed the observation tions inhibit viral DNA replication by targeting DNA poly- period without any recurrences, compared with 6% of merase. In the development of new therapeutic agents, it patients receiving vehicle. With respect to tolerability, would be beneficial to consider drugs capable of blocking resiquimod 0.05% twice weekly caused inflammation at DNA replication through inhibition of other molecular lesion sites, whereas other regimens were well tolerated targets, and to consider other stages of the viral cycle, such [39•]. Resiquimod is currently being evaluated in phase III as attachment, entry, uncoating, protein synthesis, and clinical trials. assembly [46]. Enzymes of interest include HSV protease, which is essential in protein cleavage during virus capsid n-Docosanol maturation. Other potential targets include ribonucleotide n-Docosanol, a 22-carbon primary alcohol, has been reductase, the enzyme that catalyzes deoxyribonucleotide shown to inhibit a broad range of enveloped viruses formation, and uracil-DNA glycosylase, which functions in including HSV-1 and HSV-2, and is approved by the FDA as postreplicative DNA repair [47••]. Recently, two new an over-the-counter topical 10% cream for the treatment of classes of drugs, amino-thiazolylphenyl-containing com- cold sores. n-Docosanol exerts its antiviral effects through pounds and thiazole urea derivatives, have been shown to inhibition of viral fusion with host cell membranes, thus possess both in vitro and in vivo anti-HSV properties. preventing nuclear localization and limiting viral replica- These compounds, which target HSV helicase-primase, tion [40]. Evidence suggests that the anti-HSV actions of n- were shown to be superior to acyclovir in the healing of docosanol require cellular uptake and metabolism of the HSV disease in animal models, and clinical studies may be drug [41]. The clinical efficacy of topical n-docosanol for warranted [48,49]. the treatment of herpes labialis has been studied in a mul- ticenter trial [42]. In this study, patients with histories of herpes labialis were randomized to receive either n- Conclusions docosanol 10% cream or placebo five times daily, and Herpes simplex viruses cause a variety of diseases for which began therapy in the prodrome or erythema stage of an there are excellent treatment and preventative interven- episode, with treatment continuing until healing occurred. tions. However, latent HSV infection remains incurable. It was determined that the mean time to healing in indi- The major treatment modality remains the oral adminis- viduals treated with n-docosanol was 18 hours shorter tration of nucleoside analogue antivirals—acyclovir, valaci- 26 Antimicrobial Agents

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