New antiviral agents
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《美国医学杂志》
Division of Infectious Diseases, Children's Hospital of Michigan, Carman and Ann Adams, Department of Pediatrics, Wayne State University, School of Medicine, USA
Abstract
During the last three decades, a better understanding of viral replication and disease states caused by viral infections have led to the development of newer antiviral agents with enhanced activity and better tolerability. This review focuses on newer systemic and topical antiviral agents that are used in treatment of herpes viruses including herpes simplex type-1 (HSV-1) and type-2 (HSV-2), varicella-zoster virus (VZV) and cytomegalovirus CMV) as well as the human papilloma virus (HPV). Included in this article are the agents famciclovir, penciclovir, valganciclovir, imiquimod, docosanole and brivudin.
Keywords: Viral infecting; Systemic and topical antiviral agents; Herpes viruses
As intracellular pathogens, viruses depend on the host cells for survival and replication. Antiviral agents that have been developed interfere with viral entry into cells, replication, protein synthesis and release with minimal or acceptable side effects. Actively replicating viruses are the main targets of antiviral therapy. Therefore, most common employed strategy of antiviral use is treatment of active viral disease. However, prophylactic and pre-emptive uses of antivirals have been increasingly recognized especially among patients at risk of contracting infection such as immunocompromized patients and organ transplant recipients.
Famciclovir
Acyclovir has been considered as the drug of choice for treatment of herpes infections. However, acyclovir has limited oral bioavailability (10-20%) and short intracellular half life (less than one hour).[1] To overcome these limitations more bioavailable anti-herpes agents such as famciclovir and valacyclovir were developed. Famciclovir is the prodrug (diacetyl 6-deoxy derivative) of penciclovir.[2] Famciclovir is rapidly absorped following oral administration with an absolute bioavailability of 77%.[3] Prolonged intracellular half life has also been demonstrated in cells infected with HSV-1, HSV-2 and VZV. Thus famciclovir has been introduced as anti-herpes virus agent with a much improved pharmacokinetic and bioavailability profile when compared to acyclovir.[4]
Mechanism of action
Famciclovir is very stable within duodenal contents accounting for its consistently good absorption. It is converted into its active metabolite penciclovir via two steps of enzymatic hydrolysis and oxidation. The first step occurs in the intestine and results in removal of one ester group. The second step of deacetylation and oxidation occurs in the liver.[2] Peak serum concentrations of penciclovir are achieved in one hour of an oral dose.[3] Penciclovir is only 20% protein bound. No significant metabolism occurs and approximately 60% of an oral dose of famciclovir is secreted in the urine as unchanged penciclovir.[3] The elimination half life of penciclovir is 2 hours in healthy adult volunteers and 3 hours in patientes with herpes zoster. However, prolonged intracellular half life has been demonstrated in cells infected with VZV (9-14 hours), HSV-1 (10 hours) and HSV-2 (20 hours).[5], [6] Reduction in renal function causes linear decrease in drug clearance and dosage adjustment is needed.[7] Patients with hepatic insufficiency have 44% reduction in penciclovir mean plasma concentration and prolongation of the time to mean plasma concentration compared to controls.[8] Famciclovir availability is not affected by food and may be taken without regard to meals.[4] The pharmacokinetics of famciclovir is being evaluated in children.
Penciclovir is converted into penciclovir monophosphate in viral infected cells by the viral thymidine kinase. Only minimal amounts of penciclovir are phosphorylated in normal cells.[5],[6] Subsequently penciclovir monophosphate is phosphorylated by cellular kinases to the active form, penciclovir triphosphate which inhibits viral replication by competitive inhibition of viral DNA polymerase.[9] The affinity of viral thymidine kinase to acyclovir is 100-fold less than penciclovir. In vitro inhibitory effects of famciclovir has been demonstrated against HSV-1, HSV-2, VZV and hepatitis B virus.[10], [11]
Clinical indications
Famciclovir is indicated for treatment of herpes zoster infection (shingles). Treatment should begin as soon as possible and within 72 hours of the onset of rash. Compared to placebo, famciclovir reduced the time to full lesion crusting, loss of vesicles, loss of ulcers and loss of crusts. Famciclovir also shortened the duration of viral shedding in zoster patients.[12], [13]
Famciclovir is used in the treatment of HSV infections including recurrent herpes labialis, recurrent genital herpes simplex infection in immunocompetent patients, recurrent and first episode genital herpes.[14] In HIV infected adult patients with recurrent mucocutaneous herpes simplex infection, famciclovir 500 mg twice daily for 7 days was comparable oral acyclovir 400 mg 5 times daily for 7 days.[15]
The safety and efficacy of oral famciclovir in children is being evaluated in clinical trials.
Dosage and administration
Dosage administration are only available for adults at this point. Famciclovir 500 mg orally every 8 hours for 7 days is given to treat herpes zoster infections. For recurrent genital herpes, the dose is 125 mg twice daily for 7 days. An oral suppressive dose of 250 mg twice daily for up to one year has been used for recurrent genital herpes. For recurrent orolabial or genital herpes in HIV infected patients, 500 my twice daily for 7 days may be used.[16] The doses should be adjusted (decreased) in patients with renal impairment.[7]
Side effects
Famciclovir was well tolerated in adult clinical trials for HSV and VZV infections. The most common adverse events were headache (9.3%), nausea (4.5%) and diarrhea (2.4%). Other reported adverse events are vomiting and abdominal pain. These reported adverse events were not serious and were comparable in incidence to the placebo group. No differences in adverse events were noted between acyclovir and famciclovir. Famciclovir is not recommended for use during pregnancy.[17]
Contraindications/precautions
Famciclovir is contraindicated in patients who are allergic to famciclovir or penciclovir.
Penciclovir
Recurrent herpes simplex infections especially herpes labialis are common among otherwise healthy children and adults. Herpes labialis or cold sores are characterized by recurrent attacks of vesicular lesions on the lips and the skin around the mouth. Although different systemic antivirals have been used for this condition, topical treatment remains the most convenient method of treatment.[18] Penciclovir is a nucleoside analogue that inhibits HSV1 and HSV2 similar to acyclovir, but has the advantage of prolonged half life in infected cells. Penciclovir 1% cream has been introduced as an effective topical treatment of herpetic eruptions independent of the stage of development of lesions.[19]
Mechanism of action
Penciclovir is a nucleoside analogue that has similar in vitro efficacy and mechanism of action to acyclovir. Penciclovir is phosphorylated first by viral thymidine kinase to the monophosphate form and subsequently phosphorylated by the host kinases to the active triphosphate form.[5] Active penciclovir inhibits viral DNA polymerase and subsequent DNA synthesis.[20], [21] Penciclovir has in vitro activity against HSV1 and HSV2, varicella-zoster virus and Epstein-Barr virus.[22] The active form of penciclovir is more stable than acyclovir in HSV infected cells and has a half life of 10-20 hours. This gives the advantage of more stability and greater efficacy than topical acyclovir as well as the need for less frequent dosing. The oral form of penciclovir has poor bioavailabilty and is clinically not available. The intravenous form is still undergoing clinical evaluation.
Clinical indications
Penciclovir is indicated in the treatment of patients 12 years of age and older with recurrent herpes labialis (cold sores). Recurrent herpes labialis occurs with a frequency of 1-12 attacks per year (average: 1-3 attacks per year.) Untreated recurrent attacks last 8 to 10 days.[23] Topical acyclovir has been shown to have little therapeutic benefit in treatment of recurrent herpes labialis.[24] Topical acyclovir is ineffective in treating late phase HSV infection.[25] In immunocompetent patients with recurrent herpes labialis, topical 1% penciclovir has been shown to be more effective than placebo in reducing pain, healing of lesions and viral shedding.[26] Penciclovir cream applied every two hours while awake for 4 days reduced the average healing time by 0.7 days and the duration of pain by 0.6 days compared to placebo. In contrast to topical acyclovir, clinical improvement was reported in patients who applied penciclovir cream early during the prodrome or erythema stage as well as during the late or papule stage.[26]
In a clinical trial, 1% penciclovir cream and 3% acyclovir cream were comparable regarding cure rates and safety. However, penciclovir treated patients had shorter time to cessation of new blisters and resolution of all symptoms and loss of crust compared to acyclovir treated patients. The clinical scores at 5 and 7 days were also significantly lower in the penciclovir treatment group.[27] Another study demonstrated that penciclovir is effective and superior to 5% acyclovir cream in treatment of recurrent herpes labialis.[28]
Dosage and administration
Penciclovir 1% cream is recommended for treatment of herpes simplex labialis of the lips and face in patients 12 years of age and older. The cream should be applied, as early as possible, every two hours during waking hours for 4 days.
Side effects
Infrequent local adverse reactions include erythema, local edema, itching and contact dermatitis. Systemic absorption of topical penciclovir is negligible and systemic adverse events were similar to placebo.[26]
Contraindications/precautions
Penciclovir is contraindicated in patients who are known to be allergic to penciclovir or famciclovir. Penciclovir cream should not be applied to mucous membranes nor in or around the eye.[29]
Valganciclovir
Valganciclovir hydrochloride is the L-valyl ester of ganciclovir. Valganciclovir is a prodrug that is rapidly hydrolyzed in plasma to ganciclovir. Valganciclovir was developed to improve the oral bioavailability of ganciclovir. The improved bioavailability of valganciclovir has provided a potential convenient oral alternative for treating systemic cytomegaloviris (CMV) infections that would otherwise be treated with intravenous ganciclovir.[30]
Pharmacokinetics/Mechanism of action
Valganciclovir is rapidly absorbed following oral administration and metabolized by esterases in the intestine and the liver to ganciclovir.[30] Peak plasma concentrations occur in 1 to 3 hours. The availability of valganciclovir is 60%, which is 10 times higher than that of oral ganciclovir (6%).[31] Food enhances the absorption of valganciclovir.[32] Valganciclovir is renally excreted as ganciclovir via both glomerular filtration and active tubular secretion. The half life of valganciclovir is 3.8-4.6 hours but can reach 68 hours in patients with end stage renal disease.[31] 50% of ganciclovir is removed by hemodailysis. Therefore, valganciclovir dose should be adjusted in patients with altered renal function.[31]
Valganciclovir by itself has no antiviral activity and should be converted to ganciclovir to be active.[33] Ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase. Subsequent phosphorylation to the di- and triphosphate forms occurs via cellular kinases. By acting as a competitive inhibitor of the substrate deoxyguanosine triphosphate, ganciclovir triphosphate inhibits viral DNA polymerase and subsequent DNA synthesis. Metabolism occurs slowly in virally infected cells resulting in an intracellular half life of 18 hours.[33]
Clinical indications
Valganciclovir has been approved for the treatment (both induction and maintenance) of CMV retinitis in adult patients with AIDS. It has been shown that valganciclovir at a dose of 900 mg twice daily is as effective as intravenous ganciclovir at 5 mg/kg every 12 hrs given for 3 weeks as induction therapy.[34] Valganciclovir was also effective in the maintenance phase of treatment as demonstrated by a longer median time to progression of CMV retinitis in patients who received ganciclovir (160 days) compared to those who received intravenous ganciclovir (125 days).[34]
Valganciclovir is indicated in the prevention of CMV disease in adults with heart, kidney and kidney-pancreas transplantation. In patients who were donor positive/recipient negative, valganciclovir was not inferior to oral ganciclovir in the prevention of CMV disease when given during the first 100 days post-transplantation.[35], [36] However, for unclear reason, liver transplant recipients who received oral valganciclovir had a higher incidence of tissue invasive CMV disease than those who received oral ganciclovir. Although the USA Food and Drug Administration (FDA) has not approved valganciclovir in the prevention of CMV in liver transplantation recipients, it is approved for this indication in Europe.[33] The safety and efficacy of valganciclovir in the prevention of CMV disease in other solid organ transplant recipients have not been established.[37] Valganciclovir may be considered in preemptive therapy of CMV disease in solid organ transplant recipients with evidence of CMV replication by PCR or CMV pp65 antigenemia.[38]
Valganciclovir efficacy and safety in the prevention of CMV disease among patients with hematopoietic stem cell transplantation (HSCT) has not been well established. The use of valganciclovir in HSCT recipients in the immediate post-transplant period and before engrafment may be associated with exacerbation of neutropenia.[35] In addition, recipients of HSCT have a high incidence of graft versus host disease including involvement of the gastrointestinal tract. This may lead to subsequently reduced bioavailability and efficacy of valganciclovir in this patient population.[33]
The safety and efficacy of valganciclovir in pediatric transplant patients has not been well studied. However, preliminary reports suggest that valganciclovir may be effective in preventing CMV in transplanted children.[39] Children have lower systemic exposure after valganciclovir administration and probably need larger proportionate doses than adults to achieve adequate dosing.[40]
Although no specific antiviral therapy is approved for treatment of congenital CMV infection, recent studies have suggested that intravenous ganciclovir may be associated with reduced incidence of hearing loss.[41] Trials are underway to study the safety and efficacy of IV ganciclovir for neonates with CMV infection. The pharmacokinetics of valganciclovir in neonates is also being studied.
Dosage and administration
No dosage information is currently approved for children. The single adult dose is 900 mg given twice daily for treatment indications and once daily for prophylactic indications. Children may require proportionately higher doses than adults.[40]
Side effects
Hematologic toxicities such as anemia (26%), neutropenia (27%) and thrombocytopenia (6%) are among the most frequently reported adverse events in clinical trials. Thus in patients receiving valganciclovir, complete blood counts should be monitored throughout therapy.[35] Cytopenias are reversible and improvement in blood counts begins 3 to 7 days after discontinuing valganciclovir.[37] Other commonly reported side effects in patients with AIDS are diarrhea, fever and retinal detachment.[34] Less frequent side effects reported in both AIDS and organ transplant patients include abdominal pain, nausea, vomiting, insomnia, tremors, paresthesia and peripheral neuropathy.[34], [35]
Contraindications/precautions
Valganciclovir is contraindicated in patients with history of hypersensitivity to ganciclovir or valganciclovir. It is also contraindicted in patients with significant hematologic cytopenias such as absolute neutrophil count of less than 500/mm 3, platelet count of less than 25,000/mm 3 and hemoglobin of less than 8 g/dl.[37]
Ganciclovir was found to have carcinogenic, mutagenic and teratogenic effects in preclinical animal studies. Therefore, women of childbearing age should be advised to use effective contraception during valganciclovir use. Similarly, men should practice barrier contraception while receiving ganciclovir for at least 3 months after treatment. Valganciclovir may impair fertility in men and women.[37]
Concomitant use of probenecid and ganciclovir may lead to decreased clearance and increase toxic effects of valganciclovir. Zidovudine (AZT) use with ganciclovir may lead to an increase in hematologic toxic effects such as anemia and neutropenia. Patients receiving full doses of AZT and valganciclovir should be monitored with complete blood counts.[37]
Imiquimod
Imiquimod is an imidazoquinoline, a synthetic low molecular compound that has been introduced to dermatologic and genitourinary medicine as a topical immune modifier for treatment of condyloma acuminata.[42]
Mechanism of action
Imiquimod is a topical immune modulator that upregulates the immune response at the site of infection. Imiquimod activates immune cells such as monocytes/macrophages and dendritic cells by binding to specific receptors and subsequently stimulating the release of cytokines and chemokines by these cells and by keratinocytes.[43] Release of cytokines and chemokines including tumor necrosis factor-a, interferon - a, interleukin (IL)-12, IL-1, IL-6, IL-8 and IL-10 will lead to inhibition of viral replication and stimulation of local cell-mediated immunity. Imiquimod also stimulates NK cells and indirectly stimulates Th-1 cells to release interferon -gamma which plays a major role in cytotoxic T-cell killing of viral infected cells and tumors. [42],[43],[44]Imiquimod has no direct antiviral properties.
The immune effects of imiquimod are especially important in treatment of condyloma acuminata and molluscum lesions. HPV infects epidermal keratinocytes and the infection is not cytolytic and not associated with an inflammatory response. HPV is not associated with antigen presentation and activation of the innate immune system cells. Imiquimod is a novel topical therapeutic agent that is associated with enhanced clearance of virus by the immune cells.[43]
Clinical indications
Imiquimod has been approved for treatment of external genital and perianal warts caused by HPV. Genital HPV infections are very common among sexually active adults. Most infections are transient.[45] Low oncogenic HPV subtypes 4 and 11 typically cause codyloma acuminata, while high-oncogenic risk subtypes 16 and 18 are associated with malignancies of the anus and genital tract.[46], [47] Treatment of condyloma acuminata lesions has been not specific and largely depend on physical and cytotoxic ablation methods. Because HPV subsequently remains in the surrounding tissues, recurrence rates of HPV had been high (20-70%). In several placebo controlled trials[48],[49],[50],[51], topical application imiquimod 5% cream had been associated with complete clearance of anogenital warts in 37-52% of patients. The lesions cleared in 8-16 weeks and the median time to complete clearance was 8.8 weeks. The recurrence rates of lesions after 3 and 6 months follow up were 8.8% and 23% respectively. In patients who had recurrence of warts, re-treatment with imiquimod was effective in 70%. Total clearance of genital warts was higher in women (73%) than in men (33%). This may be explained by the lower degree of keratinization at the vulva, most common wart site in women, than the penile shaft in men.[52]
Imiquimod cream 5% has also been shown to be effective in treatment of anogenital warts in infants and children.[53], [54]
Imiquimod has been used to treat nongenital warts including common, flat, plantar and periungual warts.[55],[56],[57] Because of high keratinization, common and plantar warts require more frequent applications of imiquimod than other warts. Among patients with common warts, 30% had total clearance of lesions and 50% had partial reduction in size of the warts. The clinical response was better in patients with lesions on the trunk, face and hand than those with lesions on the feet. [55],[56],[57]
Imiquimod 1% cream had been shown to be more effective than placebo in treatment of molluscum contagiosum lesions.[58] Application of the cream 3 times daily for 5 days a week for a total of 4 weeks was associated with a cure rate of 82% compared to 16% in the placebo control group. Another study has demonstrated that application of 5% imiquimod cream to common warts and molluscum contagiosum lesions was associated with a total clearance rate of 56% and reduction of wart size in 26% of patients. The mean duration of treatment was 9.2 weeks. Imiquimod treatment was well tolerated and side effects were minimal.[55]
The role of imiquimod in herpes simplex infection is controversial. Topical application of imiquimod to herpes simplex lesions was effective in case reports, however, no apparent effect on the short-term history of genital herpes simplex lesion recurrences was observed with imiquimod compared to placebo.[59]
Dosage and administration
Imiquimod was manufactured by 3M pharmaceuticals and marketed under the brand name Aldara. The optimal dose is three times per week on non-consecutive days. The cream should be applied to the effected area at bedtime as a thin film to the wart area until it vanishes. The cream is left for 6-10 hours and then removed with soap and water. Warts usually clear by 8-10 weeks. The maximum duration of treatment is 16 weeks. [48],[49],[50],[51]
Side effects
Topical imiquimod is generally well tolerated. Systemic side effects are not reported. The most frequent adverse event is local erythema in 33-80% of patients and may correlate with the local immune response induced by imiquimod. Other local adverse events include pruritus (26%), burning (16%), tenderness and stinging (4%). Adverse events are mild-moderate in severity and usually disappear in 2 weeks of discontinuing imiquimod. Localized hypo or hyperpigmentaion has occasionally been reported. [48],[49],[50],[51]
Contraindications/precautions
Imiquimod is contraindicated in patients with allergy to the components of the cream. Imiquimod should not be used during pregnancy (category B). Precautions should be taken with sexual contact as the risk of transmission of HPV following application of imiquimod is unknown. Imiquimod cream may weaken condoms and diaphragms and sexual contact should be avoided while cream is on the skin.[60]
Docosanol
Docosanol (also known as n-docosanol or behenyl alcohol) is a saturated primary alcohol that has in vitro inhibitory effects against enveloped viruses such as HSV-1, HSV-2, CMV and human herpes virus 6.[61] Docosanol 1% cream (Abreva) has been approved by the FDA and is available over the counter in the USA for topical treatment of herpes labialis (cold sores).[62]
Mechanism of action
Docosanol is a 22-Carbon saturated fatty alcohol derived from plant extracts and is highly lipophilic.[61],[63] Docosanol has no direct viricidal activity by itself. However, the antiviral properties are due to its inhibition of viral entry to the cells. Docosanol inhibits lipid-enveloped viruses by fusion to the plasma membrane and thus inhibiting viral migration to the nucleus and subsequent viral replication. Enveloped viruses that are inhibited in vitro by docosanol include HSV-1 and 2, VZV, HHV-6, Influenza A, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV).[63], [64]
Clinical indications
Docosanol is indicated in treatment of recurrent oral-facial herpes simplex. Docosanol 10% cream applied 5 times daily was compared to placebo (ethylene glycol) in adult patients presenting with recurrent herpetic lesions at the prodrome or erythema stage. Treatment was continued until healing occurred. The median time to healing of lesions in a recurrent episode among patients who applied docosanol was about one day shorter than placebo treated patients (p=0.008). In addition, patients who applied docosanol had statistically significant reductions in the durations of associated symptoms of pain, burning, itching and tingling (p<0.03). Docosanol also reduced the time of the most severe stage of (ulcer, soft crust) of the lesion that correlates with the peak period of inflammation and viral replication.[65]
Topical docosanol 5 times daily was used in ten HIV-1 infected patients with Kaposi's sarcoma. After 28 days of treatment, two patients had reduction in the size of skin lesions. With extended treatment, two more patients had partial improvement.[66] Further studies are needed before docosanol therapy can be routinely used in KS patients.
Dosage and administration
Docosanol 10% cream is applied topically to herpetic lesions 5 times a day until the lesions heal. The cream is indicated for patients 12 years of age or older.[62]
Side effects
Headache was reported in patients who were enrolled in the docosanol treatment study. Local adverse events occurred with low frequencies (<2%) and included application site reactions, rash, pruritus, dry skin and acne. [62], [65]
Contraindications/precautions
Docosanol is contraindicated in patients with hypersensitivity reactions. Caution should be employed in patients who develop allergic phenomena with topical medications. Docosanol is only approved to treat oral (lip)-facial HSV lesions. The safety and efficacy of docosanol in treating HSV in other sites is not known. [62]
Brivudin
Brivudin or BVDU is E-5-(2-bromovinyl)-2'deoxyuridine, a 5' halogenated thymidine nucleoside analogue. [67] Brivudin, though not available in the USA, is currently used in several European countries for treatment of VZV and HSV-1 infections. In vitro , Brivudin has been shown to be more potent than acyclovir and penciclovir against VZV. [68] Brivudin is currently available in oral and topical forms (0.1% eye drops and 1% eye ointment).
Mechanism of action
Oral brivudin is rapidly absorbed following oral administration. Oral bioavailability is 33%. Inhibition of viral replication starts 1-4 hours after administration. Brivudin is selectively uptaken by cells infected by HSV-1 or VZV. [67] Brivudin is phosphorylated by the virus encoded thymidine kinase to the 5'-monophosphate and 5'-diphosphate. Further phosphorylation by cellular kinases occurs with subsequent formation of BVDU 5'triphosphate (BVDU-TP) that interacts with the viral DNA polymerase. BVDU-TP incorporates into the DNA chain and interferes with replication and transcription processes.[69]
Brivudin is highly potent against HSV-1 but not HSV-2. This selective antiviral effect is due the inability of HSV-2 encoded thymidine kinase to phosphorylate BVDU-monophosphate to the diphosphate form.[70],[71]
Clinical indications
Oral brivudin may be as or even more effective than acyclovir in treatment of VZV infection.[67] In a randomized trial of treatment of herpes zoster in immunocompromized patients, 5-day courses of either brivudin (125 mg every 6 hours) or acyclovir (10 mg/kg every 8 hours) were compared. They were equally effective with regard to clinical response, incidence of dissemination and in the time to full lesion crusting.[72] A similar study in immunocompromized children comparing acyclovir 1,500 mg/m2/day with oral brivudin at 15 mg/kg/day showed no difference in therapeutic efficacy in the two groups.[73] Intravenous acyclovir and oral brivudin were well tolerated in both clinical trials. Oral brivudin (125 mg once daily) for 7 days was found to be superior to oral acyclovir at 800 mg given 5 times daily in inhibiting viral replication as measured by time to last appearance of VZV lesions in immunocompetent patients.[74] Brivudin was comparable in efficacy to famciclovir. However, in patients with ophthalmic zoster, cessation of vesicle formation occurred 31% faster with brivudin than with famciclovir.[75]
Brivudin 0.1% eye drops have been used to treat herpetic keratitis caused by HSV-1. Efficacy of brividun was demonstrated in patients with different stages of infection including dendritic and geographic ulcers and herpetic keratitis.[76] Clinical improvement occurred in patients who failed treatment with other topical antivirals such as idoxuridine, trifluridine, vidarabine and acyclovir. Topical brivudin 1% eye ointment was also more effective than other topical antiviral agents in a group of patients with uncomplicated herpetic keratitis that has not been previously treated. The cure rate in this study was 95%.[77]
Dosage and administration
The recommended dose for treating VZV infections in children is 15 mg/kg/day in one dose or 3 divided doses given orally for 5 days.[73] Topical application of 0.1% eyedrops is given hourly while awake or 5 times daily. [77]
Side effects
Most reported adverse events were mild, transient and the association with brivudin was not clear. The most commonly reported adverse events associated with oral brivudin use were nausea, vomiting and loss of appetite and headache. Other adverse events are proteinurea, glucosurea and dizziness.[67] No carcinogenic or mutagenic potential of brivudin has been demonstrated in animal studies.[78] The effects of brivudin during pregnancy have not been clarified. Local hypersensitivity reactions may occur with topical brivudin use.[76],[77]
Contraindications/precautions
Brivudin is contraindicated in patients who had previous hypersensitivity to brivudin. Significant interaction may occur with 5-fluorouracil (5-FU), tegafur and other antimetabolites. Brivudin is a substrate of thymidine phosphorylase that converts brivudin (BVDU) to bromovinyluracil (BVU), which is a potent inhibitor of the enzyme dihydropyrimidine dehydrogenase (DPD). [79] This enzyme is employed in first step of the catabolic pathway of pyrimidines. DPD is needed for the breakdown of 5 -FU. Thus brivuin use may cause marked increase in the half-life of 5-FU and enhance its antitumor activity.[79] However, combined use of brivudin with 5-FU may cause increase in 5-FU toxic effects such as diarrhea and marked decreases in white blood cell and platelet counts. [80], [81]
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Abstract
During the last three decades, a better understanding of viral replication and disease states caused by viral infections have led to the development of newer antiviral agents with enhanced activity and better tolerability. This review focuses on newer systemic and topical antiviral agents that are used in treatment of herpes viruses including herpes simplex type-1 (HSV-1) and type-2 (HSV-2), varicella-zoster virus (VZV) and cytomegalovirus CMV) as well as the human papilloma virus (HPV). Included in this article are the agents famciclovir, penciclovir, valganciclovir, imiquimod, docosanole and brivudin.
Keywords: Viral infecting; Systemic and topical antiviral agents; Herpes viruses
As intracellular pathogens, viruses depend on the host cells for survival and replication. Antiviral agents that have been developed interfere with viral entry into cells, replication, protein synthesis and release with minimal or acceptable side effects. Actively replicating viruses are the main targets of antiviral therapy. Therefore, most common employed strategy of antiviral use is treatment of active viral disease. However, prophylactic and pre-emptive uses of antivirals have been increasingly recognized especially among patients at risk of contracting infection such as immunocompromized patients and organ transplant recipients.
Famciclovir
Acyclovir has been considered as the drug of choice for treatment of herpes infections. However, acyclovir has limited oral bioavailability (10-20%) and short intracellular half life (less than one hour).[1] To overcome these limitations more bioavailable anti-herpes agents such as famciclovir and valacyclovir were developed. Famciclovir is the prodrug (diacetyl 6-deoxy derivative) of penciclovir.[2] Famciclovir is rapidly absorped following oral administration with an absolute bioavailability of 77%.[3] Prolonged intracellular half life has also been demonstrated in cells infected with HSV-1, HSV-2 and VZV. Thus famciclovir has been introduced as anti-herpes virus agent with a much improved pharmacokinetic and bioavailability profile when compared to acyclovir.[4]
Mechanism of action
Famciclovir is very stable within duodenal contents accounting for its consistently good absorption. It is converted into its active metabolite penciclovir via two steps of enzymatic hydrolysis and oxidation. The first step occurs in the intestine and results in removal of one ester group. The second step of deacetylation and oxidation occurs in the liver.[2] Peak serum concentrations of penciclovir are achieved in one hour of an oral dose.[3] Penciclovir is only 20% protein bound. No significant metabolism occurs and approximately 60% of an oral dose of famciclovir is secreted in the urine as unchanged penciclovir.[3] The elimination half life of penciclovir is 2 hours in healthy adult volunteers and 3 hours in patientes with herpes zoster. However, prolonged intracellular half life has been demonstrated in cells infected with VZV (9-14 hours), HSV-1 (10 hours) and HSV-2 (20 hours).[5], [6] Reduction in renal function causes linear decrease in drug clearance and dosage adjustment is needed.[7] Patients with hepatic insufficiency have 44% reduction in penciclovir mean plasma concentration and prolongation of the time to mean plasma concentration compared to controls.[8] Famciclovir availability is not affected by food and may be taken without regard to meals.[4] The pharmacokinetics of famciclovir is being evaluated in children.
Penciclovir is converted into penciclovir monophosphate in viral infected cells by the viral thymidine kinase. Only minimal amounts of penciclovir are phosphorylated in normal cells.[5],[6] Subsequently penciclovir monophosphate is phosphorylated by cellular kinases to the active form, penciclovir triphosphate which inhibits viral replication by competitive inhibition of viral DNA polymerase.[9] The affinity of viral thymidine kinase to acyclovir is 100-fold less than penciclovir. In vitro inhibitory effects of famciclovir has been demonstrated against HSV-1, HSV-2, VZV and hepatitis B virus.[10], [11]
Clinical indications
Famciclovir is indicated for treatment of herpes zoster infection (shingles). Treatment should begin as soon as possible and within 72 hours of the onset of rash. Compared to placebo, famciclovir reduced the time to full lesion crusting, loss of vesicles, loss of ulcers and loss of crusts. Famciclovir also shortened the duration of viral shedding in zoster patients.[12], [13]
Famciclovir is used in the treatment of HSV infections including recurrent herpes labialis, recurrent genital herpes simplex infection in immunocompetent patients, recurrent and first episode genital herpes.[14] In HIV infected adult patients with recurrent mucocutaneous herpes simplex infection, famciclovir 500 mg twice daily for 7 days was comparable oral acyclovir 400 mg 5 times daily for 7 days.[15]
The safety and efficacy of oral famciclovir in children is being evaluated in clinical trials.
Dosage and administration
Dosage administration are only available for adults at this point. Famciclovir 500 mg orally every 8 hours for 7 days is given to treat herpes zoster infections. For recurrent genital herpes, the dose is 125 mg twice daily for 7 days. An oral suppressive dose of 250 mg twice daily for up to one year has been used for recurrent genital herpes. For recurrent orolabial or genital herpes in HIV infected patients, 500 my twice daily for 7 days may be used.[16] The doses should be adjusted (decreased) in patients with renal impairment.[7]
Side effects
Famciclovir was well tolerated in adult clinical trials for HSV and VZV infections. The most common adverse events were headache (9.3%), nausea (4.5%) and diarrhea (2.4%). Other reported adverse events are vomiting and abdominal pain. These reported adverse events were not serious and were comparable in incidence to the placebo group. No differences in adverse events were noted between acyclovir and famciclovir. Famciclovir is not recommended for use during pregnancy.[17]
Contraindications/precautions
Famciclovir is contraindicated in patients who are allergic to famciclovir or penciclovir.
Penciclovir
Recurrent herpes simplex infections especially herpes labialis are common among otherwise healthy children and adults. Herpes labialis or cold sores are characterized by recurrent attacks of vesicular lesions on the lips and the skin around the mouth. Although different systemic antivirals have been used for this condition, topical treatment remains the most convenient method of treatment.[18] Penciclovir is a nucleoside analogue that inhibits HSV1 and HSV2 similar to acyclovir, but has the advantage of prolonged half life in infected cells. Penciclovir 1% cream has been introduced as an effective topical treatment of herpetic eruptions independent of the stage of development of lesions.[19]
Mechanism of action
Penciclovir is a nucleoside analogue that has similar in vitro efficacy and mechanism of action to acyclovir. Penciclovir is phosphorylated first by viral thymidine kinase to the monophosphate form and subsequently phosphorylated by the host kinases to the active triphosphate form.[5] Active penciclovir inhibits viral DNA polymerase and subsequent DNA synthesis.[20], [21] Penciclovir has in vitro activity against HSV1 and HSV2, varicella-zoster virus and Epstein-Barr virus.[22] The active form of penciclovir is more stable than acyclovir in HSV infected cells and has a half life of 10-20 hours. This gives the advantage of more stability and greater efficacy than topical acyclovir as well as the need for less frequent dosing. The oral form of penciclovir has poor bioavailabilty and is clinically not available. The intravenous form is still undergoing clinical evaluation.
Clinical indications
Penciclovir is indicated in the treatment of patients 12 years of age and older with recurrent herpes labialis (cold sores). Recurrent herpes labialis occurs with a frequency of 1-12 attacks per year (average: 1-3 attacks per year.) Untreated recurrent attacks last 8 to 10 days.[23] Topical acyclovir has been shown to have little therapeutic benefit in treatment of recurrent herpes labialis.[24] Topical acyclovir is ineffective in treating late phase HSV infection.[25] In immunocompetent patients with recurrent herpes labialis, topical 1% penciclovir has been shown to be more effective than placebo in reducing pain, healing of lesions and viral shedding.[26] Penciclovir cream applied every two hours while awake for 4 days reduced the average healing time by 0.7 days and the duration of pain by 0.6 days compared to placebo. In contrast to topical acyclovir, clinical improvement was reported in patients who applied penciclovir cream early during the prodrome or erythema stage as well as during the late or papule stage.[26]
In a clinical trial, 1% penciclovir cream and 3% acyclovir cream were comparable regarding cure rates and safety. However, penciclovir treated patients had shorter time to cessation of new blisters and resolution of all symptoms and loss of crust compared to acyclovir treated patients. The clinical scores at 5 and 7 days were also significantly lower in the penciclovir treatment group.[27] Another study demonstrated that penciclovir is effective and superior to 5% acyclovir cream in treatment of recurrent herpes labialis.[28]
Dosage and administration
Penciclovir 1% cream is recommended for treatment of herpes simplex labialis of the lips and face in patients 12 years of age and older. The cream should be applied, as early as possible, every two hours during waking hours for 4 days.
Side effects
Infrequent local adverse reactions include erythema, local edema, itching and contact dermatitis. Systemic absorption of topical penciclovir is negligible and systemic adverse events were similar to placebo.[26]
Contraindications/precautions
Penciclovir is contraindicated in patients who are known to be allergic to penciclovir or famciclovir. Penciclovir cream should not be applied to mucous membranes nor in or around the eye.[29]
Valganciclovir
Valganciclovir hydrochloride is the L-valyl ester of ganciclovir. Valganciclovir is a prodrug that is rapidly hydrolyzed in plasma to ganciclovir. Valganciclovir was developed to improve the oral bioavailability of ganciclovir. The improved bioavailability of valganciclovir has provided a potential convenient oral alternative for treating systemic cytomegaloviris (CMV) infections that would otherwise be treated with intravenous ganciclovir.[30]
Pharmacokinetics/Mechanism of action
Valganciclovir is rapidly absorbed following oral administration and metabolized by esterases in the intestine and the liver to ganciclovir.[30] Peak plasma concentrations occur in 1 to 3 hours. The availability of valganciclovir is 60%, which is 10 times higher than that of oral ganciclovir (6%).[31] Food enhances the absorption of valganciclovir.[32] Valganciclovir is renally excreted as ganciclovir via both glomerular filtration and active tubular secretion. The half life of valganciclovir is 3.8-4.6 hours but can reach 68 hours in patients with end stage renal disease.[31] 50% of ganciclovir is removed by hemodailysis. Therefore, valganciclovir dose should be adjusted in patients with altered renal function.[31]
Valganciclovir by itself has no antiviral activity and should be converted to ganciclovir to be active.[33] Ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase. Subsequent phosphorylation to the di- and triphosphate forms occurs via cellular kinases. By acting as a competitive inhibitor of the substrate deoxyguanosine triphosphate, ganciclovir triphosphate inhibits viral DNA polymerase and subsequent DNA synthesis. Metabolism occurs slowly in virally infected cells resulting in an intracellular half life of 18 hours.[33]
Clinical indications
Valganciclovir has been approved for the treatment (both induction and maintenance) of CMV retinitis in adult patients with AIDS. It has been shown that valganciclovir at a dose of 900 mg twice daily is as effective as intravenous ganciclovir at 5 mg/kg every 12 hrs given for 3 weeks as induction therapy.[34] Valganciclovir was also effective in the maintenance phase of treatment as demonstrated by a longer median time to progression of CMV retinitis in patients who received ganciclovir (160 days) compared to those who received intravenous ganciclovir (125 days).[34]
Valganciclovir is indicated in the prevention of CMV disease in adults with heart, kidney and kidney-pancreas transplantation. In patients who were donor positive/recipient negative, valganciclovir was not inferior to oral ganciclovir in the prevention of CMV disease when given during the first 100 days post-transplantation.[35], [36] However, for unclear reason, liver transplant recipients who received oral valganciclovir had a higher incidence of tissue invasive CMV disease than those who received oral ganciclovir. Although the USA Food and Drug Administration (FDA) has not approved valganciclovir in the prevention of CMV in liver transplantation recipients, it is approved for this indication in Europe.[33] The safety and efficacy of valganciclovir in the prevention of CMV disease in other solid organ transplant recipients have not been established.[37] Valganciclovir may be considered in preemptive therapy of CMV disease in solid organ transplant recipients with evidence of CMV replication by PCR or CMV pp65 antigenemia.[38]
Valganciclovir efficacy and safety in the prevention of CMV disease among patients with hematopoietic stem cell transplantation (HSCT) has not been well established. The use of valganciclovir in HSCT recipients in the immediate post-transplant period and before engrafment may be associated with exacerbation of neutropenia.[35] In addition, recipients of HSCT have a high incidence of graft versus host disease including involvement of the gastrointestinal tract. This may lead to subsequently reduced bioavailability and efficacy of valganciclovir in this patient population.[33]
The safety and efficacy of valganciclovir in pediatric transplant patients has not been well studied. However, preliminary reports suggest that valganciclovir may be effective in preventing CMV in transplanted children.[39] Children have lower systemic exposure after valganciclovir administration and probably need larger proportionate doses than adults to achieve adequate dosing.[40]
Although no specific antiviral therapy is approved for treatment of congenital CMV infection, recent studies have suggested that intravenous ganciclovir may be associated with reduced incidence of hearing loss.[41] Trials are underway to study the safety and efficacy of IV ganciclovir for neonates with CMV infection. The pharmacokinetics of valganciclovir in neonates is also being studied.
Dosage and administration
No dosage information is currently approved for children. The single adult dose is 900 mg given twice daily for treatment indications and once daily for prophylactic indications. Children may require proportionately higher doses than adults.[40]
Side effects
Hematologic toxicities such as anemia (26%), neutropenia (27%) and thrombocytopenia (6%) are among the most frequently reported adverse events in clinical trials. Thus in patients receiving valganciclovir, complete blood counts should be monitored throughout therapy.[35] Cytopenias are reversible and improvement in blood counts begins 3 to 7 days after discontinuing valganciclovir.[37] Other commonly reported side effects in patients with AIDS are diarrhea, fever and retinal detachment.[34] Less frequent side effects reported in both AIDS and organ transplant patients include abdominal pain, nausea, vomiting, insomnia, tremors, paresthesia and peripheral neuropathy.[34], [35]
Contraindications/precautions
Valganciclovir is contraindicated in patients with history of hypersensitivity to ganciclovir or valganciclovir. It is also contraindicted in patients with significant hematologic cytopenias such as absolute neutrophil count of less than 500/mm 3, platelet count of less than 25,000/mm 3 and hemoglobin of less than 8 g/dl.[37]
Ganciclovir was found to have carcinogenic, mutagenic and teratogenic effects in preclinical animal studies. Therefore, women of childbearing age should be advised to use effective contraception during valganciclovir use. Similarly, men should practice barrier contraception while receiving ganciclovir for at least 3 months after treatment. Valganciclovir may impair fertility in men and women.[37]
Concomitant use of probenecid and ganciclovir may lead to decreased clearance and increase toxic effects of valganciclovir. Zidovudine (AZT) use with ganciclovir may lead to an increase in hematologic toxic effects such as anemia and neutropenia. Patients receiving full doses of AZT and valganciclovir should be monitored with complete blood counts.[37]
Imiquimod
Imiquimod is an imidazoquinoline, a synthetic low molecular compound that has been introduced to dermatologic and genitourinary medicine as a topical immune modifier for treatment of condyloma acuminata.[42]
Mechanism of action
Imiquimod is a topical immune modulator that upregulates the immune response at the site of infection. Imiquimod activates immune cells such as monocytes/macrophages and dendritic cells by binding to specific receptors and subsequently stimulating the release of cytokines and chemokines by these cells and by keratinocytes.[43] Release of cytokines and chemokines including tumor necrosis factor-a, interferon - a, interleukin (IL)-12, IL-1, IL-6, IL-8 and IL-10 will lead to inhibition of viral replication and stimulation of local cell-mediated immunity. Imiquimod also stimulates NK cells and indirectly stimulates Th-1 cells to release interferon -gamma which plays a major role in cytotoxic T-cell killing of viral infected cells and tumors. [42],[43],[44]Imiquimod has no direct antiviral properties.
The immune effects of imiquimod are especially important in treatment of condyloma acuminata and molluscum lesions. HPV infects epidermal keratinocytes and the infection is not cytolytic and not associated with an inflammatory response. HPV is not associated with antigen presentation and activation of the innate immune system cells. Imiquimod is a novel topical therapeutic agent that is associated with enhanced clearance of virus by the immune cells.[43]
Clinical indications
Imiquimod has been approved for treatment of external genital and perianal warts caused by HPV. Genital HPV infections are very common among sexually active adults. Most infections are transient.[45] Low oncogenic HPV subtypes 4 and 11 typically cause codyloma acuminata, while high-oncogenic risk subtypes 16 and 18 are associated with malignancies of the anus and genital tract.[46], [47] Treatment of condyloma acuminata lesions has been not specific and largely depend on physical and cytotoxic ablation methods. Because HPV subsequently remains in the surrounding tissues, recurrence rates of HPV had been high (20-70%). In several placebo controlled trials[48],[49],[50],[51], topical application imiquimod 5% cream had been associated with complete clearance of anogenital warts in 37-52% of patients. The lesions cleared in 8-16 weeks and the median time to complete clearance was 8.8 weeks. The recurrence rates of lesions after 3 and 6 months follow up were 8.8% and 23% respectively. In patients who had recurrence of warts, re-treatment with imiquimod was effective in 70%. Total clearance of genital warts was higher in women (73%) than in men (33%). This may be explained by the lower degree of keratinization at the vulva, most common wart site in women, than the penile shaft in men.[52]
Imiquimod cream 5% has also been shown to be effective in treatment of anogenital warts in infants and children.[53], [54]
Imiquimod has been used to treat nongenital warts including common, flat, plantar and periungual warts.[55],[56],[57] Because of high keratinization, common and plantar warts require more frequent applications of imiquimod than other warts. Among patients with common warts, 30% had total clearance of lesions and 50% had partial reduction in size of the warts. The clinical response was better in patients with lesions on the trunk, face and hand than those with lesions on the feet. [55],[56],[57]
Imiquimod 1% cream had been shown to be more effective than placebo in treatment of molluscum contagiosum lesions.[58] Application of the cream 3 times daily for 5 days a week for a total of 4 weeks was associated with a cure rate of 82% compared to 16% in the placebo control group. Another study has demonstrated that application of 5% imiquimod cream to common warts and molluscum contagiosum lesions was associated with a total clearance rate of 56% and reduction of wart size in 26% of patients. The mean duration of treatment was 9.2 weeks. Imiquimod treatment was well tolerated and side effects were minimal.[55]
The role of imiquimod in herpes simplex infection is controversial. Topical application of imiquimod to herpes simplex lesions was effective in case reports, however, no apparent effect on the short-term history of genital herpes simplex lesion recurrences was observed with imiquimod compared to placebo.[59]
Dosage and administration
Imiquimod was manufactured by 3M pharmaceuticals and marketed under the brand name Aldara. The optimal dose is three times per week on non-consecutive days. The cream should be applied to the effected area at bedtime as a thin film to the wart area until it vanishes. The cream is left for 6-10 hours and then removed with soap and water. Warts usually clear by 8-10 weeks. The maximum duration of treatment is 16 weeks. [48],[49],[50],[51]
Side effects
Topical imiquimod is generally well tolerated. Systemic side effects are not reported. The most frequent adverse event is local erythema in 33-80% of patients and may correlate with the local immune response induced by imiquimod. Other local adverse events include pruritus (26%), burning (16%), tenderness and stinging (4%). Adverse events are mild-moderate in severity and usually disappear in 2 weeks of discontinuing imiquimod. Localized hypo or hyperpigmentaion has occasionally been reported. [48],[49],[50],[51]
Contraindications/precautions
Imiquimod is contraindicated in patients with allergy to the components of the cream. Imiquimod should not be used during pregnancy (category B). Precautions should be taken with sexual contact as the risk of transmission of HPV following application of imiquimod is unknown. Imiquimod cream may weaken condoms and diaphragms and sexual contact should be avoided while cream is on the skin.[60]
Docosanol
Docosanol (also known as n-docosanol or behenyl alcohol) is a saturated primary alcohol that has in vitro inhibitory effects against enveloped viruses such as HSV-1, HSV-2, CMV and human herpes virus 6.[61] Docosanol 1% cream (Abreva) has been approved by the FDA and is available over the counter in the USA for topical treatment of herpes labialis (cold sores).[62]
Mechanism of action
Docosanol is a 22-Carbon saturated fatty alcohol derived from plant extracts and is highly lipophilic.[61],[63] Docosanol has no direct viricidal activity by itself. However, the antiviral properties are due to its inhibition of viral entry to the cells. Docosanol inhibits lipid-enveloped viruses by fusion to the plasma membrane and thus inhibiting viral migration to the nucleus and subsequent viral replication. Enveloped viruses that are inhibited in vitro by docosanol include HSV-1 and 2, VZV, HHV-6, Influenza A, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV).[63], [64]
Clinical indications
Docosanol is indicated in treatment of recurrent oral-facial herpes simplex. Docosanol 10% cream applied 5 times daily was compared to placebo (ethylene glycol) in adult patients presenting with recurrent herpetic lesions at the prodrome or erythema stage. Treatment was continued until healing occurred. The median time to healing of lesions in a recurrent episode among patients who applied docosanol was about one day shorter than placebo treated patients (p=0.008). In addition, patients who applied docosanol had statistically significant reductions in the durations of associated symptoms of pain, burning, itching and tingling (p<0.03). Docosanol also reduced the time of the most severe stage of (ulcer, soft crust) of the lesion that correlates with the peak period of inflammation and viral replication.[65]
Topical docosanol 5 times daily was used in ten HIV-1 infected patients with Kaposi's sarcoma. After 28 days of treatment, two patients had reduction in the size of skin lesions. With extended treatment, two more patients had partial improvement.[66] Further studies are needed before docosanol therapy can be routinely used in KS patients.
Dosage and administration
Docosanol 10% cream is applied topically to herpetic lesions 5 times a day until the lesions heal. The cream is indicated for patients 12 years of age or older.[62]
Side effects
Headache was reported in patients who were enrolled in the docosanol treatment study. Local adverse events occurred with low frequencies (<2%) and included application site reactions, rash, pruritus, dry skin and acne. [62], [65]
Contraindications/precautions
Docosanol is contraindicated in patients with hypersensitivity reactions. Caution should be employed in patients who develop allergic phenomena with topical medications. Docosanol is only approved to treat oral (lip)-facial HSV lesions. The safety and efficacy of docosanol in treating HSV in other sites is not known. [62]
Brivudin
Brivudin or BVDU is E-5-(2-bromovinyl)-2'deoxyuridine, a 5' halogenated thymidine nucleoside analogue. [67] Brivudin, though not available in the USA, is currently used in several European countries for treatment of VZV and HSV-1 infections. In vitro , Brivudin has been shown to be more potent than acyclovir and penciclovir against VZV. [68] Brivudin is currently available in oral and topical forms (0.1% eye drops and 1% eye ointment).
Mechanism of action
Oral brivudin is rapidly absorbed following oral administration. Oral bioavailability is 33%. Inhibition of viral replication starts 1-4 hours after administration. Brivudin is selectively uptaken by cells infected by HSV-1 or VZV. [67] Brivudin is phosphorylated by the virus encoded thymidine kinase to the 5'-monophosphate and 5'-diphosphate. Further phosphorylation by cellular kinases occurs with subsequent formation of BVDU 5'triphosphate (BVDU-TP) that interacts with the viral DNA polymerase. BVDU-TP incorporates into the DNA chain and interferes with replication and transcription processes.[69]
Brivudin is highly potent against HSV-1 but not HSV-2. This selective antiviral effect is due the inability of HSV-2 encoded thymidine kinase to phosphorylate BVDU-monophosphate to the diphosphate form.[70],[71]
Clinical indications
Oral brivudin may be as or even more effective than acyclovir in treatment of VZV infection.[67] In a randomized trial of treatment of herpes zoster in immunocompromized patients, 5-day courses of either brivudin (125 mg every 6 hours) or acyclovir (10 mg/kg every 8 hours) were compared. They were equally effective with regard to clinical response, incidence of dissemination and in the time to full lesion crusting.[72] A similar study in immunocompromized children comparing acyclovir 1,500 mg/m2/day with oral brivudin at 15 mg/kg/day showed no difference in therapeutic efficacy in the two groups.[73] Intravenous acyclovir and oral brivudin were well tolerated in both clinical trials. Oral brivudin (125 mg once daily) for 7 days was found to be superior to oral acyclovir at 800 mg given 5 times daily in inhibiting viral replication as measured by time to last appearance of VZV lesions in immunocompetent patients.[74] Brivudin was comparable in efficacy to famciclovir. However, in patients with ophthalmic zoster, cessation of vesicle formation occurred 31% faster with brivudin than with famciclovir.[75]
Brivudin 0.1% eye drops have been used to treat herpetic keratitis caused by HSV-1. Efficacy of brividun was demonstrated in patients with different stages of infection including dendritic and geographic ulcers and herpetic keratitis.[76] Clinical improvement occurred in patients who failed treatment with other topical antivirals such as idoxuridine, trifluridine, vidarabine and acyclovir. Topical brivudin 1% eye ointment was also more effective than other topical antiviral agents in a group of patients with uncomplicated herpetic keratitis that has not been previously treated. The cure rate in this study was 95%.[77]
Dosage and administration
The recommended dose for treating VZV infections in children is 15 mg/kg/day in one dose or 3 divided doses given orally for 5 days.[73] Topical application of 0.1% eyedrops is given hourly while awake or 5 times daily. [77]
Side effects
Most reported adverse events were mild, transient and the association with brivudin was not clear. The most commonly reported adverse events associated with oral brivudin use were nausea, vomiting and loss of appetite and headache. Other adverse events are proteinurea, glucosurea and dizziness.[67] No carcinogenic or mutagenic potential of brivudin has been demonstrated in animal studies.[78] The effects of brivudin during pregnancy have not been clarified. Local hypersensitivity reactions may occur with topical brivudin use.[76],[77]
Contraindications/precautions
Brivudin is contraindicated in patients who had previous hypersensitivity to brivudin. Significant interaction may occur with 5-fluorouracil (5-FU), tegafur and other antimetabolites. Brivudin is a substrate of thymidine phosphorylase that converts brivudin (BVDU) to bromovinyluracil (BVU), which is a potent inhibitor of the enzyme dihydropyrimidine dehydrogenase (DPD). [79] This enzyme is employed in first step of the catabolic pathway of pyrimidines. DPD is needed for the breakdown of 5 -FU. Thus brivuin use may cause marked increase in the half-life of 5-FU and enhance its antitumor activity.[79] However, combined use of brivudin with 5-FU may cause increase in 5-FU toxic effects such as diarrhea and marked decreases in white blood cell and platelet counts. [80], [81]
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