Acyclovir
Acyclovir tablets can be taken with meals, since food intake does not significantly interfere with its absorption. The tablets should be taken with a full glass of water.
Adults
Treatment of infections caused by herpes simplex virus
For the treatment of infections caused by the herpes simplex virus, the recommended dose of Acyclovir is 200 mg 5 times a day (every 4 hours, except during night sleep). Usually the course of treatment is 5 days, but can be extended for severe primary infections.
In case of severe immunodeficiency (for example, after bone marrow transplantation) or in case of impaired absorption from the intestine, the oral dose of Acyclovir can be increased to 400 mg. As an alternative, the possibility of using acyclovir in a lyophilisate dosage form for the preparation of a solution for infusion may be considered.
Treatment should begin as soon as possible after infection occurs; in case of relapses, it is recommended to prescribe the drug already in the prodromal period or when the first elements of the rash appear.
Prevention of recurrent infections caused by the herpes simplex virus in patients with normal immune status
To prevent relapses of infections caused by the herpes simplex virus in patients with normal immune status, the recommended dose of Acyclovir is 200 mg 4 times a day (every 6 hours).
For many patients, a more convenient treatment regimen is suitable: 400 mg 2 times a day (every 12 hours).
Sometimes lower doses of Acyclovir are effective: 200 mg 3 times a day (every 8 hours) or 200 mg 2 times a day (every 12 hours).
Some patients may experience exacerbation of infection when taking a total daily dose of 800 mg.
Treatment with Acyclovir should be periodically interrupted for 6-12 months to identify possible changes in the course of the disease.
Prevention of infections caused by herpes simplex virus in patients with immunodeficiency
For the prevention of infections caused by the herpes simplex virus in patients with immunodeficiency, the recommended dose of Acyclovir is 200 mg 4 times a day (every 6 hours). In case of severe immunodeficiency (for example, after bone marrow transplantation) or in case of impaired absorption from the intestine, the oral dose of Acyclovir can be increased to 400 mg 4 times a day. As an alternative, the possibility of using acyclovir in a lyophilisate dosage form for the preparation of a solution for infusion may be considered.
The duration of the preventive course of therapy is determined by the length of the period when there is a risk of infection.
Treatment of chickenpox and herpes zoster
For the treatment of chickenpox and herpes zoster, the recommended dose of Acyclovir is 800 mg 5 times a day (every 4 hours, except during night sleep). The course of treatment is 7 days.
In patients with severe immunodeficiency (for example, after bone marrow transplantation) or in cases of impaired absorption from the intestine, it is necessary to consider the possibility of prescribing acyclovir in a lyophilisate dosage form for the preparation of a solution for infusion.
Treatment for herpes zoster should begin as soon as possible after the rash appears, as in this case the treatment will be more effective.
Treatment of chickenpox in patients with normal immune status should begin within 24 hours of the onset of the rash.
Special patient groups
Children aged 3 years and older
Treatment of herpes simplex virus infections: prevention of herpes simplex virus infections in immunocompromised patients
- aged 3 years and older - the same doses as for adults.
Treatment of chickenpox
- at the age of 6 years and older - 800 mg 4 times a day;
- aged 3 to 6 years - 400 mg 4 times a day.
More accurately, the dose can be determined at the rate of 20 mg/kg body weight (but not more than 800 mg) 4 times a day. The course of treatment is 5 days
Prevention of recurrence of infections caused by the herpes simplex virus in patients with normal immune status; Treatment of herpes zoster There are no data on the dosage regimen.
Elderly patients
The likelihood of renal failure in elderly patients must be taken into account, and doses should be adjusted according to the degree of renal failure (see subsection "Patients with renal failure"). It is necessary to ensure that adequate water balance is maintained.
Patients with impaired renal function
Caution must be exercised when prescribing Acyclovir to patients with impaired renal function. It is necessary to ensure that adequate water balance is maintained. In patients with renal failure, taking acyclovir orally at recommended doses for the treatment and prevention of infections caused by the herpes simplex virus does not lead to the accumulation of the drug to concentrations exceeding established safe levels. However, in patients with creatinine clearance less than 10 ml/min, the dose of Acyclovir is recommended to be reduced to 200 mg 2 times a day (every 12 hours).
For the treatment of chickenpox and herpes zoster, the recommended doses of Acyclovir tablets are:
- with creatinine clearance less than 10 ml/min - 800 mg 2 times a day (every 12 hours);
- with creatinine clearance 10-25 ml/min - 800 mg 3 times a day (every 8 hours).
Acyclovir-Belmed tablet 200 mg in container pack No. 10x2
Name
Acyclovir-Belmed.
Description
The tablets are round, flat-cylindrical, with a chamfer and a score on one side, white or almost white.
Main active ingredient
Acyclovir.
Release form
Pills.
Dosage
200 mg.
pharmachologic effect
Acyclovir is a synthetic analogue of a purine nucleoside that has the ability to inhibit in vitro and in vivo human herpes viruses, including herpes simplex virus types 1 and 2, varicella zoster virus and herpes zoster virus. The inhibitory effect of acyclovir on Herpes simplex viruses type 1 and 2, Varicella zoster is highly selective. Acyclovir is not a substrate for the thymidine kinase enzyme in uninfected cells, therefore acyclovir is of low toxicity to mammalian cells. Thymidine kinase of cells infected with Herpes simplex viruses type 1 and 2, Varicella zoster converts acyclovir into acyclovir monophosphate, a nucleoside analogue, which is then sequentially converted into diphosphate and triphosphate under the action of cellular enzymes. Acyclovir triphosphate interacts with DNA polymerase and inhibits the replication of viral DNA, is included in the viral DNA chain, which leads to chain termination. In patients with severe immunodeficiency, long-term or repeated courses of acyclovir therapy may lead to the emergence of resistant strains, so further treatment may be ineffective. The majority of isolated strains with reduced sensitivity to acyclovir had a relatively low content of viral thymidine kinase and a disorder in the structure of the viral thymidine kinase or DNA polymerase. The effect of acyclovir on Herpes simplex strains in vitro can also lead to the formation of strains less sensitive to it. A correlation has not been established between the sensitivity of Herpes simplex strains to acyclovir in vitro and the clinical effectiveness of the drug.
Indications for use
- treatment of primary and recurrent infections of the skin and mucous membranes caused by the Herpes simplex virus (types 1 and 2), including genital herpes (with the exception of neonatal herpes and severe infections caused by the herpes simplex virus in children with immunodeficiency); - prevention of exacerbations of recurrent infections caused by the Herpes simplex virus (types 1 and 2) in patients with normal immune status; - prevention of primary and recurrent infections caused by the Herpes simplex virus (types 1 and 2) in patients with immunodeficiency; - chicken pox, herpes zoster (shingles).
Directions for use and doses
Acyclovir-Belmed can be taken with food, since food intake does not significantly interfere with its absorption. The tablets should be taken with a full glass of water. It is necessary to ensure that the patient is adequately hydrated when taking high doses of acyclovir. Adults - for the treatment of infections caused by Herpes simplex types 1 and 2, the recommended dose is 200 mg 5 times a day every 4 hours, except during nighttime sleep. Usually the course of treatment is 5 days, but can be extended for severe primary infections. In cases of severe immunodeficiency (eg, after bone marrow transplantation) or in cases of impaired intestinal absorption, the dose may be doubled to 400 mg, or intravenous acyclovir should be considered as an alternative. Treatment should begin as soon as possible after infection occurs; in case of relapses, it is recommended to prescribe the drug already in the prodromal period or when the first elements of the rash appear. — for suppressive treatment of infections caused by Herpes simplex types 1 and 2, in patients with normal immune status, the recommended dose is 200 mg 4 times a day every 6 hours. Many patients are suitable for a more convenient treatment regimen: 400 mg 2 times a day every 12 h. In some cases, lower doses of acyclovir are effective: 200 mg 3 times a day (every 8 hours) or 2 times a day (every 12 hours). Treatment with acyclovir should be periodically interrupted for 6-12 months to identify possible changes in the natural history of the disease. - for the prevention of infections caused by Herpes simplex types 1 and 2, in patients with immunodeficiency, the recommended dose is 200 mg 4 times a day every 6 hours. In case of severe immunodeficiency (for example, after bone marrow transplantation) or if absorption from the intestine is impaired, the dose may be doubled to 400 mg or intravenous acyclovir should be considered as an alternative. The duration of the preventive course of therapy is determined by the duration of the period of existence of the risk of infection. — for the treatment of chickenpox and herpes zoster, the recommended dose of acyclovir is 800 mg 5 times a day every 4 hours, with the exception of the period of night sleep. The course of treatment is 7 days. In cases of severe immunodeficiency (for example, after bone marrow transplantation) or in cases of impaired absorption from the intestine, intravenous acyclovir should be considered as an alternative. The drug should be prescribed as soon as possible after the onset of infection. Treatment for herpes zoster has the best results if started as soon as possible after the rash appears. Treatment of chickenpox in patients with normal immune status should begin within 24 hours after the onset of the rash. Children - treatment and prevention of infections caused by Herpes simplex viruses in children with immunodeficiency: for children aged 2 years and older, doses recommended for adults should be used. Children under two years of age should be given half the adult dose. For the treatment of neonatal herpes, intravenous acyclovir is recommended. - treatment of chickenpox: children aged 6 years and older are prescribed acyclovir 800 mg 4 times a day, 2-5 years - 400 mg 4 times a day, up to 2 years - 200 mg 4 times a day. Treatment should be continued for 5 days. More precisely, a single dose can be determined at the rate of 20 mg/kg body weight (but not more than 800 mg of acyclovir) 4 times a day. There are no data on the use of acyclovir for the prevention of relapses of infections caused by Herpes simplex viruses and in the treatment of herpes zoster in children with normal immunity. Elderly Patients The possibility of renal impairment in the elderly should be considered and the dose should be adjusted accordingly. Elderly patients taking high doses of oral acyclovir should maintain adequate hydration. Patients with renal failure It is necessary to ensure that the patient is adequately hydrated when taking high doses of acyclovir. During the treatment of infections caused by the herpes simplex virus in patients with renal failure, the use of recommended oral doses does not lead to the accumulation of acyclovir in the body at concentrations higher than those considered safe during intravenous administration of the drug. However, when treating an infection caused by the herpes simplex virus in patients with severe renal impairment (creatinine clearance less than 10 ml/min), it is recommended to adjust the dose: 200 mg of acyclovir 2 times a day after 12 hours. In the treatment of herpes zoster: it is recommended to adjust the dose to 800 mg of acyclovir 2 times a day with a 12-hour interval for patients with severe renal impairment (creatinine clearance less than 10 ml/min) and 800 mg of acyclovir 3 times a day with an interval of 8 hours - in patients with moderate renal impairment (creatinine clearance within 10-25 ml/min). Patients with hepatic impairment No dosage adjustment is required for patients with mild or moderate hepatic impairment. Clinical experience with the use of the drug in the late stages of cirrhosis (with impairment of the synthesizing function of the liver and the presence of signs of portal block) is limited, but pharmacokinetics indicators indicate that there is no need for dose adjustment. If the next dose of acyclovir is missed, the drug must be taken as soon as possible. However, if it is almost time to take the next dose of Acyclovir-Belmed, the missed dose should be omitted. Do not take a double dose of Acyclovir-Belmed to make up for a missed dose!
Use during pregnancy and lactation
The use of acyclovir during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. There are post-marketing data on the use of various dosage forms of acyclovir in pregnant women, which do not indicate an increase in the incidence of birth defects compared to the general population. The observed birth defects were not unique, suggesting a causal relationship with acyclovir. In standard studies of systemic use of acyclovir in rabbits, mice and rats, embryotoxic and teratogenic effects were not detected. In unconventional studies on female rats, the occurrence of congenital malformations was observed only after subcutaneous administration of high doses, which also caused toxic symptoms in mothers. The clinical significance of these observations is unknown. After oral administration of acyclovir at a dose of 200 mg five times a day, its concentration in breast milk ranged from 60% to 410% of the drug concentration determined in blood plasma. This concentration of acyclovir in breast milk could lead to the drug being supplied to the child at a daily dose of up to 0.3 mg/kg body weight/day. Therefore, special care should be taken when using the drug in nursing mothers. Fertility. There is no data on the effect of acyclovir on fertility in women. In a study of 20 men with normal sperm counts who took oral acyclovir at a dose of up to 1.0 g per day for up to 6 months, there was no significant clinical effect on sperm morphology, count or motility.
Precautionary measures
When treating genital herpes, sexual contact should be avoided, since acyclovir does not prevent sexual transmission of herpes. During the period of use of the drug, it is necessary to monitor kidney function. State of hydration. In patients receiving high doses of acyclovir, care should be taken to ensure adequate hydration. To prevent the formation of acyclovir crystals in the renal tubules, it is recommended to take large amounts of fluid during the treatment period. The risk of renal failure increases when taken together with other nephrotoxic drugs. Elderly patients and patients with renal impairment have an increased risk of developing neurological side effects, these reactions are usually reversible after discontinuation of treatment. Long-term or repeated courses of treatment with acyclovir in immunocompromised individuals may lead to the development of virus strains with reduced sensitivity to acyclovir. Available clinical trial data are not sufficient to suggest that treatment with acyclovir reduces the incidence of herpes zoster complications in immunocompromised patients. No dose adjustment is required for patients with mild or moderate liver dysfunction. Clinical experience with the use of the drug in the late stages of cirrhosis (with impairment of the synthesizing function of the liver and the presence of signs of portal block) is limited, but pharmacokinetics indicators indicate that there is no need for dose adjustment. Acyclovir-Belmed tablets contain lactose, so patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
Interaction with other drugs
Acyclovir is excreted mainly in the urine by active renal tubular secretion unchanged. Any medications used simultaneously; which are eliminated in the same way, can compete with acyclovir and increase its concentration in the blood plasma. Probenecid and cimetidine increase the AUC of acyclovir through this mechanism and also decrease the renal clearance of acyclovir. Plasma AUCs of acyclovir and the inactive metabolite of mycophenolate mofetil, an immunosuppressive drug used in transplantation, similarly increase when administered concomitantly. However, no dose adjustment is required due to the broad therapeutic index of acyclovir. A pilot study in five men showed an approximately 50% increase in theophylline concentrations when taken concomitantly with acyclovir. It is recommended to measure plasma theophylline concentrations during concomitant therapy with acyclovir.
Contraindications
Increased individual sensitivity to acyclovir or valacyclovir, or to any of the excipients.
Compound
Each tablet contains the active substance: acyclovir - 200 mg; excipients: microcrystalline cellulose, sodium starch glycolate (type A), povidone, magnesium stearate, lactose monohydrate.
Overdose
Acyclovir is only partially absorbed from the gastrointestinal tract. When taking acyclovir up to 20 g at a time, as a rule, no toxic effects are observed. In case of unintentional repeated (over several days) oral overdose, gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion) are observed. Treatment: symptomatic. Hemodialysis significantly accelerates the removal of acyclovir from the blood and therefore may be considered as a treatment option in cases of symptomatic overdose.
Side effect
The frequency of side effects is given in the following gradation: very often (≥1/10); often (≥1/100,
Storage conditions
In a place protected from moisture and light at a temperature not exceeding 25 °C. Keep out of the reach of children.
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Instructions for use for Acyclovir-Belmed tablet 200 mg in container pack No. 10x2
Recommendations for the treatment of genital herpes
Genital herpes is a sexually transmitted disease manifested by recurrent lesions of the genital organs. The causative agents are herpes simplex viruses, predominantly type II, although over the past two decades the etiological role of type I virus has increased significantly.
Table. Doses of medications for the treatment of genital herpes
Despite the severe clinical manifestations of primary infection and potentially dangerous complications leading to hospitalization and death, genital herpes has received insufficient attention in the non-specialized medical literature. Meanwhile, the spread of the disease has become epidemic, which is associated with a large number of undiagnosed and untreated cases and a high frequency of asymptomatic and subclinical course (2). Symptomatic genital herpes affects 86 million people worldwide. The total number of people affected by the virus cannot be determined, but it is assumed that, for example, in the United States, every fourth to sixth person is a carrier of the virus (3-4).
The main drugs for the treatment of genital herpes are antiviral drugs from the group of nucleoside analogues. The most widely used drug continues to be acyclovir, which appeared on the global pharmaceutical market about 20 years ago. Being an analogue of nucleosides, the drug undergoes phosphorylation under the influence of viral thymidine kinase, and then, with the help of host cell enzymes, is converted into di- and triphosphate. The latter acts as a substrate for viral DNA polymerase, thus leading to disruption of DNA virus replication.
The effectiveness of acyclovir for the treatment of genital herpes has been shown in numerous clinical studies. When taken orally, the drug is well tolerated by patients and has an excellent benefit/risk ratio. Side effects occur in less than 10% of patients and are usually limited to nausea, vomiting and headache (5).
The main disadvantages of acyclovir include low bioavailability (15-20%) and short half-life from tissues (0.7 hours) and blood plasma (2.7 hours) (5). To maintain therapeutic concentrations in the body, the drug must be taken up to 5 times a day, which negatively affects patients’ accuracy in following the treatment regimen and can lead to a decrease in the effectiveness of therapy.
The pharmacokinetic disadvantages of acyclovir were largely overcome with the development of valacyclovir, a prodrug that is metabolized in the intestinal wall and liver to form acyclovir. Valacyclovir has significantly greater oral bioavailability (54%) and provides higher and longer-lasting serum acyclovir concentrations (6-8), allowing twice-daily dosing. With repeated oral administration of valacyclovir in high doses (4-8 g/day), the concentrations of the active substance in the blood are comparable to the concentrations created by intravenous administration of acyclovir (5-10 mg/kg 3 times/day) (8, 9).
The kinetics of acyclovir released from valacyclovir is similar to the kinetics of acyclovir preparations in healthy volunteers, patients with kidney disease, HIV infection (10), elderly patients and senile volunteers, both receiving and not receiving concomitant diuretic therapy (11).
The safety profile of valacyclovir is not significantly different from the safety profile of acyclovir. Better absorption results in a lower incidence of gastrointestinal adverse reactions (5). In patients with AIDS and other immune disorders, thrombotic microangiopathy has been described when using valacyclovir in high doses (8 g/day), but the cause-and-effect relationship between the drug and this complication has not been definitively confirmed (12). Thrombotic microangiopathy was not observed in patients receiving high doses of valacyclovir after renal transplantation (13). In addition, for the treatment of genital herpes, the drug is used in significantly lower doses.
The third nucleoside analogue, famciclovir, like valacyclovir, is a prodrug that is converted into penciclovir in the intestinal wall and in the liver. Penciclovir has a mechanism and spectrum of antiviral action similar to acyclovir, but due to low bioavailability it can only be used topically (5). When administered orally, penciclovir has a bioavailability of 77% (14). Compared to acyclovir, penciclovir has a significantly longer tissue half-life (10–20 h) (15). Intracellular concentrations of penciclovir triphosphate are approximately 30-fold higher than those of acyclovir triphosphate (16). However, herpes simplex virus DNA polymerase has a greater affinity for acyclovir triphosphate than for penciclovir triphosphate. Thus, the differences in the mechanism of action between penciclovir and acyclovir are predominantly quantitative and tend to balance each other out (16).
Acyclovir and penciclovir do not differ in activity against herpes simplex virus in cell culture, but after discontinuation of acyclovir, viral replication resumes much faster than after discontinuation of penciclovir (13). Famciclovir is superior to valacyclovir in its ability to reverse “competent latency,” a state in which the virus is able to reactivate and cause disease relapse (18, 19). In an observational study, patients treated with famciclovir (250 mg 3 times a day for 5 days) had fewer relapses within 1-6 months after the first episode than patients treated with acyclovir (200 mg 5 times a day). within 5 days) (20).
Famciclovir has an excellent safety profile. A tolerability analysis based on the results of 13 clinical trials showed that the adverse reaction profile of famciclovir in patients with genital herpes (791 patients) was no different from placebo (21). Studies in healthy male volunteers did not reveal clinically significant pharmacokinetic interactions of famciclovir with allopurinol, digoxin, cimetidine, zidovudine, or theophylline (22). The bioavailability of penciclovir from the metabolism of famciclovir is independent of food intake (23). Its pharmacokinetics do not differ between young and elderly individuals (24). When taken for 4-12 months by healthy male volunteers, the drug had no negative effect on sperm (25).
Acyclovir, valacyclovir, and famciclovir exhibit comparable clinical efficacy, resulting in decreased duration and severity of genital herpes episodes and decreased viral shedding (26–28). However, they have no effect on viruses in the dormant stage.
Treatment of
the first episode of genital herpes
The first episode of primary genital herpes is considered to be the clinical manifestation of the disease in patients without antibodies to herpes simplex viruses type I or II. The first episode is characterized by the most severe course. Typically, in addition to local lesions that persist for 2-3 weeks, systemic symptoms and regional adenopathy are observed. A small number of patients, often those who are immunocompromised, develop viral meningitis.
Symptomatic treatment of the first episode consists of prescribing analgesics. Opioid medications should be avoided as they cause constipation. For etiotropic treatment, nucleoside analogues are used.
The effectiveness of oral acyclovir at a dose of 200 mg 5 times a day. for 5-10 days is indicated in double-blind, placebo-controlled clinical studies (29, 30). In patients receiving acyclovir, the period of virus shedding, crust formation time, and healing time were significantly shortened. Increasing the oral daily dose of the drug to 4 g did not lead to an increase in the effectiveness of therapy (31). In addition, gastrointestinal side effects were significantly more common with the high dose (8%) than with the standard dose (0%).
In order to improve patient adherence to treatment, the US Centers for Disease Control and Prevention (CDC) recommends the use of acyclovir 400 mg 3 times a day, but this regimen is not approved by the FDA. Topical acyclovir cream is not effective (6). Addition of the cream to oral therapy also did not improve clinical outcomes (32). In severe cases with neurological complications, acyclovir is recommended to be administered intravenously at 5-10 mg/kg 3 times a day (5).
Valacyclovir at a dose of 1 g 2 times a day. shows equal effectiveness with acyclovir at a dose of 200 mg 5 times a day. during the first episode of genital herpes in immunocompetent patients (33). The tolerability of valacyclovir is similar to that of acyclovir (33). In different countries, valacyclovir is approved at a dose of 500 mg or 1 g 2 times a day for the treatment of the first episode of genital herpes. within 10 days (25).
Famciclovir was studied in comparative clinical studies with acyclovir (200 mg 5 times a day) in doses of 125, 250 and 500 mg 3 times a day (27, 28). No study showed significant differences between comparison groups. For the treatment of genital herpes, famciclovir is recommended to be prescribed at a dose of 250 mg 3 times a day. for 5 days, for severe infection - 10 days (25).
Episodic
treatment of recurrent genital herpes
In clinical studies, when using acyclovir in a standard daily dose (200 mg 5 times / day) for episodic treatment of recurrent genital herpes, a shortening of the period of virus shedding, crusting time and healing time was noted. The duration of symptoms and the timing of new relapses were not affected by the drug (28, 34). Recommendations for the management of genital herpes issued in 1998 by the US Centers for Disease Control and Prevention (CDC) suggested the use of acyclovir in doses of 400 mg 3 times a day. or 800 mg 2 times/day. within 5 days. However, these treatment regimens have not been studied in adequate clinical studies.
When applied topically in the form of a 5% polyethylene glycol ointment, acyclovir led to a decrease in the period of virus shedding, but did not cause clinical improvement (6).
Valaciclovir at a dose of 500 or 1000 mg 2 times a day. for 5 days, prescribed on the first day after the onset of symptoms, significantly reduced the period of virus shedding and accelerated the healing of lesions compared to placebo (35). Tolerability of the drug did not differ from tolerability of placebo. One study showed that fewer patients (10%) developed vesicululcerative lesions with valacyclovir than with placebo (25). Another study suggests, based on the natural shedding period of the virus, that a 3-day course of valacyclovir treatment is as effective as a 5-day course (36). In July 2001, the FDA approved a 3-day course of treatment for recurrent genital herpes with valacyclovir (500 mg twice daily). Comparative studies with acyclovir showed equal clinical efficacy of both drugs (37). An important advantage of valacyclovir is its more convenient mode of administration.
Famciclovir at doses of 125, 250, and 500 mg twice daily given within 6 hours of symptom onset resulted in decreased healing time, viral shedding time, and duration of lesion swelling compared with placebo (38). With its use, pain, burning, tingling, and tenderness to the touch significantly decreased. Side effects of famciclovir were no different from placebo. Famciclovir is recommended for episodic treatment of recurrent genital herpes at a dose of 125 mg 2 times a day. within 5 days. The advantages of famciclovir, like valacyclovir, are that the treatment regimen is more convenient compared to acyclovir.
The effectiveness of episodic treatment of recurrent genital herpes depends on the time of initiation of medication. A Canadian study showed that when famciclovir was started within 6 hours of the onset of prodromal symptoms or first genital lesions, there was a significant reduction in viral shedding and faster healing of lesions. Moreover, taking the drug before the onset of viral shedding increased the likelihood of preventing viral shedding during relapse (39). Treatment of relapse should begin as quickly as possible, so patients must always have a supply of the drug.
Continued
suppressive therapy
For patients with frequent (more than 6-8 per year) and severe relapses, psychological trauma or disruption of normal lifestyle caused by the disease, ongoing suppressive therapy is indicated. For this purpose, acyclovir 400 mg 2 times a day is used for a long time (for 6-12 months); valacyclovir 500 mg 1 time/day. (if the number of relapses is 10 or less per year) or 1000 mg 1 time / day. (with more than 10 relapses per year) or famciclovir 250 mg 2 times a day. Daily acyclovir has been shown to reduce relapse rates by 80%, with 25-30% of patients remaining relapse-free (40). Similar results were obtained in studies with valacyclovir and famciclovir. When using famciclovir in a daily dose of 500 mg, divided into 2 doses, for 16 weeks, relapses did not develop during the treatment period in 78% of patients (41), when using valacyclovir in the same dose - in 69% of patients (33). All three drugs have proven to be effective for long-term suppressive therapy of recurrent genital herpes. Apparently, the decisive factors when choosing a specific drug should be the cost of the annual dose and the convenience of the regimen for the patient.
Suppressive therapy is well tolerated. Its safety has been demonstrated with daily use for 5 years (42). However, before prescribing suppressive therapy, it is recommended to conduct hematological and biochemical studies and determine the state of renal function. During treatment, patients should be under medical supervision; women are advised to avoid pregnancy.
Daily suppressive therapy leads to a significant reduction in asymptomatic viral shedding, but does not completely eliminate it. The patient should be warned when deciding on its appointment. As an alternative, the patient should be offered selective prophylaxis (eg during periods of stress). To date, a reduction in the risk of infection transmission under the influence of suppressive therapy has not been proven.
Regardless of whether suppressive treatment is given or not, relapse rates decrease on average 7 years after the first episode, so lifelong treatment is usually not necessary.
Treatment of
genital herpes in pregnant women
Women suffering from genital herpes during pregnancy have an increased risk of spontaneous abortions and the birth of low-weight children. In rare cases, a congenital infection in the fetus may develop. The risk of infection is highest during the passage of the child through the birth canal. The risk of transmission is estimated to be 50% for primary maternal herpes during childbirth and 0–3% for recurrent herpes (43). Most often, infection occurs from asymptomatic mothers (44).
In newborns, the disease occurs in three main forms: localized, with damage to the central nervous system, and disseminated. Mortality is 15% for infection involving the central nervous system and 57% for disseminated infection (45).
In order to reduce the risk of subclinical viral shedding and relapse episodes during labor, many clinicians recommend suppressive antiviral therapy for pregnant women. Nucleoside analogues are not officially approved for use during pregnancy, but many studies have shown the safety of acyclovir (46, 47). Valacyclovir and famciclovir, according to the FDA classification, are classified as group B, i.e., drugs for which no teratogenic effect was detected in animal experiments, and adequate clinical trials in humans have not been conducted. Studies are currently underway to determine the effectiveness and safety of valacyclovir during pregnancy.
Data on the effectiveness of suppressive therapy in preventing infection in the fetus are extremely limited. A randomized trial of 46 women with a first episode of genital herpes was unable to determine the effectiveness of treatment with acyclovir started at 36 weeks' gestation because no newborns developed infection. However, in the group of patients receiving suppressive therapy, a significant reduction in the rate of cesarean section was noted (48). Another placebo-controlled study of 150 women with a history of genital herpes (49) showed that acyclovir (200 mg three times daily) given from 38 weeks of pregnancy was able to prevent relapses. In patients receiving acyclovir, relapse did not occur in any case, while in the control group there were 33 relapses, of which 21 occurred during childbirth.
Treatment
of genital herpes caused by acyclovir - resistant strains
Long-term treatment with nucleoside analogues, as a rule, is not associated with the risk of developing viral resistance. In immunocompetent patients receiving suppressive therapy, acyclovir-resistant strains of the herpes simplex virus were isolated, but correlations between in vitro
and therapeutic efficacy of the drug was not observed (25). The most common mechanism of resistance is a gene mutation that disrupts thymidine kinase production (50), and acyclovir-resistant strains typically exhibit cross-resistance to penciclovir. Much less common are mutations that lead to dysfunction of thymidine kinase and DNA polymerase (50, 51). In these cases, selective resistance to one of the drugs is possible. Mathematical analysis suggests that changes in the current viral resistance pattern may take decades (52).
In immunocompromised patients with long-term use of antiviral drugs, resistance develops in approximately 5% of cases and can lead to treatment failure (53, 54). Clinically significant resistance has also been described in patients who have undergone bone marrow transplantation (55).
Foscarnet is currently considered as the drug of choice for the treatment of acyclovir-resistant herpes simplex virus infections (56). It is a non-competitive inhibitor of viral DNA polymerase. The drug blocks receptors for binding to viral DNA pyrophosphate and disrupts the elongation of its chain. Unlike acyclovir and penciclovir, it does not require phosphorylation by thymidine kinase and is active against acyclovir-resistant thymidine kinase-deficient strains (56).
Foscarnet has low bioavailability when taken orally, so it is administered intravenously and locally. The effectiveness of intravenous foscarnet for genital herpes caused by acyclovir-resistant strains has been shown in several clinical studies. In an uncontrolled study, the drug was effective in 81% of patients with acyclovir-resistant genital herpes that developed against the background of HIV infection (57). In another study in patients with HIV infection, foscarnet was superior to vidarabine in terms of time to healing of herpes mucocutaneous lesions caused by acyclovir-resistant strains and the time to cessation of viral shedding (58). When applied topically, the drug did not show sufficient effectiveness (25).
Foscarnet is a potentially toxic drug. Side effects include renal dysfunction, gastrointestinal disorders, disturbances in magnesium and calcium metabolism, anemia, genital ulceration, and seizures (59). To prevent serious side effects, treatment should be carried out under close medical supervision, an adequate level of hydration should be maintained, and concomitant administration of pentamidine should be avoided.
The use of foscarnet limits the intravenous route of administration. Resistance to it can develop due to mutations in DNA polymerase (60). Clinical strains of herpes simplex virus that are resistant to both acyclovir and foscarnet have been described (61).
Pronounced activity against herpes simplex virus in vitro
and
in vivo
exhibited by cidofovir (62, 63). It is an acyclic analogue of phosphanate and has a broad spectrum of antiviral activity. The drug is phosphorylated by cellular enzymes into active diphosphate, bypassing the first step of phosphorylation with viral enzymes required for acyclovir and penciclovir (64). Cidofovir has low bioavailability when taken orally (less than 5%), which allows it to be used only topically. The advantage is the long half-life from the cell. Intracellular concentrations of cidofovir mono- and diphosphate are maintained for 24 and 65 hours, respectively (65).
The effectiveness of a single dose of the drug compared with placebo was shown in immunocompetent patients with recurrent genital herpes (66). In this study, 12 hours after the onset of the first lesions, patients received cidofovir gel at a concentration of 1.3 or 5% or placebo. Local toxic reactions of the drug slowed down the healing of injuries in a number of patients. They were dose-dependent in nature and were observed in three of 23 patients treated with 5% gel and in 1 of 21 patients treated with 3% gel. Further studies are needed to determine the maximum gel concentration that is well tolerated by patients.
In a placebo-controlled clinical trial, cidofovir gel applied once daily for 5 days showed significant virological and clinical effects in patients with acyclovir-resistant genital herpes associated with HIV infection (67). Complete resolution of clinical symptoms was observed in 27% of patients receiving cidofovir 0.3%, 33% receiving cidofovir 1%, and 0% of patients receiving placebo. The median reduction in lesion area was 58% in patients treated with cidofovir, compared with 0% in the control group. Unfortunately, the small number of patients participating in this study does not allow us to assess the statistical significance of the results obtained.
In a clinical study in bone marrow transplant patients, cidofovir was effective against genital herpes caused by viral strains resistant to acyclovir and foscarnet (61).
There is experience with the use of tifluridine ophthalmic solution for the treatment of genital herpes caused by acyclovir-resistant strains (). Tifluridine is a pyrimidine nucleoside analog that, like cidophyr, acts independently of viral thymidine kinase. High toxicity does not allow taking the drug orally. Small clinical trials have shown a beneficial effect of tifluridine in acyclovir-resistant genital herpes in patients with HIV infection (68). In infections caused by acyclovir- or acyclovir/foscarnet-resistant herpes simplex viruses, tifluridine exhibited a synergistic effect with interferon-a (69). However, further study in large controlled studies is necessary to determine the therapeutic value of tifluridine for genital herpes.
Several studies examining the effectiveness of topical interferon formulations for the treatment of genital herpes have reported conflicting results. Local application of interferon α-2a 6 times a day. in the form of an aqueous solution was found to be ineffective for the treatment of herpes genital lesions (70). In contrast, a placebo-controlled study that included 387 patients showed the effectiveness of interferon α-2a gel when used 4 times a day. within 4 days if genital herpes recurs (71). In patients of both sexes, the period of virus shedding decreased; in addition, in men there was a significant decrease in pain, itching and crust formation time. A study of 25 patients showed a beneficial effect of interferon-β (72).
In Germany and Canada, edoxudin, an analogue of deoxythymidine that exhibits pronounced antiherpes activity in vitro,
and
in vivo
(73, 74). The mechanism of action of the drug is similar to acyclovir. When applied topically, it is better absorbed than polyethylene glycol-based acyclovir ointment. In a multicenter, placebo-controlled study, edoxudine 3% cream applied for 5 days significantly reduced viral shedding in patients of both sexes (75). Women also experienced a decrease in pain and adenopathy in the groin area.
A dosage form of acyclovir with controlled release of the active substance has been developed (76). Its advantage is the extension of the half-life of acyclovir. Clinical trials conducted in Europe indicate that long-acting acyclovir is equally effective as short-acting acyclovir. It has been suggested that the use of a drug with an extended half-life may lead to a reduction in relapse rates during suppressive therapy, but this requires further study.
Experiments on guinea pigs and a clinical study showed the beneficial effect of resiquimod, an immune response modifier from the group of imidazoquinolines (77, 78). In patients with genital herpes, when local treatment was started within 24 hours after the onset of symptoms, an increase in the time until relapse occurred. In 52 immunocompetent patients with a history of at least 6 relapses per year, the median time to first relapse was 169 days with resiquimod and 57 days with placebo (79). The drug is currently undergoing phase III clinical trials.
Despite advances in the treatment of genital herpes over the past few years, the epidemic of the disease continues to spread throughout the world. The main drugs used to treat infection are nucleoside analogues. The emergence of generic acyclovir drugs has significantly reduced the cost of treatment. New drugs in this group - the prodrugs valacyclovir and famciclovir - have better pharmacokinetic properties compared to acyclovir, which can improve patient compliance with the treatment regimen. When treating the first episode of genital herpes, the drugs show comparable clinical efficacy.
There have been no head-to-head comparative studies between the three nucleoside analogues in the episodic treatment of recurrent genital herpes. Apparently, the selection of an antiviral agent should be individual. To determine the patient's preferences, all three drugs should be tried (not simultaneously).
Episodic treatment is not suitable for all patients. Due to good efficacy and safety, suppressive therapy is now becoming increasingly widespread. It has been suggested that suppressive therapy, by reducing asymptomatic viral shedding, can stop the spread of infection, but this has not been proven to date. Acyclovir has been successfully used for suppressive therapy. It is not inferior in effectiveness to valacyclovir. Once daily dosing of valaciclovir is convenient for patients with a low relapse rate. Comparative studies of acyclovir and famciclovir have not been conducted.
Relapses of the disease can also develop during suppressive therapy, which is associated with the short half-life of antiviral drugs. If suppressive therapy is discontinued, the risk of infection transmission may increase. This issue needs to be studied in dedicated clinical studies. Until the results of these studies are available, suppressive therapy should be discontinued carefully, with the patient counseled about the safety of sexual behavior.
Chronic recurrent herpes (herpes chronicus recidivans)
Complex treatment is carried out: at different stages of the disease, etiotropic and pathogenetic treatment is used, which, on the one hand, is aimed at suppressing the pathogen, and on the other, at increasing the body’s immune reactivity.
When choosing treatment, the stage of the disease should be taken into account: in case of relapse, it is recommended to prescribe antiviral chemotherapy drugs - interferon and its inducers, deoxyribonuclease, levamisole, etc. During the period of remission of chronic recurrent herpes, immunomodulators, pyrogenal, and herpetic vaccine are used.
Antiviral chemotherapy drugs are prescribed in the first hours and days after the appearance of the rash. The use of acyclovir 0.2 g 5 times a day for 5 days for relapses of chronic herpes reduces the duration of exacerbation of the disease and reduces pain in the affected areas.
Bonafton is also prescribed orally at 150 mg per day for 5-7 days. At the same time, you can use 0.5% bonaftone ointment.
You can also use other antiviral drugs: alpizarin, riodoxol, helepin, tebrofen, florenal, megosin, metisazone.
Interferon and its inducers (gossypol, megasyn) are used for relapses of chronic herpes infection. Their action is most effective in the prodromal period and when the first signs of relapse appear. Dibazole, which is prescribed 0.01 g 2 times a day for a month, has a good interferonogenic effect.
Antiviral ointments are used locally from the first days of relapse, leukocyte interferon, a solution of which is applied in the form of applications to the affected area 5-6 times a day.
Laser therapy (helium-neon, infrared lasers) is effective.
Large doses of ascorbic acid are usually prescribed internally.
Deoxyribonuclease (DNase) has a slightly less therapeutic effect, which is administered intramuscularly at 10-25 mg, after dissolving the powder in distilled water or isotonic sodium chloride solution. Injections are given every other day; for a course of 6-10 injections.
For disorders of the immune system, courses of immunocorrective therapy are effective. Taktivin is administered 50 mcg subcutaneously every other day, for a course of 5-8 injections. A similar drug, timoptin, is administered subcutaneously at a dose of 100 mcg, per course of 4-5 injections with intervals between injections of 4 days.
Levamisole (Decaris) has a beneficial effect on the course of recurrent forms of herpes simplex, reducing the duration of relapses, lengthening periods of remission and reducing the pain of rashes. The drug is prescribed at a dose of 50-150 mg in the first 3 days of each week with breaks between courses of 5-6 days; only 2-4 courses.
In order to prevent exacerbations of frequently recurrent forms of herpes, patients for whom previous treatment has proven ineffective are prescribed a herpetic vaccine. The drug is administered intradermally during the period between relapses, 0.3 ml in the area of the flexor surface of one of the forearms. The first 5 injections are given at intervals of 3-4 days, the next five - after a two-week break (once every 5-7 days). This is the main course of treatment, which consists of 10 injections. After its completion, after 3-6 months, 1-2 revaccination cycles are carried out, each of which consists of 5 injections (the interval between injections is 7-14 days). The interval between treatment cycles is 6-8 months. Over the next 2 years, 1 cycle of revaccination is carried out (5 injections every 8-12 months). At the injection site, after 18-24 hours, a local reaction develops in the form of erythema with a diameter of 2-5 cm with a papule in the center, accompanied by a burning sensation. During vaccination, an exacerbation of recurrent herpes is possible. In this case, take a break in treatment for 2-3 days. Contraindications to vaccine treatment are damage to parenchymal organs, diabetes mellitus, stage II-III hypertension, acute infections and allergic diseases, heart disease in the stage of decompensation, and pregnancy.
During the inter-relapse period, gammaglobulin is administered intramuscularly - 3 ml per day with an interval of 3-4 days, for a course of 6 injections; the interval between courses is 2 months.
A thorough examination of patients with recurrent herpes is necessary to identify and eliminate foci of chronic infection in the body, including in the oral cavity (periodontitis, periodontitis, tonsillitis, sinusitis, etc.). Eliminate local factors that contribute to relapses (chronic injury, dry lips, chronic lip cracks).
