What is the long-term effectiveness of medical and surgical therapies for gastroesophageal reflux disease (GERD)? A study explores the outcomes of different treatment approaches and provides valuable insights for managing GERD in the long term.

The Significance of GERD and Long-Term Treatment Strategies

Gastroesophageal reflux disease (GERD) is a prevalent condition, affecting approximately 10-20% of the American population. It is characterized by the repeated or prolonged exposure of the esophageal lining to acidic stomach contents, leading to symptoms and potential complications. Effective long-term management of GERD is crucial, as untreated or improperly treated GERD can result in serious complications.

The current medical treatment options for GERD include the use of proton pump inhibitors (PPIs) to limit acid secretion in the stomach, as well as surgical interventions aimed at increasing the pressure in the lower esophageal sphincter and preventing reflux. Both therapies have demonstrated effectiveness in controlling GERD symptoms, but the long-term outcomes of these approaches have been a subject of investigation.

Exploring the Long-Term Outcomes: A Comprehensive Study

A study by Spechler et al., published in JAMA, aimed to determine the long-term outcomes of medical and surgical therapies for GERD. The study initially enrolled 247 patients with severe GERD and followed them for 10-13 years. After the follow-up period, 129 individuals (91 in the medical treatment group and 38 in the surgical treatment group) participated in the study.

The researchers used a variety of measurements to assess the long-term outcomes, including quality of life scores, severity of esophageal inflammation (esophagitis), frequency of treatment for esophageal stricture, subsequent anti-reflux surgery, satisfaction with treatment, survival, and the incidence of esophageal cancer.

Comparing the Long-Term Outcomes: Medical vs. Surgical Therapy

The study revealed several key findings:

• 62% of the surgically treated patients still used anti-reflux medications regularly, while 92% of the medically treated patients regularly used medications.
• One week after discontinuation of medication, GRACI symptom scores (a measure of reported symptom type, frequency, and severity) were less in the surgical patients than in the medically treated patients.
• Both treatment groups showed substantially the same degrees of esophagitis severity, frequency of treatment for stricture, and additional anti-reflux surgery.
• Both groups also indicated similar physical and mental quality of life scores, as well as similar levels of satisfaction with treatment.

Insights into Barrett’s Esophagus and Cancer Risk

The study also provided valuable insights regarding the incidence of Barrett’s esophagus, a potentially pre-cancerous condition associated with GERD. Previous reports have estimated an annual incidence of cancer with Barrett’s esophagus of up to 1.9%. However, in the Spechler et al. study, only 0.4% of patients with Barrett’s esophagus developed cancer. Another recent study placed the annual incidence at 0.5%.

These findings suggest that the risk of esophageal cancer in patients with Barrett’s esophagus may be lower than previously thought. This information is crucial for determining the optimal course of treatment and monitoring strategies for individuals with GERD and Barrett’s esophagus.

Implications for Long-Term GERD Management

The study’s findings have important implications for the long-term management of GERD. While surgery for GERD has been commonly advised as a means to provide long-term benefits and eliminate the need for medications, the study suggests that this approach should be considered carefully. Anti-reflux surgery itself carries the risk of complications that are not present in patients using medications.

Furthermore, the study indicates that both medical and surgical treatments for GERD have similar long-term outcomes in terms of symptom control, esophageal inflammation, and quality of life. This suggests that a comprehensive approach, involving a combination of medical management and regular monitoring, may be a viable and effective strategy for the long-term treatment of GERD.

Individualized Approach to GERD Management

The study highlights the importance of an individualized approach to GERD management. Factors such as the severity of the condition, the presence of Barrett’s esophagus, and the patient’s preferences and overall health status should be carefully considered when deciding on the most appropriate long-term treatment strategy.

Regular evaluation by a healthcare provider is recommended to determine the optimal course of treatment and to monitor for potential complications. This approach can help ensure that individuals with GERD receive the most effective and tailored care to manage their condition in the long term.

Conclusion

The comprehensive study by Spechler et al. provides valuable insights into the long-term management of gastroesophageal reflux disease (GERD). The findings suggest that both medical and surgical therapies have similar long-term outcomes, and that a comprehensive, individualized approach to GERD management, involving a combination of medical treatment and regular monitoring, may be the most effective strategy for ensuring long-term disease control and prevention of complications.

Long Term Treatments – About GERD

Study Looks at Long-term Effectiveness of GERD Treatments

Gastroesophageal reflux disease (GERD) is a common disorder. About 10% to 20% of Americans have frequent heartburn, the most common symptom of GERD. The disease is characterized by symptoms and/or tissue damage that results from repeated or prolonged exposure of the lining of the esophagus to acidic contents from the stomach. This occurs when acidic stomach contents flow backward (reflux) into the esophagus. If untreated or treated incorrectly it can lead to complications. Current medical treatment includes the use of medications, such as proton pump inhibitors (PPIs) that work by limiting acid secretion in the stomach, and surgery where the goal is to increase pressure in the lower esophageal sphincter and prevent reflux.

Both anti-reflux therapies have been shown to be effective in controlling GERD symptoms. But what is the long-term effectiveness of either of these therapies in preventing complications from GERD? That question was explored in a study by Spechler et al, reported in JAMA, with the stated aim to determine the long-term outcome of medical and surgical therapies for GERD[1].

Initially, 247 patients with severe GERD were enrolled in the prospective randomized study. After 10-13 years, 239 participants were found and a total of 129 individuals (91 in the medical treatment group and 38 in the surgical treatment group) participated in the follow-up. The study used a variety of measurements to determine outcomes. These included quality of life scores, severity of esophageal inflammation (esophagitis), frequency of treatment for stricture (an abnormal narrowing of the esophagus), subsequent anti-reflux surgery, satisfaction with treatment, survival, and incidence of esophageal cancer.

The study found that 62% of the surgically treated patients still used anti-reflux medications regularly; 92% of the medically treated patients regularly used medications. One week after discontinuation of medication, GRACI symptom scores (an index used to measure reported symptom type, frequency, and severity using a daily diary) were less in the surgical patients than in the medically treated patients. However, both treatment groups showed substantially the same degrees of esophagitis severity, and frequency of treatment for stricture or for additional anti-reflux surgery. Both groups also indicated substantially the same physical and mental quality of life scores as measured on a standardized survey (SF-36), as well as substantially the same level of satisfaction with treatment.

Measuring Quality of Life

The SF-36 is a 36-item instrument for measuring health status and outcomes from the patient’s point of view, designed for use in surveys of general and specific populations, health policy evaluations, and clinical practice and research. The SF-36 measures the following eight health concepts, which are relevant across age, disease, and treatment groups:

• Limitations in physical activities because of health problems
• Limitations in usual role activities because of physical health problems
• Bodily pain
• General health perceptions
• Vitality (energy and fatigue)
• Limitations in social activities because of physical or emotional problems
• Limitations in usual role activities because of emotional problems
• Mental health (psychological distress and well-being)

The survey’s standardized scoring system yields a profile of eight health scores and a self-evaluated change in health status.

(Source: Medical Outcomes Trust)

New Findings Regarding Barrett’s Esophagus

One possible complication that occurs in about 10% of those with GERD is a condition called Barrett’s esophagus. This condition involves a change in the tissue lining the esophagus associated with repeated or prolonged exposure to reflux. It causes concern because it is considered a potentially pre-cancerous condition, although the incidence is quite low. Previous reports have estimated an annual incidence of cancer with Barrett’s esophagus of up to 1.9%. However, in the Spechler, et al. study only 0.4% with Barrett’s esophagus developed cancer and another recent study placed the annual incidence at 0.5%. [Note: In the absence of Barrett’s esophagus there is no strong evidence that GERD is a risk factor for developing cancer. Periodic evaluation by a physician is recommended for individuals to determine if their current course of treatment for GERD is optimal.]

Conclusions

Surgery for GERD is often advised as a means to provide a long-term benefit and eliminate the need for medications. However, anti-reflux surgery itself introduces risks of complications that are not introduced in patients using medications. Furthermore, the study suggests that surgery should not be advised based on the expectation that medications will no longer be needed. Reflux symptoms may persist even after surgery and regular use of anti-reflux medications continue. Moreover, surgery should not be advised based on the expectation that it is a cancer-preventing procedure. The risk of cancer associated with severe GERD and Barrett’s esophagus appears to be lower than previously thought and this must be evaluated in proportion to the risks associated with the surgical procedure itself. Those who are satisfied with PPI therapy should be advised to continue the treatment. Surgery might best be reserved for individuals with unique circumstances, such as those intolerant or unresponsive to PPIs or other medical treatments.

[1] Spechler SJ, Lee E, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA. 2001 May 9;285(18):2331-8.

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Why You Shouldn’t Delay Care for Chronic Acid Reflux.

Millions of people across the country experience heartburn, a burning sensation that starts in the chest and radiates up the throat. And while many people deal with the uncomfortable symptom with an over-the-counter antacid, it’s not something that should be ignored long-term. 

It’s normal for the stomach to produce acid that aids in digestion. But if the esophageal sphincter (or valve) that is designed to prevent this stomach acid from splashing back up through the esophagus is weakened or too relaxed, it can cause acid reflux. Also known as gastroesophageal reflux disease (GERD), this condition is common and harmless for many people. However, it can lead to more serious problems if it’s ignored, including cancer in the esophagus. That’s why it’s important to alert your primary care provider if you have frequent heartburn—or any other symptom.  

Not everyone with GERD has symptoms.

Nearly half of all patients with GERD don’t have any symptoms, which means it’s possible to have abnormal reflux and not even know it. Those that do have GERD symptoms most frequently report heartburn and a bitter taste in their mouth. These signs may worsen when you’re laying down or after eating certain foods, like those high in fat, caffeine, or tomato-based ingredients.

There are other more vague and less common symptoms, including:

• Cough
• Phlegm in the throat
• Trouble swallowing
• Chest pain

Many people don’t bother mentioning heartburn to their doctor at regular check-ups, but over-the-counter medications only mask the underlying cause. 

Even if medication relieves your heartburn, you should still get evaluated by a gastroenterologist.

Once you have reflux, it tends to be chronic, or repeated throughout your lifetime. There are several medications available for relieving mild, moderate, and severe heartburn, but these don’t necessarily fix the problem. Tums, for example, help to eliminate discomfort caused by GERD by making the acid less irritating. Similarly, Pepcid AC decreases the amount of acid your stomach makes which means there’s less acid to splash up. Many people think that if their symptoms are gone, then the reflux is too. While both of these medications may effectively help to manage symptoms, neither of them address the root cause. 

GERD occurs because of an abnormality in the esophageal sphincter, or muscles between the esophagus and the stomach. If this valve relaxes too much, too frequently, or is weakened for some reason, acid will continue to backflow which can cause serious inflammation in the esophagus. In adults over the age of 40, this can lead to a precancerous condition called Barrett’s esophagus. If left unmonitored and untreated, this can lead to esophageal cancer.

Acid reflux, or #GERD, can lead to esophageal cancer, left untreated. On the #MedStarHealthBlog, our GI experts explain how you can treat it and minimize your cancer risk: https://bit.ly/3ybdjot.

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That’s why it’s important to let your doctor know about any frequent or recurring signs of GERD, even if your symptoms are managed. Your doctor may refer you to a gastroenterologist who can perform diagnostic tests and procedures to evaluate the severity of your condition and regularly monitor any changes to your esophagus.

Diagnostic tests allow your doctor to monitor for signs of long-term damage.

If you suspect you have acid reflux, your doctor may recommend conservative treatment options first to manage your symptoms. Mild symptoms may respond well to dietary modifications, like limiting foods that cause the esophagus sphincter to relax. They may also recommend avoiding eating before bed and elevating your head while you sleep, which can decrease symptoms. 

For immediate and short-term relief, medications can help manage symptoms. If your symptoms respond well to antacids, we can presume you have acid reflux. But to definitively diagnose the condition, a gastroenterologist may perform endoscopy and/or pH tests. 

Endoscopy is a procedure that is done while you’re sedated or asleep. It allows a doctor to evaluate the esophagus using an endoscope, a long, thin tube attached to a camera. The endoscope is gently placed in the esophagus through the mouth, allowing your gastroenterologist to check for signs of inflammation or damage that could lead to cancer.

If we don’t see anything suspicious, we move to pH testing, which measures whether stomach acid is moving from the stomach to the esophagus. There are two different types:

• The wireless Bravo capsule is a small capsule with a sensor the size of coin that measures pH data in the esophagus over two to three days. It’s inserted into the bottom part of the esophagus lining during an endoscopy, for which you’re sedated. It stays there for up to 96 hours as you return home, sending pH data to a small receiver recorder worn around your waist. It’s painless and gathers real-time data about your reflux before falling off on its own and passing through a bowel movement.
• Alternatively, a pH impedance catheter is lined with sensors and carefully inserted through the nose into the esophagus. It remains there for 24 hours, gathering information about the presence of any acid throughout the entire esophagus.

An accurate diagnosis is important for confirming that GERD is what’s causing your symptoms. For patients with severe symptoms or those who cannot or do not want to take medications, surgery may be the best treatment option. You’d only want to undergo surgery if you know definitively that it will address the cause of your problems.

Surgery is the only way to address the root cause of GERD.

If you have chronic acid reflux, surgery is an effective option for fixing the underlying cause. You may want to consider surgery, especially if:

• You don’t want to be on antacid medications
• You are allergic to antacid medications
• Your symptoms aren’t responding to antacid medications
• Your reflux is causing other health complications

The esophageal sphincter is meant to prevent acid from washing up the esophagus. If you have GERD, then we need to treat the source of the issue. Studies show that surgery is more than 90 percent successful in eliminating GERD long-term. 

There are two minimally invasive procedures that we can perform through small incisions:

• Laparoscopic Nissen fundoplication is considered the “gold standard” approach. It involves taking the top of the stomach and wrapping it behind and around the esophagus.
• Laparoscopic magnetic sphincter augmentation (LINX) tightens the lower esophageal sphincter opening using linked titanium beads with magnetic centers.

Depending on your procedure, surgery may take one to three hours. Some patients can go home on the same day, while others stay in the hospital one night. You may experience some soreness briefly following surgery but this should disappear about 48 hours later. In addition, you’ll need to modify your diet to allow the esophagus to heal. Most patients will follow a liquid diet for two weeks to allow swelling to go down. 

After two weeks, we’ll discuss your next steps at a follow-up visit. By this point, you’ll know if you’re “fixed.” In fact, many patients report the first night after surgery as one of their most restful ones since having the condition because symptoms disappeared. Many patients can resume normal eating at this point, although you’ll want to take small bites, chew thoroughly, and eat slowly as your body adjusts.

Watch our Facebook live interview below with doctors Patrick Jackson, MD, John Carroll, MD, and Angelica Nocerino, MD to learn more about acid reflux:

If you have acid reflux, it’s not your fault. But we need to treat it so it doesn’t become something worse.

For 90 percent of people with reflux, it’s a nuisance but not a health risk. However, for a small portion of the population over 40, it can lead to cancer. And, your risk of esophageal cancer isn’t necessarily tied to the severity or frequency of your symptoms. You can’t prevent GERD or the related complications, but you can seek help. 

A gastroenterologist can help to identify and/or monitor any signs of Barrett’s esophagus in your 40’s before it leads to cancer in your 60’s or 70’s. They’ll also recommend the right treatment approach for you, considering your age, health, and symptoms. At MedStar Health, our team of experts work together through a multidisciplinary approach. This means doctors with training in different areas meet regularly to discuss your best treatment options. Then, one doctor presents our collective recommendation in one appointment so you don’t have to see eight different specialists. 

Our gastroenterologists specialize in treating GERD and other conditions affecting the esophagus. We also have access to the latest technology, which allows us to accurately identify the cause of your issue and treat it with the least invasive, most effective approach. All of this care is delivered with you and your needs at the center, with compassion and empathy from your entire care team.

Don’t ignore your heartburn. We can help to get rid of it and ensure it doesn’t lead to something worse.

Do you have chronic acid reflux?

We can help. Meet with a MedStar Health gastroenterologist today.

Request an Appointment

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Valaciclovir for herpes: indications and nuances of use

Valaciclovir for herpes: indications and nuances of use

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• Valaciclovir for herpes: indications and nuances of use

Most people are infected with herpes simplex viruses (HSV), but not everyone has clinical manifestations. In some cases, an acute “cold on the lips” or an episode of genital herpes occur immediately after infection, and then the infection does not manifest itself for many years. However, about 20% of those infected have a recurrent form of herpes with periodic exacerbations that reduce the quality of life and lead to complications. This variant of the disease requires specific treatment.

When to use suppressive therapy for herpesvirus infections

Treatment of recurrent herpes involves 2 approaches: episodic systemic therapy with antiviral agents or suppressive (preventive) therapy. In the first variant, drugs are prescribed only during an exacerbation. To obtain the fastest possible effect, treatment is started in the period of precursors or within 24 hours from the onset of characteristic symptoms. If therapy is started later, it will not be effective enough, the patient will have to suffer from unpleasant symptoms for a long time.

The second approach is suppressive treatment with specific antiviral drugs. Therapy is prescribed for a long time (on average 6-12 months) to suppress the reproduction of the pathogen, reduce the frequency and severity of exacerbations. Its efficiency is about 80%. In addition, a properly selected course of medication reduces the likelihood of infection of a sexual partner with genital herpes.

Suppressive therapy is prescribed for infections caused by HSV: herpes labialis (rash around the mouth) and genital herpes (rash on the genitals). Indications for its use:

● more than 6 relapses of herpes during the year;

● prolonged and severe exacerbations that reduce the patient’s quality of life;

● treatment of women of reproductive age after the first episode of HSV;

● pronounced psycho-emotional reactions to the disease;

● the need to reduce the risk of virus transmission (eg for healthcare workers).

Characteristics of Valaciclovir and other drugs for suppressive therapy

The most common preventive treatment for recurrent herpes is Valaciclovir. It is a derivative of Acyclovir, the first specific anti-HSV drug. Valaciclovir has several advantages over its predecessor:

● new chemical formula increases drug bioavailability by 3-5 times;

● convenient for the patient mode of taking the drug only 1 time per day;

● the clinical effect of oral forms corresponds to that of the injection of Acyclovir;

● increased efficacy in the treatment of recurrent miscarriage in patients with genital herpes;

● more pronounced therapeutic effect in patients with HSV and concomitant HIV infection.

Famciclovir is also used for suppressive therapy. Its efficacy and safety are comparable to those of Valaciclovir, but the need to take the drug twice a day reduces patient adherence to treatment.

Vaccination Vitagerpavak is an effective treatment for herpes

An alternative treatment for recurrent herpetic infections is the Vitagerpavak vaccine, which is effective against HSV types 1 and 2. It stimulates the mechanisms of cellular immunity and prevents exacerbations of the disease. To obtain a stable therapeutic effect, a course of 5 injections of the drug at intervals of 7 days or 10 days (with a complicated form of herpes) is required. After 6 months, the vaccination course is repeated.

The Vitagerpavak vaccine is used only in the remission period after 5 or more days after the complete disappearance of the symptoms of herpes recurrence. For its successful use, the patient must have a relapse-free interval of about 1.5 months.

If a patient has more than 10 exacerbations of infection per year with short intervals between them, immunization is difficult. In such situations, combination therapy is recommended. First, suppressive treatment with Valaciclovir is prescribed, and after achieving a long-term remission, Vitagerpavak is used.

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Genital Herpes Treatment Guidelines uMEDp

Genital herpes is a sexually transmitted disease characterized by recurrent lesions of the genital organs. The causative agents are herpes simplex viruses, predominantly type II, although the etiological role of type I virus has increased significantly over the past two decades.

Table. Doses of drugs for the treatment of genital herpes

Despite the severe clinical manifestations of the 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 infected with the virus cannot be determined, but it is assumed that, for example, in the United States, every fourth to sixth inhabitant of the virus is a carrier (3-4).

The main means 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 world 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, it turns 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 develop 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 a short half-life from tissues (0.7 h) and blood plasma (2.7 h) (5). To maintain therapeutic concentrations in the body, the drug must be taken up to 5 times a day, which negatively affects the accuracy of the treatment regimen by patients and may lead to a decrease in the effectiveness of therapy.

The pharmacokinetic shortcomings of acyclovir were largely overcome in the development of valaciclovir, a prodrug metabolized in the intestinal wall and liver to form acyclovir. Valaciclovir has a significantly higher oral bioavailability (54%) and provides higher and longer serum concentrations of acyclovir (6-8), which allows it to be taken twice a day. With repeated oral administration of valaciclovir 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 that 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 does not differ significantly from that of acyclovir. Better absorption results in fewer gastrointestinal adverse reactions (5). Thrombotic microangiopathy has been described in patients with AIDS and other immune disorders when using valaciclovir in high doses (8 g/day), but the causal relationship between the drug and this complication has not been conclusively confirmed (12). In patients receiving high doses of valaciclovir after kidney transplantation, thrombotic microangiopathy was not observed (13). In addition, for the treatment of genital herpes, the drug is used in much lower doses.

The third analogue of nucleosides, famciclovir, like valaciclovir, is a prodrug that is converted in the intestinal wall and in the liver into penciclovir. Penciclovir has a similar mechanism and spectrum of antiviral action to acyclovir, however, due to low bioavailability, it can only be used topically (5). With oral famciclovir, the bioavailability of penciclovir is 77% (14). Compared to acyclovir, penciclovir has a significantly longer half-life from tissues (10-20 hours) (15). Intracellular concentrations of penciclovir triphosphate exceed those of acyclovir triphosphate by about 30 times (16). However, herpes simplex virus DNA polymerase has a greater affinity for acyclovir triphosphate than for penciclovir triphosphate. Thus, the differences in mechanism of action between penciclovir and aciclovir are predominantly quantitative and tend to balance each other out (16).

Acyclovir and penciclovir do not differ in their activity against herpes simplex virus in cell culture, however, after acyclovir is discontinued, virus replication resumes much faster than after penciclovir is discontinued (13). Famciclovir is superior to valaciclovir in its ability to eliminate “competent latency”, i.e., the state in which the virus is able to reactivate and cause relapses of the disease (18, 19). In an observational study, patients treated with famciclovir (250 mg 3 times/day for 5 days) had fewer relapses within 1-6 months after the first episode than patients treated with acyclovir (200 mg 5 times/day for 5 days) (20).

Famciclovir has an excellent safety profile. A tolerability analysis based on the results of 13 clinical studies showed that the adverse reaction profile of famciclovir in patients with genital herpes (791 patients) did not differ from placebo (21). In studies on healthy male volunteers, no clinically significant pharmacokinetic interactions of famciclovir with allopurinol, digoxin, cimetidine, zidovudine, or theophylline have been identified (22). The bioavailability of penciclovir, which is formed during the metabolism of famciclovir, does not depend on food intake (23). Its pharmacokinetics do not differ between young and old people (24). When taken for 4–12 months in healthy male volunteers, the drug did not adversely affect sperm (25).

Aciclovir, valaciclovir and famciclovir show comparable clinical efficacy in reducing the duration and severity of genital herpes episodes and reducing virus shedding (26-28). However, they have no effect on dormant viruses.

Treatment first episode genital herpes

The first episode of primary genital herpes is considered 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. As a rule, in addition to local lesions that persist for 2-3 weeks, systemic symptoms and regional adenopathy are observed. A small number of patients, more often immunocompromised, develop viral meningitis.

Symptomatic therapy of the first episode consists in the appointment of analgesics. Opioid drugs should be avoided as they cause constipation. Nucleoside analogues are used for etiotropic treatment.

Efficacy of oral acyclovir at a dose of 200 mg 5 times / day.
within 5-10 days is indicated in double-blind, placebo-controlled clinical trials (29, 30). In patients treated with acyclovir, the virus shedding period, crusting time, and healing time were significantly shortened. An increase in 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 (8%) were significantly more common with the high dose 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). Adding 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).

Valaciclovir at a dose of 1 g 2 times / day. shows equal efficacy with acyclovir at a dose of 200 mg 5 times / day. in the first episode of genital herpes in immunocompetent patients (33). The tolerability of valacyclovir is similar to that of acyclovir (33). In different countries, valaciclovir is approved for the treatment of the first episode of genital herpes at a dose of 500 mg or 1 g 2 times a day. within 10 days (25).

Famciclovir has been studied in comparative clinical trials with acyclovir (200 mg 5 times a day) at doses of 125, 250 and 500 mg 3 times a day (27, 28). None of the studies showed significant differences between the comparison groups. For the treatment of genital herpes, famciclovir is recommended to prescribe 250 mg 3 times / day. within 5 days, with severe infection – 10 days (25).

Episodic treatment relapses genital virus

In clinical studies, with the use of acyclovir at a standard daily dose (200 mg 5 times / day) for the episodic treatment of recurrences of genital herpes, a shortening of the period of virus shedding, crusting time and healing time was noted. The duration of symptoms and the time of occurrence of new relapses did not change under the influence of the drug (28, 34). The guidelines for the management of genital herpes, issued in 1998. The US Centers for Disease Control and Prevention (CDC) suggested the use of acyclovir in doses of 400 mg 3 times / day. or 800 mg 2 times / day. within 5 days. However, these treatment regimens have not been studied in adequate clinical trials.

When applied topically in the form of a 5% polyethylene glycol ointment, acyclovir resulted in 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 / day. for 5 days, administered on the first day after the onset of symptoms, significantly reduced the period of virus shedding and accelerated the healing of lesions compared with placebo (35). Tolerability of the drug did not differ from that of placebo. One study showed that fewer patients (10%) developed vesiculo-ulcerative lesions with valaciclovir than with placebo (25). The results of another study suggest, based on the natural period of virus shedding, that a 3-day course of treatment with valaciclovir is as effective as a 5-day course (36). In July 2001, the FDA approved a 3-day course of treatment for recurrences of genital herpes with valaciclovir (500 mg 2 times a day). Comparative studies with acyclovir showed equal clinical efficacy of both drugs (37). An important advantage of valaciclovir is a more convenient mode of application.

Famciclovir at doses of 125, 250, and 500 mg twice daily, given within the first 6 hours of symptom onset, resulted in a reduction in healing time, viral shedding, and duration of edema of lesions compared with placebo (38). When it was used, pain, burning, tingling, and soreness on touch were significantly reduced. The side effects of famciclovir did not differ from those of placebo. Famciclovir is recommended for the episodic treatment of recurrences of genital herpes at a dose of 125 mg 2 times a day. within 5 days. The advantages of famciclovir, as well as valaciclovir, are in a more convenient treatment regimen compared to acyclovir.

The effectiveness of episodic treatment of recurrences of genital herpes depends on the time of the start of taking the drugs. A Canadian study showed that when famciclovir was started within the first 6 hours after the onset of prodromal symptoms or the first genital lesions, there was a significant reduction in virus shedding and faster healing of the lesions. Moreover, taking the drug before the onset of virus shedding increased the likelihood of preventing virus shedding during a relapse (39). Relapse treatment should be started as soon as possible, so patients should always have a supply of the drug.

Ongoing suppressive therapy

Patients with frequent (more than 6-8 per year) and severe relapses, psychological trauma or disruption of a normal lifestyle caused by the disease are shown to continue suppressive therapy. For this purpose, acyclovir 400 mg 2 times / day is used for a long time (within 6-12 months); valaciclovir 500 mg 1 time / day. (with the number of relapses 10 or less per year) or 1000 mg 1 time / day. (with the number of relapses more than 10 per year) or famciclovir 250 mg 2 times / day. Daily aciclovir has been shown to reduce relapse rates by 80%, with 25-30% of patients not relapsing (40). Similar results were obtained in studies with valaciclovir and famciclovir. When using famciclovir at 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 valaciclovir at the same dose – in 69% of patients (33). All three drugs have proven to be effective agents for long-term suppressive therapy of recurrent genital herpes. Apparently, the cost of the annual dose and the convenience of the regimen for the patient should be the decisive factors in choosing a particular drug.

Suppressive therapy is well tolerated. It has been shown to be safe 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 kidney function. During the treatment period, 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 (for example, 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, the recurrence rate decreases on average 7 years after the first episode, so lifelong treatment is usually not needed.

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 children with low weight. In rare cases, a congenital infection may develop in the fetus. The highest risk of infection is during the passage of the child through the birth canal. The risk of transmission has been estimated at 50% for primary maternal herpes during delivery 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 infections 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 that pregnant women receive suppressive antiviral therapy. Nucleoside analogues are not officially approved for use during pregnancy, but many studies have shown the safety of acyclovir (46, 47). Valaciclovir and famciclovir, according to the FDA classification, belong to group B, i. e. to drugs for which no teratogenic effect has been detected in experiments on animals, and adequate clinical trials in humans have not been conducted. Studies are currently underway to determine the efficacy and safety of valaciclovir during pregnancy.

Data on the effectiveness of suppressive therapy in preventing infection in the fetus are extremely limited. In a randomized trial including 46 women with a first episode of genital herpes, it was not possible to determine the effectiveness of treatment with acyclovir started on
36 weeks of gestation, as none of the newborns developed an infection. However, in the group of patients receiving suppressive therapy, a significant decrease in the frequency of caesarean section was noted (48). In another placebo-controlled study that included 150 women with a history of genital herpes (49), it has been shown that acyclovir (200 mg 3 times / day), taken from the 38th week of pregnancy, is able to prevent recurrence of the disease. In patients treated with acyclovir, no relapse occurred in any case, while in the control group there were 33 relapses, 21 of them during childbirth.

Treatment of genital herpes , caused by aciclovir – resistant strains

Long-term treatment with nucleoside analogs is generally 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 no correlation was observed between in vitro resistance and the therapeutic efficacy of the drug (25). The most common mechanism for the development of resistance is a gene mutation that leads to impaired thymidine kinase production (50), so aciclovir-resistant strains usually show 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 methods of analysis suggest that decades are needed to change the current model of virus resistance (52).

In immunocompromised patients with long-term use of antiviral drugs, resistance develops in about 5% of cases and can lead to treatment failure (53, 54). Clinically significant resistance has also been described in patients undergoing bone marrow transplantation (55).

Currently, foscarnet is considered as the drug of choice for the treatment of acyclovir-resistant infections caused by herpes simplex virus (56). It belongs to non-competitive inhibitors of viral DNA polymerase. The drug blocks the receptors for binding to viral DNA pyrophosphate and disrupts the elongation of its chain. Unlike acyclovir and penciclovir, it does not require thymidine kinase-mediated phosphorylation and is active against acyclovir-resistant thymidine kinase-deficient strains (56).

Foscarnet has a low oral bioavailability, so it is administered intravenously and topically. The effectiveness of intravenous foscarnet in 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 on the background of HIV infection (57). In another study in patients with HIV infection, foscarnet was superior to vidarabine in terms of the healing time of herpes mucocutaneous lesions caused by acyclovir-resistant strains and the period of cessation of virus shedding (58). When applied topically, the drug did not show sufficient effectiveness (25).

Foscarnet is potentially toxic. Side effects include impaired kidney function, gastrointestinal disturbances, magnesium and calcium metabolism disorders, anemia, genital ulceration, and seizures (59). To prevent serious side effects, treatment should be carried out under close medical supervision, maintain an adequate level of hydration, and avoid the simultaneous administration of pentamidine.

The use of foscarnet limits the intravenous route of administration. It can develop resistance due to mutation of DNA polymerase (60). Clinical strains of herpes simplex virus have been described that are simultaneously resistant to acyclovir and foscarnet (61).

Cidofovir shows pronounced activity against herpes simplex virus in vitro and in vivo (62, 63). It is an acyclic analog of phosphonate and has a wide spectrum of antiviral activity. The drug undergoes phosphorylation under the influence of cellular enzymes into active diphosphate, bypassing the first stage of phosphorylation with the participation of virus enzymes, which is necessary for acyclovir and penciclovir (64). Cidofovir has a low oral bioavailability (less than 5%), which allows it to be used only topically. The advantage is a 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 has been 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 lesions in a number of patients. They were dose-dependent 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 well tolerated by patients.

In a clinical placebo-controlled study, cidofovir gel applied once a day for 5 days showed a pronounced virological and clinical effect in patients with acyclovir-resistant genital herpes on the background of HIV infection (67). Complete resolution of clinical symptoms was observed in 27% of patients treated with cidofovir 0.3%, in 33% of patients treated with cidofovir 1%, and in 0% of patients treated with placebo. The median reduction in the area of ​​damage was 58% in patients treated with cidofovir compared with 0% in the control group. Unfortunately, the small number of patients who participated in this study does not allow us to assess the statistical significance of the results obtained.

In a clinical study in bone marrow transplant recipients, cidofovir was effective in treating genital herpes caused by virus 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 the drug to be taken orally. Small clinical studies 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 showed a synergistic effect with interferon-a (69). However, to determine the therapeutic value of tifluridine in genital herpes, further study is needed in large controlled studies.

Several studies examining the efficacy of topical interferon formulations for the treatment of genital herpes have yielded conflicting results. Local application of interferon α-2a 6 times / day. in the form of an aqueous solution proved to be ineffective for the treatment of herpes genital lesions (70). In a placebo-controlled study that included 387 patients, on the contrary, the effectiveness of interferon α-2a gel was shown when applied 4 times / day. within 4 days in case of recurrence of genital herpes (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 crusting time. In a study including 25 patients, a beneficial effect of interferon ß was shown (72).

In Germany and Canada, edoxudin, an analog of deoxythymidine, has been approved for the treatment of genital herpes, showing pronounced antiherpes activity in vitro and in vivo (73, 74). The mechanism of action of the drug is similar to that of acyclovir. When applied topically, it is better absorbed than polyethylene glycol-based acyclovir ointment. In a multicentre, placebo-controlled study, edoxudin 3% cream applied for 5 days significantly reduced viral shedding in both sexes (75). In women, there was also a decrease in soreness and adenopathy in the inguinal region.

A dosage form of acyclovir with controlled release of the active substance has been developed (76). Its advantage is the prolongation of the half-life of acyclovir. Clinical trials conducted in Europe show 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 decrease in the number of relapses during suppressive therapy, but it requires further study.

In experiments on guinea pigs and in a clinical study, the beneficial effect of resiquimod, an immune response modifier from the imidazoquinoline group, has been shown (77, 78). In patients with genital herpes, when topical treatment was started within a day after the onset of symptoms, there was an increase in the time before a relapse occurred. In 52 immunocompetent patients with a history of at least 6 relapses per year, the median time to the first relapse was 169days 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 for the treatment of infection are nucleoside analogues. The emergence of generic acyclovir preparations has significantly reduced the cost of treatment. New drugs from this group – the prodrugs valaciclovir and famciclovir – have better pharmacokinetic properties compared to acyclovir, which allows to increase the degree of patient compliance with the treatment regimen. In the treatment of the first episode of genital herpes, the drugs show comparable clinical efficacy.

Direct comparative studies between the three nucleoside analogues in the episodic treatment of relapses of genital herpes have not been conducted.