Don't overlook the herpes simplex virus that "lurks.")

Herpes simplex virus (HSV), named after vesicular dermatitis (i.e., herpes simplex) that occurs in the acute phase of infection. Common clinical manifestations of HSV infection are mucosal or cutaneous localized herpes. Its infected population is extremely common, and after the initial infection, it turns into a latent infection in neurons, which can cause recurrence after external stimulation.

01

Stealth transmission is becoming more and more serious

HSV can be divided into HSV-1 and HSV-2 according to antigenicity.

HSV-1 is transmitted primarily through oral-oral contact, which can cause cold sores. This type of viral infection usually occurs in childhood and can also be sexually transmitted. Cold sores can recur and, rarely, may lead to more serious complications such as encephalitis or keratitis.

HSV-2 is primarily sexually transmitted infection and is one of the most common sexually transmitted diseases. It predominantly presents with genital herpes, including genital or blisters, ulcers, and pain. Symptoms of new genital herpes infection usually include fever, systemic soreness, and lymphadenopathy. Most genital herpes recur on a regular or irregular basis, having a significant impact on the quality of life of patients.

In the initial infection of HSV, about 80% of infected people have no obvious clinical symptoms or symptoms are not recognized, which is an important factor in the prevalence of HSV infection.

Many people infected with HSV have mild or unrecognizable symptoms, but experience intermittent viral shedding in the anogenital region. As a result, most genital herpes is transmitted through unsuspecting HSV-infected people. HSV-1 and HSV-2 have been shown to co-infect the same anatomical site.

Due to the privacy and concealment of HSV infection, and the large number of hidden infected people, it brings great challenges to the realization of the goal of blocking infection in the whole society.

02

The harm has long been underestimated

According to the World Health Organization, 20 million new HSV genital herpes infections are added worldwide each year. The huge patient population base and high recurrence rate not only bring long-term mental and physical distress to patients themselves, but also bring huge burdens and harms to society.

According to the World Health Organization, in 2012, 3.709 billion people aged 0 to 49 years worldwide caused cold sores due to HSV-1 infection, accounting for about 67% of the global population, and its prevalence increases with age. Another 2016 statistical analysis found that 13.2% of the world's population (about 490 million people) had genital herpes due to HSV-2 infection. In sub-Saharan Africa and Latin America, many populations have seroprevalence rates of more than 90 percent. In many areas, the rate of HSV infection among people over the age of 50 is close to 100%.

The recurrence rate of HSV-2 genital herpes is significantly higher than that of HSV-1, which is about 6 times that of HSV-1. The results of a long-term follow-up study in the United States showed that 89% of patients with HSV-2 infection had at least 1 recurrence during the follow-up period after a symptomatic first infection, 38% had at least 6 recurrences in the first year, and 20% had more than 10 recurrences. Patients with severe primary HSV-2 infection (lasting more than 35 days) had a recurrence rate of almost 2 times that of the former, and the time of first recurrence was shorter, compared to patients with a shorter onset. Another study suggests that patients may experience an average of 5 clinical episodes per year in the first 2 years after the first episode in patients with HSV infection, after which the frequency of seizures may decrease.

People infected with HSV face the dilemma of repeated episodes of genital herpes. This not only brings long-term mental and physical distress to the patients themselves, but also greatly increases the burden of medical resources and brings a series of social problems. In addition, women who carry the virus may also transmit the virus to newborns during childbirth, causing damage to the newborn's nervous system and even endangering their lives.

There is already evidence that HSV increases the susceptibility and infectivity of HIV (human immunodeficiency virus), which increases the risk of acquiring new HIV infections by about 3 times, and people with both HIV and HSV infections are more likely to transmit HIV to others. HSV infection in people living with HIV and other immunocompromised people tends to be clinically severe and relapse frequently. Herpes occurs most often in the intercostal and trigeminal nerve areas, with severe pain, ulceration, or hemorrhagic necrosis. In advanced HIV infection, HSV can lead to more serious complications such as hemorrhagic necrotizing encephalitis, esophagitis, hepatitis, pneumonia, retinal necrosis, or disseminated infection.

03

Prevention and treatment deserve attention

The World Health Organization has called for the prevention and treatment of HSV to be given priority. At present, the HSV vaccine is still in the early stage of research and development, and the demand for antiviral drug treatment is huge and urgent.

At present, in addition to some supportive treatments, the main clinical use of nucleoside (acid) anti-HSV drugs such as acyclovir and valacyclovir is used to control symptoms and recurrence. The adverse reactions of such drugs are large, and the cross-resistance is increasing year by year. For HSV-infected patients, the use of antiviral drugs only suppresses the virus, not complete clearance, and the disease may recur because of the lifelong carrying of the virus. Long-term medication is more risky and prone to cross-resistance. Once drug resistance develops, it may face the situation of no drug available.

The research and development and marketing of new anti-HSV drugs have become an urgent need for clinical and patients. The new target HSV-helicase-primer enzyme inhibitor drugs first entered the clinic. The mechanism of action of these drugs is to prevent the virus from synthesizing from scratch by inhibiting the HSV helicase-primerase complex. It does not need to be activated by viral thymidine kinase in HSV-infected cells and, therefore, also has a protective effect on uninfected cells.

Nucleosides need to be taken multiple times a day, so adherence and effectiveness may be reduced. In contrast, the half-life of the new mechanism anti-HSV drug is as long as 80 hours, which can be taken once a day, which can effectively improve patient medication compliance. It is worth expecting that two drugs, preirivir and HN0037 independently developed by the mainland, have entered the clinical stage.

According to the statistics of clinical trial registration information of drug registration at home and abroad, no new drugs in the field of anti-HSV have been successfully listed in the past 20 years. HSV-infected patients also struggle with recurrent disease attacks, single options for treatment, multiple adverse reactions, and increasing viral resistance year by year. It is expected that more new mechanisms, safe and effective anti-HSV drugs and HSV vaccines will be successfully developed as soon as possible to benefit a wider range of people and society.

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Author: Jiang Rongmeng and Li Xingwang, Beijing Ditan Hospital affiliated to Capital Medical University

Planner: Fang Tong

Editor: Hu Bin