Development of safe novel antiviral agents with increased efficacy, including penetration across the blood-brain barrier, for neonates with HSV infection. Investigation of the potential benefit of combination antiviral therapies for neonates with HSV infection.
Financial support. Potential conflicts of interest. Both authors: No reported conflicts. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. National Center for Biotechnology Information , U.
J Pediatric Infect Dis Soc. Scott H. James , 1 Jeanne S. Sheffield , 2 and David W. Kimberlin 1. Jeanne S. David W. Author information Article notes Copyright and License information Disclaimer. Corresponding Author: David W. E-mail: ude. Received Mar 17; Accepted May 7. All rights reserved. For Permissions, please e-mail: journals. This article has been cited by other articles in PMC. Keywords: herpes simplex virus type 1, herpes simplex virus type 2, perinatal transmission.
Table 1. The effect of maternal suppressive antiviral therapy on the incidence of neonatal HSV infection Research and development of optimal treatment strategies for the management of HSV discordant couples to prevent acquisition of HSV infection during pregnancy Vaccine strategies aimed at preventing maternal transmission of HSV The feasibility of rapid-turnaround peripartum screening of asymptomatic women with HSV polymerase chain reaction The efficacy of preemptive antiviral therapy in neonates born to women asymptomatically shedding HSV at the time of delivery Development of safe novel antiviral agents with increased efficacy, including penetration across the blood-brain barrier, for neonates with HSV infection Investigation of the potential benefit of combination antiviral therapies for neonates with HSV infection.
Open in a separate window. Acknowledgments Financial support. References 1. Whitley RJ. Herpes Simplex Virus. Infections in the Central Nervous System. Akhtar J, Shukla D. Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry. FEBS J. Roizman B. The structure and isomerization of herpes simplex virus genomes.
Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. Seroprevalence of herpes simplex Virus types 1 and 2—United States, — J Infect Dis. Kimberlin DW. The scarlet H. Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students.
Sex Transm Dis. Clinical management guidelines for obstetrician-gynecologists. Management of herpes in pregnancy. Obstet Gynecol. Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy.
N Engl J Med. Seroepidemiology of herpes simplex virus type 1 and 2 in pregnant women in Switzerland: an obstetric clinic based study. The acquisition of herpes simplex virus during pregnancy. Herpes causes blisters or sores in the mouth or on the genitals Genital Herpes Genital herpes is a sexually transmitted infection caused by the herpes simplex virus that causes recurring episodes of small, painful, fluid-filled blisters on and around the genitals.
Usually, doctors easily recognize the sores caused by herpes, but sometimes analysis of material from a sore or blood tests are necessary. No drug can get rid of the virus, but antiviral drugs Antiviral drugs A virus is composed of nucleic acid, either DNA or RNA, surrounded by a protein coat. Herpes simplex is one of several types of herpesviruses Overview of Herpesvirus Infections Some common viral infections are caused by herpesviruses.
Eight different herpesviruses infect people: Three herpesviruses—herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster There are two types of herpes simplex virus HSV :. HSV-1, which is the usual cause of cold sores on the lips herpes labialis and sores on the cornea of the eye herpes simplex keratitis Herpes Simplex Keratitis Herpes simplex keratitis is an eye infection that involves the cornea the clear layer in front of the iris and pupil and is caused by herpes simplex virus.
Eye pain, tearing, redness, a feeling HSV-2, which is the usual cause of genital herpes Genital Herpes Genital herpes is a sexually transmitted infection caused by the herpes simplex virus that causes recurring episodes of small, painful, fluid-filled blisters on and around the genitals.
This distinction is not absolute: Genital infections are sometimes caused by HSV Infection can also occur in other parts of the body such as the brain a serious illness or gastrointestinal tract.
Widespread infection may occur in newborns or in people with a weakened immune system Overview of the Immune System The immune system is designed to defend the body against foreign or dangerous invaders.
Such invaders include Microorganisms commonly called germs, such as bacteria, viruses, and fungi Parasites HIV is transmitted HSV is very contagious and can be spread by direct contact with sores and sometimes by contact with the mouth oral area or genitals of people who have HSV infection even when no sores are can be seen. After the first primary infection, HSV, like other herpesviruses, remains inactive dormant or latent in the body for life.
A latent infection may not cause symptoms again, or it may periodically reactivate and cause symptoms. The primary HSV infection produces an eruption of tiny blisters. After the eruption of blisters subsides, the virus remains in a dormant state inside the collection of nerve cells ganglia near the spinal cord that supply the nerve fibers to the infected area. Periodically, the virus reactivates, begins multiplying again, and travels through the nerve fibers back to the skin—causing eruptions of blisters in the same area of skin as the earlier infection.
Sometimes the virus is present on the skin or mucous membranes even when no blisters can be seen. The virus may reactivate many times. Reactivation of a latent oral or genital HSV infection may be triggered by the following:.
Suppression of the immune system for example, by a drug taken to prevent rejection of an organ transplant Drugs Used to Prevent Transplant Rejection Transplantation is the removal of living, functioning cells, tissues, or organs from the body and then their transfer back into the same body or into a different body.
The most common type of An episode of cold sores can develop after physical trauma, such as a dental procedure or overexposure of the lips to sunlight. Often, the trigger is unknown. The first oral infection with HSV usually causes many painful sores inside the mouth herpetic gingivostomatitis.
Herpetic gingivostomatitis most commonly develops in children. Before the sores appear, people may feel a tingling discomfort or itching in the area. In addition, people usually feel sick and have a fever, a headache, and body aches.
The mouth sores last 10 to 19 days and are often very severe, making eating and drinking extremely uncomfortable. As a result, people may become dehydrated. Occasionally, no symptoms develop. Recurrences usually produce a cluster of sores on the rim of the lip. The sores then rupture and crust over. The lip sore is called a cold sore or fever blister so named because they are often triggered by colds or fevers. Other triggers include sunburn on the lips, anxiety, certain dental procedures, and any condition that reduces the body's resistance to infection.
Before a cold sore appears, people usually feel a tingling at the site, lasting from minutes to a few hours, followed by redness and swelling. Usually, fluid-filled blisters form and break open, leaving sores. The sores quickly form a scab. After about 5 to 10 days, the scab falls off and the episode ends.
Less often, tingling and redness occur without blister formation. Genital herpes Genital Herpes Genital herpes is a sexually transmitted infection caused by the herpes simplex virus that causes recurring episodes of small, painful, fluid-filled blisters on and around the genitals.
In women, internal blisters may develop in the vagina or on the cervix. Internal blisters are less painful and are not visible. The blisters develop 4 to 7 days after people are infected. The blisters go away but may come back recur because the virus never truly leaves the body. The primary vessel containing the patient sample must be sent in a covering tube within a labelled transport container cardboard box with adsorbing material.
In general samples can be sent at room temperature unless the material is being sent for virus isolation, in which case cooling is recommended. The laboratory diagnosis of acute genital HSV infection or asymptomatic virus shedding is made via direct viral detection Table 1.
The method of choice is demonstration of viral genomes in skin or mucous membrane swabs using the polymerase chain reaction PCR The content of vesicles provides the best swab material.
The sample should be sent in physiological saline solution or viral transport medium. In the presence of complications involving other organs the examination of liquor, tissue samples, bronchoalveolar lavage, amniotic fluid, intraocular fluid, serum or EDTA blood should be considered.
Alternatively, acute genital HSV infection or asymptomatic viral shedding can be diagnosed by growing the virus in tissue cultures, whereby typing of viral isolates is performed by immunofluorescence using appropriate fluorescein labelled HSV serotype-specific monoclonal antibodies.
However in view of its higher sensitivity 33 , PCR is rightly regarded as the gold standard of diagnosis in many laboratories. Virus isolation continues to be recommended as an alternative method for diagnosis of genital herpes It must be remembered that direct viral detection does not differentiate between primary and recurrent infection or asymptomatic virus shedding.
Examination material: vesicle content in virus transport medium with special swabs, liquor, tissue sample, bronchoalveolar lavage, EDTA blood, amniotic fluid, intraocular fluid. Examination material: vesicle content in virus transport medium with special swabs, tissue sample, bronchoalveolar lavage.
Examination material: cell-rich vesicle content in virus transport medium with special swabs, tissue sample. Detection of viral type-specific antibodies against viral glycoproteins gG-1, gC-1, gG Detection of non-type-specific viral antibodies with total viral antigen determination from HSV-1 or HSV-2 infected cell cultures.
Qualitative determination of viral type-specific IgG antibodies against viral glycoproteins gG1, gG2 in serum. The detection of virus-specific antibodies for confirming HSV infection is widely used in clinical practice. One should however be aware of the limited value of serology results. HSV serology Table 1 is mainly useful for confirming seroconversion following primary infection, through demonstration of IgG. This can be of particular value in the diagnosis of HSV-2 infections in the context of antenatal care.
Thus a patient in whom anti-HSV-2 IgG is detected can be considered a potential virus shedder and transmitter who may also suffer from anogenital HSV infection. If an initial serum sample is available from the early stage of a herpes genitalis infection, primary and recurrent infections can be differentiated from one another through the detection of virus type-specific DNA by PCR in combination with virus type-specific IgG As an example, this means that when HSV-2 is detected on genital swab in a pregnant woman, primary genital herpes can be differentiated from a recurrence up to a few weeks before delivery using HSV type-specific IgG.
This differentiation is of great significance, since the risk of severe neonatal HSV infection is many times higher following primary infection than with recurrent infection. Although HSV type-specific antibody tests have been commercially available for approx.
Avidity testing can also assist in differentiating between primary and recurrent infections although to date experience with this method is limited False positive IgM results are possible due to cross-reactivity with other herpes viruses, e. It must however be noted that the positive predictive value of anti-HSV IgM is low, and that it does not allow differentiation between primary and recurrent infection.
Although IgM is usually positive following primary infection it can also be positive in the context of recurrence, independent of clinical symptoms. The rather unreliable measurement of HSV type-specific IgM antibodies should be avoided in clinical practice Recommended viral diagnostic algorithm for herpes genitalis.
PCR — polymerase chain reaction, TK — thymidine kinase. Standard first-line drugs include acyclovir, valacyclovir and famciclovir. The specific antiviral action of these acyclic nucleoside analogues 44 is based on their phosphorylation to monophosphate form by thymidine kinase TK , the key enzyme of HSV-1 and HSV-2, with subsequent phosphorylation via di- to triphosphate form by cellular enzymes.
Famciclovir may be incorporated into the growing DNA chain. Acyclovir is the first choice therapeutic agent for HSV infections, including herpes genitalis. Infections of the skin and mucous membranes including herpes genitalis are treated orally in immune competent people. Severe HSV infections, particularly in immunodeficient patients, should be treated with intravenous i. Acyclovir dosage for the treatment of herpes genitalis is dependant on infection status, immune competence and whether or not the patient is pregnant.
The benefits of prophylaxis have been proven particularly during pregnancy Topical acyclovir is only recommended for herpes labialis, herpes keratoconjunctivitis and mildly symptomatic herpes genitalis. Officially acyclovir is not licensed for use in pregnancy, though administration should be avoided particularly before the 15th week of gestation Results from a pregnancy register published by an acyclovir producer and the Centers for Disease Control and Prevention USA 47 as well as results of a retrospective cohort study in Denmark 48 have shown, however, that oral and topical acyclovir do not appear to increase the rate of congenital anomalies.
Since these data are not sufficient for general authorisation, particularly in early pregnancy, pregnant patients must be informed about the limited evidence on use in pregnancy off-label use. Occasional central nervous system side effects have been described following i. Nephrotoxic substances should not be administrated concurrently and both renal and liver laboratory parameters should be monitored.
Valacyclovir is a prodrug an L-valyl ester of acyclovir suitable for oral administration. After ingestion it is converted to acyclovir by the hepatic enzyme valacyclovir hydrolase. This allows increased dose intervals and is associated with better compliance. Valacyclovir is also a standard treatment for herpes genitalis in immunocompetent patients and studies have shown its efficacy for viral suppression and prevention of recurrent herpes genitalis Valacyclovir is not licensed for antiviral treatment in children and adolescents since its efficacy and safety profiles have not yet been adequately studied in this population.
This applies to pregnancy too as there is also little data on its safety in this context Possible side effects are similar to those of acyclovir. Famciclovir is the inactive diacetyl ester prodrug of the only topically effective acyclic nucleotide analogue penciclovir, which arises after cleavage of two ester groups in the small bowel and liver.
Famciclovir is also regarded as one of the standard therapeutic agents for herpes genitalis, along with acyclovir and valacyclovir, and is also not licensed for use in children and adolescents, immunosuppressed patients under the age of 25 years or in pregnancy.
It should therefore not be used as the treatment of choice in pregnancy In rare cases famciclovir can cause headaches, nausea and confusion. In such cases the pyrophosphate analogue foscarnet Table 3 is recommended as alternative treatment Since this substance does not need to be metabolised in order to inhibit viral replication it is also effective against TK-negative HSV strains, which are resistant to nucleoside analogues.
Important side effects include renal dysfunction and toxin-induced ulcers of the urogenital mucous membranes. Since the 3 times daily i. Cidofovir is exclusively licensed for treatment of cytomegalovirus retinitis in the context of HIV, however it is also effective against HSV. Marked nephrotoxicity and a lack of clinical experience with its use in treating HSV infections are significant barriers to the use of cidofovir in clinical practice. In view of the often atypical presentation of genital herpes systemic treatment with foscarnet or cidofovir is generally required.
Important contraindications include renal dysfunction, hypersensitivity, pregnancy and breastfeeding. The helicase blockers, a new class of drug that is currently still in clinical development and testing, may improve the antiviral treatment of herpes genitalis significantly in future.
Thus far effective inhibition of HSV replication has been demonstrated in cell cultures, animal models and initial clinical studies without evidence of major side effects. It is thought that helicase blockers bind to the helicase-primase complex, a protein component essential for virus replication, effectively inhibiting DNA synthesis and thus viral replication.
Indeed, better results have been achieved in vitro and in vivo than for acyclovir and valacyclovir. Helicase blockers have also been shown to be effective against acyclovir resistant HSV strains Phenotypic resistance tests in particular are time consuming, requiring at least 7—10 days, so that when severe resistance is present clinically appropriate changes to treatment should not be delayed until results become available.
The sensitivity of HSV to virostatic agents can be measured on the basis of inhibition of morphologically induced, virus-specific cell changes; so-called cytopathic effects. It is therefore necessary to run a control using a TK-positive reference strain along with each test. The main advantage of phenotyping is that the interpretation of results is unequivocal, which is why this method continues to be regarded as the gold standard for HSV resistance testing.
Disadvantages include the fact that it is time consuming, the high cost of materials needed for isolation and testing of HSV strains in cell cultures, and the lack of standardisation.
Phenotypic resistance testing is practically only possible when vesicle or respiratory tract swabs are available from which HSV can be easily isolated. In the majority of cases attempts to isolate the virus from liquor, blood or eye samples are unsuccessful. Genotypic resistance testing usually involves amplification and sequencing of the TK and DNA polymerase genes The data are then compared to a sensitive reference strain from the gene bank e.
HSV-1 strain 17 accession no. Findings suggestive of resistance include frameshift mutations, extra stop codons and non-synonymous nucleotide substitutions in conserved and functionally important gene regions. Interpretation of amino acid substitutions outside of active or conserved gene regions requires access to a data bank in which all resistance mutations described in the literature are pooled Matching of resistance pheno- and genotypes of HSV isolates is the most reliable and practical method available for confirming the resistance associations of new, as yet unknown amino acid substitutions.
The essential advantage of genotyping is that direct testing of patient samples is performed, making virus isolation in cell culture unnecessary. Depending on virus load results may be available within two days, which is of immense importance for clinical decision-making. The question of possible immunisation is often raised not only by doctors but also by many patients affected by herpes genitalis.
To date, however, there is no licensed vaccine against herpes genitalis, though research has been ongoing for a number of decades. Whereas therapeutic vaccines aim to prevent recurrent HSV infections and asymptomatic viral shedding in people with latent HSV infection, prophylactic vaccines are intended to prevent primary infection and subsequent virus latency.
Here HSV-2 has been the main focus of research. A large number of vaccines have been tested in vaginal animal models mouse and guinea pig 60 , though currently vaccines based on recombinant viral proteins appear to be the most promising Although these vaccines are not associated with a risk of vaccine virus infection and latency, there have been significant difficulties in meaningfully reducing the number of recurrences and preventing primary genital infection with both HSV-1 and HSV Thus vaccine-induced cellular immunity must be stronger than that following natural HSV infection.
Sound, comprehensive partnership counselling is an essential component of the medical management of herpes genitalis patients. If no HSVspecific antibodies can be detected in the partner of an HSV-2 seropositive person the couple should be advised to use condoms If herpes genitalis symptoms are present sexual intercourse should be discouraged Since these measures are particularly important for the prevention of viral transmission during pregnancy both partners should be informed about their HSV serostatus and the possible consequences of viral transmission, both with symptomatic herpes genitalis and asymptomatic viral shedding.
0コメント