Minaev N.N., Bugrimov D.Ju., Klimovich A.A
Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) – is a widespread viruses that can form a lifelong infection and persistence. Genital herpes in women of childbearing age is a serious risk of vertical transmission from mother to fetus. Primary HSV infection and the first episode of genital HSV infections are particularly high risk of infection of the fetus and newborn.  The infection rarely occurs in the uterus. Most often the virus is transmitted during childbirth. The greatest risk of transmission to the fetus and the newborn in the case of primary maternal infection occurred during the second half of pregnancy.  The risk of transmission from mother to fetus and newborn, can be reduced or the appointment of antiviral drugs,or in specific cases, caesarean section. The purpose of this paper is to propose a possible strategy to prevent transmission of the virus from an infected mother to the fetus.
Key words: recurrent HSV-2, pregravid preparation, maternal antibodies, Toll-like receptors 9, Ferrovir
The authors declare no possible conflicts of interest.
For citation: Minaev N.N., Bugrimov D.Ju., Klimovich A.A. The significance of immunomodulatory therapy in pregravidal preparation of the patients with recurrent HSV type 2. Akusherstvo, ginekologiya i reproduktsiya / Obstetrics, gynecology and reproduction. 2015; 1: 18-30 (in Russian).
Received: 20.02.2015; in the revised form: 14.02.2015; accepted: 25.03.2015.
Herpes simplex virus 2 (HSV-2) is classified together with HSV-1 in the subfamily Alphaherpesvirinae and is one of the very common sexually transmitted infections way around the world. The prevalence the virus is from 15 to 20% in Europe and the United States, and to 90% in some African populations of Sub-Saharan Africa .
Herpes simplex virus (HSV) - is ubiquitous, tunicary, with a double-stranded DNA virus belonging to the family of herpes viruses transmitted through mucous membranes and damaged skin. Subsequently, it migrates to the nerve tissue, where stored in a latent state. HSV type 1 (HSV-1) prevails in the orofacial lesions, and usually persists in the trigeminal ganglia, while the HSV type 2 (HSV 2), the most common in the lumbosacral ganglia . However, this second serotype may occur at orofacial lesions and at genital area. Changes in sexual behavior of young people can be partly to explain its high incidence of [9.16]. A distinctive feature of HSV-2 infection is the lack of painful lesions, and the majority of seropositive patients, the disease are the asymptomatic, so they are unaware of their diagnosis [10.19]. Primary infection is developing upon contact with the virus in susceptible individuals without HSV-1 and HSV-2 antibodies . The first clinical episode in primary infected individual occurs when a person with his existing antibodies to HSV type 1 or type 2 the first in contact with the opposite type of HSV . Due to the protective function of the available antibodies systemic symptoms, during such episodes, usually shorter and less expressed . The recurrent infection develops in patients who have antibodies against the same type of HSV, with whom they are in contact . It is defined as an episode of herpes sores in women with homologous IgG antibodies to HSV the appropriate type. Recurrent infections are most common during the first three months after the initial infection, especially with HSV-2. Approximately 15% of all pregnant women with a history of HSV-2 infection have disease recurrence during childbirth. Acute lesions usually last for 9 days, and the residual effects - about 4 days. The viral load at relapses is usually lower than in the primary lesions, and decreased immediately after the prodromal and early of the secondary clinical episode. IgG level returns to the original value until resolution the incident . Vertical transmission of HSV-2 can cause eye, skin lesions, widespread meningoencephalitis, and systemic lesions of the internal organs or fetal malformation.  In general, HSV-2 seropositive women before pregnancy have a reduced risk of neonatal transmission, attributed to transplacental migration of antibodies to the fetus. But women with recurrent episode of herpes at childbirth, as a rule, should be delivery by Caesarean section to prevent the transmission of infection to the newborn . Women, seronegative before pregnancy, have a higher risk of vertical transmission of HSV-2 and neonatal complications . Maternal age younger than 21 years is a factor of higher risk for vertical transmission of the disease . Approximately 5% of all cases of neonatal herpes infection occur intrauterine transmission of the virus. During primary infection there is transient viremia. HSV-2 has a pronounced potential hematogenous spread to the placenta and fetus. This can lead to a whole range of pathologies typical of the complex TORCH-infection (toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus), such as microcephaly, microphthalmia, intracranial calcification and chorioretinitis . Transmission during childbirth is most cases of neonatal injury and happening during the passage of the fetus through an infected birth canal. Application of the single spiral scalp electrode increases the risk of transmission during delivery.  From 75 to 90% of children are born with neonatal HSV from asymptomatic infected mothers who have no history of disease episodes.
The frequency of transmission of HSV-2 in childbirth depends on the type of clinical infection. Decline in the presence of protective maternal antibodies that cross the placenta:
- Primary infection with HSV-2 transmission frequency - 50%;
- The first clinical episode in primary infected individuals with antibodies to HSV - transmission frequency - 33%;
- Recurrent or asymptomatic infection - transmission frequency - 0-4%.
The overall incidence of neonatal infection of the fetus from asymptomatic women infected with HSV-2 in the laboratory anamnesis is less than 4 per 10,000, or 1% risk of asymptomatic disease in the mother, multiplied by 4% of risk of vertical transmission .
It can thus be generalized as follows:
- The frequency of neonatal infection is highest in seronegative women, which confirms the importance of maternal antibodies in the prevention of vertical transmission;
- Presence of mother not only HSV-2 antibodies, but also HSV-1 antibody reduces the number of infants with HSV-2 virus;
- The number of infected infants both with primary and recurrent form are more for HSV-1 versus HSV-2;
- Caesarean section is protective surgical intervention to prevent neonatal infection .
1. Study of HSV-culture has long been is the standard criterion of the diagnosis of herpes infection, with a sensitivity of 70% and a specificity of nearly 100%. The final answer diagnostics of culture can take up to seven days. The sensitivity of the test of culture is related to the type of HSV and the place of the fence material. The sensitivity of the test is the highest during the prodrome and low in a period of recovery, especially in the chronic course of the process. Sensitivity of culture test below for of HSV-2 then HSV-1. In women with asymptomatic disease sensitivity is maximal when the material is taken from the cervical canal and from the place of relapse, even if the lesion is not visualized .
2. Currently, more and more widely used for the diagnosis of HSV is polymerase chain reaction (PCR), is a molecular test, which is easy to use and, ultimately, can replace the study of HSV-culture in a standard test [5,6, 18]. As the culture test, PCR can differentiate between HSV-1 from HSV-2. Performing the test takes about one day, and this method has the potential for more rapid detection of the virus than the test HSV culture. Unfortunately, PCR can`t distinguish between actively replicating herpes simplex virus from the viral DNA present in a latent state.
3. In the case of asymptomatic herpetic infection or when the results of PCR analysis are questionable additional information may provide serological testing of antibodies to HSV. Type-specific antibodies of class G to herpes simplex virus 1 and 2 of types indicate previous or current infection. Type-specific IgG persist throughout life. This phenomenon is called seropositivity. Recurrent herpes usually proceeds on the background of high levels of IgG, showing the constant antigenic stimulation of the body [2, 3,15].
Acyclovir is the most prescribed medication for the treatment of HSV infection. He was available for clinical use for nearly three decades and has demonstrated a high level of safety and efficacy in the treatment of all forms of herpes infections, from mild to very severe, as in ordinary patients as well as patients with impaired immune response, including and neonates. Acyclovir is an analogue of deoxyguanosine. After the priority absorption of virus-infected cells is phosphorylated it is virus-associated thymidine kinase. Then there is preparation of di- and triphosphorylation of drug, catalyzed enzymes infected cells. The resulting acyclovir triphosphate terminates viral DNA synthesis by inhibition of viral DNA polymerase by acting as a terminator of chain fusion. The drug acts selectively on the synthesis of viral DNA. On DNA replication of the host cell (human cells) acyclovir triphosphate virtually no effect. Valacyclovir (Valtrex) - preparation of a second generation is identical acyclovir. It was obtained by adding the side chain of the ester, which increases its bioavailability. After absorption in the body it is converted to acyclovir. It allows receiving a high serum level of the drug at reducing the frequency of administration.  In view of the above two circumstances can conclude the following: 1) the incidence of neonatal infection is highest in seronegative women, which confirms the importance of maternal antibodies in the prevention of vertical transmission; 2) the presence of the mother, not only HSV-2 antibodies, but also the presence of HSV-1 antibodies can reduce the number of infants with HSV-2 infection .
We hypothesized that the increase in type-specific IgG titer in the blood planning pregnancy asymptomatic infection or seronegative women will reduce the likelihood of vertical transmission of the virus in patients with HSV infection. This increase of the titer possible when used in the background pregravid preparation natural origin drug Ferrovir®, its active substance is sodium deoxyribonucleat in combination with iron.
Ferrovir® - antiviral drug with immunomodulating and protective action. Ferrovir® is an agonist of toll-like receptor 9 (Toll-like reseptors 9, TLR 9, CD 289). The preparation contains in its composition oligonucleotides of salmon DNA, 50% of cases ending nonmethyllated CpG motifs that are specific ligands of TLR 9. Toll-like reseptors 9 are intracellular, accurately endosomal localization and expressed by monocytes (macrophages) plasmacytoid dendritic cells and B-lymphocytes. Stimulated by Ferrovir through TLR 9 plasmacytoid dendritic cells are able to influence on the differentiation of Th0 to Th2 (naïve T-helper cells to T-helper type 2). Under the influence Th 2 happening differentiation of B-cells into plasma cells secreting IgG 2, IgG 4 . A typical and explainable turned out to be fact of the increasing avidity IgG, synthesized at of the plasma cells. In proliferating centroblasts (activated B-cells) is the process of formation of additional of antibody diversity in the process of somatic hypermutation in the already rearranged V-immunoglobulin genes . Thus, increased avidity synthesized antibodies despite nonspecific antigenic stimulation of B cells of Ferrovir®. It is logical assume that the increase in the mother's blood type-specific antibody titers, crosses the placental barrier, will provide the fetus the necessary their number for opsonization viral antigens and their subsequent phagocytosis of cells mononuclear phagocyte system (MPS).
The aim of the study was to show that the increase in type-specific IgG titer and increasing their avidity under the influence of the drug Ferrovir® authentically increases the pregnancy rate, and reduces the number of abortions and premature births in women infected with herpes simplex virus 1 and / or 2 serotypes.
Materials and methods.
The study included 101 patient of reproductive age from 25 to 31 years with primary or recurrent, or with a single episode of genital herpes. Most of the patients after the course antiviral therapy for 12 months successfully conceive a child, carrying of a pregnancy and given birth the child. All patients had laboratory evidence of infection with HSV 1 or 2 d serotype that was twice confirmed by PCR by examining scraping from the cervix for 5-7 days of the menstrual cycle. To establish of the form of infectious process, and most importantly, to determine the level of seropositivity patients was conducted serological with measurement of blood levels of type-specific IgG, and their degree of avidity. Under indications them were performed ultrasound of the pelvic organs, colposcopy, and all the patients were taken smears from the cervix to oncocytology and pathogenic / opportunistic microflora. It was carried out dynamic monitoring of, the patients immediately after the treatment through 2 weeks, 1, 3, 6, 9 and 12 months. The main criteria for the inclusion of women in the study had their infection with HSV-1 and / or 2 d serotype and planning their pregnancy. The main exclusion criteria were the following: the fact of any patient receiving immunomodulators during at least six months prior to the study, women planning pregnancy during therapy Ferrovir, that it has an autoimmune disease. All women participating in the study give written informed consent and were able to, in our opinion, keep a diary of self-esteem and comply with the requirements of the protocol. Throughout the existing work evaluated the safety of the drug Ferrovir®, by the criterion of complications or adverse reactions. Refusal to participate in study could be initiated as a patient, and by researchers for example in case of compelled reception of by her antiviral or immunomodulatory drug. Statistical analysis was performed by the method of variation statistics and correlation analysis using Microsoft Excel 7,0 (Windows 7, Microsoft Office 2007), with the definition of Student's t test (t) for independent groups. To evaluate the protective effect of antiviral immunomodulator drug Ferrovir® at the infected of the fetus and habitual loss of pregnancy and compare of its with the pathogenetic opposite antiviral drug Valtrex, by random sampling all HSV-infected women, planning pregnancy, (101 patients) were divided into three representative groups:
- The control group (37 patients) received standard therapy with Valtrex 500 mg 2 times a day. Within 7 days;
- First study group (32 patients) received therapy with in the injections, (solution for intramuscular injection of 15 mg / ml). Method of application the drug Ferrovir® consists in intramuscular injection of 5 ml solution (75 mg), 1 per day after 24 hours within 10 days, 10 injections for the course.
- The second study group (32 patients) received the combined therapy Valtrex + Ferrovir® in dosages which was applied by the first test group and in the control group, respectively.
Age of the patients of the comparison group (37 women) amounted to 28,8 ± 0,43 years. Everyone at the beginning of research at the gynecological examination of cervical pathology was absent. The average age of menarche was 13,3 ± 0,2 years. Beginning sex life was with 16,7 ± 0,29 years. In the group had an average 2,5 ± 0,07 pregnancies, 0,9 ± 0,01 birth, 1,3 ± 0,07 abortions, 0,3 ± 0,04 abortions. From gynecological diseases at the clinical examination in the comparison group before the study accounted for 21 endocervicitis, 8 colpites, 4 adnexitises and 4 patients showed no other gynecologic pathology than HSV. According to the ultrasound (U\S), 2 patients’ diagnosed adnexitis, 5 diagnosed of endometriosis and 29 women in this group was not determined on the U\S pathology. Oncocytology has identified in the group: the inflammation in 12 cases, dysplasia in 8 cases and the lack of pathology in 17 cases. According to the colposcopy, at the beginning of the study 14 the patients showed signs of inflammation and 23 women had the favorable colposcopic results.
Age of the first patients of the study group (32 female) was 27 ± 0, 36 years. Pathology of the cervix is absent in all the patients in this group. The mean age of menarche 13,2 ± 0,08 years; the sexual debut at 17,5 ± 0,22 years. In the group had an average 2, 4 ± 0, 11 pregnancies, 0, 8 ± 0, 33 birth, 1, 4 ± 0, 08 abortions, 0, 2 ± 0, 04 abortions. From gynecological diseases on clinical examination on the comparison group before the study accounted for 12 endocervicitis, one case of endometriosis. In 19 patients did not reveal other gynecologic disease other than HSV. According to the ultrasound, four patients diagnosed adnexitis, four endometriosis and 24 women in this group was not determined on the ultrasound pathology. Oncocytology identified in a group picture of inflammation in nine cases, dysplasia in six cases and the absence of pathology in 17 cases. According to the data colposcopy, at the beginning of the study 16 patients revealed the signs of inflammation and 16 women had a favorable colposcopic picture.
Age of the patients of the second study group (32 women) was 27, 8 ± 0, 33 years. Pathology of the cervix is absent in all the patients in this group. The mean age of menarche 13, 1 ± 0, 1 year; the sexual debut at 16, 2±0, 34 years. In the group had an average 2, 3 ± 0, 07 pregnancies, 0, 9 ± 0, 03 birth, 1, 1 ± 0, 03 abortions, 0, 3 ± 0, 05 abortions. From gynecological diseases on clinical examination on the comparison group before the study account for 19 endocervicitis, one colpitis, four adnexitis, and eight patients did not reveal other gynecologic pathology other than HSV. According to the data U\S, four patients diagnosed adnexitis, three endometriosis and 25 women in this group was not determined on the ultrasound pathology. Oncocytology revealed in a group picture of inflammation in 11 cases, dysplasia in six cases and no pathology in 15 cases.
According to the data colposcopy, at the beginning of the study 13 patients revealed the signs of inflammation and 19 women had a favorable colposcopic picture.
In all three groups there was a similar picture of patients infected with HSV-1 or HSV-2 before treatment.
There was statistically significant between the groups described clinical parameters. The confidence level of P ≤ 0, 01-0,05.
Figure 1. There is infection of HSV in the comparison group (Valtrex), according to the ELISA. (Index of IgG positivity in all patients before treatment by an average is > 1.1).
*Note: P ≤ 0, 05.
In the comparison group (see Fig. 1) draws attention a progredient reduction of the effect of the standard treatment of Valtrex for a year. After 9 months in the control group of seronegative patients was not. All indicators type-specific IgG returned to values "before the treatment."
Figure 2. There is infection of HSV in the comparison group (Ferrovir®), according to the ELISA. (Index of IgG positivity in all patients before treatment by an average is > 1.1).
*Note: P ≤ 0, 05.
In the first test group (see Fig. 2) is seen a distinct trend to increase the number of seronegative patients by applying Ferrovir®, a solution of 15 mg / ml.
Figure 3. There is infection of HSV in the comparison group (Valtrex + Ferrovir®), according to the ELISA. (Index of IgG positivity in all patients before treatment by an average is > 1.1).
*Note: P ≤ 0, 05.
In the second study group (see Fig. 3) the trend to maintain the antiviral effects during treatment of antiviral drug Valtrex with immunomodulating effect Ferrovir® (15 mg / ml) was even more obvious
Figure 4. IgG avidity index change in the comparison group (Valtrex)
*Note: P≤0, 01.
In the comparison group, which conducted the standard officially recommended therapy of Valtrex (see Fig. 4) is not marked increase in the number high avidity IgG. This is consistent with the mechanism of action of the antiviral Valtrex is not related to the impact on B-cells.
Figure 5. It is viral load in the comparison group (Valtrex), according to the PCR.
Viral load in the comparison group (Valtrex), (see Fig. 5) is reduced during the first month of treatment, due to the rapid virucidal and virustatic action of Valtrex. Also, it obligates increases throughout the remainder of the observation period, as Valtrex has no cumulative effect and pharmacologically stimulating effect on the immune system. Increased viral load, according to PCR, explains the decrease of the immune competence of HSV-infected persons or activation of latent persistent virus under the influence of adverse external influences on the body.
Figure 6. IgG avidity index change in the first test group (Ferrovir®, 15 mg / ml).
*Note: P ≤ 0, 01.
In the first study group, which was conducted Ferrovir® monotherapy, 15 mg / ml (see Fig. 6), can be seen a distinct trend of increasing avidity index of type-specific IgG. It is good explainable an immunomodulatory mechanism of antiviral action Ferrovir®. This includes stimulating TLR 9 B-lymphocytes (centroblasts). In them there is an active process of somatic hypermutation, leading to formation of antibody diversity and increase their avidity.
Figure 7. It is viral load in the first test group (Ferrovir®, 15 mg / ml), according to PCR.
*Note: P ≤ 0, 05.
Viral load in the first study group patients on background of therapy with Ferrovir®, 15 mg / ml (see Fig. 7) decreases is gradually and reaches the minimum values of the third month of treatment. This can be explained by an immunomodulating character of antiviral action of Ferrovir which requires certain time for antigen-positive selection of B – cells, and their transformation into plasma cells, and the synthesis of the latest, a sufficient number of type-specific IgG. But on the other hand, create a clone of plasma cells synthesizing high-avidity, type-specific antibody IgG, provides long-term control over the foci of latent persistence of HSV.
Figure 8. Change of index avidity IgG in a second treatment group (Valtrex + Ferrovir® + 15 mg / ml).
*Note: P ≤ 0, 01.
Women in the second treatment group receiving Valtrex and Ferrovir® + 15 mg / ml (see Fig. 8), increase in titer high-avidity, type-specific IgG is somewhat less pronounced than in the first group. This can be explained by the presence in the scheme of pregravid preparation of Valtrex, provider virustatic action which in its turn, reduces antigenic diversity HSV, and accordingly reduced the ability of antigen-positive selection of B-cells in the germentativnyh centers of the lymph nodes, that provides somatic hypermutation and increased avidity antibodies.
Figure 9. It is viral load in the first test group (Valtrex + Ferrovir®, 15 mg / ml), according to PCR.
*Note: P ≤ 0, 05.
Dynamics of viral load in the second study group (Valtrex and Ferrovir® + 15 mg / ml) (see Fig. 9) was similar to the comparison group in terms of its sharp drop in the first month of treatment due to the rapid effect of Valtrex. And, at the same time, the curve indicator of viral load at the end of the observation period reaches a low value, as in the first study group, that is caused by prolonged immunomodulating effect of Ferrovir, 15 mg / ml.
Figure 10. Indicators smear in the comparison group (Valtrex) during pregravid preparation.
*Note: P ≤ 0, 05.
In this group (see Fig. 10) the trend at reducing the non-specific inflammation is minimal, it is easily explained the specific selective antiviral mechanism of action of Valtrex, has no effect on eukaryotic vaginal flora.
Figure 11. Indicators smear in the first study group (Ferrovir®, 15 mg / ml) during pregravid preparation.
*Note: P≤ 0, 05.
In women who received only therapy Ferrovir (see. Fig. 11) can be seen a distinct trend in the reduction of non-specific inflammation, which is obligate, caused an immunomodulating character effect of this drug.
Figure 12. Indicators smear in the first study group (Valtrex +Ferrovir®, 15 mg / ml) during pregravid preparation.
*Note: P≤ 0, 05.
Similar tendency of decrease the level of non-specific inflammation, provided by Ferrovir®, noted in the second study group (see Fig. 12).
There is frequency of the pregnancy.
*Note: P≤ 0, 05.
We noted a higher pregnancy rate in the groups where in pregravid of preparation was included Ferrovir®. This, in our opinion, is explained an immunomodulating character effects of the drug Ferrovir®, reduces the manifestations of PID, and accordingly improves the quality of the smear on the pathogenic and / or conditionally pathogenic flora.
There is frequency of pregnancy loss.
*Note: P≤ 0, 05.
The frequencies of pregnancy loss from various causes (miscarriages in the early stages, in cases of undiagnosed pregnancy, miscarriages till 8 weeks, after the 8 weeks), was significantly lower in group’s pregravid preparation, are included in the program Ferrovir ®. We attribute this to an immunomodulating character effect of the drug, which reduces symptoms of PID. It is also probable that a significant role in preserving of pregnancy plays a sufficient level of maternal type-specific, high-avidity IgG in the blood of fetus from the first weeks of pregnancy.
- Use in pregravidal preparing standard officially recommended the treatment regimen of Valtrex has obvious disadvantages manifested in the exclusion out the epidemiological situation "virus - host" of the immune system of the patient. They, in particular, expressed in the principle impossibility of the organism to involve the innate and the acquired immune response to antigens of HSV-2.
- These deficiencies are well compensated for inclusion in the scheme pregravid preparation antiviral drug immunomodulatory effects Ferrovir®
- Observed the distinct increase of the index type-specific, high-avidity IgG against HSV-2 in the group of patients treated with Ferrovir®.
- The pregnancy rate for patients in the groups with preparation of Ferrovir® significantly higher than in the monotherapy group of Valtrex.
- The frequency of fetal loss syndrome in patients with high index type-specific, high-avidity IgG, generated application of Ferrovir, significantly lower than women in the comparison group with fixed rates IgG titer and the avidity index.
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About the authors:
Minaev Nikolai Nikolaevich − PhD, MD, professor, Head of the Department of Obstetrics and Gynecology. The Institute of Advanced Training. Voronezh State Medical Academy named after NN Burdenko Russian Ministry of Health. address: 394036, Russian Federation, Voronezh, Studencheskaya str. 10. Тел.: +79036502044. E-mail: firstname.lastname@example.org.
Bugrimov Daniil Yur'evich − PhD, advisor RAE master MANEB, Senior Researcher, Director of the Institute of Experimental Biology and Medicine (EBM Research Institute), Voronezh State Medical Academy named after NN Burdenko Russian Ministry of Health, address: 394036, Russian Federation, Voronezh, Studencheskaya str. 10. Тел.: +9515512557; +791923490 49. E-mail: email@example.com.
Klimovich Andrew Alekseevich − researcher of the Institute of Experimental Biology and Medicine (EBM Research Institute), Voronezh State Medical Academy named after NN Burdenko Russian Ministry of Health. address: 394036, Russian Federation, Voronezh, Studencheskaya str. 10. Тел.: +7906590529410. E-mail: firstname.lastname@example.org.