Status and Future Management of Congenital Cytomegalovirus and Neonatal Herpes Simplex Virus Infections

Evangelia Steletou, M.D., M.Sc.¹ Richard Whitley, M.D.²

1. Post Doctoral Fellow, Department of Pediatrics, The Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL; USA
2. Distinguished Professor, Loeb Scholar I Pediatrics, Professor of Pediatrics, Microbiology, Medicine and Neurosurgery; The Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL; USA

 

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PUBLISHED: 30 November 2024

CITATION Steletou, E. and Whitley, R., 2024. Status and Future Management of Congenital Cytomegalovirus and Neonatal Herpes Simplex Virus Infections. Medical Research Archives, [online] 12(11).
https://doi.org/10.18103/mra.v12i11.5976

COPYRIGHT © 2024 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI https://doi.org/10.18103/mra.v12i11.5976

ISSN 2375-1924

 

Abstract

Cytomegalovirus (CMV) and herpes simplex virus (HSV) infections are among the most common viral infections of the newborn in the world. CMV infections can cause sensorineural hearing loss, which is the most prevalent long-term neurodevelopmental disability in children. This review summarizes the current knowledge regarding congenital CMV and neonatal HSV infections, including their diagnosis, management, and future directions for research.

Keywords

• Congenital Cytomegalovirus
• Neonatal Herpes Simplex Virus
• Infections
• Diagnosis
• Management

Introduction to Congenital Cytomegalovirus Infection

The diagnosis and management of congenital cytomegalovirus (CMV) introduces unique problems. First, most congenital infections are acquired from maternal transmission across the placenta to the fetus. Second, most infants are born totally asymptomatically, whereas only 10% have clinical evidence of disease at birth. In either case, the outcome can be devastating as hearing loss is a primary problem, even in those children born with an asymptomatic infection. Recognizing that infection is acquired early in gestation, introduces unique therapeutic problems. Namely, is it possible to treat a chronic viral infection acquired early in gestation, particularly when these babies excrete >6 logs of virus in their urine? Similarly, with the advances in therapy that have been developed, can we now treat babies with asymptomatic infection in hopes of reducing subsequent hearing loss? The ideal solution would be the development of a vaccine to prevent both maternal primary infection as well as vertical transmission of infection in the seroimmune woman. Efforts to develop a CMV vaccine have been entertained for decades, but all have failed. We will consider potential future approaches to this problem.

Epidemiology

Congenital cytomegalovirus (CMV) infection is the most common viral infection in the developed world, creating an extensive disease burden.¹˒² The current estimated incidence of vertically infected infants is approximately 3–7/1000 newborns globally, while in the United States (US) nearly 1 in 3 children are infected with CMV by age five.¹˒³ Socioeconomic and regional disparities in the prevalence of congenital CMV infection have been documented in the US; for example, non-Hispanic Black newborn infants exhibit significantly higher congenital CMV infection rates (9.5/1000 live births) compared to other racial/ethnic groups.²˒⁴ Transplacental transmission can occur in women with either primary or preexisting CMV infection by viral reactivation or acquisition of a new strain. Although the timing of maternal infection is not related to the risk of congenital infection and clinical presentation, severe sequelae are more commonly identified in women infected early in pregnancy. In addition, most congenital cases in the US occur in infants born to women with a primary infection while the more severe cases in other populations with higher rates of maternal CMV seroprevalence occur in newborns of mothers with preexisting infection.⁴

Disease Burden and Outcomes

At birth, 90% of infants with congenital CMV infection are asymptomatic and the remainder symptomatic, but still being at higher risk for severe complications.⁴ CMV infection can affect multiple organs and predisposes infants to reticuloendothelial and central nervous system disease.⁵˒⁷ The most common clinical presentation in symptomatic newborns includes jaundice, petechiae, purpura, hepatosplenomegaly, microcephaly, periventricular calcifications and retinitis.⁴ Thrombocytopenia, conjugated hyperbilirubinemia and elevated liver enzymes are often laboratory abnormalities.⁴ In terms of neurodevelopmental involvement, sensorineural hearing loss (SNHL) and cognitive delay are the most serious permanent sequelae.⁴ Clinical presentation with microcephaly and neurological symptoms, and abnormal neuroimaging findings detected within the first month of life, are considered strong predictors of adverse neurological outcomes in symptomatic infants.⁵˒⁷ Of note, SNHL occurs in up to 50% of symptomatic children with congenital CMV infection, while up to 15% of asymptomatic newborns at birth will eventually develop SNHL.⁴ Approximately 40% of CMV-related SNHL cases in children have delayed onset that cannot be detected during the first month of life, making management more challenging.⁴ Hearing loss might be either unilateral or bilateral and can also deteriorate over time, requiring continuous monitoring.⁴˒⁷

The prevalence of adverse outcomes highlights the chronicity and complexity of congenital CMV infection and indicates the disproportionately higher disease burden and associated disabilities compared to other well-known conditions of childhood, such as Down’s syndrome and fetal alcohol syndrome.⁸ In turn, the financial toll of congenital CMV infection is high, attributed to both direct medical costs of managing and treating the condition born by healthcare systems, payers, and parents/caregivers and to indirect and intangible societal costs.¹˒⁹˒¹⁴

Diagnosis

Congenital CMV infection can be diagnosed at birth by polymerase chain reaction (PCR) assessment of urine or saliva, with saliva PCR being the preferred method due to the ease of collection and high sensitivity of the assay.⁴ Since universal screening is not an established routine yet, some centers perform targeted CMV screening on newborns who fail a hearing test within 3 weeks of birth.¹⁴ However, the benefits of a hearing-targeted strategy might be limited because, as noted above, some newborns with congenital CMV infection successfully pass their initial hearing test but develop SNHL later in life.¹⁴˒¹⁵ Otherwise, early detection of CMV is advised. Notably, there is a growing trend in the US for routine screening of all live born children. Early detection of CMV in the neonatal period is important since hearing loss might present later in previously asymptomatic children.⁵ From a cost-effectiveness perspective, either targeted or universal screening might be superior compared to the clinical diagnosis, considering that early detection and proper treatment could result in improved outcomes at lower costs.⁵˒¹²˒¹⁶˒¹⁸ Despite the limited data on long-term sequelae and costs of congenital CMV infection, existing studies suggest that the implementation of newborn CMV screening is warranted.⁵˒¹²˒¹⁶˒¹⁸ For that purpose, a saliva real-time PCR on Guthrie card has been proposed as a potential tool for universal congenital CMV screening, exhibiting high sensitivity and specificity.¹⁹

Treatment

Current treatment guidelines for symptomatic congenital CMV infection include 6 months of oral valganciclovir initiated within the first month of life (32 mg/kg/day in two divided doses), while no treatment is indicated for asymptomatic patients.⁴˒²⁰˒²¹ Compared to intravenous ganciclovir, valganciclovir is an oral prodrug that provides the same systemic exposure without the challenges of intravenous therapy.²²˒²³ During treatment, close monitoring of patients receiving valganciclovir is required due to potential serious side effects. Valganciclovir is associated with neutropenia (most commonly presenting within the first 6 weeks), thrombocytopenia, anemia, and elevated liver enzymes. These adverse effects are reversible after discontinuation of the drug. Ganciclovir can theoretically cause long-term effects as observed in animal models and are related to increased risk of carcinogenesis and reproductive organ toxicity.²²˒²³

Oral valganciclovir has been successful in treating congenital CMV infection, with only a few reported, isolated cases of resistance to drug.²⁴˒²⁶ While antiviral treatment decreases the viral load, it also allows the immune system to work better in defending against infection.⁴ The long-term benefits of treatment include the prevention of further hearing loss and neurodevelopmental deterioration.²⁷ Data from ongoing studies are expected to provide evidence on treatment benefits, but further research on long-term complications is warranted. In addition, new antiviral approaches are being investigated and a phase I clinical trial is currently underway in the US. In this clinical trial, the safety of oral letermovir will be assessed in neonates with symptomatic congenital CMV infection when administered with valganciclovir.²⁸ Letermovir acts by inhibiting the viral terminase subunit pUL56, subsequently disrupting the production of new virions. The primary goal of this ongoing study will be to determine the pharmacokinetics of oral letermovir in infants, based upon previous observations and data from valganciclovir.²⁸

Failure of Late Therapy to Impact Hearing Loss

While current guidelines from the American Academy of Pediatrics recommend the initiation of treatment for symptomatic CMV infection in the

neonatal period, evolving evidence suggests that antiviral treatment might be beneficial for patients without any clinical findings and patients with either isolated or late-onset hearing loss, although the data are limited and uncontrolled.³˒⁴˒²⁷˒³⁰ Results from a 2020 study from Israel suggested that treatment of congenital CMV infection initiated after the neonatal period was associated with better outcomes for both symptomatic and initially asymptomatic children who presented with late-onset hearing loss.³¹ The results indicated an improvement in hearing during the 1-year follow-up period for most patients, but this study was observational with a small sample, indicating the need for additional and long-term, controlled studies with larger samples.³¹ In contrast, results from a recent randomized clinical trial conducted in the US and United Kingdom indicated that oral valganciclovir initiated beyond the neonatal period failed to improve hearing outcomes in children with SNHL associated with congenital CMV infection.³²

The efficacy of valganciclovir treatment in isolated CMV-related SNHL has been the subject of investigation in recent clinical trials in Europe and the United States, aiming to evaluate the impact both on hearing and developmental evaluations.³³˒³⁵ A phase II clinical trial in the US aimed to assess the role of valganciclovir treatment in hearing loss prevention in infants with asymptomatic congenital CMV infection was suspended due to safety concerns.³⁶ Promising data from another recently published clinical trial suggested a beneficial effect of antiviral treatment in infants with isolated hearing loss in the setting of congenital CMV infection.³⁷ These discrepancies in results warrant clarification.

To date, only one study has provided data regarding children older than 12 years with symptomatic congenital CMV infection, finding that most symptomatic patients developed severe hearing loss regardless of whether or not they were treated with ganciclovir for 6 weeks.³⁸ Thus, research to better understand the long-term impact of the standard 6-month valganciclovir regimen is needed.³⁸

Maternal – Prevention, Screening, and Treatment

In addition to newborn screening and management, antenatal intervention options have been explored to prevent both primary CMV infection in pregnant women and maternal-to-child transmission.³⁹˒⁴⁰ The spread of CMV can occur through exposure to saliva and urine from infected individuals, mostly from children in the household and childcare centers to mothers and other caregivers.⁴ Thus, hygienic interventions can contribute to preventing seronegative pregnant women from acquiring CMV, while raising awareness regarding maternal CMV infection is also critical to contain CMV burden.³⁹˒⁴¹˒⁴² Of note, evidence suggests that the majority of women are not informed about CMV; even healthcare professionals are often not well-equipped to advise pregnant women regarding CMV-related matters, highlighting the need for educational strategies targeting both the public and healthcare professionals.⁴³˒⁴⁵ Although serologic screening during pregnancy is useful for detecting prior exposure, it is not recommended by the official guidelines, as it is not considered to be cost-effective.²⁰˒⁴⁶˒⁴⁷ Early recognition of maternal CMV cases is important, and currently, different secondary measures have been proposed to prevent maternal-to-child transmission. Passive immunization of pregnant women with hyperimmunoglobulin has been investigated as a secondary prevention measure, but existing studies have yielded mixed results.⁴⁸˒⁵⁰ Promising data from observational studies suggested that a high dose of hyperimmunoglobulin biweekly in women with primary CMV infection early in pregnancy decreased maternal-fetal transmission.⁴⁸ On the other hand, clinical trials of CMV hyperimmunoglobulin administration in pregnant women with primary CMV infection carried out in Italy and the United States failed to demonstrate benefit and, consequently, is not recommended.⁴⁹˒⁵⁰

Finally, data are emerging to support the use of valacyclovir during pregnancy as an option to prevent congenital CMV infection.⁵¹ In these studies, treatment of primary CMV infection in pregnant women with valacyclovir (8gr/day orally) was associated with a reduction in congenital CMV infection (defined by amniocentesis) compared to the no-treatment group.⁵³˒⁵⁵ In addition, secondary outcomes of a study in Italy suggested a reduction in symptomatic congenital CMV infection at birth in infants born to mothers treated with valacyclovir during pregnancy compared to those born to mothers who were not treated.⁵³ Valacyclovir was overall well tolerated in most cases with minimal but reversible adverse effects after treatment discontinuation.⁵³ However, these studies included data for pregnant women with primary CMV infection only, in the absence of universal CMV screening strategy during pregnancy and, therefore, they lack generalizability. Moreover, the quality of evidence that prenatal valacyclovir decreases the risk of vertical CMV transmission was deemed very low, highlighting the need for future research.⁵⁶

A randomized clinical trial is currently underway, assessing the role of letermovir, a CMV-specific antiviral drug noted above, in prenatal treatment of first-trimester primary CMV infection cases.⁵˒⁷ Compared to other known antiviral agents licensed for use in immunosuppressed transplant patients (ganciclovir, foscarnet, cidofovir), both letermovir and valacyclovir are safe during pregnancy, not teratogenic, and effectively cross placenta. Investigators hypothesize that letermovir’s efficacy will be greater than valacyclovir in inhibiting fetal CMV replication and will result in undetectable CMV viral load in newborns, which is the primary endpoint of this study. Evaluation includes long-term outcome over the first two years of life.⁵˒⁷ Subsequently, if efficacy of maternal treatment for primary CMV infections in the first trimester is proven, the need for early recognition will be intensified and a universal CMV screening approach during pregnancy might be reevaluated.

The development of a maternal vaccine to prevent vertical transmission of CMV has been an urgent priority during the 21st century, according to the US Institute of Medicine (now National Academy of Medicine) of the United States, but none has been licensed to date.⁵⁶˒⁵⁹ Various vaccines with different targets have been investigated over the last few decades, and the launch of an effective CMV vaccine is considered feasible in the next 5 to 10 years.⁵⁹˒⁶¹ The development of a vaccine against CMV is challenging since the infection occurs in the presence of both humoral and cell-mediated immune responses.⁵⁹˒⁶¹ Previous attempts with candidate vaccines utilizing recombinant surface protein glycoprotein B (gB) in seronegative women had limited efficacy with waning immunity over time.⁶²˒⁶³ Recently published data showed that an mRNA-based CMV vaccine (mRNA-1647) that codes for the pentamer complex antigen induced polyfunctional and durable CMV-specific responses, with higher neutralization and antibody-dependent cellular cytotoxicity compared to another gB subunit vaccine, placing it as the most promising candidate.⁶⁴ Currently, a Phase 3 clinical trial is underway investigating the efficacy of the mRNA-1647 vaccine focusing on healthy CMV-seronegative women of childbearing age from 16 to 40 years old.⁶⁵ The recruitment was completed but the observation period has currently been extended to assess the seroconversion. Results are expected in 2026.⁶⁵

Alternative methods of diagnosis and identifying those at higher risk for vertical CMV transmission and severe permanent sequelae have been explored.⁶⁶˒⁶⁹ Identification of potential biomarkers is necessary, as they might guide decision-making. A meta-analysis published in 2022 described the value of amniocentesis results in pregnant women with CMV infection in predicting the risk of fetal infection.⁶⁷ A negative amniocentesis result was associated with a lack of severe symptoms at birth and lack of long-term complications, even if vertical transmission had occurred. In addition, a recent randomized controlled trial which was conducted in the US indicated that amniocentesis results can be used as an accurate predictor of congenital CMV infection.⁶⁸ An in-progress clinical trial aims to explore non-invasive biomarkers of CMV fetal disease, avoiding amniocentesis when it is not indicated.⁷⁰

Conclusion

While significant progress has been made in the diagnosis and treatment of congenital CMV infection, much remains to be accomplished. Taking lessons learned in the management of human immune deficiency virus infection, combination antiviral therapies must be developed to accelerate the clearance of virus from these babies. The combined use of valganciclovir and letermovir, drugs with different mechanisms of action, offers such a possibility.

Importantly, further research is an urgent priority to guide policymakers about maternal and newborn screening, long-term sequelae, predictors and potential biomarkers, and optimal treatment for women and infants.

Introduction to Neonatal Herpes Simplex Virus Infection

Herpes Simplex Virus (HSV) infections are ubiquitous. By the time individuals reach adulthood, as many as 60% of individuals in the developed world and over 90% in the developing world have been infected by this virus. Under rare circumstances, HSV will cause life-threatening disease, namely, herpes simplex encephalitis and neonatal herpes simplex virus infection. While therapies have been developed, specifically acyclovir, that have improved outcome, much remains to be accomplished. Specifically, even with therapy mortality is significant. As with chronic viral infections, mentioned above, combination therapy is warranted to further improve outcome. Clearly drugs with a different mechanism of action that penetrate the central nervous system are essential toward improved neurologic outcome. As with CMV, efforts to develop an HSV vaccine have gone on for nearly a century but again, to no avail. The strengths and weaknesses of advancing the field will be discussed.

Epidemiology

While herpes simplex virus (HSV) infections are ubiquitous and well-documented in adults, neonatal HSV infections are less common but can cause neurologic disability and even death if left untreated.¹˒⁷² Genital herpes, both HSV-1 and HSV-2, in women, can be transmitted to children.⁷³ Newborns usually contract HSV as they pass through an infected maternal birth canal, but in a few cases, infection can occur earlier in utero as an ascending infection or postnatally horizontally from a parent, sibling, or other caregivers.⁴ The risk of maternal-to-child transmission is significantly higher with primary maternal infection during the third trimester of gestation compared to neonates born to mothers previously infected who reactivate the virus during pregnancy (25–60% versus <2%).⁴ The use of fetal scalp electrodes has also been identified as a risk factor for maternal-to-child transmission of HSV.⁷⁴˒⁷⁵ Due to the lack of symptoms in most maternal infections, it is difficult to distinguish between primary and recurrent infection based on maternal history. Therefore, it is not helpful to assess the risk of transmission to their child.⁴

The incidence of neonatal HSV infection is approximately 1/3000 live births in the United States with increasing incidence noted in the last few years. The global rate is estimated at 10/100,000 births.⁴˒⁷⁶˒⁷⁸ HSV infection in newborns can present in three different ways: skin-eye-mouth (SEM) disease – 45%, central nervous system (CNS) disease – 30%, and disseminated – 25%.⁴ Typically, initial signs are evident within the first month of life. Furthermore, SEM and disseminated disease usually occur earlier in the neonatal period, as opposed to the CNS infection, which usually presents between the second and third week of life. Any neonate with culture-negative sepsis, severe liver dysfunction, consumptive coagulopathy or suspected viral pneumonia must be evaluated for disseminated HSV infection. More specifically, signs and symptoms such as fever, vesicular rash or seizures with abnormal CSF indices can be indicative of HSV infection. When present, a vesicular rash is typical of SEM disease, but can also occur in CNS or disseminated disease with potentially later onset.⁴ Importantly, even though it is uncommon, suspicion is required to diagnose

and promptly treat HSV infection with CNS involvement.⁷⁹

For diagnostic purposes, the Tzanck test, a histologic examination of lesions for presence of multinucleated giant cells, was previously used, but it is not currently recommended due to low sensitivity.⁴ At present, PCR or culture (if available) is being used for the diagnosis of neonatal HSV infection. The samples used can be “surface specimens” from the mouth, nasopharynx, conjunctiva, and anus, specimens of skin vesicles, CSF sample or whole blood. To avoid false-positive results due to contamination after intrapartum exposure, specimens should be obtained 12–24 hours after birth. In addition, HSV viremia can be present in all manifestations of neonatal infection (SEM, CNS, disseminated), therefore a positive PCR result does not necessarily mean that the neonate has disseminated disease, so these results cannot be used to determine disease severity and guide the treatment duration.⁴

The prognosis of neonatal HSV infection varies widely based on multiple factors, including disease classification, the time of transmission and the extent of organ involvement.⁷¹ SEM disease exhibits better outcomes compared to the other disease types from a morbidity and mortality perspective, but it is usually followed by frequent skin recurrences.⁷¹ Infants presenting with severe symptomatology, especially with CNS involvement, are at increased risk for long-term neurodevelopmental deficits.⁷¹ Ocular complications can occur and lead to visual impairment or blindness.⁷¹ Due to the advances in antiviral therapy, the prognosis has been improved, and mortality rates have declined, but continuous efforts in this direction are needed.⁷¹˒⁸⁰˒⁸³

Treatment

The adverse and potentially detrimental outcomes of neonatal HSV infection and the emotional burden placed on patients and their families, render the management of the condition more challenging and require collaborative approaches of a multidisciplinary team.⁷¹˒⁸¹ Early recognition of the disease and initiation of treatment is critical to contain disease burden and manage the infection.⁸⁰ Treatment with high-dose intravenous acyclovir (20 mg/kg/tid) is the standard of care, with a 14-day course for SEM cases and a 21-day course for CNS or disseminated disease. In CNS involvement, repeat CSF near the end of treatment is needed to determine that the PCR is negative. In the event of a positive result, treatment for 7 more days is required, with repeat lumbar puncture until the PCR is negative. After completion of IV treatment, suppressive therapy with oral acyclovir is initiated in all cases for a 6-month duration.⁴˒⁷¹ In theory, suppressive treatment can address low-level replication of the virus and prevent or at least decrease the number of future recurrences, while also being associated with improved neurodevelopmental outcomes in infants with CNS involvement.⁸⁴

Intravenous acyclovir has been successful in treating HSV infections, but it can have adverse effects such as nephrotoxicity and bone marrow suppression; resistance to this regimen has been observed, but the prevalence in neonates is unknown.⁸⁵˒⁸⁶ Treatment resistance should be suspected in cases with persistent symptoms or positive CSF PCR results. Oral acyclovir is not used as an alternative treatment option due to poor bioavailability. In contrast, oral valacyclovir has better bioavailability, but its use has not been adequately studied.⁸⁵ Unfortunately, shortage of acyclovir supply is common, particularly over the past few years, with limited options for alternative regimens.⁸⁵ Intravenous ganciclovir is the first-line option in case of acyclovir shortage, with intravenous foscarnet as the second-line alternative.⁴ More importantly, IV acyclovir should be reserved for proven neonatal HSV disease and encephalitis.⁴

Future Approaches

Current studies focus on new treatment options and evaluate different potential targets for drug development.⁸⁷ A new agent for inhibiting HSV replication is the helicase-primase inhibitor, IM-250, which has shown high potency and crosses the blood-brain barrier.⁸⁸ This new drug is promising,

particularly for severe HSV cases resistant to nucleoside analogs such as acyclovir.⁸⁹ A combination strategy of a new inhibitor with acyclovir could also maximize efficacy, leading to improved clinical outcomes.⁸⁸ In addition, a recent clinical trial is evaluating valacyclovir pharmacokinetics and pharmacodynamics in neonates, in comparison to intravenous acyclovir, which is currently the standard of care.⁹⁰ Continuous research is required, as an orally bioavailable treatment of neonatal HSV infection could potentially decrease the emotional burden on families and the healthcare costs of intravenous therapy and long hospital stays in those babies with non-life threatening disease.⁷⁶

Given the evidence that neonates born to mothers with non-primary, recurrent genital HSV infection have a lower risk of infection, and assuming they have protection by the antibodies transferred through the placenta, an antibody-based therapy might be a place in future approaches.⁹⁵ HSV-specific monoclonal antibodies have shown promising results in animal models, but further human-based research is warranted.⁹⁵ Based on this rationale, another step towards long-term prevention of recurrent HSV infection or initial infection is the development of a vaccine against HSV, which is one of the 2023–2028 goals in the strategic plan for HSV research, according to NIH.⁷⁷˒⁹⁶ Finally, the huge burden of HSV and the existing scientific needs require persistent efforts and innovation in drug development exploring alternative mechanisms of action or other interventions to treat or prevent HSV infections.

Prevention

Focusing on pregnant women to prevent HSV transmission to their child is a significant component in the effort to reduce the disease burden.⁹¹ Serologic testing for HSV is currently available in commercial labs, and it can reliably detect type-specific antibodies in pregnant women, but there is no evidence for routine screening.⁹² For pregnant women with recurrent genital herpes, suppressive antiviral treatment should be offered beyond 36 weeks of gestation. PCR screening of women in the delivery suite can also be an excellent tool in HSV management.⁹³ According to the American Academy of Pediatrics, current evaluation and management algorithms for newborns are based on the mother’s classification of HSV infection.⁹⁴ Cesarean section is recommended for mothers with active genital HSV lesions to prevent newborn exposure during delivery.⁹² In addition, careful hand hygiene is important postnatally in mothers with active lesions while handling their infants.⁴

Conclusion

Neonatal HSV infection, like CMV, requires combination therapy with drugs having different mechanisms of action. Perhaps IM-250 plus acyclovir will help address this important need. Further, an oral formulation of valacyclovir, the prodrug of acyclovir with improved bioavailability, would make ambulatory care significantly easier for families and the child. At the present, valacyclovir has to be compounded before it can be administered.

Conflicts of Interest Statement:
The authors have no conflicts of interest to declare.

Funding Statement:
This work was supported by the Department of Pediatrics, Heeersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL; 35224

YoReference

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