Update on antiviral therapy for herpes simplex virus infection

ABSTRACT: The prevalence of infection with herpes simplex virus (HSV) continues to increase largely due to the inability of current antiviral agents to eradicate latent infection. This article reviews strategies to slow the transmission of HSV infection, most importantly through the development of vaccines, as well as established and emerging choices for treatment of primary and recurrent genital herpes, herpes labialis, infections in immunocompromised hosts, and acyclovir-resistant infections. The role of chronic suppressive therapy in the management of genital herpes as well as its potential impact on transmission rates will also be discussed.
Herpes simplex virus (HSV) is a widespread pathogen in the United States, with more than 100 million U.S. citizens having serologic evidence of HSV-1 infection and 40–60 million, nearly one-fifth of the adolescent and adult population, infected with HSV-2 (1,2) . The prevalence of HSV-2, the major cause of genital herpes, has increased 30% since the late 1970s (2) . The fact that most of those infected with HSV are asymptomatic and yet may still be subclinically shedding virus further complicates efforts to slow the spread of transmission (3) . Therefore proper management of herpetic infections requires that the clinician be able to effectively diagnose those with HSV infection, to educate them regarding means of spread and symptoms indicative of infection, and to adequately treat infections which are identified in order to alleviate patient symptoms and slow the transmission of the virus. We review options for preventing infection, treating primary infections, and treating recurrent infections in order to accomplish these goals.     

带状疱疹抗病毒药物的合理选择

抗病毒治疗是带状疱疹治疗的核心, 本文结合最新研究、共识和指南, 探讨抗病毒药物种类和剂量的合理选择。伐昔洛韦口服生物利用度高, 且用药更方便, 一般是口服抗病毒药物的首选;而对于一些特殊情况, 如免疫力低下患者, 应酌情选择静脉滴注阿昔洛韦。对于严重肾功能不全的患者, 溴夫定往往是更好的选择;对阿昔洛韦耐药的患者应考虑使用泛昔洛韦或者其他抗病毒药物治疗;而对于免疫力低下同时合并阿昔洛韦耐药的患者可选择静脉滴注膦甲酸钠。使用口服抗病毒药应达到足够的剂量。选择合适的抗病毒药物及剂量能有效缓解患者急性期症状, 同时降低发生带状疱疹后神经痛的可能性。     

Natural history of genital herpes simplex virus type 1 infection

BACKGROUND: Herpes simplex virus type 1 (HSV-1) has been increasingly reported as a cause of genital herpes, yet there have been few studies on the long-term natural history of this infection.GOAL The goal was to examine the clinical course of genital HSV-1 infection. STUDY DESIGN: This was a cohort study of patients presenting with culture-proven primary genital HSV-1 infection. RESULTS: The median follow-up of the 77 patients was 736 days. The overall rate of recurrences was 1.3/year in the first year of infection, decreasing to 0.7/year in the second year. In the first year of infection, 43% of study patients did not have a recurrence. In the second year of infection, 67% of study patients did not have a recurrence. CONCLUSION: Genital HSV-1 recurs infrequently in most patients, and the rate decreases further in the subsequent years of infection. Because the prognoses of genital HSV-1 and HSV-2 infections differ, determination of the viral type is important for patient counseling.     

Cytologic diagnosis of herpes simplex virus infection

Alterations in epithelial cells infected with herpes simplex viruses (HSV) have been described repeatedly^1–7 since Tzank,⁸ in 1947, advocated the use of cytology for the diagnosis of these infections. In spite of successful use of this technique in the following years by Blank and his collaborators,^9,10 enthusiasm for this diagnostic method gradually waned because of the emergence of other, more sophisticated, laboratory tests for viral diagnosis (culture, serology, antibody determination, animal inoculation, electron microscopy, etc.).¹¹For the last 20 years, with the use of the Papanicolaou staining method, cytology has proven to be a fairly reliable, rapid, and simple method of diagnosis of HSV infections. The Pap stain gives better nuclear detail of the alcohol-fixed cells than the original Tzank smear, which was air-dried and Giemsa stained. This cytologic diagnosis has been and continues to be especially significant in detecting cervical herpetic infections through the use of Papanicolaou smears for cancer screening of asymptomatic women.¹²     

HSV-2与HIV-1感染相关性研究进展

HSV-2与HIV-1的感染有协同作用,HSV-2感染可增加HIV-1的感染率,并可能提高HIV-1的传播率.生物学实验证据表明,HSV-2合并感染可以促进HIV-1的增殖,流行病学数据也表明HSV-2感染与HIV-1感染的相关性.概述两者相关性的流行病学证据和生物学作用机制,为将HSV-2作为HIV-1感染的危险因素以及通过行为干预、抗病毒治疗HSV-2来防控HIV-1的传播提供理论依据.

Abstract：

Herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1)are synergistic copathogens. Biological and epidemiological evidence suggests that HSV-2 infection increases the risk of HIV-1 acquisition and may facilitate the transmission of HIV-1. This review focuses on the epidemiological relationship and biological interaction between HSV-2 and HIV-1. Based on these data, HSV-2infection should be targeted as a risk factor for HIV-1 acquisition, and more prevention through behavioural interventions and antiviral suppression should be incorporated into the strategy for HIV-1 prevention.     

新生儿单纯疱疹病毒感染1例

报告1例新生儿单纯疱疹病毒感染。患儿男，出生时全身已有广泛的皮损，表现为红斑、瘀斑，水疱和血疱，水疱发生在红斑的基础上。血清特异性单纯疱疹病毒抗体阳性，皮损活检后经电镜检查找到单纯疱疹病毒(HSV)颗粒、心脏B超检查示动脉导管未闭和卵圆孔未闭。经积极的抗感染和支持疗法治疗无效，患儿最终死于肺部感染和多器官功能衰竭。     

Treatment of herpes simplex virus infection: rationale for occlusion

Orofacial herpes is a widespread benign malady that is also commonly known as herpes labialis or cold sores. Herpes of this type is generally caused by herpes simplex virus type 1 (HSV-1) and, to a lesser degree, herpes simplex virus type 2 (HSV-2), both of which are DNA viruses. The clinical presentation of herpetic lesions is normally located on mucocutaneous areas of the face and may eventually erode and ulcerate, leaving wounds that are known to be difficult to successfully treat. Focus of treatment has been related to treatment of the viral infection, and limited attention has focused on the resultant wounds. Clinical observation and recent histologic evaluation has demonstrated these wounds to extend through a disrupted cutaneous basement membrane into the dermis, suggesting that HSV is capable of causing partial-thickness wounds. This observation suggests a role for occlusion in the treatment of herpetic-induced partial-thickness wounds because occlusion is well recognized as the treatment of choice for other types of partial-thickness wounds.     

单纯疱疹病毒感染的复发机制与治疗的研究进展

单纯疱疹病毒可潜伏于宿主感觉神经节并周期性地再激活引起感染复发,其部分基因产物可帮助维持潜伏状态,并可抑制感染细胞自噬及宿主的抗病毒作用以逃避宿主的免疫监视。耐药病毒株的出现使传统抗病毒药物的作用受限,近年来研究发现新型抗病毒药物如Pritelivir和Amenamevir可显著抑制病毒复制,减少病毒脱落,本文对单纯疱疹病毒的复发机制及治疗进展进行了综述。     

小檗碱衍生物HB-13体外抗单纯疱疹病毒的研究

目的 探讨小檗碱衍生物HB-13及其前体小檗碱体外抗HSV-1和HSV-2的活性.方法 利用Vero细胞体外培养模型,以阿昔洛韦(ACV)为对照药,通过观察细胞病变效应,检测HB-13和小檗碱的细胞毒性、HSV-1和HSV-2液的病毒滴度及药物抑制病毒致细胞病变效应.结果 HB-13、小檗碱和阿昔洛韦的半数中毒质量浓度(TC50)分别为31.99,380和>800 μg/mL;对HSV-1的半数抑制质量浓度(IC₅₀)分别为1.328,>100和0.443 μg/mL,治疗指数分别为24.09,<3.80和>1805.87;对HSV-2的IC₅₀分别为1.344,>100和0.679μg/mL;治疗指数分别为23.80,<3.80和>1178.20.结论 HB-13具有明显的抗HSV作用,而小檗碱无实用抗HSV活性.     

Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students

A retrospective review of genital herpes simplex virus (HSV) isolates collected in a university student health service over a 9-year period showed that an increasing proportion of isolates were HSV-1 rather than HSV-2. HSV-1 accounted for 78% of all genital isolates in this population by 2001, compared with 31% of isolates in 1993. BACKGROUND: Herpes simplex virus (HSV) type 1 is usually thought to cause less than 30% of genital herpes infections in the United States, but the proportion of infections resulting from HSV-1 is increasing in some populations. GOAL: The goal was to review the relative proportion of HSV-1 and HSV-2 as the cause of newly diagnosed genital herpes infections in a population of U.S. college students and to assess trends in the change of this proportion over time. STUDY DESIGN: Genital HSV isolates collected at a university student health service from 1993 to 2001 (n = 499) were reviewed retrospectively. Analyses included comparisons of isolates by HSV type, age group, and sex. RESULTS: The proportion of newly diagnosed genital herpes infections resulting from HSV-1 increased from 31% in 1993 to 78% in 2001 (P <0.001, linear trend P <0.001). HSV-1 was more common in females than males, but increases were noted for both sexes. HSV-1 was more common in persons aged 16 to 21 than in persons aged 22 or older. CONCLUSIONS: HSV-1 has become the most common cause of newly diagnosed genital herpes infections in this population of college students and reflects a reversal of the usual HSV-1/HSV-2 ratio.     

The psychosocial impact of serological diagnosis of asymptomatic herpes simplex virus type 2 infection

OBJECTIVES: To evaluate the impact of a positive herpes simplex virus type 2 (HSV-2) serological test on psychosocial functioning among people with no known history of genital herpes. METHODS: Individuals (age 14-30 years) without a history of genital herpes were recruited from an urban university setting and sexually transmitted diseases (STD), primary care, and adolescent clinics. Participants completed a questionnaire addressing psychological functioning, psychosocial adjustment, and perceived quality of sex and were offered free HSV-2 antibody testing. 33 HSV-2 positive people and 60 HSV-2 negative people demographically matched from the same source of recruitment were re-evaluated at a 3 month follow up visit. HSV-2 positive participants also completed a genital herpes quality of life (GHQOL) measure. RESULTS: Of the 33 who were HSV-2 seropositive, four did not recall their diagnosis. In comparing those who were HSV-2 positive with those who were negative, repeated measures analysis of variance indicated there were no significant differences over time on any of the measures. None the less, many HSV-2 positive individuals indicated that the diagnosis had a notable impact on their quality of life. Also, among the HSV-2 positive people, lower GHQOL at the 3 month follow up was predicted by higher interpersonal sensitivity (r = -0.44, p<0.05), lower social support (r = 0.40, p<0.05), and quality of sex (r = 0.62, p<0.01) at baseline. CONCLUSIONS: A diagnosis of asymptomatic HSV-2 infection does not appear to cause significant lasting psychological difficulties. Those for whom the diagnosis had the greatest impact were interpersonally vulnerable before the diagnosis. These results suggest that assessment of interpersonal distress may be important to include as part of pretest and post-test counselling.     

Reactivation of latent herpes simplex virus infection by ultraviolet light: a human model

Infection with herpes simplex virus often results in a latent infection of local sensory ganglia and a disease characterized by periodic viral reactivation and mucocutaneous lesions. The factors that trigger reactivation in humans are still poorly defined. In our study, five patients with documented histories of recurrent herpes simplex virus infection on the buttocks or sacrum were exposed to three times their minimal erythema dose of ultraviolet light. Site-specific cutaneous herpes simplex virus infection occurred at 4.4 +/- 0.4 days after exposure to ultraviolet light in 8 of 13 attempts at reactivation. We conclude that ultraviolet light can reactivate herpes simplex virus under experimentally defined conditions. This model in humans should prove useful in evaluating the pathophysiology and prevention of viral reactivation.     

非淋菌性尿道炎患者中单纯疱疹病毒感染的流行病学分析

为探讨非淋菌性尿道炎（NGU）患者中单纯疱疹病毒（HSV）感染的流行病学特征,用聚合酶链反(PCR)检测患者尿道或宫颈分泌物中的HSV－2,并对阳性患者用盐酸万乃洛韦（明竹欣）作抗病毒治疗7－10天,作追踪观察。结果发现约20．8％的NGU患者HSV－2阳性,经治疗后HSV－2均转阴性,但仅2例患者同时伴临床症状的消失。女性、性伴数＞5、伴其它STDs、病程长及抗生素疗效不佳等特征的NGU患者感染HSV的可能性大。     

Image Gallery: Lenalidomide for the treatment of pseudotumoral herpes simplex virus type 2 infection in human immunodeficiency virus infection

In situ melanoma (MIS) is the very early stage of a skin tumour called melanoma. In recent decades, the incidence rate for melanoma has increased by 2.6% per year and MIS is the main diagnosis responsible for this increase. It is important to recognize MIS, since in this phase (called the intraepidermal phase) cancer cells don't have the opportunity to spread anywhere in the body. Since MIS can be challenging to distinguish from benign (harmless) pigmented lesions, such as normal moles, this study, from Reggio Emilia, Italy, looked at two ways of diagnosing skin cancers that are non‐invasive (meaning they don't require any surgery), called reflectance confocal microscopy (RCM) and dermoscopy, to see if their use can help detect intraepidermal melanomas. Dermoscopy is a cheap, 20‐year‐old method used worldwide, in which doctors use a handheld device called a dermatoscope to look at the skin magnified by about ten times, allowing them to see things that would not be visible to the naked eye. RCM is a more recent technique, but not so readily available, that creates a grey‐scale image of a section of the skin, allowing doctors to see abnormalities, magnified by about 500 times. The authors analysed images of 120 MIS and 213 nevi (moles) using dermoscopy and RCM, which allowed them to identify several features related to MIS diagnosis (RCM aspects of intraepidermal melanoma were not yet well‐known). These features were then combined in a multi‐step diagnostic algorithm which is able to aid the physician to decide if a given pigmented lesion is an early melanoma or not (a score ≥2 signifies melanoma) with a very low margin of error. This new diagnostic algorithm, which is easy to apply, could become helpful in doctors’ clinics.     

Prevalence of infection with herpes simplex virus types 1 and 2 in Australia: a nationwide population based survey

BACKGROUND: Studies demonstrating previous herpes simplex virus (HSV) type 2 infection as a risk factor for HIV transmission, and the development of a HSV vaccine candidate, have emphasised the need for worldwide population based studies of HSV seroprevalence. The only nationwide seroprevalence studies have been conducted in the United States. METHODS: An Australia-wide, population based study of HSV-1 and HSV-2 seroprevalence was conducted, using serum and sociodemographic data collected between 1999-2000, for a representative study of risk factors for diabetes in over 11 000 adults. A stratified random sample of 4000 was tested for HSV-2 and 1000 for HSV-1, with sampling and weighting for various demographic factors. RESULTS: Seroprevalence of HSV-2 in Australian adults was 12%. Prevalence in women (16%) was twice that in men (8%). Rural populations had a lower prevalence (9%) than metropolitan (13%), and Indigenous had a higher prevalence (18%) than the non-Indigenous populations (12%). The seroprevalence of HSV-1 was 76% with significant differences by age group, sex and Indigenous status. CONCLUSION: These are the first nationwide data to compare with US studies. HSV-2 infection is less common in Australia than the United States, and this will allow planning for combating HIV transmission in high prevalence populations in northern Australia. In addition, the high HSV-1 seroprevalence will be important for future deployment of genital herpes vaccines.