Human herpesvirus 8 epidemiology

Introduction Human herpesvirus 8 (HHV-8), also known as ‘Kaposi's sarcoma-associated herpesvirus’ (KSHV), was first identified in 1994 [1]. Its discovery is a good example of how epidemiological and molecular-biological data can be combined to evaluate causality for a putative agent [2]. In fact, before the discovery of HHV-8, the analysis of surveillance data had suggested that, in HIV-infected individuals, there existed an infectious co-factor other than HIV that was critical to the development of Kaposi's sarcoma (KS), leading to the identification of HHV-8 in KS tissues [3]. HHV-8 is now considered to be the necessary cause of all variants of KS, including AIDS KS, classic KS, endemic KS and iatrogenic KS, and is a determinant of other rare diseases, such as primary effusion lymphoma, or body cavity-based lymphoma and multicentric Castleman's disease [4,5]. However, various aspects of the epidemiology of HHV-8 infection still need to be clearly defined: in particular, the evolution of the HHV-8 epidemic, the appropriate serological assays and their application, the distinct distribution features of HHV-8 in relation to KS, transmission modalities, and the natural history of infection. In the present text, we provide a synopsis of what we do and do not know about the epidemiology of HHV-8 infection, especially with regard to Africa. It is therefore not intended to provide an exhaustive review but to highlight the current thinking about HHV-8, as guided by the pioneering research performed to date. Molecular epidemiology HHV-8 is an ancient virus. The HHV-8 genome shows variation almost exclusively in the K1 gene. Phylogenetic analysis has revealed several distinct subtypes, which are believed to have diverged at least 10 000 years ago. Based on variation in open reading frame (ORF) K1, the first subtypes to be identified were A, B, C, and D, followed by subtypes E and N [6,7]. Subtypes A and C are genetically less distant from each other than they are from subtype B. Within subtype C, at least two distinct subgroups have been identified [8]. In addition, variations were identified at the right end of the genome in ORF K15 that reveal evidence for recombination and distinction between two diverged types with variability that is not linked to ORF K1 [9]. The geographical distribution of predominant subtypes is shown in Fig. 1. Subtypes A and C predominate in Europe, whereas subtype B predominates in Africa [8,10]. Subtype D is rare and has been found in individuals of Polynesian and Australian aboriginal origin with classic KS. Subtype E has been reported to be hyperendemic in Brazilian Amerindians [11]. Subtype N, a novel subtype, has been identified only in South Africa [12].Fig. 1.: Epidemiological patterns of human herpesvirus 8 infection. Countries were allocated to specific patterns on the basis of human herpesvirus 8 (HHV-8) prevalence data. For Mediterranean countries such as Greece, which lacks seroprevalence data, or Egypt, where data are available only for the city of Alexandria, allocation was based on patterns of Kaposi's sarcoma (KS) occurrence. Seroprevalence data for Albania are still unpublished (G.R. personal observation). The letters in the figure refer to HHV-8 genotype.The human herpesvirus 8 epidemic versus the AIDS epidemic In Europe, HHV-8 subtypes do not cluster within specific geographical areas, and types A and C were present in Europe long before the advent of the AIDS epidemic [8]. The various subtypes may have co-evolved with certain human populations [13]. KS was endemic in South Africa even before the advent of the AIDS epidemic [14]. In this and other African regions of KS endemicity, the onset of AIDS has led to an increased prevalence of KS. Similarly, among the subgroup of homosexual men in industrialized countries, HHV-8 has caused numerous cases of KS, once the HIV epidemic has led to widespread immunosuppression. A virus needs a route of transmission to sustain its presence after introduction, and such a route was apparently present, for example among these men. Some studies conducted among homosexual men in north America and Europe [15,16] suggested that there existed concurrent epidemics of HHV-8 and HIV infections and that the two infections have modalities of transmission in common. However, other studies suggested that the prevalence of HHV-8 infection was already high among homosexual men when the HIV epidemic began. Although some initial increases in the prevalence of HHV-8 infection were reported among homosexual men at the start of the HIV epidemic in the early 1980s, the prevalence has since remained at a nearly constant level [17–19]. The discrepancy in prevalence trends over time between HIV and HHV-8 indicate that there must be different or at least additional transmission routes for HHV-8 when compared with HIV. Serological assays Currently used serological assays The currently used serological assays are: Western blot, immunofluorescence assays or enzyme immunoassays. In general, these assays are based on latent antigens expressed by ORF 73, lytic antigens expressed by ORF 65, or both, but their accuracy (i.e. sensitivity and specificity) has not been established. There is no gold standard for HHV-8 because the virus cannot be reliably cultured. Currently, negative reference sera are obtained from individuals at a low risk of KS, such as women without KS in northern Europe, whereas positive reference sera are obtained from individuals with KS. However, as individuals with KS generally have higher HHV-8 titres than individuals without KS, the estimated sensitivity may likewise represent an overestimate [20], and as one can never be sure that individuals at low risk of KS are not infected with HHV-8, the estimated specificity may also represent an overestimate. As immunofluorescence assays that detect lytic antigens are generally more sensitive than other assays, their use results in higher estimates of prevalence [21]. In addition, assays based on antigens expressed by ORF K8.1 have relatively high specificity and sensitivity [22]. The existing serological assays nonetheless need to be further refined, and new assays need to be developed. The combining of assays in screening algorithms, as well as the development of new assays, is an area of continuing progress [23–25]. The application of serological assays in epidemiological studies The development of serological assays capable of detecting antibodies against HHV-8 has paved the way for large-scale epidemiological studies, which have provided important information on HHV-8 infection. For example, several cohort studies on HIV and AIDS, in which stored sera were screened for HHV-8 antibodies, have allowed the temporal relationship to be established between HHV-8 infections and KS occurrence in HIV-infected individuals [26–28]. However, the various serological assays are still imperfect, resulting in the misclassification of HHV-8 test results, which influences the results of epidemiological studies. This shortcoming probably accounts for a substantial part of the differences in prevalence rates among studies. However, although absolute prevalence estimates cannot be generated, the distribution of HHV-8 infection among HIV risk groups and geographical areas has been quite comparable in most studies (see the following sections on the distribution of HHV-8 infection). In high-prevalence settings, suboptimal specificity and sensitivity will most likely cause the magnitude of the associations to be underestimated, at least when the misclassification of the outcome is unrelated to the risk factors of interest. In low-prevalence settings, particular caution is recommended, because the number of false positives can exceed the number of true cases, leading not only to the underestimation of risks but also to spurious associations when comparing seronegative with seropositive individuals. The application of serological assays with an optimal level of specificity is thus crucial in such low-prevalence settings as the African countries of Gambia and Botswana [24,29]. Table 1 illustrates the effect of suboptimal serological assays in terms of the positive predictive value and the rate of false positivity.Table 1: Examples of the variation in positive predictive value in generation of false positive cases caused by different sub-optimal serological assays in low prevalence settings (2.5%) and intermediate/high prevalence settings (25%).The distribution of human herpesvirus 8 infection in relation to Kaposi's sarcoma The distribution of human herpesvirus 8 infection by HIV exposure category Among HIV exposure categories at risk of AIDS KS in north America and Europe, the prevalence of HHV-8 shows a distinct spread. Within a defined geographical area, this prevalence is highest among HIV-infected homosexual men, lower among HIV-infected injecting drug users (IDU) [21,30–35] or HIV-infected non-IDU heterosexual individuals, and among children the prevalence of HHV-8 is the lowest [21,36,37]. Interestingly, in one US region, the HHV-8 prevalence rates among young homosexual men (i.e. 15–22 years of age) were comparable with the rates among young heterosexual men, and both were noticeably lower than rates among older homosexual men in that region [38,39]. Overall, the distribution of HHV-8 infection between HIV risk groups mirrors the pattern of KS occurrence in HIV-infected individuals. Most cases of KS occur among HIV-infected homosexual men, for whom KS has been one of the most common AIDS-defining illnesses, representing 22–29% of such illnesses before the introduction of highly active antiretroviral therapy (HAART) [40,41]. Among HIV-infected IDU and non-IDU heterosexual individuals KS is very rare. The geographical distribution of human herpesvirus 8 infection Although the geographical distribution of HHV-8 infection in the general population has not been completely defined, it is similar to that of KS [42], with a high prevalence in sub-Saharan Africa, relatively high or intermediate prevalence in southern Italy and other Mediterranean areas, and very low prevalence in northern Europe and the United However, these areas variations within that need to be For example, in the prevalence between less than in the to more than in the South with the highest rates on the of and variations have been even within areas, such as northern where the prevalence from less than in the city of to more than at the lower end of the The highest prevalence in the Mediterranean area has been reported in Alexandria, A low prevalence has been found in and in various although these are considered to have a relatively high risk of KS. rates are low in The lowest HHV-8 prevalence has been reported in northern Europe and the United where KS accounts for only of all In these areas, HHV-8 infection is among homosexual men at risk of HIV infection The HHV-8 prevalence is low or even very low in countries of in and in and where KS is very A high prevalence has been among populations in of and areas endemic for Kaposi's the of Africa The highest prevalence of KS has been reported in sub-Saharan Africa, where endemic KS has been reported to In this area, the HHV-8 seroprevalence among children from in to in and from in to in among from in Africa to in high between and have been reported in the and in Botswana and among older in and The that most geographical differences in the occurrence of KS are caused by variations in the prevalence of HHV-8 infection is by data shown in Fig. It HHV-8 prevalence rates reported by several studies and the level of KS as defined by the or the of KS between human herpesvirus 8 prevalence and the occurrence of Kaposi's Kaposi's sarcoma rates men and the of all are (i.e. in In one (i.e. in refer only to spurious associations and the for in the development of Kaposi's sarcoma The epidemiological pattern of HHV-8 infection to be the determinant of the geographical variations in KS in fact, a between HHV-8 prevalence and classic KS occurrence has been shown by studies in areas and to be by of data at the level However, HHV-8 prevalence may not completely the geographical variations in KS several to the In Alexandria, in areas of the and new and in areas of the prevalence of HHV-8 infection is the occurrence of KS is between HHV-8 and KS distribution may In some areas, the of KS may be because of or for example, a of KS in to this geographical of HHV-8 prevalence may be by differences in the of the used assays (i.e. sensitivity and low of the populations (i.e. differences in and variations (i.e. For example, the high prevalence of HHV-8 infection found in some African countries with no KS endemicity, such as Gambia or the be the of or a low specificity of It be that the development of KS was not in a of to although a specific Western found that HHV-8 was common in a subgroup of these This discrepancy as but they also the from the development of KS A different distribution of the risk of KS in areas with similar HHV-8 but in that the factors considered to for KS the basis of at least be after for factors that the risk of KS, such as and do not geographical such as may be but no evidence of their effect after for HHV-8 infection has been factors (i.e. the of different HHV-8 are not likely to an important because there is no evidence of differences in subtype and the of different subtypes is common. However, the effect of factors needs to be more has been to For example, KS has been with exposure to and to be more common in areas at over although high rates have been found at a of and in to the pattern of lymphoma HHV-8 which is high the of Africa, probably accounts for the high of KS in that area, although a effect on the risk of KS by other factors cannot be HHV-8 infection is also likely to in an area with endemic may be a risk for KS. This has been found in Italy but only in Africa, where of the highest estimated KS rates have been reported in areas in which is data do not an between HHV-8 and but do not a for in the risk of KS among individuals. A be the of from a from an HHV-8 to the has to be modalities of human herpesvirus have they been human herpesvirus 8 transmission modalities with of other specific studies have been performed to the of HHV-8 but the results, the specific routes in HHV-8, as virus is among the as in Fig. However, the transmission modalities of HHV-8 to be in between of and of an virus that is HHV-8 transmission modalities to between highly endemic and The number of HHV-8 is higher in than in or It has been suggested that HHV-8 can in the There is evidence of of Human herpesvirus 8 in relation to other human epidemiological and human HHV-8, human herpesvirus virus. Phylogenetic from with studies transmission are they to certain that will be of human herpesvirus 8 studies have provided some evidence that HHV-8 can be by or Some studies, which were performed in intermediate or high endemic have shown that the prevalence is higher among IDU compared with the general or they have an between HHV-8 infection and injecting In countries or populations that are highly endemic for HHV-8, transmission by is not believed to be a but a In low-prevalence areas, the prevalence of HHV-8 is generally similar between IDU and the general Among although is a common of B virus and C it in a similar of HHV-8 It is likely that in low-prevalence areas transmission by very The introduction of HHV-8 in low-prevalence populations occur by individuals had had with homosexual or men or by individuals from areas that are endemic for HHV-8 infection. transmission A of HHV-8 prevalence within reported high rates among individuals with classic KS and their and these rates were higher than among a of individuals from the general population were by and from countries that are endemic for HHV-8 infection that the virus can be among and that transmission is with and are also for other including B, and transmission and transmission are rare in the United and Europe, but do occur in countries where HHV-8 infection is more such as African and Mediterranean countries The high prevalence of infection before in endemic areas and the higher of the of HHV-8 in compared with provide evidence of It is thus that be in transmission in endemic countries, although this is not by studies of transmission are shown by cases of to HHV-8 after and indicate that HHV-8 be from the transmission There is evidence of the transmission of HHV-8 transmission is suggested by the high found in several studies and transmission to with titres However, most studies have shown that HHV-8 prevalence in children increases with their and that most children to have antibodies and by of In transmission is very to although evidence is still to human herpesvirus 8 Among with transmission have not been established transmission is not likely to be a route and to exposure to to be in have a high number of or a disease Among homosexual men, there is that the transmission of HHV-8 is thus in this population AIDS KS can be considered to be a disease However, the specific a of Some of the early studies on the relationship between KS and reported an between and AIDS KS studies have an between the presence of HHV-8 antibodies and and with an studies have the risk factors for HHV-8 infection, and all found evidence of transmission among homosexual men, with an a risk for one specific to to be a risk studies of have shown that HHV-8 is not in or but is found in the of some individuals is a common among homosexual men, as is is a of HHV-8, it may The risk of HHV-8 transmission or may be even because or no virus has been in or However, is in it is not in low endemic countries have such a low prevalence compared with homosexual men. the that homosexual men generally more in various when compared with heterosexual individuals may their of the virus. in epidemiological studies on transmission In of the in their studies identified the the highest risk of HIV As was associations of a magnitude for HIV a certain of as that caused by and thus can still be the results of HHV-8 studies, the associations we in HHV-8 transmission are probably of low detect studies be to as as by the use of optimal serological assays and information and by the of In to there are other for the differences in the on risk factors obtained in various countries and In certain such as homosexual men, there may routes or a certain transmission route or that is more because of such as higher virus the of an must be for each population or geographical A transmission route may for more infections in a high-prevalence than in a low-prevalence because the to the virus is do we know about the natural history of human herpesvirus 8 The natural history of HHV-8 infection is still KS, the with HHV-8 infection, in a of infected individuals certain are present, especially or immunosuppression. and studies have provided important for the natural history of HHV-8 infection, as in Fig. can now the determinant of KS development to a the development of such as primary effusion lymphoma and multicentric Castleman's in which HHV-8 infection has been to a such as and will not be considered because of the of the The natural history of human herpesvirus 8 and of HHV-8, Human herpesvirus KS, Kaposi's herpesvirus 8 primary disease There are of cases of disease to primary HHV-8 infection in or individuals. The first an HIV-infected homosexual with a of the onset of and Within there was of the and (i.e. and of to HHV-8 was estimated to have from to before the onset of cases of primary HHV-8 disease were reported in two after they KS and an by and with at the time of had been but the first available obtained when the to HHV-8 A of the of HHV-8 in a with suggested that may occur in with primary The of the in these was to the and was not what be in the HHV-8 primary infection of an In a of homosexual men were negative for HHV-8 cases of primary HHV-8 infection and were with and of and In a conducted in primary HHV-8 infection was with a among within after the onset of HHV-8 infection may thus occur in both and with a different level of The with which may occur is still and of to Kaposi's sarcoma The of KS after is than in the general population to of KS, on their geographical origin and the of In a cohort of KS within in two of the had a primary HHV-8 infection after but in of were HHV-8 positive before an that 10 of KS were HHV-8 seropositive before whereas only one had a primary HHV-8 infection data are by of which that KS in of the were HHV-8 seropositive before but in of after the that, at least in highly endemic areas, individuals are already infected before are more likely to KS than infected they are by studies that HHV-8 may after HIV-infected individuals HIV-infected individuals have a risk of KS that is of higher than that of the general studies of in the of individuals with AIDS KS evidence of HHV-8 infection well before the occurrence of KS In a of HIV-infected homosexual men, were followed for a of more than of had HHV-8 by in the had to KS within years HHV-8 studies that the of KS was among men were HIV-infected at studies of HHV-8 individuals with known of HIV found an rate of nearly after HIV other cohort studies of individuals with known of HIV and HHV-8 infection that the risk of KS is higher when HHV-8 after HIV with risk between and The of KS from infection to by more than for each of infection with HIV before HHV-8 data that KS among HIV-infected individuals is more likely to occur when an more are by of an between the to KS and low of the development of KS among individuals, such as high HHV-8 titres and high HHV-8 have also been identified KS to occur less with infection than with infection, even when the two HIV types are by the level of HHV-8 This that other to as to are in the development of KS KS very well to and has been shown to such This is by in the of AIDS KS since the use of widespread were to in HHV-8 but this was when the of on KS was The in KS rates after the introduction of led to the that the This has been by the identification of an effect of in population There is information on the risk of KS among individuals. This of data results, at least from the low of KS in the general studies on the risk of KS among individuals. A conducted among individuals over years of on of the Mediterranean (i.e. and rates from 1 to 1 among men and from 1 to 1 10 among The between and that factors may differences in the development of KS The of is further by the of almost rates of HHV-8 infection among men and women in different areas of the in with of KS with which may be as high as 10 especially in to the risk of the development of KS in HHV-8 endemic areas, KS after years of is thus an established co-factor for the development of KS among individuals. the early of HHV-8 may be a to KS is The of other factors needs to be after for HHV-8 infection. in highly endemic areas of KS in or factors that the risk of KS (i.e. some or or this risk (i.e. with regard to the with classic KS are by (i.e. level of or although an of cannot be (i.e. lower caused by low A of individuals with and without KS found to be for KS, because of its effect on but this needs to be the different HHV-8 subtypes in or is still It has been suggested that subtype A is more than subtypes B or C but were based on a number of HIV-infected individuals and more current HHV-8 serological assays are it is to HHV-8 and in in settings, a HHV-8 serological is because misclassification can to are developed. The distribution of HHV-8 infection clearly with the distribution of KS. This not completely the that other the different areas of the may some of the However, most of the of KS identified before the discovery of HHV-8 are now The of or not HHV-8 can be by is important because of its for by is probably very rare in countries of low endemicity, where groups at high risk of HIV thus of are already from However, transmission is a that must be considered in high endemic Although there is evidence that HHV-8 may be additional studies are to transmission routes and the of as well as transmission both in endemic areas and in countries with a The identification of transmission routes can to the risk of KS among HIV-infected individuals and among individuals at high risk of iatrogenic KS. The natural history of HHV-8 infection to be completely disease has been but its is studies have provided estimates of the risk of KS among HIV and individuals to a among information is available on the risks and of KS among apparently individuals. Although have been since the identification of HHV-8, The of of transmission and natural and serological assays, and to present a for various of The to for on an and for the