Epidemiology And Routes Of Transmission

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The prevalence of HHV-8 infection has not yet been firmly established, but it seems to vary among different populations and in different regions of the world. Unlike most other herpesviruses, HHV-8 infection does not seem to be widely distributed in most populations. The frequency of infection appears to be low in the general population in North America, certain Asian countries, and in northern European nations such as the United Kingdom and Germany (18,19). In these countries, the seroprevalence of HHV-8 in different risk groups mirrors the incidence of AIDS KS, with a seroprevalence rate of between 25 and 50% among homosexual men. In other countries such as Italy, Greece, and Israel, especially southern Italy, the infection rate seems to be much higher in the general population and is more variable, ranging between 5 and 35%.

In contrast to North America and Europe, HHV-8 infection is widespread on the African continent. High seroprevalence rates between 40 and 50% have been found in central, west, and South Africa (20-23). Therefore, HHV-8 seroprevalence tracks very closely with KS, with the highest infection rates in geographic areas where classic or endemic forms of KS are more common. KS has a particularly high incidence in central African countries like the Republic of Congo, Uganda, and Zambia; these countries also have the highest HHV-8 infection rates in the world (21).

At the moment, the exact risk factors and routes for HHV-8 transmission are not clear. Epidemiological evidence suggests that the virus is largely transmitted sexually in North America and certain northern European countries. There is a higher rate of infection in homosexual AIDS patients as compared to heterosexual AIDS patients. In the United States, the San Francisco Men's Health study showed that HHV-8 infection in this group of homosexual men was high and was linearly associated with the number of male sexual partners (24). Similarly, a study of a cohort of Danish homosexual men also showed that HHV-8 infection was associated with receptive anal intercourse (25). The likely sources of infection in this population are infected semen and feces.

The virus has not yet been found in fecal matter, but viral DNA can be detected in the semen by the polymerase chain reaction (PCR) technique. It has been reported that HHV-8 can be detected in the PBMCs in between 12 and 25% of homosexual men with KS but has not been consistently detected in semen samples of HIV-infected men without KS or from HIV-negative men (26-28). HHV-8 infections of the urogenital and prostate tissue of healthy men also do not appear to occur frequently. Therefore, the role of HHV-8 transmission via semen is still not clear. Apart from the implication of a linkage between HHV-8 infection and sexual activity suggested by the strong correlation between HHV-8 infection and homosexuality in North America and northern Europe, convincing evidence of heterosexual transmission of HHV-8 has not as yet been found. There are studies suggesting that commercial sex workers are more likely to be infected by HHV-8, and that heterosexual activity appears to be a risk factor for infection (29,30), but other risk factors such as drug use and HIV-1 infection could also play a role in HHV-8 transmission (31). It was suggested that genetic factors might also play a role in infection. A study in French Guinea, where HHV-8 infection is epidemic, suggested that a recessive gene may control susceptibility or resistance to HHV-8 infection (32).

Besides the potential role of sexual contact in HHV-8 transmission, it is likely that nonsexual routes can transmit HHV-8 as well. Among cases of classical KS, even though homosexual transmission may account for some of the cases, an undefined mode of nonsexual transmission must account for most of the other cases of classical KS (33). In developing countries, in contrast to the United States and other Western countries, HHV-8 infection is widespread in both men and women and in children. This suggests that horizontal, nonsexual transmission may be the predominant mode of transmission in these countries.

There could be several routes of nonsexual transmission. One is transmission via blood. However, unlike HIV-1, HHV-8 does not appear to be transmitted readily by blood even though viral DNA can be detected in 10-15% of the PBMCs of healthy HHV-8 seropositive individuals (13,34). However, a history of blood transfusion has been linked to KS in a San Francisco Health study (24), and infectious viruses have been isolated from a blood donor's PBMCs (35). If transfusion-related transmission does occur, it is likely to be uncommon.

HHV-8 transmission, however, has definitely been linked to transplantation. Transplant recipients have been documented to be infected by HHV-8 via allograft transmission. A study involving a cohort of 220 Swiss transplant patients demonstrated that 25 patients seroconverted within a year after transplantation (36). In another case, an organ recipient was shown to be infected after transplant (37). Another study demonstrated that a group of Italian patients who were infected by HHV-8 prior to transplantation developed KS afterward, suggesting that virus reactivation occurred after immunosuppression (37). Therefore, screening of organ donors and recipients for HHV-8 infection, especially in areas with high seroprevalence, should be considered.

A likely route of nonsexual transmission is via saliva. Oral and nasal secretions have been hypothesized to be a source of HHV-8 infection, similar to other herpesviruses. HHV-8 DNA has been detected in saliva (38), tissues (39), and oral KS lesions (40). Even though viruses can be detected in oral secretions, it is unlikely that this is the major route of transmission in North America and northern Europe because of the low seroprevalence rate in the general population. However, this may represent a major route of transmission in endemic regions like Africa, especially in transmissions to children in those areas. This route of transmission may also be responsible for infection among homosexual men (14).

Another potential route of HHV-8 transmission from infected mothers to their infants is via breast milk. A number of human herpesviruses, including cytomegalovirus, EBV, and herpes simplex virus type 1 have been detected in breast milk or shown to be transmitted via breast-feeding. The presence of HHV-8 in breast milk might suggest that this agent may also be transmitted via breast-feeding. A study from Zambia, however, failed to readily detect any HHV-8 DNA in breast milk from HHV-8-seropositive Zambian mothers (both HIV-positive and -negative). In contrast, 21% of the samples studied were positive for EBV DNA (41). This study suggests that breast milk transmission of HHV-8 is an unlikely route of transmission, but further studies will be needed to substantiate this conclusion.

In summary, the exact routes of HHV-8 transmission are unknown. The routes may be different among different populations and in different parts of the world. The sexual mode of transmission may be predominant in the homosexual male population, whereas for other risk groups, nonsexual routes such as horizontal transmission via saliva and organ transplantation may occur.

Infection in Women and Children

Different forms of KS, including African KS and classical KS, occur more commonly in men than in woman and seem to have a bimodal age distribution. Classic KS occurs predominantly in elderly male patients of southern European ancestry. Before the AIDS epidemic, African KS occurred primarily among men. Hormonal differences between genders had previously been implicated as the basis for this observation. In contrast to the known high HHV-8 seroprevalence in the homosexual male population, very little is known about the epidemiology of HHV-8 infection among women. Previous studies have indicated that the rate of HHV-8 infection among HIV-infected women may be much lower than that among HIV-infected homosexual males (42).

A multisite cohort of HIV-infected and high-risk HIV-uninfected women in the United States demonstrated that 15% of the HIV-1-infected and 6.3% of HIV-1-nega-tive women were infected by HHV-8 (43). This was higher than the prevalence rate reported for the heterosexual women population (44). However, much higher rates of infection were reported in KS-endemic regions such as sub-Saharan Africa (45). Of the normal female population, 40% were found to be infected by HHV-8 in Zambia (22), and the infection rate here seems to be as high in the female as the male population.

There are a number of risk factors associated with HHV-8 infection. A history of injection drug use and sexually transmitted diseases such as syphilis are known to be risk factors for infection in women (29). The presence of HIV-1 infection was also found to be consistently associated with HHV-8 infection (29,43). These findings support the notion that HHV-8 can be transmitted sexually in women and through needle sharing during injection drug use. It is likely that the virus is inefficiently transmitted via blood or blood products as HHV-8 infection has only infrequently been linked to transfusion.

Infection by HHV-8 appears to be rare in infants in North America and northern Europe. In endemic countries in sub-Saharan Africa, there seems to be a continuous increase in HHV-8 seroprevalence with age, transmission appears to increase after the age of 2 years, and the infection is likely to be acquired before puberty (23,46-48). Studies suggest that nonsexual transmission may be the predominant mode of transmission in children. In studies from Uganda and Zambia, infants as young as 7 months were documented to have KS (49,50), suggesting that vertical transmission from mother to child is also possible. It has been reported that HHV-8 can be detected in newborn infants in Zambia (51,52), although another study involving a group of Italian women tested during pregnancy and at delivery did not find any evidence of vertical transmission (53). This discrepancy could be caused by different populations in different geographical locations.

Taken together, there is sufficient evidence to show that newborns can acquire HHV-8 infection in utero, and that vertical transmission of HHV-8 can occur. The frequency of its occurrence, however, is probably rare. In this regard, the pattern of HHV-8 transmission to infants is very similar to other herpesviruses. The major route of HHV-8 transmission to infants and children may be horizontal, as would occur within families, such as between siblings, and from either parent to the children (54-56).

In conclusion, HHV-8 infection in women and infants varies depending on the geographical location; infection is rare in the Western countries but is quite prevalent in the HIV epidemic countries in Africa. It is not known whether there is an increased risk of HHV-8 infection in pregnant women, but the transmission of HHV-8 from infected mothers to their infants during pregnancies is extremely rare even in the epidemic regions. The majority of the infected children probably acquired the virus horizontally via household contacts.

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