INTRODUCTION — The first disease associated with human herpesvirus 8 (HHV-8) infection was Kaposi sarcoma (KS). Subsequently, several other conditions, such as primary effusion lymphoma (PEL, also known as body cavity based lymphoma) and Castleman's disease (CD), were also linked to this virus. A severe inflammatory syndrome attributed to interleukin-6 production has also been described among HHV-8 infected individuals and is known as the Kaposi sarcoma-associated herpesvirus inflammatory cytokine syndrome (KICS) [1]. Host factors and other related issues influence disease expression, since HHV-8 infection is relatively common. The onset of disease typically occurs several years after acquisition of infection. HHV-8 can also induce a primary infection characterized by fever and a maculopapular rash in children and more marked manifestations in immunocompromised individuals.
The diagnosis of HHV-8 infection and the possible role of antiviral therapy will be reviewed here. The epidemiology, mode of transmission, and disease associations of HHV-8 infection are discussed separately. (See "Virology, epidemiology, and transmission of human herpesvirus 8 infection" and "Disease associations of human herpesvirus 8 infection".)
DIAGNOSIS — The development of diagnostic testing for human herpesvirus 8 (HHV-8) has been hampered by the lack of a cell line that can serve as a culture system for isolating the virus from tissue or mucosal sites. The identification of HHV-8 positive immortalized lymphoma cell lines (eg, BCBL-1, KS-1) has been an important step in maintaining virus for study and in the development of serologic testing. These cell lines contain latent virus in an episomal form that can be stimulated by phorbol esters or butyrate into active replication with production of intact virions [2].
Polymerase chain reaction — Several different polymerase chain reaction (PCR) assays employing primers unique for HHV-8 have been described. HHV-8 DNA can be identified using PCR in virtually all biopsies of Kaposi sarcoma (KS), including AIDS-associated KS, classic KS, and endemic KS [3-9].
PCR techniques for investigation of disease associations and molecular epidemiology have proven to be of enormous value, but the following caveats must be kept in mind:
●Most PCR-based methods have used DNA-based assays, which detects both latent and lytically replicating virus. Differentiation between these two forms of viral infection may have both diagnostic as well as therapeutic importance regarding the potential benefit of antiviral therapy.
●Because HHV-8 is often present sporadically in tissue, low copy numbers are frequent.
●Laboratory contamination can arise with PCR leading to false positive results; conditions with low copy numbers make this possibility more likely. Sequence variability between isolates can help to define this issue more completely.
Clinical applications of PCR for HHV-8 disease are limited. The detection of HHV-8 DNA in the peripheral blood can support a diagnosis of KS. The prevalence of viremia in persons asymptomatically infected with HHV-8 ranges from 4 to 20 percent [10,11]. Among persons with HIV infection, the detection of HHV-8 in the peripheral blood is associated with an increased risk for development of KS [11]. Even among persons with KS, however, viremia is not universal, limiting the utility of PCR for the diagnosis of KS [11,12]. In sub-Saharan Africa, where the detection of HHV-8 in the peripheral blood is more common among individuals with KS [13], the quantity of HHV-8 DNA in the plasma was useful in both predicting survival and response to treatment after a diagnosis of KS [14].
In the three HHV-8-associated lymphoproliferative disorders, multicentric Castleman disease (MCD), Kaposi sarcoma-associated herpesvirus inflammatory cytokine syndrome (KICS), and primary effusion lymphoma (PEL), the detection of HHV-8 by PCR is more common and may be clinically useful [15].
Asymptomatic individuals with HHV-8 associated multicentric Castleman disease (MCD) are universally viremic with active disease flares [16,17]. HHV-8 quantification in plasma or peripheral blood mononuclear cells by PCR may be a useful means for diagnosing an active flare of MCD or following response to treatment [18]. Since patients with MCD also have higher quantities of HHV-8 DNA detected in the blood, it has been suggested that the detection of more than 10,000 copies/mL of HHV-8 DNA in the peripheral blood be used as a sensitive and specific discriminator between patients likely to have MCD versus KS [17]. (See "HHV-8/KSHV-associated multicentric Castleman disease".)
Although less-well studied, patients symptomatic with KICS are also nearly universally viremic, with quantities of HHV-8 in plasma very similar to patients with active MCD flares [19]. Finally, because of the rarity of the disease, large series of patients with PEL are not available, but one small series suggested that high quantities of HHV-8 DNA in pleural fluid could be used to assist in the diagnosis of PEL [20].
Serology — Several types of serologic assays have been used to measure antibodies to HHV-8. These assays are moderately sensitive and specific for the detection of previous infection with HHV-8, but are of limited clinical utility. The indirect immunofluorescence assay (IFA) which measures inhibition of fluorescence against HHV-8 infected cells has been used the most extensively [21]. Approximately 85 percent of persons with KS from whom HHV-8 DNA has been detected in lesions have antibodies to HHV-8 by IFA, and these antibodies are usually of high titer [22].
With the production of recombinant proteins to the virus, additional serologic assays have been developed. One difficulty with serologic tests in general is that serology only indicates past exposure to an agent. Because only a small portion of HHV-8 infected individuals are thought to develop clinical disease, such as KS, a positive serologic test in an asymptomatic individual could represent subclinical infection or a false positive result due to nonspecific serologic cross reactivity.
Immunofluorescence assay — In the IFA assay, serum is reacted against HHV-8 immortalized lymphoma cell lines; bound human antibody against viral antigens is visualized with fluorescent labeled antihuman IgG antibodies. The assay can be used to detect antibodies against latent phase viral antigens that will produce a characteristic nuclear pattern [22]. Alternatively, the virus can be stimulated with phorbol esters to produce full lytic antigens that will allow testing for lytic phase antibodies [21].
Most patients with KS have antibodies to both latent and lytic phage antigens. In comparative studies between laboratories, relatively good consistency has been achieved with IFA measuring antibodies against latent antigens [23]. However, the results of assays directed at lytic antigens are more variable and have given rise to controversy about the true prevalence of HHV-8 infection in different populations [24,25].
Western blot — A number of Western blot assays have been developed using recombinant proteins produced from the HHV-8 genome. Latent antigens that have been used include a protein produced from a part of the genome identified as open reading frame (ORF) 73, which is named latency associated nuclear antigen (LANA) [26,27]. Recombinant lytic antigens have also been produced and used in Western blot assays. These proteins have included ORF 65 (a capsid related protein), K 8.1, and ORF 26 (minor capsid protein) [22,28-30]. Although it might be assumed that the Western blot assays have better specificity than IFAs, the testing characteristics for these assays have not been systematically established.
Enzyme immunoassays — Both whole virus lysate and recombinant proteins have been used for enzyme linked immunosorbent assays (ELISA) [23,31-33]. The optimal serologic assay technique cannot be determined at present. A study comparing seven different immunofluorescence and ELISA assays found that, while the sensitivity for detecting HHV-8 antibodies was fairly good in patients with KS (67 to 100 percent), there was significant discordance among the various methods in low risk populations (eg, blood donors) [23]. This variability between different testing modalities makes it difficult to know which test is most accurate for seroprevalence studies in the general population. It has been suggested that a combination of whole virion ELISA and lytic IFA may be the most sensitive method for diagnosing HHV-8 [23,33-35]. Hopefully, with refinements in serologic testing over the next several years, making the correct diagnosis of HHV-8 infection should grow easier.
Luciferase immunoprecipitation assays — Given the suboptimal test characteristics of single-antigen immunologic assays, technology has been developed to simultaneously survey antibodies to multiple HHV-8 antigens. In one study, luciferase immunoprecipitation assays targeting a combination of latent and lytic antigens helped differentiate patients with KS from those with MCD [36]. However, there was significant overlap in assay results between persons with HHV-8-associated disease and persons selected as healthy controls, calling into question whether this technology could accurately differentiate persons with and without HHV-8 infection.
TREATMENT — Various modalities have been used to prevent and treat human herpesvirus 8 (HHV-8)-related diseases. Current strategies include targeting HHV-8 replication, reconstituting the immune system in immunosuppressed patients, and chemotherapy aimed at transformed cells in HHV-8 associated malignancies.
Antiviral therapy — The effect of antiviral agents on HHV-8 replication has not been extensively studied. There are several reports of in vitro testing of herpesvirus DNA polymerase inhibitors against HHV-8. These agents would presumably be effective against the lytic phase of the virus but would probably have less activity in the latent phase in host or tumor tissues.
In vitro activity — The activity of different agents can be compared by testing the ability to block stimulation of lytic replication in HHV-8-infected cell lines (eg, BCBL-1) [37-41]. Ganciclovir, cidofovir, foscarnet, adefovir, and lobucavir all have some in vitro activity in this type of testing system. By contrast, acyclovir does not appear to have high levels of activity [42]. The HIV protease inhibitor (PI) nelfinavir was shown to have an inhibitory effect on HHV-8 replication in vitro, which was similar to that seen with ganciclovir [43]. Nelfinavir has previously been shown to inhibit the growth of Kaposi sarcoma (KS) tumors in vitro [44]. The inhibition of HHV-8 replication in vitro was notably restricted to nelfinavir when a broad panel of PIs was tested. Finally, arbidol, a medication that has been used outside the United States as treatment for influenza, also has potent activity against HHV-8 in vitro, but no clinical studies have been conducted and the mechanism of action remains unclear [45].
In vivo activity — In vivo data are limited. A double-blind, placebo-controlled, crossover trial assessed the efficacy of oral valganciclovir (900 mg once daily) versus placebo in 26 men infected with HHV-8 [46]. Valganciclovir use was associated with significantly less oropharyngeal shedding of HHV-8 as detected by daily quantitative polymerase chain reaction (PCR) assays (23 versus 44 percent with placebo).
In contrast, a report of seven HIV-infected individuals receiving intravenous ganciclovir or foscarnet for CMV retinitis found no difference in pre- and post-treatment HHV-8 DNA levels in peripheral blood mononuclear cells [47].
An analysis of HIV-1 seropositive men in Seattle and Peru showed that both valacyclovir and famciclovir use was associated with modest but significant reductions in the frequency of HHV-8 detection in saliva [48]. The clinical significance of these findings remains to be determined. The use of antiretroviral therapy (ART), however, was associated with a nearly 90 percent reduction in the frequency of HHV-8 detected at the oropharynx, and could help explain why KS incidence has decreased so dramatically in resource-rich settings where ART has been widely used.
Possible therapies for AIDS-related Kaposi sarcoma and two other HHV-8 related diseases, primary effusion lymphoma and Castleman's disease, are discussed separately. Antiviral therapy plays a role in the treatment of HIV-associated, multicentric Castleman's disease [49]. (See "AIDS-related Kaposi sarcoma: Staging and treatment" and "Primary effusion lymphoma" and "HHV-8/KSHV-associated multicentric Castleman disease".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)
SUMMARY AND RECOMMENDATIONS
●The first disease associated with human herpesvirus 8 (HHV-8) infection was Kaposi sarcoma (KS). Subsequently, several other conditions, such as Castleman disease (CD), primary effusion lymphoma (PEL), and Kaposi sarcoma-associated herpesvirus inflammatory cytokine syndrome (KICS) were also linked to this virus. The onset of disease typically occurs several years after acquisition of infection. HHV-8 primary infection may be characterized by fever and a maculopapular rash in children and more marked manifestations in immunocompromised individuals. (See 'Introduction' above.)
●HHV-8 DNA can be identified using polymerase chain reaction (PCR) assays in virtually all biopsies of KS, including AIDS-associated KS, classic KS, and endemic KS. Among persons with HIV infection, the detection of HHV-8 in the peripheral blood is associated with an increased risk for development of KS. Even among persons with KS, however, viremia is not universal, limiting the utility of PCR for the diagnosis of KS. (See 'Polymerase chain reaction' above.)
●In contrast to KS, asymptomatic individuals with HHV-8 associated multicentric Castleman disease (MCD) and KICS are universally viremic with active disease flares. The quantity of HHV-8 detected may both allow for differentiation between KS and MCD or KICS and help predict survival in patients with KS. Data are limited on the role of HHV-8 DNA quantification from clinical samples in PEL, but high quantities of the virus in effusions from patients suspected to have PEL can help support the diagnosis. (See 'Polymerase chain reaction' above.)
●Several types of serologic assays have been used to measure antibodies to HHV-8. These assays are moderately sensitive and specific for the detection of previous infection with HHV-8, but are of limited clinical utility. (See 'Serology' above.)
●Various modalities have been used to prevent and treat HHV-8-related diseases. Current strategies include targeting HHV-8 replication, reconstituting the immune system in immunocompromised patients, and chemotherapy aimed at transformed cells in HHV-8 associated malignancies.(See 'Treatment' above.)
●Ganciclovir, cidofovir, foscarnet, adefovir, lobucavir, and nelfinavir all have some in vitro activity against HHV-8. By contrast, acyclovir does not appear to have high levels of in vitro anti-HHV8 activity. Studies in HIV-positive men support the ability of ganciclovir, valacyclovir, famciclovir, and antiretroviral therapy to suppress HHV-8 replication. Possible therapies for AIDS-related Kaposi sarcoma and two other HHV-8 related diseases, PEL and CD, are discussed separately. (See 'Antiviral therapy' above and "AIDS-related Kaposi sarcoma: Staging and treatment" and "Primary effusion lymphoma" and "HHV-8/KSHV-associated multicentric Castleman disease".)
