Progress Toward HHV-8 Prevention After Transplantation: In Search for Optimal Diagnostic Strategies

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In certain geographic regions and at-risk populations, infection with human herpesvirus 8 (HHV-8) after transplantation may lead to Kaposi sarcoma (KS), and less commonly, Castleman disease, primary effusion lymphoma, and serious nonmalignant conditions (Table 1).1 To assess the risk, it is suggested that transplant candidates and donors from endemic regions, and individuals with epidemiological exposures, are screened serologically for HHV-8.2,3 However, a major hurdle is a lack of reliable method for detecting HHV-8 antibodies. Several serological assays are available but vary in analytical performance.1 This is highlighted by Chiereghin and colleagues where 6 serological tests (4 indirect immunofluorescence assays and 2 enzyme-linked immunosorbentassays) were used to screen donors and organ recipients in north-central Italy.4 Lacking a “gold standard,” they predefined a criterion of having 2 positive tests as “reference standard.” With this criterion, they observed HHV-8 seroprevalence of 4% among 249 donors and 18% among 517 organ recipients.4 Notably, only 2 of the 6 assays have almost perfect agreement with the “reference standard.” If their results are validated by others, one could envision using 1 of the 2 lytic antigen-based immunofluorescence assays to reliably screen donors and recipients from endemic regions and consequently inform their risk of HHV-8 infection after transplantation.
Using their “reference standard,” Chiereghin and colleagues stratified their transplant population into moderate (HHV-8 seropositives) and high-risk (D+/R- mismatch) groups. Only 2.1% of 93 HHV-8 seropositive patients developed reactivation, whereas 25% of 12 HHV-8 D+/R- patients developed primary infection,4 confirming D+/R- mismatch as a risk factor.5 In transplant patients considered at risk, serial nucleic acid testing (NAT) is suggested to complement physical examination (with special attention to skin and mucosal surfaces) for monitoring HHV-8 infection after transplantation.3 However, the preferred NAT, the frequency of monitoring, and the clinically relevant HHV-8 viral load threshold are not established.1 Using 2 nucleic acid tests (an in-house nested polymerase chain reaction [PCR] and a quantitative conventional PCR) to monitor their at-risk patients, Chiereghin and colleagues detected HHV-8 viremia in 6.8% and 2.9%, respectively.4 The differences in detection rate between the 2 PCR assays highlight the need for HHV-8 NAT standardization. Currently, HHV-8 NATs are laboratory-developed assays with different platforms, primers, and processes.1 Accordingly, HHV-8 NATs lack standardization and are not directly comparable. Nonetheless, studies have demonstrated the clinical use of HHV-8 NATs for surveillance after transplantation.1 One study reported that NAT identified 5 of 179 liver recipients with HHV-8 infection, including KS, Castleman disease, and nonmalignant disorders.5
Ideally, HHV-8 NAT should be quantitative, sensitive, and predictive, so it can reliably guide prevention strategies.6 Once HHV-8 NAT is positive above a viral load “threshold,” it is recommended to cautiously reduce immunosuppression to allow for the recovery of virus-specific immunity.7 An immunosuppressive regimen switch to sirolimus, an anti-proliferative drug,8 and preemptive antiviral therapy with ganciclovir, foscarnet, or cidofovir have also been suggested upon HHV-8 detection to prevent its progression into clinical disease.9
However, the frequency of posttransplant HHV-8 NAT surveillance is not defined. Chiereghin and colleagues performed once monthly testing for all at-risk patients but also more frequently during the first 3 months in HHV-8 D+/R- group. However, one HHV-8 seropositive patient who developed KS had no detectable viremia, whereas one D+/R- patient had seroconversion with no documented viremia.4 The lack of detectable viremia in these 2 HHV-8–infected patients could be due to suboptimal testing frequency, issues with assay sensitivity, or the limitation of blood NAT in detecting compartmentalized diseases that are localized to skin or end organs.
The comprehensive screening performed by Chiereghin and colleagues in a region not otherwise considered endemic is a step toward the ultimate goal of HHV-8 disease prevention.
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