A Lack of Clinical Correlation between the Presence of HHV-8 DNA in PBMCs and Staging of Kaposi’s Sarcoma

The ability to stage disease severity allows clinicians to recommend the proper therapies in the treatment of disease. Human herpesvirus type 8 (HHV-8) appears to be involved in the etiology of Kaposi’s sarcoma (KS), and researchers are attempting to associate viral markers with the staging of KS. Although disease exacerbations are associated with an increased viral burden in a form of multicentric Castleman’s disease [1], other investigators have not been able to correlate an increased viral load of HHV-8 in peripheral blood mononuclear cells (PBMCs) [2] or latent antibody titers [3] with the staging of disease in KS. Recently, Boneschi et al. [4] have reported in this journal a study aimed at proving the hypothesis that detection of HHV-8 DNA in PBMCs might be related to the clinical aspects of KS. Their central finding in 40 classical KS patients was that the ‘detection of HHV-8 in peripheral blood mononuclear cells seems to correlate with the more aggressive stages and the rapid evolution behaviour of Mediterranean Kaposi’s sarcoma’. When they grouped the patients by a modified Kriegel classification system, KS patients at stages I and II presented with detectable viral sequences in 47.6% of their PBMCs, whereas stage III and IV patients had a higher proportion, 73.6%. Similarly, by using their institution’s staging system that combines evolutive patterns and the presence of complications, the authors reported that fewer patients with slowly evolving KS presented with viral sequences in their PBMCs than did patients with rapidly evolving KS, 41% vs. 74%, respectively. The authors firmly concluded that ‘. disease recurrences or a more aggressive behaviour are accompanied by a greater probability of finding viral DNA sequences in PBMC’. We feel this might suggest that, if HHV-8 sequences were detected in PBMCs from a person with classical KS, that result would function as a prognostic indicator of more advanced disease. At first glance, the proportional increases in HHV-8 DNA detection seemed impressive; however, the authors provided no statistical analyses to support their conclusions. Their findings are based upon the results presented in their table 3 [4, p. 21], which presents the proportions of viral DNA in polymerase chain reaction-positive PBMC samples found in each of the KS stages and evolutive categories. However, when these data were subjected to our own statistical analyses, we found that their statements were not supported by the data. A ̄ 2 analysis of the data reveals that the presence of viral DNA is not significantly associated with the disease stages ( ̄2 = 2.82, p = 0.0928). Furthermore, the odds ratio of being in stage III–IV disease given the presence of viral DNA is only 0.32 (95% confidence interval (CI = 0.38–1.47), and the relative risk of being in stage III–IV given the presence of viral DNA is 0.65 (95% CI = 0.38–1.09). Only the fast evolutive type of KS can be statistically but marginally associated with the presence of viral DNA in PBMCs by ̄2 analysis ( ̄2 = 4.36, p = 0.036); however, the clinical relevance of this finding cannot be substantiated statistically, and therefore the finding is not generalizable [odds ratio = 0.25 (95% CI = 0.05–1.13); relative risk = 0.56 (95% CI = 0.30–1.09)]. It is also interesting to note that Lebbe et al. [5] did find a statistically significant association in the proportion of detectable HHV-8 DNA sequences in PBMCs between KS stages I–II and III–IV ( ̄2 = 4.68, p = 0.038; our analyses), but there too, the odds ratio did not indicate an increased clinical risk [odds ratio = 0.16 (95% CI = 0.02–1.16); relative risk = 0.40 (95% CI = 0.17– 0.93)]. In summary, although Boneschi et al. [4] present data and claim a correlation between the presence of HHV-8 DNA in PBMCs and, therefore, an increased probability for greater severity of disease in classical KS, their conclusions are not supported statistically. In order to support these possible correlations, the inclusion of more samples in future studies may provide the statistical confidence needed to better resolve the hypothesis.