Re: Re: Re: Re: Clinical trials of antioxidants 17 February 2005
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Nicholas Bennett,
Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse, NY

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Re: Re: Re: Re: Re: Clinical trials of antioxidants

I appreciate Mr Whitehead's clarification - the quote makes rather more sense knowing it came from that particular source.

The mice developed the disease after repeated cross-matings, which apparently activated ERV's from each inbred species (which then became exogenous!). The disease was present in donors and recipients. As far as I'm aware no herpes virus was present (or even looked for!) but it did appear as if the combination of activated endogenous RVs was able to induce a hemoproliferative disease that looked similar to KS. I can see no theoretical reason why one particular RV can't induce a proliferative disease in lymphocytes, and another in reticulocytes or whatever.

KS does occur in people with higher CD4 counts that most AIDS- defining OI's, but they are still suppressed to a degree. The correlation is less, I agree, because it seems to require lower levels of immune suppression (hence perhaps why it is so much more common in HIV+ people compared to uninfected controls). The Thai data is very interesting, since the serology to HHV8 seems reasonably high compared to the clinical picture. Something is clearly different compared to the American experience.

As regards liver versus kidney transplants, I think this is due to the particular anti-rejection drugs being used. Amazingly the Andreoni study's results were not statistically significant regarding KS appearance between liver and kidney transplant recipients (despite having a rate of zero in liver transplant recipients)! They do however address the issue by pointing out that:

"In fact, the type of immunosuppressive therapy used differs for renal transplant and liver transplant recipients. In our study, the majority of liver transplant recipients did not receive corticosteroids, whereas all renal transplant recipients were treated with cortisone. It was recently demonstrated in vitro that hydrocortisone acts directly on the activation of the lytic cycle of HHV-8 in latently infected cells." [1]

Which as well as pointing out a potential confounding factor, further implicates HHV8 in causing KS. What should be obvious though, is that if Yang et al can cause a near-idential lesion to KS in transgenic mice with a single gene of HHV8, what prevents this from happening in the majority of those with clinically inapparent HHV8 infection? Maybe the Thai data will shed some light on this, if further investigations have been/are to be performed.

Speaking of which: the necessary steps involved in organising a clinical study of the kind proposed are relatively simple, providing one has the infrastructure in place. Superficially it looks likely to get through an Institutional Review Board and then all you would need would be funding and a patient base. Mostly likely, for statistical power, it would have to be a multicenter study, which significantly complicates the matter (especially with regard to funding). It would be very important too to properly design the study to have enough power to detect and control for any differences between various arms.

Nick Bennett

1. Andreoni J Infect. 2001 Oct;43(3):195-9. "Prevalence, incidence and correlates of HHV-8/KSHV infection and Kaposi's sarcoma in renal and liver transplant recipients."

Competing interests: None declared