Treatment

Treatment of HHV-6 infection has not received much attention in the literature. The obvious initial consideration for a treatment strategy would be antiviral therapy. Several antiviral agents are now available for the prevention and treatment of the herpes viruses (HSV 1 and 2, VZV, and CMV) (82). The role of these agents in the treatment of HHV-6 infections is not well established due to limited data. In vitro studies with HHV-6 have shown that the virus is resistant to acyclovir (Zovirax) at achievable serum levels (83, 84, 85). Although not specifically studied, the other oral agents, famciclovir (Famvir) and valacyclovir (Valtrex) are likely to be ineffective as well. The parenteral antiviral drugs that have activity against cytomegalovirus (CMV) have been studied in vitro against HHV-6, with conflicting results (83, 84, 85). Albiet HHV-6 has been sensitive to ganciclovir (Cytovene) and foscarnet (Foscavir), some studies have shown resistance, especially with ganciclovir and the HHV-6A variant (85). Resistance may be strain dependent. Both agents have been used successfully to treat life threatening HHV-6 infections in transplant patients, including encephalitis (86, 87). Cidofovir (Visitide) would be an attractive consideration, given its broad antiviral activity, however it has not been studied with HHV-6. The toxicity of cidofovir may also be a problem, especially with more prolonged use. In acute HHV-6 infections, as is the case in the transplant patients, the anti-CMV agents may be very useful (86, 87). The role of the parenteral agents currently used for CMV infections in chronic active HHV-6 infection may be more limited. The reasons for this include: inconvenient route for chronic administration (intravenous), risk of catheter complications with chronic use, toxicity (particularly cumulative toxicity over time), and relapse of infection when therapy is discontinued. We have administered IV ganciclovir to several selected patients with MS or severe unrelenting CFS in which there was ongoing active HHV-6 infection of the bloodstream documented by repeatedly positive blood cultures. Analysis of this data has lead to several preliminary observations. The clinical and virologic responses have been variable. A subset of patients with both MS and CFS clearly seemed to respond to ganciclovir. In the "responders", there appeared to be diminished viral activity (decreased number of positive viral blood cultures) but we rarely saw complete clearance of viremia. These patients also showed evidence of a clinical response (an example, is an MS case that we have previously reported, who had a marked decrease in MS relapses on therapy) (27). Also, in the group of patients who "responded" clinically and virologically, there was a tendency to relapse when antiviral therapy was discontinued (even after 6 months or more of therapy). Immune function (low NK function) did not improve on ganciclovir therapy, which may partially explain the tendency to relapse. There was another group of patients that did not respond to the ganciclovir. Although the reason for this is unknown, we would postulate strain specific resistance as a likely explanation. We found that ganciclovir was well tolerated in these patients. One study of CFS patients treated with IV ganciclovir (for 30 days) has been reported in the literature (88). Using functional status, there was improvement in 13 of 18 patients at 24 weeks after ganciclovir. The remainder of patients failed to improve. HHV-6 was not addressed in this study and long term follow up data was not provided. This type of data, at 24 weeks, would be generally consistent with our observations. We have given IV foscarnet to two patients with active HHV-6 infection. In both, therapy was discontinued by the fourth week due to toxicity. Oral antiviral therapy may be more practical and amenable to long term maintenance therapy. Unfortunately, as noted above, none of the currently available agents appear to be particularly attractive based on their in vitro activity. Acyclovir (or valacyclovir) may have some limited, strain dependent activity. One study showed that acyclovir reduced the frequency of disease exacerbations in MS patients. Valganciclovir, an oral form of ganciclovir with serum levels similar to the IV formulation, is currently being evaluated in clinical trials of patients with CMV infections. Several drugs that have a very broad antiviral spectrum (including herpes viruses) are being evaluated as potential antiviral agents. Some of these agents (e.g. PMPA) may surface in the future as effective agents for HHV-6.

Given the immune deficiency that results from chronic active HHV-6 infection, immune modulation is another attractive avenue for consideration. Beta interferon has been shown to decrease MS relapses and decrease the number of active lesions on MRI head scans in controlled studies (both Beta 1a and Beta 1b types) (89). The proposed mechanism is an immune regulatory role (down regulation of CMI) by the interferon. Since interferon has known anti-viral properties, another explanation for the positive results could be an anti-viral effect on HHV-6. In our observations of MS patients with HHV-6 viremia, we have not seen a lower rate of positive HHV-6 blood cultures or higher NK function assay results in patients on either of the beta interferon preparations (unpublished data). However, this would not rule out an anti-viral effect of interferon, particularly a partial effect. Since the beta interferon studies included large numbers of patients, our observations in a small number of patients is likely too small of a sample to see a statistically significant difference. The anti-viral effects of the interferon preparations on HHV-6 have not been studied. Defining the effect of interferon on HHV-6 will be an important area of research. Intravenous gamma globulin has been given to both MS and CFS patients with improvement in clinical parameters, but results in the literature have varied (90, 91). Other immune modulators such as G-CSF and GM-CSF have not been studied.

Another immune modulator that may have substantial promise is transfer factor (TF). There are several reasons to consider TF. TF has consistently shown efficacy in the prevention and treatment of viral infections. Studies reporting efficacy of specific TF have been reported with HSV 1 and 2, VZV, EBV, and CMV (93, 94, 95, 96). TF has proven to be extremely safe with virtually no significant adverse effects (96). Since TF acts on CMI, this type of agent may improve the immune dysfunction that is a key feature of chronic active HHV-6 infection (97). Recent techniques obtaining TF from bovine colostrum provides a way to recover TF in large enough amounts for commercial preparation (98). We have done some preliminary studies in patients with CFS and chronic active HHV-6 infection using a TF preparation derived from bovine colostrum that has activity for HHV-6 included in its scope of TF activities. Albeit the data is still preliminary, this type of immune modulation appears to be very promising. We have seen significant symptom improvement, consistently negative HHV-6 blood cultures and marked improvement in NK function in patients taking this particular TF (unpublished data).

Another interesting treatment concept involves the use of anti-coagulants. Given the issue of activated coagulation pathways in these patients (endothelial cell tropism and vasculopathy), anti-coagulation may improve oxygen delivery and help with the symptoms that have been caused by a hypercoaguable state and fibrin deposition (99). One study has demonstrated symptom improvements in CFS patients treated with heparin (99). Several studies have shown that herpes viruses attach to cell surfaces via heparan sulfate receptors and that exogenous heparin can block this interaction and viral infectivity (100, 101). Thus, heparin may have some antiviral properties for herpes viruses. Patients with hereditary hypercoaguable syndromes (thrombophilia or hypofibrinolysis) may be at further risk for substantial hypercoaguable related problems and require anticoagulation. One evolving concept involves blocking viral activation (antiviral agents or immune modulation such as TF) combined with anticoagulants (heparin or coumadin). A model for a hypercoaguable state in patients with active HHV-6 infection and possible management strategies of the patient with a hypercoaguable state and associated active HHV-6 infection are outlined in Table 2 and 3.