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Interview with Drs. Erik De Clercq and Lieve Naesens, June 2007

What is the most effective prescription drug to combat HHV-6 infection?
The answer is not straightforward since clinical studies on the effect of antiviral drugs in
HHV-6-infected patients have not been performed on a large scale. We can only draw
tentative conclusions from small-scale studies in which the drugs were administered for
shorter periods. The antiviral drugs foscarnet (or Foscavir®) and cidofovir (or Vistide®)
have shown good activity in laboratory tests and single patients. Both compounds can
cause kidney toxicity and, hence, long-term use of foscarnet or cidofovir is problematic.
Ganciclovir (or Cymevene®) has also been reported to be effective in case studies. Since
ganciclovir needs to be administered by intravenous infusion, its oral form
(valganciclovir or Valcyte®) would be preferred in long-term studies. But chronic use of
ganciclovir or valganciclovir can cause white blood cell depletion due to bone marrow
toxicity. So at this moment, we do not have a prescription drug that is ideally suited for
long-term use in HHV-6-infected persons.
What are the most promising drugs in the pipeline?
Current research mainly focuses on new antiherpetic drugs with a mode of action that
differs from that of foscarnet, cidofovir or ganciclovir. However, these new products are
mainly developed for herpesviruses other than HHV-6. The most advanced in clinical
development is maribavir, a compound that is developed for cytomegalovirus, which,
unfortunately, is not active against HHV-6. Another compound, cyclopropavir, has good
activity against HHV-6, but is still in the preclinical stage. Besides, a few experimental
compounds have been reported to have anti-HHV-6 activity in cell culture, but these have
not yet advanced to preclinical development.

Are there any natural products or herbs that have in vitro efficacy against HHV-6?
Natural products containing seaweeds (such as red marine algae) inhibit HHV-6
replication in cell culture. These products contain negatively charged sugar molecules
(also called ‘polyanionic polysaccharides’) which block the first step in the viral
replication cycle, namely absorption of the virus to the cells. In cell culture, these
polyanionic compounds are very efficient against HHV-6 as well as other herpesviruses.
However, their clinical benefit when given as an oral tablet or capsule is questionable
since their absorption from the gut into the blood stream is very limited.
Do the antiviral drugs vary significantly in their effectiveness between HHV-6A and
Classical antiviral compounds targeted against the viral DNA polymerase, such as
foscarnet, ganciclovir and cidofovir, are equally active against HHV-6A and HHV-6B.
From the experience in our laboratory, we know that new compounds with a mode of
action unrelated to the viral DNA polymerase, may have a different effect on HHV-6A
and HHV-6B. Since their mode of action is not completely understood, we have no
obvious explanation for this variant-dependency. Note that the cell culture tests with
HHV-6A and HHV-6B are performed in different cell lines, so this is a complicating
We know that ganciclovir and foscarnet pass the blood brain barrier reasonably well.
What about cidofovir?
In normal individuals, the penetration of cidofovir into the central nervous system is low.
However, cidofovir has proven to be effective against severe viral infections of the brain
such as ‘progressive multifocal leukoencephalopathy’ (PML). In these pathologic
circumstances, the virus-induced brain inflammation results in a malfunction of the blood
brain barrier, allowing cidofovir to enter into the central nervous system.

Will there be an oral form of cidofovir available on the market soon?
A phase I clinical study on an oral form of cidofovir (known as CMX001 or HDP-
cidofovir) is ongoing. If this study is successful, this compound will still need to proceed
through phase II and III trials before reaching the market. So even if everything proceeds
as planned, the development will still take several years.
Do Valtrex or Famvir have any activity against HHV-6?
Valtrex® (Zelitrex®) and Famvir® are the oral forms of acyclovir and penciclovir,
respectively. In cell culture, acyclovir has only weak activity against HHV-6. For
penciclovir, the activity is even less pronounced.
A new paper out of the NINDS has linked HHV-6B to mesial temporal lobe epilepsy.
You recently tested a number of epilepsy drugs for antiviral efficacy against HHV-6B.
Do you suspect that the mechanism of action with some of these epilepsy drugs is
Antiepileptic drugs are thought to act by direct or indirect inhibition of receptor-mediated
neurotransmission. We consider it unlikely that this mode of action could explain a
potential antiviral effect on HHV-6, since our HHV-6 tests are done in lymphocyte cells
which are very different from neurons.
You and Henry Agut have found that lamotrigine and valproate are both weakly
effective against HHV-6B. Are these results clinically relevant?
For valproate, the anti-HHV-6 activity was not very convincing. The activity of
lamotrigine is clearly better. Although its anti-HHV-6 concentrations in cell culture were
quite high, they appear to be in the same range as the maximum drug concentrations
obtained in blood or brain during use of lamotrigine in patients.

Given that valproate doubles the serum level of lamotrigine, would it make sense to use
a combination of the two drugs?
Yes. There are a number of clinical reports on the usefulness of this two-drug
combination for some psychiatric or epileptic disorders (Pisani 1999, Morris 2000,
Aldenkamp 2002, Cuadrado 2002, Thome - Souza 2003) However, please be aware that
higher lamotrigine levels could be associated with increased toxicity.
What do we know about Lamotrigine’s mechanism of action?

Lamotrigine blocks neuronal voltage-activated sodium channels, and hence inhibits the
release of excitatory amino acids such as glutamate.
You published a paper on arylsulfone derivatives. Do these compounds have the
potential to be as effective as foscarnet or ganciclovir?
Yes. In our cell culture studies, these arylsulfone derivatives produce a consistent and
complete inhibition of both HHV-6A and HHV-6B. Their therapeutic index (the margin
between their antiviral and cytotoxic concentration) is comparable to that of foscarnet and
superior to that of ganciclovir.
You have found that amantadine exhibits weak anti-HHV-6 activity. This drug is used
by MS patients to relieve fatigue. HHV-6A has been associated with MS. Do you
expect that the amantadine doses prescribed for MS might have antiviral effects?
According to a recent literature survey, there is insufficient evidence to conclude that
amantadine is effective in reducing fatigue in MS patients. The maximum drug plasma
levels obtained with current amantadine doses (100 or 200 mg) are 25- to 150-fold below
the concentrations required to inhibit HHV-6 in cell culture. Administration of
amantadine at higher doses is unrealistic since this would result in unwanted side effects.
Thus, although the moderate antiviral activity of amantadine is an intriguing experimental
observation, we believe that this has little clinical relevance.

Has there been any progress on animal models to test HHV-6 antivirals?
The development of animal models for HHV-6 is hindered by the fact that this virus only
replicates in human cells. There is one report (by Dr. C. Genain) on an MS-like disease
that was induced in marmoset monkeys by injection of HHV-6-infected cells. This
intriguing observation still needs to be confirmed by other groups. Also, antiviral drug
evaluation in this animal model is highly warranted.
Now that there seems to be a strong interest in HHV-6, will you be stepping up
research efforts at Rega Institute to look for improved compounds?
Our Laboratory has a long expertise in antiviral drug development, including antivirals
for herpesviruses. We have an ongoing antiviral program for HHV-6, but our funding
resources are quite limited, making further expansion difficult.
Is there anything you can tell us about your research objectives?
In the past, we have identified a number of promising lead compounds, such as the
arylsulfone derivatives mentioned above, new compounds related to cidofovir, and
protein kinase inhibitors such as CMV423. Further optimization of these lead compounds
in collaboration with medicinal chemists is ongoing. Besides, we have identified a few
novel compounds with modest activity against HHV-6 in cell culture. An intensified
input from medicinal chemists, who would have to synthesize new analogues, and a basic
understanding of the mode of action of these compounds would be needed to correctly
estimate their potential as anti-HHV-6 agents. More funding would be required to
achieve these goals.



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