Dharam V. Ablashi 8 - 12 viruses and CFS
by John W. Addington
May 2, 2003
Dharam V. Ablashi, DVM, MS, Dip.Bact., co-discoverer of unusual "juicy" white blood cells and current American Association of Chronic Fatigue Syndrome President, has done much to advance the understanding of the cause of Chronic Fatigue Syndrome (CFS).
Dr. Ablashi has many more credits to his name. He is internationally renowned for his work with herpes viruses and has served on national and international scientific committees including NIH and W.H.O. He is Director of the Herpesvirus Programs at Advanced Biotechnologies Inc, and Adjunct Professor of Microbiology at the Georgetown University School of Medicine in Washington, D.C. Furthermore, Dr. Ablashi has shared in the publishing of over 285 scientific papers, 11 books, and he has lectured worldwide.
However, it is Ablashi's research regarding human herpes virus 6 (HHV-6) particularly that has involved him with Chronic Fatigue Syndrome.
Ablashi was working with the National Cancer Institute in the mid-80's when he and his associates discovered odd balloon-shaped white blood cells which they described as “juicy.” These researchers published their findings about this new virus in 1986. Later they confirmed this was a herpes virus, and as it was the sixth such virus to be discovered it was called human herpes virus 6.
Other Herpes Viruses
Other herpes viruses are involved in cytomegalovirus, chickenpox, infectious mononucleosis, herpes simplex, and shingles. The herpes virus that causes mononucleosis, Epstein-Barr virus, also know as HHV-4, was initially suspected as a cause of CFS. Ablashi has done research on this virus also and he published in 1995 that "the involvement of Epstein-Barr virus in CFS patients is diminishing." Nevertheless, he stated that there could "be a subset of CFS patients in whom Epstein-Barr virus may be a major contributing factor to disease manifestation."
As a childhood infection, HHV-6 can cause the rash-like condition roseola. Dr. Ablashi explains that, "HHV-6 infection usually occurs in childhood during the first year of life and then the virus becomes latent." HHV-6 has two forms designated as HHV-6A and HHV-6B. It is HHV-6B that is associated with roseola and over 90% of adults retain this virus dormant in their system throughout their lives. Ablashi states that "variant A is more common in AIDS patients and patients with CFS."
As the research developed with HHV-6, many researchers, including Ablashi, performed studies to determine whether that virus might be the cause of CFS. These studies, while not always consistent, have often found a majority of CFS patients show signs of recurrent HHV-6 infections. This is not so with healthy persons.
In a study published in the Journal of Clinical Virology, Dr. Ablashi and associates looked for unique signs of HHV-6 infection in 35 CFS patients. While dormant, HHV-6 can be detected in most adults. These researchers studied immune system markers that would detect reactivation or possibly active HHV-6 infection.
Among the CFS patients, 54% showed evidence of HHV-6 reactivation whereas this was only true in 8% of the healthy individuals. Further testing over a two and a half year period revealed two subsets of CFS patients had persistent HHV-6 infection. Ablashi and his co-authors wrote that these results "show a significantly high frequency of HHV-6 reactivation in CFS patients…and a decrease in cellular immune responses."
Hormone Imbalance and HHV-6
Neuroendocrine function has often shown to be imbalanced in CFS patients. Neuroendocrine refers to the brain's control of proper hormone balance for good health. Thus the question arises as to how this relates to Ablashi's research on HHV-6.
Dr. Ablashi offered this explanation. "First, the data generated by us clearly show that HHV-6 variant A is present in the cerebral spinal fluid of most, but not all, CFS patients. The virus seems, therefore, to be carried to the central nervous system (CNS) via [white blood cells], where it has been found to be latent. When the [white blood cells] come in contact with [brain] cells/tissues, somehow the virus becomes activated, spreads to the CNS and induces CNS manifestations. …This may be a method in which HHV-6A participates in neuroendocrine dysfunction."
When asked about the potential treatment of HHV-6 infection for those with CFS, Dr. Ablashi offered some insightful comments. He states, "Dr. Daniel Peterson, with whom I collaborated on a CFS project, tried ganciclovir, foscarnet and Ampligen in his CFS patients, who were identified by us and two other labs, to contain active HHV-6 infection."
"Four patients treated with ganciclovir showed the presence of HHV-6A, even after anti-viral treatment. Only one patient improved slightly for a short while."
"Two patients treated with Ampligen improved initially and did make remarkable recoveries. When treatment was discontinued after 1 1/2 years, however, HHV-6A was found to be activated from latency and these patients started to show signs of the illness."
"The patient treated with foscarnet improved greatly since he returned to work on a full time basis. We found no HHV-6A infection after foscarnet treatment. Another CFS patient treated elsewhere with foscarnet also improved greatly and returned to college. In her case, the viral DNA copies in the plasma and CNS after treatment were greatly reduced. Foscarnet, therefore, is quite effective in suppressing HHV-6A infection, but it is also associated with toxicity. Most physicians, because of this, are not willing to experiment with it."
Whey Protein Combined with Foscarnet
Patients considering foscarnet may be interested in research by Dr. Ablashi which tested the drug's effectiveness in combination with whey protein. Ablashi found that when used in combination with foscarnet, the effect is greater than each has individually.
Both through his ongoing research and his work with the American Association of Chronic Fatigue Syndrome, Dr. Ablashi has extended himself on behalf of those with CFS. And for that, the CFS community applauds him.
For assistance with issues related to CFS and HHV-6, Dr. Ablashi can be contacted through: The American Association of Chronic Fatigue Syndrome, online at www.aacfs.org
E-mail: Admin@aacfs.org; Voice mail: 206-781-3544.
Dr Alblashi HHV-6 Foundation
The HHV-6 Foundation is also engaged in finding and/or developing effective antiviral agents. Progress in this area has been slow; they have checked out over 60 compounds, only two of which (red marine algae, amantadine) have worked in more advanced testing. Dr. Ablashi noted, however, a variety of antivirals (ampligen, Isoprinosine, alpha 2a interferon (?), acyclovir, valcyclovir, valganclyclovir) that have been successful in small trials. Three of these will be covered in the Clinical trials session of the conference.
Susan Levine. Incidence of HHV-6 and EBV infection in Chronic Fatigue Syndrome patients.
The herpesviruses have long been of interest in CFS. Several researchers believe that EBV and HHV-6 reactivation plays an important role in a subset of CFS patients. Questions regarding proper diagnostic procedures have, however, muddied this issue considerably. Dr. Levine’s study was designed to bring some clarity to this issue.
Dr. Levine employed a variety of different tests (EBV, HHV-6 – IgG, IgM, PCR; EBV – viral capsid antigen (VCA), early antigen (EA), EBV nuclear antigen (EBNA); HHV-6 – antigenemia), to determine if HHV-6 and EBV reactivation was present in CFS patients, and if it was, to determine the best means of testing for it.
She found that CFS patients tested normally to two common antibody tests (VCA, EBNA) but that about a third of CFS patients – compared to zero controls – tested positive for high levels of antibodies to EBV’s early antigen (AG). About a third of the CFS patients also exhibited elevated levels of antibodies to HHV-6 and about 20% were positive in the HHV-6 antigenemia tests vs. zero controls.
PCR tests of the blood lymphocytes indicated that the CFS patients all harbored the HHV-6A virus while the controls harbored the HHV-6B virus. Several researchers believe that not only are these different viral types but they are completely different viruses and should be denoted as such. (See HHV-6 and CFS).
Dr. Levine’s study, then, presented evidence that a substantial subset of CFS patients have an active chronic low level herpesvirus infection. Antibody tests suggest that HHV-6A is active and replicating in about 30% of CFS compared to zero controls. EBV replication, on the other hand, does not appear to be occurring. Instead this study appears to back up Dr. Glaser’s theory that EBV is active enough in CFS to produce immune system altering proteins but is shut down before it can replicate.
Chronic Fatigue Syndrome (ME/CFS) Studies - Amantadine was poorly tolerated by ME/CFS patients and showed little benefit in a cross-over study with carnitine.
Chronic Fatigue Syndrome (ME/CFS) Doctors Report - Over a small sampling of patients Dr. Bell found that 40% could not tolerate the drug (mostly due to jitteriness and anxiousness) and 40% reported from moderately improved to excellent results. Amantadine seemed to be most effective in treating moderately ill patients. Dr. De Meirleir reports Amantadine relieves fatigue in some ME/CFS patients.
Recent research by others has shown that amantadine successfully inhibits Borna disease virus (BDV) in both cultured cells and in an infected human. Among the CFS patients we studied, some had antibodies against BDV in their plasma and BDV RNA in their blood. One group of these patients, from a single family, began using amantadine and found improvement in their CFS symptoms.
To further investigate this dymanic, we administered amantadine to 22 patients with CFS. Three patients withdrew from the study because of side-effects from the treatment. The other 19 took 200 mg per day of amantadine for eight weeks. When we evaluated the effects of the substance on patients with and without antibodies against BDV in their plasma, 6 of 11 patients with BDV antibodies showed a good response, whereas only 2 of 6 patients without the antibodies showed improvement.
There have been many conflicting reports about the effectiveness of amantadine on BDV. So the mechanism of the effect of this substance is unclear, but we consider it one of a range of therapies for some CFS patientsAmantadine and L-carnitine treatment of Chronic Fatigue Syndrome.
Carnitine is essential for mitochondrial energy production. Disturbance in mitochondrial function may contribute to or cause the fatigue seen in Chronic Fatigue Syndrome (CFS) patients. Previous investigations have reported decreased carnitine levels in CFS. Orally administered L-carnitine is an effective medicine in treating the fatigue seen in a number of chronic neurologic diseases. Amantadine is one of the most effective medicines for treating the fatigue seen in multiple sclerosis patients. Isolated reports suggest that it may also be effective in treating CFS patients. Formal investigations of the use of L-carnitine and amantadine for treating CFS have not been previously reported. We treated 30 CFS patients in a crossover design comparing L-carnitine and amantadine. Each medicine was given for 2 months, with a 2-week washout period between medicines. L-Carnitine or amantadine was alternately assigned as fist medicine. Amantadine was poorly tolerated by the CFS patients. Only 15 were able to complete 8 weeks of treatment, the others had to stop taking the medicine due to side effects. In those individuals who completed 8 weeks of treatment, there was no statistically significant difference in any of the clinical parameters that were followed. However, with L-carnitine we found statistically significant clinical improvement in 12 of the 18 studied parameters after 8 weeks of treatment. None of the clinical parameters showed any deterioration. The greatest improvement took place between 4 and 8 weeks of L-carnitine treatment. Only 1 patient was unable to complete 8 weeks of treatment due to diarrhea. L-Carnitine is a safe and very well tolerated medicine which improves the clinical status of CFS patients. In this study we also analyzed clinical and laboratory correlates of CFS symptomatology and improvement parameters.
Dr Myhill: Acumen laboratories now routinely check A-L-carnitine levesl for me and they are almost always low in CFSs.
This phosphonic acid derivative (marketed by Clinigen as foscarnet sodium under the trade name Foscavir) is an antiviral medication used to treat herpes viruses, including drug resistant cytomegalovirus (CMV) and herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2). It is particularly used to treat CMV retinitis. Foscarnet can be used to treat highly treatment experienced patients with HIV as part of salvage therapy.
Mechanism of action
Foscarnet is a structural mimic of the anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases at concentrations that do not affect human DNA polymerases. Because foscarnet is not activated by viral kinases it maintains activity against viruses like HSV and VZV that have respectively developed mutant thymidine kinase and UL97 encoded protein kinase, to gain resistance to other DNA polymerase inhibtors, like acyclovir and ganciclovir. Therefore, foscarnet is often used in acyclovir- or ganciclovir-resistant disease.
However, acyclovir- or ganciclovir-resistant mutants with alterations in viral DNA polymerase may be resistant to foscarnet.
Administration Intravenous only
Nephrotoxicity - Increase in serum creatinine levels occurs on average in 45% of patients receiving foscarnet. Other nephrotoxic drugs should be avoided. Nephrotoxicity is usually reversible and can be reduced by dosage adjustment and adequate hydration.
Electrolyte disturbances - Changes in calcium, magnesium (Harisson 16th ed page2244) potassium and phosphate levels occurs commonly and regular monitoring of electrolytes is necessary to avoid clinical toxicity.
Genital ulceration - Occurs more commonly in men and usually occurs during induction use of foscarnet. It is most likely a contact dermatitis due to high concentrations of foscarnet in urine. It usually resolves rapidly following discontinuation of the drug.
CNS - Paraesthesias,irritability and hallucinations