Treatment

Chimerix, the manufacturer of the herpesvirus drug, brincidofovir (formerly known as CMX001), recently went public and the guess is that they’re very confident about getting FDA approval. On your alternative treatments page you note brincidofovir appears to be 100x’s more powerful that Cidofovir (Vistide). Do you have anything to say about this drug?    

Several more effective antiviral drugs are under development or in trials

This drug is has terrific potential. It is currently undergoing Phase III trials for transplant patients with reactivated cytomegalovirus (CMV or HHV-5). Brincidofovir is combined with a lipid tag added that allows it to be taken orally and enhances absorption into the cells. Brincidofovir is broad spectrum so it  will work on all the herpesviruses as well as a wide range of other viruses.

Still, brincidofovir is not a magic bullet because like the other three drugs available to treat HHV-6 (cidofovir, foscarnet and ganciclovir/valganciclovir) it has no activity against the virus when it is “semi-latent” (active enough to throw off chemokines and cytokines) but not replicating. This class of drugs can only prevent replication. In other words they can put out the fire, but can’t help with the smoldering coals. That may be one reason why longer treatment periods seems to work better in these patients. The smoldering coals will eventually die down.

A Massachusetts drug company called Microbiotix has a new drug in the pipeline called MBX-400, a nucleoside analog DNA polymerase inhibitor. It is 7x stronger than ganciclovir against HHV-6 and 4x stronger than valganciclovir with a better safety profile. It also works for the other herpesviruses. The drug has orphan status and the company is currently raising funding for Phase Ib and Phase II trials.

Dr. Pridgen at the University of Alabama is in the middle of a multi-center trial using a novel combination of Valtrex and Celexicob, a COX-2 inhibitor, against herpes simplex virus infections in fibromyalgia. If this works out is there any reason this protocol should not be effective against HHV-6 or other herpesviruses in chronic fatigue syndrome. Do you have any thoughts on using Celexicob as an antiviral? 

In the lab, COX-2 inhibitors can block the replication of herpesviruses. Pridgen’s fibromyalgia study results will be released in March

If it works, that would be wonderful. Several fascinating in vitro and animal studies have shown that COX-2 inhibitors can block replication of CMV which is closely related to HHV-6. Typically drugs that work for CMV work for HHV-6 as well. Dharam’s view is that it would be very difficult (with existing assays) to determine if the drug combination is treating an active (vs latent) HSV-1 virus in the sensory nerves, or to rule out that it could be treating another virus altogether.

The anti-malarial drug Artesunate is an intriguing possibility. It crosses the blood/brain barrier, is ‘very good’ at knocking HHV6 down in vitro and poses little risk.  It’s also been used in the US to treat cytomegalovirus infection. Is Artesunate being used much to treat HHV6 infection?

Artesunate, a derivative of the Chinese herb artemesinin, has a great deal of potential for HHV-6 (and all herpesviruses) because it is the only known antiviral that works at the early stage to prevent abortive infection. The other antivirals (foscarnet, cidofovir, ganciclovir) all inhibit replication but can do nothing about a smoldering virus except prevent reactivation. A case report was published recently, demonstrating that Artesunate worked for an infant with biopsy-proven persistent HHV-6 myocarditis.

It also worked for a case of HSV-1 encephalitis that was resistant to acyclovir. A small study was done in Israel that suggested Artesunate has promise in treating drug resistant CMV disease in transplant patients. Generally, what works for CMV, works for HHV-6. Sadly, very little work is in progress, because the patents in place are not strong enough to warrant drug development. However, a group of Johns Hopkins has developed a different derivative called dimer 838 that is even more potent than ganciclovir and it permanently inhibits CMV activity.

Artesunate’s patent problems could prevent it from being developed as an antiviral, but it may be able to affect the ‘smoldering’ or abortive herpesvirus infections believed found in some people with chronic fatigue syndrome. Dr. Cheney has used artesunate in his patients.

Artesunate is difficult to obtain, although some Chinese pharmacies and herbal stores do sell it. To make matters more complicated, the World Health Organization now insists that Artesunate may be sold only in combination with another antimalarial drug, in order to prevent the development of antimalarial resistance. Our Foundation funded the first study of Artesunate for HHV-6 and tried to help a research group obtain a patent, but the patent situation is muddy enough that it is unlikely to ever be developed as an antiviral.

Several heart medications (digoxin, digitoxin, and ouabain) inhibit CMV replication, and may inhibit HHV-6 as well. Statins also inhibit CMV. In a small study we funded in 2006, lamotrigine and amantadine  had mild activity against HHV6. There are several studies suggesting that phoshodiesterase inhibitors/ smooth muscle relaxing agents have antiviral properties. One 1987 paper found that nitroprusside, verapamil and papaverine all inhibited the replication of cytomegalovirus. There are also quite a few herbs that have antiviral potential and red marine algae has been shown to inhibit viral activity.

Micro RNA’s (miRNA’s) – small bits of RNA that are able to modulate gene expression – are getting more and more interest.  At the Paris HHV6 Conference   a Japanese team reported it had identified several miRNA’s HHV6 produced that was able to interfere with he immune systems ability to track down and destroy it.  Does this suggest that the HHV6 drug of the future might not be an antiviral but a drug that targets miRNA’s?

Although this type of therapy is in development for hepatitis C, I suspect HHV-6 will be pretty far down the list for miRNA drug development.

When someone is identified with having an HHV-6A infection is the treatment goal to beat the infection down so that it’s not a problem anymore or is it eliminate the virus entirely from the body? 

Several immune supplements theoretically should be able to assist the immune system in getting herpesviruses under control

Yes, the objective is to keep the virus under control. Patients with persistent HHV-6 reactivation generally either have chromosomally integrated HHV-6 or some sort of an immune defect. Some immune defects are easy to find (e.g. low IgG subclasses, natural killer cell function defect, poor CD4 immune response). Others are  most likely inherited genetic defects yet to be discovered or perhaps nutritional deficiencies such as low zinc, copper or magnesium.

There are a number of immune supplements that in theory should boost cellular and humor immune response keep these infections under control. Examples of these include Avemar and AHCC. Immune supplements that boost cellular (as opposed to humoral) response don’t risk exacerbating an autoimmune condition. As you know, enterovirus expert and infectious disease specialist John Chia has developed his own supplement to boost the immune system and fight persistent enterovirus infections, called Equilibrant.

Since most of the immune supplements available are natural compounds that are not patentable, they will never be FDA approved or marketed. As a result, most physicians are unaware of these compounds or concerned about legal risks of suggesting immune supplements. Patients need to do their own research on boosting cellular immune response.

Testing 

Quantitative PRC DNA tests on plasma or serum do accurately diagnose active HHV6 infections  (200 copies/ml) but you can have an active infection without testing positive on this test.  A highly elevated IFA IgG test can also indicate an active infection but it too will miss some infections.  Do you have any idea what percentage of active infections these two tests are able to catch?

The standard qPCR tests are rarely positive for ME/CFS patients unless they have CIHHV-6. Antibody testing isn’t perfect either because some of these patients have low or borderline low total IgG, or poor humoral response. These patients might not have elevated antibody titers. On the other hand some healthy individuals mount very strong antibody responses and might have a high titer on an antibody test. This test is only useful as a clue.

Experienced physicians such as Dr. Montoya use several factors, including test results and clinical signs to determine which patients might benefit from antivirals.

If a 35 year old patient walks in with an HHV-6 IgG level of 1:1280 or any level of positive HHV-6 IgM, this suggests a recent reactivation of HHV-6. Generally HHV-6 antibodies should decline gradually over time after the primary infection in early childhood.  CIHHV6 patients generally have a relatively low HHV-6 IgG titer. Since they are born with the virus, they don’t mount a strong antibody response.

At Stanford, Jose Montoya makes an educated guess based on clinical signs, and uses elevated antibody titers (>1:320 on an IFA test done at Quest/Focus Diagnostics) as only one factor in his decision to treat with antivirals. He also considers cognitive dysfunction, swollen glands and other signs of a viral picture.

A qualitative PCR DNA test can differentiate between HHV6-A  – the HHV6 virus most closely associated with chronic fatigue syndrome – and HHV6B, which almost everyone carries.  How definitive is this test?  If HHV6-A DNA does show up in a test results what are the next steps?

The interpretation depends on the material tested.

For a ME/CFS patient, if HHV-6 is found in plasma by quantitative PCR in a commercial lab, that patient probably has CIHHV-6. Typically, CIHHV-6 patients will have between 1,000 and 5,000 copies/ml in the plasma but over 1 million copies per ml in the whole blood. Occasionally an ME/ CFS patient might test positive at a low level (say 200 copies / ml), but it is rare. To make matters more complicated, viral loads at different laboratories vary tremendous, depending on techniques used.

A few labs catering to ME/CFS patients have used nested PCR that detects HHV-6 DNA on whole blood (the test used at the former VIPdx, WPI and REDLABS). These results are less meaningful because this test measures primarily latent HHV-6B.  In research labs, many healthy adults have latent HHV-6B DNA detectable by nested PCR. A positive whole blood PCR result for HHV-6A is more meaningful because it is not expected in PBMCs, so it should be followed up with a quantitative PCR test on whole blood at Quest/Focus or Viracor (in the US) to rule out ciHHV6.

Dr. Descamps recently reported that PCR saliva testing may be effective in assessing HHV-6 reactivation in drug hypersensitivity syndrome (DRESS). Is this test ‘validated’ or available? Could it be an easy way of assessing HHV-6 reactivation in chronic fatigue syndrome?

No, saliva testing probably only useful as a diagnostic tool for subacute infections. By the time DRESS is diagnosed, the HHV-6 infection is usually acute and there is DNA in the plasma. It was interesting to see in Descamp’s study that HHV-6 and CMV DNA levels were high in DRESS patients but not in the saliva of controls, while EBV and HHV-7 were high in controls as well as patients. This tells you that EBV and HHV-7 take up residence in the salivary glands.

• Kristin Loomis Pt I – on the Lipkin study, vagus nerve infection hypothesis and HHV-6