Wednesday, July 14, 2010

HAART and IRIS


Highly Active Antiretroviral Therapy &
Immune Reconstitution Inflammatory Syndrome

After Science published Dr. Judy Mikovits’s paper linking XMRV to ME/CFS in October 2009, some patients began investigating antiretroviral therapy.  A few have already begun. The FDA/NIH study has also found XMRV in the majority of ME/CFS patients, and when the paper's published, no doubt more patients will be looking into antiretroviral drugs.  No one yet knows, however, whether XMRV is the cause, collateral damage, or even a major player in Chronic Fatigue Syndrome.  That said, several readers have asked for information on antiretroviral treatment; hence this post.

HIV drugs and IRIS
During HAART, which stands for Highly Active Anti-Retroviral Therapy, infectious-disease doctors prescribe a three-drug cocktail (or sometimes more) to treat HIV.  The drugs work synergistically to keep HIV levels low, which keeps the patient healthy and helps prevent the mutations that lead to drug resistance.  AZT, tenofovir and raltegravir are the only three FDA-approved antiretroviral drugs with efficacy against XMRV, in the test tube. 

One of the problems with using antiretrovirals in HIV is a well-known phenomenon called IRIS, which stands for immune reconstitution inflammatory syndrome.  It occurs in some patients soon after beginning drug therapy.  Suddenly, the patients’ viral-load counts plummet and the restored immune system, which had been too immobilized to mount an effective immune defense to any number of viral, bacterial and fungal infections—from herpes viruses to tuberculosis to pneumocystis pneumonia to cryptococcal meningitis—goes into overdrive to beat down those infections. 

Unmasking versus paradoxical
The result can be unbridled inflammation, which is potentially more destructive than the HIV infection itself and can even be deadly.  There are two kinds of IRIS:  unmasking and paradoxical. In the former, the patient has an undocumented infection that becomes apparent when the immune system starts to recover and attempts to take down the invader, leading to inflammation.  Targeted treatment for the particular infection usually resolves the problem. 

In paradoxical IRIS, the symptoms of an infection that’s already resolved reappears, sometimes due to a stubborn infection or drug resistance, but often cultures are sterile, which means there’s no active infection.  Instead the body is railing against the persisting antigen or dead pathogen.  Usually paradoxical IRIS resolves on its own.

IRIS shouldn’t be confused with a Herxheimer reaction, another inflammatory reaction.  In a herx, which occurs early in the treatment for syphilis and Lyme disease, rapidly killing off spirochetes releases toxins and causes inflammation that make the patient ill. 

Predictably, IRIS usually strikes the sickest AIDS patients—those with CD4 (also known as T4 or, colloquially, T-cell) counts below 100.  Normal CD4 counts range from 500 to 1,200; HIV officially morphs into AIDS when CD4 counts dip below 200.

The sickest patients tend not only to have lower CD4-cell counts, they usually have higher HIV levels as well.  The patients with the strongest and most rapid response to HAART are ironically those most likely to experience IRIS.  In HIV, older patients and African Americans are also more at risk.  As with most medical phenomena, genetics play a role. About a third of HIV patients with low CD4 counts experience IRIS.

Viral-load tests
In HIV patients, IRIS usually begins between week one to week 12 of antiviral treatment and continues for a few weeks, and occasionally much longer.  Retroviral load testing is the most reliable way to determine if the patient who feels worse than he did before treatment actually has IRIS.  If the viral load drops precipitously and the patient’s symptoms worsen, it usually indicates IRIS.  If the viral load hasn’t budged or has increased, then most likely it's not IRIS and could mean that the disease itself is progressing.

Unlike HIV, there are no viral-load tests yet for XMRV, so anyone on or contemplating anti-retroviral therapy for XMRV is at a disadvantage here. 

Whether ME/CFS patients on antiretrovirals will experience IRIS isn’t known. While both HIV/AIDS patients and ME/CFS patients have damaged immune systems, they’re damaged in different ways:  ME/CFS patients have more defects in natural killer cells and B cells; HIV patients, in CD4 cells.  In addition, ME/CFS patients tend to have fewer opportunistic infections than AIDS patients.  On the flip side, many ME/CFS patients are exquisitely drug-sensitive and sometimes mount what appears to be an autoimmune response—the body attacking itself. 

The AIDS patients I interviewed about the experimental HIV and ME/CFS drug Ampligen in the "The AIDS Drug No One Can Have" for Philadelphia magazine didn’t get sick from the drug and improved quickly.  But most of the ME/CFS patients—especially those who had been sick for several years—experienced flu-like symptoms for a couple of months and didn’t begin to improve for three to four months.  Ampligen—a toll-like receptor agonist that stimulates the body to churn out infection-fighting chemicals called interferons—is a different class of drug from any HIV antiretroviral drug, so the jury’s out on how ME/CFS patients will respond. 

Dr. Jamie Deckoff-Jones, a physician with ME/CFS who is XMRV positive, is blogging about her journey on a HAART triple cocktail of AZT, tenofovir and raltegravir—the aforementioned FDA-approved drugs with efficacy against XMRV, at least in the test tube. Her daughter, who also suffers from ME/CFS and is XMRV positive, is taking the same meds.  The side effects for them have been relatively mild in the four months since they started, with Deckoff-Jones reporting a mild flare in her neurological symptoms for the first couple of weeks on each drug.  Her daughter has had an easier time of it.  Both report more functionality and a lessening of their ME/CFS symptoms.

Preventing IRIS
One way to minimize the potential for IRIS in HIV is to pre-treat patients for any known concomitant infections before beginning antiretrovirals. University of California at San Francisco biochemist Dr. Joe DeRisi developed the revolutionary ViroChip, which tests for all known animal and human viruses.  The average ME/CFS patient registers a whopping 30 to 50 or more actively replicating viruses on the chip, including several herpes viruses, so pretreatment would be a tall order.  (The average healthy person, in contrast, has about three or four actively replicating viruses.)  One option for treating patients for paradoxical IRIS is to treat simultaneously with medications that reduce inflammation.  Among them:

Steroids.  Proven effective for treating tuberculosis-associated, pneumonia-associated and herpes zoster (shingles)-associated IRIS, among other infections, the steroid Prednisone is the most prescribed medication to treat IRIS. 

Leukotriene receptor antagonists.  Perhaps the most promising and well-tolerated new treatment for IRIS is the heavily advertised asthma drug Singulair (montelukast). Leukotrienes are fatty molecules that contribute to asthma, hay fever and other allergic symptoms.  One group of British researchers found that three patients with severe IRIS who didn’t respond to steroids responded rapidly and dramatically to Singulair.  The medication blocks leukotrienes D4, LTC4 and LTE4.  

Another leukotriene receptor antagonist and asthma medication is Accolate (zafirlukast), which blocks cysteiny leukotrienes, but whether the drug is effective for patients suffering from IRIS isn’t known.  A third asthma med, Zyflo (zileuton), stops leukotriene synthesis by inhibiting an enzyme called 5-lipoxygenase.  Again, it’s not known if Zyflo prevents or treats IRIS.

Ibuprofen treats pericarditis (inflammation of the heart) caused by IRIS.  However, patients on certain antiretroviral drugs, including tenofovir and AZT, should not use ibuprofen and other NSAIDS regularly, as the pain-reliever can compound the kidney toxicity of the two antiretrovirals.

Hydroxychloroquine (Plaquinel), an old-line malaria drug, has been reported anecdotally to reduce IRIS-associated inflammation. 

Thalidomide (Thalomid) has anecdotally been reported to treat IRIS.  Pregnant women should not take the drug, as it is a well-known teratogen and causes limb deformities.

***

This post should not be construed as medical advice.  Nor is this post an endorsement of the use of antiretrovirals for ME/CFS patients and an XMRV diagnosis.  I am a science writer, not a physician or a researcher.  Consult your health-care professional before beginning any treatment plan.

That said, getting information on treatment protocolsthe good and the bad, the risk to reward ratiois essential on blogs such as these, since there has been so little viral research into ME/CFS until the past year.  Many patients have been ill for decades, some have died waiting for an effective treatment, and most are hungry for answers and help.  One patient organization keeps tabs on patients’ deaths.

For those who have stumbled upon this blog and aren’t familiar with Chronic Fatigue Syndrome, it does, thanks to its unfortunate name, sound like a trivial disease unworthy of big-gun medications.  But in reality, as more than two thousand studies have documented, ME/CFS is a neuroimmune disease that causes, among other problems: seizures, fevers, vertigo, swollen lymph nodes, immune abnormalities, cancers (particularly lymphomas), autonomic dysfunction, cardiac abnormalities, short-term memory loss, abnormal brain scans, and death.  In short, it’s not a disease about being tired.  Dr. Mark Loveless, a longtime ME/CFS and HIV physician testified before Congress in 1995 that a “Chronic Fatigue Syndrome patient feels effectively the same every day as an AIDS patient feels two months before death.”

Those who feel the need to bully, frighten or lecture those who post questions or comments about antiretrovirals—or any other treatment—consider getting professional help instead.  CFS Central will be a safe forum to exchange information. 

Patients who want to share their own experiences with antiretroviral medications can post on this blog or contact me directly at Mindy Kitei CFS Central, as I’ll be writing more articles on the subject.  I know readers are also interested in posts from patients on antiretrovirals who’ve experienced IRIS—and those who haven’t. 

I’d also like to hear from patients who’ve developed ME/CFS within weeks after a blood transfusion, as I’m going to post on this as well.



This article, “HAART and IRIS” is copyright CFS Central 2010.  All Rights Reserved. You may quote up to 150 words from this article as long as you indicate in the body of your post (as opposed to a footnote or an endnote) that the excerpt is by Mindy Kitei for CFS Central.  You may not reprint more than 150 words from this article on blogs, forums, websites or any other online or print venue.  Instead, refer readers to this blog to read the article.


25 comments:

  1. The situation with XMRV and its effects on the immune system is quite complex.In essence it is a TH2/TH17 pattern of immunomodulation.Low Nk function is part of a much wider pattern of abnormality. It is unlikely that antiretrovirals will work on their own.Unlike a lentivirus such as HIV xmrv has a much lower replication rate and spends a great deal of its life cycle integrated into the hosts DNA.Hence inhibiting the viruses replication while desirable is not the major factor.XMRV is a MuLV class virus.Other viruses of this class,when integrated into the hosts DNA,cause the same pattern of immodulation as seen in people with CCC ME/cfs.They do so by inserting into the start codons of genes that regulate the immune system. Such an insertion can either upregulation ,or more commonly, the silencing of these genes.A number of studies have demonstrated that this pattern of immunomodulation actually serves to keep the virus latent.We are thus left with the issue of eradicating this latent virus resevoir. They have a similar problem with treating the Aids virus albeit on a much smaller scale.The drug which appears able to excise HIV from its points of insertion in the DNA is prostratin and I also believe new drugs that achieve the same ends are also available.Without being able to excise the XMRV provirus antiretrovirals (with the possible exception of restrictase inhibitors, are unlikely to have an effectiveness profile which outweighs the considerable risks of long term antiretroviral triple therapy.The dangers of antretroviral therapy may well be exacerbated in people with ME because of pre-existing mitochondrial damage

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  2. "Those who feel the need to bully, frighten or lecture those who post questions or comments about antiretrovirals—or any other treatment—consider getting professional help instead. CFS Central will be a safe forum to exchange information."

    Thank you, Mindy. Sadly, this can't be said often enough.

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  3. Thanks Mindy - I've been trying to get a handle on all of this and it was nice to have it all in one place.

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  4. Nina - You beat me to it.
    Mindy, Thank you for making this very important point - no bullying! If you have time on your hands and are inclined to personally attack someone, I agree that we'll all be better off if you spend your time seeking professional help!

    Gerwyn - There is a lot that remains unknown, some of it very key to understanding the potential risks and perhaps benefits of anti-retroviral therapy. Thanks for adding to the conversation.

    I'm not ready to consider HAART myself (my XMRV results aren't back and my infectious disease doc might say we're involved in an encouragingly successful program to "pre-treat" co-infections (in part to prevent IRIS?).

    That said, I appreciate the severity of this disease and the desperate situation for many patients. I know first hand that it is life threatening. Before treatment with anti-virals (under the very close supervision of an ID doc) I probably would have been willing to start on a trial of HAART.

    Anti-viral treatment has bought me a significant amount of time and the luxury of being able to wait for more research on the potential role and treatment of XMRV.

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  5. Providing balanced scientific information is not bullying.If you perceive it to be then I suggest that you are the one in need of psychological help.

    XMRV does not induce pathology in the same manner as HIV.Therefore the chances of success using a anti retroviral are much less and the chances of serious toxicity or death are much higher

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  6. Gerwyn, I agree that providing balanced scientific information is not bullying. You provided balanced information in your post, and I appreciate your insights. There is a difference between giving the facts with pros and cons versus castigating someone for the choices he or she makes. Your post is the former.

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  7. > Other [MuLVs],when integrated into the hosts DNA,cause the same pattern of immodulation as seen in people with CCC ME/cfs.They do so by inserting into the start codons of genes that regulate the immune system.

    Is that a theory, or are you saying that this is the consensus about the various long-studied MuLVs. If the latter, do you have any refs at hand?

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  8. I really like this HAART and IRIS for dummies-post. Mindy, you seem to be very much in touch with the topics that patients want/need to know about. You've become a great resource of facts and inspriration.

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  9. Thank you for the article Mindy. Reading about IRIS was very interesting. I wonder if that is why so many people with CFS are having problems with LDN?

    And if this is the case, wouldn't you think that after nine months, I would have reached some kind of toleration for the drug?

    Lynn

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  10. Eric Johnson,
    This info came from Gerwyn:

    Antiretroviral activities of protease inhibitors against murine leukemia virus and simian immunodeficiency virus in tissue culture.
    P L Black, M B Downs, M G Lewis, M A Ussery, G B Dreyer, S R Petteway Jr and D M Lambert
    Southern Research Institute-Frederick Research Center, Maryland 21701

    The same compounds which inhibited the infectivity of HIV-1 also produced activity against SIV and R-MuLV. Electron microscopic examination revealed the presence of many virions with atypical morphologies in cultures treated with the active compounds. Morphometric analysis demonstrated that the active compounds reduced the number of membrane-associated virus particles. These results demonstrate that synthetic peptide analog inhibitors of retroviral proteases significantly inhibit proteolytic processing of the gag polyproteins of R-MuLV and SIV and inhibit the replication of these retroviruses
     
     This is an example of what I mean . HIV is an extremely fast replicating virus. It does its damage by replicating.XMRV does its damage while in the DNA so stopping or reducing its replication might stop the symptoms getting worse but would not make them better.
     

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  11. Robin sent this comment, but for some reason Blogger won't post it:

    I'm glad you explained the true meaning of "herx"; my pet peeve is when patients assign the term to any adverse event from any medication or supplement!

    "Dr. Joe DeRisi developed the revolutionary ViroChip, which tests for all known animal and human viruses. The average ME/CFS patient registers a whopping 30 to 50 or more actively replicating viruses on the chip, including several herpes viruses, so pretreatment would be a tall order."

    Mindy, is this published research, or a notes from conference presentation? Where can I read more about it?

    Robin: here's the reference:
    http://aboutmecfs.org/Conf/IACFSME09WPI.aspx
    Do a search for "30." It's not a published study.

    Hope this helps.

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  12. Very shortly after undergoing chemotherapy for breast cancer, my symptoms of weakness dramatically lessened. For the first time in years, I was able to go for a walk with no symptoms! My doctor mentioned that CFS patients often improve on chemotherapy. While we are searching for the meaning of xmrv, I wonder if some of the sickest patients wouldn't benefit more from chemotherapy drugs than from retrovirals.

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  13. Thank you, thank you, thank you! Right now I just don't have the words for how much I appreciate your clear writing and information. Thank you also to those who leave informative comments.

    I am hoping many doctors will soon get on board and learn how to treat ME/CFS patients effectively and appropriately. For the majority of us I suspect the information is almost without use unless we have doctors who can help us navigate the various treatment options, if and when they become more widely available.

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  14. Thank you for your excellent article, Mindy.

    Question: should researchers be using Virachip to capture the complete infectious etiology of ME/CFS and clinicians to identify treatable co-infections to minimize IRIS?

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  15. Hi Erik

    here is an example one of many!

    Free and Integrated Recombinant Murine Leukemia Virus DNAs Appear ...
    by W Herr - 1984 - Cited by 19 - Related articles
    the viral DNAs we were studying were integrated into the genomic DNA. ..... By the same criterion, the free MuLVs in samples 1, 3, 6, 9, ...
    jvi.asm.org/cgi/reprint/50/1/155.pdf

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  16. This shows why XMRV acts as a gene regulator

    Xenotropic murine leukemia virus-related virus (XMRV) is a new human gammaretrovirus identified in prostate cancer tissue from patients homozygous for a reduced-activity variant of the antiviral enzyme RNase L. Neither a casual relationship between XMRV infection and prostate cancer nor a mechanism of tumorigenesis has been established. To determine the integration site preferences of XMRV and the potential risk of proviral insertional mutagenesis, we carried out a genome-wide analysis of viral integration sites in the prostate cell line DU145 after an acute XMRV infection and compared the integration site pattern of XMRV with those found for murine leukemia virus and two human retroviruses, human immunodeficiency virus type 1 and human T-cell leukemia virus type 1. Among all retroviruses analyzed,

    XMRV has the strongest preference for transcription start sites, CpG islands, DNase-hypersensitive sites, and gene-dense regions; all are features frequently associated with structurally open transcription regulatory regions of a chromosome.

    Analyses of XMRV integration sites in tissues from prostate cancer patients found a similar preference for the aforementioned chromosomal features. Additionally, XMRV integration sites in cancer tissues were associated with cancer breakpoints, common fragile sites, microRNA, and cancer-related genes, suggesting a selection process that favors certain chromosomal integration sites. In both acutely infected cells and cancer tissues, no common integration site was detected within or near proto-oncogenes or tumor suppressor genes. These results are consistent with a model in which XMRV may contribute to tumorigenicity via a paracrine mechanism.

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  17. Mindy – I echo everyone else above in my sincere thanks for your ongoing coverage. You are one of only a tiny few in the general community who have grasped not just the horrific nature of this illness but also the highly charged political environment within which people with ME/CFS live and die. There is so much to the history of this illness that is waiting to be told – and in writing you and Hilary are bringing the truths to the surface.
    I deeply admire Dr Deckoff for sharing her story of ARV therapy. As a physician she has had to make a tough decision – as a mother she has had to make a near impossible decision. This decision has been forced upon her shoulders as a result of medical and scientific neglect. If the FDA findings do support WPI and if national governments throughout the world fail to invest quickly and aggressively in clinical trials of drugs… then I may just follow Dr Deckoff’s lead…

    Thank you again.

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  18. From Lynn:
    "Reading about IRIS was very interesting. I wonder if that is why so many people with CFS are having problems with LDN? And if this is the case, wouldn't you think that after nine months, I would have reached some kind of toleration for the drug?"

    I’m sorry, Lynn, I don’t know the answer to either question about LDN (low-dose Naltrexone).

    From Anonymous:
    "Very shortly after undergoing chemotherapy for breast cancer, my symptoms of weakness dramatically lessened. For the first time in years, I was able to go for a walk with no symptoms! My doctor mentioned that CFS patients often improve on chemotherapy. While we are searching for the meaning of xmrv, I wonder if some of the sickest patients wouldn't benefit more from chemotherapy drugs than from retrovirals."

    Anonymous, This has been reported by many cancer patients who have ME/CFS, particularly lymphoma patients. One theory is that the chemo kills many infected cells, thereby decreasing the pathogen load.


    From Gemini:
    "Question: should researchers be using Virochip to capture the complete infectious etiology of ME/CFS and clinicians to identify treatable co-infections to minimize IRIS?"

    Gemini, Dr. Montoya at Stanford is conducting a study on the 50 to 60 pathogens reported to be important in ME/CFS to figure out the range, patterns, distribution, etc. Perhaps we’ll know more after that study is complete.

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  19. Thanks Mindy for keeping us so informed on a weekly basis, I too appreciate your clear writing and informative posts as well as the great questions and comments from your readers.

    I wish reporters would cover the history before CFS, when ME was the proper name for the disease and viral causation widely accepted. CFS is a silly name and it has cost too many lives. If not for XMRV we would still be in the gutter.

    I was curious about the Virochip so thank you for posting about the Montoya study, it shows how sick we are to have so many viruses - 30-50 is a lot! I am also curious to read more about treatments we can't have, like Ampligen and Xyrem (sodium oxybate) which helps with sleep.

    Lynn: You could be sensitive to LDN or not getting pure naltrexone from a reputable compounding pharmacy. Naltrexone tablets crushed and diluted into a solution are no good as they contain fillers and other things. I hope you are able to solve the problem.

    Good luck everyone, I hope we are almost there!

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  20. Thanks for the article on IRIS. I guess it maybe beneficial for us to be working on our concomitant infections while waiting for possible future HAART.

    And the prostratin seems like it takes the retro out of retrovirus. .. maybe a necessary part of a true cure. And it comes from a Samoan tree remedy, I think.

    I wonder if the HAART meds work just as well in tissue as in blood. Sure hope someone finds those reservoirs. XMRV might be replicating faster there, especially if we have lymph node cancer prostate (LNCaP). Maybe it's a low grade cancer that lets XMRV grow in us. I think Goff has another cell line that stimulates XMRV.

    So I'm also very interested in chemotherapy. Couple of friends did very well on it. Prednisone and something-mycin (antibiotic I assume) were the only meds I recognized in another friend's lymphoma chemo cocktail. Surprised to see an antibiotic (I assume) in there. His lymphoma description sounded just like a slow infection to me, just like CFS.

    I think Mikovits has been working with cancer drugs for decades. She may be perfectly positioned to test it on CFS.

    If I go on chemo, I guess I should document it somewhere.

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  21. Just a quick note on ralteravir, the most potent inhibitor of XMRV which is the compound that blocks the viral integrase protein. The problem with ralteravir is that it causes autoimmune problems in mice - something that could be problematic for at least some subsets of CFS patients.

    The Virochip is one approach to testing patients for multiple viruses, another way is metagenomics and millions are currently being pumped into such studies for CFS and other diseases.

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  22. my blood tests repeatedly showed raised ESR; this is something my doctor thought was significant but the "specialist" at liverpool thought was due to the fact that I am overweight, as apparently overweight people have raised ESR levels, so this was dismissed and not looked into. Reading above though, I wonder about the implications of raised ESR. I've come across other CFS patients with this too and yet no one seems to look into it any more.

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  23. Esonophils and monocytes have everything to do with the fact that your body is fighting some sort of infection or allergy but if the numbers are continually out of range then it is more probable that you are fighting an infection that your body cannot clear up on its own. This from personal bloodwork for last 3 years and diagnosed XMRV+ for last 9 months.

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  24. Charles Beuttel (charlesbeutt@Gmail.com)February 2, 2011 at 9:35 AM

    Hey Gerwyn,

    Myself and a friend both suffer from severe Chronic Fatigue syndrome symptoms. She wanted me to ask about valproic acid as a possible method of stimulating XMRV to reproduce, so it can be killed.

    My question: how long do you think it will take before prostratin is available for the chronic fatigue community? I have also read that testosterone stimulates XMRV reproduction, would exercise be something to consider, once you have started antiretrovirals?

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  25. I just wanted to comment that there are some of us out here who do not have HIV - who took the HAART medications as Post Exposure Prophylaxis, and developed Inflammatory Immune conditions after just 30 days on AZT and (in my case) three other antivirals to *prevent* infection. I had the telltale bodywide IRISH rash but absolutely zero doctors acknowledge this is possible without immune suppression (via existing HIV infection). False. There are many who take HIV Prophylaxis and struggle with ongoing immune inflammatory syndromes that never calm down. I know of one who developed full blown Sarcoidosis (inflammatory immune), others who have developed GBS, CIDP, and myself - Neuromyotonia - yet another inflammatory immune syndrome. I am thankful for this article as 100% of physicians out there reject any discussion on the possibility that HAART can make healthy people very ill, long term. I will be trying Singulair soon after nearly 16 months of health problems ... after only 30 days on a heavy duty 4 drug regimen. On the bright side - it worked to prevent HIV infection.

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