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.

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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 protocols—the good and the bad, the risk to reward ratio—is 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.



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