Primer for doctors and researchers

Chronic fatigue syndrome (CFS) is also known as myalgic encephalomyelitis (ME) or ME/CFS. There are many clinical and research definitions, which creates confusion for doctors, researchers, and patients.

It is worth noting that chronic fatigue (without the "syndrome") is a symptom of many diseases, illnesses, depression, and drug therapies. This term is not interchangeable with the grossly misnamed disease CFS. https://www.youtube.com/watch?v=pqDubEeIBtA

The core ME/CFS symptoms are: chronic fatigue (CF); post-exertional malaise (PEM); unrefreshing sleep/sleep problems; and cognitive impairment/brain fog and/or orthostatic intolerance (OI). A patient can have many more symptoms and meet different criteria. Systemic Exertion Intolerance Disease (SEID), an ME/CFS criteria, allows for a patient to be diagnosed with the minimum core symptoms  and the patient may have other symptoms. The Canadian Consensus Criteria (CCC) requires the core symptoms and neurological, autonomic, neuroendocrine, immune system, and myalgia symptoms to meet its ME/CFS diagnostic criteria. The International Consensus Criteria (ICC) is used to diagnose myalgic encephalomyelitis (ME) which requires the core symptoms and neurological, immune/gastrointestinal/genitourinary impairment, and energy metabolism/ion transport impairment symptoms for a diagnosis.

Although the Fukuda and the Oxford Criteria are used for diagnosing CFS, they are both overly broad and there is criticism that patients are being misdiagnosed in both clinical and research settings as having CFS when in fact they are suffering from the symptom chronic fatigue (CF). There have been media reports of athletes diagnosed with myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) who have recovered in a relatively short period of time after rest, supplementation, and diet changes;   these athletes may have had overtraining syndrome (which has the symptom of CF) and not ME, CFS, or ME/CFS. Some people with adrenal fatigue are sometimes diagnosed with CFS.

The acronym ME/CFS is widely used in research, by research and patient organizations, and patients.

"The most common overlapping condition with ME/CFS is fibromyalgia." While some have posited ME/CFS and fibromyalgia are variants of the same illness, Benjamin Natelson, MD summoned considerable amounts of data that suggest the two illnesses differ with different pathophysiologic processes leading to different treatments.

Unfortunately, a psychiatric approach has been taken with ME/CFS, but this is changing. At this time there are no approved drug treatments. Graded exercise therapy (GET) and cognitive behavioral therapy (CBT) are used in the UK inappropriately for treating ME/CFS. The Centers for Disease Control and Prevention (CDC) website states "ME/CFS is a biological illness, not a psychologic disorder" and impacts multiple body systems. The CDC recognizes the hallmark symptom of PEM which is a worsening of symptoms after physical or mental activity and says ME/CFS is a "disabling and complex disease."



Disease onset and course of illness
ME/CFS can begin from many acute/sudden events: usually viral or bacterial infections, but also trauma, surgery or childbirth, allergic reaction, and stress. There is also a gradual onset in some people, that is not attributed to any one event. Occasionally, ME/CFS has been triggered by environmental toxins or the receipt of an immunizing injection. Some say that the disease ME always has an acute/sudden infectious onset.

The disease ME/CFS is often diagnosed when a person does not recover from a flu-like illness, mononucleosis or another herpesvirus, Q fever, an unidentified virus, or other infection, and meets one or more diagnostic criteria for either ME, CFS, or ME/CFS. Patients experience numerous symptoms and disease severity which fluctuate from day to day, week to week, month to month, year to year, and even decade to decade. Furthermore, symptoms and disease severity vary among patients.

The CDC recognizes that there can be different causes and it is possible that two or more things could cause the illness. Areas of research include infections, immune system changes, stress affecting body chemistry, changes in energy production, and a possible genetic link. The CDC notes there are abnormalities with the immune system, cellular metabolism, neuroendocrine disturbances, and blood pressure or heart rate regulation.

Not a mental health disorder
In the past, CFS was believed to be a mental health disorder. This is why the CDC now states: "ME/CFS is a biological illness, not a psychologic disorder. Patients with ME/CFS are neither malingering nor seeking secondary gain. These patients have multiple pathophysiological changes that affect multiple systems."

ME/CFS is not contagious
There is no evidence that ME/CFS patients are contagious. Initial infectious triggers have led to outbreaks over the years and 72% of ME/CFS patients report an onset of a viral or bacterial infection. Families, partners, and friends do not report contracting ME/CFS from someone with the disease ME/CFS nor do patients report passing it on to others. Because ME/CFS can run in families, a genetic link is a recommended line of research by the CDC.

Blood donation and organ transplant
Blood donation prohibition had been enacted in the United States (US) and United Kingdom (UK) at one time due to the research of XMRV as being the infectious trigger of CFS and that patients carried the virus. Two papers on XMRV were retracted as it was a laboratory contamination. The US American Red Cross and UK National Health Service Blood and Transplant sites no longer have statements barring transfusions or transplants for CFS. Australia has a prohibition on blood transfusion as a precaution.

Mini-Docs
https://www.youtube.com/watch?v=Fb3yp4uJhq0 What happens when you have a disease doctors can't diagnose By Jen Brea/TED

Five years ago, TED Fellow Jen Brea became progressively ill with myalgic encephalomyelitis, commonly known as chronic fatigue syndrome, a debilitating illness that severely impairs normal activities and on bad days makes even the rustling of bed sheets unbearable. In this poignant talk, Brea describes the obstacles she's encountered in seeking treatment for her condition, whose root causes and physical effects we don't fully understand, as well as her mission to document through film the lives of patients that medicine struggles to treat.

https://www.youtube.com/watch?v=9_HwOUiImvw

Invisible Illness - Stories of Chronic Fatigue Syndrome By Veronica Weber/Palo Alto Online

This mini documentary reveals 3 stories of people who have been impacted by Chronic Fatigue Syndrome - a little known disease that affects roughly 836,000-2.5 million people in the U.S. and receives little research funding. They share emotions of treating loved ones with the disease, their frustrations of being ignored by members of society and the healthcare industry and express hopes of treatment and research. Video by Veronica Weber/Palo Alto Online

https://www.youtube.com/watch?v=RC9TjgE_PlU

Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome By Dr. David Kaufman/Unrest

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is part of the Unrest Continuing Education module, made available through the American Medical Women’s Association and Indiana University School of Medicine, and in partnership with #MEAction. US medical providers can visit: https://www.unrest.film/cme to register to watch Unrest online for free and receive Continuing Education credit.

Epidemiology
In the United States, 836,000 - 2.5 million people suffer from ME/CFS. "The total economic costs of ME/CFS are estimated at $17 to $24 billion annually." Some CFS patients can work with job accommodations but 1/3 to 1/2 become unemployed and many rely on SSDI/SSI.
 * Epidemiology
 * All races and cultures are afflicted with ME/CFS. Children and adolescents are also diagnosed.


 * Female predominant diseases
 * Like many autoimmune and neuro-immune diseases where mostly women are afflicted, the ME/CFS female/male patient ratio per Capelli et al. is 6:1 while the CDC states 4:1.


 * Pediatric
 * Pediatric ME/CFS is defined by the CDC and the National Academy of Medicine (NAM) although it is usually diagnosed in adults. "Children below the age of 8 or 9 do not have the symptom pattern of adolescents past puberty. If the onset of the disease occurs during adolescence, the most common time of onset, the pattern is similar to that of adults." The prognosis in adolescents is considered to be better than in adults. Children are diagnosed with ME/CFS at three months of illness under SEID and CCC and ME is diagnosed immediately under ICC.


 * Prevalence
 * "Worldwide, there may be as many as 17 – 24 million people with ME/CFS." 25% of ME/CFS patients are housebound or bedbound at some point in their illness. 90% of patients are undiagnosed.


 * Prognosis
 * The prognosis for a patient diagnosed with ME/CFS is considered to be poor with only a minority (a median estimate of 5%) returning to pre-morbid levels of functioning. The majority of patients remains significantly impaired. A substantial improvement however is noted in an estimated 40% of patients.

Symptoms
Symptom presentation varies enormously between individuals. Symptom presentation also varies within individuals, as individuals often report that symptoms change over time (increasing or decreasing) and new symptoms may appear while others disappear. There are many symptoms which people with ME/CFS experience, though those listed below are the core symptoms found in all patients.













"This is a term which describes a symptom in which exercise or exertion can bring on malaise (illness). In the case of people with ME/CFS, malaise often occurs during a period some 24-72 hours after exertion. For example, in some cases, a short walk can worsen ME/CFS symptoms two days later. This lack of understanding about the delayed onset of symptoms has, in the past, made it harder to test for ME/CFS. Follow up tests, taken less than 24 hours after an initial exercise test, may show that the patient can still perform activities at the same level (before post exertional malaise has a chance to take hold)."
 * Post-exertional malaise (PEM) is the hallmark symptom of ME/CFS. After physical or mental exertion (which for some patients can be a shower or making out a to-do list, others grocery shopping, socializing or reading a news article, while some just walking to the mailbox, getting to the doctor or mentally following a T.V. program)  there is a payback of worsening ME/CFS symptoms which can be delayed 24-72 hours or more  and can last 24 hours and even days, weeks, or months. The patient will experience even greater fatigue as well as exasperate the flu-like symptoms and body pain. Every patient experiences different symptoms and symptom severity from different activities and exertion output according to how sick he or she is with the disease.    Regarding PEM the CFIDS Association of America states:
 * chronic fatigue
 * cognitive dysfunction


 * orthostatic intolerance (OI) such as postural orthostatic tachycardia syndrome (POTS) or neurally mediated hypotension (NMH)
 * unrefreshing sleep See also: sleep disturbance

Other possible symptoms

 * chronic pain
 * immune system
 * neurological signs and symptoms See Also: neuroinflammation.
 * List of symptoms in ME/CFS

Comorbids

 * fibromyalgia (FMS)
 * irritable bowel syndrome (IBS)
 * multiple chemical sensitivity (MCS)
 * temporomandibular joint disorder (TMJ)

Government guides on symptoms
US Government guides on symptoms
 * Clinicians Guide via The Institute of Medicine report
 * CDC - ME/CFS Primary Symptoms

Canada guides on symptoms
 * Alberta Clinicians Guide

Biological abnormalities
Because there is currently no biomedical test for ME/CFS, many have incorrectly assumed that there are no medical abnormalities found in people with the condition. As a result, ME/CFS symptoms are often considered to be medically unexplained, and therefore psychological in origin. While it is true that the condition is poorly understood, many biological abnormalities have been found in a range of different body systems, particularly in the central nervous system, autonomic nervous system, immune system, and energy metabolism. Unfortunately, none have yet proved to be specific enough to ME/CFS as to be useful as a biomarker of the condition, and many were identified in small studies, which need replication. Whilst there have been abnormalities identified to be associated with the condition, it cannot yet be determined whether these are a cause or consequence of the condition.
 * Gastrointestinal system
 * Natural killer cell findings

Notable studies

 * Cytokine ("Notable studies")
 * Immune findings by Mady Hornig & Ian Lipkin
 * List of enterovirus infection studies

"Bilateral white matter atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a biomarker for CFS."
 * 2014/15, Neuroinflammation Japanese Neuroinflammation study, Younger's Leptin study
 * 2014, Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome
 * 2014, Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder By David Tuller - New York Times: Well




 * 2016, Metabolic features of chronic fatigue syndrome


 * 2019, Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy
 * 2018, ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study (TALK)

Causes & triggers

 * Outbreaks - see List of outbreaks
 * Possible infectious triggers: Enteroviruses, Herpesviruses including Epstein-Barr virus, Q fever , Ross River virus , (Ebola?)
 * Non-viral triggers - trauma, chemical

Epidemiology
Prevalence estimates for ME/CFS range between 0.2-2.5%, depending on the definition of the condition used. In the US, estimates range between 836,000 and 2.5 million people with the condition, though true numbers are under-reported. It is estimated that 84-91% of people with the condition remain undiagnosed.


 * Level of disability (Norwegian study HRQoL) (suggests quality of life is LOWER than for many cancers, heart diseases, brain stroke, diabetes I & II, rheumatoid arthritis, chronic renal failure, sclerosis, schizophrenia, COPD, etc)

Severely ill patients
Considerable variation exists in the severity of the condition. The International Consensus Criteria lists the following severity levels (it should be noted that even "mild" ME/CFS consists of significant debility):


 * Mild = 50% reduction in pre-illness activity levels
 * Moderate = mostly housebound
 * Severe = mostly bedridden
 * Very Severe = totally bedridden, and needing help with basic functions.

At least 25% of people with ME/CFS are bed-bound or housebound, often for years or even decades, so are largely an invisible population. So invisible in fact, that they have rarely been included as part of research because their level of debility precludes them from traveling to laboratories for required testing. The Open Medicine Foundation's ME/CFS Severely Ill, Big Data Study will be the first in-depth study of people with a severe form of ME/CFS.

Notable patients with severe ME/CFS include Whitney Dafoe, Karina Hansen (had been sanctioned), Laura Hillenbrand, Tom Kindlon, Doctor Speedy, Naomi Whittingham, Jen Brea,  and Emma Shorter.

Though uncommon, there have been instances of deaths which have been attributed to the condition. See: Sophia Mirza (sanctioned and now diseased) and Merryn Crofts. Also, see Vanessa Li and Lynn Gilderdale.

Centers for Disease Control and Prevention (CDC)

 * Jul 3, 2017, the CDC's Chronic Fatigue Syndrome page has been changed to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and graded exercise therapy (GET) and cognitive behavioral therapy (CBT) recommendations have been removed.


 * Jul 12, 2018, the "Information for Healthcare Providers" tab and its sub-tabs were updated.
 * Feb 25, 2019, Dr. Elizabeth Unger, Chief of CDC's Chronic Viral Disease Branch (CVDB), that houses the ME/CFS program, in collaboration between Medscape and the CDC put out brief video and commentary page with links to the CDC's July 12th, 2018 updates for medical professionals: Chronic Fatigue Syndrome: It's Real, and We Can Do Better.

MEAction input
 * Jul 29, 2018, CDC Revises its Information on ME MEAction report on the CDC July 2017 and July 2018 website updates. Recommendations for the CDC's ME/CFS page have been created from patient feedback on the updates as well as asking for further patient input.

Tests

 * Natural killer cell (NKC) Blood Test


 * Sleep study for sleep apnea, restless leg syndrome, and other sleep disturbances.
 * Tilt table test for OI or POTS.

Treatments
There are currently no FDA approved treatments for ME/CFS. Treatments consist mostly of symptom management, rather than treatment of the underlying cause of the condition, which is not yet understood. There are many potential treatments, though their evidence-base is limited, as most research into treatments has gone into psychological approaches to treatment.

Drugs
Two treatments that have garnered much attention are Ampligen, produced by Hemispherx Biopharma, and Rituximab. Many people have reported enormous benefit from Ampligen; some doctors have been prescribing it for ME/CFS for decades.

Attempts to obtain FDA approval for Ampligen in the United States have failed so it is unavailable to many. Argentina has approved the use of Ampligen for severe ME/CFS in 2016. Also in 2016, it was made available on a limited basis in Europe. July of 2018, Hemispherx Biopharma, Inc "announced the immediate expansion of its Treatment Protocol/Expanded Access Programs for ME/CFS in the United States, known as AMP-511, to new enrollees for the first time in more than a year." AMP-511 "will allow treatment of up to 100 ME/CFS patients at any one time at approved clinical infusion therapy sites."

Rituximab, a lymphoma drug, had shown promising results in initial trials in Norway, and there were groups crowdsourced funding for further trials in other countries. On Nov 21, 2017, Drs. Øystein Fluge and Olav Mella announced that their Rituximab trial had failed. They stated that they would focus their efforts on attempting to identify a subgroup of ME/CFS patients with an immune profile that would be responsive to Rituximab. The doctors will publish a paper next year with the specifics of the failed trial.

Jarred Younger announced he will be undertaking a trial of low dose naltrexone (LDN) in ME/CFS.

Treating other conditions
Different forms of OI are treated with Beta-blockers (Metopropol), Fludrocortisone (Florinef), and Pyridostigmine. When treating other diseases, illnesses, and conditions, and ME/CFS comorbids and overlapping conditions such as sleep difficulties, cognitive problems, pain, and other symptoms it is important to remember that patients are sensitive to medications. The CDC advice to health care practitioners is to be aware that because all drugs can cause side effects, ME/CFS patient symptoms can worsen. "This is particularly true of any medication that acts on the central nervous system, such as sedating medications: therapeutic benefits can often be achieved at lower-than-standard doses. Patients with ME/CFS might tolerate or need only a fraction of the usual recommended doses for medications. After initial management with lower dosing, one or more gradual increases may be considered as necessary and as tolerated by the patient." For instance, tricyclic drugs can improve mood and help with sleep and pain. However, in some in can worsen OI.

Exercise as treatment
Two common treatment recommendations for ME/CFS are GET and CBT. These treatments are based on the hypothesis that the condition might have begun with a viral infection but has been perpetuated by deconditioning from lack of activity, and fear and avoidance of activity. GET & CBT are aimed at addressing these hypothesized causes by challenging the unhelpful thoughts that result in avoidance of activity and reconditioning through a gradual increase in exercise. These treatments are controversial and are at odds with much of the research literature, which suggests that exercise may actually be harmful to people with ME/CFS. A large patient survey of treatment responses found that 74% of people who had tried GET, reported that their symptoms subsequently worsened, which is consistent with other patient surveys.

The PACE trial, published in 2011, is the largest GET trial ever conducted. It has received much publicity as a result of its recovery rate claims, though it has come under strong criticism from within both the scientific and patient community for significant flaws in its design, and for overstating (and in some cases misrepresenting) outcomes in both the initial trial, and follow-up studies. The study was the subject of a series of investigative pieces by journalist David Tuller in late 2015, that were highly critical of the trial. A petition signed by almost 12,000 ME/CFS patients and allies, and an open letter signed by 42 ME/CFS experts from around the world, were sent to The Lancet, both calling for the data to be reanalyzed. Twenty-four ME/CFS organizations from 14 different countries have written to Queen Mary University London requesting that the trial data be released for reanalysis. To date, the authors of the trial and editor of The Lancet have refused such requests. Despite such criticism, the PACE trial continues to influence both government and the medical profession's approach to the treatment of ME/CFS in many countries.

One of the reasons that exercise may be harmful to people with ME/CFS, is the presence of post-exertional malaise (PEM), which is an exacerbation of symptoms following physical, mental or even emotional exertion. Studies have revealed immunological, muscular, neurological, autonomic and cardiovascular abnormalities in response to exercise in people with ME/CFS. As these results are not also found in healthy sedentary controls, the adverse effects of exercise cannot be said to be due to deconditioning.

People with ME/CFS should approach exercise with caution, as there is much potential for harm.

Anaerobic threshold, use of HR monitors for activity and pacing. Analeptic, not aerobic. Energy envelope/pacing - people do better if stay within their envelope than to push to increase activity

Graded exercise therapy & Cognitive behavioral therapy


GET and CBT are usually employed in the UK, Ireland and some parts of Europe through ME Clinics. They are highly controversial and not recommended by patients, most patient advocates, and research organizations nor by many doctors or researchers outside of the UK. Based on the disproven biopsychosocial model of ME/CFS, backed up by the flawed PACE trial which used the flawed Oxford criteria to diagnose and recruit patients, GET and CBT found its way into treating people with ME/CFS.

Exercise, especially GET, can injure an ME/CFS patient further.


 * Jennifer Brea walked home from her Neurologist's office and became wheelchair bound.
 * This is an experience of serious injury due to GET shared by K. Miles, via Tom Kindlon on Twitter.
 * Emma Shorter was able to walk a few minutes a day until GET put her in a wheelchair.
 * Dr Maik Speedy was also seriously injured by GET and has been bedbound since.
 * British MP Brynmor John collapsed outside the House of Commons gym in 1998 and died, as a result of following his doctor's advice to exercise back to health.

Claims of recovery and cures
Charlatans claim they can cure CFS (per the CDC "there is no cure" ) when in reality they may be able to treat chronic fatigue (CF) which is not the result of the neurological illness CFS. Some people misdiagnosed and "recovered" from CFS most likely had CF which can be caused by many illnesses, diseases, and drug therapies or a bad year or two perhaps with mononucleosis followed by a bout or two of influenza. These individuals were experiencing a proper immune response whereas ME/CFS patients experience an ongoing improper immune response and other abnormalities for at least 6 months straight with a reduction in activity with a specific symptom set for at least 50% of the time.

Additionally, there have been media reports of some athletes diagnosed with CFS that recovered in a relatively short period of time after rest, supplementation, and diet changes   that may have had overtraining syndrome, a condition they sometimes acquire, while some people with adrenal fatigue are sometimes diagnosed with CFS.

Notable studies

 * Pathways to prevention report (P2P)
 * Institute of Medicine report
 * PACE trial is a highly criticized UK trial designed by psychiatrists to promote GET and CBT as therapy which is deemed harmful and useless for ME/CFS patients by many clinicians, researchers, patients, and advocates.

Continuing education (CME and CE)

 * Update on Chronic Fatigue Syndrome Part 1: Clinical Diagnostic Criteria for Chronic Fatigue Syndrome/CFS now called Myalgic Encephalomyelitis or ME/CFS (CME)
 * Update on Chronic Fatigue Syndrome Part 2: Uniting Compassion, Attention and Innovation to treat ME/CFS. (CME)
 * Diagnosing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Experts Weigh In (CME/CE)
 * Watch Unrest and Receive Continuing Medical Education (CME /CE) Credit

History

 * Osler's Web is a book by Hillary Johnson on the early history of CFS.
 * Thirty Years of Disdain by Mary Dimmock and Matthew Lazell-Fairman picks up on the ME/CFS history where Osler's Web leaves off.

Deaths of ME/CFS patients

 * Causes of death
 * Suicide

Death certificates with ME or CFS
 * Merryn Crofts' death is attributed to ME.
 * Sophia Mirza's death is attributed to CFS.

In the UK, United States, and Australia there are claims loved ones have died due to ME/CFS. See Editor's Note

Learn more
Films
 * Forgotten Plague is a US documentary about Ryan Prior, an afflicted journalist who investigates the disease and its history and why the CDC has left millions sidelined from life; available for streaming and DVD purchase. (2015)
 * Unrest is a US documentary film that aired on PBS's Independent Lens in 2018 and is available for streaming and DVD purchase. Jennifer Brea, a person with ME, directs. (2017)

ME/CFS organization's and researcher's material
 * Beyond the Data – Chronic Fatigue Syndrome: Advancing Research and Clinical Education
 * Caring for People with Myalgic Encephalomyelitis
 * IACFS/ME Primer for Clinical Practitioners - 2014 Edition
 * ME Association clinical guidance
 * ME/CFS Diagnosis and Name with Dr Nancy Klimas (video)
 * ME/CFS Treatment Resource Guide for Practitioners by A Martin Lerner, MD
 * Myalgic Encephalomyelitis - Adult & Pediatric - International Consensus Criteria Primer for Medical Practitioners
 * What is ME/CFS?

Patient mental health


 * Patients
 * Karina Hansen is a young Danish woman taken from her family for 3 1/2 years due to Per Fink's insistence her ME was due to mental health issues.
 * Sophia Mirza was taken forcibly from her home to a mental hospital only to be returned shortly after and died.
 * Ean Proctor was taken from his parents as a young boy and he was told his "parents were letting him die." He had become paralyzed and mute and was let go in the deep end to make him swim and put on a scary theme park ride to scare him into moving.

More mental health information
 * ME/CFS is not depression. It is a lack of energy, not desire.

Research
 * 2015, Institute of Medicine report (IOM Report)

Articles and blogs
 * 2016, The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem
 * 2018, The CDC based its updated ME/CFS page based on the IOM Report.
 * Notable studies
 * Feb 21, 2019 Are surgeons missing the major differential diagnosis that is more common than multiple sclerosis and HIV combined?