HIV LESSONS FROM THE MISSISSIPPI BABY

The news in July that HIV had returned in a Mississippi toddler after a two-year treatment-free remission dashed the hopes of clinicians, HIV researchers and the public at large tantalized by the possibility of a cure.

But a new commentary by two leading HIV experts at Johns Hopkins argues that despite its disappointing outcome, the Mississippi case and two other recent HIV "rebounds" in adults, have yielded critical lessons about the virus' most perplexing -- and maddening -- feature: its ability to form cure-defying viral hideouts.

Writing in the Aug. 28 issue of the journal Science, HIV research duo Robert Siliciano, M.D., Ph.D., and Janet Siliciano, Ph.D., note that such "failures" are in fact stepping stones to new understanding of what "cure" may look like and new therapies that tame the virus into long-term remission.

"Heartbreaking as these three cases are clinically, they provide a dramatic illustration of the real barrier to an HIV cure and illuminate important therapeutic strategies," says Robert Siliciano. "This is not the end of the story but the beginning of a new chapter."

The 27-month off-treatment remission experienced by the Mississippi toddler is, in and of itself, a laudable therapeutic goal, the Silicianos write, and is what cure of HIV may look like in the foreseeable future. Finding ways to induce long-term remission and to closely monitor its course will be the next frontier in HIV treatment, they write.

The ability to put the virus in remission and go off treatment for months or years at a time is an important goal, because it can spare HIV-infected people from a lifetime of daily antiviral regimens, which can be difficult to tolerate and hard to follow. Failure to comply with the strict treatment protocol, which occurs often, can lead to viral mutations that make HIV resistant to drugs.

All three cases, the Silicianos write, also reaffirm that the single most important hurdle to eradicating HIV is a tiny but extremely stable pool of virus tucked away in a handful of immune cells known as memory CD4+ T cells.

Memory T cells are the immune system's combat-trained sentinels, responsible for fighting invaders they have encountered in the past. Much of the time, memory T cells lie dormant and become active only when the body is invaded by old foes they are specifically trained to recognize. HIV invades memory T cells early in the infection, and as long as the T cells lie quiet, so does HIV inside them.However, as soon as memory T cells get stirred up by an invader, the HIV DNA inside them wakes up, cranks out new virus and reignites infection. Because antiviral drugs work only against actively replicating virus, such silent viral hideouts remain out of therapy's reach. Thus, reducing the number of latently infected cells or precluding their formation altogether is an important and -- as the three recent cases suggest -- realistic strategy, the Silicianos say.

"These cases paint several clinical scenarios where a substantial reduction of viral reservoirs would allow some patients to come off treatment for prolonged yet uncertain periods of time, but they also raise the critical question of how to best monitor them for relapse so they can resume therapy swiftly when the virus rebounds," says Janet Siliciano.

In the widely reported case of the Mississippi baby, a child born to an HIV-infected mother received a full-treatment regimen of antiviral drugs within hours of birth, instead of the customary prophylactic regimen typically used in suspected but unconfirmed newborn infections. The baby's HIV infection was subsequently confirmed. The child was lost to follow-up and went off treatment but later returned to clinic. A series of standard and ultrasensitive tests failed to detect HIV in the child's blood. In total, the child remained free of HIV infection -- with undetectable viral loads and free of HIV antibodies -- for 27 months despite receiving no treatment. By contrast, most HIV-infected people experience dramatic viral rebound within a few weeks of treatment cessation.

Described as the first documented instance of HIV remission in a child, the Mississippi case suggested that very early treatment with antiretroviral drugs quashed the formation of viral reservoirs. The child was followed by a University of Mississippi pediatrician, a University of Massachusetts immunologist and a Johns Hopkins pediatric HIV expert, Deborah Persaud, M.D., who was also the lead author on case report published Nov. 7, 2013, in The New England Journal of Medicine.

In two other "remission" cases reported in 2013, HIV ultimately rebounded in two adults after months without antiviral therapy and following bone marrow transplantation for cancer. Both patients received antiviral drugs while undergoing transplantation to prevent the donors' immune cells from becoming infected with HIV. The patients' own HIV-infected immune cells were killed off by chemotherapy and by graft-versus-host disease, a common post-transplant phenomenon in which the donor's immune cells attack and destroy the recipient's organs, tissues and cells. When antiretroviral treatment was stopped, the patients went into remission for several months, but the virus came roaring back later on, according to published reports.

"Clearly, neither approach managed to eradicate all latently infected cells, and what these cases underscore is the ability of even a few such cells to rekindle infection after prolonged remission," Robert Siliciano says.

The three cases also lend urgency to the search for better ways to monitor the presence of and measure the number of such dormant HIV reservoirs, which could be used as a rough gauge of how long remission might last. Latently infected cells can evade detection by even the most sophisticated tests, which are so exquisitely sensitive that they can sniff the presence of a single HIV-infected cell. The problem is not lack of test sensitivity, the Silicianos explain, but the size of the blood sample tested. Latent HIV reservoirs exist in a few out of millions of immune cells, but a mere 2 percent of memory T cells that harbor such reservoirs are circulating in the blood at any given time. Thus, even large blood samples may not capture the few infected cells harboring dormant virus -- a feat that becomes even more challenging as the number of reservoirs is reduced.

Even though research indicates that remission duration is linked to the amount of latently infected cells, the Silicianos caution remission time is bound to vary widely from patient to patient. Its length would depend on individual biologic factors and the occurrence of other infections that might coax latently infected immune cells out of dormancy and trigger a rebound.

A few patients may never relapse, the Silicianos say, but no patient is safe from rebound as long as he or she harbors even a single latently infected T cell. The unpredictable nature of remission and rebound will therefore require frequent blood monitoring to detect the earliest signs of viral reactivation.

"It is not too soon to begin planning for this type of 'cure' scenario," the authors conclude.

Lessons From A Life With Neuropathy

Today's post from painhq.org (see link below) is an honest, personal story of life with neuropathy. Reading it you may feel that this man's lifestyle has directly contributed to his condition but it's far too easy to criticise from a distance without first looking at our own lives. The story will certainly be recognisable for many neuropathy patients, proving that nothing is as black and white as it seems - sometimes, life just gets in the way. This man uses gabapentin with success but that is his case, that doesn't mean that gabapentin is necessarily the answer for you.

Life with neuropathy
2016

'Old Fart' William's Story

 

I am 72 years old and live alone in a single family bungalow in Peterborough. I eat too much, drink too much, and get too little exercise. I am a retired teacher and have lived alone since my wife died in 2000. I am a fat old fart who lives a fairly circumscribed life - only partly due to my neuropathy. Right now my sciatica is flaring up and is far more debilitating.

My peripheral neuropathy likely dates back to the early to mid ‘90s. I suffered from falling arches, and for some time I ascribed my foot and leg discomfort solely to that issue. It was only in 1997, when the numbness, burning, and occasional stabbing pain was keeping me awake, that I took the problem to my GP.

It is so long ago that I have little or no recollection of the original process of diagnosis. The story is complicated in my mind by my wife suffering a massive brain injury at that time. She was in an automobile accident in Ottawa, in the summer of 1996. She was in an Ottawa hospital until the spring of 1997, and again for several more visits during the next couple of years. She lived at home until her death in January, 2000. Naturally, at the time, my minor problem was peripheral to hers. It was while she was in the hospital (1996 – ’97) that the burning and tingling got so bad that I went to see my GP.  He referred me to a local neurologist who ran some tests and diagnosed peripheral neuropathy. By that time (1998 – ’99) the loss of feeling extended almost to my knees.

The neurologist had no answer as to the origin of the condition. I had been drinking heavily earlier in my life, but had been totally dry for ten years when the condition struck. My GP (at the time) in 1997-9 was convinced that I had diabetes. My blood sugar levels were consistently close to the threshold levels, so he took that leap and declared me diabetic; controlling it with diet and exercise.  It wasn’t until my present GP had me do a glucose test (in 2009) that the diabetes diagnosis was ruled out.

At the beginning I had “pins and needles”, burning on the soles of my feet, numbness or loss of feeling in my feet and lower legs, aching feet and legs (perhaps partly due to the falling arches) and occasional shooting pains or a feeling like a weak electric shock. I do not remember the specifics, but I am sure that the discomfort started in one foot at a time before it came to affect both feet and legs. I have a vague memory of it migrating from one foot to the other over the months.

Finding relief, also known as, gabapentin

Back in 1997 or ‘98 my GP prescribed a common medication used off-licence to treat nerve pain. I have no recollection of which one it was. I just remember him saying that no medication worked for any large percentage of the sufferers, but that particular one was the most efficacious. It might have been an anti-depressant, but the specifics escape me. I just remember that I got every side-effect listed on the fact sheet (dry mouth is one I remember), but it did nothing to ease my nerve pain.

The second medication he prescribed was gabapentin. It was a miracle cure. Within a few days the worst of the symptoms had eased, and after trying different dosages we settled on just 300mg per day. Over the years, I have had to increase the dosage as the pains and discomfort returned. I have never been free of the feeling that something in my feet and legs isn’t right. There is the constant numbness, the decrease in flexibility, and the fairly common occasional tingling sensation. It isn’t pain! For many years, the discomfort was almost forgettable as I went through my daily chores. I loaded my gabapentin into the evening to reduce any chance of pains that would get in the way of my sleep. I don’t think that I ever expected to avoid all of the discomfort of numbness and a bit of tingling. I was happy as long as I could get to sleep every night. I have never suffered from any side-effects related to the gabapentin; or none that I identified.

Currently, I am taking 1500mg of gabapentin daily. It has been my only medication since the late ‘90s, and the only change has been a gradual increase in the dosage over the past 15 or 16 years. I am told that I could probably take and tolerate higher doses and that some patients do take more than my dose.

Life with numbness

From the 1990s, I recognized that I was losing my sense of balance. I avoid ladders. I am far more sedentary than I was in middle age. I rarely travel and, if so, prefer to use my car. At present, I avoid activities which require much walking and standing. I do my own housework (such as it is), but hire people to look after the outside chores. At home, I spend far too much time sitting at the computer – as I am now! I assume that some of the inactivity and lethargy is a result of becoming a fat old fart. I stopped mowing my own lawn over 10 years ago lest I stumble on the uneven surface. For exercise, I walk on a treadmill rather than the sidewalk, as I fear tripping on the uneven surface. For a couple of years before I got a treadmill, I used to walk at 4:00 or 5:00 AM so that I could walk on the residential street which was smoother than the sidewalk.

As some of my foot muscles become dominant and others atrophy, walking becomes more problematic. I drag my heels and walk flat-footed. My feet are no longer flexible, so I describe the sensation as akin to walking with snowshoes. My feet and legs feel “heavy”. It is very tiring. I can’t walk nearly as fast, or as far as I used to. Much beyond a mile is getting to be a trial: not impossible, but not comfortable. My legs ache after any decent walk on my treadmill. Hiking or walking off road is almost impossible. An extended shopping trip can be problematic. Luckily, I detest shopping.

I can feel movement on my skin if a finger is rubbed across my foot or leg, but if touched gently without disturbing the hairs, I often can’t tell if my foot or leg is being touched at all. If I am poked I get no different sensation from a finger than from a needle. Some nerves seem to still work as occasionally I get a sharp pain from stubbing a toe, but most times my only clue that I have stubbed it is the blood welling out from under the nail.

For the past 2 or 3 years I have been noticing a gradual loss of sensation in my fingers. It is just the same numbness and tingling that affects my feet, but less severe as yet. As I do all my own cooking it presents the constant threat of burned fingers. I cook most of my food from fresh ingredients, so I find that my legs often get tired and achy from standing too long in the kitchen preparing vegetables or batch-cooking for my freezer. Perhaps it is the muscle changes in my feet and legs which cause me the most problem; not the occasional bout of neuropathy pain.

My physiotherapist comments that I have retained strength in my arms and legs, but I notice a lack of strength in my hands and a sensitivity in the skin which keeps me from opening jars or bottles. It can hurt to try to grasp an object too tightly. Accidentally hitting my hand on a piece of furniture or door jamb is often remarkably painful; far more so than used to be the case. I am more likely to drop a light object as I no longer sense, say, a sheet of paper in my hand. Simple tasks, such as doing up small buttons, becomes nearly impossible. My wardrobe reflects that new reality; few shirts with buttons and no tight collars. I struggled mightily to rewire a lamp the other day. My fingers were like useless - and senseless - lumps of clay. It is hard to manipulate thin wire with no sense of touch. Picking up small objects is a trial.

My days entail reading the newspaper, normal ablutions, essentials of housework (dusting is avoided at all costs), email contact with a couple of dozen people, internet surfing, walking on my treadmill or doing stretching exercises, watching videos from my PVR or streamed to my TV through my computer, football and occasional soccer matches watched live, daily food preparation, grocery shopping 2 or 3 times a week, occasional appointments and lunches with friends, usually weekly contests over a friend’s snooker table, weekly visits by a female friend. I drive to see my children and grandchildren every few weeks. I have pretty well ceased attending plays and concerts except for the occasional MET in HD performance. That is more due to the lack of a companion rather than the effects of my neuropathy. I have ceased travelling because of my inertia, and mostly the lack of a suitable travel companion. Neuropathy wouldn’t keep me at home were I really keen to take a particular trip. It would just affect the type of trip and the day’s activities – as it does at home. My inertia is only partly the result of my neuropathy.

What pain is like now

I have used gabapentin alone for over 15 years. I have never tried any other medication. I asked my GP about newer and better medications a year or so ago. He said I should stay with what is working rather than weaning me off it and then going through the process of trying to find something better. I was somewhat relieved.

All in all, I view myself as being rather lucky. I found gabapentin pretty early in the process and under normal conditions I can say that I am pain-free. I have discomfort, and my life is circumscribed, but I do not have the constant level of pain common to some sufferers.

My advice for anyone newly diagnosed with neuropathic pain?

• Seek out whatever medication will render the nerve pain bearable. Once you can limit the pain, everything else is reduced to the level of a really annoying nuisance. 
• Forget vanity and wear sensible shoes with proper orthotic support to keep you mobile. Work with a physiotherapist to develop a regimen of stretching exercises to help keep you as flexible as possible.
• Understand that you will have a constant struggle to maintain as much of your lifestyle as possible, to work around your new limitations, and to seek out any treatments or devices which will make life a bit easier. 
• It isn’t a death sentence so much as a constant set of hurdles which will make life a bit more difficult, but still enjoyable. It’s no walk in the park, but look around at your peers and all of a sudden neuropathy isn’t so bad. There are lots worse conditions to have to cope with.
• https://www.painhq.org/connect/personal-stories/detail/life-with-neuropathy