Late Summer Pickings: September 2018

Doc Gumshoe on Coffee vs. Energy Drinks, Opioid Tapering, Smallpox, Vaccinations, Lyme Disease, HIV and more...

By Michael Jorrin, "Doc Gumshoe", September 12, 2018

For those of us who live in this part of the country and spend any time messing around outdoors in the grass and weeds, this is the time to be careful about Lyme disease. I had a bout of Lyme 16 years ago, and it descended on me when we were on vacation, driving through Nova Scotia. I had no idea what had hit me – I was very chilly in the hot weather, developed a fairly high fever, and felt truly lousy. I discovered that I had a nasty bite on my leg just behind my knee, and when (after a couple of days) I consulted an MD in Northern Maine, he thought it was a spider bite. I got to feeling a little better but not a whole lot. When we returned home, I went to see my own excellent regular PCP, who took one look at me and said, “Bingo! Lyme disease! The most obvious bulls-eye rashes I’ve ever seen.”

I felt like a nincompoop, to be sure. I knew about bulls-eye rashes, but I had never actually seen one at that point. I thought they would be a whole lot more distinct – bulls-eye-ish, like a Target logo. The reality is that there is a clear border between the rash area and the unaffected skin, and the area in the middle of the rash is less red. That’s what makes it a “bull’s-eye.” I hadn’t noticed.

My doctor put me on a 28 day course of doxycycline and told me to stay out of the sun as much as I could. The next month was not much fun, but as far as I have been able to tell, I fully recovered with no residual effects whatever.

Quite naturally, my interest in the possibility of a Lyme disease vaccine spiked about that time. There actually was a vaccine for Lyme disease then. It was called LYMErix, and it had been developed a pharma outfit called SmithKline Beecham, which is now Glaxo SmithKline (GSK). After three doses of the vaccine, it was effective about three-quarters of the time. But a lot of talk soon emerged about nasty side effects, including joint symptoms similar to those experienced by persons with rheumatoid arthritis.

The combination of a vaccine that was 75% effective at most and the possibility – although unproven – that the vaccine was burdened with fairly significant side effects meant that it wasn’t taken up enthusiastically by the public. And, in addition to that, the maker was hit with a number of lawsuits from parties who claimed that LYMErix had caused them significant harm.

So SmithKline took it off the market in 2003, shortly after I had that Lyme disease episode. In the 15 years since 2003, no Lyme vaccine has been available. During that time, according to the CDC, close to half a million people in the US have been officially diagnosed with Lyme disease, and infectious disease experts believe that the actual number, including cases not reported to the CDC, may be closer to five million.

A number of highly knowledgeable infectious disease authorities consider that the withdrawal of the Lyme vaccine was something of a public health disaster. They point out that the adverse effects claim against LYMErix did not have much factual substantiation. In the clinical trial that led to FDA approval, 6,478 subjects received a total of 18,407 doses of the vaccine. The most common adverse events noted within 30 days of receiving at least one dose of the vaccine included pain or reaction at the injection site, joint pain, muscle pain, and headache. Of these, only injection site pain and reactions occurred more frequently in the vaccine recipients than in those who received a placebo.

The result of the LYMErix withdrawal essentially meant that a large number of persons – perhaps millions – were infected with Lyme disease. A considerable fraction of these persons could have been spared if the vaccine had continued to be available.

… but there’s a bit of good news!

A French pharma company that specializes in developing vaccines has completed Phase 1 investigation of a Lyme disease vaccine. This outfit, Valneva SA, is fairly small, but has operations in Austria, Sweden, the United Kingdom, France, Canada and the US. They have proprietary vaccines against cholera and infectious diarrhea, and several vaccines other than their Lyme vaccine under development.

Their Lyme vaccine, identified as VLA15, addresses the outer surface protein (OspA) of the Borrelia burgdorferi bacterium. Valneva reported positive Phase 1 results in March 2018, including a good safety profile and high antibody against all types of the target protein. FDA requirements for entering Phase 2 trials have been met, and Valneva expects to be able to present completed data for approval within five years.

If VLA15 leaps the necessary hurdles leading to regulatory approval, both here in the US and in Europe (where the official count of Lyme diagnoses is about 200,000 per year), we can hope that this much-needed vaccine does not become the target of vaccine deniers and predatory lawyers. Doc Gumshoe finds it more than a bit strange that proposed vaccines for Zika and Ebola meet with public enthusiasm, while vocal groups attack the vaccination programs for children that have hugely reduced the incidence of previously common diseases. Perhaps because the likely recipients of Zika and Ebola are in distant lands, while the vaccines that protect kids against measles and mumps are for here at home?

Coffee lunacy in California

It is a fact that a cup of coffee contains acrylamide, which heads the alphabetical list of “Probable Carcinogens” from the International Agency for Research on Cancer. Note that this chemical is followed on the list by Adriamycin (doxorubicin, a common cancer drug), anabolic steroids (used by many athletes), and art glass and glass containers.

Based on its classification as a “probable carcinogen,” a group of activists in Long Beach, the Council for Education and Research on Toxics, decided to take on coffee as a cancer risk. In a suit against coffee makers, they were able to convince Judge Elihu M. Berle in Los Angeles Superior Court that coffee was dangerous to consumers. In March of this year, Judge Berle issued a ruling that when coffee was served to a customer, it had to be accompanied by a warning that is could cause cancer. This ruling would apply to any entity that served or sold coffee, ranging from Starbucks to your local convenience store.

The supposed carcinogenicity of coffee was based on giving huge doses of highly concentrated acrylamide to those wretched mice that are constantly getting dosed with this and that.

Coffee drinkers, as well as coffee sellers, got a boon when in June of this year, the World Health Organization issued a statement that there was inadequate evidence that drinking coffee caused cancer. This statement reinforced previous findings by a panel of experts in oncology. The State of California’s Office of Environmental Health Hazard Assessment then made an unequivocal statement that chemicals that are produced as part of roasting coffee beans and brewing coffee pose no significant risk of cancer.

The basis for the cancer warning was California’s Proposition 65, passed in 1986, which was meant to warn Californians of the dangers of tainted drinking water. That law requires warnings for any product that exposes consumers to any one of more than 900 chemicals that are in any way linked to birth defects or cancer. This can include a huge range of products in everyday use, including toilet paper and the material used in tooth fillings. I recall seeing wine glasses in upscale shops on a shelf with a little printed sign warning potential buyers that the crystal in the glass might contain lead which is a threat to health. Doc Gumshoe proclaims this to be unadulterated hooey. The likelihood that lead in the crystal would leach out into the liquid in the glass is infinitesimally small – not remotely in the same category as little kids peeling lead paint chips off the walls and chewing them up.

Professor Nathan A Schachtman of Columbia University Law School has described Prop 65 as a “cottage industry of lawyers roaming around looking for violators.” The great majority of these Prop 65-based lawsuits end in settlements paid to the plaintiffs – $25.8 million in 700 cases last year alone. Defendants have a huge motivation to settle rather than contest lawsuits. The $289 million in damages assessed against Monsanto in a suit by a school groundskeeper who charged that Roundup and other Monsanto weedkillers caused his non-Hodgkin’s lymphoma weighs heavily in favor of settling. However, I would add here that there is no evidence that Roundup actually does cause this form of cancer, and a Federal judge agreed with Monsanto that no warning needed to be affixed to the Roundup label.

A bit more about coffee

In response to public misgivings, researchers in Melbourne, Australia carried out a comprehensive review of studies investigating the effect of caffeinated beverages on heart rhythm. The findings were contrary to some allegations that coffee and tea consumption constituted a hazard to cardiac rhythm. Not only did consumption of coffee and tea present no increased risk of either atrial fibrillation (Afib) or the much more serious ventricular fibrillation, the association seemed to point in the direction of benefit rather than risk.

Peter Kistler of the Alfred Heart Center in Melbourne reported the results of a review of 11 studies in 361,000 subjects. Overall, in these studies, coffee consumption was associated with lower incidences of Afib. In some cases, the protective effect of coffee appeared to be larger as consumption increased; for example, in one study, subjects who drank two to three cups of coffee per day had a 14% lower risk of Afib compared with non-coffee-drinkers, while in those who drank six to seven cups per day, the risk was 21% lower. Other analyses showed Afib reductions in coffee drinkers ranging between 6% and 13%. Green tea consumption was also linked to reduced incidence of Afib.

Consumption of energy drinks, however, did demonstrate an increased incidence of Afib. In one study of persons who consumed two or more energy drinks per day, about three-quarters of a cohort with pre-existing heart conditions reported palpitations within 24 hours. Energy drinks typically contain about 500 mg of caffeine, about five times as much as a single cup of brewed coffee, which normally tops out at about 95 mg of caffeine. A shot of espresso usually contains even less caffeine, about 65 mg.

Are you getting our free Daily Update
"reveal" emails? If not,
just click here...

The Alfred Heart Center researchers also pointed to a 2016 controlled randomized trial in 103 heart attack survivors whose caffeine intake averaged 353 mg per day. This amount of caffeine, more than three cups of coffee’s worth, was associated with improved heart rate variability, increased parasympathetic activity, and no increased arrhythmias, compared with the control cohort.

Coffee may also protect against diabetes. Doc Gumshoe mentioned this in a piece a few years back, but here’s the gist: a huge meta-analysis from the Harvard School of Public Health singled out a trial in 910 adults with impaired glucose tolerance, which is a stage leading to definite type 2 diabetes. The study reported that both past and present drinkers of coffee with caffeine had about a 60% reduction in diabetes risk, compared with coffee teetotalers. There weren’t enough decaf drinkers in the study to come to any conclusions, but caffeine by itself may not be the answer. Is there something else in the coffee? Or are the coffee teetotalers doing something else to increase their risk of diabetes, such as knocking back a sugary soft drink?

It’s possible, of course, that what’s behind the supposed benefits of caffeine noted above doesn’t really have anything to do with caffeine, but is instead related to what the coffee teetotalers consume instead of coffee. My excellent mother-in-law, now 94, starts off her day with a nice glass of cool water, but I don’t think there are a whole lot of folks out there like her. They drink something, and it might be that something that’s causing the uptick in those cardiac arrhythmias. Maybe the clinical study that needs to be done is to recruit a substantial cohort of coffee abstainers who do have cardiac arrhythmias and find out what they drink.

A dubious approach to quelling the opioid abuse problem

The state of Oregon is currently giving serious consideration to tapering chronic pain patients on Medicaid to zero opioid dosage. A proposal is under consideration to start tapering all Medicaid patients now on opioids down to zero over a twelve-month period starting in 2020. The proponents of this program assert that every effort would be made to provide patients with effective alternative pain management options.

The patients themselves, however, are extremely concerned. They commonly express the view that their current opioid medication regimen is the only thing that makes their lives in the least tolerable, and that addiction for them is not a consideration. They take their medication exclusively for pain relief. Many of them have cycled through a considerable number of pain medications that simply failed to bring them any real measure of relief.

Other states have considered instituting measures to reduce opioid prescriptions in some patient populations, such as patients who have exhibited certain risk factors for addiction. In some cases, patients are required to refill opioid prescriptions much more frequently, and always in consultation with the health-care provider. The Oregon plan, so far at least, is the only plan that would stop all opioid prescriptions to an entire patient cohort.

Critics of the plan predict that many patients in chronic pain would quickly turn to black market drugs, which are quite easily available, and which also are immensely more dangerous, since their potency is completely random and they may be laced with potentially deadly substances such as fentanyl.

Another concern is that patients would attempt to compensate for their now forbidden opioids by taking very large doses of other much less effective analgesics, which, at those hugely excessive doses, would also be accompanied by extremely serious adverse effects.

And it has been pointed out that some patients escape their uncontrolled long-standing pain by committing suicide.

All in all, it seems grossly unfair that individuals who are in chronic pain should suffer the major consequences of a plan to reduce opioid abuse – by and large, a failing of which they are not guilty.

A bit of news that will make no difference (we hope!) to anyone now alive

The FDA is expected shortly to approve a drug that in all likelihood will never be used. The drug is tecovirimat. The disease it would treat, if it still existed on Planet Earth, is smallpox. As surely you know, smallpox was eradicated back in 1980. There have been no cases in the nearly 40 years since then. However, the virus that causes small pox, variola, still exists. In the US, variola virus is maintained in laboratories.  But in the 1980s, the Soviet Union developed variola as an aerosol biological weapon and produced tons of virus-laden material intended for release via intercontinental ballistic missiles.

Smallpox has been used as a weapon of warfare, and the fear is that a terrorist organization may somehow gain access to this virus and attempt to use it as a weapon. Even if this putative villain were not able to get the actual virus, the entire genetic code of variola is known, and could possibly be recreated in the laboratory. Smallpox is among the deadliest of human diseases. About 300 million people were infected with smallpox in the 20th century and about one third of them – 100 million – died as a result.

After the eradication of smallpox 40 years ago, smallpox vaccinations dwindled and stopped. I personally was vaccinated as a matter of course when I was a tot. But at present, great swaths of the earth’s population are unvaccinated and susceptible to the disease, and herd immunity consequently has about vanished. On average, each person with smallpox infects five to seven other persons – that’s known as the reproduction number, and it is quite high. As a result, the multiplier effect of smallpox epidemics is frighteningly large.

Returning to the question of tecovirimat, it was discovered by means of screening about 350,000 compounds. It was tested on monkey pox, which has been validated as an animal model for human smallpox. The mortality rate for monkeys infected with monkey pox was about 95% in the absence of this drug, but when infected monkeys were treated with tecovirimat, starting four days after the emergence of skin lesions, the monkey mortality rate dropped to zero. The drug was tested in 412 healthy human volunteers to ascertain the correct dose and the adverse effects profile. These adverse effects, by the way, were similar to placebo.

So, if the variola virus should ever again become a threat to us humans, at least we have some recourse. We deeply hope we never need it.

And, as a PS to vaccination skeptics out there, vaccination was the weapon that eradicated that disease that killed so many millions of us. May it stay eradicated.

Definite progress on the HIV front

This is not quite a declaration of victory, but it’s unquestionably positive. In 2015, among patients with HIV who are being treated in HIV clinics, 86% attained levels defined as being “viral suppression,” meaning fewer than 400 copies of the virus per milliliter, which is considered to present a greatly reduced risk for transmission of the disease as well as beneficial to the patient’s health and well being. This was a major improvement in HIV treatment since 1997, when only 32% of similarly- treated HIV patients had attained that level of viral suppression.

The study, published in Annals of Internal Medicine on 21 August 2018, was based on the medical records of 31,930 patients receiving treatment at HIV clinics. Higher rates of viral suppression were found among older patients, with an increase over the median rate of viral suppression amounting to approximately 24% per decade. For black patients, the rate of viral suppression was significantly lower than for the cohort as a whole.

A major limitation of the study is that patients not receiving such treatment were not included in the study. Many persons with HIV continue to receive intermittent or no treatment, in part because of stigma associated with the disease. HIV-infected individuals may distance themselves from the health-care system because of substance abuse. Depression and behavioral disorders may also have a negative effect on the likelihood that an HIV-positive individual will adhere to a treatment regimen.

Another aspect of the campaign against HIV is the effort (particularly on the part of one prominent pharma outfit) to encourage persons at very high risk for HIV to take part in pre-exposure prophylaxis, now commonly abbreviated as PrEP. The prophylactic drug is Truvada, which is a combination of emtricitabine and tenefovir, marketed by Gilead (GILD). PrEP works very well indeed if the regimen is adhered to strictly; not so well if the at-risk individual is less disciplined. The profile of the person for whom PrEP is appropriate is as follows: he (almost invariably male) is HIV negative, regularly has sex with men, is not in a relationship with another HIV-negative male. Drug users who share hypodermic needles with other drug users are also, obviously, at very high risk for HIV, but they are not the usual PrEP targets. PrEP is far from inexpensive – about $1300 per month – but health insurance usually pays at least part of that cost, based on the calculation that prevention, even expensive prevention, is less expensive than treating an HIV infection.

Health care in the age of “artificial intelligence”

Let’s start off with an anecdote which I hope will amuse the denizens of Planet Gumshoe.

A few years back, as I was checking out after my annual physical examination, I was handed a print-out showing my results on all the tests I had undergone. Everything looked dandy, except for one startling little factoid.

According to that official document, I was obese. Obese!

I am not obese. I demanded an explanation. A little scurrying in the front office, and a somewhat supercilious person explained patiently to me what that term meant: that I had a body mass index greater than 30, which is the cut-point dividing the merely overweight from the obese. My weight, as recorded by the nurse who examined me, was 215 pounds. My height was 5’ 10”, which works out to a BMI of 30.8, just over that cut-point.

I pointed out that I am not, NOT, 5’10 in height, but 6’2” in height, and my BMI, a value which I understand very well indeed, is 27.6, squarely in the middle of the overweight range. I insisted on having my height measured again, this time by someone tall enough to see over my head. (The nurse who had weighed and measured me was too short to see the mark on that bar that sticks up at the top of the scale.) I added that a document proclaiming me to be obese could under no circumstances become part of my medical records.

I was told that the document was already part of my medical records. It had already been entered in the computerized system of this large, unwieldy medical group, whose headquarters were in another state. (I have parted company with this outfit, which my former doctor referred to as the “medical-industrial complex.”)

There in the front office, I slammed my hand on the countertop and emphatically told that supercilious person (and everyone else within earshot) that it was totally unacceptable that incorrect information should be entered into the medical records. It MUST be corrected, or I would take legal action.

Well, it turned out that it could, after all, be corrected. I was re-measured, and sure enough, I had not shrunk. The error was removed from my electronic medical records (EMRs).

But how many totally erroneous (or at least dubious) entries make their way into patients’ EMRs, and how many patients even see these EMRs, and if they do, notice errors and take the necessary steps to have them corrected? Once in the record, this information is as if set in stone, and there’s no telling who has access to those records. These entries could have really consequential implications. Being categorized as “obese” could affect my health insurance, for example. Other errors could affect patients not only financially, but in terms of the treatment they receive. Based on errors in the record, patients might be prescribed drugs they don’t need or denied drugs they do need.

The mere format of the EMR, whether on screen or printed, inspires more respect than a doctor’s or nurse’s scrawl on a sheet of paper. It looks official; it has been vetted; it has to be correct. And when it’s not, the downstream consequences can be serious – and they can run quite a long way downstream.

I am not questioning the promise of EMRs and their value in certain circumstances. For example, if you live in Calais, Maine and have been consulting a physician there regularly, and you happen to be in San Diego, California and need to be treated in a hospital on an emergency basis, your EMR can be transmitted across the country in a jiffy. That could be highly valuable, if they are correct.

But that doesn’t seem to be the real objective of EMRs. They appear to be designed with hospital administration in mind, not to provide immediately valuable information to an actual health-care provider. The focus seems to be billing rather than patient care. Not coincidentally, even though from 1990 to 2012, the US healthcare workforce grew by 75%, about 95% of that growth was in administrative staff, not physicians. By 2012, there were 16 non-doctors for every doctor, and only 6 of the 16 were involved in patient care.

EMRs tend to contain vast amounts of data that is not necessarily relevant to the care of the specific patient. The data is entered not by means of a provider actually laboriously entering information, but by checking boxes. It’s the checked box that generates the data – one box can produce quite a lot of text in the EMR. In turn, these checked boxes generate alerts – not that the provider noted the alert, but that the computer, connecting checked box A with checked box B, arrived at the conclusion that an alert was advisable. Many of these alerts are redundant, and doctors get into the habit of ignoring them.

And the requirement that physicians maintain these EMRs means that they spend less and less time with patients. Some studies report that less than 10% of their workday is actually spent talking with and listening to patients. Even in the examining room, a great deal of their focus is the computer screen. Once in a while they glance up at the patient, but then they go back to checking boxes on the screen.

Happily, when my own PCP is doing my annual physical, there’s no computer in the examining room.

A look at the bright side

About three years ago, Doc Gumshoe posted a piece entitled “Aging: What’s All This about Preventing or Slowing It Down?” One of the topics covered was the relation between the length of our telomeres and life expectancy.

Here’s the background: when cells divide, each new cell – “daughter” cells, as they are known – has to have a complete copy of the mother cell’s DNA. This is accomplished by splitting the DNA strands neatly and effectively, so that each daughter cell gets one complete strand, which is copied in the new cell. At the ends of chromosomes, the DNA strands have nucleic acid sequences called telomeres, which convey no genetic information, but serve a vital purpose, which is to protect the integrity of the vital part of the DNA during the splitting process. Each cell division results in the loss of some of the telomeres from the ends of the DNA strands, such that elderly folks have perhaps one-fifth the as many telomeres as newborns. And at a certain point in cell division, there are not enough telomeres at the ends of the strands to protect the part of the DNA that codes the genetic information, so the splitting process damages that part of the DNA strand. The cell division process peters out – cells die and are not replaced by new cells.

This happens in almost all of our body’s cells, except in cells vital to reproduction of a species, such as sperm cells and egg cells. In those cells, telomeres are protected by enzymes called telomerases, which prompt the cell to make new telomeres to protect the DNA strands. Thus, telomerases are crucial to the survival of genetic information and new cell creation. (Of course, the body has other ways of discontinuing the production of sperm cells and egg cells, regardless of the presence of telomerases.)

As it happens, cancer cells are also supplied with telomerases, which is why they are able to continue to divide and multiply indefinitely. Thus, telomerases have become a promising target for cancer therapy: inactivate the telomerase in cancer cells, and the cancer will die out on its own. An agent that has shown promise in that approach is imetelstat, from the biotech company Geron (GERN), which did much of the basic research into the role of telomerase in cancer. The 2009 Nobel Prize for Physiology or Medicine was awarded to two Geron collaborators, Elizabeth H. Blackburn and Carol W. Greider, along with Jack W. Szostak for the discovery of how chromosomes are protected by telomeres and the discovery of the enzyme telomerase.

Geron just recently released highly positive results from a Phase 2 trial with imetelstat in patients with myelofibrosis with a median life expectancy of about 7 months. The FDA has given Geron permission to continue the trial beyond the protocol end date, and these patients are now thought to have tripled their life expectancy. Imetelstat treatment did not result in any safety signals of concern in these patients.

Conducting clinical trials for prospective cancer drugs in patients with forms of cancer for which there are few treatment options and who have failed existing treatment options is the norm. The pharmas start there and then hope to move on to the mainline cancer forms; they wouldn’t have a hope of getting a trial approved in breast, lung, or prostate cancer, in which patients would be randomly assigned to an experimental drug when there are existing drugs that are known to deliver fairly good results. Imetelstat definitely looks like a promising prospect, and Geron’s collaboration with Johnson & Johnson is solid.

Meantime, there are rumors swirling all over cyberspace about “entirely natural” supplements that are sure-fire ways of lengthening our telomeres and thereby prolonging our lives. In perfect health, of course. In the Doc Gumshoe piece on aging I put out the notion that the Mediterranean diet might do just that. One of those supplements, Genesis, somehow brought Dr Blackburn (the Nobel Prize winner) into the picture. Not sure whether they took her name in vain or whether she is really an advocate of that supplement. I’ll try to give it a look.

* * * * * * *

Many thanks for all the comments. I particularly welcome comments that express interest in treatment areas that I have not yet addressed, or mention drugs, supplements, interventions, or other subjects that perhaps I haven’t become aware of. Keep those suggestions coming! Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who we like to call ”Doc Gumshoe,” is a longtime medical writer (not a doctor) who shares his mostly non-investing-related thoughts with the Gumshoe community a couple times a month. You can see all of his columns here.]