No, these bits won’t be about Melania’s kidney ailment nor yet about what Meghan wore for The Wedding. I wish them both luck – they’ll need it!. However, there continue to be developments on the medical and health-care fronts that may matter to us a good deal more than the doings of those ladies.
The first one is especially interesting in that it poses the need to balance considerations that have potential impact on the lives of millions. Here’s the story.
Antibiotics given prophylactically save the lives of children in poor regions
This was based on a study in three African nations – Malawi, Niger, and Tanzania. (Keenan JD et al. “Azithromycin to reduce childhood mortality in sub-Saharan Africa,” N Engl J Med 2018;378:1583-1592) A total of 1,533 communities in those three nations were randomized such that young children in these communities received either four twice-yearly single doses of azithromycin or placebo. All-cause mortality in these children was the single outcome measure. Children were not followed as individuals; the comparisons were between communities as a whole. The total number of children up to 5 years of age in those communities was 190,238, of which approximately 90% participated in the trial.
The single azithromycin dose was approximately 20 mg per kilogram of body weight. The usual starting dose of azithromycin is 500 mg, followed by 250 mg per day for four more days. At the 20 mg per kilogram of body weight used in the study, 500 mg would be the dose for a child weighing 25 kilograms, or about 55 pounds. I would judge that the dosage was quite robust for a single prophylactic dose, especially for the younger children in the study.
Overall mortality was 13.5% lower in children in the communities that received azithromycin compared with children in communities that received placebo; this was a highly significant difference (P < 0.001). The rate was 5.7% lower in Malawi, 18.1% lower in Niger, and 3.4% lower in Tanzania.
The overall difference was especially notable in children in the age group of 1 to 5 months. In those children, the mortality rate was 24.9% lower in the communities that received azithromycin compared with communities that received placebo.
Azithromycin, (Zithromax, from Pfizer) is an antibiotic in the macrolides class, which includes clarithromycin, erythromycin, and others. Like many antibiotics, it was developed based on a soil-dwelling bacterium. Macrolides, including azithromycin, are effective against a broad range of gram-positive pathogens, including many that cause upper- and lower-respiratory illnesses (e.g., Streptococcus pneumoniae) and also some gram-negative pathogens. They are highly valuable drugs. Azithromycin in particular is valued because, unlike many other antibiotics, the usual course of treatment is only 5 days, which reinforces patient adherence to treatment and minimizes the development of resistance. Patients are more likely to complete a shorter course of treatment; when a course of treatment is ten days or longer, some patients (or their parents!) figure that they’re “all better” a few days short of the complete course and discontinue treatment. If the pathogens have not been totally eliminated, those that survive are likely to have developed some resistance. Azithromycin eliminates the evil critters faster, and, as the saying goes, “dead bugs don’t mutate.”
But a single dose of azithromycin is clearly riskier from the perspective of inducing resistance. The study authors did acknowledge that widespread prophylactic administration of azithromycin could well have an impact on the emergence of resistant pathogens, and they emphasized the need to “strongly consider the potential effect of such a strategy on antibiotic resistance.”
The ethical balance is particularly difficult to evaluate in cases like this one. A reduction of nearly 25% in mortality in children in the 1 to 5 month age range, if carried out throughout sub-Saharan Africa, could likely safe millions of infant lives. On the other side of the balance, the consequences of the development of pathogens resistant to azithromycin, and perhaps to other macrolides, are not easy to calculate.
A spokesman for Pfizer, Dr Charles Knirsch, noted that Pfizer had donated more than 700 million azithromycin doses to the International Trachoma Initiative, and that no permanent resistance-inducing mutations have been identified in any bacteria. The emphasis here is on “permanent;” an officer of the Trachoma Initiative acknowledged that some resistant bacteria do emerge, but that they “fade out within weeks or months.” It was also pointed out that any resistance would be to drugs in the macrolide family, which are not much used in Africa.
It seems cold-heartedly calculating to balance the likely life-saving benefits of prophylactic azithromycin, which appear to be large and highly likely, against the potential harms of a resistant strain of any of the hundreds of pathogens susceptible to azithromycin. That the former would save millions of lives is highly probable, while the chances are slim that the latter would cause the loss of more than a few lives. But the dangers that antibiotic resistance presents could be colossal, such as the emergence of a pathogen that is resistant not only to azithromycin, but other available antibiotics as well.
What the data from this study tell me is that the differences in childhood mortality rates between Niger and Tanzania reveal something highly important. Delving a bit deeper, we find that whereas in Niger the annual mortality rate in communities receiving azithromycin was 22.5 per 1000 person years, in Tanzania that rate was 5.4 per 1000 person years; in communities receiving placebo, those respective rates were 27.5 and 5.5. So, while in Niger 5 children per 1000 person years were saved from death, in Tanzania only 0.1 child benefitted in that way. What accounts for this huge difference between Niger and Tanzania? I can only guess: availability of health services in the community, and the quality of sanitation and water supply.
A comparable situation is taking place in India, where health authorities encourage women to give birth in hospitals if at all possible, to counter the deplorable state of sanitation that prevails in most parts of the land. Newborns are routinely given antibiotics to try to mitigate India’s high rate of infant mortality, which in 2017 was 39.1 deaths per 1000 births. (For purposes of comparison, the infant mortality rates in most developed nations are in the low single digits, and many much less developed nations have lower rates than India’s.)
What makes the Indian plan particularly threatening is that the antibiotics given newborns in India are frequently among the most recently-developed drugs, which elsewhere are customarily held back for use specifically in cases where the pathogen, due to resistance, does not respond to treatment with the more common antibiotics. That way, the new drug is kept from wide indiscriminate use in the hopes that it will serve as backup protection against emerging resistant pathogens. Not so in India, where laboratories quickly copy new drugs and health authorities employ them broadly. This is thought to foster the emergence of multi-drug-resistant pathogens.
At least in Africa the stated intention is to keep a close watch on possible emergence of resistant bugs. The study, known as the MORDOR Clinical Trial, was funded by the Bill and Melinda Gates Foundation, and Doc Gumshoe will try to trust them to do the right thing.
Faulty software leads to the recall of record high numbers of medical devices
More medical devices were recalled – a total of 208 million – in the first three months of 2018 than in all of 2017, and software failures were the cause of 23% of all recalls, the single biggest factor. Medical devices have become increasingly complex, and increasing numbers of these devices are dependent on artificial intelligence and highly complex clinical decision algorithms.
The FDA is accepting devices that are software dependent. Traditional medical devices did no more than give the operator an image, or perhaps a simple readout of measured characteristic, leaving the clinical decision based on those results to a human. Increasingly, these devices are linked to algorithms that may actually carry out clinical decisions. A relatively simple example is the blood glucose monitor worn by diabetics that not only continuously monitors blood sugar, but communicates the data to the insulin pump, which then delivers a dose of insulin, as calculated by the algorithm which is implanted in the device’s software. The benefit is that peaks and troughs in the patient’s blood glucose are leveled, minimizing both the harms of elevated glucose and the potential for an insulin reaction. But for this to take place reliably, the software had to work without glitches, and software glitches are hardly infrequent.
… and the software in medical devices is increasingly subject to hacking
Another concern is cybersecurity. Some medical devices are particularly susceptible to attacks by hackers. About three years ago, the cybersecurity firm Symantec identified a group called Orangeworm that has been detected installing a custom backdoor called Trojan Kwampirs within the computer systems of large international corporations that operate within the healthcare sector in the United States, Europe, and Asia. Known victims include healthcare providers, pharmaceutical manufacturers, IT solution providers for healthcare and equipment and manufacturers that serve the healthcare industry.
About 40% of Orangeworm’s victims operate within the healthcare industry. The Kwampirs malware was found on machines which had software installed for the use and control of high-tech imaging devices such as X-Ray and MRI machines. Additionally, Orangeworm was observed to spy on machines used to assist patients in completing consent forms for required procedures.
Doc Gumshoe concedes that it is probably impossible to keep one’s healthcare information strictly private. But giving consent to all and sundry to have access to my healthcare records? The answer is NO.
We can’t say for certain what Orangeworm intends to do with all the data it steals through these invasions. It might be something relatively harmless, although irritating, like deluging individuals with advertising that it somehow based on their health conditions, or it might be a wide assortment of scams and swindles, or outright blackmail and extortion schemes. Another possibility is that the aim is to steal competitive information about the devices themselves that can then be peddled to would-be piratical manufacturers. Unfortunately, a reality that we need to address more and more is that if any information is on a computer somewhere, it may be vulnerable to hacking.
Some drug treatment regimens may be able to be shortened
The specific evidence for this cheerful statement comes from a study that will be presented to the American Society of Clinical Oncology in June. The finding was that women treated with the anticancer drug Herceptin for six months did just as well as those treated with Herceptin for a year.
Herceptin (trastuzumab, from Genentech) is a monoclonal antibody that inhibits the proliferation of human tumor cells that overexpress HER2, a gene that plays a role in the development of breast cancer. HER2 genes produce HER2 proteins which, when they are working properly, help control how healthy breast cells grow and divide. In some cases, HER2 genes multiply too rapidly and make too many HER2 proteins, which then cause breast cells to proliferate in an uncontrolled way – i.e., cancer.
Typically, women with HER2-positive breast cancer take Herceptin for a year. In the current large study, thousands of women in the UK were followed for more than five years, and the outcomes data supported the conclusion that a six months course of treatment was equal in efficacy to a full year of treatment. Previous smaller studies had reported that three months or even nine weeks of treatment with Herceptin produced results fully comparable to a year of treatment, but further investigation has disputed those claims. It is of course possible that the current claim of equal efficacy for six months of treatment will similarly be contested. And we should note that the current study has not yet been peer-reviewed. But the size and duration of the study inspire confidence and optimism.
It should be pointed out that the Herceptin study is highly unusual, and (in the opinion of Doc Gumshoe) very valuable, not only with regard to this particular drug. When pharmaceutical companies do clinical trials, particularly of cancer drugs, they seldom seek to pinpoint the minimum duration of treatment. They want the treatment regimen to go on long enough to maximize the chance for positive results. So, if after a killingly expensive Phase 3 trial that demonstrates that your candidate drug met its endpoint after one year of treatment, you are not going to do another killingly expensive clinical trial to see whether it would work just as well in a shorter time frame.
But from the point of view of the patient, that information would be of huge value. With regard to Herceptin, it would greatly reduce the incidence of adverse effects, which are considerable with that highly valuable drug. The list of Herceptin’s side effects is long and familiar – diarrhea, injection site reactions, various pains and aches, insomnia, nausea and vomiting. The chief difference is that very few women get through a course of Herceptin treatment without experiencing one or more of those side effects. But the side effects of greatest concern are coronary, and they are far from trivial, although rare. Weakening of the cardiac muscle, sometimes culminating in heart failure, is perhaps the most serious. And the side effects increase in severity with duration of treatment, so shortening the treatment period would be greatly beneficial. It would also save considerable money. A year of treatment with Herceptin costs about $76,000, which, divided by two, comes out to $38,000.
Bits of news also come trickling in about the possibility that shorter treatment courses may work with other drugs. Diseases that were once thought to require a lifetime of drug treatment have been found, in some cases, to remain quiescent once they have been brought under control. Patients with rheumatoid arthritis (RA), for example, interrupt their medication prior to surgery to minimize the possibility of surgical infections, because RA drugs suppress the immune response to some degree. But in some such patients, there is no uptick in disease activity after several months without drug treatment. In some HIV patients whose treatment has reduced their viral load to undetectable levels, it may be possible to discontinue antiviral treatment. In all such cases, patients need to be under continued careful observation.
What’s happening on the prostate cancer front?
Quite a lot. Let’s start out with a bit of bad news, viz, the incidence of metastatic prostate cancer in the United States has increased significantly, from 7.8 new cases per 100,000 population in 2010 to 9.2 cases per 100,000 in 2014. Also, in a time span during which overall cancer deaths have decreased, prostate cancer death rates have leveled off. This has occurred after two decades of continuing decline in prostate cancer death rates, and in a period when cancer deaths overall are decreasing. This information comes from the Annual Report to the Nation of the Status of Cancer, from the National Cancer Institute, which is part of NIH.
The reason for this distressing trend is fairly obvious. It is almost certainly due to the boneheaded recommendations by the US Preventive Services Task Force (USPSTF) that dissuaded millions of American men from having prostate-specific antigen (PSA) tests. PSA testing was widely introduced in the late 1980s and led to an immediate increase in the detection of prostate cancer, sometimes at a very early stage. Many authorities viewed this as a Bad Thing, on the grounds that a majority of those cancers detected did not require treatment, as they were likely to be very slow-growing and not pose any threat to the men in whose prostates they were growing. The easy phrase that quickly dismissed that threat, and therefore the advisability of the PSA test, was “most men die with but not of prostate cancer.” In other words, something else kills us first. So the USPSTF did what it could to discourage the use of the PSA test.
However, a clear consequence of widespread PSA testing is that prostate cancers were detected much earlier, and many men underwent treatment for their cancers, whether this treatment was absolutely necessary or not. As a result, metastatic prostate cancer and prostate cancer deaths declined markedly. But the USPSTF singlehandedly sabotaged that trend – a trend that saved many, many lives.
Here’s what the Annual Report says. (The italics are mine.)
“PSA testing began in 1986 and peaked in 1992. Reflecting changes in PSA testing rates, overall prostate cancer incidence rates rose from 1988 through 1992 but distant-stage prostate cancer rates declined between 1991 and 1994. In 2008, the US Preventive Services Task Force (USPSTF) recommended an “I” rating (insufficient evidence) for PSA-based prostate cancer screening for men younger than age 75 years, and a “D” rating (recommendation against screening) for men over 75. Subsequently, PSA testing rates declined after 2008. In 2012 the USPSTF changed their recommendation to a “D” rating regardless of age, and PSA testing rates continued to decrease. Between 2008 and 2014, the rate of distant-stage disease increased. In May of 2017, the recommendation changed to a “C” rating (decision to be screened should be an individual one) for men between the ages of 55 and 69. This may again result in changes in PSA testing as well as the rate of distant-stage prostate cancer.”
That pins the responsibility on the USPSTF – but very gently. So, perhaps finally accepting the idiocy of their initial recommendations, the USPSTF changed their mind, but not before sending a considerable number of men to their graves. As Doc Gumshoe has said previously, their recommendation amounted to making More Work for the Undertaker. Here’s what I said:
”A quick look at prostate cancer statistics would likely dim the rosy picture painted by the “with – not of – prostate cancer” scenario. Prostate cancer causes more than 26,000 deaths in the US every year, and, according to the American Cancer Society, kills one man in 39. Although the five-year survival rate for prostate cancer overall is nearly 100%, it drops to less than 30% if the cancer metastasizes to distant sites. Not such an optimistic picture. And how would one detect and treat prostate cancer without PSA screening? You tell me.”
Some bits of good news
But there are several items of genuinely good news on the prostate cancer front. Let’s assume that now that the USPSTF has faced up to the error of its ways and changed the level of recommendation for PSA screening from D (recommendation against screening) to C (based on individual decision), screening rates will once again increase, at least modestly. As before, many men will have positive results based on the PSA levels, and needle biopsies of the prostate gland will be recommended for these men. The decision whether to treat will largely be based on the Gleason score, which is a fairly complicated calculation from the results of the biopsy. In general terms, Gleason scores of 6 or lower are thought to be appropriate candidates for what is termed “active surveillance.” Speaking practically, active surveillance has generally been synonymous with periodic repeated biopsies. This can be more than a nuisance; for some men it can present a clear risk of infection.
However, perhaps that no longer needs to be the case. A recent promising study, optimistically dubbed PROMIS (Ahmed HV, Lancet 2017;389:815-829) reports that at least some men with elevated PSA levels may be able to avoid prostate biopsy and instead be tested by means of multi-parametric magnetic resonance imaging (MP-MRI).
The study demonstrated that MP-MRI was more sensitive than biopsy (93% versus 48%), although less specific (41% versus 96%). (In the medical testing realm, sensitivity refers to the ability to identify individuals with the disease – i.e., low percentage of false negatives – and specificity to the ability to identify those without the disease – i.e., ,low incidence of false positives.) Balancing those values, MP-MRI was reported to have an overall negative predictive value somewhat superior to biopsy, 89% versus 74%. The authors concluded that MP-MRI would allow about 27% of patients to avoid biopsies and would result in a diagnosis of about 5% fewer clinically insignificant cancers, i.e., cancers that definitely did not require treatment.
The MP-MRI scan can also be used to guide biopsies, and this might presumably result in the detection of more significant cancers, while at the same time reducing the overall need for biopsies for all PSA-positive patients. The authors noted that the efficacy of this method of assessing the risk of clinically significant cancer depends largely on the quality of MRI interpretation and the skill of the radiologist, which would vary between practice settings. The high rate of false positives (due to the low specificity rate) is a clearly a limitation, but the very low rate of false negatives is a strength.
.… and another bit …
This one is more complex, and I’m not going to sweat to try to explain it detail. I hope it will be enough to say that prostate cancer tumors have a built-in mechanism that puts the brake on protein synthesis. The tumors need some protein in order to grow and prosper, but too much protein kills the tumor. It seems that some treatment-resistant tumors have a couple of genetic mutations that appear to reduce the rate of protein synthesis, and these mutations result in a specific factor, which they have dubbed P-elF2a, that accomplishes that goal, which is essential to tumor survival.
Scientists at UCSF have found a potential compound that blocks the activity of P-elF2a and thereby triggers the cancer cells’ addiction to proteins. At least in the lab, they manufacture large quantities of lethal protein and thereby burn themselves out. This compound is called ISRIB. The results of tests in mice showed that this hopeful drug can shrink tumors and increase mouse survival. Clearly, it’s years away from actual use in humans, but it is definitely promising.
The first migraine preventing agent gets the FDA nod.
The drug is Aimovig (erenumab-aooe), and who got the FDA approval was Amgen. For the record, the drug is being co-marketed by Amgen and Novartis, with Amgen getting the US plus Japan, and Novartis getting Europe plus Canada. Much of the discussion around Aimovig has to do with how it will affect the fortunes of Amgen, and whether it will help to offset the current ugly buzz around Novartis. Those matters are beyond Doc Gumshoe’s purview. He will stick to his last and try to shed some light on the drug itself.
The basics are that Aimovig is, as stated in the headline, the first migraine prophylactic agent to gain regulatory approval. It is given by injection, monthly.
Aimovig targets the receptor of a peptide known as calcitonin related gene peptide (CGRP) which has been shown trigger the release of substances that cause inflammation in the brain, causing local pressure on nerve fibers and the typical migraine symptoms. The proinflammatory mediators may also increase the synthesis of CGRP, creating a feedback loop, and resulting in migraine episodes lasting up to 72 hours.
Three placebo-controlled trials led to the approval of Aimovig. In the first, a six-month study enrolling 955 subjects, those taking the active drug experienced one to two fewer migraine days per month than those in the placebo group. In the second, a three month study in 577 subjects, the benefit was just one fewer migraine day per month, while in the third study, also three months, in 667 subjects, the benefit experienced by those in the Aimovig group was two and one-half fewer migraine days per month. Across all three trials, approximately 40% of patients experienced at least a 50% reduction in the number of migraine days per month. The adverse effects experienced by patients receiving the drug were similar to those in the placebo group.
It’s obvious that the patient population for which this drug would be appropriate is limited to persons who suffer from frequent migraines. The subjects in these studies typically had about eight migraine days per month. To those afflicted individuals, having two and one-half fewer days per month might seem like a significant benefit.
Perhaps more important is the distinct possibility that migraine treatment is entering a new era with the development of several drugs that target CGRP or its receptor. A new drug, not yet approved, ubrogepant, is a CGRP receptor antagonist, and appears to be more effective to acute relief of migraine than current agents. Other monoclonal antibodies against CGRP such as eptinezumab, fremanezumab and galcanezumab, also may effectively prevent migraine attacks. Approval of these drugs is expected in the next couple of years.
Finally, the latest findings may provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine. Up to now, drugs used to mitigate migraine episodes have been somewhat effective at best. The triptans got a great deal of favorable notice when they appeared on the scene, and without question were a major improvement over the remedies that were available prior to their introduction, but they need to be taken as soon as the earliest migraine symptoms are detected. Typical analgesics do very little in dealing with migraine headaches, and nothing at all with regard to the many other migraine symptoms. As with most other afflictions that plague the human body, the key to finding effective treatment is understanding the underlying pathophysiology. Without that basic understanding, attempts to fix the problem sometimes amount to stumbling around in the dark. So, let’s hope that migraine researchers are now emerging into the light.
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A couple of weeks ago, Travis clued me in on yet another promotion from Dr Al Sears, in which he points to a new treatment for anything and everything that ails us, and which is 1329 times more potent than the regimen that put an end to polio. Of course, the FDA is trying to suppress it. I am aware of the risk I run if I find fault with Dr Sears’ line of reasoning. I am likely once again to have my status as a native of Planet Earth questioned. But I’m willing to brave the storm. If need be, I can provide the exact address of the house in which I was born and pictures of myself as a babe in arms. Dr Al Sears persists, and so will Doc Gumshoe. Thanks and best to all, Michael Jorrin (aka Doc Gumshoe)
[ed. note: Michael Jorrin, who I call Doc Gumshoe, is a longtime medical writer (not a doctor) who writes for us about medicine and health a couple times a month. He has agreed to our trading and disclosure restrictions, but does not generally write directly about investments. His ideas, thoughts and words are his own, and you can see all his past pieces here.]
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