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An ongoing dialogue on HIV/AIDS, infectious diseases,
September 28th, 2014
And if you’re wondering what the big deal is, welcome to the club. In fact, the Canadians beat us to the punch with more significant approval, the co-formulated darunavir/cobicistat, branded as Prezcobix — which sounds like one favorite British breakfast cereal.
For the record, here are a few reasons why the FDA approval of elvitegravir and cobisistat will likely have little short-term effect on clinical practice:
- Elvitegravir is already available as part of TDF/FTC/EVG/COBI.
- Cobicistat is already available as part of the same single tablet regimen.
- If not coformulated, elvitegravir alone has no major advantages over raltegravir and dolutegravir.
- If not coformulated, cobicistat alone has no major advantages over ritonavir. (Though I gather the pill is smaller. Haven’t seen it yet.)
But — what if they cost less? Especially a lot less?
September 24th, 2014
From a long-term and highly respected colleague comes this challenging query:
One of my HIV pts, doing wonderfully well, is planning to enroll in a nursing program. She does not want to disclose her HIV status (fine with me), but the hospital requests a list of current meds which, of course, would blow her cover. My inclination is simply to leave the HIV meds off the list, but I asked our legal office who advises me not to do so — they say just decline to fill out the form. However, I don’t like that advice, since it essentially means my patient cannot enroll in the program. Of course I question whether the employer has the legal right to know all the meds, but I can’t change that in the short term.
What sayest thou?
Miffed in Malden
I completely share your frustration with these forms, which have bedeviled us ID specialists for decades. One of the more excruciating questions they sometimes ask is, “Does this patient have a contagious disease?” Hate that one; I’ve figured out that it’s best to interpret it as, “Does this person have a disease that would be considered contagious in the context of these job activities?” making it much easier to answer.
But the nursing program wants to know your patients medication list, which brings up the question of why. If they find out she were taking HIV meds — or psych meds, or immunosuppressive drugs, or five antihypertensives, or echinacea — would they reject her application? I hope not, as that would be highly discriminatory — people with these conditions can certainly work in healthcare provided they are medically stable. It’s not as if she’s applying to be an airline pilot, where the FAA has a very clear list of exclusionary medical conditions and medications. (At least I hope they do.)
So yes, the form stinks. But in the meantime, you have to decide what to do, which leaves you with several alternatives — none of them perfect, but some clearly better than others.
- Decline to fill out the form. This is what your legal office advises, and while it may make sense legally, is it the right thing to do? Definitely not — in other words, I completely share your opinion. We overall want to be our patients’ advocates, especially for something that enhances their global well-being (something like enrolling in a job program). So if this isn’t the right answer (and it’s not), why did your lawyers give this advice? Let’s just say there’s a reason they went to law school, and we didn’t, and perhaps this example nicely sums up some differences between doctors and lawyers.
(Some of my best friends are lawyers. Really.)
- Leave the medication section of the form blank. While this isn’t technically lying, it raises the uncomfortable possibility they will call you: “Dr. Miffed, this is Gladys Gleepster from Regional Community Hospital, and it’s about your patient Ms. Smith — you left a section of her health form blank. Could I fax this back to you so that you can complete it?” Then what are you going to do? Fess up that you did this intentionally? Continue to stonewall? Not a comfortable situation.
- Selectively leave the HIV medications off the list. In other words, lie about it. It’s a small lie, yes, and unlikely to hurt anyone, but a policy of “No lying on forms” is something we made official in our clinic years ago, and I strongly recommend it. It became particularly important back in the late 1990s, when some of our previously disabled patients had (miraculously) become quite robust on HIV therapy — it seemed (and was) deceitful to fill out forms stating that a patient “Can walk a maximum distance of one city block” when just that day they were boasting about finishing a strenuous mountain hike or a triathlon. Plus, there was that person who asked me for a letter granting him “automatic upgrades to business class, in particular on international flights” due to his “severe claustrophobia” that, as far as I could tell, only manifested itself when he flew coach. I suggested that he have this unusual problem verified by a psychiatrist before we could write such a letter, because “we can’t lie on forms.” Policy.
- Dump the form on the primary care provider. Yikes. As someone married to a primary care provider, who is figuratively looking over my shoulder as I write this, I emphatically state that this is definitely the wrong choice. (Though tempting. Sorry.) ID doctors may be dumped on with paperwork from homecare companies who insist that you resolve the final date of home antibiotics and, while you’re at it, please tweak that vancomycin level, but this is nothing compared to the deluge of forms PCPs get. Plus, many of our longitudinal HIV patients don’t have a primary care provider, so like it or not, you’re it.
- Write, “Patient prefers to keep this information confidential.” This, I think, is the best approach — especially if it’s preceded by your telling her that this is what you’re going to write. If she doesn’t like what you propose, tell her you “can’t lie on forms,” and she’ll most certainly come around to this being the best solution. Additionally, filling out the form this way will put the ball in the hospital’s court, perhaps even forcing them to reconsider the requirement that people list their medications before joining their nursing program. And wouldn’t that be nice if they changed it!
I said none of the solutions was perfect, but that’s my take. Any other ideas?
September 13th, 2014
I was passing a colleague in the hall the other day — he’s a general internist by training, now an important hospital administrator — and he briefly stopped me to get my take on the flurry of ID-related news bombarding the world right now.
Him: Hey, Paul, good to see you.
Me: Hi Jerry.
Him: Quite a time for you guys in ID, isn’t it. Did you read the piece in the Times on Ebola? On how it could mutate to become much more transmissible? Is airborne spread really a possibility?
Me: Yes, scary.
Him: And how about this enterovirus 68 situation? No cases in Boston so far, right? But how long before it gets here? That must be inevitable.
Me: Yes, scary.
Him: One more thing. We’ve spent every Christmas holiday the past few years in the Caribbean, this year we’re tentatively planning to go to a resort in the Dominican Republic. My wife wanted me to ask you about Chikungunya — any reason to be worried? Sounds like it’s a pretty bad situation down there.
Me: Yes, scary.
Now I was a bit less repetitive (and I hope more helpful) in my responses, but the message remains the same — this is quite the time for infectious outbreaks that are, in a word, “scary.”
Which is why it was a relief this past week to get the following comment on the blog, demonstrating that there are other things going on in the world besides hemorrhagic fevers, kids with severe respiratory disease, and febrile, joint-contorting sickness, and that furthermore, our site’s spam filter is not infallible:
“this article is fine but honestly all i care about is that black sabbath are the greatest group of all time.”
Thank you very much, glad you have your priorities straight.
And hat tip to Kristin Kelley for finding this brilliant comment in the comments folder, and even more so for having the presence of mind to alert me to it.
September 7th, 2014
Some insurers would like to limit the prescribing of HCV treatment to gastroenterologists, hepatologists, or infectious diseases specialists. Not surprisingly, this doesn’t sit well with either the HIV Medicine Association (HIVMA) or the American Academy of HIV Medicine (AAHIVM), both of which have long acknowledged that some of the most seasoned HIV providers are generalists:
“There is no medical rationale for excluding some HIV providers from prescribing HCV medications,” said Donna Sweet, MD, AAHIVS, chair of the AAHIVM Board of Directors, an internist and HIV specialist. “HIV providers who have been treating HCV/HIV co-infected patients for years are uniquely qualified to manage potential drug toxicities and side effects stemming from combining treatment for HIV and HCV.”
I completely agree. Who is more qualified to prescribe HCV treatment, a provider with extensive experience managing HIV/HCV coinfection, or a gastroenterologist who has spent 90+% of his/her career practicing what some have called “lumen-oriented medicine” (see video below for explanation). And there are many ID specialists who do only inpatient ID consults — they would have as much chance correctly identifying ledipasvir, dasabuvir, and daclatasvir as winning the lottery.
The problem, of course, is that whether they say it or not, a motivation of the insurers is to delay treatment. I’m not so cynical to think it’s their only motivation, but it’s inevitably one of them. In the inherent conflict of interest that exists between medical insurance companies and expenditures for expensive short-term therapies, anything that delays treatment increases the likelihood that 1) other options will become available that drive down costs, or 2) the patient’s insurance will change, and it won’t be their problem anymore.
And as everyone learns in Econ 101, dollars spent in the future are worth less than those expended now — it’s called “discounting,” remember?
But is the concept of limiting who prescribes HCV therapy inherently wrong? Of course not — the benefit to the patient is so great, and the financial stakes are so high, it is eminently reasonable that only those qualified to do so should treat HCV.
It just shouldn’t be that the companies paying for the treatment, on their own, get to decide who the qualified providers are – they’re hardly disinterested enough to make this judgment wisely.
Everyone sing along now:
September 3rd, 2014
As August becomes September, ID fellows across the land are becoming increasingly skilled, heading rapidly upwards on that steep learning curve that is the first year of fellowship. With one-sixth of the year already in the books, it’s a wonderful thing to see.
One potential downside to this accumulating knowledge, however, is that they start to become familiar — they would say overly familiar — with the cases that make up the bread and butter of our field. “Another liver abscess? Big deal. I’ll get excited when the abscess is drained, and the cytology shows hooklets of Echinococcus — now that’s a case!”
(No one actually said that. It was a hypothetical paraphrase.)
Which is why in a month or two, they will start to wonder if they have any patients on their service that are case conference-worthy.
But the following guide will act as a reminder that yes, the ID service sees the most interesting cases in the hospital, and there is always something worth presenting at weekly case conference. Let’s take look at the options:
- The Amazing Case. These are obvious, so I will not belabor it, but typically they involve a rarely seen pathogen that somehow found its way to your hospital or clinic. Example: Just back from safari, a man came to the hospital with fever and headache — and lo, he had trypanosomes swimming around his blood smear. Needless to say, the ID fellow taking care of this man with African trypanosomiasis (a.k.a, “African Sleeping Sickness”) had no trouble selecting it for conference. That one was easy, so let’s move on.
- The Textbook Case. Every so often a patient has an illness that has not just a few, but every characteristic feature of a specific clinical syndrome — it’s as if they read a medical textbook before going to the doctor. Such cases have tremendous educational value, especially for residents and medical students — but really, who among us couldn’t use a refresher on what makes a case a “classic”? Example: The guy with several weeks of fatigue, anorexia, and low-grade fevers, physical exam with all the peripheral stigmata of endocarditis (Roth’s spots, Osler’s nodes, Janeway lesions — can you keep them straight?), a characteristic heart murmur, and a 1.5 mobile aortic valvular vegetation on the cardiac ECHO. Classic.
- The Funny Bug, Especially if in a Funny Place Case. Certain unusual microorganisms — funny bugs — can be conference-worthy on their own, especially if they have a great name (Staphylococcus lugdunensis) and/or a strong epidemiologic association (Capnocytophaga canimorsus = dogs, Erysipelothrix rhusiopathiae = lobsters, among other creatures). Now throw that funny bug into a funny (unusual) anatomic site, and bingo, you’ve got your case — even if it’s hardly a common manifestation of this infection. Example: A 31-year-old pregnant woman was admitted with abdominal pain and fever — ultimate diagnosis? Acute endometritis and bacteremia from Pasteurella multocida. Of course.
- The Now Quite Rare but Previously Very Common Case. Progress in vaccines has made certain conditions that were once standard business now quite unusual. As an example, I can count the number of cases of adult measles I’ve seen on one hand, or more precisely, on one finger. As a result, these cases are virtually always conference worthy, plus they give our more senior clinicians (ahem) a chance to wax eloquently about the bad old days. Examples: Virtually any vaccine-preventable illness (measles, mumps, Haemophilus influenzae invasive disease, even varicella). Bonus points for a case of rheumatic fever or neurosyphilis — not vaccine-preventable, but you get my drift.
- The Amazing New or Incredibly Confusing Diagnostic Test Case. Just the other day, a colleague from another hospital emailed me with excitement about a case of malaria. It wasn’t the case that was unusual — returning traveler from Africa, fever, etc. — but the fact that his hospital just got the Binax malaria rapid test, and he got the positive result back almost immediately. He was so excited he even took a picture of the positive test with his phone, sending it along with the email. Other examples: The first time you diagnose PCP with blood beta-glucan. Or a case that makes you struggle through the C. diff testing quagmire. Or one that forces you to interpret the results of an EBV antibody panel. Someone with a dozen different Lyme tests (with one of twelve positive).
- The “Wow” Image Case. Way back in prehistoric times — meaning during my ID fellowship — one of our responsibilities as an ID fellow was to gather the relevant x-rays on our cases, not only for rounds, but also for case conference. It is no understatement that this was a huge challenge — these films were frequently scattered hither and yon throughout the various hospital buildings, so much so that we suspected that the place labeled “Radiology Film Library” was just a front for the hospital casino. And there seemed to be some hospital rule that all interesting brain CTs/MRIs were kept under the call-room bed of the neurosurgical chief resident. Today we have electronic access to all the images, plus everyone is carrying a camera, so we have this great opportunity to display these during conference. Examples: The initial rash of necrotizing fasciitis. Then the operative findings. The volleyball-sized tubo-ovarian abscess in the pelvis on CT scan, prior to drainage. (“Wow,” everyone will say.) The botfly removal (caution, observe at your own risk). You get the picture (ha).
- The Public Health Case. Let’s just imagine that someone shows up in your emergency department from Liberia/Sierra Leone/Guinea/Nigeria/Senegal. Never mind that they came in for a sprained ankle, someone is going to bring up the possibility of Ebola — especially when, on further questioning, the ankle person from Western Africa admits that 1) yes, they just visited family at home, and 2) yes, they too are worried about it; wouldn’t you be, especially since there’s a bit of headache/joint pain/fever. Since a sprained ankle and Ebola are hardly mutually exclusive, we’re talking prime conference material as soon as you get the consult — golden! Other examples: Any healthcare worker with tuberculosis. Or a restaurant worker with salmonella. You get the idea.
- The Management Dilemma Case. Despite our thick textbooks and nearly the entire universe of published papers available instantly on line, there’s a ton we still don’t know. I’ve written about a bunch of these clinical situations (here’s the list), and you can tell from the poll results that there really is no right answer — but that doesn’t stop people from having opinions. Another example: 60-year-old man, professional cellist, has bronchiectasis and slightly worsening cough; a sputum culture is positive for M. abscessus, resistant (as usual) to all oral agents — he can’t imagine a life without playing the cello, and travels frequently. Should he be treated? If so, with what? (This one is from this week, would love to know.)
- The Everyone Else Was Messing Up Until We Came In and Saved the Day Case. All doctors love these EEWMUUWCIASTD cases, and they should never be underestimated as high-value material for case conference. In surgical conferences, they invariably present a patient languishing on the medical wards with abdominal pain, until “we took him to the OR and saved his life.” In ID conference, it takes a different form because we do no procedures. It usually involves some perfectly obvious (to us) historical detail that bingo, cracks a mystery case wide open — e.g., “So we simply asked her where she grew up and went to college, and when she told us Tennessee, we knew it was likely histoplasmosis”; or “They thought it was a simple community-acquired pneumonia, but we found out he had a twenty-pound weight loss, hemoptysis, and a history of an untreated positive PPD”; or “All someone had to do was ask her in Spanish/Vietnamese/Chinese/Haitian Creole what was wrong with her, and she told us”; or “He works as a touring semiprofessional golfer, had just returned from Mexico, and mentioned that he licks his golf balls before each drive for good luck.” These EEWMUUWCIASTD cases are tremendously gratifying — they reinforce the fact that we are the smartest doctors in the hospital, plus they make us feel better about the inverse correlation of intelligence with annual income.
I hope the above examples are a reminder that not all ID consults are decubitus ulcers and ICU fevers. And if I left out a category, please let me know!
August 24th, 2014
(Where oh where do companies get these names?)
A few thoughts/comments:
- The most important study for this combination was the SINGLE study, which showed that ABC/3TC + DTG (given as two pills) was superior to TDF/FTC/EFV (given as one), the difference based primarily on tolerability advantage of the former. It was a novel double-blind study, as all three drugs were different in each treatment arm.
- Another benefit DTG-based regimens — whether given with ABC/3TC or TDF/FTC as separate pills — is that to date, no treatment-naive patient with virologic failure has developed resistance to DTG. I suspect it will happen one of these days, but the data thus far suggest at the very least DTG resistance will be a rare event.
- Needless to say, but will say it anyway for emphasis, all patients starting this regimen will need to be tested for HLA-B*5701 and found to be negative. Wonder if pharmacies will enforce this, or whether it will be left up to the prescribers. Here’s the landmark study that proved this testing essentially excludes severe hypersensitivity to ABC, quite an amazing story in pharmacogenomics.
- An unresolved question is whether ABC is associated with an increased risk of cardiovascular disease. This FDA meta analysis of randomized clinical trials didn’t think so, but around half of the observational studies did, including the updated DAD study. NA-ACCORD data will be of great interest, whenever they appear.
- As of Sunday, August 24, the price of ABC/3TC/DTG is not known (at least to me) — and it could be a real game changer, since both ABC and 3TC are already generic. Says Ben Young over on TheBody: “If ViiV Healthcare manages to set the price of Triumeq in accordance with the generic status of abacavir and lamivudine, the cost should be substantially lower than the price of the other single-tablet regimens that contain all on-patent components.” Yep.
- I suspect people will call it “Trii” (rhymes with “Cy”, as in “Cy Young”) for a while, just like they called TDF/FTC/EVG/COBI “Quad”.
So what are some upcoming single-tablet regimens? Tenofovir alafenamide (TAF) with FTC/EVG/COBI. TAF/FTC/DRV/COBI. DTG/rilpivirine. And inevitably, generic TDF/3TC/EFV, which is widely available globally.
Regardless, sure beats the old days.
August 16th, 2014
From the pages of Open Forum Infectious Diseases, comes this cautionary case report:
Toxocariasis After Slug Ingestion Characterized by Severe Neurologic, Ocular, and Pulmonary Involvement
I encourage you to read the full paper, but the short story is that a previously healthy 71-year-old man was admitted to a hospital in France with fever, cough, headaches, confusion, and eosinophilia. A comprehensive (that’s an understatement) work-up found elevated antibody levels to Toxocara canis, otherwise known as the dog roundworm.
But the case truly hinges on this sensational sentence.
One month later, a reassessment of the case history revealed a long-standing daily intake of 2 or 3 raw local slugs for alternative therapy of gastroesophageal reflux; this information prompted us to perform further investigations.
Vive La France!
And oh yeah, ID doctors take the best medical histories.
August 10th, 2014
For Infectious Diseases doctors, there’s a certain life cycle to the big ID topics that make their way to the lay press, and it’s playing out right now big time with the terrible Ebola outbreak in Western Africa. It goes like this:
- Someone reports an outbreak in a venue like ProMED.
- Almost synchronously, it is covered by the news.
- Depending on the severity of the outbreak and the Gladwellian “stickiness factor,” it then becomes well known outside of the ID community. And boy, does Ebola have plenty of stickiness — much more than chikungunya or listeria in fruit, for example, to cite some recent entities that grabbed a fair amount of attention.
- Suddenly everyone wants to talk to you, Dr. ID Person, about it — the orthopedic surgeon (two of them mentioned Ebola to me last week!), the ICU nurse, the people you play canasta with (I don’t play canasta, just assuming), your Aunt Becky (I do have an Aunt Becky), and even complete strangers who, in the course of serving you food at a restaurant or fixing your car or changing the grip on your badminton racket, find out that you’re an ID doctor. You’re the expert, after all.
The problem is that going from Item #1 to Item #4 can happen awfully fast. And because these newsworthy outbreaks frequently haven’t played out before — otherwise they’d be less newsworthy — it’s virtually guaranteed you are not in fact an expert. At least not yet.
Which sends you (and all of us, trust me) scurrying to the great big web in the sky for some intense reading on the disease du jour.
So for the ID doctors reading this out there, please share your best sources for the latest in Ebola news and information. CDC, of course, and the aforementioned ProMED, the prescient HealthMap and if you want to drink from a fire hose of lay coverage, the Google news feed – where else?
And for non-ID readers, cut your ID docs a little slack if we don’t instantly know the answer to your Ebola questions. We’re working on it!
In the meantime, please don’t eat plums eaten by bats.
July 31st, 2014
Since that sentence barely conveys the transformative nature of this medical advance, allow me this tortured analogy: Before simeprevir and sofosbuvir, curing hepatitis C was like making a transatlantic journey by ship, and you had to stay in steerage — always a long and painful trip, but you’d get there if you could stand it. Now the cure is like a business-class flight — much shorter, safer, and more comfortable, but you just have to have the resources to pay for it.
But our treatments are not perfect. I was reminded of this fact when someone treated with simeprevir and sofosbuvir — or “SIM-SOF” as it’s commonly abbreviated — just relapsed a month after finishing 12 glorious, side-effect–free weeks of treatment.
In hindsight you could perhaps have predicted that this patient — or this type of patient — would be a treatment failure on these new drugs. There was prior treatment failure on interferon/ribavirin; he has genotype 1a (and hence probably Q80K, didn’t test for it); he’s overweight; he has several other medical problems, including diabetes.
And, probably of greatest importance, he has cirrhosis, diagnosed by liver biopsy several years ago.
The treatment failure sent me scurrying over to the reason we use this combination anyway — the excellent HCV treatment guidelines and the remarkable COSMOS study (just published in the Lancet) of simeprevir and sofosbuvir, with and without ribavirin, in patients with HCV genotype 1.
Here’s what recommended in the guidelines for patients who have failed prior treatment:
Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [75 kg]) for 12 weeks is recommended for retreatment of HCV genotype 1 infection, regardless of subtype or IFN eligibility.
And here are the relevant data cited:
Among those null responders with a Metavir fibrosis stage of 3 or 4 (n=47) who received 12 weeks of sofosbuvir and simeprevir, SVR4 was observed in 14 (93%) of 15 patients in the ribavirin-containing arm and 100% (all 7 participants) in the RBV-free arm.
A few things stand out from reviewing the study and the guidelines, aside from the high response rate:
- The sample size in the COSMOS study was small.
- The number with actual cirrhosis was even smaller, as they combined stages Metavir 3 and 4.
- The number with actual cirrhosis who did not receive ribavirin and received only 12 weeks of treatment was smaller still.
- And did I mention — the sample size in this study was small?
The reason I’m harping on the sample size is a lesson taught early in every Stats 101 course — namely, that a small sample size means that the outcome will not be very precise, with lots of potential wobble around the results.
The most recent data presentation of the COSMOS study allows us to drill down a bit more on the data. There were 7 patients — just 7 — with cirrhosis who received only simeprevir and sofosbuvir for 12 weeks. 6 out 7 were cured (SVR 12), for a response rate of 86%.
And the lower bound of the 95% confidence interval for this proportion? 60%, at least according to this web gizmo that does the math for us, if I’ve chosen the right “equation”. So the occurrence of relapses should not be a huge surprise, despite the > 90% response rate for the study overall.
Some take-home lessons:
- Unlike the real thing, the COSMOS study is very small. (There’s a larger study of this combination ongoing.)
- This small sample size means we can’t predict response rates with much accuracy, especially in the hardest to treat patients who were not heavily represented in the study.
- SIM-SOF (note it’s rarely “SOF-SIM”) is still a great advance in HCV treatment, but treatment failures will happen.
So what to do next? The good news is that resistance to sofosbuvir is rare even in treatment failures, and that the HCV treatment cosmos is about to get bigger — the next class of drugs (NS5A inhibitors) is on the way soon, and the data on sofosbuvir plus ledipasvir or daclatasvir look very promising.
A reason for optimism even for those for whom SIM-SOF didn’t do the trick.
July 30th, 2014
July 28 is “World Hepatitis Day” (how do they choose the dates for these things?), and I wrote a bit over on the Oxford University Press site on the incredible progress we’ve made already — with more to come.
Definitely plenty of reasons to celebrate — safe and effective immunizations for hepatitis A and B, treatment (non-curative) for hepatitis B, and astounding therapies now for HCV. Still, given the global magnitude of these infections, and the problems of access, there is plenty of work to be done to get people immunized, diagnosed, referred, and treated.
Enjoy the tune.