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August 30th, 2015

(Not) Doing the Retinal Exam, and the Importance of Acknowledging Limitations

Eye Exam by Anne SaxThis past week, the New England Journal of Medicine released one of its excellent instructional videos, detailing how to do direct ophthalmoscopy to examine the retina.

That’s the use of one of those hand-held gizmos — an ophthalmoscope, see picture on the right — to look at the back of the eye.

As usual, the video was clear, succinct and professionally done. A great resource for clinicians, young and old.

But here’s a confession — the video could be a nominee for this year’s Oscar for Best Picture, it wouldn’t help me a bit. Because I’m absolutely horrible at this procedure, always have been.

I’m as likely to see something important in someone’s eyes using an ophthalmoscope as I am using a shoe, an avocado, or a tennis racket (to choose three random things that happen to be in the room right now as I write this).

The inability to do a particular part of the physical examination creates some uncomfortable moments, in particular during medical school when learning the skill. Asked to acknowledge that yes, we do in fact see/hear/feel what we’re being taught to see/hear/feel, medical students face a dilemma when failing to do so. In essence, there are three options:

  1. Tell the truth:  “I can’t see the venous pulsations” — and ask the instructor for more guidance right there on the spot.
  2. Lie: “Oh yeah, the optic disc margin is sharp” — this gives the teacher a sense that you’ve mastered the technique, but it’s basically cheating and a very bad idea in clinical medicine, for innumerable obvious reasons.
  3. Silence: Be quiet on the matter, blending into the background and allowing the class to move on — and remain hopeful that you’ll pick up the skill later with more practice.

I wish I could say I had the maturity to go with #1, but in fact #3 was the route I chose.

Even if I had chosen #1, however, I’m not sure it would have made much of a difference.  The reason I can’t do this procedure is because my own eyes are so bad — which, for a variety of reasons having to do with the optics of it, make direct ophthalmoscopy virtually impossible.

Trust me on this one — it’s not just an excuse. (Of course it is.) The right eye is particularly useless, which means I’d have to use my left eye to look into a patient’s right eye. If you imagine doing this, it sets up a very uncomfortable nose-to-nose encounter with your patient — highly unhygienic and socially weird, a reason right there not even to try it.

In the face of limitations we have as doctors, we invariably come up with rationalizations to make ourselves feel better. And here are mine about this particular deficit:

  • Visual complaints are serious business — wouldn’t this deserve a referral to a real pro, an ophthalmologist? You can be sure that in the CMV retinitis days, my threshold for referral was very very low.
  • Similarly, let’s say I found something incidentally on ophthalmoscopy — certainly this would warrant having an ophthalmologist see the patient to confirm, right? What non-eye doctor would be 100% sure saying that what they visualized with their crude scope is benign?
  • Direct ophthalmoscopy isn’t even the best technique to look at the retina — the indirect method is far superior, preferred by all retina specialists.
  • There are many other things in medicine I can’t do (replace heart valves, biopsy colons, do immunohistochemical stains, interpret EEGs, remove thyroid tumors) — this is just one more.
  • I may not be able to see someone’s retina (especially their right retina, see above), but I’m pretty good at listening to heart murmurs, if I do say so myself. Hey, I once noticed that a patient with endocarditis developed aortic insufficiency before the cardiologist did. Granted, she hadn’t seen him that day yet, but still …

In all seriousness, the real reason for this confession is that I’m pretty sure we all have limitations. Why else would the orthopedists consult us ID doctors for essentially every infectious complication on their patients, no matter how simple? After all, before their residency, these pre-orthopods were some of the smartest medical students — did they suddenly lose their brains when they began doing knee replacements?

Not a chance. It’s simply that at some point, it makes much more sense to acknowledge these limitations — and move on — than to pretend they don’t exist, or even worse, to fake it.

August 23rd, 2015

Post-Exposure Prophylaxis for HCV Can’t Be Cost-Effective — But We Might End Up Recommending It Anyway

An email query from a colleague:

Hi Paul,
Just got a call from one of our surgeons who got a needlestick from a suture needle, small amount of blood. Patient is HCV +. Any post-exposure prophylaxis recommended?
Thanks,
Dan

The quick answer is no, it’s not recommended. From the guidelines:

MANAGEMENT_OF_ACUTE_HCV_INFECTION___Recommendations_for_Testing__Managing__and_Treating_Hepatitis_C jpg

But it’s a natural question to ask for several reasons — on first blush, PEP for HCV seems like a no-brainer, because:

  • It works for HIV.
  • There’s no vaccine.
  • Rate of transmission is approximately 10-fold higher than with HIV.
  • The HCV drugs are practically side-effect free.
  • It feels better doing something rather than nothing.

But despite the above issues that favor PEP today for HCV occupational exposures, there is absolutely zero chance this makes sense from a cost-effectiveness perspective. It’s just not possible.

A little refresher on basic principles of cost-effectiveness analysis:  something is cost-effective if you get good value for your healthcare dollar. You spend more money, and you prolong life. How much you spend compared to standard-of-care, and how more much life you get in return gives you the numerator and denominator in that all-important cost-effectiveness ratio. In the USA, if we spend <$100,000 for an extra year of life, that’s considered cost-effective; <$50,000, very cost effective.

So let’s consider the HCV needlestick scenario, with 100 exposures; all assumptions will be biased in favor of PEP, just to make the point:

  • The risk of acquiring HCV from a needlestick is 2-8%, depending on the nature of the exposure; some will clear it spontaneously. So if we do nothing, around 5 of these 100 exposures will end up with chronic HCV.
  • Let’s assume that two weeks of PEP with sofosbuvir/ledipasvir will be 100% effective in preventing HCV acquisition. There are no data, but let’s give it the benefit of the doubt. And note that the HIV PEP protocol is 4 weeks, but at least one pilot study is using 2 weeks for HCV. (Why? Not sure.)
  • Two weeks of PEP will cost $15,000 per patient — actually, a bit more, but let’s round it to $15K or a total of 1.5 million dollars for our 100 exposures.
  • If we didn’t give PEP after the exposures, we’d need to treat the 5 people who contracted HCV with 12 weeks of sofosbuvir/ledipasvir, which would cost $450,000. All would be cured.
  • The PEP strategy therefore costs $1,050,000 more than the no PEP one (1.5 million minus 450,000), and prevents 5 cases of HCV. That’s $210,000/case prevented — so a lot.
  • What about survival, the denominator part of the cost-effectiveness ratio? The projected survival of those in whom HCV was prevented by PEP vs later cured with HCV treatment should be roughly the same (no one is getting cirrhosis or hepatocellular carcinoma with early treatment) — but maybe there’s some “disutility” to getting HCV, even if it’s rapidly cured. So let’s give the PEP strategy a bit of a quality-adjusted survival advantage — how about 10 weeks, since that’s the extra time on treatment for an actual case? Of course we can only apply this to the 5 cases of HCV prevented in our 100 person cohort, so it’s an overall advantage of 0.5 weeks (10 weeks times 0.05), or roughly 0.01 years.
  • Finally, we arrive at our cost effectiveness ratio, which is $1,050,000/0.01 years, or $105 million/quality-adjusted life year.

More than 100 million dollars for a quality-adjusted life year? Yep. I told you it couldn’t possibly be cost-effective.

Now again, I biased everything in favor of PEP. What if it doesn’t always work? What if failures of PEP lead to resistance? What if the PEP regimen needs to be 4 weeks long? What if the quality-of-life adjustment is an overestimate? What if some of the patients who get HCV have a very low HCV RNA, and can be cured with 8 weeks, not 12?

Well, then you’d be spending even more than $105 million dollars per year of life saved. But whether it’s $105 million, or even half my back-of-the-envelope estimates (which could be wrong — I was an English major, after all), the point remains: This can’t be a cost-effective intervention.

But as I was sharing these thoughts with my brilliant friend and colleague Rochelle Walensky, who does this stuff for a living, she reminded me of this important fact:

I might encourage you to acknowledge that many of these kinds of decisions (PEP, safety of the blood supply) are not made on cost-effectiveness grounds … Most of the cost-effectiveness data for the screening for the blood supply demonstrates it’s not at all cost effective. You may want to acknowledge that point (we pay more for lots of things that cost-effectiveness suggests we shouldn’t, including keeping health workers safe given their dedication to care, keeping blood supply safe etc).
Acknowledged — I told you she was brilliant. Which is why, despite the fuzzy math above, it wouldn’t surprise me a bit if in the not-too-distant future, we are actually recommending PEP for HCV.Nice 6 minute lecture here. Enjoy!

August 17th, 2015

Dog Days of Summer ID Link-o-Rama

dogjump -- http://www.unprofound.com/viewpic.php?pic=dogjump.jpg&photographer=rusworks

A few ID/HIV items of note to consider as you gather up your sunscreen, flip flops, towels, and sand toys and head off to the beach:

  • Interesting review of the impact of low socioeconomic status in the recent outbreak of Legionnaires’ Disease in the South Bronx. It’s just like (almost) every infection — the combined effects of crowding, poor sanitation, and high levels of other comorbid diseases greatly amplify the risk of getting this disease.
  • Want an exception to this rule? How about Lyme Disease? Quite the statement that the linked article appeared in the Fashion and Style section of the Times! And here’s the first paragraph: “At a recent dinner party in Greenwich, Conn., Topic A was not stock futures or boarding school, but something decidedly less tony: ticks.”
  • Which is emphatically not to say that Lyme is a small problem, or just the product of the overactive imagination of the worried-well leisure class. An upcoming paper in Emerging Infectious Diseases estimates there are around 329,000 cases annually. And if you want to see the highest incidence locations, here’s a remarkable map from last month’s issue.
  • Last tick item, promise (though it is the season) — I’ve noticed a bunch of sites now refer to the Ixodes tick vector for Lyme-anaplasma-babesia as the “blacklegged” tick instead of the “deer tick.” When did that happen? Did the deer get the memo from the variegated squirrels, and are now protesting? What about all the other creatures with black legs? How do you think they feel?
  • Daclatasvir is now available, and the excellent HCV treatment guidelines have been updated. The most important change is the recommendation for treatment of genotype 3 — 12 weeks of daclatasvir/sofosbuvir if no cirrhosis, 24 weeks (with or without RBV) with cirrhosis.
  • Several more important HIV/HCV coinfection studies published:  sofosbuvir/ledpasvir, sofosbuvir plus daclatasvir, and grazoprevir/elbasvir. (Last of these slated for approval within 6 months.) All have outstanding (>95%) cure rates, comparable to those without HIV. It’s the drug-drug interactions that need watching — very useful figure here.
  • This meta analysis found impressive benefits of corticosteroids as adjunctive treatment for community acquired pneumonia. Probably not ready for standard-of-care (yet), and I like the suggestion from the editorialist to find surrogates (clinical or lab-based) for which patients would benefit the most.
  • The updated flu vaccine guidelines have been released, and as usual they are quite a mouthful: “The vaccines will contain hemagglutinin (HA) derived from an A/California/7/2009 (H1N1)-like virus, an A/Switzerland/9715293/2013 (H3N2)-like virus, and a B/Phuket/3073/2013-like (Yamagata lineage) virus … Quadrivalent influenza vaccines will contain these vaccine viruses, and a B/Brisbane/60/2008-like (Victoria lineage) virus.” Got that? Report also includes updates on the live attenuated vaccine, and indications for vaccination in general, which include basically everyone.
  • Long-term valacyclovir provides no benefit after HSV encephalitis. An important negative study, it could not have been easy to identify eligible patients and enroll them. (It took nearly 10 years to complete.) The overall excellent outcome in both arms — 86-90% with mild or no neurologic sequelae at 2 years — likely reflects the exclusion of the sickest patients with this scary condition.
  • Anyone notice an association between abacavir and anxiety? Link is to an observation (and a couple of published case reports, though the second one could have been EFV) from long-time HIV/AIDS advocate, Nelson Vergel. I personally have not seen this side effect, though it does seem that some people starting integrase-based treatments (including dolutegravir) develop insomnia.
  • Baseball/ID overlap warning — Los Angeles Dodger fans are no doubt happy that their excellent third-baseman Justin Turner is off the disabled list after a bad bout of MRSA. Contact precautions in the locker room? Gowns and gloves when he comes to bat? Purell stations at each base?

Title of this post notwithstanding, the weather in Boston this summer has been great — mostly warm days, cool nights, low humidity — hence the energetic jumping pooch in the picture (not mine, click on it for full effect). I just love the phrase, “dog days of summer”, and wanted an excuse to use it.

Hey, it’s hot somewhere!

August 9th, 2015

The Pain — and Potential Power — of Electronic Health Records in One Little Anecdote

Doctor at computerHere’s a scintillating series of events that happened recently on our inpatient consult service:

  1. Reason for consult: “Treatment of UTI in a 26-year-old pregnant woman with multiple allergies.”
  2. Culture result:  Group B strep, resistant to clindamycin and nitrofurantoin. She’s been on the latter.
  3. Patient’s allergies as listed on her chart:  Penicillins, cephalosporins, sulfonamides.
  4. Plan per OB service:  IV vancomycin, consult ID service, admit?
  5. Why they think this:  “Treatment consists of antibiotic therapy with amoxicillin, penicillin, or cephalexin … For patients who have a severe IgE-mediated hypersensitivity to penicillins and cephalosporins, clindamycin is the only oral alternative, if the isolate is susceptible.” Said so here, so it must be true.
  6. Reactions to these antibiotics she’s reportedly allergic to, per the patient chart:  No information. (This omission should be punishable by a very high fine.)
  7. Adverse outcomes associated with these antibiotics according to the patient:  She doesn’t know — she thinks they all happened when she was a baby. Ask my mother, she says. (By the way, she’s not very happy about the prospect of being admitted, understandably.)
  8. Patient’s mother is called:  No answer, voicemail is full. (Yes, it’s a national epidemic.)
  9. Patient texts mother, who eventually responds:  She says her daughter got very sick when she got penicillin as a baby. She remembers nothing about the other allergies.
  10. Did she ever have an ear infection or strep throat as a kid or teen? we ask. If she got treated with a penicillin or cephalosporin, and didn’t have a reaction, she’d be all set — oral antibiotics, no need for admission.
  11. Mother recalls strep throat maybe a couple of times as a teen. Can’t remember the antibiotics she received. (You can be sure she’s prompted — Keflex? Augmentin? Z-pak? Nada. Not sure how reliable that information would have been anyway, but worth a try.)
  12. We find out she received her pediatric care at a local multi-specialty group practice. They use the same electronic health record we do. They are supposed to communicate with each other.
  13. The promised communication — ‘interoperability” is the buzz phrase — doesn’t seem to be working on this particular patient at this particular time. We could “open a ticket” to get this fixed. Then we could access her pediatrician’s records, review what antibiotics she’s safely received in the past, and avoid an unnecessary admission.
  14. Chances of this “ticket” being resolved in time to prevent said admission:  About zero.
  15. A call is made directly to that practice. It’s after 5pm now. Long voicemail, which includes the ubiquitous, “If this call is about a medical emergency, please hang up and dial 911.” (You think? Thank you so much for that helpful advice. And could you go over again how to fasten my seatbelt before a flight? I can’t remember what to do with the buckle part and these two strips of cloth attached to them.)
  16. At the end of the voicemail recording, an option to page the pediatrician on call “in case of emergency”. Briefly consider doing so, then come to my senses.
  17. We start considering “second line” treatment options. Fosfomycin? The OBs don’t like that plan. Group B strep spooks them.
  18. Another obstetrician overhears our discussing this case. She just happens to work at this group practice one session/week.
  19. She logs into the practice’s EHR, looks up our patient’s record. (This breaks all kinds of rules. Sorry about that. Actually, not sorry at all.)
  20. And there it is, like a pot of gold at the end of the rainbow, glistening in the beautiful sunlight:  Strep throat at age 13, treated with cephalexin. No allergic reaction.
  21. Patient is reminded of this. She says, “Oh yeah.” She’s discharged home on cephalexin.
  22. There is much rejoicing.

So there you have it — in 22 excruciating steps, the electronic health record drives you crazy, and then it saves the day. After all, in the days of paper records, it would have been all but impossible to get this information after hours from a local practice not affiliated with our hospital. You’d have to break in, Watergate-style.

Yet it nearly was impossible in this case despite the presence of electronic records throughout this patient’s life — even though the EHR was the same widely-used brand in both places.

The person who cracked the case didn’t do so because she was a brilliant diagnostician, or a compassionate clinician, or an insightful researcher (though she may be all of those things). It was simply because she had electronic access to the record, though “officially” she wasn’t caring for this patient and in fact violated privacy rules.

So here’s a solution to this problem, one that should be implemented right now. Ok, if not today (which is a Sunday), then tomorrow. It goes like this:

  1. All EHRs should have web-based access.
  2. All should allow patients to sign in remotely, granting their clinicians the right to see their records to enhance their care.

Simple. Let’s get it done now.

(Thanks to the graphically gifted Anne Sax for the pic.)

August 1st, 2015

Ten Reasons to Attend Our “Infectious Diseases in Primary Care” Course

doctor lecturesWith an up-front apology for the shameless plug — sorry! — here are 10 great reasons to attend our annual postgraduate course. It’s called Infectious Diseases in Primary Care, and takes place October 14-16 here at the Fairmont Copley Plaza Hotel in Boston.

  1. All the topics are clinically relevant to day-to-day practice. Look at these topics! There’s a strict ban on basic science research (unless it’s relevant to patient care). Slides depicting gels or other complex lab experiments are prohibited.
  2. The faculty are all active in patient care and love to teach. Particular call-out to my long-time clinical mentor, Jamie Maguire. But they’re all great.
  3. Paul Farmer will be in the house. You can then say you saw him before he won the Nobel Peace Prize. (That’s my prediction. He’d never say this.) Plus, when he’s standing right next to me, it will be proof that we are not identical twins. More on Paul here. (Forgive the dated Tiger Woods analogy, it meant something at the time.)
  4. Get your ID questions answered, and more. I’ve periodically featured these questions since they are so interesting — here are some from last year’s course, for example. If you attend, ask away! We’ll do our best to answer.
  5. Keep your ID knowledge up to date. New immunization guidelines? New STD guidelines? New antibiotics? New HCV drugs? New outbreak in some travel location? No problem, we’ve got it covered. Let the record show we’ve been predicting this chikungunya thing for years.
  6. Fall is the best time to visit Boston. Like all locals, I’ve spent many hours complaining about Boston weather — not October weather, however, which is probably our best month. Comfortable days, cool nights, crisp blue skies, low humidity, fall foliage, local apples, Red Sox in the playoffs. (Oops. Probably not that last one this year, sorry.) Fall in New England is simply wonderful.
  7. The Fairmont Copley Plaza is a gorgeous hotel, with a perfect downtown location. Walk everywhere — restaurants, shopping, historic sites, picturesque neighborhoods. More about the venue here. Plus they have adorable black labs holding court in the lobby.
  8. Syllabus updated each year. Available both electronically and, for a small extra fee, print.
  9. “Name the Diagnosis” photo quiz, with a special prize. We’ll post some images of interesting and/or exotic infectious diseases — dirifilariasis in a human, for example — and ask you to name the diagnosis. The person with the most correct answers takes home a special ID-related award. Plus, you can impress your friends.
  10. Meet your CME requirements. It’s Harvard Medical School, after all — The Stanford of the East. Here are the details — we’re accredited by ACCME, the American College of Family Physicians, the Royal College of Physicians and Surgeons of Canada, the European Continuous Medical Education Council, and the Interplanetary Society of Postgraduate Medical Studies, which is based on Mars. (I made that last one up.)

There, ten reasons. Plus an added bonus — the candy that falls from the ceiling at the end of each lecture is yours to keep, which comes in handy for Halloween!

Hope to see you in October!

July 26th, 2015

Really Rapid Review — IAS 2015, Vancouver

IAS 2015Vancouver will always have a special place in HIV treatment history. It was here, in 1996, that many of us first saw the potential of combination antiretroviral therapy to control this disease.

Specifically, Study 035 of AZT, 3TC, and indinavir (presented by Trip Gulick) demonstrated the astounding finding that triple therapy induced sustained virologic suppression and dramatic immunologic improvement.

Could it be that not everyone would eventually die of AIDS? Optimists certainly felt so — and indeed they turned out to be right.

It was only natural, then, that Trip would be given the chance to give an overview of HIV therapy at the conference — he did a terrific job of reviewing “What to Start,” with a summary of where we’ve been, where we are today, and where we might be going.

(And no, he didn’t sing.)

But what about new research? Without having the density of new material presented at CROI — something of a relief, really, during these summer months — the IAS 2015 conference still featured many interesting papers, some of which I’ve summarized in this Really Rapid Review™. I refer you to the (kind of clunky) conference website for the full abstracts and slide sessions; below I’ve listed the abstract numbers, because I can’t figure out how to link the abstracts.

  • Long-term “remission” in an infected adolescent without ART. Got to start with the story that (inexplicably) got the most press: A perinatally infected child stopped HIV therapy (or more accurately, family stopped therapy) at age 6. Patient is now 18 years old and has had a detectable HIV viral load only once since stopping treatment. Remission? Or just an HIV controller? You decide, but I’m going with the latter, and no, the investigators did not use the word “cure” — which hasn’t stopped the media from tossing it around freely. [MOAA0105LB]
  • HPTN 052 final results. In the landmark study that proved HIV treatment prevented transmission, we now have evidence of eight linked transmissions from people on HIV therapy to their partners — and all occurred either early in HIV therapy (before suppression) or during treatment failure. In other words, zero transmissions from participants with stable virologic suppression. Excellent news! [MOAC0101LB]
  • And while we’re on the topic of landmark trials, Jens Lundgren presented the results of the START study on the very same day it was published in a highly prestigious medical journalKey takeaways: HIV therapy is beneficial for patients with CD4 > 500 in preventing both AIDS complications and, in developed countries in particular, non-AIDS complications (mostly cancers). And note that most of the clinical events happened when the CD4 was > 500. [MOSY0302 — but read the paper!]
  • In a large, randomized, double-blind trial done exclusively in women, elvitegravir/cobicistat/FTC/TDF is superior to TDF/FTC, ATV/r. Amazingly, the study (called WAVES) was given a poster and not an oral presentation — a completely inexplicable oversight given 1) it was a well-done study with an important result, 2) there were no other large randomized treatment trials at the conference, and 3) women have been terribly underrepresented in many recent clinical trials. Plus, the late-breaker posters were placed in the poster hall equivalent of Siberia, way over at the far edge of the room. Bizarre. [MOLBPE08]
  • This presentation included a series of remarkable figures on proportion of people with HIV who are diagnosed, on treatment, and virologically suppressed. For the record, the USA is third in percentage diagnosed (86%), ninth in successfully treated (30%) — one whole percentage point above Sub-Saharan Africa. [MOAD0102]
  • Three switch studies demonstrate the potential benefits of switching to elvitegravir/cobicistat/FTC/TAF (tenofovir alafenamide). 1) A large randomized trial compared staying on current regimen (TDF/FTC plus EFV or ATV/r or EVG/COBI) to switching, and the switch was overall superior [TUAB0102]; 2) Patients with chronic hepatitis B coinfection maintained or improved hepatitis B control [WELBPE13]; 3) Patients with stable chronic renal insufficiency (eGFR as low as 30) had stable renal function after the switch [TUAB0103]. In all three studies, switching from TDF-based treatment led to improvements in renal and bone parameters, with small increases in lipids. This “ECF-TAF” regimen is currently in the late stages of FDA review.
  • In this large Spanish cohort study, TDF/FTC/EFV given as a single tablet was better virologically and economically than 1) other multi-pill regimens, 2) the same regimen given as multiple pills. Not a controlled study, but strongly suggestive of the benefits of coformulation nonetheless. [TUPEB264]
  • In the aggregate ACTG clinical trials data that demonstrated an excess of suicidality for those randomized to EFV-containing regimens, 75% of participants participated in a genetic substudy. When these subjects were analyzed based on genetic predictors of of EFV metabolism, those with the slowest clearance of the drug had the highest relative risk of suicidality. These data do strengthen the findings from the original paper. (Disclosure: I’m a co-investigator.) [TUPEB273]
  • In virologically suppressed patients receiving a boosted PI plus 2 NRTIs, switching to the two-drug regimen of DRV/r + RPV maintained virologic suppression as well as staying on the baseline regimen. Small sample size alert (n=60), so consider this a pilot study only. [TUPEB270]
  • Another case report of resistance to dolutegravir in a treatment-experienced patient, with emergence of the R263K mutation. Additional integrase mutations emerged with ongoing failure, leading to a 5-fold loss of DTG susceptibility. Note that at baseline, the patient (a 12-year-old perinatally infected child) had no detected NRTI mutations (though extensive prior ART), and though treated with TDF/FTC + DTG, oddly did not select for RT mutations. This case (and those from the SAILING study) notwithstanding, resistance to DTG remains rare event — though it does happen. [TUPEA068]
  • At 24 weeks in a phase II randomized double-blind study, the investigational NNRTI doravirine is comparable to EFV with a lower incidence of CNS side effects.  Though the 24 week results for the < 40 cop/mL result seem unimpressive for both arms (around 70%), this is due to the patients with high baseline viral loads still having low-level viremia — no resistance detected in either arm, HIV RNA still declining. Two phase III studies of doravirine are underway. [TUAB0104]
  • BMS-955176 is a second-generation maturation inhibitor that has activity even against viruses “resistant” to the first-generation drug in this class, bevirimat. In a small randomized trial, reductions in HIV RNA were comparable with BMS-955176 plus atazanavir to a standard-of-care regimen of TDF/FTC, ATV/r.  A larger study of this two-drug combination is planned. [TUAB0106LB]
  • In a large claims analysis of newly-diagnosed patients in the USA, the rate of comorbid conditions (hypertension, diabetes, CV, renal disease) was higher in 2013 than 2003. Not surprisingly, rates of these conditions were particularly high in the Medicare group. We HIV specialists really need to buff up our management skills as our population of patients ages! Maybe get to use the shiny new lipid lowering tool! Can you say “proprotein convertase subtilisin kexin type 9″? [MOPEB157]
  • Neither DRV/r or EVG/COBI/FTC/TDF induced insulin resistance over 14 days in this normal volunteer study. LPV/r did. [TUPEB105]
  • Remember the regimen of simeprevir and sofosbuvir for HCV? That was briefly the preferred interferon-free regimen for HCV genotype 1 — way back when in early 2014, ancient history — based largely on results of the small COSMOS trial. Here the OPTIMIST-1 and 2 studies give a more precise estimate of efficacy of “SIM-SOF” in HCV monoinfected patients, with 12 weeks of treatment looking better than 8, and a higher rates of response in non-cirrhotic, treatment naive patients. Regardless, the regimen is probably not going to be used much in the post SOF/LDV era, or the one about to start (see next study), unless there is a big reduction in cost. [TULBPE10 and TULBPE11]
  • In the C-EDGE study, HIV/HCV (genotypes 1, 4, and 6) co-infected patients were treated with the one-tablet regimen of grazoprevir (protease inhibitor)/elbasvir (NS5A inhibitor), with 96% cured. Five virologic failures (all relapses) out of 218 enrolled. Based on drug-drug interactions, HIV regimens were limited to TDF/FTC or ABC/3TC plus raltegravir, dolutegravir, or rilpivirine. FDA approval likely this year. [TUAB0206LB]
  • In a compassionate use program in France, daclatasvir and sofosbuvir was highly effective in HIV/HCV coinfected patients with no other HCV treatment options and advanced liver disease. Treatment was 12 or 24 weeks, and RBV could be added at the discretion of the clinician. Overall cure rate 90-96% (tricky to get exact numbers given heterogeneity of treatments), with no apparent benefit of extending to 24 weeks or using ribavirin. Note that over 70% had cirrhosis. Note also that daclatasvir was just approved by the FDA for treatment of genotype 3 (along with sofosbuvir). [TUAB0207LB]
  • Two studies about optimizing HIV therapy during stem cell transplants cite strategies to maintain virologic suppression. This is particularly important given the risk of severe viral rebound in these patients who have both uninfected target cells and no HIV-related immune response. Both papers cite the occasional need to use enfuvirtide — talk about a niche indication! [WEPEB337 and TUPEB298]

Stanley_Park,_Vancouver_(7889964786)Finally, a little bit about the setting — Vancouver is, of course, a spectacularly beautiful city. It is much changed since 1996, with high-rise luxury office and residential buildings pretty much everywhere, and an even stronger international presence. But it’s still far from overly crowded, has those extraordinary waterfront vistas, wonderfully cool summer weather, gorgeous urban parks, great food, and the longest uninterrupted walkway in the world, the incredible Seawall.

A city biker’s dream.

Now, for a tune with a Canadian theme …

July 18th, 2015

Disrupting the Normal Microbiota Might Make Us Fat, Allergic, Asthmatic, and Lead to Celiac Disease

bacteriaOver at Open Forum Infectious Diseases, I recently had the opportunity to interview Dr. Martin Blaser, Professor of Medicine and Microbiology at New York University. He’s also the Director of the Human Microbiome Project, and author of the book, Missing Microbes: How the overuse of antibiotics is fueling our modern plagues.

Marty has been a long-time champion of the concept that our normal bacterial flora strongly influence our health. (He prefers the term “microbiota”, for the record.) He makes a compelling case that the overuse of antibiotics over the years has contributed to several modern health epidemics, including obesity, allergic diseases, asthma, and celiac disease, along with some cancers. [Edit: And now juvenile idiopathic arthritis? The list keeps growing!]

The implications of the research he cites are far reaching, suggesting that the downside of antibiotic overuse could extend way beyond selection of resistant organisms.

Full interview here, transcript here.

Highly recommended!

July 11th, 2015

Citing WHO Guidelines, Squirrels Protest Latest Virus Discovery

variagated squirrelAn open letter to the Editor-in-Chief of the New England Journal of Medicine

Saturday, July 11, 2015

Dear Dr. Drazen:

On behalf of the International Association of Variegated Squirrels, I am writing to protest the article that appeared in your July 9 2015 issue, entitled A variegated squirrel bornavirus associated with fatal human encephalitis.” 

We variegated squirrels believe the title and content of this paper are stigmatizing to variegated squirrels, and are not in keeping with recent guidance from the WHO regarding best-practices in naming new diseases.

As a reminder, variegated squirrels the world over are trying to counter literally centuries of discrimination and injustice. Indeed, the paper you published includes these chilling sentences:

All three patients [with encephalitis] were breeders of variegated squirrels (S. variegatoides). They were friends, had met privately on a regular basis, and had exchanged their squirrel breeding pairs on multiple occasions.

In our opinion, this involuntary captivity and heartless exchange of fellow variegated squirrels highlights the ongoing challenges we face on a day-to-day basis.

In addition, based on extensive communications I have had with non-variegated squirrels, I am concerned that the paper will have a similarly negative effect on all 200 squirrel species. From the five-inch African pygmy squirrel to the three-foot Indian giant squirrel, all are upset about this stigma by association. And you don’t want to get a three-foot squirrel mad at you, trust me on that one.

Squirrels — variegated and non-variegated alike — have much to be proud of. Before scientists go and name a scary viruses after us, please keep in mind the literally millions of innocent fellow squirrels who roam free, climb trees, nibble acorns and other nuts, and have never transmitted a disease to anyone.

Respectfully,

Rocky
Chairman and Spokes-Squirrel
International Association of Variegated Squirrels

(H/T to Rebeca Plank for the photo and link to squirrel facts.)

July 7th, 2015

For HIV in the USA, Not in Care Exceeds the Undiagnosed — Solutions Welcome

In last week’s post, I asked about two of the key components of the HIV care cascade — the “undiagnosed” vs the “diagnosed but not in care,” and which group was larger in the USA. Here are your answers as of now:

Undiagnosed_or_Not_in_Care__For_HIV__Which_Is_the_Bigger_Problem__-_HIV_and_ID_Observations_HIV_and_ID_Observations

The people who read this site are a pretty knowledgeable group when it comes to issues related to HIV. This is not a blog about collecting beer steins, philosophical ruminations over baseball cards, or knitting, to cite three mentioned to me by patients over the years.

(That middle one is quite something. As is his book, if you’re into that kind of thing. Which I am.)

But more than half (57%) of even this erudite readership got the question wrong — because in the United States, those diagnosed but not in regular care greatly exceed the undiagnosed. It’s by a factor of more than two-fold to one, at least if you believe the CDC data displayed in this nifty video.

In the undiagnosed, there’s been progress: making HIV testing easier has resulted in a great reduction in those who have HIV but don’t know it. The latest data from CDC have just been published, and we’re down to just 14%. Yes, 14% is still too high — and it’s up to 25% undiagnosed in certain regions (we’re looking at you Louisiana) — but it’s a vast improvement over the 30-40% estimates we were seeing 10 years ago.

And in many regions, it’s now < 10%. Meaning that more than 90% of those with HIV know that they have it, and can get on treatment, prolong their lives, and stop spreading the virus to others.

Now, about that much bigger other group — 30-40% or so of those with HIV in the USA — who know they have HIV and aren’t getting care and treatment.

What’s up with that?

Solutions to this problem eagerly awaited.

July 1st, 2015

Undiagnosed or Not in Care? For HIV, Which Is the Bigger Problem?


taking a testThese days, it’s hard to have a “closed book” examination.

The information is everywhere — on your computer, your phone, your tablet — whatever screen happens to be glowing in front of you.

“In the age of the internet, why be wrong?” is something my son used to say as we sat at the dinner table, grappling to remember who was the mother of Perseus, the flight time between Boston and Ft. Lauderdale, or the new name for Haemophilus aphrophilus.

(Still can’t get over that one. And yes, ID doctors have fascinating dinner table conversations.)

So it’s tough to ask you to try and take this quiz without heading over to the CDC and finding the answer. But give it a go because 1) I have a theory, triggered by a patient with advanced HIV disease I just saw in the hospital — which somehow always feels like a failure of our healthcare system — and 2) if you get it wrong, who cares? Nobody will know.

The question is about how we can possibly still have untreated people with HIV in this country, even though the medications are widely available, highly safe and effective, and simple to take. Plus, there are numerous programs in place to ensure that pretty much everyone who needs it can get coverage for treatment.

Is it that they are undiagnosed and hence don’t know that they should be on treatment? Or do they know that they have HIV, but for some reason aren’t engaged in regular care?

In the United States right now, which category of untreated people with HIV is bigger?

View Results

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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