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April 24th, 2014

Pioneering Measles Vaccine Researcher Has Anecdotes, Insight, Perspective, and Generosity to Spare

people_measles5In the new IDSA/Oxford University Press journal Open Forum Infectious Diseases (OFID), we plan to interview a series of great figures in ID about their experiences, posting them as podcasts with accompanying scripts.

Our first interview is with Dr. Samuel Katz, a key figure in development of the measles vaccine, and it can be heard here.

It’s timely for several reasons. First, World Immunization Week starts today; second, MMWR just released a summary of the staggering health benefits of the “Vaccines for Children” program, created 20 years ago in response to the last big measles outbreak in this country; and third, the Annals of Internal Medicine has just published a thoughtful commentary on the difficulty of identifying measles in an era when so few clinicians have ever seen a case.

I encourage you to listen to the full interview, but here are some highlights:

  • What it was like working in the lab of Nobel laureate John Enders
  • How they tested the attenuated measles virus first in monkeys, and then on themselves (!)
  • Planning and conducting the first clinical trial
  • Expansion of the vaccine to international use
  • How Dr. Katz views the anti-vaccine movement

There are some great stories in there, all suffused with an extraordinary generosity of spirit and humility. You’ve heard the phrase “humble to a fault”? We’ve got a prime candidate in Dr. Samuel Katz!

After all, what other medical advances have had quite the health benefits of a safe, highly effective vaccine — especially for a disease as contagious and potentially serious as measles? Or, to extract some key data from the MMWR cited above:

Because of vaccination, approximately 322 million illnesses, 21 million hospitalizations, and 732,000 premature deaths will be prevented among children born during [the past 20 years], at a cost savings to society of $1.38 trillion.

That pretty much says it all.

 

April 12th, 2014

Unwittingly, HCV “News” Brackets Our Current Treatment Era on Successive Days

I’ve already told you what a fan I am of Physician’s First Watch, the daily email summary of hot medical news provided by my colleagues here at the Massachusetts Medical Society.

If you haven’t signed up, you must do so — let’s play a short tune (always a favorite) for background music while you head over there and take care of it. I’ll still be here when you get back:

Linus and Lucy by Vince Guaraldi on Grooveshark

Finished? Great.

Anyway, this week the diligent First Watchers sent me this on Thursday:

The World Health Organization has issued its first recommendations on screening for and treating hepatitis C infection … Pegylated interferon with ribavirin is the recommended treatment.

Interferon plus ribavirin? Blast from the past.

Now of course the WHO guidelines are much more nuanced than that — the full document includes discussions of telaprevir, boceprevir, simeprevir, and sofosbuvir.

But on a day-to-day basis right now, in places lucky enough to have access to the newest drugs, sofosbuvir is part of every recommended regimen, so it’s startling to see interferon and ribavirin listed alone. And barely mentioned at all is the sofosbuvir plus simeprevir combination — a regimen astoundingly free of side effects, and arguably the treatment of choice today for virtually everyone with genotype 1 if drug costs were no issue. (Which they most emphatically are.)

By contrast, First Watch sent this off the very next day:

An 8-week course of sofosbuvir and ledipasvir was not inferior to a 12-week course, or to an 8-week course that also added ribavirin … Another research group studied the combination of a protease inhibitor (ABT-450)… plus two inhibitors of hepatitis C virus replication (ombitasvir and dasabuvir) for 12 weeks … [Both studies had] response rates of roughly 95%.

They were referring, of course, to two remarkable studies (here and here) just published in the New England Journal of Medicine, showing us what’s soon to come: both a sofosbuvir/ledipasvir single pill regimen for just 8 weeks, and an interferon-free approach that doesn’t include sofosbuvir at all.

So in the future we’ll have choices between several excellent options.

Now get over to the First Watch site and sign up. You won’t regret it.

April 8th, 2014

Would “HIV Controllers” Benefit from Antiretroviral Therapy?

Let me start with a disclosure — I’m the co-PI (along with Jon Li and Florencia Pereyra) on a study addressing the very question in the title.

The reason for this post is that the topic has been the beneficiary of some terrific coverage in Nature Medicine, both of this research question specifically and the whole topic of HIV controllers in general. Highly recommended.

Everyone who practices HIV medicine has encountered at least one of these lucky few who have low or even undetectable blood HIV RNA without antiretroviral drugs. And as you know, these HIV controllers represent a small subset of those with HIV — estimates vary, but it’s almost certainly < 1%.

Our message to them for years was that they didn’t need treatment, because they are already doing essentially the same thing with their own immune system.

But now there’s a body of evidence that this HIV control may have a downside, specifically an excess of immune activation and inflammation — which can, over the long term, have adverse effects on health. Cardiovascular disease (here and here). Lymphoid fibrosis. And a surprising report at CROI this year found a higher rate of hospitalization among HIV controllers compared to a control group of HIV patients who are receiving ART.

So would HIV controllers benefit from HIV treatment? That’s what we’re trying to answer — more details of the study, ACTG A5308, right here.

And if you have a few minutes, listen to this interview from Nature Medicine. It’s chock-full of thoughtful questions, and my best attempt to answer them!

April 5th, 2014

$0 for 30 Minutes of My Time? Sign Me Up!

Best e-mail survey ever, my second invitation from them — hence a “friendly reminder”:

Dear Sax,

This is a friendly reminder about the online study we recently invited you to – X5328963_HCV

Approximate interview length: 30 minutes
Honorarium: $0
Estimated end date: 2014.06.22

By clicking the survey link below, you agree to participate under the terms specified above.

Start survey.

Once complete, please click the link below to check your account balance and redeem any outstanding honoraria.

Honorarium survey

Thank you for your time — your views are important to us.

Gabriel

Doctors get a lot of survey requests, but this is the first time I’ve received one that has so accurately estimated the dollar value of an ID specialists’ time.

Let’s see — if I do a hundred of these, what would my net be? Still zero?

Oh well. At least my views are important to them.

(Full disclosure: Survey links changed — last one to a candidate for the funniest four minutes… oh, just watch it.)

March 29th, 2014

Opening Day ID Link-o-Rama

19C_baseballSeveral ID/HIV tidbits to keep you entertained until Sunday night’s opening “day” — for baseball that is.

(I hear there’s some sort of basketball tournament going on as well.)

Away we go!

  • Female-to-female sexual transmission of HIV is extremely uncommon — though one such case was diagnosed at our hospital over 20 years ago — but this most recent report from Texas is probably the strongest case report to date, with both convincing behavioral and phylogenetic evidence of the transmission. Note that the infected partner had stopped HIV treatment in 2010, and had an HIV RNA of 82,000.
  • Thoughtful and interesting piece in the New York Times by noted health-care economist Uwe E. Reinhardt about the controversy over the price of sofosbuvir. Good primer on cost-effectiveness as well. The challenge here is that sofosbuvir is both an incredibly expensive drug and an incredible advance on what we had previously. Quandary indeed.
  • We ID doctors do love ceftriaxone — almost as much as we love doxycycline — and at least anecdotally, have been pushing this envelope of this third generation cephalosporin by using it more and more for Staph aureus infections. This report of high rates of ceftriaxone resistance among MSSA isolates might give us pause, however. Important caveat: no link to clinical outcomes in ceftriaxone-treated patients.
  • Taking acetaminophen with phenylephrine — a common combination “cold remedy” — can significantly raise phenylephrine levels, potentially to dangerous levels. One of the great ironies in your drug store is the vast array of cold medicines for sale — when basically none of them works at all. Because if one did work, don’t you think that would be the one we’d all use?
  • Speaking of colds, I’d bet one of the most common questions primary care providers (and ID doctors) get is, “Is it safe to exercise when I have a cold?” Thoughtful response here on the Mayo Clinic site, which I will instantly adopt.
  • Some of my friends were surprised when I didn’t comment on this latest flurry of news about the dangers of cat bites. Hey, stuff like this is ho-hum to us ID docs, we know already that cat bites are bad — but cat-to-human transmission of tuberculosis? Now that’s news! Importantly, this was M. bovis, which responds nicely to standard TB treatment. So add Mycobacterium bovis to toxoplasmosis, Bartonella spp (cat scratch disease), Pasteurella multocida … here, kitty kitty!
  • So the “Five Second Rule” for food dropped on the floor is real: “Time is a significant factor in the transfer of bacteria from a floor surface to a piece of food.” Extraordinary! Either that, or these British researchers have way too much time on their hands. Note that carpet is safer from a microbe perspective if fluffier. For a paranoid’s view of the whole issue, plus a scientist in an oh-so natty outfit, watch this.
  • Want to make your head spin? Read the methods section in this study on the use of xenodiagnosis for Lyme disease. It can be tough going at times (“Ticks were crushed and tested by PCR and injection of the lysate subcutaneously into an SCID mouse and/or by isothermal amplification followed by PCR and electrospray ionization mass spectroscopy, IA/PCR/ESI-MS,” egad), so this commentary is a big help — especially with this statement: “…detection of borrelial DNA by xenodiagnosis is not tantamount to detection of viable spirochetes.” Agree.

Back to baseball. Here’s the best story from Spring Training, the stray dog (Hank) who wandered into the Brewers’ training facility. Sure beats some guy with a mustache sliding into a mug of beer:

March 12th, 2014

Really Rapid Review — CROI 2014, Boston

CROI2014logoDespite the winter that would never end, intrepid HIV/ID researchers and clinicians arrived in Boston for this year’s Conference on Retroviruses and Opportunistic Infections –or more accurately, Conference on Retroviruses and Flaviviridae (little ID joke there) — which just finished last week. Not that it was easy — a winter storm roared eastward as the conference got started, leading to cancellation of dozens of flights headed this way from the Mid-Atlantic states. This was followed by many numb fingers and toes from our unseasonably frosty weather — it was 9 degrees F one morning, a balmy 12 degrees the next.

As usual, CROI was densely packed with scientific presentations and posters; some could argue that the content of one CROI includes as much information as the remainder of the HIV conferences put together. Certainly it feels that way sometimes, especially when there are synchronous “can’t miss” presentations — just try to be in two places simultaneously, especially when one of the slide session rooms is full. Check out the conference site for web casts and, eventually, many of the posters.

(Can’t directly link the abstracts yet — I put the abstract numbers in brackets after each citation — but you can get the full program here.)

Organized roughly (very roughly) by clinical trials, cure research, complications, epidemiology, and miscellaneous interesting studies, here is a Really Rapid Review™ of CROI 2014, brought to you in Technicolor by …oh, let’s get on with it already, and be sure to read to the very end for the top HIV study of the year, as well as a terrific video clip:

  • Success with an NRTI-sparing regimen? Could it be? In the NEAT study, a fully powered randomized clinical trial, darunavir/r plus raltegravir was noninferior to darunavir/r plus TDF/FTC. But — and there are several buts — there was again quite poor performance of the DRV/r plus RAL in those with high viral load/low CD4 (around one-third failed), and more resistance on failure. Plus, aside from some renal markers, was it better in any way? Not really. Can’t seeing using this regimen much based solely on this trial [84LB].
  • When combined with TDF/FTC, raltegravir was significantly better than both darunavir/r and (especially) atazanavir/r, with the relatively poor result of the atazanavir/r arm driving by lots of discontinuations for jaundice [85]. Why so high in this study?  A theory: Give people the option to switch and stay in the study, and they’ll take it. Note that virologic outcomes were the same. Lipids, bone outcomes also better with raltegravir [779LB, 746].
  • In a phase II dose-finding study, the investigational NNRTI MK-1439 — hereafter to be known as doravirine — was potent and well tolerated [92LB]. Guess the big question for its development is how much we need a new NNRTI — none of our current options is perfect, true, but they are pretty good. And what will be the three-letter abbreviation of doravirine? “DRV” is already taken!
  • In the LATTE study — how can you not love that name? — a two-drug maintenance treatment of the v-e-r-y long half-life integrase inhibitor 744 and rilpivirine, both given orally, worked quite well [91LB]. There was only one case of treatment failure with resistance, occurring in a study subject who was on a heavily calorie-restricted diet — not good for rilpivirine! These results set up the potential for a future combination strategy using injectable long-acting preparations of each drug — once-monthly injections, anyone? And will that be a niche intervention or transformative antiretroviral strategy? You decide.
  • For patients starting TDF/FTC/EFV, giving vitamin D and calcium significantly reduced the degree of bone mineral loss with ART initiation [133]. But is it enough to warrant doing it for everyone? And would it work if EFV were not the drug, which induces vitamin D metabolism? Somehow I’m just so biased against supplements, my gut feeling is to hold off for now in making this standard practice. Read the rest of this entry »

March 10th, 2014

CROI Is Over — and a Baby Once Again Takes Center Stage

One of our fellows asked me this AM when I was posting a RRR (Really Rapid Review™) of CROI 2014, and my response was to clear my throat, make some vague excuses, and curse the respiratory viruses that seem as perpetual as the cold weather this year.

It’s in the works, promise — but in the meantime, did you see the New York Times Editorial Page yesterday? Under the title, “Great Hope for Babies With H.I.V.”, the editorial cites the case reported at CROI last week of a second baby possibly “cured” of HIV after starting ART soon after birth.

Why do I use the word possibly and put the word “cured” in quotes? From the Times:

The baby, now 9 months old, has no signs of virus in her blood that can be detected by the most highly sophisticated tests. She cannot be considered “cured” or even “in remission” because she is still taking the drugs.

Yes, that bolding is mine.

Isn’t it incredible how much attention this case has received, despite that oh-so-important fact?

Prediction:  One day we will be treating all babies born to HIV-infected mothers who are not receiving ART with combination therapy, at least initially.

But until we have more than a few of these anecdotes — especially those that have stopped treatment and not experienced viral rebound — let’s calm down already.

February 27th, 2014

CROI 2015 Dates Announced — And Warning, It’s Still Winter in Boston

From the CROI website:

We are pleased to announce that CROI 2015 has been scheduled!

Location: Seattle, WA, USA
Dates: Monday, February 23 to Thursday, February 26, 2015
Details and schedules: Will be posted in early summer 2014

Love their exclamation point. Yahoo indeed! Kudos to the conference organizers for getting the dates out early this year.

Meanwhile, for those of you planning to attend next week’s conference in Boston, I bring you this bit of chilling news. On the plus side, the whole convention center is interconnected with most of the conference hotels, or just a short walk away.

croi weather!But for some travel anxiety, especially for those planning on arriving Monday, here’s a good place to start.

Hey, since we can’t change the weather, might as well complain about it.

 

February 23rd, 2014

A Lower Dose of Efavirenz Works Just Fine — and Why This Matters

As we heard last year in Malaysia, and now published in The Lancet, 400 mg of efavirenz is just as effective as the standard 600 mg dose.

The proportion of participants with a viral load below 200 copies per mL at week 48 was 94·1% for efavirenz 400 mg and 92·2% for 600 mg (difference 1·85%, 95% CI −2·1 to 5·79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6—44; p=0·01).

The 400 mg dose was better tolerated, too. For the record, these data are far more convincing than prior dose-reducing strategies with other antiretrovirals (stavudine, zidovudine, ritonavir come to mind). The results of the study were no doubt outstanding.

So these results have huge implications internationally, where efavirenz-based regimens are the default first-line choice for essentially all treatment naive patients. A lower dose will make treatment cheaper, coformulations easier, the pills smaller, and the sun will shine brighter, too.

Here in the USA? As of today, these data are of limited value, and here’s why:

  1. As first-line therapy, efavirenz is overwhelmingly given as part of coformulated TDF/FTC/EFV (Atripla), which as you know includes 600 mg. Decreasing to 400 mg means increasing the number of pills, both because this splits up the coformulation and because EFV comes in 200 mg capsules.
  2. If we’re after similar efficacy and better tolerability, there are several other non-efavirenz first-line options that do the same thing, and are easy to take, too — notably TDF/FTC/rilpivirine, TDF/FTC/elvitegravir/cobicistat, and TDF/FTC or ABC/3TC + dolutegravir.
  3. Until a generic version of efavirenz is approved, there’s not all that much benefit from a cost perspective — though I do hear that TDF/FTC/EFV pricing has been going up.
  4. The 400 mg dose is not FDA approved for treatment.

So for now, I stick with my opinion about the waning of the efavirenz era – a drug which has been on an extraordinary run dating back its approval in 1998.

However, if the 400 mg dose does get FDA approved, and if there are future coformulations with EFV using this dose, and if these data are confirmed to lower toxicity while maintaining virologic efficacy, then efavirenz might make a comeback.

But it’s a long shot.

February 13th, 2014

Jeter is Retiring, and Certain ID Doctors Are Getting Old(er)

derekjeter rookieIt’s safe to say that most of the perspectives on Derek Jeter’s retiring from baseball will not be written by ID doctors, so let me seize the opportunity. And since it’s always risky to dwell on players from a certain team while living in Boston — I have friends for whom a central component of their identity is Hatred for the Yankees — this will be less about Jeter’s retirement and more about how the news made me feel.

In a word — old.

You see, I was at the game when Jeter hit his first major league home run — opening day in Cleveland, April 2 1996, weather a balmy 38 degrees. That was a remarkable year on many fronts, both personal and professional, as my daughter was born, Boston experienced its snowiest winter ever, HIV became suddenly treatable (How About That!), and well, the Yankees won the World Series, in part thanks to their rookie shortstop.

So what was it like to be an ID doctor 18 years ago? Let’s take a look at the Way Back Machine, and I caution those of a certain age that this is guaranteed to make you feel downright ancient:

  1. You were still doing gram stains in a hospital lab that was on the patient floors.
  2. Aminoglycosides were a regular part of “triples” — you know, amp, gent, clinda.
  3. Amphotericin B had no liposomal formulation, and was co-administered with all kinds of magic potions (diphenhydramine, meperidine, hydrocortisone, pixie dust) to make it better tolerated.
  4. Erythromycin was used as an actual antibiotic — sometimes even intravenously.
  5. Ritonavir was used as an actual antiretroviral, and the dose was 600 mg twice daily (yes kids, you read that right).
  6. Severe C diff was extremely uncommon, and almost never happened in an outpatient.
  7. Community-acquired MRSA might be presented at an ID case conference given its rarity.
  8. There was hardly any vancomycin-resistant enterococcus — good thing, too, since there was no linezolid.
  9. If you wanted a quinolone to treat community-acquired pneumonia, you were out of luck — levofloxacin wasn’t approved until December 1996.
  10. If your patient needed indinavir, he/she needed to get it from a single mail-order pharmacy called “Statscript.”
  11. No echinocandins, oseltamivir, tigecycline, cefepime, daptomycin.
  12. Some days you spent half of your time on rounds looking for X-rays. These were actual films, viewed on a light box — or, if you were in the radiology department, on those noisy contraptions that rotated light boxes. (What did they do with those things?)
  13. These numbers/letters meant nothing: HLA-B*5701, HPTN 052, K65R, E138K, CCR5, CXCR4, Q80K, PrEP, TDF.
  14. Target vancomycin trough level:  5-10.
  15. Some people were actually taking ddC — which, despite the medical “information” from Dallas Buyers Club, was a pretty horrible medication.
  16. Best place for drug information was often the “PDR”. If you’ve never heard of it, don’t ask.

I could go on like this all day, but why not finish on a high note?

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.