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July 30th, 2014

Hepatitis Day “Celebration” and a Reminder

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.

 

 

July 27th, 2014

Really Rapid Review — AIDS 2014, Melbourne

AIDS2014_bannerFor the second time — the first time was in Sydney, 2007 — the annual “summer” international AIDS conference took place in Australia, this time in Melbourne way down in the southern part of the country. I’ll note again how the crash of Malaysia Airlines flight MH-17 cast a sad note over the opening sessions, and throughout the conference many people gave moving tributes to friend and colleague Joep Lange.

This being the larger of the two international meetings, there was plenty of non-medical, non-scientific content, all of which I’ll completely pass over in this Really Rapid Review©.

(Except to say that Bill Clinton and security entourage walked right past me — he waved hello, though clearly not to me personally.)

With the usual up-front apologies for inadvertently omitting something important, off we go.

A few brief impressions of Melbourne, top of the World’s Most Livable City rankings by The Economist since 2011.

  1. The people were uniformly nice, polite, energetic, and helpful. All of them! There must be some ornery and disagreeable Melbourne natives someplace, but they are either extremely small in number or they are carefully hidden away, far from where tourists roam.
  2. As a tennis-crazy person, even though I knew it was illogical, I kind of expected Melbourne to be hot — think of the Australian Open in January, matches held in blistering 40 degree celsius heat with blinding sun, players taken into the locker room for IV hydration, etc. Of course this city’s location in the way south of Australia means it’s not “summer” here at all (see the first line up there), it’s just flat-out winter — cool, cloudy, kind of like Seattle in October/November — but nothing (and I mean nothing) like a Boston winter. Wear a sweater and/or a light coat and you’re fine.
  3. The city has the largest street tram service in the world, and somehow it all works: the streetcars don’t seem to interfere with the traffic or pedestrians, and the stops have incredibly clear and helpful signs telling you not only how long you need to wait for the next car, but the next 3 cars after that. Imagine that on the Boston T on Commonwealth Avenue!
  4. Food is outstanding, with strong Asian influences everywhere, and many of the restaurants are charmingly located on narrow alleyways, with indoor/outdoor dining overlapping to make the alleys seem like outdoor rooms. Tipping is barely required — kind of viewed as sort of a strange American custom. I asked about tipping in one restaurant, as I didn’t have the right currency for both the bill and a tip, and the waitress said (in all sincerity), “That’s very kind of you, but we’re just fine, thank you.”
  5. This is a city of true coffee fanatics, proven by the fact that there are only two Starbucks in all of Melbourne — but don’t go to them! From humble little snack bars to high-end bean emporia, the quality of the coffee here is off the charts sensational. Maybe that’s why everyone is so nice? Helpful for jet lag adjustment too.
  6. Given all of the above wonderfulness, perhaps it’s no surprise that Melbourne is no bargain. (#6 most expensive city in the world, according to this list.) Not eager to see my next credit card statement, yikes.

Next year’s meeting is in Vancouver, which no doubt will celebrate the incredible 1996 Vancouver meeting that introduced effective HIV therapy to the world. Or, to quote Kevin DeCock:

The International AIDS Conference in Vancouver is synonymous with the introduction of highly active antiretroviral therapy (HAART), now just referred to as ART.  

He said it, not me!

July 19th, 2014

Mood Solemn in Melbourne as AIDS 2014 Starts

There is unquestionably a shadow cast over this year’s international AIDS meeting here in Melbourne, and it’s not the result of the Australian winter. It’s the crash of Malaysia Airlines Flight 17, of course, which prematurely ended the lives of hundreds of people — including many people en route to this conference, most notably one of the field’s finest clinical researchers and leaders, Joep Lange.

I of course knew Joep (much better than he knew me), and greatly respected his work. He is especially well known for his efforts to make HIV treatments available globally. This achievement is perfectly summarized by Marty Hirsch, quoted in today’s Boston Globe:

He was a leading light, and he was a person who pushed probably as hard or harder than anyone for equity in the field, to make the drugs that we were using in the US and Netherlands available at a low cost for people in underserved areas of the world.

One of his research collaborations is particularly noteworthy given the location of this year’s conference: Along with David Cooper from Sydney and Praphan Phanuphak from Bangkok, Lange was one of the founders of the HIV-NAT Research Collaboration, with NAT standing for “Netherlands Australia Thailand”. This productive effort started in 1995 — one year before combination ART became standard of care! — and was a true model of how countries with diverse backgrounds and economic resources could work together to improve HIV care and research.

Needless to say, everyone here is heartsick about this senseless loss.

 

July 14th, 2014

Despite Baby’s Relapse, HIV Cure Research Marches On

The big news in the HIV world over the past week was of course the virologic rebound of the Mississippi Baby, who up to this point was considered possibly the second person cured of HIV.

(Timothy Brown — stem-cell transplant recipient from CCR5 negative donor — remains the first and only HIV cure. Every report on this topic needs to mention this, so now I’ve checked that box.)

Obviously this baby’s relapse after over 3 years off treatment was tremendously disappointing — a “punch in the gut” according to one researcher — and, along with the relapse in the Boston stem-cell transplant cases, underscores just how difficult it will be to find a viable strategy for curing this infection.

But it’s equally important to emphasize that significant clinical research in this area has by no means stopped. There’s a vigorous research agenda ongoing in HIV cure, as demonstrated by several studies ongoing in the research network in which I participate (there’s my disclosure), the AIDS Clinical Trials Group. Here are three approaches:

  • ACTG A5135: Romidepsin is an in vitro potent HDAC inhibitor (you knew that, right?), which potentially can stimulate latent HIV and hence make it more vulnerable to eradication. You’ll hear more about romidepsin in the upcoming AIDS 2014 Conference in Melbourne, and this ACTG study is enrolling now.
  • ACTG A5326:  The anti-PD-L1 antibody BMS-936559 can reinvigorate a “fatigued” immune response to HIV, which, along with other strategies, could lead to clearance of the virus. Another study enrolling now.
  • ACTG A5308: HIV controllers — those who have undetectable or nearly undetectable HIV RNA even without ART — have smaller HIV reservoirs than most people with HIV. This study will evaluate whether standard ART can reduce this reservoir further, along with improve immunologic abnormalities sometimes observed in these patients. Yes, still enrolling interested participants.

Now none of these will actually cure HIV on their own, but they’re potentially promising first steps. Think of the participants in these studies like these Mercury astronauts, to borrow an analogy from my friend and colleague Joe Eron.

And of course this is just a partial list, with many studies outside the ACTG network also ongoing or planned — including panobinostat (another HDAC inhibitor), zinc finger nucleases, the anti-env cytotoxin 3B3-PE38, other novel gene therapy approaches … Who knows what we’ll hear about next week in Melbourne?

And after that, we can expect more, as there is a tremendous motivation to find the analogous cure strategies to what we have now for HCV. It might be more difficult, but think about the technologies available to us now that barely existed when HIV first was discovered. Kind of like comparing the first home PC to what we have now on our smart phones.

So if the Mississippi baby isn’t cured, and neither are the Boston patients, that doesn’t mean it won’t happen eventually.

Here’s betting it will. A lot of very smart people are working on it, and that’s by no means a comprehensive list. People with lots of brains, unlike the scarecrow.

Enjoy the clip.

June 28th, 2014

CDC Nixes HIV Western Blot in Latest Testing Guidelines

Finally, it’s official — the Western blot is no longer recommended as a confirmatory test for HIV infection. From the latest Laboratory Testing for the Diagnosis of HIV Infection, updated June 27:

The HIV-1 Western blot and HIV-1 immunofluorescence assay, previously recommended to make a laboratory diagnosis of HIV-1 infection, are no longer part of the recommended algorithm.

It’s been clear now for years that the Western blot’s sensitivity for early HIV infection was markedly inferior to the latest generations of HIV screening tests; this difference became even starker with the approval of the combined “fourth generation” antigen/antibody tests.

This put clinicians in the bizarre situation of having to ignore, or disregard, the test that’s supposed to be more accurate than the screening test. Essentially every patient with a positive ELISA and negative Western blot would need a follow-up HIV RNA test of some sort to exclude early HIV. Read here for more information.

I’ve pasted the new recommended algorithm below. Let’s hope that labs that still use the old “reactive ELISA –> Western blot confirmation” practice quickly move to this new approach. And kudos again to HIV Testing Guru (yes, that’s his official title) Bernie Branson for getting this important change into the guidelines.

HIV Testing Algorithm 2014 jpg

June 24th, 2014

At Long Last, Some New Antibiotics That Might Make a Difference

Penicillin July 1943 Science PubCompared to HIV, HCV, and antifungal agents, development of novel antibacterial drugs has been in a bit of a funk for quite some time now.

Here’s what’s been approved in the past 10 years, with year of approval and a few comments:

  • Telithromycin (2004):  The first ketolide antibiotic, it was supposed to overcome macrolide-resistant respiratory pathogens. But there were huge controversies about the clinical trials that led to its approval, and major concerns about liver and other adverse effects. It’s still available, but no one in their right mind would use it.
  • Tigecycline (2005):  Although this incredibly broad-spectrum tetracycline-like agent seemed like just the ticket based on its in vitro activity, clinical experience has been only fair at best. It achieves low blood levels, so isn’t suitable for bacteremia, and is associated with extremely high rates of nausea. Plus there’s this excess death issue in pooled data from several clinical trials — never a good thing!
  • Doripenem (2007):  The most recently approved carbapenem, doripenem was shown to be inferior to imipenem for ventilator-associated pneumonia, with a lower rate of cure and a higher risk of death. (Bad.) That trial alone — sponsored by the makers of the drug, no less — should be sufficient reason never to prescribe it.
  • Telavancin (2009):  A relative of vancomycin, telavancin is approved for skin infections. It appears to be more nephrotoxic than vancomycin, however, and offers few advantages. I still have never prescribed it, and our ID PharmD says there has been only one patient in our hospital’s history who has received it.
  • Ceftaroline (2010):  The first cephalosporin with anti-MRSA activity, ceftaroline has a relatively narrow list of FDA-approved indications — namely, community-acquired pneumonia (who would use it for this?) and skin and soft tissue infections. As a result, the drug is really still trying to find itself, if I may personify Mr. C. Fosamil for a moment. What we’d really like to know is how it does for MRSA bacteremia and other severe infections, but thus far the data for these indications are quite limited.
  • Fidaxomicin (2011):  This novel treatment for C. diff may be slightly more effective than vancomycin, at least in certain populations. It is extremely expensive — it’s the current winner in the “Most Expensive Oral Antibiotic” competition — so anecdotally it’s almost always used as a second-line or salvage therapy. In addition, FMT and other microbiome-restoring treatments may ultimately make use of antibiotics for C. diff of limited use.

I’ve probably left some antibacterial out from the above list (did it by memory, except for the FDA approval dates — always risky), but think this pretty much covers the decade. Aside from ceftaroline — which again, is still kind of in a transitional phase as we gather more data — it’s not a particularly impressive group of drugs.

Hence the recent approvals of dalbavancin and tedizolid, and the likely upcoming approvals of oritavancin, ceftazidime/avibactam and ceftolozane/tazobactam, all give ample reason for hope. These incentives seem to be working!

Dalbavancin and oritavancin, with their prolonged half-lives and infrequent administration, could “profoundly affect how skin and soft tissue infections are managed, by reducing or in some cases eliminating costs and risks of hospitalization,” to quote this nice editorial in the New England Journal of Medicine.

Tedizolid is (finally) an alternative to linezolid, with once-daily dosing and likely a better safety profile.

And the two new cephalosporin/beta-lactamase inhibitor combos could provide much-needed options for highly resistant gram negative infections, which we hope would obviate or at least reduce the use of tigecycline and colistin.

Sure, we still need to see these drugs in the “real world” before we know about effectiveness, tolerability, safety, and price. But I’m cautiously optimistic.

 

June 15th, 2014

Poll: Should ID Doctors Still Do HIV Primary Care?

My friend and colleague Ken Freedberg is giving a talk soon at our regional IDSA meeting called, “Who Should Be Providing HIV Care?”

He’s a very smart guy (except during the football playoffs, when he is possessed by evil forces), so maybe he’ll answer this question that has strangely bedeviled our field for decades. But I’m sure his talk will be interesting even if he can’t solve the problem.

To recap a little history, jammed into this tiny paragraph: In the early days of the epidemic, some (but importantly not all) ID specialists didn’t want much to do with this highly charged, rapidly fatal disease of young and often stigmatized people. In response, other specialists and non-specialists got involved, forming the mixed blob of “HIV specialists” that we recognize today — a group of ID doctors, sure, but also internists, family practitioners, other medical subspecialists, nurse practitioners, PAs, etc.

Periodically, people with opinions on these sorts of things have weighed in on who provides the best care to those with HIV, or a slightly different take on the question, who should actually be doing it — especially the primary care part. A consensus has emerged that someone with experience and interest in HIV should be that person, regardless of training.

But even though the question has remained the same, the context has completely changed. Thinking back to when I saw my first outpatient with HIV in 1987, I can define roughly 4 eras:

  1. 1987-1995:  Prevention, diagnosis, and management of opportunistic infections. Palliative and hospice care. Lots of putting out fires, putting fingers in leaky dikes, and rearranging desk chairs on the Titanic. (How’s that for battling metaphors). Plenty of  tragedy, with accompanying intense family meetings.
  2. 1996-2000:   Combination therapy arrives, with highly complex and toxic regimens using early generation PIs and NRTIs:  ZDV, ddC, soft-gel saquinavir anyone? (That’s 27 pills/day, for those counting at home.) How much water should you drink each day to prevent indinavir-related kidney stones? Any downside to daily Imodium or Lomotil use? Can anyone really chew a full dose of ddI?
  3. 2001-2005:  A growing awareness of the long term toxicity of certain HIV therapies. The “when to start” debate. Treatment interruptions of various flavors. Lots of resistance testing for treatment-experienced patients, many of whom were perfectly adherent but had no active drugs. Crazy salvage regimens that included “double-boosted PIs” and “mega-HAART” (ugh).
  4. 2006-today:  More and more (and MORE!) patients every year on suppressive therapy. Clinical visits focus on prevention and screening, mostly targeting “non-communicable” comorbidities — heart disease, cancer, bone health, etc. If HIV therapy is discussed, it involves consideration of switching to simpler regimens, or whether HIV can be cured. (Can sometimes do the former; not the latter.)

During eras #’s 1-3, and the first few years of era #4, most ID doctors with HIV interest were ideally suited to doing HIV primary care. We loved this stuff, and each step forward was more and more rewarding — thrilling, even. Plus there were papers — actual data — showing that the more experience you had, the better the outcome for your patient. This paper was the most widely cited, back in Era #1. The lead author was (and is) a primary care internist, but the message resonated with ID specialists, who in many healthcare systems did the most HIV care.

Generalists, meanwhile, became progressively estranged from HIV as the eras progressed. There was a seemingly endless parade of new agents, the codes and complexities of resistance testing were befuddling, and the mile-long list of drug-drug interactions loomed ominously. I remember one (excellent) internist telling me that he got about as much out of reading an HIV resistance report as he did interpreting an EEG.

But how about today? An ambulatory practice once dominated by crisis management is now a comparably calm state of affairs, at least medically — the vast majority of people receiving care are virologically suppressed, and have been for some time. If 80% or so of patients in HIV care are stable, we can legitimately ask the provocative question — does it make sense that ID doctors still act as their primary care providers? Shouldn’t we move to the oncology model, where the specialists guide decisions about cancer treatments and complications, then the long term non-oncology follow-up of stable patients is done largely by generalists? Furthermore, aren’t generalists better at screening and prevention for non-ID issues than ID docs, who don’t focus on general medicine during their subspecialty training?

Or to take the other side: Shouldn’t ID doctors keep doing HIV primary care, since we have a nuanced view of HIV disease that didn’t come easy. The authors of these primary care guidelines, for example, are mostly ID docs. Example of “nuanced view”: We know we can largely ignore the atorvastatin-boosted PI drug drug interaction (just start with a low dose), but the fluticasone-boosted PI one can be a real nightmare. And wouldn’t our patients we’ve followed all these years wonder why we were dropping them from our primary care?

Since I’m not sure of the answer here, please take the following poll — and feel free to note your further thoughts in the Comments section.

Should ID doctors still do HIV primary care?

View Results

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June 4th, 2014

Anti-Vaccine Movement Slammed By Daily Show; ID Doctors, Pediatricians Happy

The anti-vaccine crowd gets a pretty good drubbing here from Samantha Bee on The Daily Show. I’d feel a tiny bit bad for them — gosh their opinions are pathetic — but since I’m an ID specialist married to a pediatrician, I can only rejoice in the brilliance of this piece.

And yes, stupidity crosses political party lines.

Enjoy!


Hat tip to Joel Gallant for the link.

May 28th, 2014

Some ID Stuff We’re Talking About on Rounds

Leeching-largeJust finished two weeks on the inpatient general medical service — hence the radio silence — giving me a chance to work with residents, interns, and medical students. Here’s a smattering of the ID topics we discussed, along with a comment or two:

  • “Common” causes of gram negative soft tissue infection (at least for board exam purposes), and their associations:  Pasturella multocida (cat bites), Vibrio vulnificus (salt water, especially in warmer climates), Aeromonas hydrophila (fresh water and leeches). Yes, leeches, which do have some legitimate medical indications. Our patient had Enterobacter cloacae (not leech-related), which led to a discussion about …
  • “Inducible” AmpC beta lactamases, which get expressed after in vivo exposure to cephalosporins or expanded-spectrum penicillins. These are really tricky since the microbiology lab will report enterobacter spp. as sensitive to these antibiotics unless another resistance mechanism is present. So should all patients with serious infections due to enterobacter receive a carbapenem? Probably a good idea.
  • Parasites are thought frequently to cause eosinophilia, but protozoan (single cell) parasites rarely do — except for the uncommon bugs Isospora belliDientamoeba fragilis, and Cyclospora cayetanensis. So if your patient has parasite-related eosinophilia, think worms — strongyloides, schistosomiasis, filariasis, etc.
  • Is obsessive tweaking of vancomycin levels useful if you’re not treating confirmed Staph aureus and the patient’s renal function is normal? Highly doubtful. The drive to get vancomycin troughs between 15-20 is the ID-fellow equivalent for repleting potassium — a constant annoyance, and not always necessary.
  • Watch out for ritonavir-related drug-interactions — in particular with inhaled or injectable corticosteroids. Some EHR interaction alerts should not be ignored!
  • Still confused about the diagnostic approach to C diff? Here’s a very nice summary of what most micro labs are doing.
  • Hemolytic anemia occurring weeks to months after surgery should prompt consideration of transfusion-related babesiosis. Cases may be seen year-round (but most in the summer) and throughout the USA. Median age 65.  Median time to onset of symptoms around 50 days. And no, there is currently no routine screening of blood donors — but as soon as there is a reliable screening test, suspect there will be.
  • One important cause of potentially severe hepatitis is herpes simplex virus, which can occur in both immunocompromised and immunocompetent hosts — in the latter, pregnant women seem particularly susceptible. Diagnostic test of choice is blood PCR for HSV DNA.
  • The days of Western blot used to confirm HIV diagnosis are numbered, as we head towards this new algorithm. I note that one large commercial lab has already stopped sending the Western blot in favor of the HIV-1/2 differentiation assay — progress!

Rapid fire round: If culture results say “suspected enteric gram negative rods,” it will not be pseudomonas; ditto GNR that grow in both aerobic and anaerobic blood culture bottles (true most of the time) … with disk diffusion susceptibility testing, large numbers indicate greater sensitivity (zone of inhibition), but with MICs, it’s a low number you want … a nice adaptation of the disk diffusion method is the Etest … sending sputum cultures gram stains and cultures on patients with pneumonia after they have been started on antibiotics is all but useless (does not apply to ICU intubated patients) … no one really knows the optimal management of persistent MRSA bacteremia … hepatitis B serologies are an endless source of diagnostic confusion for legions of medical students (and some house staff), so here’s a nifty chart … as we head into summer here in New England, the “doxy deficiency” work-up for febrile adults in the outpatient setting (without an obvious other source) consists of Lyme antibody, anaplasma (not ehrlichia) PCR, and babesia PCR … an organism that is resistant to ceftazidime but sensitive to cefoxitin or cefotetan will be an extended spectrum beta lactamase producer …

Finally, an observation that several commonly used drugs share the fate of trimethoprim-sulfamethoxazole, meaning they may eternally be referred to on rounds by their brand names even though they are all off patent, some for many years. The leaders are:

  • Hydromorphone (Dilaudid)
  • Levetiracetam (Keppra)
  • Furosemide (Lasix)
  • Piperacillin-tazobactam (Zosyn)

Ready for 2’45″ of fun? Off we go:

May 15th, 2014

CDC Recommends Broader Use of Pre-Exposure Prophylaxis — Can We Make It Happen?

Making a much stronger and more comprehensive statement than their earlier “Guidance,” the CDC is now recommending tenofovir/FTC (Truvada) for all Americans at high risk for HIV. More specifically, they recommend it for a broad range of people who have certain risk factors (click to see full size image):

Guidance for PrEP

One certainly gets why this was done — as summarized nicely in this Times piece, it’s easy to be “frustrated that the number of H.I.V. infections in the United States has barely changed in a decade, stubbornly holding at 50,000 a year, despite 30 years of official advice to rely on condoms to block transmission.”

Plus, we know that PrEP really does work, provided people take it. An encouraging report from CROI this year found that adherence was nearly 80% among MSM seeking PrEP in three U.S. cities (Miami; Washington, DC; San Francisco).

And I have been surprised that we haven’t yet seen much of a decline in HIV incidence, even with a broader number of our patients in care receiving suppressive antiretroviral therapy, which essentially eliminates the risk of transmission to others.

However, it’s clear that the epidemic is being sustained by those not in care, which is why PrEP is so important. It also raises the first of several major challenges for clinicians, as the highest rate of HIV in the USA right now is in a population that tends not to access care on a regular basis — young, African-American MSM.

Other challenges:

  • The risk assessment will have to be done on the front lines of care — that is, by primary care clinicians — as HIV-negative, at-risk patients do not see HIV/ID specialists.
  • These PCPs will have to get comfortable prescribing tenofovir/FTC. It’s not that it’s complicated (“take one pill daily”), it’s just that it’s not a medication they currently use.
  • They will also be responsible for monitoring both adverse events and (very importantly), incident HIV and other sexually transmitted infections.

Because of these issues, in the few years since PrEP became an option for HIV prevention, we’ve been offering our PCPs a one-time ID consult to discuss the risks and benefits, with a strategy for further follow-up outlined for the primary provider.

So can PrEP be more broadly adopted? I think we (meaning the patchwork U.S. healthcare system) can pull this off.

But it won’t be easy.

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.