An ongoing dialogue on HIV/AIDS, infectious diseases,
December 1st, 2010
World AIDS Day: See You in Kuala Lumpur
A few random thoughts on this 2010 World AIDS Day.
- Now you can mark your calendars for the next three International AIDS Society/World AIDS Meetings: 2011 in Rome, 2012 in Washington, DC — and now, 2013 in Kuala Lumpur, Malaysia. And what do all 3 of these cities have in common? Extreme summer heat! (For Kuala Lumpur, it’s actually just extreme heat, not just in the summer.) Probably some sort of weird compensation for several frigid February’s at CROI.
- Not mentioned in my discussion of the once- versus twice-daily raltegravir study was the study name — which was QDMRK. Yes, the sponsors (can you guess who they were?) continued the self-referential theme that started with BENCHMRK, followed by STARTMRK and then SWITCHMRK. Could a study of coffee be planned, “PERCMRK”? Of the Thanksgiving meal, “TURKMRK?” Or of how to avoid a task, called “SHIRKWORKMRK?”
- On the topic of study names, this really has been a banner period for acronyms. Here’s a partial list just from this year: CAPRISA, CAMELIA, PROGRESS, SPARTAN, ECHO, THRIVE, SHIELD, VERXVE, VIKING, SPRING, SPIRAL, ODIS, ROCKET, SENSE, METABOLIK, ATLAS, ATLIS (yes, there’s both an ATLAS and an ATLIS). Trust me, I live and breathe this stuff daily, and still have trouble keeping all of them straight.
- Some good news on the HIV testing front in this report from MMWR: Compared with 2001, today more people are aware of their HIV status, and “late” diagnoses are declining. However, it’s still striking that even though we’ve had effective HIV treatment for nearly 15 years, around one-third of people are still diagnosed with HIV when they’ve already had complications from AIDS or have severe immunodeficiency.
Anyway — what are your thoughts on these red ribbons? Powerful awareness tool, helpful in keeping HIV on the radar screen? Or over-commercialized, politically-correct, past-its-prime symbol? You decide …
November 29th, 2010
Once-daily Raltegravir “Not Non-Inferior” to Twice-Daily
In your electronic in-box this AM, this press release from Merck:
… although the treatment regimen that included ISENTRESS once daily enabled more than 80 percent of patients to achieve viral suppression, ISENTRESS once daily did not demonstrate non-inferiority to the treatment regimen that included ISENTRESS twice daily. Merck said that based on the initial results, and following the recommendation of an independent Data Monitoring Committee, Merck will end the study
Raltegravir is of course still a great HIV drug, and its approval in 2007 marked one of the great steps forward in the history of HIV therapeutics.
I still remember John Mellors at CROI 2007 preparing us to see the BENCHMRK data for the first time — his exact words were probably not, “this will knock your socks off”, but they could have been. Never before had any antiretroviral agent done so spectacularly well in patients with high-level resistance, and it’s hard to estimate how many patients with longstanding HIV infection have had their lives literally saved with raltegravir.
But is it a once-daily drug? Probably not based on the results of this study, where twice-daily was simply better — or, to be more statistically precise, once-daily did not demonstrate non-inferiority.
And in an odd recapitulation of the early days of the protease-inhibitor era, the story is quite similar to what happened to indinavir, another Merck antiretroviral:
- Both drugs were major advances in the field
- Both drugs had an odd disconnect between PK and response
- Both drugs failed tests of less-frequent dosing
The major difference, of course, is that even the once-daily raltegravir arm in this study did quite well — an 83% response is not too shabby.
It’s just that today, our standard-of-care for first-line therapy is (wonderfully) high, and the twice-daily treatment arm had an 89% success rate, with the advantage seen in particular in patients with HIV RNA > 100k. The difference in response put the once-daily approach just outside of the protocol-specified criterion for non-inferiority.
And this steep price of entry for treatment-naive options is why both elvitegravir/c and 572, though promising, still have their work cut out for them.
November 23rd, 2010
iPrEx: First-Ever PrEP Efficacy Study Published
It’s been quite the year (plus a month) for HIV prevention research.
That glimmer of hope from the Thai vaccine trial. The striking effect of HIV-treatment as prevention. The positive results of the CAPRISA vaginal microbicide study, which were presented to rapturous applause this summer in Vienna.
And today, the iPrEx study is published, which shows that giving TDF/FTC to HIV-negative, high-risk men who have sex with men (MSM) reduces their risk of acquiring HIV by 44%. It’s the first efficacy study of pre-exposure prophylaxis (PrEP) and will undoubtedly generate plenty of discussion.
For a detailed scientific analysis of the trial, two HIV prevention experts have already provided their commentary, Nelson Michael in NEJM and Raphy Landovitz in Journal Watch AIDS Clinical Care. I highly recommend both.
But every HIV specialist/Infectious Disease doctor will have thoughts on this important study, so in no particular order, here are mine:
- A few doctors (mostly those with patient panels with large numbers of MSM) anecdotally have already been prescribing PrEP, at least to a limited extent. If this practice expands, will insurance cover it? Like virtually everything else in our patchwork healthcare “system”, I suspect this will vary widely from plan to plan and from state to state. And you can be sure that for the time being this will not be covered under the state-based AIDS Drug Assistance Programs (ADAPs).
November 17th, 2010
Ferlater Antibiotics
In this absolutely hysterical, laugh-out-loud comedy routine, Mal Z. Lawrence describes a woman at a Catskill hotel, piling danish into her handbag.
She calls them “ferlater danish” — as opposed to the ones she’s eating at breakfast, those are “fernow.”
Did you ever have one of your patients request “ferlater” antibiotics? That is, ask that you write a prescription for an antibiotic even though they’re not sick now, just in case they become sick?
Over at the “The Ethicist” column this week in the Sunday New York Times, Randy Cohen fields a question from a woman whose husband has just developed pneumonia on a trip to Peru, even though he’d requested (and had been refused) antibiotics from his doctor before he left. “Was the doctor overly rigid?” asks the woman. Responds Cohen:
This doctor does seem disturbingly conservative… So, yes, I’m with you, and so is Dr. Jane O’Shaughnessy, an expert in emergency medicine, who e-mailed me to say, “Prescribing antibiotics and other medications tailored to the trip destination is usual practice among doctors who specialize in travel medicine.”
On first glance, this seems right, especially since the man had a history of recurrent respiratory tract infections.
But Mr. Cohen and Dr. O’Shaughnessy should know it’s not always quite so simple. First, travel medicine and ID specialists — and I wonder why Cohen asked an ER doc rather than go right to the source — recommend providing antibiotics before trips to developing countries in case diarrhea develops, but not in general for respiratory tract infections, most of which are viral anyway.
Second, let’s say he did get the antibiotics — would this have necessarily prevented the pneumonia? Who’s to say?
Third, it’s important that Times readers know just how often clinicians get asked for “ferlater” antibiotics, usually with far less justification than in the anecdote presented in the Times.
And rather than displaying excess rigidity, doctors and nurses who say no to this request are generally acting with very sound judgment.
November 12th, 2010
Tesamorelin is Approved
This just in from the FDA:
The U.S. Food and Drug Administration today approved Egrifta (tesamorelin) to treat HIV patients with lipodystrophy, a condition in which excess fat develops in different areas of the body, most notably around the liver, stomach, and other abdominal organs. The condition is associated with many antiretroviral drugs used to treat HIV.
While that opening sentence says it’s approved for “lipodystrophy”, this term alone is of course an oversimplification. The drug, a growth-hormone releasing factor, actually is indicated for visceral lipohypertrophy.
In other words, big bellies.
Those of us of a certain age can remember the first time we saw this happen to our patients. Typical case would be a person with advanced AIDS starting a combination regimen in the mid1990s, usually involving indinavir (hence “Crix belly” or “protease paunch”). In the excitement about watching viral loads go down and — more astonishingly — CD4 cell counts go up, we initially could overlook the beach ball-sized and very firm mid-section protuberance that was growing larger with each visit. “I look like Big Bird,” one of my patients memorably said. “Skinny legs, big gut.”
But eventually we had to do something, which usually led to an imaging test to exclude a mass or some other badness. When the radiologists reported the test as “negative”, we pressed them further — at which time they’d note that the abdomen was filled with fat. Not subcutaneous fat — in fact, the love handles and spare tires were usually absent — but visceral fat, lots of it literally encasing the organs.
Many of those patients are still alive, and of course there hasn’t been a whole lot we could offer them until now. And that’s what tesamorelin is for — treatment of HIV-related visceral fat accumulation.
(Quick aside: Isn’t “tesamorelin” a beautiful word? It sounds like a cross between an exotic Middle Eastern spice and a fine fabric used for making high-end Italian suits.)
So the indications for tesamorelin sound straightforward. But here are a few of the many questions raised by the approval of this unusual drug:
November 7th, 2010
Welcome to the Click-Fest
Let me start by confessing I’m something of a gadget freak. I was an early Palm Pilot adoptor, loved the iPod from the get-go, and need to avoid CNET, Engadget, Gizmodo, and David Pogue’s columns for the New York Times when deadlines loom.
Not surprisingly, I embraced the shift to electronic medical records (EMRs) enthusiastically. While I acknowledge that sometimes EMRs slow clinicians down a bit, and have terrible — horrible — interoperability (how’s that for a tech writer term?), I believe the net benefits from EMRs outweigh the problems. And our EMR has many time-saving and just plain nifty features.
However …
Every so often something happens with an EMR that is so shockingly inconvenient that it makes me wonder whether we’re on a road to EMR purgatory.
Example: prescription refills.
This is how we used to OK a prescription refill in our practice:
E-mail from RN or LPN: “Hi Paul, ok to refill Joe Smith’s Bextrim 10 mg?”
Response: “Yep, one a day, 11 refills. Thanks.”
[RN or LPN then refills via our EMR by clicking “renew” and sending electronically to pharmacy.]
Simple. Time required for MD? Around 3 seconds. Plus, easy to manage on a hand-held device — you don’t need a computer.
So here’s how we’re supposed to do it now (physician clicks or keystrokes in brackets):
- RN or LPN enters request for refill into queue.
- Email is automatically generated that gets sent to MD stating that he/she has a refill request. E-mail does not include patient name, medical record number, medication, or pharmacy info. It’s just a notification. In other words, it’s completely useless on a hand-held device — except as a form of taunting. “You have a task, but you can’t do it until you log into a computer, log into the EMR, and follow multiple steps — nah-nah, nah-nah.”
- At computer, MD clicks on email, then deletes it [clicks 1 and 2].
- MD switches to EMR [click 3].
- MD clicks on refill request [click 4].
- Refill screen appears. Screen looks like it was developed by a web designer who collects mouse clicks the way that some people collect pennies or odd bits of string — the more the better! It literally has four separate panels, each panel containing various radio buttons, check boxes, drop-down menus, scrolling lists, comment fields — a veritable panoply of web interactive tools.
- In second panel, MD clicks on “Renew” [click 5].
- At bottom of page, MD clicks on “Mark as complete” [click 6].
- At bottom of page, MD clicks on “OK” [click 7]. Yes, there are two separate clicks for “Mark as complete” and “OK.”
- “Sign” is now highlighted red in the menu. MD clicks on “Sign” [click 8].
- Sign page appears, with request to enter key. MD enters key [5 keystrokes] and clicks “OK” [click 9].
- Prescription page appears. MD clicks “Send” [click 10].
- Prescription is sent to pharmacy electronically.
Mind you, this is for one patient, and one medication. More meds and/or patients? More clicks.
I understand that there are medicolegal reasons for documenting that MDs review and approve renewals. But there has to be a better way — and of course, there are many, two of them implemented in the commonly-used electronic medical records EPIC and the terrific one at the V.A.
But until electronic medical record designers start reviewing “best-of” strategies from their competitors, I’m afraid there will be lots of these one-step-forward, two-steps-back experiences for us clinicians, just like this one.
November 4th, 2010
XMRV and CFS: More Yay and Nay
Does XMRV cause Chronic Fatigue Syndrome? Or more accurately, is it even associated with CFS?
I’ve been putting off writing about this for a while, as I knew colleagues of mine had a paper in press on the topic, and I wanted the dust to settle a bit more on the controversy.
But of course the controversy, and the scientific inquiry, are just getting started. There was a recent HHS meeting on the topic; anecdotal reports of patients with CFS receiving antiretroviral agents for treatment; patients with the condition have been discouraged by one group from donating blood.
Now, my colleagues’ paper has been published in The Journal of Infectious Diseases — and it shows no detection of XMRV in patients with CFS, and furthermore no XMRV in comparison groups of patients with HIV, rheumatoid arthritis, transplantation, or a group just presenting for general medical care.
The score is getting hard to tally, especially because negative studies get way less press. On the plus side, there was the original Science paper that got the field started, and the more recent PNAS one; the latter, oddly, found a slightly different retrovirus (MLV).
On the minus side? In addition to the JID paper from Boston, there have been negative studies from the Netherlands and two from Britain (here and here).
I am sure there are many others in various stages of gestation.
How could highly-qualified scientists come to such disparate conclusions? Here are some admittedly unoriginal thoughts:
- CFS has many causes. (See here for my view.)
- Related: Some CFS is of the “epidemic” variety; sporadic cases are different, less likely to be caused by infection.
- Geographic variability in XMRV incidence/prevalence.
- Different assays and/or different primers used in different labs.
- Contamination of assays. (It is PCR, after all. Isn’t that an inherent risk for any highly-sensitive amplification procedure?)
- Replication of XMRV is variable, or low level, a la HTLV-1 or HIV in “elite controllers.”
- XMRV detection is an epiphenomenon, and “true-true, and unrelated” — hence detection of the virus may be a random event, or merely an association.
- Some other issue no one has thought of.
Regardless, I highly recommend the editorial by Mary Kearney and Frank Maldarelli that appears in the same issue. They call for the following:
- Standardization of detection assays.
- Prospective epidemiologic surveys.
- Sharing reagents and samples. [Amazing this hasn’t been done yet!]
- Comprehensive and rigorous phylogenetic sequence analysis.
- Development of tractable animal models.
In addition, they have strong words for those who are prescribing antiretrovirals for individuals with CFS:
At this time, such an approach is premature and medically indefensible outside the secure oversight of a well‐controlled clinical trial. “Real world” coping with severe diseases like chronic fatigue syndrome and prostate cancer creates understandable desperation on the part of patients, caregivers, and health care professionals. Such pressures are not justification for testing of therapies in an uncontrolled manner. Indeed, because they are of no help whatsoever to other patients, physicians, pharmaceutical companies, or regulatory agencies, such uncontrolled therapy works directly against the goal of providing effective therapy to the million or more individuals experiencing these serious conditions.
Wise words indeed.
October 29th, 2010
With HIV Medication Adherence, It’s Not a Competition
There has been an irresistable urge for people — doctors, public health officers, politicians, journalists, the usual pundits — to compare adherence to HIV treatment in resource-rich vs. resource-limited setting.
I suspect this is because the whole issue got off to a famously bad start in 2001, when then-head of the U.S. Agency for International Development (USAID) Andrew Natsios said in an interview with the Boston Globe that Africans:
… don’t know what Western time is. You have to take these (AIDS) drugs a certain number of hours each day, or they don’t work. Many people in Africa have never seen a clock or a watch their entire lives. And if you say, one o’clock in the afternoon, they do not know what you are talking about. They know morning, they know noon, they know evening, they know the darkness at night.
Yikes.
The reality, of course, is that patients in Africa and other resource-limited settings have been just as adherent to HIV treatment as people in developed countries.
But are they more adherent?
Yes, says this article in the New York Times. And yes again, says this widely-quoted meta-analysis, published in JAMA in 2006.
But I don’t buy it — never have.
In fact, in his otherwise inspiring talks on how to bring lifesaving health care to poor countries, my doppelganger Paul Farmer has a small section I absolutely hate. (Am I allowed to criticize Paul Farmer? Sure — he knows it.) It’s where he compares adherence rates for Haitians in his community-based programs to that of patients discharged from the inpatient medical service at Grady Memorial Hospital in Atlanta.
Not surprisingly, the Haitians do better. But that’s not really a fair comparison, because in Haiti the people on treatment are actively seeking care, while with these particular patients at Grady, they are actively running away from it until they get so sick they need to be hospitalized.
At the great risk of oversimplifying the issue — and acknowledging up front that I do my work exclusively here in the USA (but in a setting with a very broad range of patients) — here’s my take:
- Most people with HIV — everywhere — are phenomenally adherent to therapy. Not only that, it gets better over time. Excellent adherence is especially common in those who, as mentioned above, are seeking care rather than trying to evade it. Remember the AZT-every-4-hours group? The indinavir-every-8-hours-on-an-empty-stomach group? With today’s easier regimens, lots of patients barely ever skip a dose, and they look at you like you’re crazy when you ask them how often they miss. And Carlos del Rio tells me that many of them are receiving care right near Grady at the outstanding Ponce de Leon Center.
- It is incorrect to think that this ability to take medications differs in different countries. In the same way that Natsios got it wrong about Africa, it’s wrong to assume that we can’t do it here based on antiquated data, examination of only a selected subset of patients, or reverse cultural assumptions. I heard someone once say at a lecture that adherence was worse in the United States than in Kenya because US HIV patients “take everything for granted.” Yikes again.
- The huge benefits of HIV therapy notwithstanding, some people just don’t get it, and they drive us crazy. Everyone knows a small group of patients — see pie graph above, as my unscientific estimate puts it at 5-15% — who just won’t play the ART game by the rules, or at least won’t do it consistently. They are in denial; or they don’t really believe you that HIV is lethal; or they have side effects to everything; or their life is in total chaos; or they have psychiatric illness; or they have drug or alcohol problems. Or all of the above. And you know what? Though small in number, such people are everywhere (even in Africa), and found with every disease. They occupy a tremendous amount of our clinical energies and a disproportionate share of resources — and not surprisingly, it’s this group that gets hospitalized repeatedly at Grady, as well as every other hospital that sees its fair share of HIV patients.
So the next time you hear someone make a broad generalization about adherence being better in City A vs B, or Country X vs Y, remind them that people are people — and adherence to HIV therapy is likely to be the same everywhere.
That is, excellent until proven otherwise.
October 22nd, 2010
How to Figure Out the Length of Antibiotic Therapy
One thing we ID doctors know — that other clinicians simply don’t — is how long to treat a patient with antibiotics.
I was reminded of this special power by these recent events:
- An excellent fellow from the hospital’s Critical Care program rotated through our division recently. When asked about what she wanted learn from the elective, the first thing she said was figuring out — finally — how long an antibiotic course should be.
- We received a consultation on an unfortunate case that had been hospitalized since approximately the time of the Gerald Ford administration. You know the type — multiple surgeries gone bad, several GI anastomotic leaks, innumerable tubes and drains, abundant highly-resistant bacteria and yeast cultured from each drain. The question: “How long should we treat the acinetobacter?”
- This great article in the New York Times by Harvard “Happiness” Professor Daniel Gilbert, who relays being given a 7-day course of antibiotics by a doctor. “I understood why I needed to complete the full course, of course. What I didn’t understand was why a full course took precisely seven days. Why not six, eight or nine and a half? Did the number seven correspond to some biological fact about the human digestive tract or the life cycle of bacteria?”
The answer, Dr. Gilbert, is that this is highly-specialized knowledge, rarefied information that only 100% Board-Certified, USDA-inspected Infectious Diseases Doctors know. And since I’m concerned that your article might give readers the wrong impression about our scientific credibility, I’ll now divulge what we’ve learned, and how to apply it.
To figure out how long antibiotics need to be given, use the following rules:
- Choose a multiple of 5 (fingers of the hand) or 7 (days of the week).
- Is it an outpatient problem that is relatively mild? If so, choose something less than 10 days. After application of our multiples rule, this should be 5 or 7 days.
- Is it really mild, so much so that antibiotics probably aren’t needed at all but clinician or patient are insistent? Break the 5/7 rule and go with 3 days. Ditto uncomplicated cystitis in young women.
- Is it a serious problem that occurs in the hospital or could end up leading to hospitalization? With the exception of community-acquired pneumonia (5 or 7 days), 10 days is the minimum.
- Patient not doing better at the end of some course of therapy? Extend treatment, again using a multiple of 5 or 7 days.
- Does the infection involve a bone or a heart valve? Four weeks (28 days) at least, often 6 weeks (42 days). Note that 5 weeks (35 days) is not an option — here the 5’s and 7’s cancel each other out, and chaos ensues.
- The following lengths of therapy are inherently weird, and should generally be avoided: 2, 4, 6, 8, 9, 11, 12, 13 days. Also, 3.14159265 days.
In this highly data-driven exercise, it is imporant also to note the number of rules — seven, as in days of the week.
That did not occur by chance.
October 12th, 2010
Worlds Collide: Roberto Alomar and HIV
Now that a second woman has accused Roberto Alomar of having HIV, it’s probably time to give this sad story a look-over. After all, how often do these two worlds of mine — HIV/ID (work) and baseball (lifetime hobby — my wife would say that’s a collosal understatement) actually meet?
For those unfamiliar with the basics: Alomar was a staggeringly good player, in the majors from 1988-2004, winning 10 Gold Glove Awards and making the All Star team 12 times. He very nearly was elected this year to the Hall of Fame in his first year of eligibility (a very big deal), and all the baseball cognescenti think he’s an eventual shoe-in since he’s one of the best second basemen in history.
That’s the good part.
On the other hand, there was this strange spitting incident. And then, in 2009, an ex-girlfriend filed a $15 million lawsuit saying he lied about his HIV status; Alomar denied the charges (sort of), and was defended by his then girlfriend — who later became his wife. Then last week, the wife sued Alomar with similar allegations.
I can’t get into the “she-said, he-said” part, as I have no information beyond what’s available in the press. But if we start with the premise that Alomar might have HIV, here are some general thoughts:
- Any reason why someone with HIV couldn’t play baseball? I can’t think of one.
- Could there be anything further from Magic Johnson’s 1991 disclosure than these sordid legal proceedings? As I recall, Johnson’s wife was extraordinarily supportive, at least as relayed to the public. Then he used his HIV diagnosis as a way to encourage people to find out their status, to protect others from getting infected, and to take advantage of treatment — an incredible example of turning something terrifying and stigmatized (especially in the early 1990s) into something good. One of John Bartlett’s favorite comments is that hepatitis C needs a Magic Johnson to make its case. (No, Evel Knievel, may he R.I.P, does not count.)
- Related to the above, you can be sure society’s reaction to Magic Johnson’s disclosure would have been different if he’d acquired HIV from injection drug use or sex with men. (Read the section “Time to Move On” here for how this issue has been reported.) One of the painful things about HIV is the tendency for many to lump cases into those perceived as “innocent” vs “he/she deserved it.”
- For another stark example of how HIV differs from other serious diseases (even those related to unhealthy choices), Hall of Famer Tony Gwynn has just been diagnosed with salivary gland cancer, likely due to chewing tobacco. The response? Mostly sympathy, very little blame or snark.
- Last, here’s a great graphic on how major league baseball players compare to the rest of society. Pretty much says it all.
My view? I hope Alomar gets elected to the Hall of Fame next year — from the baseball perspective he definitely deserves it.
And if he does have HIV, wouldn’t that be something if he acknowledged it during his acceptance speech in Cooperstown.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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