An ongoing dialogue on HIV/AIDS, infectious diseases,
March 1st, 2012
Post-Exposure Prophylaxis, the World’s Most Outdated HIV Guidelines, and What To Do About Them
Every time I cover HIV prevention in a lecture, it’s always kind of embarrassing to cite the “official” post-exposure prophylaxis (PEP) guidelines, which are here (non-occupational) and here (occupational).
That’s right, they were last updated in 2005, the year of Hurricane Katrina.
Yes — more than six years ago. The alternative choices seem particularly curious (read: don’t do it) today — indinavir/ritonavir or efavirenz for PEP? You’ve got to be kidding me.
Because here’s a short list of what’s happened since then related to the HIV prevention front:
- HPTN 052
- An HIV vaccine study that, marginal efficacy aside, at least gave us a sense of “community risk” in a low-moderate prevalence area
- iPrEx
- Landmark studies in perinatal prevention, such as this one
- That great wave of HIV drug development, which included darunavir, maraviroc, raltegravir, and etravirine
No, there’s not been much new on occupational risk of HIV acquisition, which fortunately remains incredibly rare –and has always been a relatively data-free zone. (For the record, this is pretty much it here.)
So what’s an ID/HIV specialist to do?
I’ve been told that the next round of PEP guidelines is in development, but frankly the existing guidelines have been out of date for so long that something/anything has to be done.
Hence I welcome the imminent publication of this paper on the use of tenofovir/FTC and raltegravir for non-occupational post-exposure prophylaxis.
Yes, the study is small, and there’s no control group; furthermore, given the rarity of transmission, it can’t really estimate the preventive efficacy of this intervention — we’ll probably never have that.
But it provides at least some support behind what we’ve been doing now for several months, which is frequently replacing lopinavir/r with raltegravir — leading to much better tolerability of the PEP regimen.
And our hospital is about to make it official. From my colleague Sigal Yawetz, who heads up our PEP program, comes the following:
First line empiric therapy, not pregnant, no renal problems: tenofovir/FTC, raltegravir
First line therapy, pregnant (or breast feeding, continues to breast feed though not recommended): zidovudine/3TC, lopinavir/r
First line therapy, abnormal renal function: zidovudine/3TC, raltegravir
For any exposure to known infected person: ART to be selected by HIV expert
There — PEP Guidelines updated!
February 26th, 2012
A Truly Bizarre “Systematic” Review
You know that tenofovir, emtricitabine, and efavirenz HIV regimen? The one that’s universally listed as one of the “Preferred,” or “Recommended” or “First-line” options in all HIV treatment guidelines in the universe?
And the regimen that is easily the most widely used in the USA today?
Well, here’s a surprising review from Cochrane Summaries, entitled “Effectiveness and safety of first-line tenofovir + emtricitabine + efavirenz for patients with HIV”:
We searched the Cochrane Central Register of Controlled Trials, EMBASE, GATEWAY, LILACS, PubMed, AEGIS, and the WHO prospective clinical trials registry in November 2011…Only one study [emphasis mine] involving 517 antiretroviral-naive HIV infected adults was included in this review.
The authors go on to conclude, “The effects and safety of TDF + FTC + EFV as first-line treatment for patients with HIV cannot be assessed on the basis of only one trial. Further studies evaluating the effects and safety of TDF + FTC + EFV as first-line treatment for patients with HIV are needed.”
Gosh.
This is so mind-bogglingly wrong that it’s almost as if the review appeared in the medical version of The Onion, if there were such a thing.
They write that their inclusion criteria for this review was “Randomized controlled trials that evaluated the effects and safety of TDF + FTC + EFV compared with other HAART regimens, as first-line treatment for patients with HIV.”
But maybe they used additional criteria — such as “Only studies published in a calendar year in which the St. Louis Cardinals won the World Series, and whose first author’s last name starts with the 7th letter of the alphabet will be considered for inclusion”, as the Gilead 934 study is the only one they chose.
Because for the record, there’s also this study (5202).
And this one (ECHO).
And if you want to include TDf + 3TC + EFV (why not), there’s this one (Gilead 903).
And this one (5142)…
I’m sure I’ve left something out. But you get the idea.
February 23rd, 2012
Hepatitis C and the “Retooling” of HIV/ID Specialists
The news that hepatitis C (HCV) has passed HIV as a cause of death in the United States got quite a bit of attention when it was first presented last year at ICAAC — and no doubt the published paper, in this week’s Annals of Internal Medicine, will also cause a stir.
In fact, I boldly predict that going forward, (approximately) 94.2% of HCV-related research grants, journal articles, and lay press articles will cite this paper, making it (for now) the “Palella NEJM 1998” of HCV.
(For those of you who don’t know Palella NEJM 1998, this was the first paper in a major medical journal to demonstrate the dramatic decline in HIV-related mortality due to effective HIV therapy. Figure 1 from that study is permanently emblazoned on HIV specialists’ retinas.)
But the Annals paper also reminded me — again — that there’s a significant retooling going on in the HIV/ID field to accommodate HCV. And for some docs and HIV organizations, it’s more than a retooling — it’s practically a comprehensive overhaul. What do I mean exactly? Some citations, some anecdotes:
- The International AIDS Society – USA is now officially known as the “International Antiviral Society – USA” and has HCV therapy as a major focus of its efforts.
- Two large HIV annual educational meetings — one led by Clinicial Care Options, the other called Opman — both now prominently include hepatitis as a substantial component of their conference agenda. In fact, both have even changed their names: “2012 Annual CCO HIV and Hepatitis C Symposium” and “Optimal Management of HIV Disease & Hepatitis“.
- Several of the larger clinical trials sites for HIV therapy now devote a significant proportion of their research efforts to HCV. The leader of a well-known site told me that nearly half of their studies are now HCV-related.
- Many clinical ID practices (including ours) now openly solicit patients with HCV (not just HIV/HCV co-infection).
Of course, it’s easy to see why this is happening. These HCV cases call for all the skills we’ve sharpened over 16 years of combination antiretroviral therapy — managing complex regimens, myriad side effects, virologic responses, resistance, and drug-drug interactions.
Then there’s the dynamic pace of HCV therapeutic research. Seemingly every week, there’s another major story, most of it happening too quickly for peer-reviewed medical journals. See here for an example.
Oh, and you get to cure people. Wow.
By contrast, HIV therapy is in a plateau phase, with few major recent advances in treatment. The top four recommended initial regimens haven’t changed since 2009, and they are all remarkably effective. Clinical sessions of HIV follow-up have been likened to “well-baby checks”, a startling turnaround from the drama of HIV practice just a few years ago.
Yawn. And I mean that in the best possible way. Patients are doing great!
So if HIV/ID specialists seem to be jumping on the HCV bandwagon, it’s completely understandable. Though whether gastroenterologists mind sharing this bandwagon with us is highly debatable — most would probably just as soon let us drive, given the current difference in compensation between endoscopy and office management of medically and socially complex patients.
Perhaps I should even rename this blog “HIV, HCV, and ID Observations”?
Nah, it still needs a complete name overhaul — and I’m waiting for some good suggestions.
February 14th, 2012
Is It Time To Stop Treating Acute Sinusitis?
From the pages of JAMA comes this startling clinical trial:
A randomized, placebo-controlled trial of adults with uncomplicated, acute rhinosinusitis [who] were recruited from 10 community practices in Missouri between November 1, 2006, and May 1, 2009 … [Subjects received a] ten-day course of either amoxicillin (1500 mg/d) or placebo administered in 3 doses per day … There was no statistically significant difference in reported symptom improvement at day 3 (37% for amoxicillin group vs 34% for control group; p=.67) or at day 10 (78% vs 80%, respectively; p=.71).
To be fair, I did leave out that outcomes favored the amoxicillin group at day 7. And I also left out that the validated instrument they used to gauge symptoms was called the “Sinonasal Outcome Test-16”, or “SNOT-16”
Ahem.
But still — I’m willing to wager good money that if you asked 100 primary care providers, ENT specialists, ID doctors, and patients whether they thought antibiotics helped relieve symptoms of acute sinusitis, 90% would answer “yes.”
And 99% would would want it for themselves.
Critics of this study might quibble about the inclusion criteria, or the fairly large number of screened study subjects who were not enrolled, or the selection of amoxicillin over amoxicillin-clavulanate. What, no Moraxella catarrhalis coverage?
Regardless, this trials reminds us that, even though it’s hard to believe, the human species did survive many eons before the discovery of antibiotics in the 20th century, and that furthermore, most of the common community-acquired infections resolve spontaneously.
Time will tell whether the results from the study will influence practice guidelines, patient perception, and — most importantly — clinical practice.
February 12th, 2012
Impossible Curbside at Medical Grand Rounds
Scene: Medical Grand Rounds, 5 minutes before the start. Lecture is on coronary artery disease, which may have a link to Infectious Disease even if it isn’t actually caused by Chlamydia pneumoniae or CMV after all.
A well-regarded, experienced primary care physician (PCP) approaches.
PCP: Hi Paul, I have quick question*.
[*Curbsiders often use this exact phrase — and rarely does it correlate with whether the question is actually “quick”.]
Me: Sure.
PCP: One of my patients has a urine culture that’s persistently positive for MRSA* — I’ve repeated it twice. Should I treat it?
[*Ah, our old friend MRSA. Odds of this question actually being “quick” have just plummeted.]
Me: Hmm, those results could be a sign of systemic infection, with secondary seeding of the GU tract.*
[*We ID doctors are probably — no, definitely — biased towards badness. Which makes us worriers. After all, why else do we get involved in a case?]
PCP: But he’s completely asymptomatic*. Do I need to treat it?
[*I am pretty sure, by his giving me this information, that he does NOT want to complicate matters by looking more deeply into the matter. But he’s slightly unsure about this approach, so he wants me to endorse his action. Or more accurately, his lack of action.]
Me: Then I bet it’s in his prostate — MRSA can cause prostatic abscess, or chronic prostatitis. You could get a prostatic ultrasound or pelvic CT to investigate further.*
[*At this point, our malpractice lawyers would like me to insert into the conversation defensive boilerplate language, such as, “I’ve given you some general information about a general patient, but I don’t know this case well enough for me to render specific medical advice. At your request or the patient’s request, I would be happy to become involved in evaluating him and see him for a formal consultation.” Which makes me wonder: Can you imagine if doctors actually did everything lawyers told us to do?]
PCP: Well, he’s 100 years old, and the family doesn’t want him leaving the nursing home unless it’s a true emergency.*
[*A perfect example of how you don’t get the whole story from a curbside consult. “Quick question”… yeah right.]
Me: I see.
PCP: And I’d like to avoid giving him antibiotics, since last year he had C diff twice and it nearly killed him.*
[*See above comment about not getting “the whole story.”]
Me: Got it.
The lights dim in anticipation of the lecture. Various doctors, many of them cardiologists, begin heading for their seats, readying themselves for the lecture. Time is running out!
PCP: So, what do you think I should do?*
[*I knew it would come to this. Hey, I’m trying to be helpful! Really!]
Me: I guess you’re weighing the risks of giving him antibiotics — and causing another case of C diff — with the risks of undertreating a potentially invasive infection, MRSA.*
[*Look, I know this is an incredibly obvious thing to say. But what else can I do?]
PCP: I could have told you that, and I’m no ID specialist.*
[*He didn’t actually say this, but he was probably thinking it.]
Me: Ask me about evaluating chest pain. That’s much easier.
The lecture starts. It is excellent. But people immediately take out their smart phones and check their email and Facebook updates anyway.
February 10th, 2012
Boceprevir – PI Interaction: A “Dear Doctor” Letter We Didn’t Want To Get
By now I’m sure that most of you ID folks out there have received the following letter from Merck, the makers of boceprevir:
URGENT — IMPORTANT DRUG WARNING: VICTRELIS (BOCEPREVIR)
The purpose of this communication is to inform you of recent pharmacokinetic study results evaluating drug interactions between VICTRELIS, an oral chronic hepatitis C virus (HCV) NS3/4A protease inhibitor, and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors … VICTRELIS reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir, and darunavir by 49%, 43%, and 59%, respectively. Merck does not recommend the coadministration of VICTRELIS and ritonavir-boosted HIV protease inhibitors.
Boceprevir levels were also substantially lowered by lopinavir/r and darunavir/r.
Yes, we already knew that the telaprevir-boosted PI interactions were tricky. It’s basically atazanavir/ritonavir, no other options.
(Outside of the boosted PIs, you can use raltegravir or efavirenz with telaprevir, but the latter requires, 1125 mg three times/day, upping the cost by 50%. Gasp.)
The reason this “Dear Doctor” letter was so disappointing was that boceprevir was supposed to be easier in this regard. In this study presented at IDSA of peg/ribavirin + boceprevir for co-infected patients, all boosted PIs were allowed, only NNRTIs excluded. But that study was small (n=64), and in hindsight perhaps the slower-than-expected HCV RNA reduction had a pharmacokinetic explanation.
For now, the bottom line is that there really is no optimal HCV protease inhibitor for HIV/HCV co-infected patients, especially for those on a boosted PI.
And why careful assessment of those with HIV/HCV is critical, as many patients are stable enough to wait for the next wave of HCV drugs.
February 7th, 2012
Chronic Fatigue: Is There Hope After XMRV?
I’ve been following the chronic fatigue/XMRV story from the start, which was compelling for several reasons, including:
- A potential cause was identified of a very debilitating, mysterious illness.
- Lots of very smart ID people (including some of my colleagues) studied it.
- Media coverage, notably from the Wall Street Journal and the New York Times, was particularly skillful.
In that last vein, the Times today has a fascinating summary of the current situation for this once promising link.
In a word, the link is kaput.
After numerous investigators were unable to duplicate the original results, Science issued an “Expression of Concern” about the paper they had published in 2009. Then in late December, that paper was fully retracted by the Editor of the journal, as was a key supporting paper — really the only supporting paper — that had been published in the Proceedings of the National Academy of Sciences.
Could things get any worse? Of course. Here’s what’s come of the lead investigator in the original Science paper:
Dr. Mikovits left her position as research director at the [Whittemore Peterson Institute] in a dispute over management practices and control over research materials. The institute sued her, accusing her of stealing notebooks and other proprietary items. Dr. Mikovits was arrested in Southern California, where she lives, and jailed for several days, charged with being a fugitive from justice.
Yikes.
But even with all these clouds, there’s an important silver lining to all this news nicely articulated by a noted virologist:
“The disease had languished in the background at N.I.H. and C.D.C., and other scientists had not been paying much attention to it,” said John Coffin, a professor of molecular biology at Tufts University. “This has brought it back into attention.”
I couldn’t agree more. And with that greater attention, perhaps we’ll see some discoveries that really help people.
February 3rd, 2012
More on Low (but Detectable) Viral Loads — Is Knowing This Useful?
I have a very smart, very experienced colleague — clue, his initials are CC, and he doesn’t pitch for the Yankees — who continues to use bDNA testing for HIV viral load monitoring. You know, the assay with a lower limit of detection of 75 copies.
He knows that bDNA is less sensitive than PCR.
He knows that it’s more expensive than PCR.
He even knows (I think) that it’s less accurate than PCR.
So why does he use it? Because he detests the added anxiety and aggravation that these periodic low-level results — usually 20-200 copies, or “<20 but target detected” — give his patients. More importantly, he’s not convinced it provides him with any useful information.
I certainly get that. And suspect he’s not alone in using this (ancient) test, which is probably best known for a study that put viral load testing on the map way back when.
But I can’t bring myself to use an inferior and more expensive test, so I’ve switched whole-hog to PCR. As a result, I’ve been forced to learn a whole new speech to give to patients when these results come back. It usually goes something like this:
Gerald [not his real name], the result came back at 43… Yes, this is detectable, but remember our old test only went down to 50, so in fact this is a great result — keep up the good work … No, I’m not worried … If you’re worried we can repeat it, but I can assure you I won’t recommend changing meds even if it comes back the same … Yes I’m sure … You’re welcome.
Now it’s been a few years since we’ve had these tests, and several studies (like this one) thus far didn’t even suggest any significance to these low-level detectable results.
Until now.
Over in Journal Watch AIDS Clinical Care, Helmut Albrecht summarizes a recent study that compares the likelihood of virologic rebound in 1247 patients who had viral loads measured by the RealTime PCR assay. Three groups were defined: those with results between 40-49 (Group A), < 40 but detectable (Group B), and truly undetectable (Group C):
The proportion of patients who experienced viral rebound to >50 copies/mL was 34.2% for group A, 11.3% for group B, and 4.0% for group C. The proportion with rebound to >400 copies/mL was 13.0%, 3.8%, and 1.2%, respectively. These associations were independent of adherence levels.
Based on these data, it does seem that the lower the viral load, the better — but wait!
Is there more resistance among those who rebounded? No.
Could this just be a proxy for duration of virologic suppression? Highly likely.
Is there a different clinical outcome among those who rebounded? Not commented on, but highly doubtful.
Is there any evidence that our management should be changed based on these fascinating results, however biologically plausible they may be? Emphatically NO. Or at least, not yet. Good summary of these issues in Raj Gandhi’s accompanying editorial.
Which is why CC can continue to use the bDNA — it’s defensible — and while I’ll press on with PCR and all it’s telling us about low-level viremia. Knowledge is power, after all.
I’m just not sure what to do with it yet.
January 29th, 2012
Pre-Super Sunday Scombroids
Some quick ID/HIV links while we await big guys playing the big game with a big (or at least bigger) ball.
- Did you see how this doctor cheated Medicaid out of more than $700,000 by prescribing HIV meds to people who didn’t have HIV? Not surprisingly, he’s going to jail. Proof that if there’s money behind a program — no matter how beneficial — someone will figure out a way to scam it.
- Not only is there barely any winter this year, but there’s hardly any influenza. Not a single state is reporting widespread activity. But Google Flu doesn’t think it’s quite so remarkable, especially compared to last year where flu season peaked in mid-late February.
- What we’re not getting in flu, however, we’re definitely getting in norovirus activity, at least here in Boston. Last week someone in our office turned the color of a bedsheet, then disappeared home, only to returned a few days later weak, tired and 10 pounds lighter. And she didn’t even get to go on a cruise, though maybe that’s a good thing this year.
- Good brief piece in the Times about men of a certain age getting HIV. As the author awaits the results of his test, he writes “I was feeling an incipient sense of . . . failure.” That part particularly rang true, based on my clinical experience — these men lived through the horrible early years of the epidemic, and they feel like failures to get HIV now, after all these years. Lots of self blame.
- How about we all pick up one of these beauties for our hospitals before flu season kicks in? The Mold and Germ Destroying Air Purifier “eliminates up to 100% of airborne bacteria, mold, viruses, pet dander, dust mites, and pollen without making a sound or using a filter.” I guess the key is that “up to …” phrase. (Note to catalogue copy writers: doctors never use the word “germs” unless talking to non-medical people.)
For reference, today’s title was brought to you by the makers of the ABIM Recertification Exam, who truly have a thing for fish poisonings.
January 22nd, 2012
Generic Lamivudine Has Arrived
An e-mail from a patient last week:
Just got refills. Epivir is now generic??? Refill is simply labeled Lamivudine Tablets by Aurobindo Pharma USA, Inc …but made in India. Should I be concerned about that???
John
I told John (not his real name) not to be concerned — he is merely substituting the generic for the branded version, not switching from a fixed-dose combination or from a different drug (that drug being emtricitabine, or FTC).
With all the hoo-ha about generic atorvastatin, this one is much more under the radar. And the process to approval has not been smooth, as I wrote about here and here.
But generic lamivudine for HIV treatment is a watershed moment nonetheless, since it’s really the first time there’s a generic antiretroviral that we might actually consider prescribing. (Zidovudine and didanosine have been generic for years.)
It will be fascinating to see how this plays out, both here in the US and in other developed countries.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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