An ongoing dialogue on HIV/AIDS, infectious diseases,
June 24th, 2011
Reflections on Levofloxacin as it Goes Generic
With the news that a generic form of levofloxacin has just been approved by the FDA, some thoughts about this remarkable antibiotic:
- When it was first approved in 1996, levofloxacin was the first oral antibiotic that really covered all common causes of community acquired pneumonia. Strep pneumo, H flu, mycoplasma, legionella, chlamydia — check, check, check, check, and check. Doctors realized this, of course, and prescribed it like mad.
- Grave prognostications about the threat of pneumococcal resistance to quinolones invariably followed — but this never materialized to a sufficient degree to change practice, at least not in the United States. It has remained unusual to find one of these levofloxacin-resistant pneumococci in clinical isolates, and surveillance reports show that such resistance is surprisingly rare.
- However, rates of gram negative (especially) and Staph aureus resistance to quinolones just keep going up and up. Amazing, these bugs are smarter than we are! What a concept! These UTI guidelines cite “collateral damage” of using quinolones for uncomplicated cystitis — a wise move.
- These cautionary notes notwithstanding, some medical services think it’s mandatory that every patient receive at least one dose of levofloxacin prior to hospital discharge. I made that up, and have mentioned it before, but you get my point — this is still one popular antibiotic. See #1, above.
- As numerous other quinolones fell by the wayside due to safety issues, levofloxacin has remained overall quite safe. Temafloxacin, trovafloxacin, grepafloxacin, sparfloxacin, gatifloxacin — gone, but not forgotten. Trivia question for detail-obsessed ID types (which means all of us): Why were each of these pulled off the market? And what were their trade names? (Hint: several of the trade names sounded like they were lifted right from a science fiction novel.*)
- But even though it’s relatively safe, levofloxacin does have some serious side effects. Probably the worst of these is the tendon rupture/tendinitis issue — deserving of the dreaded “black box” — but I’ve also seen anaphylaxis, delerium, QT prolongation, photosensitivity, and many many cases of C diff. Bottom line is that this is a drug: we humans did not evolve to have levofloxacin coursing through our system. (Tell that to cardiologists about statins.)
- In vitro, levofloxacin is neither the most active gram-negative or gram positive quinolone. Those would be ciprofloxacin and moxifloxacin, respectively. But it hasn’t really seemed to matter much, has it? See #1 (again), above.
- Presumably, the availability of generic levofloxacin will eventually eliminate the levofloxacin to moxifloxacin swap often mandated by payors. Since our hospital has levofloxacin as its preferred respiratory quinolone, it has set up the peculiar practice of using levofloxacin during the hospitalization, then changing to moxifloxacin on discharge. This can’t make medical sense — they are not identical after all — so I for one will be glad to see this exchange come to an end.
*An experienced starship pilot, Raxar expertly navigated his Tequin-400 aircraft through the high mountains of Trovan. This was no easy task, as the planet’s distinctive craggy peaks were nearly completely obscured by thick clouds of Omniflox — the highly-toxic gas released from volcanic eruptions. Off in the distance, he could see the bright lights of the capital city Zagam. “Home at last,” he said out loud. But Raxar spoke too soon, for little did he know that this final leg of his journey would take him to worlds unknown …
June 19th, 2011
Abacavir Agonistes
The studies on abacavir and its potential association with increased cardiovascular risk have been inconsistent ever since the news first broke at CROI 2008. But recently the data have been swirling around so fast and furious that it seems appropriate to take out this famous Greek epithet.
A summary of some recent notable studies:
- An FDA meta-analysis presented at CROI this year of randomized clinical trials — which avoids selection bias — finds absolutely no association with MI. Note that the analysis includes the studies in this ACTG report, and more.
- By contrast, a newly published observational VA study — including 11,000 patients, mostly men — demonstrates that among HIV therapies, only abacavir is associated with increased risk of cardiovascular events.
- Up in Montreal, here’s another study (n=7,000) with a positive association between abacavir and MI, this time along with several other antiretrovirals (including, oddly, efavirenz — marking the first time an NNRTI has ever been implicated in CV risk, and frankly raising more questions about study result validity than making me worried about efavirenz). Journal Watch coverage here.
- Meanwhile, the original VA abacavir study — the first one to introduce renal disease as an important possible cause of “channeling bias” back in Cape Town — has just been published, and this one includes even more patients (19,000) than the VA study cited above (I presume there’s some overlap). The result? It shows not only no significant association of abacavir with MI, but that abacavir is associated with a reduced risk of cerebrovascular disease (stroke).
- The editorialist commenting on the paper (Sam Bozzette) examines the numbers carefully and — somewhat surprisingly in light of the study findings — writes: “Moreover, the trends tend to support the controversial notion of a differential effect of abacavir [on MI risk]…”
- And what about that protective effect of abacavir on stroke seen in this study? A Danish study found just the opposite: on investigating possible risk factors for stroke among patients with HIV, the researchers showed that abacavir was associated with increased cerebrovascular events — and it was the only HIV treatment to earn this honor.
Got that?
Although it’s tempting to revert to the last refuge of the researcher, grant writer, and journalist — the generic “more research is needed” — I’m pretty sure we’ve reached a point of diminishing returns on these abacavir-cardiovascular disease studies, at least those of retrospective observational design.
And from a practical, day-to-day patient management perspective, in my view nothing really has changed despite these recent studies. It seems advisable to avoid using abacavir in patients with high cardiovascular risk if there are suitable alternatives (which there usually are), but that stable patients already on the drug should remain on it unless there’s a compelling reason to switch.
June 15th, 2011
Hockey Helicobacters
Today’s ID/HIV items come to you courtesy of a winter game being played during a summer month:
- So it appears that community-based care of HCV augmented by telemedicine is just as good as traditional clinic visits to specialists. My first thought on reading this important paper is that there are undoubtedly lots of ways to incorporate technology into patient care for the better, extending the reach of specialty services. But — and call me a cynic — if in a fee-for-service world, specialists get paid for services rendered during office visits, and not for setting up and managing telemedicine, which one do you think they’ll choose? To quote the editorialist: “It is also important to develop models for financing this innovative care model, with respect to both the specialists and the primary care providers involved.” Emphatically agree.
- Here’s a comprehensive list of sprout-related outbreaks, if you’re keeping score.
- In the flurry of recent drug approvals in the ID/HIV world — ceftaroline, nevirapine XR, rilpivirine, fidaxomicin [update: apparently not available until later this summer], boceprevir, telaprevir, generic zidovudine/lamivudine — I always wonder what the early anecdotal experience will be from experienced providers. Any first impressions? So far I’ve used ceftaroline and rilpivirine, not the others.
- Did you see this latest “scorecard” on states’ compatibility with the 2006 HIV Testing Guidelines? It includes three suggested key elements of HIV consent to facilitate testing: 1) changing from opt-in to opt-out 2) allowing general consent for care to include HIV testing, and 3) permitting written or oral consent. Good news: now only 4 states per this report have HIV testing laws outside these recommendations. In fact, there is only one state that is incompatible with all three components. And that state is … Massachusetts, thank you very much! (FYI, we’re working on changing this.)
- Can’t believe I missed commenting on this remarkable paper in Lancet ID, which clearly documents the clinical relevance of transmitted drug resistance, as well as the importance of baseline genotype testing in reducing the risk of treatment failure. It also hints that in the presence of any transmitted resistance, a boosted PI-based regimen might be the best choice, at least for virologic outcomes. Makes sense. Further commentary in Journal Watch AIDS Clinical Care here.
And as you watch tonight’s Stanley Cup final, and thoughts turn to winter, you might note that the 2012 CROI dates and location still have not been announced. Are the conference organizers awaiting the outcome of tonight’s game to decide where to go? Both Boston and Vancouver in February would be suitably cold options.
June 9th, 2011
E. Coli, ID Doctors, and Fear of Infections
This was going to be about the shiga-toxin-producing E. coli (STEC) outbreak in Germany, and I promise to get there eventually.
But to start: One very useful concept from psychiatry is “reaction formation.” For those of you who have forgotten your college Psych 101, here’s the definition:
A psychological defense mechanism in which one form of behavior substitutes for or conceals a diametrically opposed repressed impulse in order to protect against it.
Some examples: the person who controls criminal impulses by becoming a cop, or someone with a fear of heights who fixes cell phone towers.
How about ID doctors? Do some of us choose this field because we’re scared of catching nasty bugs?
Undoubtedly yes — I have one colleague who, at great personal expense, had all the windows, screens, and vents replaced in his house because he saw some bats flying around his neighborhood on a warm summer evening. He has been observed to wear a surgical mask when he looks in his patients’ ears (“just to protect you,” he lies), gets the tempura at sushi restaurants, and he wouldn’t travel to a developing country even if you gave him, for free, round-trip first-class airfare and the best suite in this resort.
He’d deny it, but I strongly suspect his choice of specialty is directly related to his fear of contagion. (That interpretation was gratis. You’re welcome.)
But then there are plenty of us who are relatively cavalier about infectious risks. In one famous example, a certain sainted ID doc (initials PF) never received vaccination for hepatitis A despite having probably the highest travel/work related risk on the planet. The result: a fairly prolonged hospitalization from acute hepatitis A. Boy was he sick. (Read all about it in this excellent book.)
Even more impressive, there are those who bravely volunteer for outbreak investigations, even for incredibly scary, mysterious, or untreatable diseases. Two recent examples that come to mind are SARS in China and the extensively drug resistant (XDR) TB cases in South Africa.
With the caveat that any self-reflection is likely to be biased, even in a highly psychoanalytic milieu (my father is a psychiatrist), I consider myself as one of those ID doctor on the less-worried side of the spectrum. I’ll take my chances with the bats (unless one actually bites me …), choose whether to eat or not to eat sushi based on taste (not because of infectious risk), and believe that most Travel Clinics cater predominantly to the worried-well — or, if you want to be less nice about it, the paranoid. Plus, I have never feared getting HIV from patients, even in the 1980s when we knew a lot less about transmission than we do today.
On the other hand, I doubt very much I’ll be raising my hand anytime soon to volunteer for on-site evaluation of an Ebola outbreak.
But getting back to this toxin-producing E. coli: here’s one infection that I do take pretty seriously — ok, I admit it scares me — and confess to being kind of rude about it.
You don’t want me at your cookout if you plan to serve hamburgers rare, as I will undoubtedly be obnoxious about sharing my fears not just with you but all the other guests as well. Maybe it’s because of stories like this one. Or perhaps because my wife has discussed with me a few truly harrowing examples of previously-healthy kids from her practice who ended up on dialysis. Or that antibiotics not only don’t help, they even increase the risk of disease. And yes, I also saw the movie “Food Inc.” (review here), which really does make you understand why ground beef in particular is so risky.
So as they investigate the source of this terrible outbreak in Germany — which appears to be non-meat related, at least based on what is known right now — do yourself a favor, and cook those burgers all the way through, and skip the sprouts. (I know burgers taste worse cooked this way, but most people don’t like sprouts anyway.) And take some comfort in the fact that at least in the USA, cases of STEC from the O157:H7 strain are actually down (Journal Watch summary here). Let’s hope it stays that way.
June 4th, 2011
HIV Epidemiology and Something Even Many Smart Medical Students Don’t Know
Periodically I like to give an informal quiz to the medical students about HIV epidemiology. It’s a multiple choice question that goes something like this:
Based on the recent epidemiology of HIV in the United States, in what group are new cases of HIV infection rising the fastest?
- Men who have sex with men (MSM)
- Injection drug users (IDUs)
- Heterosexual women
- Some other group
(Correct answer: #1.)
Now these are smart kids. Many of them have done impressive things before starting med school, including a bunch who have even worked in the HIV field (especially global HIV). Yet despite these brains and experience, you’d be amazed how often they choose the wrong answer, most commonly choosing #3 (a group in whom incidence is essentially flat or declining) or #2 (injection drug use HIV in the USA is, thankfully, disappearing).
On the 30th Anniversary of the first report of what is now known as AIDS, the MMWR has released its latest HIV Surveillance report. And, as in pretty much every year for more than a decade, here are the facts:
Surveillance data show that the proportion of HIV diagnoses occurring in MSM continues to grow. HIV incidence among MSM has increased steadily since the early 1990s. In 2009, MSM accounted for 57% of all persons and 75% of men with a diagnosis of HIV infection... Syphilis and gonorrhea are endemic among MSM; outbreaks or hyperendemic sexually transmitted infections have been reported from many communities where HIV infection also is prevalent, further increasing the risk for acquiring and transmitting HIV.
I’m not sure why this isn’t more widely known (certainly we HIV/ID specialists know it), but I have a theory. Sometimes a story has media “stickiness”, and once it’s out there, it’s hard to get rid of it. When AIDS first hit, it was overwhelmingly a disease of MSM and IDUs; quickly it became apparent, however, that it was a sexually transmitted infection so that women were at risk too. This was a big media story — famous Life Magazine cover shown above — and somehow this has never disappeared.
It’s kind of like, “tuberculosis is making a comeback in the USA” when, in fact, TB rates are historically low. The TB Comeback is just too sticky. Same thing with the generalized HIV epidemic in this country which, if you take a look at this incredibly cool map, has never happened.
Take home message: HIV prevention and testing efforts should be maximally deployed where the epidemic is still raging. Here in the USA, that means MSM and/or communities of color.
June 2nd, 2011
Original XMRV/CFS Paper Almost, Sort-of Retracted by Science
From the pages of Science
In this week’s edition of Science Express, we are publishing two Reports that strongly support the growing view that the association between XMRV and CFS described by Lombardi et al. likely reflects contamination of laboratories and research reagents with the virus … Because the validity of the study by Lombardi et al. is now seriously in question, we are publishing this Expression of Concern and attaching it to Science’s 23 October 2009 publication by Lombardi et al.
In the roughly year and half since this story first broke on XMRV as a possible cause of CFS, there have been literally dozens of scientific papers (published, unpublished, and presented), many editorial comments, conference proceedings — and probably thousands of blog posts (I’ve added to the traffic) and impassioned comments from people suffering from this condition.
As I’ve noted before, perhaps the best coverage in the non-medical/science press has been over here in the WSJ.
And while there is now significant “concern” about this XMRV/CFS association, there is little doubt about the need for more research on CFS. One problem is that the XMRV debate could become a distraction in the search for other possible causes, host factors, diagnostic tests, and treatments. Let’s hope that doesn’t happen.
May 23rd, 2011
Rilpivirine Approved — the “iPod” of NNRTIs?
From the FDA on Friday (it’s always on Friday, isn’t it):
FDA approved Edurant (rilpivirine) 25 mg tablets, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV. Rilpivirine is an antiviral drug that helps to block reverse transcriptase, an enzyme necessary for HIV replication. The recommended dose of rilpivirine is one 25 mg tablet once daily taken orally with a meal.
This approval comes as little surprise, as the large ECHO and THRIVE studies clearly demonstrated that rilpivirine (RPV seems to be the preferred abbreviation) was “non-inferior” to efavirenz as initial therapy.
More controversial were the details of the aggregate study results, which demonstrated a trade-off between antiviral activity at high viral loads (which favored efavirenz) and the overall safety and tolerability (which favored rilpivirine).
So how will clinicians use the drug?
The answer may be like the debate about iPods (and CDs vs records before that, boy I am showing my age): Audiophiles knew that the compressed sound required for iPods led to inferior sound, but the new devices were so easy to use that in most cases it didn’t really matter. Today CDs are rapidly on their way out.
So is RPV the iPod of NNRTIs? Both better and worse than current options? Maybe — that would be the best case scenario.
But if the complete iPod effect is going to take place, we probably need the single-tablet formulation of TDF/FTC/RPV, which is currently under development.
May 18th, 2011
HIV Exceptionalism and the Department of Unintended Consequences
Quick question: If there were one piece of information — clinical or lab — that you would use to determine the quality of care in an HIV 
program, what would it be? (Choose one.)
- Rates of influenza vaccine administration
- Receiving PCP prophylaxis with CD4 < 200
- Adherence counseling before starting antiretroviral therapy
- Baseline toxoplasmosis serology
- Proportion of patients on treatment with suppressed viral load
Maybe I’m being presumptuous here, but one of these — virologic suppression — completely blows the rest of them away. Sure, the others are worthwhile, but data linking them to improved outcomes for people with HIV are either pretty weak (adherence counseling, flu vaccine) or nonexistent (toxoplasmosis serology).
Even the use of PCP prophylaxis for CD4 < 200, which was highly effective and prolonged survival in the pre-ART era, doesn’t come close to the benefits of effective ART. One paper even questions whether we need it, provided that the person is on fully suppressive HIV therapy.
So why bring this up under the title of “HIV Exceptionalism”? Because a certain unnamed institution in an unnamed city (hint: begin with “B”) cannot obtain the aggregate viral load data on their own patients as part of a quality improvement initiative.
The reason? Anything with “HIV” attached to it, you see, is privacy-protected information under Massachusetts Chapter 111, Section 70F, unless the patient provides written informed consent. No exceptions listed.
Which means that people with HIV can’t participate in this quality improvement program — in effect, are discriminated against — due to a law that in the post HIPAA era should not even be necessary, since all medical information is now considered confidential.
The state law on HIV testing and privacy, by the way, dates back to when HIV was called “HTLV-III”, and it’s showing its age. Fortunately, revisions to it are in the works that allow for appropriate testing, clinical care, research, and quality improvement.
Stay tuned.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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