An ongoing dialogue on HIV/AIDS, infectious diseases,
April 6th, 2009
Delayed Opening Day Videos, and More
Some random HIV/ID issues while awaiting a delayed opening day here in cold, rainy Boston:
- If you enjoy video highlights, check out these of HIV making its way from T cell to T cell. If you’re short on time, #’s 9-12 are particularly amazing. Still, I don’t imagine that this video will make it to Youtube anytime soon:
Transfer of an entire synaptic button to the CD4+ target cell. Image is an overlay of brightfield image and green fluorescence in a maximum intensity projection of the acquired stack.
(Hat tip to J Li for the link.)
- NA-ACCORD lands, to be published in print April 30th. After a major study has been presented at a meeting twice, discussed extensively and digested, I sometimes wonder, what is the impact of actual publication? Here I’d suggest reading the fine print, as the published paper does differ in some major ways from what was presented last year at ICAAC and this year at CROI: the beneficial effect of starting earlier (with CD4 > 500) was even greater than reported earlier, but the groups who did start early differed (significantly) from those who deferred. The study’s impact on clinical practice? We’ll see, but I suspect it will be substantial given the other data supporting earlier treatment.
- Bats have an image problem. A mysterious illness — white nose syndrome — is decimating the bat population, and no one cares. Why am I not surprised? Money quote:
To a public raised on vampire movies, bats are loathsome, frightening creatures – blind, flying rodents that all carry rabies, suck human blood, and get impossibly tangled in long hair.
(They said it, not me.) Turns out that to garner support for animals, “cuteness rules” — which means that causes for polar bears (global warming) and toucans (rain forests) get much more sympathy (and $$$) than bats.
- But I love pistachio nuts! Oh well.
March 31st, 2009
Infectious Disease in the ICU: Help Please? Part II
In Part I of this topic, I commented on the ironic sameness of ICU Infectious Diseases — that incredibly sick, complex patients entered the ICU with vastly different problems, then over time, seemed to converge, presenting similar kinds of clinical issues and management challenges for the ID doc.
Or, as a visiting medical student said to me, “My ICU attending said that every patient in the ICU should be on vanc/Zosyn.”
Which brings up the issue of empiric antibiotics. On the one hand, there’s the hard-line view that we should only be giving antibiotics for clinically or microbiologically confirmed infections. All antibiotics have side effects, they select for ever more-resistant flora, and may diminish the accuracy of our diagnostic tests. In one commentary on this issue, the author wrote:
The indiscriminate use of antibiotics substantially contributes to the “spiraling empiricism” that characterizes contemporary medical therapy… Broad spectrum systemic antibiotics have become the specific treatment of fever. When I was a medical student, the medical residents taught that cephalothin was the “antipyretic of choice” …
–snip–
The decision to withhold or discontinue antibiotics, however, necessitates an extensive and compulsive physical examination and personal review of all the pertinent evidence (gram stains, urinalysis, radiographs, laboratory values). Critical historical data should be confirmed. Patients must be turned and wounds undressed. Less exhaustive evaluation is inadequate.
Yes, well…. but this view, less elegantly stated, risks sounding like ivory tower medicine at its worst, and brings to mind the sad truth that withholding antibiotics is one of the few things an ID doctor can do to sound macho.
Critically-ill patients with fever should receive some sort of empiric broad-spectrum coverage, at least initially. As one of our fellows just asked me, once the diagnostic evaluation has been done, what else can we offer them? We’ve all been in that uncomfortable position of suggesting that antibiotics be withheld or stopped, then have that critically-ill patient later develop a life-threatening bacterial infection.
Sure, it may have happened anyway — these are highly susceptible hosts, after all — but it just feels worse when it’s done without antibiotics on board. Let’s hope our diagnostic studies in these patients can improve, because absent better testing, I’m afraid we’re going to be stuck with lots of “spiraling empiricism.”
March 25th, 2009
March (Guideline) Madness …
A couple of interesting ID guidelines out this week. For those of you too busy with basketball, here are the relevant links:
- Guidance for Control of Infections with Carbapenem-Resistant or Carbapenemase-Producing Enterobacteriaceae in Acute Care Facilities. Identified in 24 states and now found “routinely” in New York and New Jersey, these carbapenem-resistant Enterobacteriaceae (“CPE” is much easier to write and say) are resistant to virtually every available antibiotic. Although these guidelines say that micro labs must do the so-called modified Hodge test (MHT) on enteric gram negatives that have elevated MICs to carbapenems — but still are within the susceptible range — it’s been shown that ertapenem resistance provides a surrogate marker for this carbapenemase production. Nice recent review of the (scary) topic here; quick summary of the guidelines here.
- Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. This massive tome (only 207 pages, 1,391 references) was originally released in an on-line version this past summer at aidsinfo.nih.gov, and I commented on it then in AIDS Clinical Care. It is an absolutely critical resource, so valuable that I’ve referred to it numerous times since then. But to spare you the task of reading through the whole thing again for revisions, I have gone right to the source — one of the people closely involved in putting the guidelines together — and asked him, so what’s changed since the summer? Here’s his answer: “The current published document notes that in HIV-infected adults who need treatment for HBV infection, treatment for both HIV and HBV infections should be initiated regardless of CD4 cell count. For persons who wish to defer HIV therapy, only anti-HBV agents without any HIV-activity should be used. Oh yeah, and some typos were corrected.”
Happy reading.
March 20th, 2009
Hair Today, Gone Tomorrow …
Since providers — especially doctors — are notoriously poor at predicting medication adherence, here’s some good news: In a paper from the Women’s Interagency Health Study, protease inhibitor levels in hair samples were the strongest independent predictor of virologic success — better than self-reported adherence, age, race, baseline viral load and CD4 cell count, and prior experience with protease inhibitors.
That’s not all: Dr. Monica Gandhi (the lead investigator) describes the technique:
“We collect a small sample of hair from the back of their head and by small I mean 10 to 15 strands. So we collect after about a month of therapy a small thatch of hair from the back of your head and then grind it up and measure the anti-retroviral in that hair. And that gives us an idea after you start a new regimen whether you have enough in your system,” she says.
And in case you were wondering (were you?):
“One thing that people ask is can we use pubic hair for these measurements. And we don’t think that those are going to be useful because hair in those areas grow to a certain length and then they stop, which is great for anyone who has this hair. But you really want to measure hair that’s sort of growing continuously and that’s really scalp hair,” she says.
Every so often I’m reminded that HIV medicine isn’t like other fields — and that paragraph says it all!
(Hat tip to R Plank for the reference.)
March 14th, 2009
Maybe It’s Not the Cheeseburgers
… At least that’s the implied message in this nice paper from the latest Annals of Internal Medicine, which evaluated responses to lipid-lowering therapy among patients with and without HIV.
The study included patients from the Kaiser Permanente of Northern California integrated health system, with 829 individuals with HIV and 6941 without.
The quick summary is that those with HIV responded less well to lipid lowering drugs than the HIV negative patients — something that comes as no surprise to HIV providers, as we’ve scratched our heads for years while various statins, fibrates, and omega-3s have made barely a dent on some pretty scary lipid profiles.
There were a couple of other key take-aways from the paper. Pravastatin — which just happens to have the fewest drug-drug interactions with HIV drugs — was less effective than other statins. (Oh well.) It’s been fairly unanimous among cardiologists I’ve spoken with that they consider pravastatin a fairly wimpy lipid-lowering drug.
In addition, those on boosted PIs had a blunted triglyceride response to gemfibrizol compared to patients on other forms of HIV therapy. These are, of course, the very people who need triglyceride-lowering the most!
In practice, most patients on a boosted PI are on it for a reason — resistance, contraindications or intolerance to other drugs — so switching them off of it is rarely straightforward. (See this cautionary tale from CROI.) Regardless, we can certainly include “lipid friendly” in our list of desirable attributes for the investigational PK boosters.
March 10th, 2009
Unwelcome Visitor: Cost of HIV Meds
Those of us who practice HIV medicine in Taxachusetts (warning, click link at your peril) live a pretty charmed life, at least so far as getting HIV medications paid for. Due to an incredibly generous AIDS Drug Assistance Program (ADAP), rare is the patient who faces financial barriers getting his or her drugs.
(By the way, we abbreviate it “HDAP” here, not ADAP. And we treat early syphilis with two shots of penicillin, not one. And we voted for McGovern. And we drive on the left.)
But the recent downturn in the economy has changed this usually comfortable situation in the Bay State.
A patient of mine called to tell me that his co-pay for a 3 month supply of his antivirals is now nearly $2000. Another one has simply stopped coming to appointments, as his wife’s insurance has such a large deductible that he will only agree to blood tests, not an actual office visit. A third asked me whether he would be better off stopping enoxaparin or his HIV meds, since he couldn’t afford both.
I am sure things are much worse in other States — after all, Houston’s Joe Gathe initially tried lopinavir/r monotherapy since he reasoned that some ART was better than none, and his patients couldn’t afford triple-therapy.
Where is this headed? It’s tough to make predictions (especially about the future), but I suspect that when 3TC and saquinavir become generic, we might be turning to them more often than we’d previously thought.
March 4th, 2009
TaqMan HIV RNA Assay: Be Careful What You Wish For
At our hospital lab, we recently switched from the bDNA viral load assay to the new Roche TaqMan real-time PCR test. The virologist in charge of our lab and the tech both agreed the assay was more accurate, more sensitive, and easier to do — so much so that we could increase the frequency of the test being run, a huge benefit for patient care. I was all for it.
So what’s the problem? As noted here in this paper from Vancouver — and anecdotally throughout the world — there’s a new epidemic of intermittent low-level viremia picked up by this assay. Every week, another one of my long-term successfully treated patients has a result come back at 125, 94 or — most cruelly — 49. (The lower limit of the assay is 48.)
Plus, there’s that issue of “<48 (viral RNA detected but below the quantifiable range of the assay)” vs “Target not detected.” Try explaining that to an obsessive patient who heretofore had been happily receiving “undetectable” viral load results through a decade of meticulous pill taking.
One view is that these are not “false positives”, but rather represent actual detection of virus though this more sensitive assay. (The Vancouver group is not so sure — read the discussion section in their paper.)
But if these small detections of HIV RNA are real, is there a clinical significance to it?
Based on the kinds of patients in whom we are seeing these results — many on first regimens, many with no history of treatment failure — I suspect the answer will be no. These low-level detectable results could be analagous to the low-level detection picked up by the single-copy assay — just a harmless release of virus from long-lived chronically productive cells, and not actual viral replication.
Or to quote my esteemed colleague:
I believe we will eventually come to recognize two related but distinct situations–patients may be “fully suppressed” — that is, have no actively replicating virus — but may or may not be “aviremic”.
So I feel a bit better. Nonetheless, if you’re planning on introducing TaqMan into your clinic, prepare yourself for some significant patient education, reassurance — and stress management.
February 26th, 2009
Meningococcal Resistance to Ciprofloxacin
Ciprofloxacin-resistant Neisseria meningitidis has now been documented in the United States. Here’s a nice summary in Journal Watch, with two different perspectives.
I suppose we shouldn’t be surprised, but it did take a while. (At least compared to that other famous neisseria-bug, Neisseria gonorrhoeae.)
Oh well.
Why is this important? As every practicing ID doc/primary care provider/public health official knows, nothing strikes fear into a community quite like a case of invasive meningococcal disease. Since household contacts of these cases have a many-fold increased risk of developing the disease, preventive therapy is recommended for any close contact — with “close” being defined nicely by one infection-control practitioner I know as “coughing distance.”
But we all know that prophylaxis extends way beyond this — not surprisingly, many more people request and get preventive therapy than actually need it, and in part this is because it’s so easy to do: a single dose of ciprofloxacin.
Now this needs to be reconsidered. Although it’s up to each local department of health to determine the recommended preventive therapy, I suspect it won’t be long before we’re all back to rifampin (four doses over two days, drug interactions) or a shot of ceftriaxone (ouch).
February 13th, 2009
CROI 2009: Greatest Hits
Fresh back from lovely Montreal, where the temperature (I’m glad to report) climbed into the balmy 40’s …
Here’s a rapid-fire listing of the Greatest Hits. As I’m sure to be leaving something off this list, happy to accept other suggestions:
- Interleukin-2 does not work. The ESPRIT and SILCAAT studies are over. Yes, the CD4’s increase, but compared to antiretroviral therapy alone, there’s absolutely no clinical benefit, and plenty of side effects.
- Should we be starting antiretroviral therapy at even higher CD4s? At ICAAC, the NA-ACCORD group said starting before 350 improved survival; here they said it was 500! The ART-CC disagreed, slightly (their estimate was around 350).
- Switching from lopinavir/r to raltegravir increases the risk of virologic failure in suppressed patients. Likely explanation: undetected NRTI resistance at baseline. This study should have no bearing on the use of raltegravir in either treatment-naive or treatment-experienced patients — essentially, the drug must be used with at least one other fully active agent. (Oh yeah, the lipids improved, not surprisingly.)
- Treating HIV during TB treatment increases survival compared with waiting until TB therapy is completed. One of the most interesting things about this study is that TB treatment outcomes were similar — but those who delayed therapy obviously had HIV disease progression. By contrast, a small study of cryptococcal meningitis from Zambia suggested that early ART was harmful — the first time early ART has been associated with worse outcomes.
- Treating HIV significantly reduces the risk of HIV transmission to a seronegative partner. This study from Zambia and Uganda involved nearly 3000 discordant couples (!), and the effect was dramatic — especially when one considers that HIV therapy was only given if clinically indicated (i.e., not to prevent transmission).
- …But the risk of transmission is not zero. Some studies showed persistent HIV shedding in semen despite effective antiretroviral therapy. No surprise — but this doesn’t diminish my enthusiasm for #5 above, as the reduction in risk from treatment is huge.
- Antivirals and cardiovascular disease. D:A:D is updated, and continues to implicate abacavir, and a French Hospital Database study does the same — and both now cite lopinavir/r as associated with increased risk as well. An ACTG database study does not find an association with abacavir, but a prospective randomized switch trial (to ABC/3TC or TDF/FTC) does — in the updated analysis, the difference was statistically significant. Regarding abacavir, pathogenesis studies were all over the place — split about evenly whether positive or negative. Peter Reiss gave a sensational summary on this complex issue — web cast highly recommended if you have 15 minutes to spare.
- Lopinavir/r is better than nevirapine for women who previously received single-dose nevirapine. This might seem intuitively obvious, but it answers an important question that has generated enormous controversy over the years. (Plus the first author is a beloved colleague.)
- Two non-ritonavir boosters are introduced. (Details here and here.) Yes, data are early, but something without the GI and lipid effects would be welcome indeed. Whether we really will need PK boosters at all remains an open question, but for now they clearly are needed for PIs and the investigational integrase inhibitor elvitegravir.
- A microbicide works. Sort of.
So what’s missing? Not a single phase III study of a novel agent, nor a phase IV comparative trial of existing drugs done in the developed world.
Yes, it’s a very “quiet” phase in HIV drug development — too quiet. If this poster is a harbinger of what’s coming with integrase resistance, let’s hope it’s not quiet for long.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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