An ongoing dialogue on HIV/AIDS, infectious diseases,
December 19th, 2008
Infectious Disease in the ICU: Help Please? Part I
I am currently attending on the inpatient service, which means I spend a good chunk of my day seeing new ID consults and rounding on follow-ups. As I’m sure is true in most hospitals, many of these consults are from the intensive care units (ICUs).
After 18 years in this ID business, I confess I still find myself quite challenged by ICU Infectious Diseases. It’s not due to the complexity of the cases, in fact just the opposite — paradoxically, there’s a sameness to the cases that is worlds away from the wonderful variety of ID/HIV elsewhere: the outpatient with fever of unknown origin, or the inpatients with endocarditis, meningitis, orthopedic infection, HIV-related complication, or tropical fever (the stuff that makes up much of the rest of the consult volume). One intensivist says that once patients get past the first few days after admission, most of the medical issues they face are similar.
From the ID perspective, this means “rounding up the usual suspects,” including searching for line infections, UTIs, C diff, sinusitis, pancreatitis, surgical site infections, acalculous cholecycstitis, drug fever, infected pressure ulcers and — especially — nosocomial pneumonia.
There’s a sameness to these investigations that makes individualizing care difficult, and often forces us to focus on the (abundant) microbiologic data as distinguishing characterisitics. Just how resistant are the bacteria isolated from this patient’s respiratory sample? How many different possible pathogens can be cultured from a surgical drain? What is the significance of candida isolated from several non-sterile sites? How about those few colonies of coagulase negative staph on a removed line tip?
So where to go for help? For a comprehensive “how to” for this patient population, check out the recent IDSA/American College of Critical Care Guidelines. It’s an impressive document.
And give yourself plenty of time — it’s 20 pages long, and has over 200 references.
(In Part II, the issue of empiric antibiotics in the ICU.)
December 5th, 2008
New Case Definition for HIV Infection? Yawn …
The CDC has revised its case definition for HIV infection and AIDS, so that now laboratory evidence — a positive antibody test, or detectable HIV RNA or DNA – is required for the diagnosis.
It’s not intended to guide clinical practice, but still — what took them so long? A clinical diagnosis of AIDS was only necessary before HIV had been discovered. I cannot imagine someone reporting a case of AIDS or HIV infection without a positive blood test, especially since there have been several well-publicized cases of erroneous HIV diagnoses when laboratory confirmation was unavailable, or not performed.
So good move here, glad the epidemiologists have caught up. And nostalgists may enjoy reading prior versions of various AIDS case definitions here.
December 4th, 2008
More Support for HIV Screening
On Monday December 1 — World AIDS Day, if you’re keeping track — the American College of Physicians released a position paper supporting routine HIV screening for adolescents and adults in the United States.
(If you don’t want to read the whole thing, we’ll have a perfectly-executed summary by the inimitable Abbie Zuger on our AIDS Clinical Care site any day now; it’s been written, but somehow getting material up there is harder than it is here. Go figure. UPDATE: Now you can read it here.)
In essence, these ACP Guidelines are highly concordant with those issued in 2006 by the CDC: One-time testing for adults in health-care settings. Frequency of repeat testing to be determined by risk assessment.
This leaves the US Preventive Services Task Force as a mild voice of dissension about the issue of HIV screening, as it neither endorses nor discourages routine screening. The USPSTF does recommend screening “at-risk” populations, a useful strategy but one that still leaves a substantial proportion of HIV diagnoses undetected.
Meanwhile, the number of states still requiring written informed consent for HIV testing continues to fall …
November 30th, 2008
How to End the HIV Epidemic
Answer: Put everyone on treatment.
Conspicuously absent for decades, the prevention part of the “when to start antiviral therapy?” question has now moved front and center in two recent papers:
- In this week’s Lancet, a group from the WHO estimated what would happen if there were annual universal HIV testing, and then immediate treatment for all found to be positive. They used South Africa — the country with the highest number of HIV cases — as a test case, and assumed heterosexual transmission of HIV. After going through the usual gyrations required in such mathematical models, they found that such a treat-everyone strategy would shift the HIV epidemic in South Africa from its current (dismal) phase to an “elimination phase” — with an ending to the epidemic feasible by 2020.
- This summer, researchers from Vancouver (of course from their Excellent “Centre for Excellence”) published a paper with largely similar findings — this time applied to an epidemic that is more typical of developed countries, predominantly made up of gay men and injection drug users. As with the WHO/South Africa paper, there would be a high up-front cost of expanding therapy, but ultimately costs would be lower because of averted infections.
The treatment-as-prevention theme, of course, got off to a roaring start this year when the Swiss National AIDS Commission issued a statement saying that people with HIV who are adherent to antiretroviral therapy, have undetectable plasma viral loads, and have no sexually transmitted infections are not infectious to others.
Very bold — especially for a country famous for chocolate, watches, and fondue.
While the certainty of this statement struck some as extreme, and others as bordering on arrogant — and this single case report is an example of how doctors should “never say never” — the principle behind the Swiss statement was sound, and quite helpful in getting the conversation started. Treatment can be prevention, and this is something we should discuss with each of our patients when reviewing the pros and cons of going on therapy.
November 25th, 2008
Coming Soon: A Great Advance in TB Diagnostics
An all-too-frequent problem in the ID clinical world is the case where tuberculosis is possibly the diagnosis, but confirming it is difficult, or impossible.
Now, in a scientific breakthrough of such magnitude that it warranted front page coverage in our local newspaper, I am pleased to report that we may have a solution: giant rats.
Yes, giant rats. In a pilot program in Daar es Salaam, rats evaluate saliva samples at a rate of 40 every 10 minutes, signaling with “unmistakable paw motions” when they detect a sputum infected with TB.
And here’s a bonus — they can also sniff out land mines, in case you happen to need that service too.
No doubt these critters will be showing up in our microbiology labs any day now. I can’t wait to read the OSHA regulations for their protection.
November 22nd, 2008
“Salvage” Rx for HIV: Macro Good News, Micro Bad News
I’ve written before how the number of treatment experienced patients who have no options for successful therapy has dwindled to a tiny — but unfortunate — few. Darunavir, maraviroc, raltegravir, and etravirine (in order of FDA approval) are that good.
Two presentations at recent scientific meetings confirmed the staggering efficacy of these newer drugs. Notably, both described response rates that exceeded what was reported in pivotal phase III studies — telling us that if anything, results in clinical practice will be better than in the trials, likely because a broader range of drugs is now available to the prescribing clinician. (By contrast, patients in the MOTIVATE studies of maraviroc couldn’t use darunavir — not yet approved.)
First, this summer at the IAC meeting in Mexico City, a French group described a 90% virologic suppression rate (< 50 at 24 weeks) for 103 patients with triple class resistance receiving raltegravir, etravirine, and darunavir (sometimes with other agents). Second, more recently at ICAAC, a group from Kaiser Permanente reported that 50 out of 53 patients in their etravirine expanded access program were virologically suppressed — many of whom did not even have full susceptibility to darunavir or etravirine.
Wow.
Which brings me to an e-mail I received this week which included the following chilling piece of information:
He has rather resistant virus, and has been on Truvada, Darunavir, Ritonavir, and Raltegravir. His most recent viral loads were 450 then 920 …
Needless to say, my response included a comment that the rising viral load on a raltegravir-based regimen was “worrisome”.
In addition, a patient who is a typical raltegravir success story from our practice — high-level triple class resistance, never previously virologically suppressed, but HIV RNA undetectable for now 2-plus years — had a viral load come back recently at nearly a thousand. (He says he had a cold.) Confirmation of this result is pending (I like to wait at least a couple of weeks before repeating these) so of course this could just be a mega-blip, but needless to say I’m worried about him too.
With the disappointing news on bevirimat presented at ICAAC — showing that some 40% of individuals harbor a polymorphism in the gag region of HIV that makes their viruses essentially resistant to the drug — we don’t really have promising drugs in the pipeline for this group of individuals, however small that group may be.
Let’s hope this precarious state of affairs is a temporary one.
November 17th, 2008
Promising C diff Rx, and Google as Surveillance Tool
A few items from recent ID/HIV news:
- Bad enough when it happens once, relapsing C diff is one of the modern plagues for which our bag of tricks sometimes comes up woefully short. (Anything that tests stool transplants as a therapy is pretty desperate.) Here was some bright news on the treatment front, however: an experimental drug named OPT-80 was just as effective as vancomycin, but with a lower rate of relapse (13% vs 24%). What kind of drug is OPT-80? Why, it’s a “macrocycle” (first I’ve heard of them, I confess), and has shown focused activity against gram positive anaerobes only — including C diff. Sounds ideal for this indication.
- Google has quietly convinced us it can do just about anything, so why not influenza surveillance? By the way, note how they switched from “google.com” to “google.org” for their philanthropic activities. Does that not-for-profit designation mean they are the future Gates Foundation, ready to offer vast sums to solve global health problems? Or is it just a subtle PR move? Likely some combination, but I like the idea of their putting their technology skills to the public good.
- I guess Tony Fauci and Robert Gallo were none too impressed with that “cured” case of HIV recently in the news. Oh well, I guess it takes a lot to impress you when you’ve been at this HIV/AIDS game from the start. Still …
November 10th, 2008
Yes, Just a Case Report, but Incredibly Cool
At this year’s Retrovirus Conference (was it really this year’s conference, seems like much longer ago than that), there was a poster presentation summarizing a very unusual case. A man with HIV, stable on antiretroviral therapy, developed acute leukemia. He underwent an allogeneic bone marrow transplant — here’s the kicker — from a donor who was homozygous for the CCR5 delta 32 mutation. In other words, the donor’s CD4 cells were all but resistant to infection with CCR5-tropic virus.
All antiretrovirals were stopped at the time of transplant, and — amazingly — no rebound in HIV viremia occurred for a year. No virus found in plasma or PBMCs; no HIV found in bone marrow or in rectal biopsies. He remained HIV seropositive, but the virus was nowhere to be found.
When I presented this single case in summaries of the highlights of this year’s CROI, inevitably the response was astonishment, even though it was just one case. But then the case disappeared from view, and I don’t believe it has been published yet in a peer-reviewed journal.
Now the story has been updated in the Wall Street Journal — the patient is now off antivirals for over 600 days, still no virus rebound. Today it’s the most e-mailed piece in the Journal.
Just a hunch, but I think this is the closest thing we’ve come to a cure for HIV infection. Granted, it’s not practical to offer bone marrow transplants to the 33 million or so people infected with HIV in the world, never mind the difficulty of finding donors who are appropriate matches and have the delta 32 mutation (the mutation occurs in only approximately 5% of individuals, and is even rarer in persons of African and Asian descent).
Regardless, if ever there were a plausible target for gene therapy, the CCR5 delta 32 mutation seems like a great place to start.
November 2nd, 2008
The Big HIV News from ICAAC/IDSA
Tons of interesting stuff at this year’s combined ICAAC/IDSA meeting, most of it in non-HIV related Infectious Diseases. In aggregate, literally hundreds of posters, presentations, and symposia on MRSA, C diff, osteomyelitis, complicated UTIs, hospital-acquired pneumonia, antibiotic resistance … It’s a great meeting to catch up on general ID, and the literature review sessions alone are practically worth the price of admission.
But there are almost always a few major HIV-related studies presented as well, and this year was no exception. These two understandably got the most attention:
- Early antiretroviral therapy increases survival [Kitahata H-896b]. The NA-ACCORD study compared all-cause mortality among more than 8,000 patients with HIV followed since 1996. Compared with those starting therapy with a CD4 cell count between 200 and 350, patients starting with CD4s between 350 and 500 had a 70% reduction in the risk of death. Wow. [Addendum: Our astute editor at AIDS Clinical Care points out that this is really a 43% reduction, as the relative hazard for mortality for the group deferring is 1.7. Still wow.] Usual caveats on the limitations of cohort studies apply, but this was a very well done study with a huge sample size; its conclusions were further bolstered by the observation that virologic suppression rates did not differ between the two groups — implying comparable levels of medication adherence. Stay tuned for a similar analysis of those starting with a CD4 > 500 cells — whispers that we’ll see this info at next year’s CROI in Montreal. Will this be the final word on the “when to start treatment” question we’ve been debating now for two decades? Should pretty much every patients with HIV be on therapy? What will happen to the planned “START” randomized trial? I sense unless something truly unanticipated happens with drug toxicity, we’re going to be starting a lot of asymptomatic patients on treatment over the next few years.
- Raltegravir vs efavirenz as initial therapy [Lennox H-896a]. Can something be as good as efavirenz (essentially our current gold standard) for initial therapy? Apparently yes — raltegravir was “non-inferior*” to efavirenz when combined with TDF/FTC in a large phase III, double-blind study: Virologic suppression rates at 48 weeks were 86% for RAL compared to 82% for EFV. There were also lower rates of drug-related averse events in the raltegravir arm, with protocol-specified CNS toxicity occurring in 18% of efavirenz and 10% of raltegravir-treated subjects. We’ve been using the 2NRTI + NNRTI or PI approach as initial therapy for a long time — here at last is a new approach.
And for the record, I’m a big fan of this combined ICAAC/IDSA meeting, but it will be separate for at least the next two years at least. Oh well.
*The use of the term “non-inferior” always sounds like pedantic statistics-ese to me. 86% “non-inferior” to 82%? But it does mean something specific — best described to me as “not too much worse than”, with “too much worse” generally defined as within 10-12%. But the lower-limit of the 95% confidence interval can’t be below this 10-12%, and that’s where peculiar statements such as “86% is noninferior to 82%” come from.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
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