An ongoing dialogue on HIV/AIDS, infectious diseases,
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.
October 27th, 2008
Antibiotics as Placebos?
(Not an ad.)
This article in the BMJ is geting lots of news: Out of 679 practicing physicians in the United States, about half admitted to prescribing placebos on a regular basis. A “small but notable proportion (13%) of physicians reported using antibiotics.”
My first instinct was surprise that the rate was this low, but then I remembered that public perception of this practice might not be so favorable. As a result, the appropriate MD response to this news is to be “shocked, schocked …” that placebos are being prescribed, and to express grave concern at the ethics of the practice. So undoubtedly some of the doctors surveyed in that study probably didn’t tell the truth.
From an ID perspective, reading that antibiotics are sometimes used as a placebo is hardly news at all. Since about half of the US population believes that antibiotics are helpful for the common cold, all a clinician has to do is prescribe a Z-pack for a runny nose to a patient expecting antibiotics, have that patient get better (colds do, after all get better eventually), and the practice is reinforced. This exact exchange must transpire hundreds of thousands of times a day in doctors’ offices and emergency rooms.
I’ve written here about one potential cure for this problem (C. diff), but it’s not exactly something you’d want instituted as a preventive measure.
Is there a way to exploit the placebo’s powerful effect in clinical practice that doesn’t seem so sneaky? And doesn’t expose patients to medication side effects? Here’s one: Our office has a terrific coffee/tea maker, and I’ve found that handing a patient with a bad cold a cup of freshly made green tea in a nice mug works wonders. I don’t believe we ever covered that in medical school.
October 18th, 2008
Back to School, Day 2
During the course, often the best questions and anecdotes come during the breaks. Here are a few:
- Tons of questions about our favorite nemesis, MRSA. What works for chronic carriers? How do you manage family members who you suspect would be culture-positive (and the source of recurrences), but are not your patient? What if the vet won’t culture the family dog? What are the guidelines for infection control in the outpatient setting? What is the best non-linezolid (which still costs > $150/day) oral antibiotic? What’s the right dose of trimethoprim-sulfa? (Many advocates for two double-strength tablets twice daily.) Number of definitive answers to any of the above questions? None. I guess misery loves company.
- A primary care MD working at a college health clinic gave me some insight into just how far we still have to go to make those revised HIV testing guidelines a reality. In this campus-based practice, if one of the students requests an HIV test, or the clinician thinks an HIV test is indicated, several restrictions are in place that go way beyond the state-mandated requirement for written informed consent. First, extensive pre-test counseling is required; second, only one of the providers is allowed to order the test (so the student must return to see that clinician if he is not available that day); third, mention of HIV testing in the medical record is forbidden; and fourth, the results of the test do not appear in the student’s chart. (They are kept in some locked remote location, no doubt.) Hey, can we stop this madness already? Is there any evidence that such policies help anyone? (The MD at our course was complaining about them, not surprisingly.) Of note, the revised HIV testing recommendations — explicitly outlining the rationale for eliminating barriers to testing — are now over two years old.
- Only two course participants thought I was Paul Farmer. Interestingly, one of them thought I was Paul Farmer immediately after he gave his lecture, during the coffee break, when the real thing was standing right across the room. My clue she had the wrong Paul Edward was when she told me my work inspired her to apply to medical school when she was growing up in Port-au-Prince. There are definitely worse people one could be mistaken for — back when I had more hair (lots more hair), someone thought I was a dead ringer for this guy. Yikes.
October 15th, 2008
Back to School, Day 1
We offer two post-graduate courses each year, one entitled Infectious Diseases in Primary Care, and the other AIDS Medicine: An Intensive Case-Based Course. The Primary Care one started today, the AIDS course starts on Monday.
(Both are equally fascinating. I am entirely unbiased.)
What is so striking is that the participants — and content — barely overlap at all. Topics for primary care course:
- Antibiotics
- UTIs
- Pneumonia
- Sore throats/colds
- Immunizations
You get the idea. For the AIDS course?
- Acute HIV infection
- Management of treatment-naive patients
- Interpretation of resistance testing
- Metabolic complications of therapy
- Legal and ethical considerations of HIV care
I suppose I should not find the lack of overlap surprising, given papers such as this one, citing that 62% of family practitioners refer their AIDS patients to specialists immediately — a big change from 1994, when only 18% did. (Even 62% seems low …)
But the irony is that with improved antiretroviral therapy — the very thing that drove some generalists away from HIV care due to its complexity — HIV patients are living longer, and hence are in greater need of the kind of care delivered best by primary care clinicians.
So maybe what we really need is a primary care course for HIV specialists?
October 8th, 2008
The French Win This One
The 2008 Nobel Prize in Medicine goes to and
For the record, if you search the Nobel press release for the word “Gallo”, you won’t find it mentioned anywhere.
Why is this notable? Seems like ancient history, but actually two groups in 1983 claimed they discovered the virus that causes AIDS, both finding a human retrovirus — the one we now know as HIV. The French group called it “lymphadenopathy-associated virus” or LAV, and the Americans (led by Robert Gallo) “human T-lymphotropic virus III” or HTLV-III. We now know it was the same virus — indeed, due to “lab contamination,” sometimes literally the same — and that the French were first, but maybe (am being generous here) the Americans were a bit more practical (and certainly louder) about the implications of the discovery.
An academic truce of sorts ensued many years later — this was much less entertaining, but perhaps a good thing for international relations, at least until “Freedom Fries.”
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
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