An ongoing dialogue on HIV/AIDS, infectious diseases,
December 11th, 2011
An Unlikely Interviewee Discusses “Six-Class” HIV Drug Resistance
He’d never acknowledge it, but in our field, it’s no secret this guy is something of a rock star.
I can think of several key principles in HIV pathogenesis and treatment that he and his research group have discovered, or elucidated most clearly, or simply explained the best — largely through his unique ability to link smart clinicians and laboratory scientists.
In other words, translational research at its finest.
Note I’m not using his name, since he’d definitely not approve of of any of this. Which is why I was particularly lucky to get him to agree to this interview, where we discuss those patients who, despite our numerous treatment options, are unfortunate enough to have HIV that is resistant to everything. “Six class” antiviral resistance.
No, he didn’t agree because I have incriminating photos or other dirt. But he owed me, since I was able to give him the correct date for his lecture at IDSA — the date was changed, and no one told him. (A recurrent nightmare of mine, by the way.)
Thanks again, SD.
December 8th, 2011
Big TB Prevention Study Important, Highly Relevant — Even Here
As I’ve noted before, tuberculosis is disappearing from the United States — which means that the bulk of cutting-edge research in TB (both clinical and basic science) has little relevance to US-based practitioners.
But over in NEJM, a much-anticipated TB study is published today that is highly relevant:
We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain … Tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points.
Just how relevant is this study?
At the risk of over sharing, I would have been eligible to participate: Back in medical school, I cared for an elderly man with cough, weight loss, and lung cancer — only he didn’t have lung cancer, he had TB (oops). My next TB skin test was positive when I started internship, and I was advised to take 9 months of preventive therapy with INH.
Only I didn’t — not initially. For whatever reason, I somehow deluded myself into thinking it was a false-positive (just a little redness … right) and continued blithely on this path through both residency and ID fellowship.
Not smart, I know. Selfish, foolish youth.
Only when I became an actual ID specialist did it finally click. Needing another skin test before starting my job, I could no longer ignore the 15 mm welt on my arm. Nor could I bear the thought of harming my patients, never mind the painful irony and public health nightmare that would ensue if an ID specialist got active TB — headline: “ID Doc Infects Dozens; Ignored Advice He Gave Others.”
I finally took the INH. Oh, and it was no big deal.
But if I had the choice back then of 12 doses, taken once a week? Somehow this seems just so much easier, and I suspect I would have accepted treatment sooner had this option been available.
And as this short-course regimen enters formal treatment guidelines, I have a hunch it will be widely adopted — without the recommended directly observed component.
Do you agree?
December 4th, 2011
Images are Back
This site has been looking awfully plain the last couple of weeks. No pictures!
The reason? You figure it out.
But now we’ve got an exciting new treasure-trove of images, and I’m going to take advantage of this resource and provide some very exciting visuals for your enjoyment.
Like this one, if you’re feeling cold:
And this one too, if you’re hungry:
And finally, this one if you want to look at slugs again:
Some fun, eh?
You’re welcome.
December 1st, 2011
World AIDS Day Wanderings
Some quick HIV and ID Observations (better blog title anyone?) for this 2011 World AIDS Day:
- Through meticulous, painstaking research that took me all of 10 seconds, I’ve learned that the first World AIDS Day was in 1988. What ever did we do before the internet?
- Looks like New York City’s health department is following San Francisco’s lead in recommending that all people with HIV get treated — for personal and public health benefit. Important for many reasons, but these two in particular: 1) New York has by far the largest number of people living with HIV of any US city, and 2) It doesn’t appear that this policy change means an infusion of new funding. Not surprised, but let’s face it — more people on treatment is initially going to cost more (meds, providers, outreach). Well worth it, in my opinion.
- Of course people can’t get treated if they’re not in care, and this MMWR report paints a pretty bleak picture of what proportion of all HIV patients in the United States are virologically suppressed — only 28%! Here’s the key finding: “Of the estimated 942,000 persons with HIV who were aware of their infection [out of an estimated 1.2 million with HIV total], approximately 77% were linked to care, and 51% remained in care.” In other words, those diagnosed and not in care greatly exceed those undiagnosed — and saying it’s important to get them back into care and on treatment is kind of like saying that people who smoke should quit. Everyone agrees, but how do we make it happen?
- As a card-carrying member of the AIDS Clinical Trials Group (ACTG — the cards they give us are really nice), I must point out that 25 years ago tomorrow — December 2, 1986 — Margaret Fischl enrolled the first patient in the first-ever ACTG study, Study 002. Lots accomplished since then by the ACTG, and there have been lots of study numbers. But here’s something you might find reassuring — no one can keep them all straight!
- Speaking of Margaret, here’s a terrific interview she did a few years back about the early days of the HIV epidemic — highly recommended.
- Finally, is anyone else bothered by the fact that coformulated medications are increasingly being written in alphabetical order? That is, “emtricitabine-tenofovir” instead of “tenofovir-emtricitabine” (as it has been for years) or, very strangely, “emtricitabine-rilpivirine-tenofovir”, which splits the NRTIs with the NNRTI in the middle. The first time I saw it was in the iPrEx study, and now it’s happening more and more. What’s up with that?
Sorry I haven’t been able to post images recently — I was quite fond of this one — but at least I can still link to them. And though it has absolutely nothing to do with World AIDS Day, here’s a personal favorite.
November 29th, 2011
HIV Cure Makes the NY Times — Anything New to Report?
It’s right there, on page 1 of today’s Science Times:
Medical researchers are again in pursuit of a goal they had all but abandoned: curing AIDS. Until recently, the possibility seemed little more than wishful thinking. But the experiences of two patients now suggest to many scientists that it may be achievable.
Two patients? What, did I miss something?
- Case One is the famous Berlin patient, Timothy Brown, who underwent a bone marrow transplant for leukemia from a CCR5-negative donor (homozygous for the delta-32 mutation). He’s been much discussed, much studied, and now much photographed. (Reminder: he’s really the second “Berlin Patient” — here’s the first — and he now lives in San Francisco; his interviews have been fascinating.)
He’s a bona fide cure, with no evidence of HIV in blood by the most sensitive techniques or in various biopsies where the virus could potentially hide out (brain, bone marrow, rectal mucosa). Plus, his HIV antibody test is fading.To date, we don’t know what exactly led to his cure — if it was the ablation procedure that precedes the transplant, the CCR5-negative donor, the beneficial effects of graft-vs-host, or some combination of these factors.
As I’ve mentioned before, we also don’t know why there hasn’t been another case yet, given that the cure was first reported in 2008 — seems likely that by now someone else with HIV would have required a bone marrow transplant and had the good fortune to have a CCR5-negative donor, though maybe that’s just the non-oncologist’s view (what do I know).
- Case Two? This case was reported at ICAAC in September, using the “zinc finger nuclease modification of CD4 cells” approach championed by Sangamo and first reported at CROI earlier this year.
(Sangamo — it’s a biotech company, not a maker of 1980s video games.)
The patient’s cells are removed from the body by pheresis, treated with the magic zinc finger nuclease which alters the surface CCR5 receptor on the CD4 cell, making these cells less susceptible to infection, then they are reinfused.
We heard at CROI that such modified cells can engraft, and at ICAAC, researchers reported that one of the patients in a small clinical study (n=6) maintained (after a brief viral rebound) undetectable HIV RNA in the blood after stopping HIV treatment.An important detail — he was heterozygous for the delta-32 mutation, meaning that already he had partial resistance to HIV, and a greater likelihood of slow HIV progression.
The reason this case is being viewed with such caution — and not trumpeted as a cure — is that the duration of follow-up has been only 12 weeks. The HIV literature includes other cases of “spontaneous” control of the virus (including the original Berlin patient!), most of which ultimately turned out to be transient. Experienced HIV clinicians probably have a few cases in their own practices who seemed to be on this exciting path back during the heyday of treatment interruption.
In other words, these were not cures.
So in fact, nothing new here in the Times on the HIV cure scorecard. One cure, and one tantalizing case that was reported two months ago.
But what is new is the level of excitement surrounding the effort. Whether it’s something analogous to the zinc finger nuclease approach, or the use of drugs to stimulate and then eradicate the latent viral reservoir, or something completely novel being dreamt up by the field’s boldest thinkers (here’s my vote for one potential candidate), we can now say to our patients that a cure for HIV infection is potentially achievable in their lifetime.
And that’s a wonderful thing to say.
November 28th, 2011
Tenofovir Gel Disappointing in VOICE Trial
From the Microbicide Trials Network:
VOICE, an HIV prevention trial that has been evaluating two antiretroviral (ARV)-based approaches for preventing the sexual transmission of HIV in women – daily use of one of two different ARV tablets or of a vaginal gel – will be dropping the vaginal gel from the study … The DSMB recommended that VOICE discontinue the tenofovir gel and placebo gel arms, because there was no difference in effect between them in preventing HIV infection.
This leaves only the TDF/FTC intervention arm still open in VOICE, as the TDF alone arm was stopped for futility by a similar DSMB action in September.
We’ll be covering these new data in greater detail in Journal Watch AIDS Clinical Care (including some speculation on why tenofovir gel here failed), but on first pass, this news comes as a big disappointment — especially in light of the CAPRISA 004 study, results of which triggered a standing ovation at the International AIDS Conference in Vienna in 2010.
In fact, HIV prevention research has been on quite a roll the past few years, so much so that maybe we’re unrealistically expecting the data equivalent of a home run with each study.
If it were that easy, however, we wouldn’t have to do the research — in other words (to continue the metaphor), that’s why they play the games on the field.
November 25th, 2011
Childhood Meningitis Terrifying, Fortunately Very Rare
Back in fellowship, we used to discuss the various reasons why we’d be called back into the hospital at night when we were on call.
Mind you, this was a fairly rare event, since unlike gastroenterology fellows doing emergency endoscopy for bleeding and cardiology fellows coming in to do the urgent cath, what were we supposed to do — the emergency 6-page consult note? Plus, given the inherently-OCD nature of our field, often we were in the hospital pretty late to begin with.
(You don’t need to get called back to the hospital when you’re already there.)
But when it did happen, it often seemed to be one of the 3 M’s — meningitis, malaria, and mad surgeons.
- Meningitis — because these cases were so darn scary, and bacterial meningitis is the very definition of an ID emergency. One sometimes wondered what additional added value we were providing in the middle of the night above antibiotic recommendations (which were given over the phone way before we got back to the hospital) — but I certainly understood, given the gravity of the cases, that those consulting us needed all the support they could get.
- Malaria — because who else would interpret a blood smear in a febrile returning traveler? Of course working in New England, and not Malawi, it wasn’t as if we were seeing dozens of cases a month and could really consider ourselves experts. But compared to your typical Boston clinician, I guess we had something to offer.
- Mad Surgeons — because they were often “mad” in both senses of the word, meaning that a bad outcome on one of their patients had left them both angry and crazy. And you can’t reason with an angry and crazy person over the telephone, especially when they are the size of most orthopedic surgeons. Remember that most ID docs (myself included) consider ear irrigation to be about the limits of our “invasive” procedures, so we are in awe of what actual surgeons do. Plus they carry sharp objects around with them.
I was thinking of these meningitis cases because here in Boston, a 12-year-old girl recently died of suspected bacterial meningitis. There has been no micribiologic confirmation, but there’s enough clinical evidence for meningococcal disease that the Department of Public Health recommended that close contacts receive antibiotic prophylaxis.
This is a horrible, tragic case — arguably worse than bacterial meningitis in adults, for obvious reasons, not the least of which is that she was apparently healthy the day before. Like all meningitis cases, it has received a lot of media attention, and a fair amount of panic.
Last week I was interviewed on WBUR (our local public radio station) about bacterial meningitis, and during the course of the interview — a part not aired or published — the interviewer made a great point, namely:
The case is all the more disturbing because fatal infectious diseases of children have pretty much disappeared.
She’s right, of course: Childhood immunizations have been nothing short of miraculous (see here for a recent example), and for that, we can be incredibly grateful — even as we are saddened by the loss of this poor girl.
November 20th, 2011
Who Should Care For The Aging HIV Patient? Everything Old is … Oh You Know
Over in Journal Watch AIDS Clinical Care, Carlos Del Rio reviews a couple of remarkable studies on HIV and aging. From one of them:
Compared with the controls, the HIV-infected patients had a higher prevalence of renal failure, bone fracture, and diabetes in every age range evaluated, as well as a higher prevalence of cardiovascular disease and hypertension at age 60… Of note, the HIV-infected patients appeared to develop polypathology at a younger age than controls, such that a 40-year-old HIV-infected patient had a risk similar to that of a 55-year-old HIV-uninfected person.
Wow, I bet that last fact gets quoted a lot.
Carlos concludes by suggesting “Now may be the time for many of us to take a refresher course in primary care for the HIV provider.”
A reasonable proposal — but one which prompted a reader to comment:
I fear this may reflect the common misperception that primary care is easier than disease specific care, especially with a disease like HIV… Perhaps we should focus on educating primary care doctors so that they feel more comfortable with HIV patients rather than HIV clinicians so that they feel more comfortable with primary care.
I completely agree — being an excellent primary care doctor has got to be one of the hardest jobs in all of medicine. I could never do it, which is why I chose to memorize all the cephalosporins, non-pathogenic intestinal protozoa, and the thymidine-associated mutations instead.
But what I find particularly interesting about this exchange is that it raises — again — the question about who should be caring for people with HIV. This has been an area of debate going way back to when the disease was first described, and the funny thing is that the perspectives keep flipping back and forth.
Back in the 1980s, it was argued that all PCPs should learn to manage common HIV-related complications because “the small number of subspecialists and other interested physicians now caring for most patients with AIDS will be overwhelmed” by the rapidly growing numbers of patients. Plus, some ID doctors (especially those spending the bulk of their time doing hospital-based consults) wanted little to do with a progressive, incurable infection that placed a premium on longitudinal outpatient and palliative care.
San Francisco was always a vanguard in the “HIV is a primary care disease” approach. In this paper from the 1990s, the authors state that the general medicine residents at UCSF rotated through the continuity HIV clinic, but the ID fellows didn’t. Amazing.
Then along came effective prevention and treatment strategies for opportunistic infections, followed by multiple advances in antiretroviral therapy, lipodystrophy, lactic acidosis, viral load monitoring, the mind-boggling complexity of resistance testing, the drug-drug interactions, and so on. With all that, HIV became the quintessential specialty disease. This was the pervasive view back in 2006, the last time we covered the topic in AIDS Clinical Care.
But today? The vast majority of people in care for HIV are virologically suppressed (especially true among those who show up for office visits), and they’re on stable HIV regimens — usually regimens that have been, and likely will remain, stable for years. That’s the good news.
Of course if you decrease deaths, you increase survival, and people get older, with older-people problems. We heard this summer at IAS that more than half the HIV population of San Francisco is now older than 50. One afternoon last week only one of the patients I saw was younger than 50, and she was 48.
(50. That’s positively ancient. Ha ha.)
All were virologically suppressed, rock-solid stable from the HIV perspective. I didn’t change a single HIV regimen, or do a single ID-related task that isn’t comfortably within the repertoire of a generalist.
So what did I do? Talked about PSA (pros/cons), bone density screening, lipid abnormalities, diabetes, various aches and pains — plus the struggles they are having with their aging parents, or the flip side, the joys of having grandchildren.
And if that sounds to you a lot like general primary care, you’re absolutely right.
So who should be providing the bulk of care for our aging HIV patients? ID/HIV specialists? Primary care providers? Some combination?
November 14th, 2011
Here Are Two Things You Don’t Hear Together Very Often: Walmart and HIV
As the parent of teenagers (and having been one myself many years ago), I’m acutely aware that everyone wants to think that he or she is special in some way.
And while that is literally true (that is, no two people are exactly alike), as anyone will tell you who looks up a Sunday Times crossword puzzle clue on Google, there are a whole lot of people out there very much like us — no matter how special we think we are.
But here are four things about me that, cumulatively, probably put me into a very small percentage of Americans my age in 2011:
- I have seen every episode of “Seinfeld” (several multiple times), but never watched a single “Friends”.
- I have never eaten at an Olive Garden restaurant. (Would love to try — how is it?)
- Despite half of my family being huge fans, I have never read any of the Harry Potter series — not a chapter.
- I have never shopped at a Walmart — in fact, I’ve never even been inside one.
This last one (a Walmart-less life) is not a conscious move, not a politically/ethically driven avoidance. It just so happens that the places I spend most of my time are not conducive to shopping at Walmart, even though there are seven of them within 15 miles of where I live.
Which is why this news, from NPR, came as something of a surprise:
Wal-Mart wants to be your doctor… The nation’s largest retailer is planning to offer medical services ranging from the management of diabetes to HIV infections, NPR and Kaiser Health News have learned.
If you don’t believe me, it’s right here on page 7, “HIV management and monitoring”, along with more than a dozen other conditions that Walmart will manage as part of the proposal to become “the largest provider of primary healthcare services in the nation.”
Walmart later backed off this claim, but still — you have to imagine they’re planning something for 2014 when the federal health law kicks in. Could this be the “disruptive” idea that helps relieve an already bursting-at-the-seams primary care system?
And as the treatment for HIV gets better and better, and our patients live longer and longer, we should start expecting to see HIV along side of many other chronic medical diseases managed by all sorts of caregivers in all sorts of ways.
Will MinuteClinic — the rhyme that’s not a rhyme — be next?
November 9th, 2011
HCV Treatment Studies at AASLD: Wow … and I Mean WOW!
I didn’t attend “The Liver Meeting” (the nickname for the annual meeting of the American Association for the Study of Liver Diseases, AASLD), but the studies presented there this week on HCV treatment were absolutely mind-boggling.
“Breathtaking!” said one of my HCV-oriented colleagues. “Hopeful is an understatement,” said another.
An example:
Dual Oral Combination Therapy with the NS5A Inhibitor Daclatasvir (DCV; BMS-790052) and the NS3 Protease Inhibitor Asunaprevir (ASV; BMS-650032) Achieved 90% Sustained Virologic Response (SVR12) in Japanese HCV Genotype 1b-Infected Null Responders
Mind you, this was only 10 patients, but 9/10 is no fluke — especially when all the responders had HCV RNA below detection by week 8, and all 9 who completed 24 weeks were cured!
Want a larger study?
PROTON: PSI-7977 & Peg/RBV in Treatment-naïve Patients with HCV GT1: Sustained Virologic Response
Here, in nearly 100 patients, the addition of 12 weeks of the nucleotide analogue polymerase inhibitor PSI-7977 to Peg/RBV led to a cure rate of over 90%, regardless of baseline IL-28B status (13/13 cured with genotype TT). Works with other HCV genotypes, too.
I chose these two studies in particular because the companies developing these drugs — BMS and Pharmasset — are working together on a prospective study that features all-oral, interferon-less strategies lasting only 12 weeks.
But there’s plenty more. Don’t take my word for it — go over to NATAP, click on the “Hepatitis C” link on the left, and start reading.
And if you have limited time, and want a glimpse of the future of HCV therapy, limit your search to studies that say “interferon-free”.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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