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November 30th, 2013
I was speaking with a British colleague the other day, and she was remarking how jealous she was that we get a Thanksgiving holiday each year. Starting with a long whine (or moan, as they would say) about the pressures, commercialization, cost, and religious aspects of Christmas, she then went on about how perfect Thanksgiving seems from her outsider perspective.
“What’s not to like? A big pot-luck dinner. Family and friends get together. No presents. A four-day weekend. And the sentiment of gratitude is so lovely.”
(That’s another one of their words — “lovely.”)
Can’t say I disagree, so in that spirit, here’s a quick list of five things from our little ID/HIV worlds to be grateful for, in no particular order:
- Vaccines. Did you see this paper in the New England Journal of Medicine? By conservative estimates, 75 million to 106 million cases of polio, measles, rubella, mumps, hepatitis A, diphtheria, and pertussis prevented by the vaccines in the United States alone. Add to this hepatitis B, H. flu, rotavirus, varicella, etc., along with the global effect of preventing all these infections, and the impact of vaccines on public and personal health cannot be overstated.
- Antiretroviral therapy. For those of us who have been doing this HIV treatment thing for a while, the movie “Dallas Buyers Club” quickly takes us back to a time that is almost unimaginable today — before effective antiretroviral therapy, before opportunistic infection prophylaxis, to a time when the clinical and research medical establishment was often at odds with the very people we were supposed to help, the people with AIDS. Sure, some of the medical details in the film are screwy — ddC a better treatment than AZT? — but it’s highly recommended nonetheless, with an unbelievably great performance by Matthew McConaughey, as you can see in the trailer below. Good to be reminded, every so often, just how transformed HIV disease is by current therapy.
- Doxycycline. How much do we ID doctors love you? Let me count the ways: Lyme disease, MRSA, anaplasmosis, ehrlichiosis, community-acquired pneumonia, urethritis, syphilis, Rocky Mountain Spotted Fever, malaria prevention, anthrax prophylaxis, pelvic inflammatory disease, brucellosis, wolbachia (that last one a trivia question for ID fellows)… And not only that, the drug is relatively safe (just don’t take it before lying down) and inexpensive (this year a bit less so, unfortunately). To continue the British theme, if you want to know every ID doctor’s “Desert Island Drug”, this is it — just be sure to bring the sunscreen. “Doxy,” thank you for being you — we are very, very grateful.
- AIDS Drug Assistance Programs (ADAPs). Here’s a challenging problem for the healthcare “system” (ha): A disease that is fatal, transmissible, stigmatized, and disproportionately targets the poor. Oh, and treatment is extremely effective, but also quite expensive. Problem? What problem? For HIV, we have a national program, administered by the states, that virtually guarantees everyone (with few exceptions) lifesaving antiretroviral therapy, regardless of their ability to pay — yes, ADAPs are truly miraculous. Sure, we worry about waiting lists and strained budgets (especially in the Southeast), but the number of people denied HIV therapy in the United States today remains small indeed. Who knows what form ADAPs will be in over the next few years with institution of the Affordable Care Act, but let’s hope this remarkable state of affairs is preserved.
- Microbiome and Resistance Awareness. Every healthcare provider has vast experience with the “green phlegm” patient encounter. It goes something like this: Patient is suffering from a prolonged cough, or runny nose, or some other respiratory symptom, and he/she keeps telling you that they have “green phlegm.” This term, you see, has long been a code for, “I need an antibiotic.” Never mind that the color of these secretions says little about whether the infection is bacterial or viral, somehow the public perception was that the only way to return to health, to eliminate the nasty green goo, was to start an antibiotic. Yet over the past few years, a Gladwellian Tipping Point has been passed: We still have the green phlegm conversations — isn’t being a doctor/nurse wonderful? — but for various reasons there are now lots of people out there who would prefer not to take an antibiotic if at all possible. Microbiome (all those good bacteria) awareness? Fear of antibiotic resistance? A friend/family member with C diff? Probably all of the above, and it couldn’t be more sensible, since of course all antibiotics can be harmful (even doxycycline).
What are you grateful for these days?
November 27th, 2013
Good news here for gynecologists who screen men for anal cancer:
A professional group that certifies obstetrician-gynecologists reversed an earlier directive and said on Tuesday that its members were permitted to treat male patients for sexually transmitted infections and to screen men for anal cancer…
It’s always impressive when a group swiftly reverses what is widely perceived to be a wrong decision, so praise to the American Board of Obstetrics and Gynecology for their flexibility.
Now as for obstetricians — sticking with a females-only policy makes all kinds of sense. Just ask the former governor of California:
November 23rd, 2013
Here’s a surprising move: The American Board of Obstetrics and Gynecology has decreed that gynecologists may only treat women. From the New York Times coverage:
In September, the American Board of Obstetrics and Gynecology insisted that its members treat only women, with few exceptions, and identified the procedure [high-resolution anoscopy] in which Dr. Stier has expertise as one that gynecologists are not allowed to perform on men. Doctors cannot ignore such directives from a specialty board, because most need certification to keep their jobs.
Many ID/HIV specialists will immediately see this move as strange, and potentially quite disruptive. At one of my practice sites, we refer all our HIV-positive patients who have anal dysplasia — men, mostly, but also women – to gynecologists who are skilled in high-resolution anoscopy, a procedure similar to colposcopy. Plus, on a national level, there’s an important ongoing clinical study that is evaluating whether this screening strategy prevents anal cancer; at least some of the co-investigators are gynecologists.
(FYI, we’ve been wondering about the efficacy of this in screening for anal cancer prevention for years.)
It’s also a strange move because, frankly, no such other restriction exists for any specialty — it’s tough even to envision such a thing, unless there’s a dermatologist somewhere out there who will only treat patients whose last names start with the letters Z, I, and T.
With the caveat that as an ID specialist, I’m far from the center of this debate, this action by the OB/GYN Board seems extreme. It’s doubtful that the relatively small number of gynecologists who perform this procedure on men will distract them sufficiently to negatively impact the health of women.
Perhaps it’s a “waiting room” phenomenon? My local expert says that women have grown comfortable seeing only other women at gynecology practices, and might find it strange to share the waiting room space with men. And we men do have a tendency to yuck things up — “boy slime,” is how my wife described the effect of sharing bathrooms with guys during college.
But she offers this logical solution: Let the gynecologists who are currently providing this clinical service and participating in research continue doing so. A statement from the board that such treatment is discouraged (but not forbidden) will certainly decrease the number of new gynecologists taking male referrals.
November 16th, 2013
Head over to this page from Janssen Diagnostics, and you’ll receive this little pop-up message:
Must say it’s in some ways sad to see it go — in my opinion the nifty work they did correlating genotype results with their database of phenotypes gave the clearest representation of what a genotype actually means. If you didn’t want to order both genotype and phenotype simultaneously — which was expensive and took weeks to come back from the lab — vircoTYPE was was the most efficient way to get information on complex resistance patterns. Sure, one could quibble about methodology and validation of the test, but it was remarkable indeed to send a genotype and get back results estimating fold-change, upper and lower cut-offs, full and partial activity — and virus clade, just for kicks.
But am I surprised it’s disappearing? Not if you think about it for a moment. As is plainly obvious to anyone doing HIV care, the incidence of new patients with the sort of HIV drug resistance for which the test was developed has plummeted. There simply aren’t many new patients out there who have multiple mutations, especially in the PI-drug class, and who will need the computational black-box firepower provided by a vircoTYPE. A regular genotype does just fine for those who are newly diagnosed, or have virologic failure on a first-line regimen due to poor adherence.
What about the existing patients with this sort of resistance? Most are virologically suppressed right now, and hence don’t need resistance tests anymore.
And in a nice irony, it’s in part the antiretrovirals made by the therapeutics branch of this company — darunavir in particular, etravirine as well — that have made the vircoTYPE obsolete.
So for posterity’s sake, here’s a “beautiful” (what a nerdy thing to write) vircoTYPE from one of those patients, the test obtained in the late 2000s:
His current situation? Virologically suppressed on darunavir, etravirine, raltegravir, of course.
November 13th, 2013
More absurd paperwork follies, this time from our friends at a mail-order pharmacy:
Here, confronted with the challenge of refilling a patient’s HIV medications — which for the record he has been receiving unchanged for over 3 years — the pharmacy decides for the first time to reject the request and send the prescription back to us (by fax of course), including a cover sheet that reads, “Required Information Missing — Pls complete ASAP.”
(No doubt they saved plenty of time by omitting 3 letters in the word “please.”)
Is there a problem with the dose? The instructions? Is there a concerning drug-drug interaction? Did we forget a key component of the regimen?
No, no, no, and no. The problem is that each medication now requires its own “Diagnosis Code,” those inscrutable numbers that already bedevil our billing sheets. Otherwise the pharmacy won’t get paid.
Of course you could ask what else could darunavir, ritonavir, raltegravir, and lamivudine be used for besides HIV, or “042” in ICD-9-ese. Or ask why suddenly now they require the code, since they never did in the past — it’s not as if the indications for these drugs have somehow changed.
And does someone really check to see that the diagnosis code matches the medication? Just to make sure, next time I need to refill HIV meds at this particular pharmacy, I plan to put 380.4 down — that’s “ceruminosis,” or ear wax, in case you’re wondering.
I’ll let you know what happens.
November 6th, 2013
In today’s New England Journal of Medicine, the SINGLE study finally makes its appearance “in print.” (The study results were first presented over a year ago.) The highlights:
- SINGLE was a double-blind, randomized clinical trial comparing abacavir/lamivudine plus dolutegravir to tenofovir/FTC/efavirenz in 833 treatment-naive study subjects. That’s right, three different drugs in each arm — you don’t see that much in HIV clinical trials these days.
- At 48 weeks, 88% of the dolutegravir group and 81% of the efavirenz group had HIV RNA < 50, making the dolutegravir arm superior. CD4 response also significantly better.
- The difference between the two arms was driven by more study drug discontinuations in those receiving the EFV regimen; virologic responses were similar.
- There was no resistance detected among those with virologic failure on dolutegravir.
Setting aside the NRTIs for now, we must again note that this is the very first time anything has beaten an EFV-based regimen, and it’s not for lack of trying. Starting with its surprising defeat of indinavir way back in the 1990s, efavirenz has subsequently bested fosamprenavir, lopinavir/r, nevirapine, nelfinavir, and abacavir.
(And let’s not forget once-daily soft-gel saquinavir/r. That’s nine pills/day just for the saquinavir/ritonavir, yikes.)
The most any challenger could do was tie — see atazanavir/r, raltegravir, elvitegravir/cobicistat — or, in the case of rilpivirine, offset lesser antiviral activity with a better tolerability profile. In short, up until the SINGLE study, one could argue that EFV-based treatments — especially TDF/FTC/EFV — represented the gold standard against which all other regimens must compete.
Has that now changed? I think it has.
Note that these SINGLE study results come out just as other data and clinical experiences have less forcefully nudged efavirenz off its perch on top of the HIV treatment world. Want a single pill for HIV treatment? There are now two other options, TDF/FTC/rilpivirine and TDF/FTC/elvitegravir/cobicistat, both of which have significantly lower rates of CNS side effects and rash; abacavir/lamivudine/dolutegravir is on its way as another option.
Furthermore, those efavirenz CNS side effects may not be so benign — a study presented at this year’s IDWeek (disclosure: I’m a co-investigator) found that those randomized to efavirenz had twice as high a rate of suicidal ideation as in the non-efavirenz treatments. Yes, the absolute risk was low, but this is a much more serious adverse effect than the famous “vivid dreams” reported so frequently by those receiving efavirenz.
So what about the rest of the world? The World Health Organization Guidelines, updated just this summer, have this to say about initial regimens:
Once-daily regimens comprising a non-thymidine NRTI backbone (TDF + FTC or TDF + 3TC) and one NNRTI (EFV) are maintained as the preferred choices in adults, adolescents and children older than three years … TDF + 3TC (or FTC) + EFV as a fixed-dose combination is recommended as the preferred option to initiate ART
Which means we are far from seeing the end of the efavirenz era globally, where the drug is widely (and accurately) viewed as effective, inexpensive, and relatively well-tolerated. All good things.
Just not quite good enough anymore, given what’s out there as competition.
November 5th, 2013
Imagine for a moment the ideal medical future … there’s a vaccine that prevents the common cold … colon cancer screening no longer requires that horrendous “prep” … electronic medical records are easily accessible, intuitive, secure, and all communicate effortlessly with one another … your doctor’s office has an actual person who answers the phone instead of a prerecorded list of “menu options” … and hepatitis C is cured with one pill a day taken for 8 weeks.
Not sure about the timeline for the first four, but based on this study of sofosbuvir and ledipasvir just published in the Lancet, the hepatitis C outcome is right around the corner:
In cohort A, SVR12 [no detectable virus 12 weeks after stopping treatment] was achieved by 19 (95%) of 20 patients (95% CI 75–100) in group 1, by 21 (100%) of 21 patients (84–100) in group 2, and by 18 (95%) of 19 patients (74–100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74–100) in group 4 and by all 21 (100%) of 21 patients (84–100) in group 5 … These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis.
You’ll note that the “groups” were pretty small, and that only one of them — group 1 — actually got just the one-pill sofosbuvir/ledipasvir combination for 8 weeks, but regardless, these are pretty spectacular results. Even the most “complex” treatment group in this study received sofosbuvir/ledipasvir plus ribavirin for only 12 weeks, which is light years from the complexity of our current interferon-based therapies. Light years better, of course.
And since sofosbuvir has already been reviewed by the FDA advisory panel, we should be getting at least this drug by December 2013 at the latest; the combination pill with ledipasvir could be available some time next year (according to this article in the New York Times), and several other investigational HCV drugs will likely be approved soon as well (simeprevir this year too).
But calm down already. Take a deep breath. It’s a small phase II study. Shouldn’t we be more cautious? Shouldn’t we avoid wildly overstating the importance of this particular treatment approach? Of course, that’s the prudent thing to do.
But can people with HCV and their treaters be ecstatic about these results anyway? You betcha.
October 30th, 2013
HIV Treatment of Serodiscordant Couples: The Home Run, Slam Dunk, and Open Goal in Clinical Research
Just in time for Game 6 of the World Series, my colleague Rochelle Walensky has published a paper in the New England Journal of Medicine (covered here in NEJM Journal Watch). evaluating the cost-effectiveness of treating HIV-infected individuals in serodiscordant couples. The results:
In South Africa, early ART was cost-saving over a 5-year period. In both South Africa and India, early ART was projected to be very cost-effective over a lifetime. With individual, public health, and economic benefits, there is a compelling case for early ART for serodiscordant couples in resource-limited settings.
I added the bolding, because in the cautious and scientific style of NEJM, you’re not allowed to do this, but it’s worth emphasizing the main point — everyone with HIV in a serodiscordant couple should be on HIV treatment, regardless of CD4 cell count.
Every so often, a research paper comes up with results that are so staggeringly TRUE that one wonders, what was the controversy? And this is one of them. Take a look at this randomized clinical trial of fecal transplant for relapsing C. diff for a non-HIV example. Or this one on the effect of H. flu immunization in children.
It’s incredibly satisfying, which is why the sports metaphors in the title come to mind.
In fact, when the senior author on the paper, Ken Freedberg, presented these data at the International AIDS Conference in Washington DC in 2012, he was asked by someone in the audience whether he thought the results should “influence policy.”
Like the slugger seeing a pitch right down the middle, the point guard stealing the ball in the backcourt, or the soccer forward beating the goalie who has come out of position, Ken salivated at the chance to answer this question, then, predictably, hit it out of the park. (Or whatever your favorite sport is.)
I don’t remember his exact words, so Carlton Fisk will have to do the talking:
October 25th, 2013
Don’t look now, but a two-drug lamivudine (3TC) + LPV/r strategy did just as well as a standard three-drug regimen of two NRTIs + LPV/r. Better, actually, since virologic outcomes were the same and the two-drug regimen had fewer side effects.
Here are the key details about the GARDEL study, presented just this week by Pedro Cahn at the European AIDS Clinical Society meeting, or EACS:
- Study design: Open-label, randomized clinical trial in 426 treatment naive patients.
- Randomization was to 3TC 150 mg BID or 3TC plus an investigator-selected 2nd NRTI; all study participants received LPV/r twice-daily.
- At 48 weeks, 88% of the double-therapy and 84% of the triple-therapy arms had HIV RNA <50 copies/mL
- 1% vs 5% (p = 0.03) in the double- and triple-therapy arms met failure criteria due to no data at week 48 due to stopping treatment or death (mostly stopping treatment; there was only 1 death).
- Rates of virologic failure and resistance were not significantly different between arms.
Ah, but we’re all thinking, what about the high viral load stratum — surely this group would need the extra potency of a three-drug regimen.
But surely we’d be wrong: 87% vs 78% were <50 at week 48, so the difference favoring double-therapy was even greater.
In the “Timing is Everything” category, my recent review of the failed MODERN study of maraviroc + DRV/r included this bit of prescience when discussing why the various two-drug regimens have failed:
What remains unclear is why these two-drug regimens have been so disappointing. Is two drugs not enough? Or maybe just the two drugs tested to date in these clinical studies? Is there something magic about the NRTIs? Or certain NRTIs? (One vote could be for 3TC or FTC, which have been part of every truly great HIV regimen since the late 1990s.)
I added the bolding, because it’s always advisable to highlight when you’re right to help balance out all those times that you’re wrong.
(And believe me, there have been lots of the latter over the years. Just ask my kids. And in HIV treatment, too — remember ddI/d4T/hydroxyurea? What were we thinking?)
So in the HIV world, this study is pretty big news, that much is clear. A two-drug regimen has never done better than a three-drug treatment in a fully powered study.
But will it influence clinical practice? Not right now, I don’t think, which makes this more of a paradigm-shifter than a game-changer. (See, doctors can mobilize business-school cliches too.)
Here are at least four reasons why:
- It’s a three-pill, twice-daily regimen, and commonly used first line regimens are now all easier than that.
- Related, boosted-PI based regimens have lots (and increasing) competition in first-line therapy, especially from integrase-based strategies.
- Clinical practice and treatment guidelines have moved away from lopinavir/r due to study data and clinical experience showing that it has higher rates of adverse effects (GI, lipids) than once-daily atazanavir and darunavir.
- The generalizability of the study results might be limited given that the most common second NRTI chosen by the investigators was zidovudine (54%), followed by tenofovir (37%) and abacavir (9%).
These caveats notwithstanding, the GARDEL study raises several interesting questions:
- Would ATV/r or DRV/r have done as well with just 3TC? Or is LPV/r in this context better? I can’t see why, but of the various two-drug PI plus raltegravir studies, this one with LPV/r seemed to do the best.
- Would once-daily 3TC have done as well? Remember, half-life of 3TC is shorter than FTC.
- What future fixed-dose regimens could we envision, especially as cobicistat-based PI combinations emerge and 3TC is now generic?
- How would a two-drug, 3TC or FTC plus boosted-PI regimen fare as a maintenance strategy? I suspect quite well, though for published data all we have is this small study with ATV/r.
So there you have it, the GARDEL study in all its disruptive innovation glory. You can mail the MBA to my home address.
October 18th, 2013
We hold an annual post-graduate course entitled “Infectious Diseases in Primary Care”. In this 2.5 day course, we ID doctors do our best to address the concerns of clinicians on the front lines — those doing primary care.
And each year, we get some great questions. Like these:
- Question: I work at a university health center, and each year we have several hundred visiting students from countries that routinely give BCG immunization. We continue to do PPDs (tuberculin skin tests, TSTs) because they are cheaper, but there are tons of positives. Should we switch to an IGRA (interferon gamma release assay)?
Answer: If ever there were an indication to use IGRAs over TSTs, this is it! Think of the potential money, time, and aggravation you’d ultimately save. Once you switch to IGRAs for those with a BCG history, here’s what you won’t have to do: 1) track down the people who don’t return to have their skin test read; 2) explain to the BCG-immunized with the reactive skin test that we don’t consider BCG in this country when we interpret TSTs (Note: No one who’s received a BCG believes us; they think we’re out of our minds.); 3) get a chest X-ray in those with reactive TSTs from BCG alone; 4) prescribe unnecessary preventive therapy for that same group. Sounds like a good trade off to me. Read more here.
- Question: For skin infections, shouldn’t we double the dose of trimethoprim-sulfamethoxazole [that's not what he said -- he said "Bactrim"] to two double-strength tablets twice daily?
Answer: I’m not sure where this one came from — and it’s a widely held belief — but as far as I know, there are no definitive data supporting a double dose of TMP-SMX for skin infections. Plus, some of the toxicity of TMP-SMX is dose-related, and those “double-strength” tablets are gigantic. Notably, this randomized study used the standard dose (1 DS twice-daily), and this one used variable weight-based dosing. If someone knows why the higher dose is anecdotally so popular, let me know! Which reminds me — what should we call this drug? I generally frown on using trade names unless absolutely necessary, but “Bactrim” (or the less-commonly-used “Septra”) are vastly superior to the mouthful that is the generic name. Some say “cotrimoxazole”, but what is that? Please weigh in by voting in the poll below, and providing your comments.
- Question: Do you need to check serologies before giving the zoster vaccine if someone says they never had chicken pox as a kid?
Answer: Nope — the good news is that per the zoster vaccine guidelines, we can consider anyone born before 1980 in the United States to be varicella immune. And the last time I checked, everyone older than 60 (for whom the vaccine is indicated) was born before 1980, though you may wish to double-check my math.
- Question: Do you recommend repeat testing for C diff after the patient has been treated?
Answer: Certainly not if he/she is improving, as a repeat positive with any of the myriad C diff tests out there is quite common shortly after C diff treatment, and treating improving/resolved C diff with antibiotics is a bad move. So when would you check again? I find repeat C diff testing helpful in someone with a recent episode who’s now having vague symptoms (e.g., not a florid relapse), as a negative result suggests that it’s probably post-infectious GI issues (alteration of normal flora would be the broad generalization of what causes this) rather than a relapse of C diff.
- Question: When is next year’s course? I’d love to attend.
Not sure — some time in October, we’re working on finalizing the dates now.October 1-3, 2014. And we guarantee the New England weather will be perfect and the Red Sox will be in the playoffs.