An ongoing dialogue on HIV/AIDS, infectious diseases,
November 27th, 2013
Gynecologists May Treat Men After All
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
OB/GYN Board Says Their Docs May Only Treat Women
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
Janssen to Stop Offering “Virtual Phenotype” Testing, and Musings on Progress
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. These two drugs, plus raltegravir, mean that most people with resistance are suppressed.
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
How Doctors, Nurses, and Other Medical Providers Spend Their Free Time
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
SINGLE Study Underscores Waning of the Efavirenz Era — But Probably Just in the USA
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.
Your thoughts?
November 5th, 2013
Sofosbuvir and Ledipasvir Phase II, and When Small Studies Make a Big Impact
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 theNew 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
GARDEL Two-Active-Drug Study Not a Game-Changer, but Might Be a Paradigm-Shifter
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
Back to School: Top Questions from “ID in Primary Care”
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.
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. And FYI, I say “trim-sulfa”, but hardly anyone does.
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.
Answer: October 1-3, 2014. And we guarantee the New England weather will be perfect and the Red Sox will be in the playoffs.
October 14th, 2013
MODERN Study Stopped: An NRTI-Sparing, Two-Drug Initial Regimen Disappoints Again
In case you didn’t know, “MODERN” is the clever name for the “Maraviroc Once-daily with Darunavir Enhanced by Ritonavir in a New regimen” trial, which compared TDF/FTC to maraviroc, both with boosted darunavir.
And once again, the NRTI-sparing two-drug regimen comes up short, this time in a fully powered, double-blind noninferiority study.
From a PDF provided by ViiV’s Regional Medical Scientists (the information isn’t on the company’s website yet), here are some pertinent details:
- The study included 791 treatment-naive patients; all had CCR5 virus at baseline.
- At week 48, 72% and 83% of the MVC and TDF/FTC patients had HIV RNA < 50 at week 48 (∆=11%, 95% CI –17.1% to –6.1%; the pre-specified criteria for noninferiority stated that the lower bound of the 95% CI be greater than –10%).
- Thirty-eight patients in the maraviroc (MVC) arm and 13 in the TDF/FTC arm experienced treatment failure.
- No new safety issues were identified in either treatment arm.
- Data are still being analyzed, with further information to come.
As noted before, the bar for successful initial therapy these days is set extremely high, with several recent studies demonstrating 85–90% suppression rates at 48 weeks using regimens with low pill burdens and excellent tolerability. 72% just isn’t going to cut it.
And for the record, here’s a list of NRTI-sparing studies that gave “meh” results at best:
- ACTG 5142 — LPV/r + EFV vs NRTIs + EFV vs NRTIs vs LPV/r.
LPV/r + EFV had high rates of hyperlipidemia; regimen was also cumbersome with lots of GI side effects. - SPARTAN — ATV + RAL vs ATV/r + TDF/FTC.
More treatment failure, more jaundice in the ATV + RAL arm. - PROGRESS — LPV/r + RAL vs. LPV/r + TDF/FTC.
Comparable success rates, but baseline HIV RNA low in the study population; 3 pill, twice-daily regimen. - ACTG 5262 — Single-arm study of DRV/r + RAL.
Unexpectedly high rates of virologic failure (with resistance), especially among those with HIV RNA > 100k at baseline. - A4001078 — ATV/r + MVC vs ATV/r + TDF/FTC
Only 75% virologic suppression rate in ATV/r + MVC arm, with more hyperbilirubinemia than the control group; study not fully powered. - RADAR — DRV/r + RAL vs. DRV/r + TDF/FTC.
63% suppression rate in the RAL arm, vs 84% for TDF/FTC; study not fully powered.
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.) Do the benefits in bone density for the NRTI-sparing strategies outweigh the lesser virologic activity? (My opinion — no.)
Regardless, HIV clinicians and researchers eagerly await the result of two completed but not yet presented clinical trials — the fully-powered NEAT study comparing RAL to TDF/FTC (both with DRV/r), and the GARDEL study, comparing 3TC to NRTI/3TC (both with LPV/r).
Until then, one should be using NRTI-sparing therapies as initial treatment only in highly select circumstances — and even then, why not include 3TC or FTC?
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
Learn more about HIV and ID Observations.
NEJM Journal Watch — Recent Infectious Disease Articles- Stopping the Cycle of Recurrent Bacterial Vaginosis
- Observations from ID and Beyond: Tragic Childhood Death from Measles Reminds Us That Some Don't Understand Either the Medical Significance or the Human Heart
- Gaining an Important Tool Against Multidrug-Resistant Gram-Negative Bacteria
- Transmission Dynamics Along the Continuum of HIV Care
- Emergence of Avian Flu in Domestic Felines: When the Canary Swallows the Cat