An ongoing dialogue on HIV/AIDS, infectious diseases,
April 8th, 2015
New HIV Treatment Guidelines, and the End of an Era
The new Department of Health and Human Services (DHHS) HIV treatment guidelines are out, and thanks to skillful direction by Alice Pau, it’s as usual a must-read document — all 288 pages, of course!
There are several major changes, so a good place to start is the all-important “What’s New in the Guidelines” summary page. Some of the biggest modifications come in the “What to Start” section:
- There’s now a more focused list of “Recommended regimens” — it’s down to just 5. Specifically, TDF/FTC plus DTG or EVG/c or RAL (that’s 3), ABC/3TC/DTG (4), and TDF/FTC plus DRV/r (5).
- The regimens that are limited to patients with low HIV RNA are now classified either as “Alternative” — TDF/FTC/RPV — or “Other” (ABC/3TC plus EFV, ABC/3TC plus ATV/r).
- TDF/FTC plus ATV/r is now an “Alternative” regimen, largely due to the results of ACTG 5257.
- TDF/FTC/EFV is now an “Alternative” regimen, largely due to issues of tolerability.
With the caveat that as a member of the Guidelines panel, I can only give you my personal perspective (not that of the committee), here are a few comments on this last one — the demotion of efavirenz from “Recommended” to “Alternative” — which seems to me a pretty big deal.
First the good stuff about EFV, which was approved by the FDA way back in 1998:
- In clinical trials, efavirenz has been better or as good virologically than all its comparators for years and years. I still remember the shock when we learned that EFV creamed indinavir — a potent protease inhibitor, who would have predicted that? — and subsequently it won or tied in numerous head-to-head studies. That success continued until the drug was compared to integrase inhibitors (in particular dolutegravir), but note that rates of virologic failure were still just as low with EFV even in this comparison. And is there any agent that so consistently does well in patients with high baseline HIV RNA and/or low CD4?
- Efavirenz has such a long half life that regimens with the drug are remarkably forgiving, even if people forget to take it every day. It’s so forgiving, in fact, that studies suggest you can do fine taking it only 5 days a week, or at a reduced daily dose. Not that we recommend these strategies, but still — we all have patients on EFV-based regimens who admit that they skip it periodically (usually because of side effects, but that’s a different story), yet they maintain virologic control.
- Although no HIV treatment is cheap, TDF/FTC/EFV is less expensive than most of the other initial regimens we use today.
- Efavirenz (with TDF/FTC or TDF/3TC) is the default initial treatment globally, where it is widely available as a single pill taken once a day. That counts for a lot — obviously the vast majority of people with HIV in the world don’t live here.
So what’s the issue? Why then is it now an “Alternative” rather than a “Recommended” option? In my opinion, it comes down to progress we’ve made in improving side effects. Many choices are available now that are simply easier for patients — and clinicians, who can skip the time on pre-treatment education and management of tricky side effects. Specifically:
- All the clinical trials comparing EFV with integrase-based options demonstrate significantly lower rates of central nervous system (CNS) side effects with the latter. As already noted, in the head-to-head study against dolutegravir, drug discontinuations due to adverse events led to a superior result for DTG. The same thing happened when EFV was compared to RPV — in the low viral load stratum, RPV was superior because it was better tolerated.
- Virtually everyone who starts EFV gets some sort of CNS side effect of varying severity in the first week or two. Not a good idea to start the day (or even a week) before a big presentation, or travel, or some other major life event. In most patients, these CNS side effects diminish rapidly over the first few weeks of therapy. However, a minority still have some residual weirdness going on long term — dizziness, abnormal dreams, morning grogginess. Some learn to live with it and are fine, but others don’t realize how off they’ve been feeling until they stop the drug. (Brief aside — what’s up with the small fraction of patients who choose to take EFV during the day? That always perplexed me.)
- More serious CNS side effects can rarely occur, in particular depression. In this retrospective analysis of four randomized clinical trials, patients randomized to EFV-based regimens had a more than two-fold increased risk of suicide or suicidal ideation compared with those not receiving EFV. And while the absolute risk was overall low, this is a severe enough adverse effect that one should be very cautious about using the drug in anyone with a history of depression. Although observational cohort and claims data have not shown this association, remember that this is a tricky thing to find in such data, and that in clinical practice we avoid prescribing EFV to patients with psychiatric disease.
- Every ID/HIV doctor has had patients who just can’t take this drug, and it’s not from depression. OK, anecdote time — here are a few of mine: The guy who drives for a living who knew immediately he wasn’t as alert on the road taking EFV. The person whose dreams were so vivid that they were essentially indistinguishable from hallucinations (and not pleasant ones). The high-functioning scientist who simply couldn’t concentrate at work. The person (actually a few) with severe rash and fevers. Of course some of the vivid dream stories were pretty funny — my favorite was someone who dreamt that her kitchen had been extensively renovated, including specific selections of cabinets and appliances. Imagine her disappointment when she came downstairs to find the scruffy old kitchen unchanged!
Yes, I still have patients on EFV-based treatment who are doing great, and they don’t want to switch — that’s fine, no reason to do so. But the bottom line is that I haven’t prescribed TDF/FTC/EFV to a patient starting HIV therapy in nearly three years. Too many other good options out there now.
Hey, progress is a good thing!
I did this poll before — now let’s try it again, a year and a half later:
April 3rd, 2015
Melting Snow ID Link-o-Rama
A few ID/HIV tidbits to contemplate as we go from slipping on ice and snow to dodging the mud:
- Beta-lactam therapy alone is non-inferior to regimens that also cover “atypicals” for hospitalized patients with pneumonia. These results challenge a dogma that has been present for a couple of decades — namely, that all patients admitted with community-acquired pneumonia should get either a quinolone or a beta-lactam plus a macrolide. But is one study done in the Netherlands enough to change clinical practice?
- Flurry of recent papers on the cost effectiveness of HCV therapy: One, two, three, and four, to be exact. Bottom line? A huge oversimplification goes like this — from a societal perspective, the new treatments are for the most part cost-effective and expensive. And, of course, from an individual perspective — meaning you are the individual being treated, or the prescriber — they are a no-brainer.
- Related: Entertaining and informative discussion of HCV pricing, and what’s going on behind the scenes from longtime ID/HIV clinician, researcher, and educator Mike Saag. When it comes to this market, what’s the opposite of transparent? Highly recommended, especially for fans of Get Smart. And if you want some additional info on the world of “Pharmacy Benefit Managers”, read this. (Thanks to Mike for the link)
- “Fourth Generation” HIV screening tests that detect both antigen and antibody can still miss acute HIV. Remember, the duration of p24 antigen detectability during acute HIV is relatively short. Important to think about this limitation, especially when evaluating patients for PrEP — we should have a low threshold to order HIV RNA.
- The outbreak of injection drug use (IDU)-related HIV in Indiana is a stark reminder of how quickly HIV can spread with the right mix of bad ingredients — rising rates of opiate addiction, poverty, and lack of access to clean needles. Notably, in the rest of the US this mode of HIV transmission has become quite rare — here in Boston, I haven’t seen a newly acquired case of HIV from IDU in years. Bad time for complacency on this issue.
- Watch out for ciprofloxacin-resistant shigella in returning travelers. As noted in the report, “shigella is transmitted easily from person-to-person”, which is something of an understatement since some people can get sick after ingesting fewer than 100 bacteria.
- The air near beef cattle feed yards carries antibiotics, antibiotic resistance genes, and resistant bacteria. Yuck, good idea to stay up-wind. Remember, 80% of our national use of antibiotics goes to livestock. Will the programs announced this week by Obama actually reduce this use?
- I recently learned that two of the HACEK organisms have new names: Haemophilus aphrophilus is now Aggregatibacter aphrophilus, and Actinobacillus actinomycetemcomitans is now Aggregatibacter actinomycetemcomitans. Wow. The mnemonic “HACEK” still works, however, standing for Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. I’m convinced some of us chose ID as a specialty just so we could know information like this.
Hey, it’s Holy Week. Colored (sometimes green) eggs and ham! Peeps! Matzo balls and brisket! Jelly fruit slices! For those of a less traditional spiritual bent, enjoy this:
H/T to Joel Gallant for the vid.
March 28th, 2015
Quick Question: Should HIV-Negative People in Serodiscordant Relationships All Get PrEP?
From a very thoughtful and experienced primary care provider came this query:
Hey Paul, quick question —
One of my patients, an HIV-negative gay man, is in a long-term relationship with one of your HIV-positive patients — my patient says his partner has been on successful HIV treatment for years. Obviously I can’t check his partner’s record to confirm this, but my patient is quite reliable and why should he be lying about this? He says they always use condoms.
He asked me today if he should go on PrEP — should he? He seems awfully low risk, denies other sexual exposures, etc.
Feel free to suggest that I send him to see you for a formal consult.
Thanks,
Roy
Unless you’ve been hiding under a rock (cold and damp down there, isn’t it?), you know by now that pre-exposure prophylaxis (PrEP) works incredibly well to prevent HIV in high risk, seronegative men who have sex with men (MSM) — even better than we thought, according to the recent PROUD and IPERGAY studies presented at CROI.
Related to my colleague’s query, note that the USA guidelines clearly state the following is an indication for PrEP in MSM:
Is in an ongoing sexual relationship with an HIV-positive male partner
So end of story — PrEP should be started, right?
But there are several reasons why it’s not quite so obvious what to do in this exact situation — which is actually quite common:
- Treatment of HIV is all but 100% effective in preventing transmission of the virus. Remember the “Swiss Statement” that condoms weren’t even required if the positive member of serodiscordant couple was virologically suppressed? The results of HPTN 052 and observational studies (most recently this one) support this prescient claim.
- Eligible participants in the MSM PrEP studies were at “high risk” for getting HIV. In IPERGAY, for example, to be eligible a person needed to report “condomless anal sex with > 2 partners within the past 6 months.” A man in a monogamous relationship with an HIV positive partner on suppressive therapy — who also uses condoms — would never have been enrolled.
- The incremental risk reduction — if any — of a man taking PrEP whose sole partner is already on suppressive ART could never be justified on a “number needed to treat” or cost-effectiveness basis. This is pretty obvious, but is worth explicitly stating, if only so that when such treatment is prescribed, we all acknowledge that it’s done for other reasons.
So what might those reasons be? First, as my friend and colleague Raphy Landovitz puts it, “people aren’t completely honest with their providers about the who’s and whats of their sexual relationships – including as it relates to condom use.” Remember HPTN 052, and those “unlinked” HIV transmissions from outside the couple? That alone should give us pause.
Second, some patients I’ve seen understandably remain very nervous about catching HIV from their partners, even if on suppressive treatment — PrEP provides them an additional layer of security. The TDF/FTC is acting here more as a benzodiazepine than an antiviral. Again, per Raphy: “It restores peace-of-mind to something that the HIV/AIDS epidemic has stolen from gay men.”
From a practical standpoint, here’s what I have done:
- See him (the HIV negative guy) alone. Or if he’s uncomfortable seeing his partner’s doctor, offer to have him see one of my colleagues.
- Reassure him that the discussion is 100% confidential.
- Tell him the pros and cons of PrEP. Efficacy, safety, and cost, of course, but also the characteristics of the patients in the studies — that they were high-risk HIV negative gay men.
- Inform him that PrEP has never been explicitly tested in the HIV negative partners of people on suppressive ART in a monogamous relationship — and likely never will be since the risk of transmission is already so low.
- Let him decide.
In my anecdotal experience thus far, some have chosen to go on PrEP, and some haven’t.
And whether those who opted in did so because they’re actually at higher risk than they’re disclosing, or for peace of mind, or some combination — does it really matter?
March 21st, 2015
ID Learning Unit: Coagulase-Negative Staph, and the “Anti-Zebra” Residents’ Report
At the risk of betraying a deep streak of nerdiness, I confess to being a huge fan of Residents’ Report. This infatuation goes back to my medical student days, when the occasional chance to watch the Chief Medical Resident — who seemed the smartest doctor on the planet — lead a discussion of an interesting case inspired all kinds of aspirations.
Alas, I was never chosen to be Chief Resident, but have been lucky enough to sit in on my fair share of Residents’ Reports over the years, including one this past week. And so glad I did, as current Chief Resident Mary Montgomery tried a new twist on the genre: Instead of presenting a fascinating rare case — a “zebra” — or a challenging ongoing diagnostic dilemma, she chose a couple of extremely non-zebroid (that’s a word) cases that involved coagulase-negative staph (CoNS), a bug that frankly most of us think is pretty ho-hum.
But you know what? It was a great report, educational and entertaining, and here’s what we learned about this commonly encountered (but frequently challenging) entity:
- In the microbiology lab, a coagulase test is done on suspected staph isolates, looking for tell-tale clumping of plasma. Clumps = coagulase-positive (Staph aureus); no clumps = coagulase-negative. Watch!
- There are over 30 species of CoNS, with Staph epidermidis the most common — but you rarely see micro reports listing Staph epidermidis, since identifying the particular CoNS species is rarely helpful.
- Staph saprophyticus is a CoNS species that is the second most common cause of uncomplicated UTIs in young women. Fortunately, it’s sensitive to most antibiotics used to treat UTIs.
- CoNS are the most common isolates from blood cultures, and also the most common contaminants. Distinguishing true- from false-positive blood cultures can be tricky, in particular with CoNS, and this home-grown study provides some guidance — indeed, it’s incorporated into our ancient electronic medical record. (See above image — soon to be retired, alas, in a move of EPIC proportions.) Question: Has this study been updated by anyone?
- Clinically important infections with CoNS frequently involve prosthetic joints, mechanical heart valves, indwelling vascular catheters, ventricular shunts, vascular grafts, pacemaker or defibrillator leads, orthopedic hardware — in short, artificial ingredients!
- Treatment of choice for CoNS infection acquired in the hospital is vancomycin, since more than 80% are resistant to beta lactam antibiotics.
- CoNS are good at sticking to things, and have a virulence factor called arginine catabolic mobile element (ACME), which they unfortunately sometimes decide to transfer to MRSA. I hate when they do that.
- Production of biofilms — slime, think of the stuff that makes rocks slippery in a stream — makes CoNS difficult to clear from prosthetic material. Here’s a whole book about biofilms, great for leisure reading.
- Among antibiotics, rifampin seems to be the best at penetrating biofilms, hence its use as adjunctive therapy for many infections involving prosthetic material.
- Around 8% of native valve endocarditis is due to CoNS, and these patients have a high likelihood of requiring surgery. In my anecdotal experience they have an extremely indolent course, but not when the CoNS is Staph lugdunensis.
- Speaking of, Staph lugdunensis is a particularly aggressive form of CoNS, a wolf in sheep’s clothing that acts much more like Staph aureus than its wimpy coagulase negative brethren. It’s usually sensitive to beta lactams, too.
Of course I could go on and on about this last bug — we ID doctors adore Staph lugdunensis, which is both fun to say and is one of those factoids that separates us from the mere mortals out there who can’t be bothered to remember this arcane stuff.
Here’s a tip for you non-ID doctors: You can really impress your ID specialist friends by bringing up Staph lugdunensis when discussing a case, or even just in casual conversation:
Non-ID doctor: Hey, have you watched the new House of Cards season yet?
ID doctor: No, am waiting until I have time to binge-watch it.
Non-ID doctor: Makes sense. By the way, Staph lugdunensis.
ID doctor: Impressive!
Yes, I know. Time to get a life.
March 8th, 2015
Measles Vaccine Videos and the Challenge of Changing Someone’s Mind
I suspect most of you have already been treated to this highly amusing video about the measles outbreak from Jimmy Kimmel — a comedy segment featuring real-life doctors, imagine that. Not your typical late-night comedy show performers, but they forcefully (and obscenely) get their message across.
If you have just returned from a tropical island where the internet connection was iffy, however, here it is for your entertainment:
Probably fewer of you saw this next one, which is quite well done and pretty accurate scientifically. It also differs dramatically in tone:
My question for you: Which one is more likely to change the views of a person with an anti-vaccine stance, and why?
March 1st, 2015
Really Rapid Review — CROI 2015, Seattle
For the 3rd time in its illustrious history, the Conference on Retroviruses and Opportunistic Infections (CROI) returned to Seattle this past week for it’s 22nd meeting. For those of us living in the North Pole, 50 degrees and drizzle never felt so wonderful!
(See image below for graphic representation — that’s my dog Louie wondering what happened to his world. Click on image for full impact.)
With 4000 attendees (capped at that number to keep it relatively “intimate”) and almost half of them from non-U.S. countries, CROI remains a dynamic, incredibly interesting meeting — in my opinion our very best HIV research gathering, guaranteed to make you sleepless while trying to cover it all. (Good thing we were in Seattle.) Where else can we get clinical, basic, translational, and behavioral researchers all together?
So on we go to a summary, a Really Rapid Review™ of some of the most interesting studies at the conference (at least from one perspective). Links are to the conference website (excellent this year), abstract #’s in brackets, and many of the oral presentations are available for webcast here. List is organized roughly by prevention, treatment, complications, cure, and miscellaneous cool stuff; please list in the comments any important studies I’ve missed!
- In a “real world” clinical trial called PROUD [22LB], pre-exposure prophylaxis (PrEP) with TDF/FTC in high risk gay men in London reduced HIV transmissions 86%. Real world” since the participants knew if they were receiving active drug or not (randomized to start right away or delay 12 months); the delayed PrEP arm extensively used PEP, making the results even more impressive. Study stopped early due to efficacy.
- As we heard in October, the IPERGAY (ha) study compared intermittent PrEP — two TDF/FTC’s before sex, one pill the next 2 days — to placebo, and was also stopped early. Efficacy of this “on demand” PreP? Again 86% [23LB]. Note that in both of these studies, incidence of HIV and protective efficacy of PrEP were higher than expected.
- More on PrEP: With evidence that risk of HIV transmission persists 6 months into ART [989], a program for discordant couples to provide PrEP for 6 months and ART to the person with HIV simultaneously makes a lot of sense — which is what they’re now doing for heterosexual couples in this program in Uganda [24].
- Here’s another study with zero transmissions in serodiscord
ant couples not using condoms when the infected partner is on suppressive ART [1019LB]. Perhaps eventually someone will report another case of HIV transmission in this setting, but it’s obviously pretty darn rare. - In the PROMISE study of prevention of mother-to-child transmission [31LB], TDF/FTC was associated with a significantly higher risk of neonatal death or very pre-term labor than ZDV/3TC. (Both were given with LPV/r.). Results unexplained — and reinforce that there still isn’t a perfect treatment for pregnant women with HIV.
- Infant outcome data from this observational study in Botswana from over 1000 pregnant women receiving TDF/FTC/EFV during pregnancy are quite reassuring [878]. Could this ironically turn out to be safer than TDF/FTC + boosted PIs?
- Now for post-exposure prophylaxis (PEP): In this Australian study [958], TDF/FTC/RPV for non-occupational PEP was safe and well tolerated, with excellent adherence. I’ve never used it for this purpose, but it makes a lot of sense — one prescription, one pill, rare severe adverse events, relatively low cost.
- More on non-occupational PEP [961]: Beware unrecognized acute HIV infection in these very high risk individuals, which presents several management challenges — especially after PEP is started. And they call it “PEPSE” (post-exposure prophylaxis after sexual exposure) in Britain — rhymes with the soft drink.
- Phenomenally good news about occupational transmission of HIV in the United States [1027], which has become vanishingly rare — only one case since 1999!
- Late diagnosis of HIV — meaning when a person already has AIDS — is down significantly here, but still occurs in 1 out of 5 new diagnoses. Check out the wide variation based on region [999].
- Interesting survey on how often HIV tests are done at visits to U.S. doctors’ offices. Guess what, it’s done very infrequently: 0.7% of visits [1082]. One tough question — given the wide variation in HIV prevalence, what is the right number?
- On the laboratory side, this is how HIV testing should be done [621]: 4th Generation antibody/antigen screen, then confirmation using a newer HIV-1/HIV-2 differentiation assay called “Geenius.” And no Western blot!
- HPTN 065 [29] is a fascinating (and long-awaited) study of the effect of financial incentives on linkage to care, virologic suppression rates, and continuity of care. Initial linkage and virologic suppression overall weren’t better with the money, but the financial incentives did improve treatment outcomes in the smallest sites and those with the lowest baseline suppression rates. Continuity also improved. Seems this should be a targeted intervention for our most difficult patients, right? The Freakonomics people would love this one.
- TEMPRANO was an incredibly ambitious, important study done in the Cote d’Ivoire testing two interventions in a factorial design: Immediate vs WHO-recommended ART and 6 months of isoniazid preventive therapy (IPT) vs none [115LB]. Both the immediate ART and the IPT significantly improved outcomes, and the former even did so for those with CD4 cell counts >500. Seems we’re just now waiting on the START study results …
- 3TC and FTC are often used interchangeably, but they are not quite the same drugs. In this analysis from the Netherlands [566], the nod goes to FTC, especially in NNRTI containing regimens.
- Wouldn’t it be great if you could objectively assess adherence in your patients with low-level viremia? This clever study [117] found that untimed drug levels strongly predicted the subsequent risk of virologic failure.
- A single-tablet regimen containing elvitegravir, cobicistat, and FTC, and tenofovir alafenamide (TAF) was noninferior to one containing TDF [113LB], with less effect on kidney function and bone [143LB]. (Disclosure: I was the presenting investigator on the latter study.) Seem likely that these safety benefits will play out to be meaningful in long-term treatment, and in those with risk factors for renal disease right now. The TAF regimen is currently under review by the FDA.
- Here’s another study showing that in second-line therapy, those with more resistance at baseline “paradoxically” have better virologic outcomes than patients with less. Lessons: 1) adherence matters A LOT; 2) NRTIs retain activity even with resistance; and 3) our resistance algorithms derived in the 1990s are lousy.
- The LATTE study [554LB] looks at oral cabotegravir plus rilpivirine as a maintenance strategy, mostly in anticipation of these two being used as long-active injectable agents. Since the last presentation, the 96-week data show this is still performing as well as EFV-based standard treatment. But in a glass half full/half empty result, two additional patients have failed, both with NNRTI resistance. (The first failure had both integrase and NNRTI resistance.)
- Remember the maturation inhibitor bevirimat (R.I.P.)? The second generation compound BMS-955176 looks much more promising [114LB], with retained activity even against viruses with baseline gag polymorphisms (the Achilles’ heel of bevirimat).
- If you’re using dolutegravir after failure of raltegravir or elvitegravir, resistance at Q148 plus two other mutations will significantly reduce DTG activity[609]. Otherwise the drug should be active.
- Is the risk of endstage liver disease in HIV/HCV coinfection reduced in the current ART era? Unfortunately no, says this Canadian analysis, making treatment of HCV in this population still critically important [638].
- In the ION-4 study for HCV genotype 1 or 4, sofosbuvir/ledipasvir for 12 weeks had a 96% HCV cure rate. The study included some very treatment-experienced patients and 20% overall had cirrhosis [152LB]. The one baseline characteristic predicting treatment failure was black race, many of whom were receiving TDF/FTC/EFV — raising questions about a possible pharmocogenomic issue leading to the interaction.
- Adding SOF/LDV to a TDF/FTC, boosted PI containing regimen increases TDF levels by 30-60%[82]. If there are baseline renal issues, probably best to switch ART before starting this HCV treatment if possible — and if not, either use a different HCV therapy (the pariteprevir/ombitasvir/etc combo if on ATV/r, or one of the few remaining indications for pegIF/RBV + SOF), or monitor renal function closely.
- In the ALLY-2 study for HCV (any genotype), sofosbuvir plus daclatasvir for 12 weeks cured 97% of coinfected study subjects, treatment naive or experienced [151LB]. An 8-week course in treatment naives was less effective (76% cure). Daclatasvir (an NS5A inhibitor) is currently under review by the FDA.
- Here’s a surprising but important negative study result: body composition (in particular regional fat gain) was not significantly different between raltegravir, atazanavir/r, and darunavir/r-based regimens [140]. Lipoatrophy may be rare, but fat accumulation (especially visceral) remains a common problem, one that discouragingly cannot be directly ascribed to any specific medication or drug class. And note that both this study and the next one on rosuvastatin were led by Grace McComsey from Case Western, clearly one of the field’s best clinical researchers.
- Rosuvastatin slows progression of carotid intima media thickness [137] and atorvastatin reduces non-calcified coronary artery plaque volume [136]. Large study of pitavastatin in HIV infected patients who otherwise wouldn’t qualify for statin therapy due to start soon.
- If you thought the NA-ACCORD analysis of abacavir and cardiovascular risk [749LB] would settle the issue of whether the drug leads to increased cardiovascular risk, no such luck: Some of the study’s analyses showed a significant association between abacavir and MI, others did not. I was reluctant to use the drug in patients with high CV risk before CROI 2015, and still am.
- Cumulative exposure to tenofovir — and even more so atazanavir — increases the risk of chronic kidney disease [142]. Suspect the latter is not well known to many HIV clinicians, but this is not the first time atazanavir has been implicated.
- More on the renal and bone safety of TAF [795]: Patients with mild-moderate renal disease (estimated GFR 30-69) who were switched to “ECF-TAF” had stable renal function, improvement in urinary protein, and an increase in bone mineral density. Note that these are exactly the kinds of patients for whom TDF and ABC treatment are currently problematic, as they may have both renal disease and CV risk factors.
- Respiratory isolation in possible TB cases in the USA is a huge pain — it makes care more difficulty, delays discharges, and is certainly no fun for the patient and providers. And of course the vast majority don’t have TB. In this important study [824], two Xpert tests ruled out active TB as effectively as 3 sputum smears. Note that the test just got approval for this indication — hope our hospital adopts this testing soon!
- It’s not a randomized clinical trial, but this systematic review [837] found no evidence that early ART worsens outcome of cryptococcal meningitis in high income settings.
- And while we’re on the topic of cryptococcal meningitis, how about a little sertraline, which seems to speed fungal clearance? Folks, we have a winner of of this year’s most surprising “off target effect” [838].
- Next to some cure studies: A toll-like receptor 7 agonist given to SIV-infected monkeys on suppressive ART did two things: 1) triggered easily measurable viral “blips”; 2) lowered SIV setpoint after stopping ART compared to monkeys receiving placebo [108]. Could this be a treatment that both stimulates and reduces the viral reservoir?
- The zinc finger nuclease approach to modifying CD4 cells is making slow progress — now with cyclophosphamide to enhance engraftment [434].
- Here’s a detailed virologic analysis of a patient who experienced virologic rebound after stem cell transplantation from a CCR5 negative donor. Appears there was pre-existing X4 using virus, which was “selected” by the CCR5 negative cells [431]. Original case reported here. This report states that there have now been 7 attempts to cure HIV via this approach, and obviously thus far only one success. Tough work.
- Some excellent plenaries (among those that I saw): Raphy Landovitz on PrEP (with very nifty PowerPoint skills), Steve Grinspoon on cardiovascular disease, Rick Elion on treatment as prevention, and David Cooper on the history of HIV treatment.
Now, about Seattle. I first visited this city in the early 1980s, and it has of course boomed since then, with many more sensational restaurants, high-rises, more traffic, hipsters (though increasingly priced out of living there), and encouragingly much greater access to it’s beautiful waterfront. A spectacular city, with a terrific convention center.
And it’s of course the home of Boeing, Microsoft — Bill Gates gave a talk at CROI in 2002 — and Starbucks, and if if you’re used to the generic Starbucks on your street corner, in your strip mall, or in your hotel lobby, they have some Starbucks in Seattle that look like coffee museums.
We’ll see you next year in Boston, my home town. And let the record show that there has never been a CROI in Boston that was in any serious way hampered by the weather.
Fingers (numb though they might be) crossed.
February 21st, 2015
Fusobacterium, Pharyngitis, and the Limits of Limiting Antibiotics
A paper on pharyngitis in young adults, just published in the Annals of Internal Medicine, is creating a controversy in the intersecting worlds of primary care and Infectious Diseases. The first author is Robert Centor, of the famous Centor criteria that assess the likelihood of group A strep. He’s been writing about our need to expand diagnostic considerations in sore throat for several years, starting with this excellent editorial.
The Physician’s First Watch summary of the new paper was spot-on, so I’ll just quote them here (bolding mine):
Some 310 young adults (aged 15–30) presenting with pharyngitis at an Alabama university clinic underwent polymerase chain reaction testing for bacteria in throat swab specimens; 180 asymptomatic students were also tested. Fusobacterium necrophorum was identified in 21% of patients with pharyngitis (and 9% of asymptomatic students), while group A streptococcus was found in just 10% of patients (and 1% of asymptomatic students). Clinical presentations were similar for F. necrophorum and group A strep.
From the perspective of patient management, there are two interpretations circulating about this paper — one that it encourages antibiotic prescribing, the other that it does no such thing.
The controversy is nicely encapsulated in this comment on a listerv (remember those?) for pediatricians, which was shared with me from a very reliable source (she didn’t write the comment):
OMG! So if it is cultured [sic] from the throat, it is the cause of the infection,right? So now everyone who has this in their throat and doesn’t feel well needs antibiotics, right?
Allow me to take both positions:
Pro Antibiotics: Some really terrible exudative pharyngitis in young adults is group A strep negative. This study shows that fusobacterium is more common than strep in this age group. We know it can cause peritonsillar abscess and, even worse, septic jugular vein thrombophlebitis (Lemierre’s syndrome), both of which are preceded by sore throat — and both of which are more common than acute rheumatic fever. If we treat the really sick teenager and young adults who are group A strep negative with an antibiotic with activity against fusobacterium — penicillin and other beta lactams, please, not azithromycin — not only will these youngsters get better faster, but we can prevent potentially life threatening complications.
Versus:
Anti Antibiotics: Most pharyngitis is causes by respiratory viruses. There is no way to detect fusobacterium as a cause of pharyngitis in clinical practice, so if most cases get treated “empirically”, this will be massive unnecessary treatment. Detection of the organism by polymerase chain reaction in the study does not prove that fusobacterium is the cause of the pharyngitis, especially since it’s found in a not insignificant proportion of asymptomatic individuals (9%). There is furthermore no proof that treatment of fusobacterium will hasten symptom improvement or, more importantly, prevent Lemierre’s.
The latter position was nicely articulated in an accompanying editorial in the Annals written by my colleague Jeffrey Linder — a primary care physician who has published extensively on this subject and admittedly a much more reliable expert on the topic than I.
But let me risk taking a position slightly different from Jeff and, I’m sure, many of my ID brethren, one that I confess is rooted not so much in data but in experience caring for several young adults with Lemierre’s. Importantly, Jeff and I don’t disagree — it’s more a matter of emphasis.
Remember this — patients with Lemierre’s are often critically ill. They frequently require ICU care, have high spiking fevers with staggeringly high white blood cell counts, and invariably have multiple septic pulmonary emboli with potentially other metastatic sites of infection, including the brain.
It’s a terrifying illness — these are most commonly previously healthy high school and college-age kids, so the stakes are high. No, we don’t know that treatment of severe pharyngitis “caused” by fusobacterium will prevent Lemierre’s, but doesn’t that make biologic sense?
So let’s go with the pediatricians’ common-sense approach to clinical care, and make a decision about antibiotics based on that sixth sense of “is the kid really sick?” If so, go with some penicillin — especially if at the first encounter they didn’t get treated, and then they come back a few days later even worse.
Or, if you prefer, listen to the guru of pharyngitis himself, Dr. Centor, and his interpretation of national guidelines:
We believe that following the American College of Physicians/Centers for Disease Control and Prevention guidelines endorsed by the American Academy of Family Physicians would decrease the risk of Lemierre syndrome in adolescents and young adults. Using these guidelines, physicians can choose to prescribe antibiotics for patients with a pharyngitis score of 3 or 4 (three or four of the following: fever, absence of cough, tender anterior cervical lymph nodes, tonsillar exudate).
Makes sense to me.
February 15th, 2015
Should Antibiotics be Part of End-of-Life Care?
There’s been some truly outstanding work done recently on end-of-life care, and how we deal with it — or more accurately, how we typically don’t deal with it until the very last moment, at which time often many unfortunate decisions and events occur. Here are three I can strongly recommend:
- Roz Chast’s Can’t We Talk About Something More Pleasant? is probably the most widely read book among my circle of friends right now, as many of us have parents of a certain age. Chast is a cartoonist best known for her distinctive squiggly cartoons in the The New Yorker — here’s one of my favorites — and is already familiar to many ID doctors because of her morbid fascination with dreadful diseases, some of them infections. But this extended memoir about her aging parents is a remarkably ambitious book, by turns funny (of course), moving, and ultimately heartbreaking, especially when touching on the fraught relationship she had with her mother.
- If drawings aren’t your thing, then give Atul Gawande’s Being Mortal a shot. In his usual clear prose — which miraculously reads neither overly technical to the lay public or overly simple to health care providers — he deftly lays out what many of the challenges are in the care of both the elderly and the terminally ill. For example, how can we negotiate the conflict between personal freedom versus safety in our loved ones who have such a limited time to live? If 90-year-old Uncle Milton with severe congestive heart failure wants to eat pickles, but pickles contain too much salt for his diet, should we stop him? The recent Frontline about Atul (we’re on a first name basis, brush with greatness) and his book make me hope that his sensible voice will lead to progress in this difficult part of health care.
- Finally, if you’re looking for a terrific podcast, check out this Radiolab piece called Dead Reckoning. The first part is about surviving rabies — good stuff for ID doctors, and yes, we’re that bizarre — but the piece finishes in more familiar territory, dealing with medical options at the end of life. In a section called “The Bitter End”, it cites a now famous study done of Hopkins med school graduates, demonstrating that doctors say they would forego end-of-life treatments if they had an incurable brain disease (something akin to dementia) — a big contrast with the people interviewed on the street, most of whom want all this stuff. The end-of-life treatments these doctors considered are shown in the figure below:
Note the ninth one on this list — antibiotics — and consider a scenario that no doubt will be familiar to doctors and nurses the world over, and not just to ID doctors: The patient who has metastatic cancer, or advanced dementia, or irreversible advanced heart or lung disease, and the decision has been made to withhold CPR, mechanical ventilation, tube feeding, and dialysis.
But antibiotics? They often remain an option to the very end, frequently in the face of other conditions with terrible prognoses and little chance for reversal. Those recurrent urinary tract infections, aspiration pneumonias, infected pressure sores, and other indignities of our failing bodies can be treated with antibiotics (though with progressively less effect) — but to what end?
So read the case, take the poll, then listen to the Radiolab piece.
A 94-year-old woman with advanced dementia is referred to the hospital from her nursing home because of fever and a change in mental status. At baseline, she can sit in a chair but cannot walk, feed, or bathe herself; she can respond to simple questions, but has little spontaneous speech. She has an existing DNR order — no CPR or intubation. There have been two admissions to the hospital over the past six months (pneumonia, urinary tract infection), after which she returned to the nursing home. In the emergency room, her evaluation is notable for a fever and somnolence. The urinalysis shows 50-100 WBC. The health care proxy, who lives in another state, is unavailable.
February 8th, 2015
Snowstorms-a-Plenty ID Link-o-Rama
A few items to discuss as we settle in for yet another Boston megastorm:
- The measles outbreak continues to bring forth excellent commentaries on the selfishness of vaccine-refusers, with this one from Frank Bruni one of my recent favorites. Question: Will it take a hospitalization — or even worse, a death — of an American child with measles to stop this ridiculousness?
- This piece in the Wall Street Journal describes the negotiations going on behind the scenes between pharmaceutical companies and payers regarding HCV therapy. I’m sure something like this has happened before in non-ID fields (Oncology or Rheumatology would be my best bet), but I have never experienced anything like this as an ID doctor — meaning, both the clinician and the patient seem to be completely left out of the discussion. Hello? Can anyone hear us?
- Can a fecal microbiota transplant from an overweight donor lead to obesity in the recipient? That’s the implication in a case report over in Open Forum infectious Diseases. While the case does not prove causality (other factors could have contributed to the weight gain), the plausibility of the FMT leading to obesity is at the very least suggested in the clinical course and supported by animal data where indeed the microbiome plays a major role in metabolism. Don’t miss this excellent editorial from real experts in the field.
- More evidence that booster vaccines for hepatitis B are probably not needed, at least according to a study in health care workers. It’s that “long-lasting amnestic response” — meaning even when antibodies decline, exposure to the antigen is rapid and protective. The hepatitis B vaccine was an extraordinary and unheralded major advance in safety for healthcare workers.
- There are lots and lots of strange bacteria in the NYC subway, says this fascinating, much-publicized and (let’s face it) extremely unsurprising report published in Cell. Best part: “Almost half of all DNA present on the subway’s surfaces matches no known organism.” If I might make a personal comment: when my family moved to New York City in the 1970s, there were no doubt even more bizarre microbes living down there. Anyone have a spare autoclave?
- The coformulations of atazanavir/cobicistat and darunavir/cobicistat are now available. Definitely more convenient to have them together (avoiding selective skipping of ritonavir), and if they’re price-equivalent to the separate dosing of the drugs, then they eventually will be widely adopted. Otherwise — and especially with the approval of generic ritonavir — they could face a tricky pharmacoeconomic challenge. Now throw in 300 mg of lamivudine and pull of a GARDEL study equivalent, now that could be transformative.
- Wonderful “Call to Arms” about the crisis facing Infectious Diseases by Ron Nahass, who in our field is something of a true visionary: He understands — and fortunately can communicate — the value of ID doctors independent of billing units in a fee-for-service environment. Required reading for the gloomy ID doc (and there are lots of us out there). My favorite line: “Develop a true value of our intellectual capital.” In other words, get paid for being smart, not for doing a procedure.
- Being cold could increase the chances of catching a cold. Score one for common wisdom!
As the latest storm intensifies up here in Boston, it’s worth disabusing the world at large of the perception that the whole Northeastern United States has the same weather. Today the high temperature in Washington DC was 68 — yes, you read that right — Philadelphia had high 40s and obviously no snow, and New York (funky subway bacteria notwithstanding) had a dreary but otherwise very manageable winter day.
Here, it’s 15 degrees, and 12-18 inches of snow are expected over the next 24 hours.
Speaking of snow — here’s something to do in your spare time:
January 28th, 2015
Quick Question: Should We Still Be Recommending This Year’s Flu Vaccine?
From a football-obsessed primary care provider, written to me on one very snowy day in New England:
Hi Paul,
I’ve been reading about this year’s flu vaccine, and how ineffective it is. Not surprisingly, my patients have been hearing this too, and it has only increased their reluctance to go through with it. Should I just cut my losses and stop recommending it this year? Seems we have much more important things to worry about, such as measles in Disney and deflated footballs.
Go Pats!
Kerry
p.s. I think the Pats are really geniuses. And they realized that if they pump the balls to 11.5 PSI right before the game, then heat them (microwave? hair dryer? ) to get up to 12.8 PSI, then hand to the refs who measure at at least 12.5 PSI, then let them cool down for a while. And, as with taxes, if it doesn’t say you can’t do it, then you can do it. Genius.
Dear Kerry,
The quick answer is yes, we should still be recommending it, but I share your pain. (I mean about the flu vaccine, not about Deflategate.) My experience this year is that when I suggest a flu vaccine, my reluctant patients not only decline, but look at me as if I’ve recommended that they undergo a colonoscopy without sedation. You must be kidding me, everyone knows this year’s vaccine is a dog.
So why recommend it? First, it still works some of the time, even if the H3N2 match isn’t good (there are influenza B strains as well that are included in the vaccine). 23% effective is better than nothing, which means that these 23% not only won’t get sick with flu themselves, but they won’t spread it to the people who are the most vulnerable (the very young, the elderly, and pregnant women).
Second, there’s really nothing else out there that works, unless you want to take oseltamivir continuously, all flu season — this is not recommended, and would be very expensive. I suppose our patients could seal themselves off in a polyurethane bubble until Spring — which would be particularly difficult if they like to ski.
Third, there’s at least a little evidence that even if the flu vaccine doesn’t work, it might attenuate the severity of clinical influenza, reducing the risk of pneumonia and hospitalization. As an optimist, I plan to believe this last item until someone proves it’s not true.
Your email also gives me a chance to link a truly outstanding review over on Medscape called, Why is Influenza So Difficult to Prevent and Treat? It’s an interview with two experts in the field, Drs. Andrew Pavia and Gregory Poland, and really the title should have been expanded to “Why is Influenza So Difficult to Predict, Prevent, and Treat?” I always get asked about the upcoming flu season by my friends, and the honest answer is — WE HAVE NO CLUE.
The Medscape piece is top-notch, a very readable update on these issues. I learned a lot about this tricky infection, including the key fact that if we delayed choosing the strain for next year’s vaccine for a few months, we’d probably have a better vaccine match from year-to-year. Plus I was introduced to the seat belts analogy, which goes like this: “Seat belts may not protect from high-speed crashes all the time, but some protection is better than none.” Exactly!
So go ahead and continue to recommend it. I find that if my patients balk, I don’t push it, but better to have a uniform medical position on flu vaccine than to waffle.
And about that game on Sunday — 20 days until pitchers and catchers report for Spring Training.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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