An ongoing dialogue on HIV/AIDS, infectious diseases,
September 24th, 2011
Warning: Viral Replication is Hazardous to Your Health
When studies evaluate the prognostic importance of measuring HIV viral load, they generally do so by assessing a single measurement rather than values obtained longitudinally. One obvious limitation of this approach is that baseline VL poorly predicts outcome after ART initiation — a finding in stark contrast to the original description of VL from the MACS cohort prior to effective HIV therapy.
Now, a collaborative group of researchers report the effect of something they call “viremia copy-years,” a marker of cumulative exposure to viral replication. This “area under the viral load” curve was calculated in 2027 patients starting ART at eight US sites from 2000-2008. Total number of VL measurements was a whopping 21,665.
The results are striking: viremia copy-years strongly predicted all-cause mortality — and did so more powerfully than either cross-sectional VL measurements or CD4-cell count. Each 1-unit increase in log10 copy years/mL was independently associated with a 44% increase in mortality risk.
The take-home message from this skillfully done study is that viral replication is bad for your health — even if your CD4-cell count is OK. And why might this be the case? The authors write:
We speculate the number of viremia copy-years, as a measure of cumulative plasma HIV burden, serves as a surrogate for and perhaps is the underlying driver of cumulative inflammation and immune system activation that approximates such long-term inflammatory biomarker effects.
A few other thoughts:
- Is high viremia copy-years a lab proxy for poor medication adherence? Probably — but this doesn’t invalidate the results.
- Of course in clinical practice, few of us have the calculus skills (remember integrals?) actually to calculate something like an area under the viral load curve. OK, I don’t have the math skills.
- A study evaluating whether pre-ART viremia copy-years influences prognosis would be particularly fascinating — and highly relevant for the when-to-start question.
- The results reinforce the findings from this interesting study linking time of uncontrolled viral replication to an increased risk of lymphoma — paper summarized in Journal Watch AIDS Clinical Care.
So even though we are unlikely to start using this viremia copy-years value in clinical practice, these data certainly make intuitive sense — and reinforce the notion that getting this lethal virus under control is the logical way to improve outcomes.
September 22nd, 2011
Common Sense on HIV Testing
There’s an editorial in today’s Boston Globe that concisely (188 words) describes the problems with both the current and proposed HIV testing laws in Massachusetts.
I’ve not been shy about the fact that I agree with every word of this piece.
And though I strongly recommend reading the whole editorial — it’s very well written — if you don’t have time, just read the title:
HIV Testing: No Need for Special Rules
That says it all.
September 17th, 2011
Drinking Coffee Prevents MRSA
I follow the medical literature on coffee very closely.
Why? Because I’m completely addicted — and, judging from the lines at the Starbucks, Dunkin’ Donuts, etc at the airports before early morning flights, I am not alone.
(It’s just one cup a day. Any more and say hello to palpitations, jitters, sweats, and long sleepless nights. Is there ever such a thing as a short sleepless night?)
So I thank a former ID fellow for pointing out this key paper:
We performed a secondary analysis of data from the 2003–2004 National Health and Nutrition Examination Survey to investigate the relationship between the consumption of coffee, hot tea, cold tea, and soft drinks, and MRSA nasal carriage …Individuals who reported consuming coffee had about a one-half reduction in the risk of MRSA nasal carriage relative to individuals who drank no coffee (odds ratio = 0.47; 95% confidence interval, 0.24–0.93).
(Brits will take solace that drinking tea was similarly effective.)
And let the record show that despite various researchers trying to blame coffee for ulcers, high blood pressure, coronary artery disease, gout, birth defects, anxiety, and several cancers — most notoriously pancreatic cancer — the evidence that it causes any of these things is weak at best. In fact, the coffee/pancreatic cancer paper is taught in some statistics classes as an example of how poorly designed case-control studies can give misleading results.
So in defense of this one cup a day addiction, let’s bring on more articles on the health benefits of coffee.
September 11th, 2011
Must-Read Paper: “Antiscience” and Lyme Disease
As I’ve written before, there are few clinical encounters more challenging for Infectious Diseases specialists than the patient who, despite negative standard diagnostic testing, believes he/she has Lyme disease.
Now, in Lancet Infectious Diseases, comes a paper entitled “Antiscience and ethical concerns associated with advocacy of Lyme disease.” It meticulously describes the distinctive world of alternative diagnosis, treatment, and passionate advocacy related to Lyme.
Some highlights — first, the background:
As with other antiscience groups, some Lyme disease activists have created a parallel universe of pseudoscientific practitioners, research, publications, and meetings, arranged public protests and made accusations of corruption and conspiracy, used harassment and occasional death threats, and advocated legislative efforts to subvert evidence-based medicine and peer-reviewed science.
And those odd diagnostic tests, often paid for out-of-pocket by the patient?
Despite warnings from the US Food and Drug Administration and the CDC about the potential unreliability of unvalidated diagnostic tests for Lyme disease, many LLMDs [Lyme-literate MDs] continue to use such assays. [Specific assays are cited in the full article.] Lyme specialty laboratories are favoured by some activists and LLMDs because their non- standard testing methods and interpretation criteria often lead to more positive results than other laboratories that rely on validated methods.
What to do?
Many patients who have been labelled as having chronic Lyme disease arrive at this diagnosis as a consequence of inadequate or frustrating previous medical care for symptoms that are difficult to define. Patients who suspect or who have been diagnosed with chronic Lyme disease should consider seeking a comprehensive assessment from an empathetic physician..
My advice: Read the full article. (That’s the polite form of RTFA.)
September 4th, 2011
“Novel” Approaches to Initial HIV Therapy: Part II
Two studies were just published on alternative strategies for initial HIV therapy. I’ve already reviewed the first one
The second paper is a single-arm (n=112) study of darunavir/r (once daily) plus raltegravir, the latest riff on the “NRTI sparing” approach.
As I mentioned when I first covered this study, the high rate of virologic failure — 26% overall, and a whopping 43% (21 of 49) with viral loads > 100,000 — came as a complete shock. In fact, I would have bet good money that this regimen would work just fine. (Glad I’m not a betting man — except in poker.) Five of the 28 virologic failures developed integrase resistance, all of them from the high VL stratum.
Why is this so surprising? You have the antiviral potency of raltegravir plus the high genetic resistance barrier of boosted darunavir — so what went wrong?
The study authors offer some possible explanations for these disappointing results (suboptimal adherence, asymmetrical dosing, lowered darunavir concentrations from raltegravir, minority variants resistant to raltegravir), but the bottom line is that this regimen just didn’t work very well. A fully-powered comparative study (darunavir/r plus raltegravir or TDF/FTC) is ongoing in Europe; I’m sure their DSMB is keeping a close eye on the results.
So two non-standard approaches to initial HIV therapy, with TDF/FTC + etravirine looking promising, and darunavir/r + raltegravir much less so.
September 3rd, 2011
“Novel” Approaches to Initial HIV Therapy: Part I
It’s been several years since the “preferred” or “recommended” initial regimens for HIV treatment have been consolidated into one of the following four:
- TDF/FTC + efavirenz
- TDF/FTC + atazanavir/r
- TDF/FTC + darunavir/r
- TDF/FTC + raltegravir
Any room for improvement in this “TDF/FTC + key third drug” approach? With the recent approval of TDF/FTC/rilpivirine, certainly this will have a role in some patients, but the issues of excess virologic failure and resistance in those with high viral loads will likely limit its use.
And though extended release nevirapine has been available for months, I confess it hasn’t really occurred to me to use it in a patient starting treatment given the other options out there. (And even those who are currently stable on NVP twice daily don’t seem eager to switch — I’ve offered.)
Now along come two interesting papers testing alternative initial treatment strategies. Both have quite interesting results that definitely got my attention when presented earlier this year at major meetings, small size of the studies notwithstanding.
The first is a blinded, randomized trial comparing etravirine and efavirenz, both given with 2 NRTIs. Note that the etravirine was dosed once-daily — not the twice-daily manner in which it is approved — and given in the older 100 mg (very crumbly) tablet formulation. Note also that the primary endpoint was the percentage of patients with Grade 1-4 drug-related CNS side effects, and not virologic efficacy. Since it was powered off differences in this side effect, only 157 patients were enrolled, not the 600 or so typically seen in a comparative study of efficacy.
Nonetheless, the results are impressive: 76% vs 74% in the etravirine and efavirenz arms respectively have VL < 50 at week 48, and for the group with baseline VL > 100,000, the results are 74% vs 67% — which is perhaps the first time in HIV study history that a regimen is numerically superior to EFV in this high viral load stratum. Also of interest, among the four patients with virologic failure on etravirine, zero show emergent resistance mutations — very unusual for an NNRTI — vs 3 of 7 for efavirenz.
Oh, and the primary endpoint — the occurrence of CNS side effects — significantly favors etravirine, as do lipid changes.
These results have to be considered encouraging on multiple fronts, including efficacy (caveat: small sample size, I know), resistance, tolerability, and lipid effects. Plus, with the newer 200 mg formulation of etravirine, this is an initial regimen of just three pills once-daily. Consider me impressed.
(Nerdy HIV specialist historical quiz question: how many pills/day was etravirine when in phase I/II studies? Hint, it was a lot.)
For another novel approach to initial therapy, read
August 31st, 2011
It’s Time for Antibiotic Placebos
As I’m sure you all agree, it’s high time we had a good antibiotic placebo.
Just think — we’d be able to prescribe a 100% effective treatment for viral respiratory tract infections, with the assurance of no risk of antibiotic resistance, C diff, allergic reactions, tendon ruptures, photosensitivity, drug-drug interactions, or any of the myriad other side effects that real antibiotics have.
Plus, based on studies like this one, we could even tell our patients that they’re receiving an antibiotic placebo, and they’d still get better. There, ethical quandaries of placebo prescribing solved.
What inspired this thought on antibiotic placebos was this email exchange:
Hi Paul,
Our primary care group would love to have you come give an update on antibiotics during our Friday conference. Am cc’ing Chuck our practice director to make sure he agrees with the topic. There’s a lot of variability in antibiotic prescribing within our group, hoping you can enlighten us.
Thanks,
Nora
So Chuck chimed in:
Sounds great. But Nora, what do you mean “variability in antibiotic prescribing” if everyone gets azithro?
Chuck
Now it hardly bears mentioning that Chuck is one of the funniest doctors I know, and that he was being facetious.
But just think how much macrolide resistance we could avoid if, instead of a “Z-pack”, we had an “S-pack” (“S” for sucrose). That’s 6 pills (two on the first day, then one a day for 4 additional days), with the promise that it will be just as effective as azithromycin.
And if you don’t believe me, read this paper in The Lancet for proof (figure from paper in above image). And this news article in The Onion for more information.
Sucramycin (brand name Sucracil®), anyone?
August 24th, 2011
Hepatitis C and … Baseball?
From the prolific folks at NATAP came this surprising announcement:
The Cardinals are stepping up to the plate against Hepatitis C. Starting Monday, August 22, fans will be able to get free Hepatitis C screenings at Busch Stadium. It’s part of a nationwide effort by Major League Baseball to bring attention to the causes and treatment of Hepatitis C.
Cardinal fans — and believe me, there are lots of them out there — will note that this opportunity comes the same month as the Willy McGee and Matt Holliday Bobblehead games, coming up this Thursday and Friday respectively.
But giveaways aside, why is MLB doing this? There are lots of diseases out there for which they could offer screening, though clearly colon cancer would be hard to pull off in a ballpark.
One possibility is that the teams that are offering it — the Cardinals, Astros, White Sox, and (of course) Cubs — need a distraction from the fact that the odds of their appearing in the post-season are fading daily.
Another is that HCV is still looking for it’s ideal Magic Johnson-like spokesperson, something John Bartlett (the Hopkins one) has always said the disease lacks. Plenty of bad candidates over the years — Evel Knieval, Jack Kevorkian, James Earl Ray, Linda Lovelace.
So is some appealing baseball superstar about to step forward?
Let’s just hope he’s not on the Brewers — beer and HCV not a great mix.
August 19th, 2011
A Reason To Continue Restrictive HIV Testing Laws? Not Really …
The pending HIV legislation is much on my mind these days, for reasons I outlined here. Bottom line is that I don’t think it’s good for patient care, and we’re missing a real opportunity to make things better here in the Bay State.
But yesterday I heard a perspective on the bill I hadn’t considered, and it went something like this:
We still need the laws about HIV testing — and the added protection of privacy — because of the disgraceful response of the medical community to AIDS when it first burst on the scene in the 1980s.
Examples: The physician who refused to operate on an AIDS patient. The hospitals that tried to avoid having AIDS cases since it would scare other patients away. The thoughtless release of the AIDS diagnosis to employers, family members, friends. And so on.
And I get that — I understand that doctors, nurses, policy makers, and the rest of the large community that makes up the “medical system” didn’t always behave so wonderfully when faced with this new and scary disease. Back in 1989, I heard a director of a Cardiac Intensive Care unit say that having an AIDS patient in his unit was a “waste of resources.” That wasn’t right then, and it isn’t right now.
But here’s some items to consider as a counter argument:
- It was people from all aspects of society behaving badly, not just the medical community. Remember Ryan White? In fact, I’d argue it was a relatively smaller proportion of health professionals compared to the rest of the population.
- Things are different now — so very different. HIV is treatable, for everyone who can get diagnosed and into care. Check out this paper from Hopkins, just published, outlining just how treatable it is, even in a mostly inner city, poor, minority population. Not meaning to diminish the seriousness of HIV in any way, I would argue that this single fact — the treatability (is that a word?) of HIV — makes restrictive HIV testing laws obsolete. Paul Farmer has said repeatedly that making a fatal disease treatable dramatically reduces it’s stigma. And who are we to disagree with Paul Farmer?
- Didn’t the medical community also have the opposite response? The doctors, nurses, social workers, research scientists, and other health professionals who devoted their combined efforts to caring for people with HIV, and improving their prognosis? Seems that this should also be acknowledged when citing painful anecdotes about bad behavior.
And since these dedicated HIV specialists are universally in favor of removing restrictions on HIV testing and the proposed barriers to provider communication, that must be telling us something.
August 11th, 2011
Next Single-Pill HIV Treatment Approved, and It’s Not Called “B-Tripla”
One famous HIV clinician/clinical researcher likens co-formulated TDF/FTC/EFV (Atripla) to a “Godzilla,” so dominant has the treatment become as initial therapy for HIV. He bases his comments on this study done at his institution, showing that in 2007, fully 85% of patients starting treatment in their clinic began TDF/FTC/EFV.
Does this big lizard of a regimen now have a competitor? Maybe:
On August 10, 2011, FDA approved Complera, a fixed dose combination (FDC) drug product containing emtricitabine/rilpivirine/tenofovir DF (FTC/RPV/TDF) for the treatment of HIV. The recommended dose of Complera™ is one tablet, containing 200mg/25mg/300mg of FTC/RPV/TDF, once daily, taken orally with a meal.
A couple of quick thoughts as I get used to the name:
- As I’ve written before, the data suggest that using TDF/FTC/RPV involves a trade-off between safety/tolerability (favoring RPV) and efficacy (favoring EFV). Will this efficacy difference be reduced now that the single-pill treatment is available? This study is testing that very question. For now, probably best to limit use to those with HIV viral load < 100,000.
- Are people going to be using TDF/FTC/RPV as a switch strategy from virologically suppressed patients? The answer to that is undoubtedly yes, though of course this will be an off-label use, and clinicians might get push-back from payors. (I did already when trying to prescribe TDF/FTC + RPV separately to a treatment-experienced patient.) Again, ongoing studies are testing this switch strategy, both from boosted PI-based regimens and from EFV — the latter particularly important since EFV induces metabolism of RPV, lowering levels for a least a few weeks.
- Rilpivirine must be taken with a meal — not just food, but a meal — and it’s not clear yet whether this will be something that all patients can reliably do in clinical practice.
- One area where I’m sure the treatment will get some traction is in women of childbearing potential, as some clinicians are leery of prescribing EFV. One caveat of course is that there are no actual pregnancy data yet on this new drug, but at least at the outset RPV is a Category B drug (EFV is category D).
- We should expect the usual delay between this approval and the appearance of the regimen on ADAP, other government, and private insurance formularies.
Isn’t it odd that pronunciation of these new drugs is often a mystery? I’m still not sure whether it’s etra-VIR-ine or e-TRA-virine, IN-telence or In-TEL-ence, and is “Edurant” pronounced EE-durant or EH-durant or ee-DUR-ant?
As for Complera, I’ll assume the accent is on the second syllable until I hear otherwise.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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