An ongoing dialogue on HIV/AIDS, infectious diseases,
April 18th, 2011
When to Start Antiretroviral Therapy, Take 3
A third observational study on “When to Start ART” has just appeared in the Annals of Internal Medicine, “The HIV-CAUSAL Collaboration.”
As with ART-CC and NA-ACCORD, it’s a large study, starting with over 20,000 people with HIV with baseline CD4s >500 receiving care in Europe and the United States. Out of this group, 8392 experienced CD4 declines into the 200-500 range and are included in this analysis. Outcomes of interest are mortality and new AIDS-related events, depending on when combination ART (“cART”) was started.
The results?
Initiation of cART at a threshold CD4 count of 500 increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 300 and 500.
The authors also cite a “number needed to treat” of 48 for starting at 500 rather than 350 for prevention of AIDS or death, a fairly low number when compared to some interventions widely adopted in cardiovascular disease.
While not the blockbuster results of the NA-ACCORD study — whose nearly two-fold reduction in mortality for starting at >500 remains both unreproduced and, let’s face it, unexplained — these results still point to a substantial clinical benefit of starting ART before CD4s fall too low.
In addition, none of these large observational studies even hints at a negative effect of starting early on clinical outcomes, and other potential benefits of treating HIV (reduced risk of HIV transmission, reduced long-term incidence of non-AIDS events) can’t be included.
As nicely summarized in the accompanying editorial, the quantitative benefits of early ART can’t come close to the benefits of late ART, which are nothing short of miraculous.
It’s up to us — patients, providers, society — to determine whether early ART is worth it.
April 15th, 2011
A “New” Antiretroviral Option Quietly Enters the Market
There’s a new antiretroviral option out there, a 400-mg extended-release tablet formulation of nevirapine that can be dosed once daily.
However, you might not have noticed, since it’s not really that new, and it’s not clear that this formulation offers any significant advantages over the nevirapine we already have. Writes Keith Henry over in Journal Watch:
Issues that will temper enthusiasm for the new formulation include continued concern about serious adverse effects with nevirapine (namely, Stevens-Johnson syndrome in the general patient population, and liver toxicity in women with CD4 counts >250 cells/mm3 and men with CD4 counts >400 cells/mm3), the availability of safe and effective non–nevirapine-containing regimens, the likely approval of additional one-pill once-daily regimens (e.g., tenofovir/FTC/rilpivirine, abacavir/3TC/dolutegravir, and tenofovir/FTC/elvitegravir/cobicistat), and the possibility of nevirapine coming off patent in 2012 (which creates potential for a lower-priced generic).
Add to these issues the need to still take* the 200 mg once-daily lead in for 14 days, and one wonders how much use this “new and improved” nevirapine is going to get.
(*I know, split infinitive — it just sounds better that way!)
April 11th, 2011
Organ Transplants from HIV-Infected Donors
On the heels of last month’s report of HIV transmission from an organ donor — covered here in Journal Watch — comes this remarkable article in the New York Times about lifting the ban on organ donation from donors known to be HIV positive.
Naturally, the first group of patients slated to receive these HIV positive organs would have HIV themselves.
But the article goes further:
But some experts, including Dr. Segev and Dr. Kuehnert, say they can foresee such transplants even for H.I.V.-negative patients because contracting H.I.V. would be preferable to kidney or liver failure.
“I don’t want to minimize living with H.I.V, but it is a medically treatable disease now,” said Charlie Alexander, president of the United Network for Organ Sharing, which manages the country’s organ transplant system. “In certain cases, I think it would be medically appropriate.”
If ever there were proof that HIV is now a highly-treatable condition, I’d say this could be Exhibit One.
April 9th, 2011
And Now, for a More Comprehensive CROI Report …
Although I’ve already provided a Really Rapid Review™ of the 18th Conference on Retroviruses and Opportunistic Infections (CROI), the editors of Journal Watch/AIDS Clinical Care have put together a more comprehensive summary here.
I sometimes wonder what research from these conferences will not only stand the test of time, but will grow in importance and be viewed one day as a landmark event.
Past notable examples include the first triple-therapy study with indinavir — which showed that virologic suppression could be durable — presented way back in 1996 at the 3rd CROI, and the phase III study of raltegravir in patients with highly drug-resistant virus, presented 11 years later at CROI 14.
My bet this time? While it’s notoriously tough to make predictions, especially about the future, my vote goes to these zinc finger nuclease studies — which are part of a very concerted and growing effort to cure HIV.
April 5th, 2011
Scamming Academic Journals
Academic scams are not just limited to meetings.
Every so often, I receive an e-mail that goes something like this:
Dear Dr. Sax,
The journal Contemporary Organic Biosynthesis [journal name made up] covers all the latest and outstanding developments in organic biosynthesis studies. It is one of the leading journals for expert reviews in the field. Please visit the journal’s Web site at www.organicbiosynthesisreviews.com to see our Mission and Scope.
It is my pleasure to invite you to submit the title of your article, a one-page abstract and the submission deadline for the Editor-in-Chief’s approval to editorial@obsr.com. We also invite you to to consider to guest edit a thematic issue to the journal of 5 – 12 invited articles from colleagues of your choice.
Guest Editors of thematic issues and all main contributing authors will receive a free online subscription to the journal for one year.
Sincerely,
Griffila Zaporsky-Branson, PhD [I also made that name up]
Editor-in-Chief
As you probably know if you’re reading this site, I am barely more qualified to write a review on “organic biosynthesis” than Oprah Winfrey. So obviously this is a form letter sent to hundreds (if not thousands) of academic MDs.
But beyond that, how do “journals” like this make money? Is there a large author fee once the scholarly review is written and “approved” by Dr. Zaporsky-Branson? Do they sell advertisements? Do they require a valid credit card before the requested reprints are sent out, with money neatly diverted to someone’s bank account?
Regardless, as with the Nigerian e-mail scams, obviously someone is biting — otherwise these emails wouldn’t exist at all.
April 1st, 2011
Clindamycin or Cephalexin for (Mostly) MRSA?
Over on the Journal Watch Pediatrics site, there’s a summary of a study that compared clindamycin with cephalexin for purulent skin infections in kids age 6 months to 18 years. The results?
MRSA and methicillin-susceptible Staphylococcus aureus (MSSA) were isolated from 70% and 19% of children, respectively … The primary outcome — clinical improvement at 48 to 72 hours — was similar in the cephalexin and clindamycin groups (94% and 97%, respectively), as was the secondary outcome — resolution of infection at 7 days (97% and 94%).
Should we be surprised that cephalexin — an antibiotic with notoriously poor systemic absorption — did so well vs. infections that were 70% resistant to the antibiotic?
Not really — after all, if antibiotics were required for skin and soft tissue infections, we would have perished as a species in the many thousands of years before the discovery of penicillin. Most of the cure comes from the local care, which was done in 97% of patients.
Plus, this study of cephalexin vs placebo in adults found the same exact thing.
Finally, it proves something that Primary Care Providers, Emergency Room Doctors, Surgeons, and Pediatricians have known for some time: If you want to use a weak antibiotic (i.e., almost a placebo) “just in case,” hardly anything beats our old friend “Keflex.”
March 30th, 2011
Journal Club: Even When You Think You Should Wait, It’s Probably Time to Start
Two papers just published in AIDS with relevance to the “when to start” antiretroviral therapy question.
Both apply to certain patients in whom we might consider waiting to start treatment– but both these studies suggest we do otherwise.
The first applies to the patients with slooooow CD4 decline. Perhaps so slow that both you and your patient are very comfortable watching it drift down over the years, from initially normal — let’s say 900 — to 700, then 500 over a 10-year period. After all, with such a slow decline, what could the harm be in waiting?
Certainly I’ve shared this kind of mutual denial with patients of mine, most of whom also have very low HIV RNA levels.
But according to this paper, it’s just this sort of patient who has the worst immunologic response to ART. In reviewing 2,038 patients with pre- and post-ART CD4 trajectories, the study finds that the patients with the slowest CD4 decline have the worst immunologic response to ART. In other words, slope going down predicts slope going up.
As the authors note in their discussion, it’s ironically the other group — those with fast CD4 decline — who have been targeted in HIV treatment guidelines for early ART regardless of CD4 cell counts. But perhaps these data (which are displayed in some very cool figures, by the way) tell us that if one important goal of treatment is maintaining a normal or near normal CD4, then the rate of decline is immaterial — just be sure to start ART before the CD4 count becomes abnormal.
A second paper, from Cote d’Ivoire, looks at patients who recently acquired HIV, another group we might traditionally hold off on treating. Looking at 304 patients with recent seroconversion, the investigators track the time to relevant CD4 thresholds for starting treatment. The results: more than half (57%) have a CD4 cell count < 500 at diagnosis, and 72% are at this level just two years later.
In short, the great majority of patients with recently-acquired HIV meet CD4 criteria for starting treatment sooner rather than later. So while the “time to AIDS” in untreated HIV might average 10 years, in no way should we count this as “time to starting HIV therapy”, which will come much sooner.
March 26th, 2011
Zoster Vaccine for Age 50 and Up? A Resounding “Yea” Vote Here
I was getting off the elevator at the hospital the other day, and a cardiologist greeted me with the phrase every ID doctor in the world will instantly recognize:
Can I ask you a quick question?
It was actually a series of questions, and, as is often the case, it wasn’t so “quick”. But I was happy to help.
Her sister — age 57, living in Virginia — had just been diagnosed with ophthalmic zoster, and was having a very rough time of it. Lots of pain, swelling, and of even greater concern, corneal involvement with markedly reduced vision.
The problem, of course, is that there’s only so much that antiviral therapy can do once shingles is diagnosed. Far better, of course, is to prevent it in the first place.
Then the next day the FDA approved the zoster vaccine for people aged 50-59, reducing the age threshold by 10 years.
The reasons for approval are plain enough. Around 200,000 people this age get shingles each year in the United States, and the vaccine reduces the risk by 70%. So it’s even more effective in this young patient population (and I chose that adjective intentionally, ahem) than in those for whom it was originally approved.
Let’s hope the distribution and cost issues — which are substantial — are resolved soon, as this is one adult vaccine I most heartily endorse.
March 18th, 2011
Friday Fosfomycins
Today’s ID/HIV comments and links are named after every ID specialist’s favorite new toy for UTIs.
- This HIV transmission from a kidney donor is getting quite a bit of media play, as such complications always do. I was at a meeting this AM when one of my colleagues (an endocrinologist) commented how horrible she thought it was. Yes… but here’s what I told her: the risk of some sort of infectious complication from transplantation, despite all our vigilance, no matter what tests we use, will never be zero. The only way to make transplants 100% safe is to stop doing them entirely. And that’s not going to happen, nor should it.
- Someone told me that CROI 2012 will be in Seattle “in late February.” CROI trivia hounds will recall it was in Seattle in 2002, when we all learned the MTD (maximal tolerated dose) of caffeine. No confirmation on the date (naturally) from the CROI web site, so I wouldn’t book your flights just yet.
- Those of you who do inpatient ID consults will recognize some of the absurd dynamics in play in this animated (literally) conversation. It’s an extreme example, but I confess I laughed out loud a few times anyway (sorry).
- Speaking of inpatient ID consults, I’m on service right now, and of course it’s staph, staph, and more staph. (First-year ID fellows sometimes think they’re doing a Staph aureus fellowship.) All this staph means I’ve had the opportunity to get some anecdotal experience with ceftaroline for MRSA. Since we learn in Statistics 101 that there’s nothing less scientific than anecdotal (especially early anecdotal) evidence, I’ll resist the impulse and see how things go for a bit longer, and will only say that the drug is tricky for home IV administration since it needs to be mixed up each day. Any other impressions out there?
- Finally, for a pretty pessimistic view of the “test and treat” HIV strategy, here’s a discouraging review of how few of the people living with HIV are actually engaged in care. By the estimates presented here, just under 20% of HIV-infected individuals in the United States have an undetectable HIV viral load. If the data are right, this figure says it all — and regardless of whether there are 209,773 or 209,774 out of 1,106,400 with suppressed HIV, there’s plenty of room for improvement.
Hat tip to the inimitable Rochelle Walensky for the video!
March 8th, 2011
Really Rapid Review of CROI 2011 — and No CROI 2012 Dates
With CROI 2011 now officially over, I offer below the following Really Rapid Review™ for ID/HIV Specialists with limited time — or for those who said they went to the conference but spent the entire week shopping in the Prudential Mall and eating at Legal Seafood:
- Lots on PrEP. Bottom line — it works if you take it, but lots of people in iPrEx didn’t take it, especially in non-US sites. And bone density goes down a bit in those receiving TDF/FTC, long-term implications not known. Based on conversations I had with colleagues, it didn’t seem that anyone had been prescribing PrEP much thus far.
- HCV treatment is about to get much more effective, and much more complicated. The drug-drug interactions with antiretroviral drugs and the first two HCV-protease inhibitors — telaprevir and boceprevir — are going to be really, really dicey. Sensational web-cast here of a plenary given by Stefan Zeuzem that summarizes lots of the key issues.
- Once-daily raltegravir doesn’t work quite as well as twice-daily. Old news, but detailed data on the trial presented here for the first time. Turns out PK does matter after all in the QD group.
- Speaking of raltegravir, if you predicted that approximately 25% of treatment-naive subjects who were put on boosted darunavir plus raltegravir would experience virologic failure, you are smarted than I am. These are two of our best drugs — how can we explain this?
- Time to learn a new drug name: “S/GSK1349572” = “572” = “dolutegravir” = “DTG”, which really does have antiviral activity against some raltegravir-resistant viruses.
- Two additional studies (here and here) show that blacks in the USA do worse than whites in clinical trials. The explanation must be at least in part socioeconomic, since clearly Africans in Africa are doing just as well on ART as people in resource-rich settings. Critical to figure out why we have this disparity.
- Many studies on inflammation and immune activation, including this incredibly counter-intuitive study of maraviroc intensification of already suppressive ART. Results are too complex for this Really Rapid Review™, but they go something like this: certain markers increased; others decreased; no one knows why; no one knows the clinical implications. Which pretty much sums up this whole “inflammation and immune activation” field right now.
- If you have active TB and advanced HIV-related immunosuppression — that is, CD4 < 50 — the time to start ART is sooner rather than later. (Similar findings in this study.) All this makes complete sense, given what we’ve seen from earlier studies in such sick patients (A5164, CAMELIA). Fact: Untreated advanced AIDS is worse than IRIS.
- Several years ago, plunked right into the middle of a slide session on clinical studies of antiretrovirals, came an out-of-nowhere basic science presentation (this might have been it) on “zinc fingers”. So odd was its appearance that it became something of an inside joke (a very inside joke) among certain HIV clinicians. (“Oh, he can’t tolerate ritonavir — maybe he’d do better on a zinc finger inhibitor.”) And guess what — zinc fingers are back! And it’s actually very cool stuff.
- Does PI-based ART in the mom lead to premature delivery? The Europeans have been saying so for some time, and this randomized clinical trial from Botswana supports that view. The questions remain — how clinically important? And what are the best alternatives?
- You know that question about whether NRTIs are needed in 2nd-line therapy (and beyond)? Based on these two studies (here and here), it certainly seems so. A randomized clinical trial — the so-called OPTIONS study — is ongoing to try and answer this question definitively.
Finally, unlike last year, if the CROI 2012 dates were announced, I didn’t hear them — nor did anyone else I spoke to at the conference. Darn. That “announcement” up there is a mock-up kindly crafted by my sister, who always did help me with my art projects in grade school.
But in case the conference organizers are still looking, there’s plenty of space at the Hynes Convention Center should they want to come back to Boston. Right now, this group is the only meeting booked for the whole month of February!
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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