HIV and ID Observations

Boy do we love end-of-year “Best of …” and “Top Stories of …” lists! Love them! They never gets old! Until January, that is.

My own particular favorites are the Best Movies of the Year lists, since for whatever reason it always seems like some masterpiece slips by. Missed it! So we leave it up to the list-makers, either critics or review-aggregating sites, to remind us. Then we can print out the page, post it next to some Netflix- or other gizmo-enabled viewing device — and, if you’re like me, watch hardly any of the films, since if they were that good and the premise appealed to us when they were first released, then we’d have seen them already in the theater. Oh well.

(While I’m on the topic: There are literally dozens of Best Movie lists to choose from — hey, a list of lists! — just select your source: Rotten Tomatoes, Metacritic — which for the record I like more than Rotten Tomatoes, even though it’s less well known — New Yorker, New Yorker again, New York Times, some other city’s newspaper’s opinion, (LA and Boston haven’t weighed-in yet), IMDB, and Little White Lies, which gave us the nifty video at the end of this post.

Anyway — back to ID/HIV. For the last several years, the nice folks over at Medscape have allowed me to post brief videos on various HIV-related topics, including a “Top Stories in HIV” one each December.

These are decidedly low-budget affairs, shot on a antiquated Flip (remember those?) knock-off and usually set in my dining or living room. Here’s the most recent one, and for a special treat filmed this time on location on Tahiti.

(Actually, it’s my office.)

And since I’ve been told that these clips must be short — optimal length is around 3-4 minutes — allow me use this space to expand a bit more on the choices, roughly divided into Prevention, Treatment, Complications, and Cure. And this brevity definitely doesn’t allow digressions about Best Movies of 2014, or the relative value of metacritic.com vs. rottentomoatoes.com, both of which are probably owned by the same giant media conglomerate anyway.

Sorry, there are only seven. Why is 10 so important anyway?

1. A more emphatic recommendation for pre-exposure prophylaxis (PrEP). I initially thought that PrEP was a niche prevention intervention, with the barriers to implementation just too high — the highest-risk patients didn’t get regular health care, compliance would be a chronic problem, and the cost of intervention unsupportable. So what changed? Plenty: a stronger endorsement to use it from CDC; research demonstrating efficacy in gay men even when they are only intermittently compliant; and the results of two other studies (PROUD and IPERGAY, ahem). This has translated into far greater enthusiasm from patients referred to me to discuss the PrEP option — all of the above has made me a believer. Not everyone agrees, of course, most emphatically the head of the AIDS HealthCare Foundation.
2. Raltegravir beats darunavir and atazanavir in head-to-head-to-head clinical trial. First presented at CROI 2014, this important study showed that virologic outcomes were the same, but the safety and tolerability of raltegravir meant that overall it was simply better. Note that if subjects wanted to switch therapy — say, for a touch of atazanavir-related jaundice — they were allowed to do so and still stay in study, with the alternative medication provided. This no doubt lowered the threshold for ATV discontinuation substantially, but it is in fact what would happen in clinical practice. Two other quick notes: 1) One could argue that the real winner of this study is, ironically, dolutegravir, which we know is just as good as raltegravir, is once-a-day, and comes in a tiny little pill; 2) this is the kind of large clinical trial that the ACTG does so well — or I should write, did so well, since the research agenda has understandably switched to the next scientific challenges of cure and pathogenesis.
3. Two-drug treatment approaches get some traction. While the NEAT study of darunavir/ritonavir plus raltegravir and the MODERN study of darunavir /ritonavir plus maraviroc added still more disappointing data on NRTI-free, two-drug combinations, along came the impressive results of lopinavir/ritonavir plus lamivudine — again just two drugs — in the GARDEL study, showing that less can definitely be more: the two-drug combination was just as effective, and better tolerated. Furthermore, the boosted PI plus lamivudine combination also seemed just fine for maintenance in the SALT and OLE trials. What about integrase/NNRTI as the two drugs? Cabotegravir (744) plus rilpivirine did quite well as maintenance in LATTE-1, suggesting a completely novel approach to less-is-more. This last result has prompted the development of a single tablet of this combination, along with the ongoing work using both of them as long-acting injectables — the LATTE-2 study, for those keeping track.
4. Efavirenz associated with a more than twofold increase in risk of suicidality. Ever since efavirenz was approved in 1998, it has been something of a miracle drug from a virologic efficacy standpoint, beating or tying all challengers until it was compared to dolutegravir in the SINGLE study. Sure, efavirenz caused wacky dreams and dizziness, but serious CNS toxicity was difficult to pin down — until now. Acting on a hunch derived from reviewing safety reports from multiple studies, lead-author Katie Mollan designed an analysis that combined several randomized controlled trials, greatly increasing the chance of finding a concerning safety signal, which the paper most certainly did. Results were strengthened by the finding that deaths from injuries or unknown causes were also more common in the EFV-treated subjects. Note that even though the absolute risk of suicidality was low, this is such a serious side effect that it really should give us all pause before prescribing efavirenz to patients with a history of psychiatric illness. (Disclosure — I’m a coauthor on this study.) 
5. Interferon-free treatment of HCV (finally) arrives. Important because 1) a significant proportion of people with HIV also have HCV ; 2) patients with HIV coinfection now appear to respond just as well as those without HIV (unlike in the interferon days); 3) interferon truly stinks (that was not the first word I typed), and ribavirin isn’t so great either; 4) the first and second generation of interferon-free options — simeprevir plus sofosbuvir then the single-pill sofosbuvir/ledipasvir — are just so amazingly well tolerated; 5) the high cost of something this much better than the existing standard of care raises enormous pharmacoeconomic challenges; and finally, 6) how could the most dramatic advance in treatment of an infectious disease since the discovery of penicillin not be listed as a top story? Enough said.
6. Early antiretroviral therapy for cryptococcal meningitis worsens outcomes. The COAT study has pretty much settled this controversial issue, with those given ART early having a 45% mortality at 26 weeks, versus 30% in subjects who waited 5 weeks to start ART. Low WBC in CSF was a particularly bad marker for poor outcome in the early ART group. Right now, cryptococcal and TB meningitis are the only exceptions to the rule that early ART is beneficial in patients with advanced immunodeficiency and AIDS-related complications. It’s likely no coincidence that both are forms of subacute meningitis associated with elevated intracranial pressure, where an increase in inflammation — IRIS — can be catastrophic.
7. Curing HIV — it was hard before, now it’s even harder. The relapses of the two stem-cell transplant patients from Boston and the baby from Mississippi underscored that not only will curing HIV be a monumental challenge, but that the necessary step of getting there — a diagnostic test to tell us if our cure efforts are successful — remains an unsolved problem. In other words, all three of these patients had undetectable (or at most extraordinarily low) reservoirs as measured by the most sophisticated techniques. Not low enough, apparently, and not sophisticated enough either. One important thing to keep in mind as this research proceeds:  we’ll need to make sure we don’t harm anyone with our investigational cure strategies, as current ART is pretty safe and effective.

Back to Top Movies of 2014, now with a video list. Just put your headphones on first.