HIV and ID Observations

Despite the winter that would never end, intrepid HIV/ID researchers and clinicians arrived in Boston for this year’s Conference on Retroviruses and Opportunistic Infections –or more accurately, Conference on Retroviruses and Flaviviridae (little ID joke there) — which just finished last week. Not that it was easy — a winter storm roared eastward as the conference got started, leading to cancellation of dozens of flights headed this way from the Mid-Atlantic states. This was followed by many numb fingers and toes from our unseasonably frosty weather — it was 9 degrees F one morning, a balmy 12 degrees the next.

As usual, CROI was densely packed with scientific presentations and posters; some could argue that the content of one CROI includes as much information as the remainder of the HIV conferences put together. Certainly it feels that way sometimes, especially when there are synchronous “can’t miss” presentations — just try to be in two places simultaneously, especially when one of the slide session rooms is full. Check out the conference site for web casts and, eventually, many of the posters.

(Can’t directly link the abstracts yet — I put the abstract numbers in brackets after each citation — but you can get the full program here.)

Organized roughly (very roughly) by clinical trials, cure research, complications, epidemiology, and miscellaneous interesting studies, here is a Really Rapid Review™ of CROI 2014, brought to you in Technicolor by …oh, let’s get on with it already, and be sure to read to the very end for the top HIV study of the year, as well as a terrific video clip:

• Success with an NRTI-sparing regimen? Could it be? In the NEAT study, a fully powered randomized clinical trial, darunavir/r plus raltegravir was noninferior to darunavir/r plus TDF/FTC. But — and there are several buts — there was again quite poor performance of the DRV/r plus RAL in those with high viral load/low CD4 (around one-third failed), and more resistance on failure. Plus, aside from some renal markers, was it better in any way? Not really. Can’t seeing using this regimen much based solely on this trial [84LB].
• When combined with TDF/FTC, raltegravir was significantly better than both darunavir/r and (especially) atazanavir/r, with the relatively poor result of the atazanavir/r arm driving by lots of discontinuations for jaundice [85]. Why so high in this study?  A theory: Give people the option to switch and stay in the study, and they’ll take it. Note that virologic outcomes were the same. Lipids, bone outcomes also better with raltegravir [779LB, 746].
• In a phase II dose-finding study, the investigational NNRTI MK-1439 — hereafter to be known as doravirine — was potent and well tolerated [92LB]. Guess the big question for its development is how much we need a new NNRTI — none of our current options is perfect, true, but they are pretty good. And what will be the three-letter abbreviation of doravirine? “DRV” is already taken!
• In the LATTE study — how can you not love that name? — a two-drug maintenance treatment of the v-e-r-y long half-life integrase inhibitor 744 and rilpivirine, both given orally, worked quite well [91LB]. There was only one case of treatment failure with resistance, occurring in a study subject who was on a heavily calorie-restricted diet — not good for rilpivirine! These results set up the potential for a future combination strategy using injectable long-acting preparations of each drug — once-monthly injections, anyone? And will that be a niche intervention or transformative antiretroviral strategy? You decide.
• For patients starting TDF/FTC/EFV, giving vitamin D and calcium significantly reduced the degree of bone mineral loss with ART initiation [133]. But is it enough to warrant doing it for everyone? And would it work if EFV were not the drug, which induces vitamin D metabolism? Somehow I’m just so biased against supplements, my gut feeling is to hold off for now in making this standard practice.
• Switching from a boosted PI- or NNRTI-based regimen to co-formulated TDF/FTC/EVG/C maintained virologic suppression in two randomized trials [551LB, 553LB]. Of course this was in patients eager to switch therapy — otherwise why do the study? — but it’s reassuring that there was no integrase resistance with failure, and the one case of tenofovir toxicity occurred in a study subject who likely had it before switching.
• Antiretroviral switch strategies specifically designed to lower costs was done successfully in this Spanish study [613]. One problem, of course, is that pricing of HIV drugs in the United States is incredibly variable, and likely to become only more so over time — the definition of a moving target!
• It seems hardly anyone is working on new drug classes for HIV therapy anymore, which is why seeing this dose-finding study of the attachment inhibitor BMS-663068 was encouraging [86]. Around a 1 log viral load decline, studies ongoing.
• The impressive SATURN-HIV study — a single-site HIV study with nearly 150 patients! — found that rosuvastatin improved hip bone density [134], reduced LDL [750], reduced markers of inflammation [335], reduced cystatin C levels [743], but seemed to worsen insulin resistance [134]. Large study of pitavastatin in HIV planned.
• On to the flavivirus of the moment (HCV), and let’s just focus on the interferon-free treatments. How about 12 weeks of the “triple therapy” (but 4 drug) regimen of ABT-450/r/267 + ABT-333 — that mouthful is a ritonavir-boosted PI, NS5A inhibitor, and a non-nucleoside polymerase inhibitor. In genotype 1b only, response rates were outstanding — a 99+% SVR12 sounds pretty good, doesn’t it [29LB]? Note that RBV will likely still be recommended for genotypes 1a. And will these compounds ever have real names?
• A different triple-therapy regimen — no ribavirin, no ritonavir — of daclatasvir (NS5A), asunaprevir (unboosted PI), and BMS-791325 (a non-nucleoside) achieved SVR 4 rates around 91&#92% (two different doses of 325 were used). Breakthrough cases tended to have resistance, though failure was rare. A fixed-dose combination of these three agents is being used in phase III studies — one pill twice daily [25].
• How about “The Molecule,” which is what I heard someone call sofosbuvir, the pan-genotypic NRTI that is already approved. While the PHOTON-1 study looked at the two-drug regimen of sofosbuvir and ribavirin in HIV-infected patients with various genotypes, response rates achieved were nothing like what is seen when sofosbuvir is combined with at least one other anti-HCV drug [26]. We’re spoiled already!
• Want an example? This three-arm study compared 12 weeks of the sofosbuvir/ledipasvir fixed-dose pill (arm 1) with two 6-week regimens: SOF/LDP plus an investigational non-nucleoside (9669) or PI (9451). Of the 60 patients in the study, 59 were cured [27LB]. Viral kinetic modeling showed addition of the third active drug led to a faster HCV RNA decline, if you can believe it. Note also that this was a difficult-to-treat inner city population, with many poor prognostic demographic factors at baseline. Adherence better with shorter course, fewer pills, not surprisingly [667].
• Daclatasvir plus simeprevir, with or without ribavirin, achieved SVR12 rates in 75-85% of genotype 1b patients  [28LB]. Amazing how this response in IF-free therapy would have been sensational just a few years ago — now, not so much (we’re spoiled, remember). Once daclatasvir is approved — late this year? early next year? — it will most likely be used with The Molecule, of course.
• Another baby “cured” of HIV? As noted here, we must view this as a promising initial report, as although the baby has no detectable HIV DNA using sensitive assays, and a negative HIV antibody, he/she remains on therapy to date [72]. Lots of media hoo-ha (e.g., here, here, and here — this last report citing 5 more babies in Canada).
• More data in favor of early — really early — therapy in this case report, in which someone in a PrEP study who started ART during the “hyperacute” period as HIV RNA was just rising appears to have limited seeding of the reservoir[397LB]. And this case report (disclosure: I’m a co-author) showed that early ART could block HIV acquisition from a blood transfusion, when transmission is usually nearly 100% [960].
• Details presented here on relapse of HIV of the two “Boston Patients”, who previously were noted to have marked reduction in HIV reservoir after allogeneic stem cell transplants, and even were able to maintain HIV control for weeks after stopping therapy [144LB]. Note how the clinical syndrome of acute HIV was fairly severe, as the new “host” had no effective immune response. A real setback in HIV cure research, raising the question of whether we ever can achieve a “sterilizing cure” of long-established HIV.
• In this analysis of mostly healthy HIV patients in the Kaiser system, MI rates were no higher than in those without HIV [737]. Results suggest that some of that excess risk we have seen in other cohorts may be related to bad old drugs, uncontrolled virus/low CD4 for many years, and high rates of traditional risk factors, especially smoking.
• Current abacavir use remains positively associated with MI risk in this updated D:A:D analysis. Interesting that overall MI rates are way down, but the point estimate was still around 2 — even though there has been “channeling” away from abacavir in high-risk patients [747LB]. Note that the original 2008 poster was in almost the exactly same spot in the conference room (way in the back). Leukocyte adhesion a possible mechanism [744].
• Since obesity is a bigger complaint in our clinics now than wasting, I thought this study was interesting outlining possible risk factors: Low pre-ART CD4 cell count, female sex, and atazanavir [802].
• This oral presentation on the high rates of transmitted resistance found if you do incredibly sensitive assays initially seemed alarming [87]. However, when you couple that with the knowledge that treatment success has been steadily increasing for years, the clinical implications of these findings must be limited.
• Mixed news on transmitted drug resistance:  Rates were surprisingly high (28.6%) in black MSM in the United States [581] in a prevention study, but an analysis of clinical trials entrants over time show the rates overall to be relatively stable [578]. Other good news from this second study — no need to do baseline integrase resistance, as only 1/1617 samples was positive.
• In this large study from Britain, approximately 12% of those stopping an NNRTI-based regimen developed NNRTI resistance [593]. Note that lots were on NVP, which limits applicability somewhat — but the message is clear that a genotype is worth checking in your patients who have stopped NNRTI-based therapy.
• A single transmitted TAM did not influence response to first line therapy [577].
• Large analysis of low-level viremia from the ART Cohort Collaboration found that 50-199 was pretty benign, but that 200-499 did predict virologic failure (but not clinical events) [1014].
• Most of the HIV infection in the United States is linked to MSM, including many incident infections that occur in heterosexual women [213]. Clearly a role for targeted prevention efforts.
• Good news here for those who believe in “Treatment is Prevention”: zero transmissions of HIV among serodiscordant couples despite “condomless sex,” provided the infected patient had an undetectable HIV viral load [153LB]. Note that highest risk behavior (unprotected receptive anal intercourse) was included in this cohort of both heterosexual couples and MSM. Yes, one day there will be another case report (there is still only one), but regardless — this form of prevention is looking darn good right now!
• Back to 744, this time looking promising as a long acting injectable for prevention in a macaque model [941LB]. Quarterly shots don’t sound too bad, especially with the poor adherence in some PrEP studies.
• What’s driving the HIV epidemic in Africa? This poster raised questions about the “Sugar Daddy” concept implicating  older male partners [145], and this other poster suggested that transmission efficiency was as if not more important than number of sexual contacts [1041].
• More data in this study from NYC outlining the limited usefulness of CD4 cell count monitoring, and the money (and implied, aggravation) we can save by doing it less often [557].
• For some reason, elite controllers were hospitalized more frequently than those on HIV treatment in this collaborative cohort analysis [556]. Surprising finding — is being on treatment a proxy for regular care? Is there some plausible biologic explanation?
• My favorite plenaries: Serena Spudich on NeuroHIV, and Stefano Bertozzi on PEPFAR. Highly recommended!
• Finally, top HIV study of the year: moderate alcohol intake reduced cardiovascular risk in the Swiss HIV Cohort, just as it does in the general population — the classic J-shaped curve [731]. Note that the senior author’s “Disclosures” mentioned that his brother owns a vineyard! Always good to see research supporting the health effects of wine, or chocolate, or coffee.

A few quick non-scientific comments:

1. Nice backpacks! Big improvement over last year’s flimsy shopping bags.
2. I’m sure the city depicted in the CROI insignia was supposed to be Boston, but darned if I can recognize half the structures.
3. “CROI” always autocorrects to “croissant” on my cell phone. Does that mean we should be pronouncing it “kwah”, like the French? What a weird language.
4. Three inches of snow expected tomorrow, for those of you who miss Boston already.

OK, that’s enough. Of course I’ve left off some major studies — please cite them in the comments! And enjoy this clip, which makes me feel oh-so patriotic.