HIV and ID Observations

As noted previously by Carlos del Rio in his nice summary, the Conference on Retroviruses and Opportunistic Infections (CROI) turned 20 this year. It also made it’s first-ever stop in Atlanta, home of many things that begin with “C” — CDC (note that insiders rarely say, “the CDC”), CNN, Coca Cola, and Carlos himself.

I’ll spare you the boring saga of just how messed up the travel was back to the Northeast as the conference came to a close — ugh — and jump right in on this Really Rapid Review™, loosely organized by prevention, treatment, and complications.

• Baby “cured” of HIV. Need I say more?  Nah.
• In the VOICE study of pre-exposure prophylaxis (PrEP), none of the interventions worked — not oral TDF, oral TDF/FTC, or vaginal TDF gel. The adherence was dismal — it seems that only around 25-30% of the more than 5000 African women took their assigned treatment. At the conference, the “joke” was that at least the side effects were minimal — hey aren’t we a funny bunch of HIV researchers. The unfunny part was the alarmingly high HIV incidence among the participants, especially the young women in South Africa.
• No excess in HIV incidence or high risk behavior after stopping PrEP in the iPrEx study. Quick aside — do you like it when the study title is declarative about the result, as in these two papers? I do.
• Interestingly, even after the 052 results were released to the study subjects, many of those randomized to deferred therapy still chose not to initiate ART. Several possible explanations — they felt fine, they had many months of clinical stability, and importantly were initially counselled that their CD4 cell counts were high enough to defer therapy.
• Can the long-acting injectable integrase inhibitor GSK1265744 be the answer to PrEP adherence issues? We’re talking REALLY long acting, with protective drug levels potentially months after the dose. If it’s an injection every 3 months, this crazy idea just might work.
• Here’s an interesting diagnostic tidbit — the 4th generation combined HIV antigen/antibody tests may have a small “window” when p24 antigen turns negative before the HIV antibody becomes detectable, analogous to the hepatitis B surface antigen/antibody window. The combined test is still better than antibody alone for early infection, but it does highlight how useful it would be to have HIV RNA (viral load) licensed for diagnosis.
• More evidence that the earlier treatment is started after HIV acquisition, the smaller the size of the latent reservoir. More reasons to treat (rather than observe) patients with acute HIV.
• In a CDC-sponsored study of 10 sentinel sites in the USA from 2007-2010, the prevalence of transmitted drug resistance among newly diagnosed patients was 16%. Breakdown by drug class:  NNRTI 8.1%, NRTI 6.7, and PI 4.5%. Compared with their prior report, the overall rate is around the same, while NNRTI resistance is rising. Given the improvement in virologic suppression rates that happened in the late 2000s, I expected transmitted drug resistance to drop — maybe next time!
• In a randomized, double-blind clinical trial in over 700 treatment-experienced patients, once-daily dolutegravir was superior at 24 weeks to twice-daily raltegravir. Every year there’s a study that gets the award for “CROI Poster That Most Deserved an Oral Presentation,” and this is the 2013 winner. FDA approval of dolutegravir expected this summer.
• On the topic of dolutegravir, treatment response in 2 treatment-naive studies was consistent among various demographic and clinical subgroups. A third study (vs. boosted darunavir) is ongoing.
• If a patient has failed treatment using the three original drug classes (NRTI, NNRTI, PI), and has more than two active drugs besides NRTIs on resistance/tropism testing, do you need to include NRTIs in the salvage regimen? According to this ambitious clinical trial, the answer is no. Virologic responses were similar, with or without the NRTIs. Oddly, there were six deaths in the NRTI arm, zero in the “no nukes” arm — hard to see that as being related to anything but chance, as the causes of death did not seem drug-related, but it’s weird nonetheless.
• After a first-line failure of a standard two NRTIs + NNRTI regimen, lopinavir/r + NRTIs and lopinavir + raltegravir were similar in efficacy. One might expect the latter to be better (two new fully active drugs, after all), but most likely adherence was the key determinant of outcome in both study arms. This was a poster too, by the way — winner of second place in that above-mentioned award.
• Could tenofovir alafenamide (TAF) be a safer version of tenofovir (TDF)? In this phase II study, renal and bone parameters were both significantly better with TAF than TDF. Virologic outcomes were similar, but the study was not powered for efficacy. Phase III studies ongoing.
• Maintenance therapy after virologic suppression with a two-drug regimen of raltegravir + maraviroc didn’t work very well (5 of 44 with virologic failure), but the study authors sure had a nifty title — ROCnRAL.
• Splitting up the TDF/FTC/EFV didn’t impair virologic suppression in this report of 478 stable patients switched to separate TDF, 3TC, and EFV. Would be interesting to see how this flies in a more challenging group of patients — e.g., inner-city Baltimore — and for a longer duration.
• Cenicriviroc is a CCR5 inhibitor that also blocks CCR2 — and hence may have anti-inflammatory properties; it was compared with EFV in this phase II study. There were more virologic failures in the cenicriviroc arm, more discontinuations for adverse events in the EFV arm, but the study was small and the formulation highly problematic. Hard to know where this is going — is cenicriviroc potentially a replacement for “key third drug”, or will it be coformulated with 3TC and replace one of the NRTIs? Or will drug development stop, since it’s not as if there’s a driving need for another CCR5 antagonist? We’ll see.
• A first look at at the antiviral effect of MK-1439, an investigational NNRTI. Decent potency, QD dosing, good activity vs 103N, 181C, 190A. The issue, of course, is that NNRTI development has been so very challenging — lersivirine the most recent example.
• In the COAT study of timing of ART initiation in cryptococcal meningitis, the early ART group had significantly shorter survival, prompting early termination of the study. Those with the lowest CSF WBC and impaired mental status did particularly poorly with early ART. A truly important study, done in Africa but with global implications.
• Do OIs still happen once the CD4 is > 500 on ART?  According to this massive cohort study, the answer is yes, but very, very infrequently. And here’s a surprise — OIs are more common in those with CD4 500-750 than >750. With such rare events, the sample size needed to be gargantuan — how does 149,730 sound?
• A first report of treating acute HCV (all in HIV positive MSM) with three drugs — peg IF, RBV, and telaprevir. Not surprisingly, it works, and works fast.
• Preliminary results were encouraging in two studies (telaprevir in one, boceprevir in the other) for HIV/HCV coinfected patients with prior HCV treatment failure on IF/RB, but …
• Enough about that inferferon stuff already! Three IF-free approaches:  1) ABT-450/r + a non-nucleoside polymerase inhibitor + RBV; 2) simeprevir + sofosbuvir +/- RBV; and 3) sofosbuvir + ledipasvir (formerly GS-5885) + RBV. Bottom line on all three was that results were outstanding, virtually guaranteeing that interferon-based treatments will soon be a thing of the past. The third of these studies — 100% response in both naives and prior null responders — provided one of the more exciting clinical trial results I’ve seen in years, small sample size notwithstanding.

Apologies if I’ve left out your favorite, would love to hear what I missed — and I reserve the right to add a few based on your suggestions.  As for the conference venue, the meeting rooms were comfortable, audiovisuals reliable, the posters easy to see, and there were plenty of Coca Cola products available during the breaks.

Last but not least, I don’t think anyone announced where or when CROI 2014 will take place. Let the speculation begin!