HIV and ID Observations

The Conference on Retroviruses and Opportunistic Infections (CROI) returned to Boston last week, bringing together over 4000 HIV researchers and clinicians from all over the world.

And note I put “researchers” first — this is certainly the only conference I attend where we are asked to list published papers as part of the registration process! You can almost imagine the program committee reviewing the papers we enter, calculating impact factor and counting first- and last-author contributions.

(I don’t think they really do this. At least I hope not.)

Challenging registration process notwithstanding, the conference organizers are to be credited with releasing the dates of CROI way in advance, greatly facilitating academic and vacation calendars. As the graphic shows, it will be in Seattle next February, back in Boston the following year.

Here is a carefully curated (I’m joking) list of highlights, a Really Rapid Review™ roughly divided into epidemiology/prevention, treatment, complications, cure — and coffee.

• In the United States, the CDC projects that the lifetime risk of acquiring HIV among men who have sex with men (MSM) is 1 in 2 for blacks, 1 in 4 Hispanics, and 1 in 11 for whites. Lots of press for these alarming data. I’m an optimist, so I’m betting the under on these estimates given our advances in HIV prevention (PrEP in particular), and the fact that we now treat everyone with HIV.
• In the iPrEx study, higher TDF/FTC levels on PrEP were associated with declines in renal function. These data, and the expected approval of TAF/FTC next month, of course raise the question about the use of TAF/FTC in PrEP. Since you asked …
• Tissue and blood levels of tenofovir after TAF administration are much lower than with TDF. Understandably, this raises a concern about use of TAF/FTC for PrEP. BUT …
• In an animal model, TAF/FTC protected 6 macaques from acquiring SIV.  These are encouraging data, and suggest we don’t really know the optimal biological correlates of protection with this drug combination. Bottom line: Whether TAF/FTC will work for PrEP in humans remains unknown — and is a big clinical research challenge.
• In this meticulously detailed case report, a person taking PrEP with TDF/FTC acquired a multi-drug resistant strain — 5 TAMS, Y181C, even integrase resistance! This rare event isn’t enough to change policy or practice, but it’s a reminder that no prevention intervention will be 100% effective 100% of the time.
• Maraviroc seems like an ideal prevention drug given its mechanism of action and expected concentrations in relevant “compartments”. However, in this study of MSM, all 5 patients who acquired infection were receiving maraviroc-based PrEP. 
• In separate studies (here and here), a dapivirine-impregnated vaginal ring significantly reduced the risk of HIV infection among African women (paper of one of the studies published here) — but the effect was modest. As in other studies, adherence played a key role, and younger women were not protected at all.
• In MSM at low risk for acquiring HIV, injectable cabotegravir was well tolerated (and preferred to oral therapy), but the q12 week injection schedule did not reliably achieve desired trough concentrations. One cabotegravir subject acquired HIV; trough concentrations were low. A q8 week schedule for PrEP seems likely.
• In this Kaiser cohort study, the “survival gap” between those with and without HIV is closing (13 years overall, 8 years if ART is started with CD4 > 500) — and much of the gap is now attributable to modifiable health risk factors, such as smoking.
• On the other side of the HIV treatment spectrum, this ambitious study evaluated the optimal strategy for retaining in care hospitalized HIV patients with addiction — including intensive patient navigation efforts and cash payments for certain desired outcomes (follow-up visits, picking up the antivirals, virologic suppression). The result? Payment “for performance” with the navigation worked — but only during the 6 months of the intervention. By month 12, the outcome of viral suppression was not significantly different in those with incentives from those who received “treatment as usual.”
• In this British Columbia cohort — where they have meticulous records of treatments and test results — HIV drug resistance to NRTIs, NNRTIs, and PIs has significantly declined since 2009, while integrase resistance has increased. The good news: Integrase resistance is still really, really rare.
• In this randomized clinical trial, stable patients taking TDF/FTC who switched to TAF/FTC maintained virologic suppression and experienced improved renal and bone outcomes. As noted above, approval of TAF/FTC is expected soon — and there are a lot of patients receiving this drug combination.
• Injectable cabotegravir and rilpivirine given every 4 or 8 weeks maintained virologic suppression as well as oral therapy. Importantly, no resistance was detected in the one patient who experienced virologic failure. Larger studies planned.
• In a reprise of the EARNEST and SECOND LINE study results, patients failing first-line dual NRTI plus NNRTI-based therapy did comparably well with LPV/r plus either RAL or NRTIs — despite having extensive NRTI “resistance”. Note the quotation marks around resistance, that was intentional since obviously there’s plenty of residual activity.
• Related to NRTI resistance — in this cohort of nearly 2000 patients with treatment failure on TDF, FTC or 3TC, and an NNRTI, the rate of tenofovir resistance ranged from 20% (Europe) to 60% (Africa). Use of 3TC (vs FTC) and NVP (vs EFV) were predictors of tenofovir resistance. Note that TAF is in vitro active vs K65R-containing viruses.
• In this clinical cohort in Amsterdam, there was an unexpectedly high rate of discontinuation of dolutegravir (16%), mostly for sleep, GI, and neuropsychiatric complaints.
• By contrast, this cohort study found no increased risk of virologic failure switching from RAL to DTG. This analysis should be repeated looking at switches from boosted PIs to DTG.
• Viral decay in the two-drug pilot trial of DTG + 3TC (PADDLE) was comparable to the three drug arms from the SINGLE and SPRING-2 studies. Another single-arm study of DTG and 3TC is ongoing (ACTG 5353).
• At 48 weeks in this phase 2 study, the NNRTI doravirine was similar to efavirenz, both arms with just under 80% virologic suppression. Despite these relatively low response rates, there was no drug resistance detected in either study arm; CNS side effects were lower with doravirine. Phase 3 studies of DOR ongoing — and yes, the drug will need to be abbreviated “DOR” since “DRV” is taken.
• This long-acting NRTI MK-8591 — and I mean really long acting, with a half-life of 150 hours with oral administration — induced nearly a 2 log decline in HIV RNA at day 7 after a single 10 mg dose. PrEP candidate? Part of an implantable device? Some other “paradigm shifting” treatment?
• In a European cohort, fractures were 3x more common in HIV positive patients than in the non-infected population. Among antivirals, only tenofovir independently increased the risk of fracture. Osteonecrosis was 100X more common; no specific drug exposure could be implicated.
• Most of the bone loss after starting ART occurs early, but in this study, a single dose of zoledronic acid completely blunted this adverse effect. If this bone loss phenomenon is due to immune reconstitution, one could imagine this intervention one day becoming standard of care.
• In the NEAT study comparing DRV/r plus either RAL or TDF/FTC, RAL increased trunk fat more than TDF/FTC. The study used DEXA, so could not determine if this was subcutaneous or visceral fat, or both.
• Compared to placebo, the quadrivalent HPV vaccine in “older” (age 27!) HIV-positive adults did not reduce new HPV infection or improve the course of anal dysplasia (HSIL). Study stopped early for futility.
• In a highly TB-endemic region, patients with a low clinical suspicion of having TB did not benefit from empiric TB treatment. In hindsight, this was kind of a self-fulfilling prophesy.
• There are many “real world” HCV treatment cohorts out there, and thus far most demonstrate outstanding cure rates in clinical practice, comparable to clinical trial results. Here’s another one (from Germany) which shows a 98% SVR12 among those treated for 8 weeks with LDV/SOF.
• In a study of 26 patients with recently acquired HCV (negative HCV antibody within past 6 months), 6 weeks of LDV/SOF cured 20, with 4 virologic failures — 3 relapses, 1 reinfection. The relapses all had HCV RNA > 9 million copies/mL, adding to data that HCV RNA is a critical determinant of optimal treatment duration.
• The ION-4 study of LDV/SOF for HIV/HCV co-infected patients, only 10/335 experienced virologic relapses. Nine (one didn’t participate) were successfully cured with a subsequent 24-week course of LDV/SOF + RBV.
• Treatment of 9 SIV infected macaques with two different TLR7 agonists induced viral blips and in some reduced the SIV reservoir. Most attention-grabbing:  two of the monkeys are now off ART for 3-4 months, with no viral rebound. Stay tuned!
• In virologically suppressed patients, romidepsin (a “latency reversing agent”) and an immunologic boost with Vacc-4x adjuvanted with GM-CSF led to a modest decline in HIV DNA (one marker of the viral reservoir). Viral rebound after stopping therapy, however, appeared unaffected.
• This patient with acute leukemia received a stem cell transplant from a CCR5 negative donor, and has no detectable using sensitive assays — sounds like the n=1 case of HIV cure. Importantly, he remains on ART. Weird that this case is also from Germany! Fingers crossed.
• This cohort analysis demonstrated improved survival among French coffee drinkers with HIV/HCV coinfection. I’ll add this to my list of studies demonstrating the health benefits of coffee — a lifelong quest.
• The plenaries/review lectures this year were excellent — including in particular Bruce Walker on cellular immunity, Jerry Friedland on the intersections of HIV, TB, and poverty, Joe Eron on HIV treatment, Grace McComsey on fat, Paddy Mallon on bone, John Brooks on the HIV outbreak in Indiana, and Eric Rubin on Cheetos — I mean TB. (You had to be there.) All are available on the CROI web site here.

A bit of Boston- and venue-specific news. First, the weather was downright balmy, with temperatures one day pushing 60 degrees and thunderstorms (!) one evening. Last year’s record snow? No problem — it melted long ago.

And I happened to chat with someone who works at the Hynes Convention center, who assured me that the WiFi would be better in 2018.

So what did I miss?