HIV and ID Observations

For the 3rd time in its illustrious history, the Conference on Retroviruses and Opportunistic Infections (CROI) returned to Seattle this past week for it’s 22nd meeting. For those of us living in the North Pole, 50 degrees and drizzle never felt so wonderful!

(See image below for graphic representation — that’s my dog Louie wondering what happened to his world. Click on image for full impact.)

With 4000 attendees (capped at that number to keep it relatively “intimate”) and almost half of them from non-U.S. countries, CROI remains a dynamic, incredibly interesting meeting — in my opinion our very best HIV research gathering, guaranteed to make you sleepless while trying to cover it all. (Good thing we were in Seattle.) Where else can we get clinical, basic, translational, and behavioral researchers all together?

So on we go to a summary, a Really Rapid Review™ of some of the most interesting studies at the conference (at least from one perspective). Links are to the conference website (excellent this year), abstract #’s in brackets, and many of the oral presentations are available for webcast here. List is organized roughly by prevention, treatment, complications, cure, and miscellaneous cool stuff; please list in the comments any important studies I’ve missed!

• In a “real world” clinical trial called PROUD [22LB], pre-exposure prophylaxis (PrEP) with TDF/FTC in high risk gay men in London reduced HIV transmissions 86%. Real world” since the participants knew if they were receiving active drug or not (randomized to start right away or delay 12 months); the delayed PrEP arm extensively used PEP, making the results even more impressive. Study stopped early due to efficacy.
• As we heard in October, the IPERGAY (ha) study compared intermittent PrEP — two TDF/FTC’s before sex, one pill the next 2 days — to placebo, and was also stopped early. Efficacy of this “on demand” PreP? Again 86% [23LB]. Note that in both of these studies, incidence of HIV and protective efficacy of PrEP were higher than expected.
• More on PrEP: With evidence that risk of HIV transmission persists 6 months into ART [989], a program for discordant couples to provide PrEP for 6 months and ART to the person with HIV simultaneously makes a lot of sense — which is what they’re now doing for heterosexual couples in this program in Uganda [24].
• Here’s another study with zero transmissions in serodiscordant couples not using condoms when the infected partner is on suppressive ART [1019LB]. Perhaps eventually someone will report another case of HIV transmission in this setting, but it’s obviously pretty darn rare.
• In the PROMISE study of prevention of mother-to-child transmission [31LB], TDF/FTC was associated with a significantly higher risk of neonatal death or very pre-term labor than ZDV/3TC. (Both were given with LPV/r.). Results unexplained — and reinforce that there still isn’t a perfect treatment for pregnant women with HIV.
• Infant outcome data from this observational study in Botswana from over 1000 pregnant women receiving TDF/FTC/EFV during pregnancy are quite reassuring [878]. Could this ironically turn out to be safer than TDF/FTC + boosted PIs?
• Now for post-exposure prophylaxis (PEP):  In this Australian study [958], TDF/FTC/RPV for non-occupational PEP was safe and well tolerated, with excellent adherence. I’ve never used it for this purpose, but it makes a lot of sense — one prescription, one pill, rare severe adverse events, relatively low cost.
• More on non-occupational PEP [961]: Beware unrecognized acute HIV infection in these very high risk individuals, which presents several management challenges — especially after PEP is started. And they call it “PEPSE” (post-exposure prophylaxis after sexual exposure) in Britain — rhymes with the soft drink.
• Phenomenally good news about occupational transmission of HIV in the United States [1027], which has become vanishingly rare — only one case since 1999!
• Late diagnosis of HIV — meaning when a person already has AIDS — is down significantly here, but still occurs in 1 out of 5 new diagnoses. Check out the wide variation based on region [999].
• Interesting survey on how often HIV tests are done at visits to U.S. doctors’ offices. Guess what, it’s done very infrequently: 0.7% of visits [1082]. One tough question — given the wide variation in HIV prevalence, what is the right number?
• On the laboratory side, this is how HIV testing should be done [621]:  4th Generation antibody/antigen screen, then confirmation using a newer HIV-1/HIV-2 differentiation assay called “Geenius.” And no Western blot!
• HPTN 065 [29] is a fascinating (and long-awaited) study of the effect of financial incentives on linkage to care, virologic suppression rates, and continuity of care. Initial linkage and virologic suppression overall weren’t better with the money, but the financial incentives did improve treatment outcomes in the smallest sites and those with the lowest baseline suppression rates. Continuity also improved. Seems this should be a targeted intervention for our most difficult patients, right? The Freakonomics people would love this one.
• TEMPRANO was an incredibly ambitious, important study done in the Cote d’Ivoire testing two interventions in a factorial design: Immediate vs WHO-recommended ART and 6 months of isoniazid preventive therapy (IPT) vs none [115LB]. Both the immediate ART and the IPT significantly improved outcomes, and the former even did so for those with CD4 cell counts >500. Seems we’re just now waiting on the START study results …
• 3TC and FTC are often used interchangeably, but they are not quite the same drugs. In this analysis from the Netherlands [566], the nod goes to FTC, especially in NNRTI containing regimens.
• Wouldn’t it be great if you could objectively assess adherence in your patients with low-level viremia? This clever study [117] found that untimed drug levels strongly predicted the subsequent risk of virologic failure.
• A single-tablet regimen containing elvitegravir, cobicistat, and FTC, and tenofovir alafenamide (TAF) was noninferior to one containing TDF [113LB], with less effect on kidney function and bone [143LB]. (Disclosure: I was the presenting investigator on the latter study.) Seem likely that these safety benefits will play out to be meaningful in long-term treatment, and in those with risk factors for renal disease right now. The TAF regimen is currently under review by the FDA.
• Here’s another study showing that in second-line therapy, those with more resistance at baseline “paradoxically” have better virologic outcomes than patients with less. Lessons: 1) adherence matters A LOT; 2) NRTIs retain activity even with resistance; and 3) our resistance algorithms derived in the 1990s are lousy.
• The LATTE study [554LB] looks at oral cabotegravir plus rilpivirine as a maintenance strategy, mostly in anticipation of these two being used as long-active injectable agents. Since the last presentation, the 96-week data show this is still performing as well as EFV-based standard treatment. But in a glass half full/half empty result, two additional patients have failed, both with NNRTI resistance. (The first failure had both integrase and NNRTI resistance.)
• Remember the maturation inhibitor bevirimat (R.I.P.)? The second generation compound BMS-955176 looks much more promising [114LB], with retained activity even against viruses with baseline gag polymorphisms (the Achilles’ heel of bevirimat).
• If you’re using dolutegravir after failure of raltegravir or elvitegravir, resistance at Q148 plus two other mutations will significantly reduce DTG activity[609]. Otherwise the drug should be active.
• Is the risk of endstage liver disease in HIV/HCV coinfection reduced in the current ART era? Unfortunately no, says this Canadian analysis, making treatment of HCV in this population still critically important [638].
• In the ION-4 study for HCV genotype 1 or 4, sofosbuvir/ledipasvir for 12 weeks had a 96% HCV cure rate. The study included some very treatment-experienced patients and 20% overall had cirrhosis [152LB]. The one baseline characteristic predicting treatment failure was black race, many of whom were receiving TDF/FTC/EFV — raising questions about a possible pharmocogenomic issue leading to the interaction.
• Adding SOF/LDV to a TDF/FTC, boosted PI containing regimen increases TDF levels by 30-60%[82]. If there are baseline renal issues, probably best to switch ART before starting this HCV treatment if possible — and if not, either use a different HCV therapy (the pariteprevir/ombitasvir/etc combo if on ATV/r, or one of the few remaining indications for pegIF/RBV + SOF), or monitor renal function closely.
• In the ALLY-2 study for HCV (any genotype), sofosbuvir plus daclatasvir for 12 weeks cured 97% of coinfected study subjects, treatment naive or experienced [151LB]. An 8-week course in treatment naives was less effective (76% cure). Daclatasvir (an NS5A inhibitor) is currently under review by the FDA.
• Here’s a surprising but important negative study result: body composition (in particular regional fat gain) was not significantly different between raltegravir, atazanavir/r, and darunavir/r-based regimens [140]. Lipoatrophy may be rare, but fat accumulation (especially visceral) remains a common problem, one that discouragingly cannot be directly ascribed to any specific medication or drug class. And note that both this study and the next one on rosuvastatin were led by Grace McComsey from Case Western, clearly one of the field’s best clinical researchers.
• Rosuvastatin slows progression of carotid intima media thickness [137] and atorvastatin reduces non-calcified coronary artery plaque volume [136]. Large study of pitavastatin in HIV infected patients who otherwise wouldn’t qualify for statin therapy due to start soon.
• If you thought the NA-ACCORD analysis of abacavir and cardiovascular risk [749LB] would settle the issue of whether the drug leads to increased cardiovascular risk, no such luck: Some of the study’s analyses showed a significant association between abacavir and MI, others did not. I was reluctant to use the drug in patients with high CV risk before CROI 2015, and still am.
• Cumulative exposure to tenofovir — and even more so atazanavir — increases the risk of chronic kidney disease [142]. Suspect the latter is not well known to many HIV clinicians, but this is not the first time atazanavir has been implicated.
• More on the renal and bone safety of TAF [795]:  Patients with mild-moderate renal disease (estimated GFR 30-69) who were switched to “ECF-TAF” had stable renal function, improvement in urinary protein, and an increase in bone mineral density. Note that these are exactly the kinds of patients for whom TDF and ABC treatment are currently problematic, as they may have both renal disease and CV risk factors.
• Respiratory isolation in possible TB cases in the USA is a huge pain — it makes care more difficulty, delays discharges, and is certainly no fun for the patient and providers. And of course the vast majority don’t have TB. In this important study [824], two Xpert tests ruled out active TB as effectively as 3 sputum smears. Note that the test just got approval for this indication — hope our hospital adopts this testing soon!
• It’s not a randomized clinical trial, but this systematic review [837] found no evidence that early ART worsens outcome of cryptococcal meningitis in high income settings.
• And while we’re on the topic of cryptococcal meningitis, how about a little sertraline, which seems to speed fungal clearance?  Folks, we have a winner of of this year’s most surprising “off target effect” [838].
• Next to some cure studies: A toll-like receptor 7 agonist given to SIV-infected monkeys on suppressive ART did two things: 1) triggered easily measurable viral “blips”; 2) lowered SIV setpoint after stopping ART compared to monkeys receiving placebo [108]. Could this be a treatment that both stimulates and reduces the viral reservoir?
• The zinc finger nuclease approach to modifying CD4 cells is making slow progress — now with cyclophosphamide to enhance engraftment [434].
• Here’s a detailed virologic analysis of a patient who experienced virologic rebound after stem cell transplantation from a CCR5 negative donor. Appears there was pre-existing X4 using virus, which was “selected” by the CCR5 negative cells [431]. Original case reported here. This report states that there have now been 7 attempts to cure HIV via this approach, and obviously thus far only one success. Tough work.
• Some excellent plenaries (among those that I saw): Raphy Landovitz on PrEP (with very nifty PowerPoint skills), Steve Grinspoon on cardiovascular disease, Rick Elion on treatment as prevention, and David Cooper on the history of HIV treatment.

Now, about Seattle. I first visited this city in the early 1980s, and it has of course boomed since then, with many more sensational restaurants, high-rises, more traffic, hipsters (though increasingly priced out of living there), and encouragingly much greater access to it’s beautiful waterfront. A spectacular city, with a terrific convention center.

And it’s of course the home of Boeing, Microsoft — Bill Gates gave a talk at CROI in 2002 — and Starbucks, and if if you’re used to the generic Starbucks on your street corner, in your strip mall, or in your hotel lobby, they have some Starbucks in Seattle that look like coffee museums.

We’ll see you next year in Boston, my home town. And let the record show that there has never been a CROI in Boston that was in any serious way hampered by the weather.

Fingers (numb though they might be) crossed.