HIV and ID Observations

The 25th Conference on Retroviruses and Opportunistic Infections (CROI) just wrapped up in warm, sunny Boston.

Everyone in attendance took advantage of the fine March weather to get some much-needed sun, to feel the sand between their toes, to sip a tropical drink, and to hear the latest in HIV research.

Well, the last part was true — CROI clearly remains our best meeting, the only one that brings together so much high quality research from so many disciplines. Clinical, basic, and behavioral researchers all have a place here.

And though the meeting was bookended by a pair of Nor’easters — the one at the start was a whopper, I thought my dog Louie would blow away in the wind — the weather during most of the conference was actually not bad at all.

On to some highlights, a Really Rapid Review®, with apologies ahead of time for the poor organization. As always, feel free to write in the comments section any important studies I might have missed.

• One-month of daily rifapentine/INH prevented TB as well as 9 months of daily INH [37LB]. First place in this RRR® goes to a TB prevention study — this is also a conference on opportunistic infections, remember? This important randomized clinical trial has the potential to change clinical practice, as clearly a one-month preventive strategy is far easier than a 9-month one. One big question — can we extrapolate to HIV negative people?
• 5 of 11 monkeys treated with both a TLR7 agonist plus a broadly neutralizing antibody did not rebound after stopping ART [73LB]. Not only that, cells from these monkeys (lymph node and PBMCs) did not transmit SHIV to other monkeys in an “adoptive transfer” demonstration of cure (or the closest thing we have to a proof of cure). Very exciting results, with the caveats being that these monkeys were treated with ART within 1-2 weeks of acquiring SHIV, this is SHIV (not HIV), and these are monkeys (not humans).
• No increase in IRIS when raltegravir added to a standard regimen of TDF/FTC/EFV [23]. Data are from the REALITY randomized trial in advanced HIV disease conducted in Africa, and contrast with information from observational studies.
• Twice daily dolutegravir plus two NRTIs is comparable to TDF/FTC EFV in TB/HIV coinfection [33]. The culprit in drug interactions for all these TB studies is rifampin, which voraciously eats many other drugs alive (that is, induces their metabolism). But doubling the dose of dolutegravir here seemed to do the trick. Note again — no increased risk of IRIS with DTG vs EFV, despite the faster virologic suppression.
• TAF/FTC [28LB] likely can be safely administered with rifampin,  but bictegravir can’t [34]. More on this theme — in the first study, while rifampin lowered plasma levels, intracellular concentrations of tenofovir diphosphate were higher than with standard dose TDF. Doubling the dose of bictegravir did not overcome the induction of the drug’s metabolism.
• Darunavir/ritonavir plus 3TC is non-inferior to darunavir/ritonavir plus TDF/FTC [489]. Further follow-up of the ANDES study, done in Argentina — think GARDEL, only with DRV/r. Only one patient developed resistance (M184V in triple-therapy arm), and there was no difference in response between high- and low- viral load strata. Study sample size is relatively small (n=145) due to funding limitations.
• For patients starting therapy with HIV RNA > 100,000 and/or CD4 < 200, INSTI- and EFV-based regimens have the lowest risk of treatment failure[493]. Since the risk of dolutegravir resistance in treatment-naive patients is so low, DTG plus TAF/FTC has been our go-to regimen in these difficult to treat patients, who are underrepresented in clinical trials.
• Switching to BIC/FTC/TAF was non-inferior to continued DTG/ABC/3TC [22].  Remarkably few differences after the switch — same renal, bone, lipid outcomes. In clinical practice, this change will lead to a smaller tablet size and avoid ABC-related cardiovascular risk concerns, but otherwise won’t change much. Speaking of …
• A series of studies provided further evidence for the association between abacavir use and cardiovascular risk. On the 10-year anniversary of the first report of this association, a bunch of studies might put an end to this “controversy” — these included mechanistic studies involving platelet reactivity [80, 673], platelets and leukocytes [674], an association with pre-clinical CAD on CT angiography [670], and the predicted clinical impact of stopping abacavir on cardiovascular risk [692]. NA-ACCORD study on this issue also just published.
• Optimal management of 3rd-line ART in resource limited settings includes the use of darunavir/r and raltegravir, sometimes etravirine [30LB]. We can add this study to the numerous others that show that in treatment failure studies, the patients with the least resistance do the worst — it’s a marker for poor adherence. It will be important to document how treatment failures evolve with the widespread implementation of DTG/TDF/FTC, a regimen with a much higher resistance barrier than those with NNRTIs.
• Patients with primary HIV infection in France had remarkably high levels of transmitted integrase resistance [529]. 7.4%, 5.6%, and 5.3% in 2014, 2015, 2016, respectively. I wonder what fraction are clinically relevant mutations vs. polymorphisms. On this same topic …
• One patient in the treatment-naive studies of BIC/FTC/TAF had transmitted resistance to dolutegravir [532]. I believe this is the first time such high-level integrase resistance has been found in a treatment-naive patient. Since baseline integrase genotyping was not required for study entry, it was picked up retrospectively. The patient was randomized to BIC/FTC/TAF, and achieved virologic suppression.
• Certain patients with a history of lamivudine resistance can maintain virologic suppression on a two-drug regimen of lamivudine plus a PI or integrase inhibitor [498]. These M184V patients did, however, have more virologic “blipping”, suggesting that HIV control was less robust than with triple therapy. It’s also an observational study, not a randomized trial, and I can’t imagine choosing to use a two-drug 3TC-containing regimen in someone who is known already to have resistance.
• Women switching to BIC/FTC/TAF tolerated the regimen well and maintained virologic suppression [500]. Most had been receiving EVG-containing regimens previously. Since the licensing studies of this regimen had so few female participants, this trial of over 400 women is important if only to show that the treatment is effective in women too.
• San Francisco has been making remarkable progress in starting ART as soon as possible in newly diagnosed patients [93]. From 2013 to 2016, the median time from first care to initiating therapy decreased from 27 days to 1. Not surprisingly, the time to viral load < 200 also dramatically dropped, from 134 days to 61 days. A decrease in time to start ART was seen in all demographic groups, including traditionally vulnerable populations (racial and ethnic minorities, homeless).
• In a randomized strategy study, same day ART initiation again proved better than standard of care in patient engagement, virologic suppression [94]. Study was conducted in Lesotho, and the novel aspect is that it was also done after home HIV testing. Paper also published in JAMA.
• Sertraline does not improve outcomes in cryptococcal meningitis [36]. This commonly used antidepressant has in vitro antifungal activity, but didn’t do anything here, prompting early discontinuation of the study for futility. It was certainly worth trying — we definitely need strategies to improve the outcomes with this challenging disease!
• Discontinuation of DTG due to CNS side effects is not associated with prior psychiatric diagnoses or plasma levels [424].  The discontinuation rate for DTG overall was 6%, and female sex and older age were risk factors. The lack of association with plasma levels differs from a previous study done in Japan.
• Patients surveyed about their preference for novel dosing strategies for ART chose “a single pill taken once a week” as preferred [503]. The other options were “two shots given in the clinic every other month” and “two small plastic implants in the forearm every 6 months.”
• Treatment of HIV controllers with TDF/FTC/RPV reduces T-cell activation and markers of immune exhaustion [229]. (Disclosure:  co-investigator.) Plasma HIV RNA also further declined, and treatment was associated with a modest improvement in quality of life. No effect on absolute CD4 cell counts or HIV DNA.
• Only 11% of MSM with acute HCV clear the virus spontaneously [129]. If there is < 2 log drop in HCV RNA by week 4, then clearance is extremely unlikely. The data suggest treatment should be offered at that earlier time point (week 4), for the benefit of both the patient and to prevent further ongoing transmission.
• In coinfected patients, FTC/TAF (as part of the BIC/FTC/TAF regimen) shows good activity vs hepatitis B [618]. In this secondary analysis of prospective clinical trials, one patient randomized to a non-TAF regimen acquired hepatitis B.
• New HIV infections in Australia have dropped dramatically in association with widespread use of PrEP [88]. The bulk of their HIV epidemic is in MSM, making the target for HIV prevention clear. Plus, one Australian clinician told me that around 95% of those in care are virologically suppressed, which beats the typical US-clinic suppression rate of 85% or so.
• Very low doses of MK-8591 protect rhesus macaques against SHIV infection [89LB]. Results suggest this drug might be suitable for less frequent dosing as a PrEP strategy.
• Crystal methamphetamine is bad for your telomeres [760]. In a cross sectional study comparing HIV infected people who do and do not use crystal meth, along with HIV negative controls, those who were HIV infected with meth use had telomere “T/S ratios” consistent with 20 years of accelerated aging. This rings true from clinical practice! What a terrible drug.

The dates of CROI are no longer a tightly kept secret (hooray!), so we already know that next year’s meeting will be in Seattle, March 4-7, 2019.

As for here in Boston, we’re getting ready for our next big storm.

So what did I miss?