HIV and ID Observations

“Look up there! It’s Microsoft and Amazon stock!” National Archives, 1962.

In a recent chat I had on a local TV network on this year’s respiratory virus season, the host mentioned that “this year felt very post-pandemic”, prompting me reflexively to knock wood — and I’m not a superstitious person.

But even we ID doctors must acknowledge the dramatic improvement in COVID severity this winter compared to the last two, both of which were severe enough to make the Conference on Retroviruses and Opportunistic Infections, or CROI, stick to the virtual-only format. And, of course, historically, CROI was the very first scientific conference to go this route, way back in March 2020, a period about which the less said the better.

(Involuntary shudder.)

But on to this year’s CROI, which was available in-person or virtual, taking place once again in Seattle, a place it’s been several times before. It’s our premiere scientific conference, covering not just HIV, but also sexually transmitted infections (STIs), hepatitis, and now SARS-CoV-2, with many excellent studies on all these scourges.

This week, in this Really Rapid Review™, I’ll cover the non-COVID studies, with take-home messages and sometimes a brief comment. You’ll see the abstract numbers in brackets and links to either the abstract (if available) or to the invaluable NATAP site, which somehow continues to aggregate many of the actual slide presentations and posters in real-time. Bravo for that, and long may it live!

• The prognosis for people with HIV has markedly improved since 2012 [870]. This multi-national, large (n=33,598) cohort study demonstrated a significant drop in risk of death during this period, regardless of cause. The leading cause of death was non-AIDS-related cancers, an observation likely to resonate with all HIV providers. Among HIV factors, CD4 <350 and RNA >200 were the strongest predictors of death.
• After treatment failure with NNRTI + 2NRTIs, DTG plus DRV/r was both noninferior and superior to standard of care [198]. This is the first time a boosted PI plus an INSTI has bested a regimen of recycled NRTIs plus a boosted PI. Given the widespread use of DTG + 2NRTIs as fixed-dose “TLD”, which also performed well in this study, I suspect the DRV/r + DTG strategy will not be used much. FYI, the study is called “D2EFT” for “Dolutegravir and Darunavir Effectiveness in adults Failing first-line Therapy” — you knew that, right?
• Switching stable PWH on BIC/FTC/TAF to long-acting injectable CAB-RPV every 2 months resulted in noninferior virologic suppression at 12 months [191]. 670 PWH were randomized 1:2 to continue versus switch to 2-monthly CAB-RPV. While the results met the criteria for noninferiority, there were 5 people on CAB-RPV (3 with resistance) with viral loads >50 in the injectable group, versus 1 in the BIC/FTC/TAF group (no resistance). Counseling people considering CAB/RPV that this therapy comes with a small (but non-zero) risk of failure with resistance is important. Treatment satisfaction improved with the switch. This is the SOLAR study, for “Switch Onto Long-Acting Regimen” — now that’s a good name!
• Switching from BIC/FTC/TAF to CAB/RPV does not lead to weight loss [146]. Data are from the above clinical trial. Meaning — do not use “maybe they will lose weight” as the motivation for the switch to long-acting injectables. Some people gain weight, some people stay stable, some people lose.
• What influences switches to either BIC/FTC/TAF or DTG/3TC [532]? The former is chosen more for those with low CD4 or risk factors for poor adherence; the latter for renal impairment or obesity. So even though these have similar indications, they are not used identically in clinical practice. (Co-author disclosure.)
• Having a detectable viral load in the year preceding a switch to CAB-RPV is a risk factor for detectable viremia following the switch [516]. This study, from the UCSD clinical program that has adopted CAB-RPV more enthusiastically than any other clinic site I’m aware of, found that 25% of switchers end up having detectable viral loads post switch — I’m sure engendering much anxiety! Importantly, one of the investigators told me that failure with resistance in their clinical cohort occurs at a rate comparable to the clinical trials (approximately 1-2%).
• PWH with uncontrolled viremia achieved high rates of virologic suppression on CAB-RPV [518]. More from the UCSF Ward 86 cohort, using CAB/RPV in a non-FDA-approved strategy. Out of 133 PWH who were very much not the usual candidates for this treatment, 57 had viremia. Suppression was achieved in 55 — astoundingly good — with only 2 developing treatment failure. A corresponding modeling study [517] showed this strategy would greatly prolong survival, even with conservative estimates about efficacy (co-author disclosure). We need this success with IM CAB/RPV in people with viremia replicated elsewhere! If it is, I suspect it could enter treatment guidelines, of course with all kinds of caveats and cautionary language.
• Lenacapavir plus two long-acting broadly neutralizing antibodies (bNAbs) given every 6 months maintained virologic suppression for 26 weeks [193]. Out of 20 participants, 1 rebounded — unclear why. A study entry requirement was pre-treatment resistance testing showing susceptibility to the bNAbs — a big hurdle if this form of treatment is ever going to be practically deployed. Another hurdle — saying the names of the bNAbs. From an always amusing friend:
  
• Islatravir (ISL) causes a dose-related drop in lymphocytes that resolves over several months [192]. Welcome back, islatravir! The suspected mechanism of this drop is intracellular accumulation of ISL-triphosphate, leading to apoptosis — not mitochondrial toxicity. The dose moving forward will be 0.25 mg daily, which should be active against wild-type and M184V-containing viruses; the weekly dose (when combined with lenacapavir) will be 2 mg. These data preceded presentations on two phase 3 switch studies of doravirine/islatravir (DOR/ISL) in stably suppressed PWH.
• Stable PWH on any regimen maintained virologic suppression comparable to their baseline treatment when switching to daily DOR/ISL [196]. There were no treatment failures on DOR/ISL versus 3 in the continued baseline regimen in this open-label study.
• Stable PWH on BIC/FTC/TAF maintained virologic suppression when switching to daily DOR/ISL [197]. This was a blinded study and encouragingly showed no difference in treatment-related side effects except for a drop in lymphocytes. (0.75 mg daily of ISL used.) There was a question from the audience about weight changes, which were not presented, but are in the public domain — no significant changes at 48 weeks after the switch. For the record, I have it on good authority that we’re not supposed to call this regimen “door-isil”.
• The weight trajectory of over 20,000 PWH in Kenya switching to dolutegravir differed by baseline regimen [617]. People switching off efavirenz had a sharp increase in weight, one not observed with baseline nevirapine — a reminder that weight effects within drug classes are not uniform, as only efavirenz (among the NNRTIs) appears to have this weight-suppressive effect.
• Weight decreases when TAF/FTC + DTG is switched to “TLD” and increases when the switch is from TDF/FTC/EFV [671]. These changes are exactly as one would predict, as the “T” stands for TDF — which has been shown in multiple studies to suppress weight, in particular when combined with EFV. The mechanism remains unclear. Linked the published clinical study from CID.
• An in vitro model showed that dolutegravir, but not doravirine or efavirenz, disrupted estrogen-mediated fat differentiation [147]. Is this the explanation for the greater weight gain on INSTIs for women than men? By the way, the full title of the presentation was A LOSS OF ERα ATTENUATES DTG-MEDIATED DISRUPTION OF THERMOGENESIS IN BROWN ADIPOCYTES, in case you were wondering. (Abstract not available.)
• Could alteration in GI microflora explain the weight differences between regimens [248]? Gut microbiota among 27 PWH switching treatment from TDF/FTC/EFV to BIC/FTC/TAF showed increased diversity (generally a sign of health), but also increased sC163 (an inflammatory marker associated with obesity) — cause versus effect? There were no controls in this study.
• When controlling for baseline risk factors, integrase-inhibitor-based regimens were not associated with elevated cardiovascular risk [149]. This is reassuring data from the Swiss HIV Cohort study, contrasting with published data from a different cohort. I confess I held my breath when reading the title of the presentation, as this class of drugs is now critical to HIV treatment worldwide.
• Multivariable analysis of a clinical trial comparing BIC/FTC/TAF and DTG+F/TDF showed that TAF looks better for HBV [116]. Predictors of HBV suppression were HBeAg-, HBV DNA <8 log, ALT >ULN and treatment w BIC/FTC/TAF. Longer follow-up of this study, presented originally at the AIDS 2022 meeting, will be important as the TDF-based regimen may eventually catch up.
• Doxycycline given as post-exposure prophylaxis after sex reduced the incidence of syphilis, chlamydia, and gonorrhea in MSM [119]. In a second randomization, the meningococcal B vaccine reduced the incidence of gonorrhea. Called the DOXYVAC study, this was one of several key presentations on the doxycycline preventive strategy during the conference.
• An analysis of bacterial resistance from the Doxy-PEP study found no increase in resistance to GC, Staph aureus, or commensal Neisseria species with PEP [120]. Reassuring data! One caveat is that resistance could happen eventually if this strategy were widely adopted. As a reminder, Doxy-PEP also found that bacterial STIs declined in MSM and trans women who took PEP, as did the original ANRS study (albeit not for GC). That makes 3 favorable studies for doxy-PEP and STI prevention in MSM.
• In women at high risk in Kenya, doxycycline PEP did not reduce bacterial STIs [121]. It’s uncertain why this intervention was not effective in cisgender women — adherence was good, and a separate PK study [118] implied that it should have worked.
• A modeling study applying favorable data on doxycycline PEP to MSM and trans women found that adopting this strategy for those with prior STIs would avert a substantial number of future infections [122]. Not surprisingly, a robust discussion ensued at this session about whether guidelines should recommend doxycycline PEP for certain populations. Though I’m not on guidelines committees for STIs, I’d vote yes — with ongoing surveillance studies for assessment of resistance. Although we use doxy-PEP for tick bites for Lyme areas, this intervention for STIs is likely to be much more frequent.
• Mpox in PWH who have advanced HIV-related immunosuppression can be a severe, disfiguring, and life-threatening opportunistic infection [173]. Mortality was 27% (!) in those with CD4 <100, and the clinical course suggests an IRIS-like phenomenon when ART is started. There is a graphic (and unsettling) display of the Mpox lesions in the published paper. These cases underscore how critical it is for PWH to get on HIV therapy before the disease progresses and also to get at-risk people vaccinated.
• A study of over 6000 women receiving TDF/FTC for PrEP found that the adherence correlates with protection were similar to what’s observed in men [516]. Effectiveness increased steeply with 4 or more pills/week. Previous studies suggested that women required higher levels of adherence than men.
• HIV acquired while receiving PrEP with cabotegravir may be clinically silent and difficult to diagnose [149]. The investigators described delayed detection, negative antigen/antibody tests, and a paucity of symptoms. They even gave this syndrome a name — LEVI, for “Long-acting Early Viral Inhibition” syndrome. Not bad. The key is to use HIV RNA for diagnosis, but these are still going to be very challenging. Here’s a real-life case, occurring in clinical practice.

Had an amazing time at #CROI2023! We were able to share our real world case of breakthrough HIV-1 infection in the setting of on-time, appropriately monitored CAB-LA for PrEP @howardbrownhc.

We greatly appreciated the insightful discussions which I’ll try to summarize below. pic.twitter.com/iLI7WtJSMj

— Anu Hazra (@AnuHazraMD) February 22, 2023

• A complex TB treatment strategy of 8 weeks (!) of bedaquiline + linezolid added to INH, PZA, and ethambutol was noninferior to the standard 6 months of therapy [113].  The study, called TRUNCATE-TB, was just published in the New England Journal of Medicine. But before getting too excited, there are caveats about implementing this challenging approach — lots of them! There is a good summary of these concerns in the accompanying editorial and in this thread.

Of course, there were numerous additional interesting studies not mentioned here, apologies if I left out your favorites — feel free to cite them in the comments.

And it was really fun to visit Seattle again, a place with a strong familial connection. Plus, the sparkling new wing of the convention center hosted the conference.

The weather? Cold and rainy — winter in Seattle, you know — and it even snowed a bit the last day. No one ever accused the CROI organizers of picking their winter locations in tropical paradise, that’s for sure.