HIV and ID Observations

A page from the CROI 2025 abstract book.

Wow, that was an interesting conference — in ways both good and bad. The good part was the content, as the Conference on Retroviruses and Opportunistic Infections (CROI) is our leading HIV research conference. There was plenty of interesting stuff.

The not-so-good part was the stunned state of many HIV clinicians and researchers. So much of national and global HIV research falls directly in the crosshairs of our current government’s actions that there was barely a conversation or topic not directly influenced in some way. Some research abstracts were withdrawn; some regular attendees canceled their attendance; some planned projects will no longer be feasible in the current funding climate.

The result of all this disruption led to interactions like one I had with a long-time HIV clinician-researcher from Canada — you know, that previously friendly neighbor of ours to the north. We were in the brightly lit poster hall, scanning for compelling studies. She approached me wide-eyed with disbelief, incredulous at the heartless cancelling of USAID programs in Africa, the punitive trade tariffs her country must face, the “51st state” comments, and the seeming passivity of our opposition.

And, instead of discussing exciting HIV research at the conference, she implored me to watch this video, from France. (Fortunately, it’s subtitled.) Highly recommended.

Is it any surprise that exchanges like this with people from other countries were common last week? Hardly.

On to the usual stuff of a Really Rapid Review™, the actual research — and stick around for a truly moving video at the end:

As initial therapy for patients with advanced HIV disease, bictegravir/FTC/TAF had better virologic outcomes than darunavir/cobicistat/FTC/TAF*. The importance of this study is that this population rarely gets enrolled into clinical trials — the median CD4 was 41, and almost half of them had HIV RNA > 500K. The composite outcome of combined clinical and virologic endpoints was not significantly different, but this result still endorses BIC/FTC/TAF (or TLD) as initial therapy even with advanced HIV disease, which is what most of us are doing.

(*Wins 2025 award for poster most deserving of an oral presentation, so I’m giving it the pole position here.)

Two experimental formulations of lenacapavir, given as intramuscular injections once-yearly, achieved levels sufficient for annual PrEP. The investigators showed some great-looking PK curves, with levels exceeding what was observed in the PURPOSE 1 and 2 trials. These data support a planned phase 3 study.

A follow-up of HIV acquisition while on cabotegravir PrEP in HPTN 083 provided some information about what happens with subsequent treatment. The study included 47 people who acquired HIV, 22 of whom went on INSTI-based ART, and 25 other regimens (PI- or EFV-based), with similar outcomes in both groups. Those with no CAB injections in the prior 6 months were less likely to have pre-ART INSTI resistance. A second study described seven people with CAB PrEP failure from clinical care, four of seven with non-reactive HIV Ag/Ab tests. Some had resistance only detected by more sensitive investigational assays, clinical significance unclear.

The weight trajectory of people on TAF/FTC for PrEP in the DISCOVER trial was statistically similar to the placebo arm from iPrEx. Although limited by being a cross-study comparison, these studies of weight changes in people without HIV are instructive, as they remove the “return to health” effects of antiviral activity on weight.

Several “real world” studies demonstrated that cabotegravir plus rilpivirine in clinical practice has low rates of treatment failure with resistance, comparable to what was observed in clinical trials. Here are four of them: one (disclosure: co-investigator), two, three, and four. Specifically, it happens in around 1% of treated people. These observational studies have limitations, most notably variability in duration of treatment and the inability to capture all patient follow-up. The fourth study cited above showed that 92 out of 465 (20%) from a single center had discontinued CAB/RPV, with injection site reactions the most common reason; only 6 (1.3%) had virologic failure.

A detailed analysis of cabotegravir and rilpivirine drug levels found an association between lower concentrations and detectable viral loads > 20 copies/mL. Whether low levels would correlate with actual treatment failure is unknown, but I suspect that with a large enough cohort, they would.

In a cohort of 81 people with viremia from Grady Hospital in Atlanta, use of long-acting ART led to viral suppression in 92%. The median baseline CD4 cell count was 186, and 44% had prior HIV-related opportunistic infections. Two experienced virologic failure with resistance to both cabotegravir and rilpivirine. Notably, regimens were diverse, employing all our injectable options:  cabotegravir/rilpivirine, +/- lenacapavir, +/- ibalizumab. Great to see these excellent results in the urban south, which is notorious for having major barriers to optimal HIV treatment outcomes.

For those experiencing low-level viremia (50-199), virologic suppression was more likely in those who switched therapy vs. those who did not. Note that this is the opposite of what most prospective intensification studies have shown, and it’s also at odds with what I’ve observed in clinical practice (unless one goes from a PI to an INSTI — not commented on here). A limitation is that it’s an observational study, and the switchers significantly differed from the non-switchers in several ways that could have impacted the outcome.

In a randomized trial, switching to every 6-month lenacapavir plus two broadly neutralizing antibodies (bNAbs) maintained viral suppression in all but one patient. A total of 53 received this treatment. Note that to be eligible for this trial, the participants’ virus had to have susceptibility to both bNAbs (teropavimab + zinlirvimab, “TAB and ZAB”); this was found in only 99 out of 200 of those screening for the study. This very long-acting injectable regimen is both very exciting and very unlikely to have broad use — just too many hurdles for successful implementation.

After ART cessation, administration of two long-acting bNAbs significantly delayed virologic rebound by week 20 compared with placebo. Suppression was observed in 75.0% of participants switched to bNAbs vs 8.8% in placebo. Of those who rebounded on bNAbs, some did so quickly, some it was more delayed. If the placebo result of 8.8% maintaining suppression seems high to you — after all, they’ve stopped ART! — it’s because the study population included only suppressed PWH who started treatment during early HIV, which is known to be associated with a lower viral reservoir (and a higher prevalence of post-interruption viral control).

The monoclonal antibody N6LS, given every 4 months, was tested with monthly cabotegravir. The good news is that most of the participants maintained viral suppression. The less good news is that despite screening with virus sensitive to N6LS, 4 of 99 receiving this treatment had confirmed virologic failure — with 1 of them developing a new INSTI mutation (Q148R). Can you tell I remain not very enthusiastic about bNAbs for HIV treatment?

4% of people discontinuing all treatment maintained virologic control at day 84. Such surprising viral suppression was observed in 6% for early-ART and 1% for late-ART initiators. Median time to rebound > 50 copies/mL was 16 days. Since this study captured data on 382 individuals, it will provide good background information on whether various cure interventions have an impact on time to virologic rebound.

An person who was an elite controller for 32 years lost virologic control but contributed extensive samples for research during that time. The investigators found that in this person, the balance between the reservoir and immune response was dynamic, despite the static nature of the undetectable viral load. They used the label “Exceptional Elite Controllers” to describe people who have HIV control for > 20 years; many (like this woman) are also exceptional for their generosity to HIV research.

Two randomized clinical trials demonstrated that the single pill of doravirine/islatravir (DOR/ISL) can maintain viral suppression comparable to baseline regimens. In one study, the starting regimen was BIC/FTC/TAF; this was blinded. The other trial was open label, and compared DOR/ISL to any baseline ART. While it was encouraging that this one-pill, once-daily treatment did not have the lymphocyte suppression seen with higher doses of islatravir, there did not appear to be any clear benefits from the switches. A treatment-naive study of this combination vs BIC/FTC/TAF is ongoing; it’s similar to the prior published study, only with this lower dose of islatravir (0.25 mg/day).

Switching from DTG/3TC to BIC/FTC/TAF vs. continuing DTG/3TC showed comparable effects on weight, cholesterol levels, and systemic inflammation (IL-6) compared to continuing DTG/3TC. In some ways this is an “intensification” study of DTG/3TC by adding TAF, if we assume that BIC = DTG and FTC = 3TC. It’s also the opposite of the DYAD study, in which patients started on BIC/FTC/TAF. Bottom line — aside from the PASO DOBLE results (which I’m still trying to get my head around), there doesn’t seem to be much of a difference between these two treatments when it comes to metabolic and inflammatory characteristics.

An experimental integrase inhibitor given on days 1 (baseline), 4, and 7 induced a greater than 2-log viral load reduction, comparable to what was observed with dolutegravir as monotherapy. The drug, called VH-184 for now, has activity against many INSTI-resistant strains, and is being developed for long-acting therapy.

There are two additional cases of potential HIV cures — one from Chicago and one from Oslo. Both had hematologic malignancies and received cells from donors with the CCR5-delta 32 genetic mutation conferring resistance to HIV. Both are now off ART, though the Chicago case did have a viral rebound initially (and ART was resumed). Of course, the key question is what these cases can teach us about HIV cure without resorting to this extremely toxic (and costly) procedure.

In a randomized clinical trial, semaglutide stabilized epigenetic aging in PWH who had lipohypertrophy compared to placebo. In plain English, “epigenetic aging” is a molecular marker of biologic rather than chronologic aging; this process is accelerated by HIV in some people. These results (and many others) prompt me to wonder, is there anything these drugs can’t do?

In an open-label randomized trial, letermovir for CMV suppression led to some surprising benefits in markers of inflammation, immune activation, CD4 counts, and even one test of functional status. Why surprising? Because the study was actually stopped early for futility due to unexpected increases in sTNFR2 (I guess that’s usually a bad signal). These unexpected benefits raise the question of whether CMV suppression can improve real clinical outcomes — important to determine this because letermovir is currently extremely expensive, even for a short course of therapy, and hardly an intervention that should be adopted now by clinicians.

Tecovirimat did not shorten time to clinical resolution of Mpox compared to placebo. The time-to-improvement curves truly overlap in this study; it was really negative. Viral clearance was also not faster. While there was tremendous enthusiasm for this treatment during the summer of 2022, the results of two separate studies show the critical importance of doing randomized trials in unproven therapies.

In a large North American cohort, the incidence of HCV infection increased two-fold among MSM without IDU from 1995–2005 to 2015–2023. By contrast, incidence was stable (but high) among those who inject drugs. The authors offered no explanation, though I suspect the “U=U” message and use of PrEP has understandably led to more condomless sex among MSM.

The HepB-CpG vaccine (brand name Heplisav-B) provided better and more durable seroprotection than the standard HepB-alum vaccines. This included both those who where previously nonresponsive to HBV vaccination those without prior HBV vaccination. 3 doses were better than 2, but it’s not clear to me that this benefit warrants making the extra dose standard of care, since the usual recommended schedule is 2 doses separated by a month.

Brief COVID-19 Section

For household contacts of COVID-19, ensitrelvir for five days led to a 67% reduction in the incidence of infection compared to placebo. This is the first antiviral to demonstrate protection against COVID-19 for post-exposure prophylaxis (both molnupiravir and Paxlovid did not work), perhaps due to the drug’s very long half-life. It already is approved for treatment in Japan and Singapore; hope we get approval in the USA for this PEP indication soon.

In the ACTIV-6 randomized clinical trial, metformin did not shorten the time to symptom resolution in adults with mild to moderate COVID-19. The study population was predominantly healthy, especially compared to other COVID-19 treatment studies. It will be interesting to see the study has any secondary endpoints of interest that favor treatment, such as viral load reduction or subsequent development of Long Covid.

In a phase 2 study, SNS812, an aerosolized broad-spectrum antiviral small interfering RNA (siRNA), significantly hastened time to resolution of several key symptoms of COVID-19. It also improved time to viral clearance. The treatment is notable both for its mode of administration (inhalation) and predicted activity not only against SARS-CoV-2 variants, but potentially other coronaviruses as well.

That’s a wrap — I’m sure I’m forgetting something important. Let me know in the comments!

Meanwhile, I’d like to highlight this opening plenary talk by Rebecca Denison. She tells a compelling story about receiving her HIV diagnosis in 1990, several years before we had effective treatment. As she notes, it wasn’t uncommon to receive the grim news about prognosis while simultaneously experiencing enormous societal and personal stigma. The happy outcome she relates is a tribute both to her strength of character over the years, and to extraordinary progress in HIV research and care.

Her story particularly resonated with me as her diagnosis occurred the same year I started working as an ID doctor, one who chose to focus on HIV. But her talk was so wonderful that I suspect many would benefit from hearing this inspirational and moving account.

Many thanks to Drs. Eileen Scully, Joseph Llibre, and Renslow Sherer.