CROI 2023: Pipeline HIV drugs and formulations for treatment and PrEP
As with previous meetings, CROI 2023 included a strong selection of studies reporting on upcoming new drugs and formulations for treatment and prevention.
These continue to prioritise long-acting compounds and delivery systems and for combinations that use two rather than three active drugs.
The following summaries signpost to many of the most relevant and interesting studies.
- Six-monthly dosing using lenacapavir with bNAbs. The first results using capsid inhibitor in combination with two long-acting bNAbs where a single administration provided ART cover for six months. This phase 1b switch study in 20 participants on suppressive ART who were sensitive to both bNAbs maintained viral suppression for 26 weeks, with viral rebound in one participant who re-suppressed on oral ART (one withdrawal while suppressed. [1, 2]
- Another six lenacapavir studies updated results from treatment-naive and treatment-experienced studies, on activity against HIV-2, having a four-week window for subsequent dosing and on use as PrEP. These studies are reported in detail in a separate article in this issue of HTB. 
- More than a dozen studies covered different aspects of broadly neutralising antibodies (bNAbs) including those being developed by Gilead (teropavimab/GS-5423 and zinlirvimab/GS-2872) and used in the lenacapavir study above, and ViiV (N6LS) that includes a new extended dose delivery system.
- The Gilead bNAbs are also being studied in cure-related studies that include an analytic treatment interruption (ATI). The phase 2a Titan study showed that the two groups receiving the dual bNAbs sustained undetectable viral load for 119 days (IQR: 77 to 175) and 98 days (IQR: 70 to119). This study included weekly bNAb infusions for eight weeks and did not use the long-acting formulations. Unfortunately there was no benefit in delay to viral rebound from using the TLR9 agonist lefitolimod. 
- The BEAT2 study used the same two bNAbs given at weeks 0, 2, 4 ,8 ,12, 16 and 20 (these were not long-acting formulations) with weekly injections of PEG-IFN-α2b. After an ATI, viral load remained undetectable <20 copies/mL for six months in 10/12 participants, but resistance developed to the bNAbs as drug levels dropped to low levels. No evidence was found for a vaccine-like effect from the bNabs. [5, 6, 7]
- Predicting bNAbs sensitivity at baseline is still difficult and a useful poster compared results from genotypic and phenotypic tests for the Gilead bNAbs.  Phenotypic testing of 124 participants found 75% were susceptible to GS-5423, and 65% to GS-2872. The test failed to generate a result in 15/124 people. Phenotypic results were also compared with two different genotype tests. Although there was generally good correlation between tests, genotypic signatures predicted phenotypic susceptibility (in in 59/109 proviral sequences), with high specificity (93 to 100% GS-5423, 71 to 96% GS-2872), but low sensitivity (24 to 11% GS-5423, 76 to 8% GS-2872).
- Another useful poster reported the comparative suppression profiles of VRC01LS, VRC07-523LS, VRC01v23, N6LS and 1-18LS in ex vivo assay, reporting that resistance to one bNAb can sometimes be overcome by another. 
- Using bNAb in newborn infants as HIV prophylaxis has previously been published but a small study on acceptability to caregivers in Malawi included that 87% preferred monthly infusions rather than daily oral medications. 
- Efficacy depends on bNAb sensitivity however, and might need dual bNAb combinations as baseline maternal resistance was high in a small US study. 
- N6LS is a CD4-binding bNAb similar to VRC01 being developed by ViiV as VH3810109. New data at CROI included a sustained delivery system using recombinant human hyaluronidase PH20 (HuPH20) that allows high volume subcutaneous delivery for six months rather than more frequent infusions, making a pouch under the skin to inject the bNAb that then contracts over the next day or so. [12, 13]
- A phase 1 safety and PK PrEP study using a dual bNAb combination of CAP256V2LS and VRC07-523LS, delivered using HuPH20, maintained target drug levels for six months in 42 HIV negative women in South Africa. 
Islatravir is the highly potent NRTTI being developed by Merck/MSD that was put on hold for the last year because of an unexpected side effect that reduced CD4 counts.
Two presentations explained the cause being due to high-level accumulation of intracellular islatravir triphosphate but that these can be safely overcome by using lower oral doses: 0.25 mg for daily and 2 mg doses for weekly dosing. [15, 16]
Even though the development programme to use islatravir for PrEP and PEP has been stopped to focus on a related second-generation molecule, two studies reported on new delivery formulations. One reported on a biodegradable subcutaneous islatravir implant that protected 12 macaques from 12 sequential vaginal SHIV challenges over six weeks. Control animals were infected after a median of 2.5 weeks. 
A second study described a refillable titanium slow release implant that uses a silicon nanomembrane to deliver, in this case, 160 microns/day of islatravir at a constant rate for 20 months. This provided both sustained effective drug levels in plasma but also limited levels of intracellular triphosphate that caused the lymphocyte toxicity. 
The group also reported that islatravir remains stable at 37 degrees for over three years.
Full protection (100%) was reported in animal studies after multiple weekly SHIV rectal challenge in male animals and vaginal challenge in females (n=6 in both groups), with all control animals becoming quickly infected. In terms of systemic exposure, even after 20 months, there were no changes in creatinine, ALS, AST, lymphocytes, or absolute CD4 and CD8 counts.
The technology was NIH-funded but it is not clear whether the delivery system can be used for other molecules including the follow-on compound being developed by Merck/MSD.
Researchers from the University of Nebraska – rather than Gilead – presented PK results from two lead nanoformulations of the integrase inhibitor bictegravir. A single intramuscular injection produced sustained drugs levels above the protein-adjusted IC90 for more than seven months in rodents and for more than three months in macaques. 
Elvitegravir/TAF PrEP implants
Two studies were also presented on using elvitegravir and tenofovir alafenamide coformulated as a rectal or vaginal implant for use as PEP. [20, 21]
The overlap in development of new compounds and new delivery models shows the potential for even longer acting drugs for HIV treatment and prevention.
If developed from these early stages through to phase 3, additional studies will need to cover older participants, use during pregnancy, preexisting renal and hepatic complications, cardiovascular disease, mental health issues etc who are often excluded from early studies and also to understand interpatient PK variability and whether these are affected by weight, BMI and sex. 
There might also be variability of the received dose depending on small differences in the way an injection is administered. Whether intramuscular injections are placed deep or in peripheral tissue, or if they miss the muscle completely. Whether the rate of release is constant throughout the dosing period, and whether any swelling afterwards affects drug release. 
Unless stated otherwise, references are to the Programme and Abstracts of the 30th Conference on Retroviruses and Opportunistic Infections, 19 – 22 February 2023, Seattle and hybrid.
Some 2023 abstracts are available via the online CROI abstract database, generally posters do far rather than for oral presentations.
- CROI 2023: Six-monthly ART – lenacapavir + dual bNAbs maintains undetectable viral load for 26 weeks after single doses. HTB (1 March 2023).
- Eron J et al. Lenacapavir with bNAbs GS-5423 and GS-2872 dosed every 6 months in people with HIV. CROI 2023, Seattle. Oral abstract 193.
- CROI 2023: Other lenacapavir studies – experienced and naive updates, the dosing window, HIV-2 and PrEP. HTB (1 March 2023).
- Gunst JD et al. The impact of 3BNC117, 10-1074, and lefitolimod on HIV-1 persistence: the TITAN trial. CROI 2023, Seattle. Oral abstract 136.
- Tebas P et al. BEAT2 primary trial outcomes: PEG-IFN-α2b +3BNC117 & 10-1074 in chronic HIV infection. Poster abstract 431.
- Joy J et al. BEAT2: PEG-IFN-ALPHA + 3BNC117 & 10-1074 rebound virus phenotype and evolution. Poster abstract 326.
- Betina Pampena M et al. Evaluation of HIV-specific T cell response in BEAT2 clinical trial. Poster abstract 319.
- Selzer et al. Susceptibility screening to bNAbs GS-5423 and GS-2872 in ART-suppressed participants. CROI 2023, Seattle. Poster abstract 580.
https://croi.blob.core.windows.net/documents/CROI_2023_Susceptibility_Screening_Poster_02.10.23-133208737957024179.pdf (poster via login)
- Hait SH et al. Efficacy and complementarity of HIV-1 suppression by CD4- binding bNAbs. CROI 2023, Seattle. Poster abstract 307.
- Mosetlhi M et al. Caregivers of children with HIV in Botswana prefer monthly IV bNAbs to daily oral ART. Poster abstract 828.
- Karthigeyan KP et al. Maternal broadly neutralizing antibody activity and perinatal transmission of HIV-1. Poster abstract 780.
- Leone P et al. Impact of baseline factors on virologic response to bNAb VH3810109 (N6LS) in Banner study. CROI 2023, Seattle. Poster abstract 520.
- Wu R et al N6LS with rHuPH20 enables safe high-dose monoclonal antibody subcutaenous delivery. CROI 2023, Seattle. Poster abstract 499.
- Mahomed S et al. Phase 1 trial of CAP256V2LS and VRC07-523LS antibodies among women in South Africa. Poster abstract 988.
- Squires KE et al. 92 Effect of islatravir on total lymphocyte and lymphocyte subset counts. Oral poster 192.
- Vargo R et al. Modeling to optimize islatravir QW dose in HIV virologically suppressed PWH. Poster abstract 497.
- Daly MB et al. Vaginal PrEP efficacy of biodegradable islatravir implants in macaques. Poster abstract 989.
- Pons-Faudoa F et al. Ultra long-acting refillable islatravir implant fully protects NHP against SHIV. CROI 2023, Seattle. Poster abstract 165.
- Nayan MU et al. Ultra-long-acting bictegravir nanoformulations. CROI 2023, Seattle. Poster abstract 540.
- Riddler SA et al. Safety and PK/PD of a tenofovir alafenamide/elvitegravir insert administered rectally. Oral abstract 164.
- Makarova M et al. Extended post-exposure protection against SHIV vaginal infection with TAF/EVG inserts. Poster abstract 990.
- Khoo S. Long-acting ARVs: Research into the pharmacology of treatment and prevention. HANC HIV AIDS Network. (30 April 2021).
- Dayananda et al. Intended intramuscular gluteal injections: Are they truly intramuscular? J Postgrad Med. 2014:60.175-8. DOI:10.4103/0022-3859.132334.
This report was first published on 2 March 2023.