CROI 2022: Strategies to suppress viral load off-ART with 3BNC117, 10-1074 and other bNAbs
1 March 2022. Related: Conference reports, Cure-related research, CROI 29 (Retrovirus) 2022.
Some of the most intriguing results presented at CROI 2022 included several studies using two broadly neutralising antibodies (bNAbs) – 3BNC117 and 10-1074 – both developed at the Rockefeller University and have since been bought by Gilead.
This combination has shown the potential to be able to maintain viral suppression for six months after ART has been discontinued, including two cases where this continued for over a year. [1]
Together, they have 96% coverage in vitro in neutralising of a wide panel of pseudoviruses and clades and 83% coverage when tested against non-B primary isolates.
Research studies are looking at a potential role in reducing the viral reservoir and in whether bNAbs can generate a vaccine-like immune response in addition to their direct antiviral action as treatment and PrEP.
CROI included at least a dozen studies using these immune-based treatments in different clinical settings. Important differences between the studies include whether long-acting (LS) rather than original formulations were used, timing of antibody treatment and whether viral load was undetectable, and whether baseline screening for sensitivity to these compounds was included.
The oral presentations included a phase 1 study using both long-acting formulations, a paediatric study using monthly bNAbs instead of daily ART and two presentations from using bNAbs in early ART (with or without romedepsin) that reported a vaccine-like effect with one participant remaining off-ART out to 3.7 years.
Marina Caskey, from Rockefeller University, presented results from a phase 1 study of long-acting versions of 3BNC117 and 10-1074 (with half-lives of approximately 62 and 80 days respectively) given by infusion to six HIV positive men with CD4 counts >300 cells/mm3 and detectable viral load, having been off ART for at least four weeks for personal reasons, often for several years. One participant was ART-naive. [2]
Previous modelling predicted that dosing at 30 mg/kg and 10 mg/kg would produce therapeutic levels for a year.
Baseline characteristics included median age 34 (range: 24 to 56) with median CD4 count 523 cells/mm3 (range: 360 to 891) and viral load of 48,000 copies/mL (range: 1,050 to 257,000).
Viral load declined in all participants with a median maximum decline of –1.86 log (range: 1.1 to 2.49; SD: 0.48) reached at a median of 1.5 weeks after dosing. This was not significantly different to the original formulations (p=0.81).
Reductions were transient in 4/6 men (~4 weeks) who had higher viral load at baseline despite good plasmas concentrations. In contrast, 2/6 with baseline viral load <4 log copies/mL achieved durable viral suppression.
Restarting ART was recommended at week 8 but this was only followed by the 4/6 participants with viral rebound.
Viral load remained undetectable in 2/6 without ART for the 24 weeks of follow up. One participant was reported to still be on study as viral load stayed undetectable for a further 12 weeks.
It is unfortunate that bNAb sensitivity was only reported afterwards and as a post hoc analysis. The four people whose treatment failed showed reduced sensitivity at baseline to either bNAb, and would therefore have been treated with effective monotherapy. The two viral responders were sensitive to both compounds at baseline (and achieved viral load reductions of 3.0 and 3.5 logs).
The PK analysis showed 10-1074-LS to have a slower clearance than 3BNC117-LS and that levels of both were lower than historical controls that were HIV negative or on ART.
There were no infusion reactions or grade 3/4 side effects and no grade 2 or higher lab abnormalities.
This study has since been published in Nature and included that one participant was a trans woman. [16]
In this case, the bNAbs were VRC01-LS and 10-1074 and participants were 28 children >2 years old who started ART after birth and who had undetectable viral load for at least the previous 6 months.
This proof-of-concept study included at least eight weeks overlap of ART with bNAbs before interrupting HIV treatment. Median age was 3.6 years (range: 2.4 to 5.6) and all children were taking lopinavir/r-based ART.
Viral load remained <40 copies/mL through to week 24 in 11/28 children (44%, 95%CI: 24 to 65%). Viral load rebounded >400 copies/mL in 14/28 at a median of 4 weeks (range: 1 to 20) and immediately re-started on ART. Median viral load rebounded to 4.42 log copies/mL (range: 2.87 to 6.42) with resuppression achieved in all children after a median of 4.1 weeks (range: 0.9 to 20.3).
The bNAbs were generally well-tolerated with five grade 3 events (one neutropenia considered possibly study drug-related). This alternative was reported to be highly acceptable by parents of the children, reducing the difficulties associated with daily oral ART.
This study is also reported in detail in a separate i-Base report. [4]
A study from the IMPAACT network presented new results in a poster by Coleen Cunningham and colleagues on the safety and PK from using long-acting VRC07-523-LS as PrEP in 22 HIV-exposed but uninfected infants in the US and South Africa, supporting 3-monthly dosing. [5]
Other oral presentations, reported the durable impact of two infusions of 3BNB117 in early ART, also with romedepsin in a randomised study that included an analytic treatment interruption (ATI) after a year.
The remarkable aspect of this study was this long delay between the immune-mediated treatment and the ATI, that still showed clinical benefits in the 3BNC117 plus romidepsin arm that included one participant sustaining viral suppression for over 3.7 years. [6]
This study is also reported in more detail in a separate HTB report. [7]
In a second oral presentation from the same romedepsin study Míriam Rosás-Umbert from Aarhus University Hospital in Denmark reported the vaccine-like effect from giving 3BNC117 with ART. [8]
Although all four randomised groups had similar levels of HIV-specific CD4 and CD8 T cells responses at baseline, the frequency of Gag-specific CD8 T cells was significantly higher in participants who received 3BNC117 both at 3 months (median 0.69% vs 0.29%, p=0.04) and at 12 months (median 0.91% vs 0.31%, p=0.03). This was together with ART but irrespective of romidepsin.
Other selected posters included a phase 1b study adding bNAbs to people already on effective ART, another study using pegylated interferon and three studies looking at testing for bNAb sensitivity.
In the first poster, Christian Gaebler and colleagues reported a phase 1b, open label study of 3BNC117 and 10-1074, in 26 participants (23 men, 3 women) who had been on stable ART for at least a year. This study did not include baseline screening for bNAb susceptibility. [9]
Participants were randomised to discontinue ART two days before the bNAb infusions (Group 1, n=18) or to remain on ART throughout (Group 2, n=6). All participants received up to seven infusions of 30 mg/kg of each antibody over 20 weeks (at weeks 0, 2, 4, 8, 12, 16 and 20), with follow-up out to a year.
Viral suppression in Group 1 was maintained for a median of 28 weeks that continued out to week-48 in two participants. This was longer than previous historical controls using either bNAb monotherapy or using six-weekly dosing (p=0.0224).
Viral rebound generally coincided with drug levels of one of the antibodies dropped below the target therapeutic threshold of 10 ug/mL.
In a second poster, Pablo Tebas and colleagues presented results from the open label BEAT2 study in 14 participants on stable ART (12 men, 2 women; 11 African-American) who were given ‘combination immunotherapy’ using weekly pegylated interferon-alpha2b (peg-IFN) and seven cycles of both bNAbs (also at weeks 0, 2, 4, 8, 12 ,16 and 20), during an HIV treatment interruption of up to 26 weeks. [10]
Median age was 50 years (range: 31 to 60) and baseline CD4 count was 869 cells/mm3 (IQR: 739 to 1079).
Entry criteria included CD4 count >450 cells/mm3 and sensitivity to both 3BNC117 and 10-1074 at baseline. ART was restarted if viral load rebounded to >1000 copies/mL for six consecutive weeks or if CD4 count dropped below 300 cells/mm3.
Two participants had viral rebound during immunotherapy (at week 8 and week 14) with 10/14 maintaining undetectable viral load for 26 weeks. Three participants experienced chills during the 3BNC117 infusion, and 2/3 discontinued (at week 5 and week 10), both while viral load was undetectable. Further analyses will report on the impact of treatment on the viral reservoir.
It will also be important to distinguish the role played by weekly peg-IFN, which as a treatment for HCV has usually been reported to have a difficult side effect profile.
The three other posters reported on baseline sensitivity to these bNAbs. Although not always carried out in earlier research, screening for sensitivity at baseline is now essential and comes with the challenge that testing itself is not always successful.
Luis Montaner and colleagues used the PhenoSense mAb Assay to evaluate susceptibility to 3BNC117 and 10-1074 in 61 participants on ART with undetectable viral load (<20 copies/mL), CD4 counts >450 cells/mm3 and nadir >200. Baseline demographics included 9 female, 1 transgender, 53 African American and 8 Caucasian (3/8 Hispanic). [11]
A total of 54 samples were amplified (two after repeat testing) and seven were not able to be tested.
Of these, 41/54 (76%) were susceptible to 3BNC117, 37/54 (69%) to 10-1074 and 30/54 (56%, 95% CI: 41 to 69) were susceptible to both bNAbs.
Importantly, age, gender and race were not associated with susceptibility.
A second sensitivity poster was presented by Penny Zacharopoulou and colleagues from the UK RIO and RIVER studies. RIO is currently enrolling participants to use both bNAbs for a new ATI study, with many potential participants coming from the earlier RIVER study. [12]
This study analysed samples from 173 people who started ART within six months of seroconversion and who had been undetectable on ART for at least one year.
Of these 147/173 (85%) produced amplifiable proviral env samples and an average of 20 sequences per sample led to 3138 proviral env sequences being tested (70% were clade B).
Resistance to one or both bNAbs was detected in 48% of participants, with 29% (43/147) including any mutations associated with resistance to 10-1074, 13% (19/147) to 3BMC117 and 3.4% (5/147) to both. Phylogenetic analysis suggested evidence for both transmitted resistance and in-host evolution.
The led researchers to report that overall “approximately 40% of individuals treated during PHI in this cohort had potential pre-existing resistance to 10-1074 and 3BNC117 based on current in silico approaches” and that “screening may be key to guide effective treatment”.
A third poster compared three different bNAb sensitivity tests (on 59 treatment naive participants): a phenotypic test from Monogram and two genotypic algorithms developed by Rockefeller and the US NIH. Sensitivity was defined if >90% of env samples for an individual were sensitive to the bNAbs tested (10-1074 and 3BNC117). [13]
Sensitivity was concordant using all three methods for 79% and 52% of participants for 10-1074 and 3BNC117, respectively. Compared to the phenotypic test, the algorithms had 87% and 83% sensitivity to 10-1074, with 60 and 75% agreement for 3BNC117.
Finally, an oral presentation by Boris Julg from Massachusetts General Hospital reported a phase 1 study using triple bNAb combination of PGDM1400, PGT121 and VRC07-523LS (which target V2, V3 and CD4 binding sites, respectively). [14]
This included randomising small groups of HIV negative people (n=3) to different doses of PGF121 with PDDM1400; and an open label study adding VRC017-523LS in four HIV positive people who were treatment-naive.
In people receiving the triple therapy, viral load reduced by –1.7 log at day 7 (with nadir of –2.0 log at day 10) but rebounded a median of 20 days post nadir (range: 13 to 70 days). Although 1/4 participants was lost to follow-up, baseline and rebound resistance is reported below for the 3/4 remaining participants.
- Baseline: partial resistance to PGT121: rebound fully resistant to PGT121 and PGDM1400.
- Full resistance to both PGT121 and PGDM1400 at baseline and rebound, also with partial resistance to VRC017-523LS at rebound.
- Baseline: full sensitivity to all three bNAbs. Rebound partially resistant to PGT121 and PGDM1400.
This third case suggests different barriers to resistance for different bNAbs, even with triple therapy. Good plasma concentrations were reported VRC017-523LS at rebound (93 ug/mL; target 10 ug/mL).
Tolerability was good with the single grade 3 event was elevated CK, unrelated to the study drugs.
The half-life of PGDM1400 was about 20 days alone and when given with PGT121 in HIV negative people but dropped to about 11 days in HIV positive people with viraemia.
comment
Although these studies report early stage research, the results hint at alternative approaches to managing HIV that might not just depend on antiretroviral treatment.
However, pre-existing resistance at baseline is common and vulnerability to developing new resistance on suboptimal treatment, shows that combination therapy with potent bNAbs should follow the same cautions as other antiretroviral drugs. This challenge is highlighted by limited agreement between the current available sensitivity tests.
The UK RIO study includes long-acting formulations of both 3BNC117 and 10-1074 to look at viral suppression during an ATI off-ART. It is currently enrolling participants on stable ART who started treatment in primary infection (within six months of becoming HIV positive) and includes baseline screening for bNAb sensitivity. [15]
References
- Dual bNAb maintains viral suppression for median 21 weeks off-ART. HTB (November 2018).
https://i-base.info/htb/35248 - Caskey M et al. Phase 1 study of long-acting 3BNC117 and 10-1074 in viremic adults living with HIV. CROI 2022. 12-16 February 2022, virtual. Oral abstract 140.
https://www.croiconference.org/abstract/phase-i-study-of-long-acting-3bnc117-and-10-1074-in-viremic-adults-living-with-hiv/ (abstract)
https://croi2022.onlineeventpro.freeman.com/sessions/23875389/HIV-ANTIVIRALS-AND-OUTCOMES (webcast) - Shapiro R et al. treatment with broadly neutralizing antibodies in children with HIV in Botswana. CROI 2022. 12-16 February 2022, virtual. Oral abstract 32.
https://www.croiconference.org/abstract/treatment-with-broadly-neutralizing-antibodies-in-children-with-hiv-in-botswana/ (abstract) - Clayden P. Dual bNAb treatment maintains undetectable viral load off-ART in 44% of children in the Tatelo Study. HTB (February 2022).
https://i-base.info/htb/42175 - Cunningham CK et al. Extended safety and pk of anti-hiv monoclonal Ab VRC07-523LS in HIV-exposed infants. CROI 2022. 12-16 February 2022, virtual. Poster abstract 732.
https://www.croiconference.org/abstract/extended-safety-and-pk-of-anti-hiv-monoclonal-ab-vrc07-523ls-in-hiv-exposed-infants/ (abstract) - Gunst JD et al. The impact of 3BNC117 and romedepsin treatment at ART initiation of HIV-1 persistence. CROI 2022. 12-16 February 2022, virtual. Oral abstract 62.
https://www.croiconference.org/abstract/the-impact-of-3bnc117-and-romidepsin-treatment-at-art-initiation-on-hiv-1-persistence/ (abstract) - Jefferys R. Targetting reservoir with ART + bNAb 3BNC117 + romidepsin maintained undetectable viral load off-ART for 3.7 years in one case. HTB (March 2022).
https://i-base.info/htb/42209 - Rosás-Umbert M et al. Administration of 3BNC117 at ART initiation induces long-term HIV CD8 T-cell immunity. CROI 2022. 12-16 February 2022, virtual. Oral abstract 62.
https://www.croiconference.org/abstract/administration-of-3bnc117-at-art-initiation-induces-long-term-hiv-cd8-t-cell-immunity (abstract) - Gaebler C et al. Prolonged viral suppression by immunotherapy with anti-HIV antibodies 3BNC117/10-1074. CROI 2022. 12-16 February 2022, virtual. Poster abstract 686.
https://www.croiconference.org/abstract/prolonged-viral-suppression-by-immunotherapy-with-anti-hiv-antibodies-3bnc117-10-1074/ (abstract) - Tebas P et al. BEAT2: PEG-IFN-Α2B + 3BNC117 and 10-1074 keeps hiv at <20 c/μl during 26 week ATI.
https://www.croiconference.org/abstract/beat2-peg-ifn-2b-3bnc117-and-10-1074-keeps-hiv-at/ (abstract) - Montaner LJ et al. Susceptibility to 3BNC117 and 10-1074 in ART-suppressed chronically infected persons. CROI 2022. 12-16 February 2022, virtual. Poster abstract 503.
https://www.croiconference.org/abstract/susceptibility-to-3bnc117-and-10-1074-in-art-suppressed-chronically-infected-persons/ (abstract) - Zacharopoulou P et al. Mutational landscape of 10-1074 and 3BNC117 sensitivity in a UK population with PHI. CROI 2022. 12-16 February 2022, virtual. Poster abstract 505.
https://www.croiconference.org/abstract/mutational-landscape-of-10-1074-and-3bnc117-sensitivity-in-a-uk-population-with-phi/ (abstract) - Pahus MH et al. Performance of a phenotype and 2 genotype algorithms for bNAb sensitivity prediction. CROI 2022. 12-16 February 2022, virtual. Poster abstract 504.
https://www.croiconference.org/abstract/performance-of-a-phenotype-and-2-genotype-algorithms-for-bnab-sensitivity-prediction/ (abstract) - Julg B et al. Viral escape during triple broadly neutralizing antibody therapy against HIV-1. CROI 2022. 12-16 February 2022, virtual. Oral abstract 139.
https://www.croiconference.org/abstract/viral-escape-during-triple-broadly-neutralizing-antibody-therapy-against-hiv-1/ (abstract) - The RIO study.
https://riotrial.org - Gaebler C et al. Prolonged viral suppression with anti-HIV-1 antibody therapy. Nature. 2022 Apr 13. doi: 10.1038/s41586-022-04597-1.
https://www.nature.com/articles/s41586-022-04597-1
This report was first published on 19 February 2022. It was updated in April 2022 to include reference 16.