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Disappointing Results With VRC01 bNAb Plus ART to Limit Infant Reservoirs
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AIDS 2022, July 29-August 2, Montreal
Mark Mascolini
Adding the broadly neutralizing monoclonal antibody (bNAb) VRC01 to antiretroviral therapy (ART) to help clear viral reservoirs in infants had no discernible impact when compared with ART alone in a 60-infant randomized trial [1]. But this trial in Africa and Brazil used outmoded ART regimens and some infants had pretreatment resistance to the nonnucleoside and nucleosides used while others had resistance to VRC01. So the results cannot be interpreted decisively.
IMPAACT 2008 researchers who conducted this trial reminded colleagues that every year tens of thousands of infants worldwide acquire HIV infection. Early establishment of latent viral reservoirs in infants poses a daunting challenge to achieving antiretroviral-free remission in this population or later in life. But research shows that starting ART early can keep viral reservoirs smaller in infants, and bNAbs could be a valuable complement to early ART because they directly target HIV-infected cells and may have immune mechanisms, the researchers postulated.
VRC01 inhibits HIV binding to T cells by preventing the virus from hooking onto to its main cellular receptor, CD4. IMPAACT investigators cited studies showing that VRC01 monotherapy slows viral rebound when ART stops in adults. In a study in infants, dual bNAb therapy maintained viral suppression for 24 weeks without ART in 44% of infants who got early therapy.
IMPAACT 2008 aimed primarily to compare VRC01 plus early ART versus early ART alone for their impact on HIV DNA levels in infants. The trial enrolled infants with HIV who were 72 hours to 84 days old and started ART within 14 days beforeentering the study. Researchers randomized them to ART alone (a regimen reflecting the country standard) or to ART plus VRC01 at weeks 0, 2, 6, and 10 at a subcutaneous dose of 40 mg/kg.
The trial assigned 30 infants to VRC01 plus ART and 31 to ART alone. Thirty infants in each study arm completed week 14, and 28 in each arm completed week 48. Participating countries were Malawi (42 infants), Botswana (7), Zimbabwe (6), and Brazil (6). Numbers of females were 14 (47%) in the VRC01 arm and 21 (68%) in the control arm. Most infants (83% and 84%) were black, while the rest were Hispanic. Median age at study entry measured 72 days in the VRC01 group and 73 days in the ART-only group. Median entry plasma HIV load stood at 4.1 and 4.4 log10 copies/mL, while last available pre-ART loads were 5.8 and 5.9 log10 (about 631,000 to 794,000 copies). In the VRC01 arm and the control arm, 87% and 65% of infants had a pre-ART viral load above 100,000 copies.
Sixteen infants in the VRC01 group (53%) took a nevirapine regimen and 14 (47%) took a lopinavir combination. In the ART-only arm, 9 (29%) took nevirapine and 21 (71%) lopinavir. The nucleosides were zidovudine, lamivudine (3TC), and abacavir. Ten infants in the VRC01 group and 8 in the control arm had virus resistant to nevirapine going into the trial. Two infants in the control arm and none in the VRC01 arm had resistance to both nucleosides in their regimen. No infant had resistance to lopinavir. Five of 17 infants (29%) with available results had week 0 resistance to VRC01.
About 90% of infants had an injection site reaction to each of the VRC01 doses, but all reactions were mild to moderate. Local reactions usually resolved within 1 day and did not worsen over time. At treatment week 14, similar proportions in the VRC01-plus-ART arm (40%) and the ART-only arm (47%) had any grade 3 or worse adverse event, usually anemia of neutropenia in each group.
Median VRC01 plasma trough level stood at 83 mcg/mL (interquartile range 36.1 to 111.8) 28 days after dosing, but 31% of infants had a below-target level—under 50 mcg/mL. VRC01 plasma concentrations were consistently lower than those predicted in an earlier study of HIV-exposed but uninfected infants. Researchers detected no VRC01 antidrug antibodies during the trial.
Through 14 weeks of treatment, viral load (HIV RNA) response differed hardly at all between the VRC01 group and the ART-only group. The 14-week viral load response was a little better in the VRC01 group without VRC01 resistance. Through 14 weeks, HIV DNA in peripheral blood mononuclear cells fell 0.41 log10 copies in the VRC01 group and 0.53 log10 copies in the control group, a nonsignificant difference (P = 0.42). VRC01concentration at week 14 did correlate inversely with 14-week change in HIV DNA—the higher the VRC01 concentration, the lower the HIV DNA (Spearman correlation -0.42, P = 0.03).
IMPAACT 2008 investigators suggested the disappointing HIV RNA and HIV DNA results could reflect pretreatment antiretroviral and VRC01 resistance and the variable, often low, VRC01 trough levels. They suggested success with this strategy may depend on using combination bNAbs and stronger contemporary antiretroviral regimens.
In a recent review HIV immunology experts like Boris Julg and Dan Barouch voiced optimism on the potential role of bNAbs in HIV prevention and therapy, noting recent advances in extending bNAb half-life and expanding their breadth and functionality [3].
References
1. Khaitan A, Lindsey J, Capparelli E, et al. Phase I/II study of monoclonal antibody VRC01 with early antiretroviral therapy to promote clearance of HIV-1 infected cells in infants (IMPAACT 2008). AIDS 2022, July 29-August 2, Montreal.
2. ClinicalTrials.gov. Evaluating the safety and antiviral activity of monoclonal antibody VRC01 in HIV-infected infants receiving combination antiretroviral therapy. ClinicalTrials.govidentifier NCT03208231. https://clinicaltrials.gov/ct2/show/NCT03208231
3. Julg B, Barouch D. Broadly neutralizing antibodies for HIV-1 prevention and therapy. Semin Immunol. 2021;51:101475. doi: 10.1016/j.smim.2021.101475. https://www.sciencedirect.com/science/article/abs/pii/S1044532321000063
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