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  Reported by Jules Levin
IDWeek Oct 26-30
New Orleans 2016
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Monotherapy With Anti-CD4 Monoclonal Antibody
Cuts Viral Load 10-Fold in 7 Days

  IDWeek 2016, October 26-30, 2016, New Orleans
Mark Mascolini
Ibalizumab, a long-acting anti-CD4 humanized monoclonal antibody, cut viral loads by an average 1.1 log10 after 7 days of monotherapy in a phase 3 trial that enrolled people with heavy treatment experience and multidrug-resistant HIV [1]. The trial continues with an optimized background regimen added to ibalizumab.
Ibalizumab does not inhibit HIV gp120 binding to CD4 on T cells. Instead, it prevents CD4-bound gp120 from interacting with the CCR5 or CXCR4 coreceptors and thus prevents HIV from entering CD4-bearing cells [2]. This anti-CD4 monoclonal antibody has a long half-life that allows dosing by infusion every 2 weeks. In a study testing ibalizumab against 116 pseudoviruses often used to assess HIV vaccine candidates, ibalizumab neutralized 92% of the viruses at the 50% inhibition level at a median neutralization potency (IC50) of 0.03 ug/mL, much lower (stronger) than the neutralization potency of two other well-studied monoclonal antibodies, PG9 and VCR01 [3].
Because of its unique mechanism of action, ibalizumab should not be cross-resistant with existing antiretrovirals. Research so far shows no drug-drug interactions between ibalizumab and other antiretrovirals or other drugs. Metabolized by CD4 receptor internalization, ibalizumab has no significant impact on liver or kidney metabolism.
The phase 3 trial, TMB-301, recruited people with a viral load above 1000 copies, at least 6 months of antiretroviral therapy, and documented HIV resistance to at least one antiretroviral in 3 classes [4]. All participants had virus sensitive to at least one antiretroviral that could be used in an optimized background regimen that could be added to ibalizumab, and everyone took the same regimen for at least 8 weeks before screening for the phase 3 trial. The study excluded people with an active AIDS illness, prior use of ibalizumab, any grade 3 or 4 lab abnormality, or use of any immunomodulatory therapy, systemic chemotherapy, or systemic steroids in the 12 weeks before enrollment.
The trial has three periods: (1) a control period on days 0-6 in which participants continue their current failing regimen, (2) a monotherapy period on days 7-13 in which participants continue their current regimen and receive a 2000-mg intravenous dose of ibalizumab on day 7, and (3) a maintenance period on day 14 through week 25, in which participants start an optimized background regimen on day 14 and receive an 800-mg intravenous dose of ibalizumab on day 21 then every 2 weeks. The primary endpoint was the proportion of people with at least a 0.5-log10 (3-fold) reduction in viral load at day 14, 7 days after the initial ibalizumab infusion.
The 40 study participants had HIV infection for an average 21 years, 85% were men and 45% nonwhite. Viral load averaged 100,000 copies, and 7 participants (18%) had a viral load above that level. Half had a CD4 count below 100 and one third a count below 10. Eleven participants (28%) had used at least 10 antiretrovirals, and 17 people (43%) used a second investigational antiretroviral in their optimized background regimen. Proportions of participants with major resistance mutations to nucleosides were 93%, nonnucleosides 85%, protease inhibitors 83%, and integrase inhibitors 61%. Half of study participants had resistance to all antiretrovirals in at least 3 classes.
Seven days after the 2000-mg ibalizumab loading dose, 83% of participants had a viral load reduction of 0.5 log10 or greater, compared with 3% during the 6-day control period before ibalizumab administration (P < 0.0001). At the same point, 60% of participants (versus none in the control period) had at least a 1-log10 (10-fold) viral load reduction (P < 0.0001). Viral load drops in the 7 days after ibalizumab infusion averaged 1.1 log10 (12.6-fold).
In the first 7 days of ibalizumab use, researchers reported no treatment-related serious adverse events. The most frequent treatment-emergent adverse events were dizziness in 10%, asthenia/fatigue in 5%, nausea/vomiting in 5%, and rash in 2.5%.
An expanded-access program for ibalizumab is open. Eligibility requirements and contact information are available at the link following reference 5 below. The initial dose of ibalizumab takes 30 minutes and the doses then administered every 2 weeks take 15 minutes.
1. Lalezari J, Fessel WJ, Schrader S, et al. Primary efficacy endpoint and safety results of ibalizumab in a phase 3 study of heavily treatment-experienced patients with MDR HIV-1 infection. IDWeek 2016, October 26-30, 2016, New Orleans. Abstract LB-6.
2. Bruno CJ, Jacobson JM. Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1 infection. J Antimicrob Chemother. 2010;65:1839-1841. http://jac.oxfordjournals.org/content/65/9/1839.long
3. Pace CS, Fordyce MW, Franco D, Kao CY, Seaman MS, Ho DD. Anti-CD4 monoclonal antibody ibalizumab exhibits breadth and potency against HIV-1, with natural resistance mediated by the loss of a V5 glycan in envelope. J Acquir Immune Defic Syndr. 2013;62:1-9.
4. ClinicalTrials.gov. Ibalizumab plus optimized background regimen in patient with multi-drug resistant HIV. ClinicalTrials.gov identifier NCT02475629. https://clinicaltrials.gov/ct2/show/NCT02475629
5. ClinicalTrials.gov. Compassionate use of ibalizumab for the treatment of HIV infection. ClinicalTrials.gov identifier NCT02028819. https://clinicaltrials.gov/ct2/show/NCT02028819