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By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a new treatment for HIV-infected individuals who have failed available therapies. Ibalizumab-uiyk is a humanized IgG4 monoclonal antibody produced in murine myeloma cells that acts as a CD4-directed post-attachment HIV-1 inhibitor without affecting CD4 function.1 This blocks the entry of the HIV-1 virus particles into the host cell, preventing viral transmission. It is the first drug in a new class, differing from previous drugs considered as entry inhibitors, including enfuvirtide and maraviroc. The FDA designated ibalizumab-uiyk as breakthrough therapy and assigned it orphan status and priority review.2 It is marketed as Trogarzo.
Ibalizumab-uiyk, in combination with other antiretrovirals, is indicated for the treatment of HIV-1 in heavily treatment-experienced adults with multidrug-resistant HIV infections failing their current regimens.1
The recommended dose is a loading dose of 2,000 mg, given intravenously, followed by a maintenance dose of 800 mg every two weeks. Ibalizumab-uiyk is available as a 200 mg (150 mg/mL) single-dose vial.
Ibalizumab-uiyk provides an option for salvage therapy in patients with multidrug resistance. It is active against HIV-1 that is resistant to all approved antiretroviral agents and demonstrates a long half-life, permitting dosing every two weeks.1
Decreased susceptibility after multiple administrations has been reported in some patients.1 Ibalizumab-uiyk requires intravenous administration by a trained medical professional every 14 days. Primary resistance is estimated at approximately 10%.3 Immune reconstitution inflammatory syndrome has been reported in one subject who was treated with ibalizumab.1
The safety and efficacy of ibalizumab-uiyk was evaluated in a single-arm study in 40 heavily treatment-experienced HIV-1-infected subjects with multidrug resistance.1 Subjects were required to exhibit a viral load > 1,000 copies/mL, with documented resistance to at least one drug from each of three classes of antiretroviral drugs (NRTI, NNRTI, and PI). Subjects also had to be treated for at least six months and were failing or had recently failed therapy. Many subjects (53%) were treated with ≥ 10 antiretroviral drugs.
The study was comprised of three periods. The first was a control period (day 0-6) when subjects were monitored to established baseline HIV viral load as they stayed on their current failing therapy or on no therapy if they discontinued therapy. In the second period (day 7-13), all subjects received the loading dose on day 7, and those on failing regimens continued that failing course. During the last period (day 14-week 25), viral load was assessed; thereafter, the background regimen was optimized to include at least one drug (investigation drugs were allowed) to which the subject’s virus was susceptible. Maintenance dose of ibalizumab-uiyk was started on day 14 and administered every two weeks through the end of the study. The primary endpoint was the proportion of subjects achieving a viral load ≥ 0.5 log10 reduction at the end of the second period compared to the proportion after the first period.
The results were 83% compared to 3%. At Week 25, 50% of subjects demonstrated viral load < 200 copies/mL and 43% < 50 copies/mL. Those with a baseline viral load of ≤ 100,000 copies/mL were more likely to achieve levels < 50 mL (49% vs. 14%) and 48% exhibited a ≥ 2 log10 reduction. The most frequent (≥ 5%) adverse reactions were diarrhea (8%), dizziness (8%), nausea (5%), rash (5%), increase in creatinine levels (10%), increase in bilirubin and lipase levels (5%), and decrease in leukocytes and neutrophils levels (5%).
HIV-1 features a high mutation rate, which allows the virus to rapidly generate new variants, leading to development of antiretroviral resistance.4 HIV/AIDS guidelines recommend that in patients who experience treatment drug resistance or treatment failure, a new regimen (preferably three fully active agents and possibly those with a novel mechanism of action) should be sought based on the patient’s antiretroviral therapy history and current and past drug resistance testing history.5 For some highly treatment-experienced patients with extensive drug resistance, maximal virologic suppression may not be possible. Options for these patients would be enrollment in a clinical trial of investigation agents. Ibalizumab-uiyk provides an option with a new mode of action for these patients. The cost for ibalizumab-uiyk is $2,270 for a 2,000 mg single-dose vial.
Financial Disclosure: Internal Medicine Alert’s Physician Editor Stephen Brunton, MD, is a retained consultant for Abbott Diabetes, Becton Dickinson, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi; he serves on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk. Contributing Editor Louis Kuritzky, MD, is a consultant for and on the speakers bureau of Amgen, Boehringer Ingelheim, and Shire. Peer Reviewer Gerald Roberts, MD; Editor Jonathan Springston; Executive Editor Leslie Coplin; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.