Ibalizumab Shows Promising Activity in Patients with Multidrug-Resistant HIV

In individuals infected with HIV-1 RNA whose current antiretroviral therapy is not effective, their condition can continue to worsen, and drug resistance can occur.

Now, a new drug has been found to reduce viral replication and increase immune cells in individuals with advanced, drug-resistant HIV infection in a phase 3 trial. When combined with existing HIV medications, the drug offers a promising option for these hard-to-treat patients. The drug in question? Ibalizumab.

Ibalizumab was approved by the US Food and Drug Administration (FDA) in March, making it the first monoclonal antibody approved to treat HIV in adults who have experienced resistance to past treatments and are currently failing in their current antiretroviral regimen.

“Ibalizumab actually doesn’t prevent virus, the gp120, from binding CD4. What it does is, it prevents the conformational change that’s required for viral entry,” Brinda Emu, MD, assistant professor of medicine, Yale University, told Contagion^® in a previous interview. “By doing so, it’s almost an entry inhibitor, [it] prevents virus from entering the CD4.”

In a phase 3 trial conducted by Dr. Emu and colleagues, the investigators found that in participants with MDR HIV-1 infection, the drug had significant antiviral activity for the duration of the trial, 25 weeks.

For the single-group, open-label trial, investigators enrolled a total of 40 patients who were monitored during 3 time periods. The participants had viral loads of more than 1000 copies of RNA per milliliter during receipt of high active antiretroviral therapy for at least 8 weeks before screening. Additionally, participants were required to have received antiretroviral drugs for at least 6 months and have documented resistance to at least 1 drug in at least 3 classes. Patients were also required to continue their previous treatment regimen before initiating an optimized backround regimen, which was chosen based on each patient’s treatment history.

In the control period (day 0 to 6) participants were monitored as they received their current therapy. The next period (days 7 to 14) patients received an IV of 2000 mg of ibalizumab at baseline as current therapy continued. During the maintenance period (day 14 to week 25) patients initiated a regimen of 800 mg of ibalizumab administered via IV every 14 days.

The trial’s primary endpoint was defined as the proportion of patients who had a decrease in viral load at day 14 of at least 0.5 log₁₀ copies per milliliter occurred in 33 of 40 patients (95% confidence interval [CI], 67 to 93) during functional monotherapy period, representing decrease in viral load as compared with the control period (P<0.001).

“Secondary end points, were the mean change in viral load on day 14, the proportion of patients who had a decrease in viral load of at least 0.5 log₁₀ copies per milliliter or at least 1.0 log₁₀ copies per milliliter at week 25, the proportion who had an HIV level of less than 50 copies per milliliter or less than 200 copies per milliliter at week 25, and the mean changes in viral load and CD4 count at week 25,” according to the study, published in the New England Journal of Medicine,

From the original 40 participants, 32 (80%) individuals received all scheduled doses and 31 (78%) completed the scheduled visits. Four individuals died of unrelated causes during the study, 1 participant discontinued because of a serious adverse event, and 4 participants withdrew for other reasons.

After analyzing the primary efficacy endpoint on day 14, investigators noted a decrease in viral load of at least 0.5 log₁₀ copies per milliliter in 33 of the 40 patients (83%; 95% confidence interval [CI], 67 to 93) during the monotherapy period (days 7 to 13), which indicates a significant decrease in viral load compared with the control period, the authors write.

At the end of the maintenance period (25 weeks), the majority of participants were found to experience a decrease in viral load, with about half seeing viral load suppression drop below the level of detection. Specifically, investigators noted an HIV RNA level of less than 50 copies per milliliter in 17 patients (43%) and a level of less than 200 copies per milliliter in 20 patients (50%).

“These patients had extremely advanced HIV and resistant virus with limited options,” Dr. Emu said in a statement. “To see viral suppression in a significant percentage of these patients at six months is heartening. The result represents a much-needed new mechanism of action for patients who have highly resistant HIV."

The investigators also reported an increase in CD4 T-cells, a marker for immune strength. Specifically, the mean CD4 count was noted to have a mean increase of 62 per microliter, going from 150 per microliter at baseline—as measured in 40 patients&mdash;to 240 per microliter at week 25&mdash;as measured in 27 patients.

Pharmacokinetic and pharmacodynamic features were found to be consistent with previous studies on the drug, with the mean CD4 receptor occupancy remaining at more than 85% throughout the period of administration.

Limitations of the trial, the authors write, included small size, uncontrollable study design, and a limited time frame for analyzing secondary and safety endpoints.

"We must also keep in mind that ibalizumab was approved with a smaller number of patients treated than other medications due to the rarity of patients with multi-drug resistant HIV,” Dr Emu stressed in the statement. “As such, patients and providers must remain vigilant for side effects and adverse events."