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Case Reports
. 2011 Dec;92(3):484-7.
doi: 10.1016/j.antiviral.2011.09.010. Epub 2011 Oct 4.

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment

W Jeffrey Fessel  1 , Brooke Anderson, Stephen E Follansbee, Mark A Winters, Stanley T Lewis, Steven P Weinheimer, Christos J Petropoulos, Robert W Shafer
Affiliations
Case Reports

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment

W Jeffrey Fessel et al. Antiviral Res. 2011 Dec.

Abstract

The availability of 24 antiretroviral (ARV) drugs within six distinct drug classes has transformed HIV-1 infection (AIDS) into a treatable chronic disease. However, the ability of HIV-1 to develop resistance to multiple classes continues to present challenges to the treatment of many ARV treatment-experienced patients. In this case report, we describe the response to ibalizumab, an investigational CD4-binding monoclonal antibody (mAb), in a patient with advanced immunodeficiency and high-level five-class antiretroviral resistance. After starting an ibalizumab-based salvage regimen, the patient had an approximately 4.0 log(10) reduction in viral load. An inadvertently missed infusion at week 32 led to the rapid loss of virologic response and decreased susceptibility to the remainder of the patient's salvage therapy regimen. Following the reinstitution of ibalizumab, phenotypic and genotypic resistance to ibalizumab was detected. Nonetheless, plasma HIV-1 RNA levels stabilized at ∼2.0 log(10) copies/ml below pre-ibalizumab levels. Continued ARV drug development may yield additional clinical and public health benefits. This report illustrates the promise of mAbs for HIV-1 therapy in highly treatment-experienced patients. Therapeutic mAbs may also have a role in pre-exposure prophylaxis in high-risk uninfected populations and may facilitate directly observed therapy (DOT) if two or more synergistic long acting agents become available.

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Figures

Figure 1
Figure 1
The patient’s plasma HIV-1 RNA levels (log copies/ml) during the 13 years prior to enrollment intoTMB-202 (A, left panel) and during the 44 weeks following enrollment into TMB-202 (B, right panel).The mAb ibalizumab was administered as part of a placebo-controlled trial for 24 weeks and open-label thereafter. The orange arrows indicate monthly intravenous infusions of 2,000 mg of ibalizumab. In December 2009, it was discovered that the patient had been randomized to receive ibalizumab. However, a drug labeling error led to receipt of placebo rather than ibalizumab at week 32. Between 1997 and 2009,the patient experienced three transient decreases in plasma HIV-1 RNA levels coincident with the administration of new ARV regimens containing efavirenz (EFV, 1998), enfuvirtide (2006), and darunavir plus raltegravir (DRV+RAL, 2007). The ▴ symbol indicates plasma HIV-1 RNA levels above the limit of quantification (500,000 copies/ml). The ▾ symbol indicates plasma HIV-1 RNA levels below the limit of quantification (75 copies/ml). The week 36 plasma level measurement was performed on a diluted sample and determined to be approximately 5.0 million copies/ml. The results of six-class phenotypic susceptibility testing prior to study enrollment (June 2009) and following virologic rebound(March 2010) are shown in Table 1.
Figure 2
Figure 2
Ibalizumab susceptibility prior to TMB-202 (June 2009) and seven months following re-institution of ibalizumab following the week 32 unintended interruption (October 2010). The dose-response curve of the June 2009 virus exhibited a classic sigmoidal shape with a maximum percent inhibition (MPI) approaching 100% and an IC50 value within the normal range for ibalizumab treatment-naïve viruses. In contrast, the dose response curve of the October 2010 virus indicated that only 50% of virus infection was susceptible to ibalizumab inhibition (MPI=50%). Sequencing the HIV-1 envelope gp120 region from the June 2009, July 2010, and October 2010 viruses demonstrated the acquisition of a T (Thr) to I (Ile) mutation in the July 2010 isolate and a T (Thr) to I (Ile) or L (Leu) mutation in the October 2010 isolate which resulted in the disruption of a potential N-linked glycosylation site (N-X-S/T-X (PNGS) in the HIV-1 envelope V5 loop.
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