CCR5 antagonists are a new class of antiretrovirals unlike any to date

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Certain forms of HIV viruses (R5 tropic viruses) require the CCR5 receptor as a “co-receptor” to gain entry to the cell. However, when the CCR5 antagonist is bound to the receptor, the virus cannot interact with the receptor and thus viral entry is blocked.

This is the first antiretroviral drug that targets the hosts cells rather than targeting the virus directly. CCR5 antagonists block the mechanistic pathway the virus uses to gain entry to the host.

Four possible effects of co-receptor antagonists on the tropism of HIV-1 population in patients with R5 HIV-1 are described below.

1. HIV RNA Suppression It is anticipated that patients with R5 HIV will experience sustained suppression of HIV replication when a CCR5 co-receptor antagonist is used as a component of potent antiretroviral therapy. This has been demonstrated in clinical trials of a CCR5 co-receptor antagonist in treatment experienced individuals (MOTIVATE 1 and 2). In these studies patients with R5 HIV receiving maraviroc as a component of an optimized antiretroviral regimen had greater reductions in HIV-1 RNA levels (–1.95 and –1.97 mean HIV-1 RNA log₁₀ copies/mL) and greater increases in CD4+ cell counts (+102 and +111 cells/mm³) at 24 weeks compared to those receiving an optimized regimen without maraviroc (MOTIVATE 1 and 2 respectively).^11,12

2. Tropism Shifting or Switching: In an HIV positive patient viral tropism is not fixed at primary infection but may evolve towards CXCR4 use over time. In some patients only a small amount of CXCR4-using virus may be present possibly existing below the limits of detection by current technologies. In such cases exposure to a CCR5 co-receptor antagonist may allow ‘outgrowth’ or 'expansion’ of the CXCR4-using viruses to levels at or near those present prior to co-receptor antagonist exposure. This drug-associated shift or switch in the population tropism will result in a change in the tropism call, e.g., from R5 to dual/mixed or X4 tropism. It has not yet been determined whether such a co-receptor antagonist-associated switch/shift has an impact on disease progression over longer term follow-up. If a negative impact is observed then monitoring of tropism in the setting of CCR5 co-receptor antagonist-associated treatment failure may be clinically relevant.

3. Unmasking caused by co-receptor antagonist exposure: This is a distinct kind of tropism change seen with co-receptor antagonist exposure. It may occur when CXCR4-using viruses are maintained at very low levels within a majority R5 HIV population. In this setting, treatment with a co-receptor antagonist will suppress the majority R5 population revealing the underlying CXCR4-using viruses which continue to circulate only at low HIV RNA levels.