Maraviroc

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Maraviroc is a chemokine receptor antagonist. It is designed to prevent HIV infection of CD4 T-cells by blocking the CCR5 receptor. When the CCR5 receptor is unavailable, ‘R5-tropic’ HIV cannot engage with a CD4 T-cell to infect the cell. This variant of the virus is common in earlier HIV infection, while ‘X4-tropic’ viruses adapted to use the CXCR4 receptor gradually become dominant later in disease.

Maraviroc is being developed by Pfizer. During development, it was called UK-427,857. It is the first agent in its class to be tested in people with HIV infection.

Preliminary results of a phase I study were presented in 2003. Twenty-four HIV-positive patients with R5-tropic virus were randomised to receive maraviroc at 25mg once daily or 100mg twice daily, or placebo for 14 days as monotherapy. Steady state drug levels were reached within seven days, with higher drug levels in patients who had fasted. By day 14, the 100mg group had experienced a viral load decline of 1.4 log10, compared with 0.4 log10 in the 25mg group. The drug was well tolerated, and viral load did not rebound immediately upon cessation of the drug, indicating that a proportion of receptors remain blocked for some time.

A similar study comparing a range of doses also showed viral load reductions of more than 1 log10 at doses above 100mg once or twice daily, with no effect of food on the drug’s antiviral efficacy. A placebo-controlled safety study of maraviroc 100 and 300mg twice daily in 54 HIV-negative adults showed no effect on lipids, blood chemistry or the activity of the heart. The dose of 300mg twice a day seems to be the most promising choice for future development, although 300 and 600mg once a day are also being investigated in current trials.

Since maraviroc binds to the CCR5 co-receptor, there has been some concern that its use in patients with R5-tropic HIV might stimulate a conversion to HIV that uses the alternative CXCR4 co-receptor. In addition to causing resistance to maraviroc, this may be linked to more rapid disease progression. In a study of 62 patients with R5-tropic virus given maraviroc alone for ten days, only two patient’s virus became X4-tropic, before reverting to use of the CCR5 co-receptor after treatment was stopped. Subsequent analysis revealed that the X4-tropic virus in these two patients emerged from the patients’ stores of the virus, rather than due to the R5-tropic virus mutating into X4-tropic as a result of the presence of maraviroc. However, investigators plan to keep track of the co-receptor use of HIV in longer-term trials of the drug.

A phase IIb / III study of once- and twice-daily maraviroc in combination with AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir) in patients who have never taken anti-HIV drugs before is currently underway. This study is comparing three doses of maraviroc to efavirenz (Sustiva). All of the patients in this study are thought to be susceptible to maraviroc after a test for R5-tropic virus.

In December 2005, one hepatitis C co-infected patient in this trial developed liver toxicity after five day’s treatment with maraviroc. This was so severe that the patient required a liver transplant. However, the study’s data and safety monitoring board judged this to be due to other medications the patient was taking to prevent tuberculosis and Pneumocystis pneumonia (PCP), although they could not rule out a contribution of maraviroc. Although only one case out almost 1000 patients taking maraviroc in the trial, this finding was of concern since trials of GlaxoSmithKline’s entry inhibitor aplaviroc were stopped in October 2005 following reports of severe liver toxicities.

A similar study was started in patients who have experience of HIV treatments. However, the once-daily maraviroc arm of this study was halted in January 2006, since this arm’s responses were non-inferior to the efavirenz arm.

A third study is testing maraviroc in combination with an optimised background regimen in 186 highly treatment-experienced patients who have both R5- and X4-tropic HIV. Although the trial failed to show a benefit of once- or twice-daily maraviroc over placebo in terms of viral load suppression in this group of patients, maraviroc did bring about an increase in CD4 cell counts. Although the suppression of R5-tropic HIV led to an increase in the proportion of patients with X4-tropic virus, this was not associated with a fall in CD4 cell counts or disease progression, in contrast to what is observed in HIV-positive patients with X4-tropic virus.

Maraviroc is a substrate of the CYP3A4 enzyme, and has potential interactions with other drugs that are broken down by this enzyme, particularly protease inhibitors. For example, levels of maraviroc are increased in patients also taking atazanavir (Reyataz), ritonavir-boosted lopinavir (Kaletra) and ritonavir (Norvir)-boosted saquinavir (Invirase).



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