A review from the Australian Prescriber website of a new drug for the treatment of HIV infection:
Maraviroc
Celsentri (Pfizer)
150 mg and 300 mg film-coated tablets
Approved indication: HIV infection
Australian Medicines Handbook section 5.4
Highly active antiretroviral therapy has improved survival for patients infected by HIV, but long-term toxicity and the development of viral resistance are problematic. There is still a need to develop new drugs to treat people with clinically advanced disease which is resistant to several classes of antiretroviral drugs. The entry of HIV into a patient’s cells is one target of research and has led to the development of fusion inhibitors such as enfuvirtide (see ‘HIV fusion inhibitors: a review’, Aust Prescr 2008;31:66–9).
Maraviroc blocks the entry of HIV into cells, but it is not a fusion inhibitor. It acts on human chemokine co-receptor 5 (CCR5) which is found on the cell membrane. Some strains of HIV (CCR5-tropic HIV-1) enter the cell after interacting with this receptor. By selectively binding to the receptor, maraviroc prevents HIV from penetrating the cell surface. This ultimately results in reduced viral replication.
The approval of maraviroc was based on the interim results of two clinical trials involving a total of 635 patients. These patients were infected with CCR5-tropic HIV-1 and had more than 5000 copies of viral RNA/mL despite previous treatment with at least one drug from at least three different classes of antiretroviral drug. A group of 209 patients were randomised to take a regimen of three to six antiretroviral drugs, while 426 added maraviroc 300 mg twice daily to this regimen. After 24 weeks the viral RNA in 23% of the patients taking the ‘optimised background regimen’ was less than 50 copies/mL. In the group which added maraviroc 45% had less than 50 copies/mL. The increase in the concentration of CD4 lymphocytes was 57 cells/mm3 with the regimen alone and 106 cells/mm3 when maraviroc was added.
When these trials were published they reported on outcomes at 48 weeks, having randomised 1075 patients. Viral RNA had fallen to less than 50 copies/mL in 17% of the patients taking the optimised regimen. The same outcome had been reached by 46% of the patients taking maraviroc twice daily and by 43% of patients using a once-daily regimen. CD4 lymphocytes increased by 61 cells/mm3 in the control group, by 124 cells/mm3 with twice-daily maraviroc and by 116 cells/mm3 with once-daily maraviroc.1,2
Adding maraviroc to the treatment of patients taking multiple other drugs does not greatly affect the number of adverse reactions. Nausea, diarrhoea and headache are common. Adverse events which occurred more frequently when maraviroc was added to treatment include paraesthesia, muscle aches, cough, fever, infections and rashes. Liver enzymes were more likely to increase in patients taking maraviroc and in the USA the drug has a black box warning about hepatotoxicity. There is little information about the safety of the drug in patients with liver disease, especially those who are infected with hepatitis B or C. It is uncertain if the cardiovascular events reported in patients taking maraviroc were related to the drug.
The absorption of maraviroc is variable, possibly because of saturation of the P-glycoprotein transporter. Although absorption can be reduced by a high fat meal, there are no restrictions on taking maraviroc with food. As maraviroc is mainly metabolised by cytochrome P450 3A4, there are many potential drug interactions. A lower dose of maraviroc is recommended if the patient is prescribed an inhibitor of this enzyme such as clarithromycin, itraconazole and the protease inhibitors (except tipranavir/ritonavir and fosamprenavir/ritonavir). A higher dose is recommended if the patient is taking an enzyme inducer such as rifampicin, efavirenz and carbamazepine. Patients should not take St John’s wort as it is likely to decrease concentrations of maraviroc. The usual twice-daily dose has a half-life of 16 hours with most of the metabolites being excreted in the faeces.
Maraviroc is being studied in previously untreated patients, but its role in therapy depends on whether the patient is infected with CCR5-tropic HIV-1. CCR5-tropic HIV-1 predominates early in the infection, but viral forms emerge which can use another co-receptor to enter the cell. The use of maraviroc is therefore limited to patients only infected with CCR5-tropic virus. It can take several weeks to test for CCR5-tropic HIV-1, so testing may be a barrier to treatment. The effectiveness of maraviroc will also be reduced if the virus develops a reduced sensitivity to the drug. Like other antiretroviral drugs approved on surrogate end points, maraviroc will require more research to determine its optimal use in combination regimens.
manufacturer provided clinical evaluation
References †
Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008;359:1429-41.
Fatkenheuer G, Nelson M, Lazzarin A, Konourina I, Hoepelman AI, Lampiris H, et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008;359:1442-55.