Maraviroc (Celsentri)

Maraviroc (known by the trade name Celsentri in Europe and Selzentry in the United States) remains the only drug to be licensed from a class of antiretrovirals called CCR5 inhibitors. Maraviroc prevents HIV from entering uninfected cells by blocking the predominant route of entry on the surface of some immune cells, the CCR5 receptor.

In 2007, the drug was approved for use in combination with other antiretrovirals, by treatment-experienced individuals with a confirmed CCR5-tropic virus in the US. Marketing approval in Europe for treatment-experienced people followed soon after. Maraviroc received licensing for use in antiretroviral-naive patients in the US in November 2009, but is not licensed for antiretroviral-naive patients in Europe.

Effectiveness

UK 2016 treatment guidelines recommend that maraviroc should be considered as a component of treatment regimens after the failure of first-line treatment when resistance to one or more classes of antiretroviral drug is present. US guidelines issued in 2021 recommend that the use of maraviroc should be considered after the failure of a second-line regimen where an antiretroviral with a different mechanism of action is needed.

ART-experienced patients

Approval of maraviroc for treatment-experienced individuals was based on results from the MOTIVATE studies. (Lalezari) The MOTIVATE studies enrolled highly treatment-experienced individuals with CCR5-tropic HIV. All participants had resistance to at least one agent from each of the three major drug classes, including at least two protease inhibitors. In both studies, participants were provided with background therapy optimised by resistance testing. (Nelson) Participants were randomised to receive either a placebo, or a once-daily 300mg dose of maraviroc, or a twice-daily 150mg dose of the drug. Significantly more individuals who had twice-daily maraviroc added to optimised background antiretroviral therapy (ART) achieved viral load below 400 copies/ml (56% vs 22%) and below 50 copies/ml (45% vs 16%) as compared to individuals who received optimised background plus a placebo.

Maraviroc-containing treatment is more likely to fail in people who had developed X4-tropic or dual/mixed tropic virus in addition to the CCR5-tropic virus that maraviroc was designed to suppress. However, CD4 cell counts were found to be higher even in people who experienced maraviroc treatment failure, and if maraviroc treatment was ceased in those who experienced a tropism shift, the virus population was observed to shift back to R5 tropism within one month in almost all cases. (van der Ryst)

ART-naive patients

MERIT was a phase III study comparing the efficacy of maraviroc (Celsentri / Selzentry) to that of efavirenz (Sustiva), in combination with zidovudine/lamivudine (Combivir) in people who were antiretroviral-naive. All participants in the study were thought to be susceptible to maraviroc after a test for R5-tropic virus. (Saag, 2007)

In the first analysis, participants on the maraviroc treatment arm were slightly less likely to achieve HIV viral load less than 50 copies/ml than those on the efavirenz arm. However, when the 96-week analysis used an enhanced tropism test to rule out results from individuals who did not have CCR5-tropic virus, comparable virological efficacy was seen in the treatment arms. (Saag, 2009)

Tropism testing

CCR5 antagonists work by blocking the CCR5 co-receptor, one of the two pathways HIV can use to enter cells. An individual’s virus may be exclusively CCR5-tropic, CXCR4-tropic (using the other co-receptor), or dual- or mixed-tropic (able to use both pathways). CCR5 antagonists only work against CCR5-tropic HIV.

The British HIV Association recommends that tropism testing should take place before switching to maraviroc, using a genotypic test.

Taking it

Maraviroc is available as a film-coated tablet in strengths of 150 and 300mg. It has been approved for use in combination with other antiretrovirals. Standard dosing for maraviroc is 300mg twice daily; however, the dose is dependent on other drugs being taken as part of an ART regimen.

Two twice-daily doses of maraviroc have been approved:

• 150mg dose when used with protease inhibitors (with the exception of tipranavir/ritonavir) or cobicistat
• 300mg dose when combined with tipranavir/ritonavir, efavirenz, nevirapine, enfuvirtide, and other drugs that are not strong CYP3A inhibitors or inducers.

Maraviroc can be taken with or without food.

Side effects

The most commonly observed side effects of maraviroc are anaemia, loss of appetite, depression, difficulty in sleeping, nausea, flatulence, weakness, rash, abdominal pain, and increases in liver enzymes.

A hypersensitivity reaction 2-6 weeks after starting treatment has been reported as a very rare side effect of maraviroc. The symptom are severe rash and fever, sometimes accompanied by liver failure. Maraviroc should be stopped if a hypersensitivity reaction is suspected.

Maraviroc should also be stopped if signs of acute hepatitis such as jaundice, dark urine, vomiting or abdominal pain develop, especially if accompanied by rash or fever.

Caution must be used when prescribing maraviroc to anyone with pre-existing liver dysfunction or who has co-infection with hepatitis B or C.

Resistance

Resistance to maraviroc occurs through the escape of X4-tropic virus that is not suppressed by maraviroc’s action as a CCR5 antagonist.

Overall, more treatment failures occurred in the MOTIVATE study, and occurred more quickly, in persons who developed shifts away from purely R5-tropic virus. At baseline, 751 maraviroc-treated people had purely R5-tropic virus. Of these, 63 treatment failures occurred in people who had developed X4-tropic or dual/mixed virus, compared to 35 failures in people who still displayed only R5-tropic virus. Time to failure with an X4 or dual/mixed virus was approximately 30 days shorter than for failure with R5-tropic virus.

Although it was not surprising that treatment failure would be associated with the emergence of X4- or dual-tropic virus, a less expected finding was that increases in CD4 cell counts were seen even if maraviroc treatment failed virologically. (van der Ryst)

Maraviroc has no cross-resistance to drugs from other classes.

Drug interactions

As a substrate of the CYP3A4 enzyme, maraviroc has potential interactions with other drugs broken down by this enzyme. When maraviroc is given with CYP3A inhibitors, the dose should be reduced to 150mg twice daily. These drugs include most protease inhibitors (except for tipranavir/ritonavir), etravirine used with darunavir/ritonavir, ketoconazole, itraconazole, clarithromycin, nefazadone, telithromycin, among others. (Muirhead) (Abel)

Maraviroc should not be used with St John’s wort.

Maraviroc dosing must be increased in the presence of a number of drugs due to their effects on its metabolism through the cytochrome p450 system. The 600mg twice-daily dose of maraviroc should be used with all CYP3A inducers (without a CYP3A inhibitor), including efavirenz, rifampicin, carbamazepine, phenobarbital, and phenytoin.

Children

Maraviroc has been approved in the European Union for use in treatment-experienced children aged 2 and over weighing 10kg or more.

Pregnancy

There is insufficient information about the effects of maraviroc on the foetus, but no evidence of a potential for harm from animal studies. Maraviroc blood levels are not significantly altered in pregnancy.