Maraviroc (known by the trade name Celsentri in Europe and Selzentry in the United States) is the first drug to be licensed from a new 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 and 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.
Approval of maraviroc for treatment-experienced individuals was based on 24-week results from the MOTIVATE studies. (Lalezari) Significantly more individuals who had maraviroc added to optimised background antiretroviral therapy (ART) achieved viral load below 400 copies/ml and below 50 copies/ml as compared to individuals who received optimised background plus a placebo.
MOTIVATE 1 and 2 were phase IIb/III studies, designed to investigate the safety and effectiveness of maraviroc. Both studies were of similar design and involved highly treatment-experienced individuals with CCR5-tropic HIV. MOTIVATE 1 took place in the US and Canada and MOTIVATE 2 included individuals from Europe and Australia, as well as North America.
Individuals with CCR5-tropic HIV and viral loads above 5000 copies/ml on current treatment were recruited. 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) They were then randomised to receive either a placebo, or a once-daily 300mg dose of maraviroc, or a twice-daily 150mg dose of the drug. The dose of maraviroc that individuals in the treatment arms of the study received was determined by the drugs in their background regimen.
Of note, 69% of the once-daily maraviroc group and 75% of the twice-daily group had two or fewer active drugs in their background regimen. None of the participants used boosted darunavir and around 10% included boosted tipranavir in their regimen. (Fatkenheuer) (Gulick)
The proportion of people with undetectable viral load declined slightly after week 24 in the maraviroc treatment groups, but at week 48, nearly 47% of people had viral load below 50 copies/ml versus 16% of the placebo group. A majority of people (~58%) had viral load below 400 copies/ml as compared to just 22% of those in the placebo group at week 48. There were sustained CD4 cell gains in both maraviroc-containing treatment arms (+113 and 122 cells/mm3 in the once- and twice-daily treatment arms respectively).
At 48 weeks, 61% of those individuals previously naive to T-20 who included it as part of an optimised ART background achieved viral load below 50 copies/ml on the twice-daily maraviroc treatment arm and 71% on that treatment arm had viral load below 400 copies/ml. In those with prior T-20 experience, just 32% reached a viral load less than 50 copies/ml. (Gulick)
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 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)
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. (By this time, the once-daily maraviroc arm was stopped and everyone switched to twice-daily dosing.) 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)
The study recruited 721 individuals (29% women) with an average age of about 37 years. Nearly 400 were from the Northern hemisphere and just over 300 were from the Southern hemisphere countries of Argentina, Australia, and South Africa.
The efavirenz-treated arm experienced more AIDS-defining illnesses, grade 3/4 adverse events, and malignancies (4 vs 1). Just 4% (22) of maraviroc-treated people stopped therapy due to adverse events, compared with nearly 14% (56) in the efavirenz arm. Grade 3/4 transaminase abnormalities were similar between groups. There was a slightly greater CD4 cell increase in the maraviroc arm, but the clinical relevance of that finding is not clear.
Those using efavirenz were more likely to experience neuropsychiatric side-effects such as dizziness and abnormal dreams, while those using maraviroc had somewhat more nose and throat infections, and more bronchitis.
Participants on the efavirenz arm experienced larger increases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (all associated with a higher risk of cardiac disease), but also larger increases in protective high-density lipoprotein (HDL) cholesterol.
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.
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)
- 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.
The most commonly observed side-effects of maraviroc are cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.
Caution must be used when prescribing maraviroc to anyone with pre-existing liver dysfunction or who has co-infection with hepatitis B or C. Symptoms such as rash, jaundice, dark urine, vomiting, or abdominal pain should be investigated. In 2% of people, Grade 3-5 adverse events occurred that included elevated bilirubin, amylase, lipase, AST, and ALT levels.
There have been concerns that CCR5 inhibitors as a class involve a risk of serious liver side-effects and the US Food and Drug Administration’s approval for maraviroc states that the product label should include a boxed warning about liver toxicity.
The warnings/precautions section of the drug information leaflet also cautions about the possibility of an increased risk of cardiovascular illness such as heart attack or dizziness when standing up quickly, particularly in people with pre-existing renal impairment.
Safety analyses done at 48 weeks continue to show no unexpected adverse events. There was no difference between the placebo group and maraviroc group in rates of discontinuation due to adverse events (around 6%) or in serious adverse events (grade 3-4, around 17%). (Hardy)
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.
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 150 mg twice daily. These drugs include most protease inhibitors (except for tipranavir/ritonavir), ketoconazole, itraconazole, clarithromycin, nefazadone, telithromycin, among others. (Muirhead) (Abel)
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.
Etravirine (Intelence), a potent inducer of the cytochrome p450 CYP3A4 pathway, has been found to speed up the metabolism of maraviroc enormously and it reduces total maraviroc concentrations over a 12-hour period by 53% (AUC12) and peak levels of maraviroc (Cmax) by 60%. Consequently, if an individual is not also taking a potent CYP3A4 inhibitor, such as a protease inhibitor, the recommended clinical dose for maraviroc alongside etravirine is 600mg twice daily. However, if maraviroc is being dosed alongside etravirine and darunavir together, the 150mg twice-daily dose is sufficient. Co-administration of etravirine/darunavir/ritonavir with maraviroc increased the exposure of maraviroc by 210% (AUC12) and peak levels (Cmax) by 77% compared to maraviroc alone.
These results, where the combination of a potent inducer of CYP mediated metabolism (etravirine) and a potent inhibitor of CYP mediated metabolism (darunavir/ritonavir) yields a net increase in maraviroc concentrations, are consistent with previous inducer/inhibitor combination data, where the net effect appears to be inhibition.
Etravirine pharmacokinetic data showed no effect of maraviroc on etravirine pharmacokinetics. Therefore, no dose adjustment of etravirine is necessary. The dose remains 200mg twice daily. Safety data from the study indicated that co-administration of etravirine and maraviroc was generally safe and well tolerated.
Maraviroc has been approved in the European Union for use in treatment-experienced children aged 2 and over weighing 10kg or more.
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.
Lalezari J et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24 week results from a phase 2b/3 study in the US and Canada. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 104bLB, 200.
Nelson M et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia and North America: 24 week results. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 104aLB, 2007.
Fatkenheuer G et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. New England Journal of Medicine, 359: 1442-55, 2008.
Gulick RM et al. Maraviroc for previously treated patients with R5 HIV-1 infection. New England Journal of Medicine, 359: 1429-1449, 2008.
van der Ryst E et al. Changes in HIV-1 co-receptor tropism for patients participating in the maraviroc MOTIVATE 1 and 2 clinical trials. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-715, 2007.
Saag M et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV] / lamivudine [3TC]), for the treatment of antiretroviral naïve patients infected with R5 HIV-1: week 48 results of the MERIT study. Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sydney, abstract WESS104, 2007.
Saag M et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96-week results. Fifth IAS Conference on HIV Treatment, Pathogenesis and Prevention, abstract TUAB103, 2009.
Hardy D et al. Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE studies. 15th Conference on Retroviruses and opportunistic Infections, Boston, abstract 792, 2008.
Muirhead G et al. An investigation into the effects of atazanavir and ritonavir boosted atazanavir on the pharmacokinetics of the novel CCR5 inhibitor UK-427,857. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P283, 2004.
Abel S et al. An open, randomized, 2-way crossover study to investigate the effects of darunavir/ritonavir on the pharmacokinetics of maraviroc in healthy subjects. Eighth International Workshop on Pharmacology of HIV Therapy, Budapest, abstract 55, 2007.