Effectiveness

Approval of maraviroc for treatment-experienced individuals was based on 24-week results from the MOTIVATE studies.¹ 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.² 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.^{3 4}

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.⁴

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.⁵

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.⁶

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.⁷

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.