teaser
Maraviroc belongs to a new class of anti-HIV drugs named CCR5 antagonists, which block HIV entry into cells. Given its exclusive activity against CCR5 tropic strains, viral tropism testing is mandatory before its use in clinical practice
Massimiliano Lanzafame
Emanuela Lattuda
Unit of Infectious Diseases
GB Rossi Hospital
Verona, Italy
The emergency of resistance and toxicities caused by long-term use of therapies in HIV-1 seropositive patients have fuelled the search for new drug classes with a novel mechanism of action.
Inhibition of the human immunodeficiency virus coreceptor is an encouraging new approach to pharmacotherapy. Maraviroc is the first CCR5 co-receptor antagonist approved for clinical use for treatment of experienced patients; clinical trials have attested its efficacy and tolerability, even if there has been debate on their long-term safety because of the role in innate
immunity and possible use in drug-naive patients. However, given its exclusive activity against CCR5 tropism strains, viral tropic testing is mandatory before its use in clinical practice.
Long-term studies should be performed to explore critical issues of this drug, both for safety and new target of employ. Recommended regimens to treat HIV infection today consist of a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor.[1]
The emergency of resistance and toxicities caused by long-term use of therapies have fuelled search for new drug classes with a novel mechanism of action. Inhibition of the human immunodeficiency virus type 1 co-receptor is an encouraging new approach to pharmacotherapy for patients with HIV infection.[2]
HIV infects different cell types, including CD4+cells; the infectious cycle begins with fusion of viral particles to the CD4+ receptor at the cell surface; this interaction leads to a conformational change and subsequent interaction with a co-receptor, either CCR4 or CXCR5.[3]
The fusion inhibitor enfuvirtide and the small molecule CCR5 antagonist, maraviroc (Selzentry or Celsentri) are the first entry inhibitors approved for clinical use in HIV-infected persons.
Maraviroc is the only approved CCR5 antagonist and the single oral HIV entry inhibitor in clinical use; it specifically inhibits the replication of R5-tropic HIV variants by an allosteric mechanism after binding to the transmembrane CCR5 co-receptor cavity.
The antiviral activity of maraviroc was tested in a monotherapy dose-ranging study that compared different doses of maraviroc with placebo in HIV infected drug-naive individuals with R5 virus phenotype;[4] subsequently in the MOTIVATE 1 and MOTIVATE 2 trials, triple class-resistant patients with the same type of virus were randomised to receive either maraviroc or placebo, each with an optimised background regimen (OBT).[5,6]
As a result, after 48 weeks the proportion of patients with a plasma HIV-RNA load of less than 50 c/ml was doubled in the maraviroc arm compared with the placebo one; the greatest virological efficacy was demonstrated, as expected, in treatment-experienced patients when used with at least one active agent in OBT. In particular, a beneficial effect was observed from combining maraviroc and enfuvirtide. Also, with
regard to immunological recovery, MOTIVATE 1 and 2 trials demonstrated significantly greater increases in CD4+ T-cell count in the maraviroc arms.
Postural hypotension was the most common doselimiting adverse effect observed with maraviroc; no warnings were reported with doses less than 600 mg. Rare abnormalities in liver enzyme were observed; so until further data are available it may be advisable to avoid using the drug in cases of severe hepatic disease. Some other common adverse events reported
by patients in the MOTIVATE trials were upper respiratory tract infection, cough, pyrexia, rash, dizziness, gastrointestinal and abdominal pain, appetite disorders, insomnia, sinusitis, bronchitis, herpes infection and constipation.[5,6]
The antiretroviral activity of CCR5 antagonists is limited to R5 viruses; so treatment candidates are patients who lack detectable X4 viruses or dual tropic viruses. Several assays have been developed to determine HIV tropism in clinical samples.[7] The Trofile assay[8] has been used in clinical trials and is currently used for testing viral tropism in patients for whom HAART with maraviroc may be considered.
A limit of the test is the limited sensitivity for the detection of dual tropic viruses when presented as minority or low-frequency species, even if their presence also in this condition seems to decrease antiviral activity. The reduced antiviral activity of maraviroc, due to X4 variants below the limit of detection of the Trofile, has been postulated to explain the virological failure in some patients undergoing this therapy.
Monogram Biosciences has developed an improved version of the Trofile assay which is able to detect X4 variant representing only 0.3% of the total viral population.[9] At present, there has not been estimated a cutoff for the proportion of X4/dual tropic variants, above which virological failure would be predicted.
Resistance to maraviroc could be due to emergence of X4 or dual tropic viruses or to selection of mutations in the HIV-1 gp120 molecule that allows thevirus to bind to the drug-bound form of the CCR5 coreceptor;[10,11] data from the MOTIVATE trials suggest that among treatment failures the majority of patients experienced a shift from R5 to X4 or dual mixed tropic
viruses.[6] Interestingly, after maraviroc discontinuation, R5 viruses tend to recover predominance in the virus population, suggesting that X4 enrichment during therapy is not long lasting.
A switch of the HIV-1 coreceptor from CCR5 to CXCR4 is usually seen in the natural history of HIVinfected patients, associated with disease progression and acquired immunodeficiency syndrome. In general, X4 viruses emerge in almost 50% of populations with a CD4 count below 50 cells/mm3, suggesting that probably maraviroc should be used earlier in the treatment before advanced immunodeficiency.[12] The MERIT study is a multicentre, non-inferiority, randomised trial designed to compare safety and efficacy of maraviroc versus efavirenz in antiretroviral-naive patients infected with HIV-1.[13] The analysis performed on patients prospectively included in the study shows that maraviroc fails to prove non-inferiority to efavirenz; otherwise, the initial re-analysis of the data on patients without switch tropism between screening and start of maraviroc demonstrates that it is potent as efavirenz.
Moreover, the recent finding that many of most commonly prescribed antiretroviral drugs may be associated with increased cardiovascular risk[14,15] has pointed out the need for a switch to better tolerated drugs.
Concern, however, exists regarding the potential long-term oncologic and immunologic risks associated with co-receptor antagonism; in fact, chemical or genetic CCR5 knockout could be deleterious for other processes implicated in pathogen response. Co-receptors have a natural rule in viral, bacterial, fungal and parasitic diseases;[16–19] attention must be reserved also to non-infectious diseases, such as rheumatoid arthritis. Finally, the second CCR5 antagonist under clinical evaluation, vicriviroc, was initially associated with the development of malignant tumours.[20]
So, longer-term studies on the effects of CCR5 inhibition, particularly those involving immune functions, need to be carried out, and general recommendations should be given to patients treated with maraviroc in particular circumstances.
Maraviroc is a substrate for the cytocrome P450 and P-glycoprotein, both of which are involved in the metabolism of multiple other agents, including several antiretroviral drugs; therefore drug interactions should be kept in mind while using CCR5 inhibitors.
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