First Chemokine Receptor Antagonist Available Under Expanded Access
Abstract & Commentary
By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Dr. Winslow is a consultant for Bayer Diagnostics, and on the speaker's bureau for GlaxoSmithKline and Pfizer.
Uk-427,857 (Maraviroc) is an investigational small-molecule HIV entry inhibitor that binds to the CCR5 chemokine receptor on the surface of T-cells. This chemokine receptor is normally the receptor for the chemokines MIP-1 alpha and RANTES.1 In HIV infection after initial binding of HIV's external envelope protein, gp120, to CD4, conformational change occurs in the trimeric structure of gp120 allowing its binding to generally one of 2 co-receptors (CCR5 or CXCR4, the latter being the normal receptor for SDF-1). Following this, regions of the transmembrane glycoprotein, gp41, fuse with the cell membrane, followed by uncoating of the virus with vRNA being reverse transcribed within the cytoplasm of the host cell. In acute and early HIV infection, virus isolated from most patients generally displays tropism for the CCR5 co-receptor (R5 virus). Later as infection progresses, one commonly observes switch of virus co-receptor usage to CXCR4 (X4) or dual tropism with the virus able to use both co-receptors. In vitro, R5 virus tends to be monocytotropic, but can be cultured in PHA/IL-2 stimulated PBMC's, whereas X4 virus tends to not be monocytotropic but can be cultured in lymphoblastoid cell lines such as MT-2 as well as stimulated PBMC's. HIV co-receptor tropism can be examined in vitro traditionally by a virus's ability to grow in T-cell lines (CXCR4 tropism) and can also be determined by various recombinant viral assays.
The only currently commercially available attachment/entry inhibitor is enfuvirtide (Fuzeon), which blocks the gp41-mediated membrane fusion event. Unfortunately enfuvirtide is a large recombinant molecule that is not orally bioavailable, requires twice daily subcutaneous injection, and is often poorly tolerated due to painful injection-site reactions. Maraviroc is a small molecule with good oral bioavailability that binds non-competitively to CCR5, causing a conformational change in the extracellular loops of CCR5 that renders it unrecognizable to wild type R5-tropic HIV. While retaining activity against HIV resistant to the traditional 3 classes of antiretrovirals, maraviroc has no activity against viruses that use CXCR4 for cell entry.2 Maraviroc is a substrate for the cytochrome P450 3A/4 isoform and P-glycoprotein. Therefore, plasma levels are increased by Cyp 3A4 inhibitors such as ritonavir and antifungal azoles and levels are decreased by enzyme inducers such as rifampin and efavirenz.
In short term monotherapy trials in treatment naïve patients a clear dose-response antiretroviral effect was observed with plateau of antiretroviral effect at maraviroc doses ≥ 100 mg BID. Mean viral load reductions were about 1.5 log10. Most studies conducted in treatment experienced patients are still ongoing. The drug is well-tolerated with no substantial difference in frequency of adverse events between the maraviroc and placebo arms.
Commentary
Maraviroc represents a potentially exciting new approach to treat HIV infection based on its mechanism of action inhibiting virus co-receptor binding. While controlled clinical trials are still ongoing, a number of issues may limit the eventual clinical utility of this drug (and other co-receptor inhibitors in development with other pharmaceutical companies). These include: (1) Relative weak potency compared to existing agents such as nnRTIs and PIs (and other investigational agents such as the integrase inhibitors) where 2-3 log10 reductions of HIV RNA are observed in treatment naïve individuals. (2) The fact that R5 tropic HIV is relatively rare in patients who have advanced infection and have failed first and second line antiretroviral regimens. (3) Possible selection of X4 tropic virus in vivo with the potential for accelerated disease progression. (Fortunately, this possibility does not appear to be likely based on at least one Pfizer-sponsored trial conducted in patients infected with X4 or dual R5/X4 tropic virus where maraviroc appeared to confer neither harm nor benefit.)
The Pfizer HIV EAP Program is being coordinated by the Contract Research Organization, Parexel (1-888-275-4478). The study is open label and is open to treatment-experienced patients with R5-tropic HIV who have limited therapeutic options. Patients must have an HIV RNA > 1,000 copies/mL. Maraviroc will be added to an investigator selected Optimized Background Therapy (OBT) regimen. Because of pharmacokinetic interactions as noted above, patients will be dosed at 300 mg BID (or daily) if dosed with tipranavir/ritonavir or nucleosides in the absence of potent CYP3A4 inhibitors or inducers; 150 mg BID (or daily) when dosed with other ritonavir boosted PIs, clarithromycin or antifungal imidazoles; and 600 mg BID (or daily) when dosed with a potent CYP3A4 inducer such as efavirenz or rifampin.
References
- Samson M, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR5 chemokine receptor gene. Nature. 1996;382:722-725.
- Huang Y, et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996;2: 1240-1243.
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