HIV Treatment Bulletin - Vol. 8, No. 8/9, August-September 2007

Simon Collins, HIV i-Base

Several studies presented new information on the CCR5 inhibitor maraviroc.

Michael Saag from University of Alabama at Birmingham and colleagues presented 48-week results from a randomised, double-blind study comparing maraviroc to efavirenz, each with background AZT+3TC, in 721 treatment-naïve drug-sensitive patients (28% women). The study was designed to assess non-inferiority between efavirenz (QD) and maraviroc (BID).[1]

Baseline median CD4 (range) was 241 (5-1422) and 254 (8 – 1053) cells/mm³ and mean viral load was about 4.9 logs (SD±0.7) respectively in the maraviroc and efavirenz arms.

By 48 weeks, efficacy results favoured efavirenz. 11.9% versus 4.2% discontinued treatment due to viral failure (with 70% vs 73% patients suppressed to <400 copies/mL and 65% vs 69% suppressed to <50 copies/mL) in the maraviroc and efavirenz arms respectively.

The lower confidence interval was –9.5% for suppression to <400 and –10.9% for <50 copies/mL. As the predefined lower bound was set at 10%, maraviroc could only be shown to be non-inferior compared to efavirenz for suppression to <400 copies/mL, but not for the more important <50 copies/mL viral endpoint. When stratified by baseline CD4 count >100,000 copies/mL, suppression to <50 copies/mL occurred in 60% of maraviroc patients vs 67% with efavirenz.

However, mean CD4 count increase from baseline was greater in the maraviroc arm (+170 vs +143 cells/mm³) with a significant difference (+26.0 95%CI, 7.0, 46.0). Tolerability also favoured maraviroc (4.1% versus 13.6% discontinued due to side effects, with the efavirenz having a higher report of grade3/4 events. Four malignancies were reported in the efavirenz arm (2 Hodgkins disease, 1 NHL, 1 KS) compared to one case of NHL in the maraviroc arm.

The incidence of grade 3/4 transaminase abnormalities was similar between the two groups.

Change in median lipids (TC, HDL, LDL and TG) were stable or non-significant for maraviroc arms, and increased in the efavirenz groups, similar to that reported in previous naïve studies.

One as yet unexplained finding was that these results were significantly different by North/South region. There was similar suppression to <50 copies/mLin patients from North America and Europe (68.0% vs 67.8%), but not in patients from Argentina, South Africa and Australia (62.1 vs 71.0), and this has driven the difference in the overall study.

Comment

Failure to achieve non-inferiority at suppression to <50 copies/mL in the study was dependent on the choice of –10% as a lower cut-off, although other FDA regulatory studies have set this at 12%. However, this still leave the scenario of having a drug that is 9% less potent than standard of care.

This, together with poorer response rates when starting with baseline viral load >100,000 copies/mL and a BID formulation, will limit interest in use for first-line treatment. However, as risk of developing X4 tropism increases with duration of infection, defining an optimum time to use maraviroc remains unclear.

Wider use may also be more likely if the geographical differences can be explained, perhaps relating to the sub-type or clade of HIV infection, and in patient dependent on a higher CD4 response.

It is difficult to understand why treatment naïve trials still enroll patients with very advanced HIV in to an investigational trial (both arms included at least one patient with CD4 <10 cells/mm³). It is also difficult to understand why anyone with a CD4 count over 1000 cells/mm³ would be encouraged to enter the study.

Treatment advocates have long argued for upper and lower CD4 cut-offs (around 100-500 cells/mm³), both to guarantee that people most in need of treatment receive at least the minimum standard of care, and that the results are generally applicable for people who will use the results in a real world setting.

Ref: Saag M, Ive P, Heera J et al. Amulticentre, randomised, 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 subjects infected with R5 HIV-1: week 48 results of the MERIT study. IAS Conf HIV Pathog Treat 2007 Jul 22-25;4th: (Abstract No. WESS104).

2007-08-10
IB070808-07

©2007. I-BASE HIV Treatment Bulletin. Permission to reproduce courtesy of HIV i-Base, Third Floor East, Thrale House, 44-46 Southwark Street, London SE1 1UN - T: +44 (0) 20 7407 8488 F: +44 (0) 20 7407 8489

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2007. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2007. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.