HTB

Adding maraviroc does not boost CD4s inrandomised trial

1 December 2010. Related: Conference reports, Antiretrovirals, .

Mark Mascolini, natap.org

Adding maraviroc to a suppressive regimen taken by people with a meager CD4 response did not boost CD4 count or CD4 percentage over 12 weeks in a small randomised trial. [1]

Maraviroc-induced improvement of certain T-cell subsets suggested this intensification strategy may have some immunologic advantage. But whether such an advantage yields clinical benefits that outweigh maraviroc-related risks and cost remains to be seen.

This multicenter Italian study recruited people with a prompt sub-50 virologic response to antiretroviral therapy who had sluggish CD4 gains. Stefano Rusconi (Universiti degli Studi di Milano) and colleagues randomised 50 people to add maraviroc and 50 to continue their current regimen. This planned 12-week analysis involved 37 people adding maraviroc and 27 in the control arm who reached that point. Follow-up will continue for 12 months.

Median CD4 count rose from 190 (range 144 to 237) to 211 (184.5 to 285.5) at week 12 in the maraviroc group, and from 170 (131.5 to 218) to 174 (126 to 247) in the control arm, a nonsignificant difference (p=0.241). Median CD4 percentage remained stable in the maraviroc group (14.8% at baseline to 14.4% at week 12) and in the control arm (12.7% at baseline and 12.9% at week 12).

Median CD8 count fell from 775.5 to 661.5 in the control arm, while climbing from 603 to 759 in the maraviroc arm, a significant difference (p=0.004). Pfizer investigator Hernan Valdez has proposed that this seemingly inauspicious jump in CD8 cells represents early redistribution of CD8 cells from cellular compartments, which stops after about 24 weeks. [2]

Ninety-six-week follow-up of antiretroviral-naive people randomized to maraviroc in two trials found little overall CD8-cell change in that span, but antiretroviral-experienced people who took maraviroc in the MOTIVATE studies had a big CD8 gain through 96 weeks. [3]

Rusconi compared week-12 T-cell subset changes in 12 people who added maraviroc and 12 who did not. The maraviroc group tended to gain more memory CD4 and CD8 cells than the control group, with no significant loss in naive T cells. Rusconi and colleagues proposed these shifts suggest “a role of maraviroc in reducing peripheral antigen-driven T-cell death, possibly preserving new T-cell production.” Levels of activated (HLA-DR+ CD38+) T cells declined similarly in people adding or not adding maraviroc. CD8-cell expression of Ki67, a proliferation marker, fell in the maraviroc group (p=0.06) but not in the control group.

Except for five blips between 50 and 125 copies, everyone in the trial maintained virologic suppression during the first 12 weeks, and the researchers saw no clinical setbacks. There were 12 adverse events in the maraviroc arm (32%), but only one was judged related to maraviroc. Nonetheless, 3 people stopped maraviroc because of adverse events. Eight adverse events were recorded in the control arm (30%).

Adding maraviroc to a suppressive regimen also failed to hoist CD4 cells in an earlier pilot study. [4]

Two meta-analyses of CD4 responses in clinical trials yielded conflicting conclusions on whether CCR5 antagonists hold an edge over other antiretroviral classes [5, 6], though these meta-analyses could not adjust for factors predicting CD4 cell restoration.

References:

  1. Rusconi S et al. Maraviroc intensification for HIV-1-positive immunological non-responders despite virological suppression during HAART. 10th International Congress on Drug Therapy in HIV Infection. 7–11 November 2010. Glasgow. Abstract O421. Published in Journal of the International AIDS Society 2010, 13(Suppl 4):O44. doi:10.1186/1758-2652-13-S4-O44. http://www.jiasociety.org/content/13/S4/O44
  2. Valdez H et al. Effect of age on baseline CD4+ cells and immunologic response to regimens with or without Maraviroc. First International Workshop on HIV and Aging. 4-5 October 2010. Baltimore. Abstract O_04.
  3. Lazzarin A et al. Maraviroc increases CD4+ and CD8+ cells: long-term data from the maraviroc clinical development program. 10th International Congress on Drug Therapy in HIV Infection. 7–11 November 2010. Glasgow. Abstract O422. Published in Journal of the International AIDS Society 2010, 13(Suppl 4):O45. doi:10.1186/1758-2652-13-S4-O45. http://www.jiasociety.org/content/13/S4/O45
  4. Wilkin T et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG 5256. 17th Conference on Retroviruses and Opportunistic Infections. 16-19 February 2010. San Francisco. Abstract 285. http://www.retroconference.org/2010/Abstracts/39637.htm
  5. Pichenot M et al. CCR5 inhibitors and CD4 cell count change in treatment experienced patients. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy. 12-15 September 2010. Boston. Abstract H-1813.
  6. Wilkin T et al. The relationship of CCR5 inhibitors to CD4 cell count changes: a meta-analysis of recent clinical trials in treatment-experienced subjects. 15th Conference on Retroviruses and Opportunistic Infections. 3-6 February 2008. Boston. Abstract 800. http://www.retroconference.org/2008/Abstracts/31374.htm

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