In response to our recently published trial,1  Psomas et al present new microbial translocation data from another recently published uncontrolled trial of maraviroc intensification in HIV-infected individuals with incomplete CD4+ T-cell recovery.2  They observed significant reductions in plasma 16S ribosomal DNA levels, which is consistent with the significant reductions in plasma lipopolysaccharide (LPS) levels observed in our trial.1  Although both of these observations support the hypothesis that maraviroc decreases microbial translocation, it is important to emphasize that the plasma LPS declines observed in the maraviroc arm of our trial were not significantly different than those observed in the placebo arm. To date, no randomized controlled trial has proven that maraviroc decreases microbial translocation. Indeed, in another uncontrolled trial of maraviroc intensification, plasma LPS levels actually increased.3  We highlighted the reduction in plasma LPS levels in the maraviroc arm of our study because it occurred despite a tendency for neutrophil counts and soluble markers of monocyte activation to increase. We thus speculated that an increase in monocyte, macrophage, and neutrophil activation might contribute to increased clearance of microbial products. We recognize that this is a hypothesis that has yet to be proven, but it remains a viable potential explanation for the immunologic changes we observed.

Psomas et al also highlight the different conclusions reached by our trials regarding the effects of maraviroc intensification on changes in T-cell activation and monocyte activation. As discussed in our recent paper,1  we agree that technical issues and differences in patient populations may have contributed to the reductions in T-cell activation observed in several uncontrolled trials of maraviroc intensification.2-4  Psomas et al discount the possibility that increased adherence to the background antiretroviral therapy regimen could have contributed to the decreased T-cell activation levels or plasma 16S ribosomal DNA levels observed in their study because levels did not significantly change between enrollment and the start of study medication, but adherence typically improves when trial subjects start taking a study medication, particularly when they know that pills are being counted. This appeared to be the case in the placebo arms of our trial and another recent placebo-controlled treatment intensification study.1,5  This is one of the reasons why double-blind randomized placebo-controlled trials are the gold standard for evidence in clinical research. We agree that further research will be necessary to understand many of the unexpected effects of maraviroc intensification on the immune system in treated HIV infection, but strongly suggest that this work be conducted in the context of adequately powered randomized controlled trials so that observed effects can be clearly attributed to the intervention.

Authorship

Acknowledgments: The original study was funded by investigator-initiated research grants from Pfizer, Inc, and the American Foundation for AIDS Research (amfAR, http://www.amfar.org/, 107170-44-RGRL). Additional support was provided from the National Institutes of Health (P30 AI27763 and UL1 RR024131). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Contribution: P.W.H. wrote the first draft of the manuscript; and M.M.L. and S.G.D. assisted with the interpretation, discussion, and editing of the letter.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Peter W. Hunt, UCSF Positive Health Program, SFGH Building 80, Ward 84, 995 Potrero Ave, San Francisco, CA 94110; e-mail: phunt@php.ucsf.edu.

References

References
1
Hunt
PW
Shulman
NS
Hayes
TL
, et al. 
The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial.
Blood
2013
, vol. 
121
 
23
(pg. 
4635
-
4646
)
2
Cuzin
L
Trabelsi
S
Delobel
P
, et al. 
ANRS 145 MARIMUNO Study Group
Maraviroc intensification of stable antiviral therapy in HIV-1-infected patients with poor immune restoration: MARIMUNO-ANRS 145 study.
J Acquir Immune Defic Syndr
2012
, vol. 
61
 
5
(pg. 
557
-
564
)
3
Gutiérrez
C
Díaz
L
Vallejo
A
, et al. 
Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: effect on T cells latently infected.
PLoS ONE
2011
, vol. 
6
 
12
pg. 
e27864
 
4
Wilkin
TJ
Lalama
CM
McKinnon
J
, et al. 
A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4+ T-cell recovery despite sustained virologic suppression: ACTG A5256.
J Infect Dis
2012
, vol. 
206
 
4
(pg. 
534
-
542
)
5
Hatano
H
Scherzer
R
Wu
Y
, et al. 
A randomized controlled trial assessing the effects of raltegravir intensification on endothelial function in treated HIV infection.
J Acquir Immune Defic Syndr
2012
, vol. 
61
 
3
(pg. 
317
-
325
)