THE CD4/CD8 RATIO AS A PREDICTOR OF NON-AIDS EVENTS DURING ANTIRRETROVIRAL THERAPY: CONFIRMATION OF ITS PREDICTIVE VALUE AND IMPACT OF MARAVIROC IN TREATMENT-EXPERIENCED PATIENTS

Proposal
945

Title of Proposed Research

Lead Researcher

Santiago Moreno

Affiliation

University Hospital Ramón y CajalMadrid, Spain

Funding Source

None

Potential Conflicts of Interest

ViiV board membership, consultancy and unrestricted grants.

Data Sharing Agreement Date

23 April 2014

Lay Summary

A low CD4/CD8 ratio is considered a surrogate marker of immunosenescence and is an independent predictor of all-cause mortality. We have recently described in long-term virally suppressed HIV infected subjects a negative correlation between the CD4/CD8 ratio and inflammation/inmmunosenescence. We also observed that is independently associated with surrogate markers of age-associated disease and non-AIDS-related morbidity and mortality. Collectively, these studies suggest that a low CD4/CD8 ratio despite otherwise effective ART might identify a new clinical phenotype of patients needed of novel interventions. Given the strong clinical implications of a novel and accessible diagnostic tool that might identify patients at higher risk of disease progression, the predictive importance of the CD4/CD8 ratio during treated HIV infection must be confirmed in large prospective studies. Five-year follow-up data on two large studies of maraviroc in treatment-experienced individuals with a registry of non-AIDS events have been reported, where the prognostic significance of the CD4/CD8 ratio during long-term ART can be conveniently addressed.

Study Data Provided

[{ "PostingID": 1402, "Title": "VIIV-A4001029", "Description": "Trial of Maraviroc (UK-427,857) in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of Antiretroviral-Experienced NonCCR5-Tropic HIV-1 Infected Subjects

Medicine: maraviroc, Condition: Infection, Human Immunodeficiency Virus, Phase: 2/3, Clinical Study ID: A4001029, Sponsor: ViiV" },{ "PostingID": 1403, "Title": "VIIV-A4001028", "Description": "Trial of Maraviroc (UK-427,857) in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of HIV-1 Infected Subjects

Medicine: maraviroc, Condition: Infection, Human Immunodeficiency Virus, Phase: 2/3, Clinical Study ID: A4001028, Sponsor: ViiV" },{ "PostingID": 1404, "Title": "VIIV-A4001027", "Description": "Trial of Maraviroc (UK-427,857) in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of HIV-1 Infected Subjects

Medicine: maraviroc, Condition: Infection, Human Immunodeficiency Virus, Phase: 2/3, Clinical Study ID: A4001027, Sponsor: ViiV" }]

Statistical Analysis Plan

For the principal objective, the outcome variable will be the time to the clinical event. The primary correlate of interest in the analysis of time to clinical event will be the time-updated binary indicator of CD4:CD8 normalization. Kaplan Meier methods for time-dependent covariates will be used to examine the associations of CD4:CD8 normalization with the incidences and rates of survival and selected clinical event. Proportional hazard models will be used to estimate the association of CD4:CD8 normalization with incidences and rates of survival and selected clinical events, after adjusting for other variables hypothesized to be associated with non-AIDS-related events, based on the background literature. When covariates are considered to be collinear (such as IDU and hepatitis C), the variable with the strongest association will be included in the multivariable model. The final model will be adjusted at least by the following variables: age, gender, risk factors for HIV acquisition, year of ART initiation, type of ART regimen (maraviroc vs placebo plus optimized background ART), baseline CD4+ T-cell count and CD8+ T-cell count and time-updated HIV RNA.
For the secondary objective, longitudinal changes in CD4 and CD8 counts and in the CD4/CD8 ratio will be assessed using linear mixed models with random intercepts. Age, gender, risk factors for HIV acquisition, year of ART initiation, baseline CD4+ T-cell count and CD8+ T-cell will be included in multivariate analyses as fixed-effects. Interaction terms were created to assess whether these changes over time differed significantly between ART regimens (including maraviroc or placebo plus optimized background therapy).
For both objectives, sensitivity analyses will be conducted to examine the effects of 1) defining normalization of the CD4:CD8 ratio as >0.5, >0.8, >1 or >1.5, 2) excluding late presenters, defined as having an AIDS-defining events within 3 months after ART initiation and 3) including only patients reaching >500 CD4/uL during follow-up. Missing data will be handled using multiple imputation.

Publication Citation

Serrano-Villar S, Caruana G, Zlotnik A, Pérez-Molina JA, Moreno S. Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals. Antimicrobial Agents and Chemotherapy. 2017; 61(12). doi: 10.1128/AAC.01763-17.PMID: 28993335.
https://aac.asm.org/content/61/12/e01763-17.full