Cumulative Viral Load and Virologic Decay Patterns after Antiretroviral Therapy in HIV-Infected Subjects Influence CD4 Recovery and AIDS

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Abstract

Background

The impact of viral load (VL) decay and cumulative VL on CD4 recovery and AIDS after highly-active antiretroviral therapy (HAART) is unknown.

Methods and Findings

Three virologic kinetic parameters (first year and overall exponential VL decay constants, and first year VL slope) and cumulative VL during HAART were estimated for 2,278 patients who initiated HAART in the U.S. Military HIV Natural History Study. CD4 and VL trajectories were computed using linear and nonlinear Generalized Estimating Equations models. Multivariate Poisson and linear regression models were used to determine associations of VL parameters with CD4 recovery, adjusted for factors known to correlate with immune recovery. Cumulative VL higher than the sample median was independently associated with an increased risk of AIDS (relative risk 2.38, 95% confidence interval 1.56–3.62, p<0.001). Among patients with VL suppression, first year VL decay and slope were independent predictors of early CD4 recovery (p = 0.001) and overall gain (p<0.05). Despite VL suppression, those with slow decay during the first year of HAART as well as during the entire therapy period (overall), in general, gained less CD4 cells compared to the other subjects (133 vs. 195.4 cells/µL; p = 0.001) even after adjusting for potential confounders.

Conclusions

In a cohort with free access to healthcare, independent of established predictors of AIDS and CD4 recovery during HAART, cumulative VL and virologic decay patterns were associated with AIDS and distinct aspects of CD4 reconstitution.

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Most cited references 50

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HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy.

J M Coffin (1995)

Several recent reports indicate that the long, clinically latent phase that characterizes human immunodeficiency virus (HIV) infection of humans is not a period of viral inactivity, but an active process in which cells are being infected and dying at a high rate and in large numbers. These results lead to a simple steady-state model in which infection, cell death, and cell replacement are in balance, and imply that the unique feature of HIV is the extraordinarily large number of replication cycles that occur during infection of a single individual. This turnover drives both the pathogenic process and (even more than mutation rate) the development of genetic variation. This variation includes the inevitable and, in principle, predictable accumulation of mutations such as those conferring resistance to antiviral drugs whose presence before therapy must be considered in the design of therapeutic strategies.

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Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies.

Matthias T F Wolf, George N. Phillips, Jonathan Sterne … (2002)

Insufficient data are available from single cohort studies to allow estimation of the prognosis of HIV-1 infected, treatment-naive patients who start highly active antiretroviral therapy (HAART). The ART Cohort Collaboration, which includes 13 cohort studies from Europe and North America, was established to fill this knowledge gap. We analysed data on 12,574 adult patients starting HAART with a combination of at least three drugs. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. We considered progression to a combined endpoint of a new AIDS-defining disease or death, and to death alone. The prognostic model that generalised best was a Weibull model, stratified by baseline CD4 cell count and transmission group. FINDINGS During 24,310 person-years of follow up, 1094 patients developed AIDS or died and 344 patients died. Baseline CD4 cell count was strongly associated with the probability of progression to AIDS or death: compared with patients starting HAART with less than 50 CD4 cells/microL, adjusted hazard ratios were 0.74 (95% CI 0.62-0.89) for 50-99 cells/microL, 0.52 (0.44-0.63) for 100-199 cells/microL, 0.24 (0.20-0.30) for 200-349 cells/microL, and 0.18 (0.14-0.22) for 350 or more CD4 cells/microL. Baseline HIV-1 viral load was associated with a higher probability of progression only if 100,000 copies/microL or above. Other independent predictors of poorer outcome were advanced age, infection through injection-drug use, and a previous diagnosis of AIDS. The probability of progression to AIDS or death at 3 years ranged from 3.4% (2.8-4.1) in patients in the lowest-risk stratum for each prognostic variable, to 50% (43-58) in patients in the highest-risk strata. The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART. Our findings have important implications for clinical management and should be taken into account in future treatment guidelines.

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Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment.

Colleen Kelley, Christina Kitchen, Peter W. Hunt … (2009)

Although antiretroviral therapy has the ability to fully restore a normal CD4(+) cell count (>500 cells/mm(3)) in most patients, it is not yet clear whether all patients can achieve normalization of their CD4(+) cell count, in part because no study has followed up patients for >7 years. Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level 1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4(+) cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques. The majority (83%) of the patients were men. The median CD4(+) cell count at the time of therapy initiation was 201 cells/mm(3) (interquartile range, 72-344 cells/mm(3)), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5-9.7 years). CD4(+) cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4(+) cell count 300 cells/mm(3) were able to attain a CD4(+) cell count 500 cells/mm(3), 44% of patients who started therapy with a CD4(+) cell count 500 cells/mm(3) over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4(+) cell count <500 cells/mm(3) at year 4 had evidence of a CD4(+) cell count plateau after year 4. The frequency of detectable viremia ("blips") after year 4 was not associated with the magnitude of the CD4(+) cell count change. A substantial proportion of patients who delay therapy until their CD4(+) cell count decreases to <200 cells/mm(3) do not achieve a normal CD4(+) cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4(+) cell count over time, many do not. These individuals may have an elevated risk of non-AIDS-related morbidity and mortality.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2011

Publication date (Electronic): 20 May 2011

Volume: 6

Issue: 5

Electronic Location Identifier: e17956

Affiliations

[1 ]Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America

[2 ]Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America

[3 ]Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, United States of America

[4 ]Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center, Fort Sam Houston, Texas, United States of America

[5 ]Infectious Disease Service, Walter Reed Army Medical Center, Washington, D.C., United States of America

[6 ]Infectious Disease Clinic, National Naval Medical Center, Bethesda, Maryland, United States of America

[7 ]Infectious Disease Clinic, Naval Medical Center San Diego, San Diego, California, United States of America

[8 ]National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

[9 ]Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, Texas, United States of America

[10 ]Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, Texas, United States of America

[11 ]Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, United States of America

[12 ]Department of Microbiology and Immunology, and Biochemistry, University of Texas Health Science Center, San Antonio, Texas, United States of America

University of Liverpool, United Kingdom

Author notes

* E-mail: vcmarco@ 123456emory.edu (VCM); kulkarnih@ 123456uthscsa.edu (HK)

Conceived and designed the experiments: VCM HK SKA JFO MD. Analyzed the data: HK VCM GG JFO. Contributed reagents/materials/analysis tools: HK SKA BA MP. Wrote the paper: VCM HK SKA GG. Gathered clinical data: VCM JFO GW AG NCC ML MD BA IDCRP-HWG. Analysis interpretation and manuscript review: VCM GG JFO GW AG NCC MP ML SKA BA HK.

¶ Membership of the IDCRP HIV Working Group is provided in the Acknowledgments.

Article

Publisher ID: PONE-D-10-03075

DOI: 10.1371/journal.pone.0017956

PMC ID: 3098832

PubMed ID: 21625477

SO-VID: 1aa09dce-919b-433d-bd06-2acd5c1a75a9

Copyright © This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

History

Date received : 6 October 2010

Date accepted : 19 February 2011

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Pages: 9

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Cumulative Viral Load and Virologic Decay Patterns after Antiretroviral Therapy in HIV-Infected Subjects Influence CD4 Recovery and AIDS

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Abstract

Background

Methods and Findings

Conclusions

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PLOS Climate

Most cited references 50

HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy.

Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies.

Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment.

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