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Cumulative Viral Load Predicts Mortality for Untreated People with HIV

"Viremia copy-years," or cumulative HIV viral load over time, was a good predictor of deaths due to all causes among people on combination antiretroviral therapy (ART), independent of cross-sectional, or one-time, viral load measurements or CD4 T-cell counts, researchers reported in the September 2, 2011, advance online edition of Clinical Infectious Diseases.

Michael Mugavero and Michael Saag from the University of Alabama at Birmingham and fellow investigators with the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) Cohort Study looked at the cumulative effect of time spent with active HIV replication on mortality after ART initiation.

Cross-sectional plasma viral load has proven invaluable for clinical and research purposes, the study authors noted as background. Although it remains the standard for monitoring ART effectiveness, cross-sectional measures fail to capture cumulative plasma HIV burden over time.

This study included more than 2000 treatment-naive HIV patients starting ART for the first time at 8 CNICS sites between 2000 and 2008. Participants had quite advanced immune deficiency, with a median baseline CD4 count of 222 cells/mm³ and a median viral load of 4.8 log copies/mL.

The researchers determined viremia copy-years -- a time-varying measure of cumulative plasma HIV exposure -- for each participant using viral load area under the curve. They explained that 10,000 viremia copy-years is equal to having a viral load of 10,000 copies/mL for 1 year, or a viral load of 1000 copies/mL for 10 years.

They then used multivariate models to evaluate the independent association between viremia copy-years and all-cause mortality.

Results

• 2027 participants contributed a total 6579 person-years.
• Participants had a median of 8 viral load tests over a median follow-up period of 2.7 years, for a total of 21,665 measurements.
• About 80% of patients achieved undetectable HIV RNA after 24 weeks on ART, and a similar proportion of viral load measurements were undetectable during follow-up.
• The overall median viremia copy-years, or cumulative viral load, was 5.3 log copies x year/mL.
• A total of 85 participants (4.2%) died during follow-up, for a mortality rate of 1.3 per 100 person-years.
• When evaluated separately, the following factors were significantly associated with increased mortality:
  • Viremia copy-years: hazard ratio (HR) 1.81 per log copy x year/mL, or 81% increase;
  • Viral load 24 weeks after starting ART: HR 1.74 per log copies/mL, or 74% increase;
  • Most recent viral load: HR 1.89 per log copies/mL, or 89% increase.
• In a multivariate analysis controlling for other factors, viremia copy-years independently predicted increased mortality risk (HR 1.44 per log copy x year/mL, or 44% increase).
• In this analysis, no cross-sectional viral load measurements were independently associated with mortality.

·      Older age was also a significant predictor of increased mortality, while higher CD4 cell count was protective.

Based on these findings, the researchers concluded, "Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional viral load measures and time-updated CD4+ T-lymphocyte count in ART-treated patients, suggesting cumulative HIV replication causes harm independent of its effect on the degree of immunodeficiency."

These findings contribute to the growing body of evidence that continued HIV replication can accelerate disease progression and increase the risk of non-AIDS conditions such as cardiovascular disease, independent of CD4 cell depletion, perhaps by maintaining persistent inflammation.

Cumulative viral load may be a "surrogate for and perhaps the underlying driver of cumulative inflammation and immune system activation," the study authors suggested.

Investigator affiliations: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL; Department of Medicine, Division of Infectious Diseases, and Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD; Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, WA; Department of Medicine, Division of Infectious Diseases, Johns Hopkins University, Baltimore, MD; Department of Medicine, Division of Infectious Diseases, University of California at San Francisco, San Francisco, CA.

10/4/11

Reference

MJ Mugavero, S Napravnik, SR Cole, et al (Centers for AIDS Research Network of Integrated Clinical Systems Cohort Study). Viremia Copy-Years Predicts Mortality Among Treatment-Naive Human Immunodeficiency Virus-Infected Patients Initiating Antiretroviral Therapy. Clinical Infectious Diseases (abstract). September 2, 2011 (Epub ahead of print).