Cumulative viral load: an important measure of risk of death in patients with HIV

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Cumulative viral load - the total amount of viral replication measured over a long period - is associated with the risk of death for patients with HIV, US research published in the online edition of Clinical Infectious Diseases shows.

The investigators calculated cumulative viral load, or “viremia copy years” for 2027 patients.

They explain: “10,000 copy-years of viremia is equal to having a VL [viral load] of 10,000 copies/ml for one year or a VL of 1000 copies/ml for ten years.”

Glossary

viraemia

The presence of virus in the blood.

 

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

immune system

The body's mechanisms for fighting infections and eradicating dysfunctional cells.

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

After adjusting for potential confounders  - including CD4 cell count -  the investigators found that each log10 increase in viremia copy-years increased the risk of death by 44%.

“These findings substantiate growing recognition that HIV replication may cause or accelerate disease independent of its effect on…CD4 cell depletion,” comment the investigators.

Viral load is one of the key tests used to monitor patients with HIV and is an important research tool.

However, reliance on single, “snap-shot” viral load results fails to measure a patient’s cumulative exposure to viral replication over time.

High levels of HIV replication are known to lower CD4 cell count. But there is also a growing realisation that uncontrolled HIV infection can cause irreparable damage to the immune system and organs. Moreover, the inflammatory effects of HIV replication may also contribute to the development of cardiovascular disease and some other illnesses not normally associated with HIV.

Investigators from the US Centers for AIDS Research Network of Integrated Clinical Systems speculated that there would be a strong relationship between cumulative viral load, or viremia copy-years and the risk of death for patients with HIV.

They therefore monitored patients who started HIV therapy for the first time between 2000 and 2008.

At baseline, median CD4 cell count was 222 cells/mm3 and median viral load was 4.8 log10 copies/ml (63,000 copies/ml).

Patients were followed for a median of 2.7 years and contributed a total of 6579 person-years of follow-up.

Each patient had a median of eight viral load tests, and the total number of viral load measurements was 21,665.

Treatment outcomes were excellent. After 24 weeks, 81% of patients had an undetectable viral load, and during the total period of follow-up 82% of viral load measurements were below the limit of detection.

Over the course of the study, the median viremia copy-years was 5.3 log10 (199,500) copies x years/ml.

A total of 85 patients (4%) died, a mortality rate of 1.3 per 100 person years. The median time to death was two years.

The investigators’ first set of analysis showed that each one log10 viremia copy x years increased the risk of death was 81% (HR = 1.81; 95% CI, 1.51-2.18; p < 0.001). Mortality risk was also associated with viral load after 24 weeks of treatment (p < 0.001) and most recent viral load (p < 0.001).

A statistical model that included the patients’ demographic and clinical details as well as their baseline, 24-week and most recent viral load was then designed.

This showed that each one log10 viremia copy x years increased the risk of death by 44% (HR = 1.44; 95% CI, 1.07-1.94; p = 0.02).

“Viremia copy years, a measure of cumulative plasma HIV RNA exposure…demonstrated a strong association with all-cause mortality in a large sample of HIV-infected patients who started ART,” write the authors.

“We suggest that viremia copy-years play an important and complementary role to cross-sectional VL measures and transform the role of VL in future…research initiatives as well as in clinical care.”

Each ten-year increase in age was associated with a 51% increase in mortality risk (HR = 1.51; 95% CI, 1.18-1.94; p = 0.001). However, each 100 cell/mm3 increase in CD4 cell count significantly reduced the risk of death (p < 0.001).

The investigators believe that cumulative viral exposure is a “surrogate for and perhaps the underlying driver of cumulative inflammation and immune system activation,” leading to an increased risk of inflammation-related diseases for patients with uncontrolled viral load.

Because of the ageing of the HIV-infected population and therefore their increased risk of inflammation-related diseases, the investigators believe that “cumulative measures of HIV burden may take on increased importance in the coming years.”

However, they admit that their study has limitations, highlighting both its cross-sectional design and relatively short follow-up period. Moreover, they did not have sufficient information on causes of death to evaluate the relationship between viremia copy-years with AIDS and non-AIDS-related deaths.

“Future research should evaluate the relationship between viremia copy-years and biomarkers of inflammation and immune system activation longitudinally, as well as the value of this measure in predicting AIDS and non-AIDS clinical events, and in modelling the HIV transmission risk over time.”

References

Mugavero MJ et al. Viremia copy-years predicts mortality among treatment-naïve human immunodeficiency virus-infected patients initiating antiretroviral therapy. Clin Infect Dis, online edition, doi: 10.1093/cid/cir526, 2011 (click here for the free abstract).