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.”
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.”