HIV therapy that achieves even modest
reductions in viral load can have profound immunological benefits for people with
triple-class treatment failure, European investigators report in the online
edition of the Journal of Infectious
“There is close to a linear inverse relationship between log
viral load and CD4 count,” write the authors. “The…relationship between log
viral load and CD4 count indicates that there are likely CD4 count benefits of
lowering viral load even by modest amounts that do not lead to undetectable
viral load levels.” They believe their findings are especially important “for patients with low CD4 cell counts and few drug options.”
The aim of antiretroviral therapy is an
undetectable viral load. Ongoing HIV replication during treatment can lead to
the emergence of drug resistance, limiting future treatment options and
possibly leading to a poorer prognosis.
There have been considerable improvements
in HIV therapy in recent years, and a number of new classes of antiretrovirals
have been developed. Nevertheless, treatment remains based on the three main
classes of anti-HIV drugs: nucleoside reverse transcriptase inhibitors (NRTIs);
non-nucleoside reverse transcriptase inhibitors (NNRTIs); and ritonavir-boosted
protease inhibitors (PI/r).
A small, but growing, number of people
have experienced the failure of all three of these drug classes. Even with new
therapies, their treatment is challenging. Rather than suppressing viral load, the
object of treatment for people in this situation is often supporting CD4 cell count to
reduce the risk of serious HIV-related illness. Understanding the factors
associated with immune status after triple-class failure is therefore
As a result, investigators from the
European COHERE study examined the records of 2424 people who had experienced
triple-class failure since 1998.
Most of the patients (67%) were men and
their median age was 40 years. The patients had been taking antiretroviral
therapy for a median of four years before triple-class failure was diagnosed.
Median viral load at this time was 4 log10 copies/ml, whereas median
CD4 cell count was 270 cells/mm3.
The investigators’ initial analysis showed
a strong linear association between CD4 cell count and viral load after
treatment failure. CD4 cell count was 48 cells/mm3 lower per 1 log10
increase in viral load.
Only a small minority of people were
treated with newer classes of antiretrovirals such as fusion inhibitors (7%),
integrase inhibitors (9%) and CCR5 inhibitors (1%).
The investigators modelled changes in CD4
cell count two years after the emergence of triple-class failure. The model
assumed that patients had a CD4 cell count of 300 cells/mm3 at this
Their calculations showed that people
with a viral load of 2 log10 copies/ml would have a CD4 cell count
of 386 cells/mm3 at the two-year time point. CD4 cell count fell
steadily with each log10 increase in viral load, meaning that
people with a 6 log10 viral load would have a CD4 cell count of
just 213 cells/mm3.
“We have shown that current virus
concentration in plasma is the single most important predictor of the current
CD4 cell count attained among 2424 people who started ART since 1998 and then
experienced triple-class failure,” comment the authors.
They believe their findings have important
implications for the care of people with limited treatment options. “Any
degree of viral suppression is likely to bring benefits in terms of CD4 count
and hence risk of clinical disease,” the investigators comment. “While in those
with high CD4 count it may be possible to wait until new active drugs are
available, for those with low CD4 count it is important to use the regimen most
likely to achieve maximal viral suppression. We found that the current viral
load is closely linked to the CD4 count, suggesting a rapid benefit of viral
load suppression, so in an individual who is not fully adherent, any increase
in adherence is likely to provide immediate benefits in terms of reduced risk
of clinical disease.”