Starting antiretroviral therapy (ART) soon
after HIV diagnosis led to better outcomes than delayed treatment in all
population sub-groups in the START trial, researchers reported at the 21st International AIDS Conference (AIDS 2016) last week in Durban, South Africa. But some people saw greater risk
reductions, including those over age 50, those with a lower CD4:CD8 ratio and higher
viral load, and those with cardiovascular risk factors.
has accumulated in recent years showing that starting HIV treatment promptly,
rather than waiting for the CD4 T-cell count to fall below a certain threshold,
is associated with reduced disease progression and death. Some of the most
definitive evidence comes from the large START trial, which randomly assigned
people with high CD4 counts to either immediate or deferred therapy.
At last year's International AIDS Society (IAS) Conference
and in the 27 August, 2015, edition of the New
England Journal of Medicine, START investigators
reported that people who initiated treatment immediately
after diagnosis had a significantly lower risk of illness and death than those
who waited until their CD4 count fell below 350 cells/mm3.
At AIDS 2016 Jean-Michel Molina of the University of Paris Diderot presented further findings from
the trial looking at benefits of early treatment in different subgroups based
on demographics, disease status and other risk factors.
START enrolled 4685 previously
untreated HIV-positive adults with CD4 counts above 500 cells/mm3;
the median was about 650, but 11% had more than 900. Nearly three-quarters were
men and the average age was 36 years. Participants came from 35 countries,
including about half from low- and middle-income countries; about 45% were
white, 30% were black, 14% were Hispanic/Latino and 8% were Asian. Median
pre-treatment viral load was approximately 12,800 copies/ml, though 10% had
over 100,000 copies/ml. About 6% had hepatitis B or C co-infection, 2% had high
Framingham cardiovascular risk and nearly a third were smokers.
investigators looked at a combined primary endpoint of serious AIDS events, serious
non-AIDS events or death in pre-specified
population subgroups (except for the CD4:CD8 ratio analysis, which was added
later). They calculated event rates per 100 person-years (PY), absolute risk reduction
(ARR) associated with immediate treatment and the number of people who needed
to start immediate ART in a year to prevent a single event (number needed to
treat, or NNT).
Overall, there were 42 of these events (0.60 per 100
PY) among people randomised to immediate treatment compared to 96 events (1.38
per 100 PY) in the deferred therapy group – a hazard ratio of 0.43, or 57%
lower risk. Absolute risk reduction worked out to be 0.78 per 100 PY and the
number needed to treat was 128.
Looking at demographic subgroups, all groups showed a
relative risk reduction, or proportional change in risk with immediate ART.
Hazard ratios were generally similar, ranging from 0.18 to 0.85, indicating that
everyone benefitted from early treatment. But absolute risk reduction,
considering actual numbers of events, revealed greater differences across
Broken down by age, absolute risk reduction ranged
from 0.49 for those under 30 years, to 0.66 for those age 30-49, to 2.24 for
those age 50 and older. While 206 people under 30 and 151 people age 30 to 49 would
need to be treated to prevent one event, this fell to just 45 for the over-50s – a statistically significant difference (p = 0.01).
Men and women had an absolute risk reduction of 0.74
and 0.93, respectively, and a number needed to treat of 136 and 108,
respectively – not a significant difference (p = 0.63). Risk reduction was also
statistically similar for racial/ethnic groups (ARR 0.70 for black people and 0.92
for white people; NTT 142 and 109, respectively, p = 0.69) and for high-income and
low/middle-income countries (ARR 0.86 vs 0.69; NTT 116 vs 144, p = 0.62).
Analysing by baseline disease status, people with a
CD4 count < 600 cells/mm3 had an absolute risk reduction of 1.10
compared to 0.68 for those with 600-800 and 0.51 for those with > 800.
Numbers needed to treat were 91, 147 and 196, respectively, which was not a
significant difference (p = 0.41). Categorising by CD4:CD8 ratio, however, did
show a highly significant difference: absolute risk reduction was 1.67 for
those with a ratio < 0.5, 0.47 for those with 0.5-0.8 and .040 for those with
> 0.8 (NTT 60, 214 and 248, respectively, p = 0.005).
Looking at baseline viral load, absolute risk
reduction was just 0.10 for those with < 3000 copies/ml, rising to 0.82 for
those with 3000-50,000 copies/ml and 1.48 for those with > 50,000 copies/ml.
Numbers needed to treat were 992, 122 and 67, respectively – the largest
numerical difference, but just short of statistical significance (p = 0.06).
Finally, people with a low Framingham 10-year risk of
heart disease had an absolute risk reduction of 0.36 compared to 0.90 for those
with medium risk and 1.45 for those with high risk. Numbers needed to treat
were 276, 111 and 69, which again did not reach the threshold for significance
(p = 0.13).
"In asymptomatic ART-naive adults with >500
CD4+ cells/mm3, immediate ART was superior to deferred ART across
all sub-groups with similar relative risk reduction," the researchers
concluded, noting that higher absolute risk reduction and lower NNT were found for
participants older than 50 years, with HIV
RNA levels > 50,000 copies/ml, with CD4:CD8 ratios < 0.5 and with Framingham 10-year risk score > 10%.
The investigators did not analyse
subgroups that had fewer than ten events in both study arms combined, but nevertheless
cautioned that "NNT estimates can be unstable when event rates
are small, and need to be interpreted with caution."
Based on these findings, they suggested that people in
the groups that saw greater absolute risk reductions "might be prioritised
for immediate access to ART" in settings where universal prompt treatment
for everyone diagnosed with HIV is not yet feasible.
They emphasised that immediate treatment also reduces HIV
transmission risk, which should be considered along with the number needed to
treat when assessing the cost effectiveness of ART.
Prof Molina said that these results are from
univariate analyses and the team is currently working on a multivariate
analysis to shed light on how these factors interact with each other. They hope
to use this data to develop a risk scoring system.