The START Data Safety and Monitoring Board (DSMB)
stopped the randomised portion of the trial ahead of schedule in May 2015 when
it determined that there was enough evidence to show a significant benefit of
immediate treatment. All remaining untreated participants were offered the
option to start therapy. They will continue to be followed for long-term
outcomes, and a set of sub-studies is looking at specific manifestations
including neurological function, artery function, bone density and liver
"The HIV research community needs to have solid evidence for making
global recommendations on treatment..now we have evidence that aligns
individual benefit and prevention benefit without harm." Jens Lundgren
At the time the study was halted, participants had
been followed for an average of three years, accruing a total of 14,060
person-years of follow-up time. Most (94%) in the immediate arm were on still
on treatment and 28% in the deferred arm had started. Retention in START was ‘excellent’ according the researchers, and
adherence was good once treatment was initiated.
People in the deferred group started treatment in a
median of three years – less than the predicted four years. Nearly a third
started ART with a CD4 count of 250-350 cells/mm3, but 8% did not do
so until they fell below 250 cells/mm3. The rest did so at higher
levels than the trial's treatment-initiation threshold, including 8% who
started with more than 750 cells/mm3.
Over the course of follow-up, people in the deferred therapy group had
CD4 counts that were 194 cells/mm3 lower, on average, than those who
started treatment immediately.
Looking first at the combined primary
endpoint of serious AIDS-related events, serious non-AIDS events or death, there were 42 of
these events (1.8%, or 0.60 per 100 person-years [PY]) among people randomised
to immediate treatment, compared to 96 events (4.1%; 1.38 per 100 PY) in the
deferred treatment group, for a 57% lower risk (hazard ratio [HR] 0.43; 95% CI
The researchers also analysed the endpoint components
separately. Serious AIDS events included opportunistic infections and
AIDS-defining cancers (cervical cancer, Kaposi’s
sarcoma [KS] and certain types of lymphoma), while serious non-AIDS
events included cardiovascular disease,
end-stage kidney disease, decompensated liver disease and non-AIDS cancers (all
Serious AIDS events
There were 14 serious AIDS events (0.20 per 100 PY) in
the immediate treatment group and 50 events (0.72 per 100 PY) in the deferred
group, for a 72% risk reduction (HR 0.28; 95% CI 0.15-0.50, p<0.001). The
difference in rates of AIDS events became apparent around 24 months and
then continued to diverge, Lundgren reported.
Looking at the types of events, TB was the most common
event in both the immediate and deferred treatment arms (6 vs 20 cases,
respectively). Opportunistic conditions including lymphoma (3 vs 10 cases), KS
(1 vs 11 cases) and Pneumocystis
pneumonia (1 vs 5 cases) occurred much more often in the delayed treatment
group. This was true even though most people who delayed treatment spent most
of their time in the study with a CD4 count well above the traditional 'danger
zone' below 200 or 350 cells/mm3.
Serious non-AIDS events
Turning to serious non-AIDS events – including deaths
due to other non-AIDS causes – there were 29 events (0.42 per 100 PY) in the
immediate group and 47 events (0.67 per 100 PY) in the deferred group, for a
39% risk reduction (HR 0.61; 95% CI 0.38-0.97, p = 0.04). Here, the curves for
the occurrence of these events "did not split as quickly or markedly"
as for AIDS events, Lundgren said.
The most frequent non-AIDS events were non-AIDS
cancers (9 in the immediate vs 18 in the deferred group) and cardiovascular
disease (12 vs 14 cases, respectively). Serious liver or kidney disease were
rare in both arms (1 case in the immediate arm vs 2 in the deferred arm).
Looking at overall deaths, there were 12 (0.17 per 100
PY) in the immediate group and 21 (0.30 per 100 PY) in the deferred group.
However, this 42% reduction in risk was not statistically significant (HR 0.58;
95% CI 0.28-1.17, p = 0.13).
In both arms, the leading cause of death was
accidents, violence or suicide (four in the immediate and six in the deferred
arm). There was one death due to active HIV/AIDS in the immediate group
compared with four in the deferred group. But other causes of death were
scattered between the two groups with very small numbers and "no clear
pattern", according to Lundgren.
Cancer and cardiovascular disease
Focusing on cancer, there were 14 cases of any type
(0.20 per 100 PY) in the immediate treatment group and 39 cases (0.56 per 100
PY) in the deferred group, a 64% risk reduction that was significant (HR 0.36;
95% CI 0.19-0.6, p = 0.001). This difference became apparent after 12-16 months
and from then on there was a clear separation, Lundgren said.
AIDS-defining malignancies KS (1 vs 11 cases) and
lymphoma (3 vs 10 cases) were much more frequent in the deferred treatment
group. But for other cancer types the numbers were small and there were no
notable differences. This was true for both cancers caused by infectious agents
– such as human papillomavirus (HPV) for
anal and cervical cancer – and for those with no known infectious cause.
Serious cardiovascular events occurred with similar
frequency in the immediate and deferred groups (12 vs 14 cases). There were three
cardiovascular deaths in the early ART arm compared with one in the delayed
group, but these numbers are too small to draw conclusions. At any rate,
Lundgren said, there is no evidence from this study to demonstrate any benefits
of early treatment for cardiovascular disease, but this also cannot be ruled
Finally, the researchers looked at adverse events in
the study, assessed in both ART-treated and untreated participants. Separately,
rates of serious (grade 4) adverse events, unscheduled hospitalisations and
deaths from any cause did not differ significantly in the immediate and
deferred ART arms. However, when these events were combined there was a
significant advantage in the early treatment group (HR 0.82; p = 0.01). The
only specific adverse event with a notable difference was bacterial infections,
which were significantly more common in the delayed treatment arm.
Despite the long-standing concerns about early ART
leading to added side-effects, Lundgren said there was "no apparent
increased toxicity", seen in this study.