Starting HIV treatment at high CD4 counts

protects against both AIDS and non-AIDS

events: overall and in subgroup analyses of
START study
1 August 2015. Related: Antiretrovirals, Conference reports, Treatment strategies, IAS 8
Vancouver 2015.
Simon Collins, HIV i-Base
The international START study produced headline news at IAS 2015 that
confirms benefits from starting antiretroviral treatment (ART) at CD4 counts
above 500 cells/mm3. The study also reported no upper CD4 threshold that was
protective against AIDS-related events, even though the overall absolute risk
of events in START was low.

Professor Jens Lundgren presenting ground-breaking results from the START study, with other key
members of the study team, Abdel Babiker and Jim Neaton at lower right.

The START study is notable for reporting results 18 months ahead of schedule, following
a recommendation by the studies independent Data and Safety Monitoring Board (DSMB)
in May that participants in the arm deferring ART until their CD4 count reached 350
cells/mm3 should be offered immediate treatment, and that follow-up should continue as
planned for both arms.
The results were presented by Professor Jens Lundgren from University of Copenhagen
on behalf of the START study team in two sessions at the conference: an opening plenary
on the first day and the International AIDS Society members meeting later in the
programme. [1, 2] The study was also simultaneously published online in the New
England Journal of Medicine. [3]
This HTB report combines results from both IAS 2015 and NEJM paper.

Although preliminary findings were released on 27 May 2015 based on the dataset used
for the DSMB decision, the expanded results cover three key areas:

The additional endpoints in the final dataset modifies the primary endpoint results
by finding that the reduction in non-AIDS events now reaches significance in favouring
early ART. Back in May, this endpoint fell short of significance.

New details about the AIDS and non-AIDS events seen in each arm and still finding
that AIDS events drove the primary results and occurred at high CD4 counts.

In subgroup analyses, early ART was consistently protective for all key baseline and
demographic subgroups. It is important to stress that benefits from the study were not
just for people with the highest risks.

Methods and baseline characteristics

From December 2009 to December 2013, START randomised 4685 HIV positive
treatment-naive adults with CD4 counts >500 cells/mm3 to either an immediate (IMM) or
deferred (DEF) ART, with the deferred group waiteing until their CD4 count reached 350
cells/mm3.
The combined primary endpoint included AIDS related and non-AIDS related
complications including grade 4 events and deaths from any cause.
The study included 215 sites in 35 countries, equally divided between high and
low/middle income countries. Baseline demographics have already been widely reported
and published online [4, 5] and included approximately 27% women, 55% MSM, with a
median age 36 years (IQR 29 to 44). Median CD4 and viral load were 651 cells/mm3 (IQR
584 to 765) and 12,700 copies/mL (IQR 3,000 to 43,000), respectively, with no significant
differences between groups. At study entry, median time since HIV diagnosis was 1.0
years (IQR: 0.4 to 3.1).

Primary and key secondary endpoint results

Mean follow-up was 3.0 years (median 2.8; IQR 2.1 to 3.9) with 23% having greater than
4 years follow up. Endpoint results were available for 96% and 95% of the IMM and DEF
groups respectively.
By 26 May 2015, 98% vs 48% of the IMM vs DEF participants had started ART (at median
CD4 count of 651 vs 408 cells/mm3 respectively). Although ART in the study was
provided free from a central repository, and included the choice of all or nearly all
approved drugs, the majority of patients in both arms used tenofovir/FTC as background
NRTIs (approximately 90%). Efavirenz was the most widely used third drug, by 73% and
51% of the IMM vs DEF arms respectively, with atazanavir/r, darunavir/r, rilpivirine and
raltegravir making up the majority of other combinations. The study reported high rates
of viral suppression with 98% vs 97% of those on treatment having <200 copies/mL at
month 12.
The final dataset included a total of 140 primary endpoint events: 42 (1.8%) in the IMM
arm vs 96 (4.1%) in the DEF arm, equivalent to rates of 0.60 vs 1.38 per 100 patient
years, respectively. The hazard ratio (HR) for the composite primary endpoint was 0.43
(95% CI: 0.30 to 0.62), significantly in favour of the IMM group, p<0.001. Hazard ratios

for other key secondary endpoints also significantly favoured the IMM group: 0.28
(95%CI: 0.15 to 0.50) for serious AIDS-related events (p<0.001) and 0.61 (95%CI: 0.38 to
0.97, p=0.04) for serious non-AIDS-related. There was no significant difference between
groups for all cause mortality: HR 0.58 (95%CI: 0.28-1.17, p=0.13). See Table 1.
IMM (N =
2326)

DEF (N =
2359)

HR (95% CI)

P
value

no. rate/100 P no. rate/100 P

Y
Y
Composite
primary endpoint

42

0.60

96 1.38

0.43 (0.30 to
0.62)

<0.001

<0.001

Secondary end points

Serious AIDS
events

14

0.20

50 0.72

0.28 (0.15 to
0.50)

Serious non-AIDS
events

29

0.42

47 0.67

0.61 (0.38 to
0.97)

0.04

Death from any

cause

12

0.17

21 0.30

0.58 (0.28 to
1.17)

0.13
NS

Table 1: Hazard ratio (HR) of primary and key secondary

endpoints
Key: IMM=immediate arm. DEF=deferred arm, HR=Hazard Ratio, NS=Non Significant.

Clinical endpoints
An unexpected outcome in START is the degree to which AIDS events were more
common at high CD4 counts than non-AIDS events. Throughout the study, the greatest
impact of early ART was expected to be reduced inflammation-related events. Also,
consistent with the planned study design, only 4% of follow-up time in the deferred arm
occurred at a CD4 count <350 cells/mm3 and accounted for only 5 primary events.
The most common events were cardiovascular disease (29% vs 15%), non-AIDS cancers
(21% vs 19%) and tuberculosis (14% vs 20%) in the IMM vs DEF groups respectively.
Endpoints that were significantly reduced in the IMM group included TB (HR 0.29; 95%CI:
0.12 to 0.73), p=0.008) and Kaposis Sarcoma (HR 0.09; 95%CI: (0.01 to 0.71, p=0.02)
but not malignant lymphoma (p=0.07), non-AIDS cancers (p=0.09), cardiovascular
disease (p=0.65), Grade 4 events (p=0.97), unscheduled hospitalisation (p=0.28) and
combined Grade 4 event, unscheduled hospitalisation, or death from any cause
(p=0.25). See Table 2.
IMM (N =
2326)

DEF (N =
2359)

no.

rate/100 PY no.

rate/100 PY

0.09

0.28

Tuberculosis
20

HR (95% CI)

0.29 (0.12 to
0.73)

P
value

0.008

Kaposis
sarcoma

0.01

11

0.16

0.09 (0.01 to
0.71)

0.02

Malignant
lymphoma

0.04

10

0.14

0.30 (0.08 to
1.10)

0.07

Non-AIDS
cancers

0.13

18

0.26

0.50 (0.22 to
1.11)

0.09

Cardiovascular
disease

12

0.17

14

0.20

0.84 (0.39 to
1.81)

0.65

73

1.06

73

1.05

1.01 (0.73 to
1.39)

0.97

Grade 4 events
Unscheduled
hospitalisation

262 4.02

287 4.40

0.91 (0.77 to
1.08)

0.28

Grade 4 event,
unscheduled
hospitalisation,
or death from
any cause

283 4.36

311 4.78

0.91 (0.77 to
1.07)

0.25

Table 2: Other important clinical secondary endpoints

This category excludes hospitalizations for AIDS-related illnesses.

Clinical events by geographical region

Earlier treatment had better outcomes in both high and low/middle income countries,
although there were differences in the type of events by geographical region. Most of the
TB cases (16/20) were in Africa and most of the cancers (22/27) and cardiovascular
events (19/26) occurred in Australia, Europe, Israel and the US.

Subgroup analysis consistently support earlier treatment

Another unexpected outcome from START was the consistency for the primary endpoint
results in sub-group analysis for baseline demographics and other risk factors of serious
events, all favouring the early treatment arm.
The expectation that events would only occur in the groups at highest risk and that
lowest risk groups would be protected from events was not supported by the results.
This included analyses by age, sex, race, geographic regions, smoking status,
cardiovascular risk or baseline CD4 and viral load. Even when 95%CI for the HR crossed
1.0 for several parameters (highest CD4 and CHD risk and lowest VL), none of the pvalues for the interaction approached significance. See Table 3.
Table 3: Hazard rates (HR) for primary end point by subgroup
HR in favour of early ART p for
interaction
Age

0.98

<35

0.47

>35

0.42

Sex

0.38

Male

0.47

Female

0.31

Race

0.65

Black *

0.57

White

0.40

Other

0.37

Region

0.55

High income

0.39

Low/middle income

0.48

Baseline CD4

0.71

< 600

0.28

600-800

0.50

> 800 *

0.56

Baseline viral load

0.25

< 5,000 *

0.66

5,000-30,000

0.38

>30,000

0.37

Smoker

0.93

Yes

0.43

No

0.44

10 year CHD Framingham

risk

0.56

<0.8 *

0.46

0.8 to 3.6

0.39

> 3.6

0.50

* Although the individual 95% CI crossed 1.0 for these categories the p-value for trend
for the subgroup was not statistically significant.
In conclusion, START results support the importance of providing ART for all HIV positive
people.

They reinforce the need for further research to understand the pathogenesis of HIV in
early infection and the urgency of achieving funding to ensure universal ART becomes a
global reality.
Simon Collins is a member of the Community Advisory Board (CAB) for the START study.
COMMENT
START has produced a dataset that defines level of risk for not using ART,
irrespective of any individual decision to start treatment. The level of
confidence for doctors recommending early ART will now increase, even if the
scale up issues for universal treatment when global coverage has not yet met
this based on CD4 thresholds of 500 or even 350 cells/mm 3.
Earlier treatment was already recommended in guidelines due to the impact
that ART has on dramatically reducing the risk of onward transmission.
However, START demonstrates the key missing evidence that this approach
also produces clinical benefits for the person taking treatment.
These results are expected to change treatment guidelines globally. UK BHIVA
guidelines have removed CD4 threshold as a criteria for starting ART in the
2015 draft. [6]
At IAS 2015, WHO announced that the updated 2015 guidelines will also
recommend treatment for all HIV positive people. [7, 8]
Follow up for all participants continues until at least the end of 2016 but the
unique nature of this group would also support a further extension.
References:
Unless stated otherwise, references are to the Programme and Abstracts of the 8th IAS
Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015), 19 22 July
2015, Vancouver.
http://pag.ias2015.org
1.
Lundgren J et al, The START study: design, conduct and main results. The Strategic
Timing of AntiRetroviral Treatment (START) study: results and their implications. IAS
2015, Session MOSY03. Webcast and panel discussion after the presentation:
2.
3.
4.
5.
6.
7.

IAS members meeting. IAS 2015, TUSS02. 14.00-15.30. Room 118-120.

Lundgren J et al. Initiation of antiretroviral therapy in early asymptomatic infection.
NEJM (20 July 2015). DOI: 10.1056/NEJMoa1506816.
http://www.nejm.org/doi/full/10.1056/NEJMoa1506816
Annual DSMB open reports 2009 2015.
https://insight.ccbr.umn.edu/start/index.php?
HIV Medicine supplement. The START Trial Characteristics at Study Entry. HIV
Medicine Special Issue: April 2015; 16(S1):1-146.
http://onlinelibrary.wiley.com/doi/10.1111/hiv.2015.16.issue-s1/issuetoc
British HIV Association. Treatment of HIV-1 positive adults with antiretroviral
therapy. DRAFT guidelines for comment. (July 2015).
http://www.bhiva.org
Hirnschall G. WHO Global HIV Guidelines: How innovations in policy and
implementation can pave the way to achieving 90-90-90. UN 90-90-90 Target
workshop: lessons from the field.18 July 2015. Vancouver.

http://www.treatmentaspreventionworkshop.org
http://i-base.info/htb/28597
8.
Hirnschall G. Panel discussion following START presentation. IAS 2015, Session
MOSY03.

i-Base Q&A on the START study results

27 May 2015. Related: News.

What is the START study?

The START study is a large international HIV study.
It looks at the risks and benefit of early HIV treatment.
Early is defined as having a CD4 count above 500. Results are compared to a later group that
waited until the CD4 count was 350.
People were randomised to one of these two groups, so no-one was able to choose which group
they joined. This study design makes the results more reliable and strong.
START stands for Strategic Timining of AntiRetroviral Treatment. It is one of the largest ongoing
HIV studies.
What is the news about START?
On 27 May 2015, early results showed that the early treatment group was doing better.
The details were given in a press release from the US National Institute of Health, who are a
major funder of the study.
One of the surprises is that even at very high CD4 counts, treatment reduces the risk of HIV
related illnesses.
What were the study outcomes?
START looked at the risk of serious medical events. These events were looked at separately
depending on whether they were related to HIV.

AIDS events included a list of illnesses that were more common before we had effective
treatment. These are all proven to have a clear link to HIV.

Non-AIDS events included serious illnesses that also are common in people who do not
have HIV. They may be related to HIV, but the link is not so clear. These include heart disease,
liver disease, kidney disease and some non-AIDS cancers.
Early treatment was expected to have fewer serious events. Because everyone had a high CD4
count, early treatment was expected to reduce on non-AIDS events the most.
Why are the results so early?
Large studies often have a small group of independent experts called a DSMB. This stands for
Data and Safety Monitoring Board. Unlike everyone else working on the study, this group can
follow the ongoing results. They are responsible for overall safety in the study,
On 13 May 2015, the DSMB saw that early treatment was now significantly better. The DSMB
recommended that the study be changed. Instead of continuing with both groups, all participants
can now change to early treatment.
This was also a surprise because START results were not expected until 2017. So, the research
question has been answered at least 18 months early. This was after an average of 3 years
follow-up rather the planned 4.5 years.
Does this mean that the START study will now close?
No. The study will continue to monitor and treat everyone until at least the end of 2016.
This follow-up will provide important information from both groups.
How definite are the results?
The results are very clear.
Approximately half as many serious events (53% less) occurred in the group using early
treatment.
When planning the study the research team thought that this reduction would only be about one
third less (36%).
What happens to people in START?

People already on treatment will continue with monitoring and treatment.

People in START who are not yet on treatment will now have the chance to start treatment.
In many countries, this would not be possible if they were not in the study.
Clinics will be contacting people in the study over the next few weeks to talk about the results.
What if people want to start early treatment who are not in the study?
The START results are likely to make it easier to start treatment at higher CD4 counts.

Whether you can do this will depend on where you are treated. It will depend on the guidelines in
your country.
Although guidelines sometimes take time to respond to new results, this news is likely to change
guidelines in most countries.
As with all treatment questions, this is something to talk to your doctor about.
Who was in the study?
The study enrolled 4685 people from 35 countries.

33% were in Europe.

5% in South America or Mexico.

21% in Africa.

11% in the US.

8% in Asia.

2% in Australia.
Age ranged from 18-81, with an average age of 36 (and half were aged between 29 and 41).
More than half were gay men and more than a quarter were women.
Half the participants joined the study within a year of their HIV diagnosis.
Everyone had a CD4 count above 500 and 20% had a CD4 count above 800.
The number of other medical complications in people joining the study is important, given that
this is generally a young group with early HIV infection.

Almost one-third were current smokers.

Half had at least one important risk for heart disease.

Almost 1 in 5 either had high blood pressure or were being treated for this.

About 1 in 12 either had high blood lipids or were on lipid lowering drugs.

Just over 3% had diabetes, were using diabetes treatment or had high fasting glucose.

Just under 3% had hepatitis B or and just under 4% had hepatitis C.

Other important health issues included about 150 (3%) people with alcohol or substance use
issues and 270 people (6%) had a psychiatric diagnosis (including depression, bipolar and other
conditions).
How many serious complications occurred?

The decision to change the study was based on 127 serious events: 41 in the early treatment
group and 86 in the deferred treatment group. This was much lower than expected.
In 2013, the researchers worked thought that 213 events would be needed to see a clear
difference between the groups.
It is very good that the study question was answered with fewer events.
What were the number of events in each group?
Tables 1a and 1b below give the results based on the analysis in March 2015. They show the
different results for the two groups: early vs late. They show the results for the three different
ways that serious events were categorised.
It also reports the results in three different ways.
1.

The actual number of events. For example, by category 1 there were 41 events in the
early treatment group compared to 86 events in the late treatment group. (Table 1a).

2.

The event rate in each group per 100 patient years. For category 1, the rates were 0.6
compared to 1.25 per 100 patient years of follow up (PYFU). (Table 1b).

3.

The difference between the two rates is then calculated so that the overall reduced risk
from earlier treatment can be given as a percentage. For category 1, the 0.47 when
subtracted from 100 shows that early treatment reduced the risk by 53%. The range in
brackets, relates to the researchers being 95% confident that the actual percentage is
somewhere between 32% and 68%. It is a way of allowing for the fact that some results
happen by chance. (Table 1b).

Table 1a. Number of primary endpoints in each arm (15 May 2015)
Number of events
Early arm (A)

Later arm (B)

Category 1:AIDS, serious non-AIDS,

or death (primary).

41

86

Category 2:AIDS or AIDS death.

14

46

Category 3:Serious non-AIDS or

non-AIDS death.

28

41

Table 1b. Relative rates of primary endpoints in each arm (15 May 2015)
Rate per 100 PY
Hazard Ratio
Early arm (A)

Late arm (B)

Arm A/B (95% CI)

Category 1:AIDS,
serious non-AIDS, or
death (primary).

0.60

1.25

0.47 (0.32 to 0.68)

Category 2:AIDS or
AIDS death.

0.20

0.66

0.30 (0.17 to 0.55)

Category 3:Serious
non-AIDS or non-AIDS
death.

0.41

0.59

0.67 (0.42 to 1.09)

NS **

* PY = patient years, ** NS = not statistically significant

What were the main illnesses reported?
There are so far only some limited details.
Overall, 127 complications only occurred in both groups. This included 41 in the early group and
86 in the late group.
What is important is these serious events occurred about twice as often in the group not on
treatment. The result was similar when looking at all serious events whether or not they were
generally related to HIV.
Many of these complications were serious but treatable. Non-fatal AIDS-related complications
included TB and cancer. Non-fatal non-AIDS complications included cardiovascular (heart, stroke)
and other cancers. Both the AIDS-related and non-AIDS related events occurred less often in the
early treatment group.
Non-AIDS related complications were a major focus for the study. These were defined as heart
disease complications, liver or kidney complications or non-AIDS cancers.
Non-AIDS complications occurred less than expected.
Were the results the same in different countries?
START includes sites in many different countries. There are 2530 participants in low/middle
income countries and 2,155 people in high income countries.
The benefits of earlier treatment were seen in both settings.
Were the results different for some groups of people?
More detailed analyses will look at whether the results are results to other factors including age,
race, sex, HIV history etc.
Following thousands of people for more than three years has created a huge database.
This will allow many other questions to be asked about different risks.

When will more detailed results be available?

Only the main summary results were included in the press statement. This is because the
detailed results are still being analysed.
The next results are likely to be presented at the International AIDS Conference being held in
Vancouver in July 2015.
This conference might also include early results from some of the sub-studies.
Why are the results so important?
Up until now, very large database studies had not been able to find additional benefits of starting
treatment at high CD4 counts.
Because START is a randomised study, this make the findings unlikely to just be by
chance. Because it is such a large study, the results are also very significant.
The new results will affect treatment guidelines in rich and poor countries alike. They are likely to
influence global guidelines from the World Health Organization (WHO).
The results may even cause stock prices to rise for a while for the drug manufacturers.
More importantly, the results will make treatment easier for people to access across the world.
Does this mean that drug companies are behind the results?
No. START was led by the large team of independent researchers in the INSIGHT network.
Main funders were public health institutions.
Drug manufacturers supported the study by donating their medicines. This was a tremendous
help, but the companies did not design and run the study and they had no influence on the
results.
Even within the study, participants and their doctors decided which treatments to use.
Some people say early treatment was always going to be better?
In designing the study, the researchers thought that early treatment would have advantages.
But START is an essential study for providing good quality evidence rather than opinion.
This was always a central part of the study, irrespective of the final results.
This huge study provided excellent health care for many years, often in settings where treatment
would not be available at higher CD4 counts.
In providing the highest quality evidence, START will have one of the biggest influences globally
in changing guidelines to make treatment available for everyone.

It took a brave and determined research team to set up and run the START study. It was also
dependent on thousands of HIV positive people supporting the research in order to benefit the
wider community.
It is significant that the study questions have been answered earlier than expected, and involved
fewer people having to experience serious complications.
Why was it important to get this evidence?
Getting good evidence is a key success in START. Until now, many people had hoped and guessed
that early treatment might be better. The evidence for this though was not very good. Some
studies found benefits and other found little difference.
Although we rely on our doctors for information, often there might not be good quality evidence
even for advice in treatment guidelines. Your doctor should really explain when the lack of
evidence makes it difficult to know which option is best.
When rating evidence, randomised studies score highest, database studies score mid-way and
expert opinion is rated last.
START is a randomised study. Previously, database studies disagreed on whether early treatment
was good, so the recommendations to start earlier was mainly based on opinion.
Who ran the START study?
Four international research centers coordinated the work of the 215 sites in START.

The Medical Research Council (MRC) Clinical Trials Unit at University College London.

The Copenhagen HIV Programme at the Rigshospitalet, University of Copenhagen in

Denmark.

The Kirby Institute at the University of New South Wales in Sydney, Australia.
The Veterans Affairs Medical Center affiliated with George Washington University in
Washington, DC.
The University of Minnesota served as the statistical and data management center and trial
sponsor.
Who funded the START study?
The main funder was the US National Institute of Allergy and Infectious Diseases (NIAID).
Additional funding for the START trial was also provided by other US organisations:

National Cancer Institute.

National Heart, Lung and Blood Institute.

National Institute of Mental Health.

National Institute of Neurological Disorders and Stroke.

Eunice Kennedy Shriver National Institute of Child Health and Human Development.

NIH Clinical Center.

National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Funding was also provided by the many national health agencies:

Agence Nationale de Recherches sur le SIDA et les Hpatites Virales (ANRS) in France.

Bundesministerium fr Bildung und Forschung in Germany.

European AIDS Treatment Network.

Government organizations based in Australia, Denmark, and the United Kingdom.

Further information