HIV Treatment at High CD4 Counts Protects Against Both AIDS and Non-AIDS Events in the START Study: Overall and in Subgroup Analyses

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.
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 international START study produced headline news at IAS 2015 that confirm 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 thought the overall absolute risk of events was low.

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 now finding that the reduction in non-AIDS events now reaches significance in favouring early ART. Back in May, this endpoint fell short of significance.
  • By providing 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.
  • That 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 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 waited until the 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 in online [4, 5] and included approximately 27% women, 55% MSM, and 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 component, 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 includes 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.

Table 1: Hazard Ratio (HR) of Primary and Key Secondary Endpoints
 IMM (N = 2326)DEF (N = 2359)HR
(95% CI)
P value
no.rate/100 PYno.rate/100 PY
Composite primary endpoint420.60961.380.43
(0.30 to 0.62)
<0.001
Secondary end points
Serious AIDS events140.20500.720.28
(0.15 to 0.50)
<0.001
Serious non-AIDS events290.42470.670.61
(0.38 to 0.97)
0.04
Death from any cause120.17210.300.58
(0.28 to 1.17)
0.13 NS

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. Throughout the study it was expected that the greatest impact would be to reduce 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 an 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 tuberculosis (HR 0.29; 95%CI: 0.12 to 0.73), p=0.008) and Kaposi's 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.

Table 2: Other Important Clinical Secondary Endpoints
 IMM (N = 2326)DEF (N = 2359)HR (95% CI)P value
no.rate/100 PYno.rate/100 PY
Tuberculosis60.09200.280.29 (0.12 to 0.73)0.008
Kaposi's sarcoma10.01110.160.09 (0.01 to 0.71)0.02
Malignant lymphoma30.04100.140.30 (0.08 to 1.10)0.07
Non-AIDS cancers90.13180.260.50 (0.22 to 1.11)0.09
Cardiovascular disease120.17140.200.84 (0.39 to 1.81)0.65
Grade 4 events731.06731.051.01 (0.73 to 1.39)0.97
Unscheduled hospitalisation §2624.022874.400.91 (0.77 to 1.08)0.28
Grade 4 event, unscheduled hospitalisation, or death from any cause2834.363114.780.91 (0.77 to 1.07)0.25

§ 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 analysis 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 p-values for the interaction approached significance. See Table 3.

Table 3: Hazard Rates (HR) for Primary End Point by Subgroup
 HR in favour of early ARTp for interaction
Age 

0.98

<35
>35
0.47
0.42
 
Sex 0.38
Male
Female
0.47
0.31
 
Race 0.65
Black
White
Other
0.57 *
0.40
0.37
 
Region 0.55
High income
Low/middle income
0.39
0.48
 
Baseline CD4 0.71
<600
600-800
>800
0.28
0.50
0.56 *
 
Baseline viral load 

0.25

<5,000
5,000-30,000
>30,000
0.66 *
0.38
0.37
 
Smoker 0.93
Yes
No
0.43
0.44
 
10 year CHD Framingham risk 0.56
<0.8
0.8 to 3.6
>3.6
0.46 *
0.39
0.50
 

* Individual 95% CI crossed 1.0 for these subgroups p-value for trend remained not statistically significant.

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 hasn't yet met this based on CD4 thresholds of 500 or even 350.

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, with UK BHIVA guidelines already removing CD4 threshold as a criteria for ART and an early announcement at IAS 2015 that WHO will also recommend treatment for all HIV positive people. [6, 7]

Continued follow up for all participants continues until 2017.

Simon Collins is a community representative on the Community Advisory Board (CAB) for the START study.

References

  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.
  2. IAS members meeting.
  3. Lundgren J et al. Initiation of antiretroviral therapy in early asymptomatic infection. NEJM (20 July 2015). DOI: 10.1056/NEJMoa1506816
  4. Annual DSMB open reports 2009 - 2015.
    https://insight.ccbr.umn.edu/start/index.php?
  5. HIV Medicine supplement.
  6. British HIV Association. Treatment of HIV-1 positive adults with antiretroviral therapy. DRAFT guidelines for comment. (July 2015).
  7. 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.