Strategic Timing of AntiRetroviral Treatment
Phase: PHASE4
Conditions: HIV Infection
Sponsor: University of Minnesota



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TABLE OF CONTENTS 
 
1 SYNOPSIS ........................................................................................................1 
2 BACKGROUND AND RATIONALE .................................................................7 
3 METHODOLOGY ........................................................................................... 11 
3.1 Study Design .................................................................................................. 11 
3.2 Extended Follow-up Objectives .................................................................... 11 
3.2.1 
Primary Objective and Hypotheses ..................................................... 11 
3.2.2 
Secondary Objectives .......................................................................... 12 
3.2.3 
Other Objectives .................................................................................. 13 
3.3 Primary Study Endpoint ................................................................................. 14 
3.4 Statistical Considerations ............................................................................. 14 
3.5 Participant Selection ...................................................................................... 15 
3.6 Study Plan ....................................................................................................... 16 
3.6.1 
Treatment Strategies ........................................................................... 16 
3.6.2 
Concomitant Medications .................................................................... 17 
3.6.3 
Baseline Screening .............................................................................. 17 
3.6.4 
Participant Follow-up ........................................................................... 18 
3.6.5 
Participant Relocation to a New Site ................................................... 21 
3.6.6 
Stored Samples and Future Research ................................................ 21 
4 CLINICAL MANAGEMENT ISSUES ............................................................. 21 
4.1 Antiretroviral Treatment ................................................................................. 21 
4.2 HIV Transmission Counseling ....................................................................... 21 
4.3 Study Withdrawal ........................................................................................... 21 
4.4 Co-enrollment in Other Studies .................................................................... 22 
5 EVALUATION ................................................................................................ 22 
5.1 Data Analysis .................................................................................................. 22 
5.2 Data Monitoring .............................................................................................. 23 
6 PROTECTION OF HUMAN SUBJECTS & OTHER ETHICAL 
CONSIDERATIONS ............................................................................................ 24 

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6.1 Local Review of Protocol and Informed Consent ........................................ 24 
6.2 Ethical Conduct of the Study ........................................................................ 24 
6.3 Informed Consent of Study Participants ...................................................... 24 
6.4 Confidentiality of Study Participants ............................................................ 24 
7 OTHER IMPORTANT DOCUMENTS AND POLICIES ................................. 25 
7.1 Reference Documents.................................................................................... 25 
7.2 Data Collection and Monitoring .................................................................... 25 
7.3 Publications and Presentations .................................................................... 25 
 
APPENDICES 
 
 
A. 
Primary Endpoint Definition 
B. 
References on INSIGHT Website 
C. 
List of Acronyms 
D. 
Sample Informed Consent 
 
REFERENCES 
 

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1 Synopsis 
The START trial was designed to address the following question:  In HIV-1 
(subsequently referred to as HIV) infected asymptomatic participants with a CD4+ 
count greater than 500 cells/mm3, is immediate use of antiretroviral therapy (ART) 
superior to deferral of ART until the CD4+ count declines to 350 cells/mm3 or AIDS 
develops in terms of morbidity and mortality?  In this international randomized trial, 
participants were randomized in a 1:1 allocation ratio to the immediate (early) or 
deferred ART group.  The design is illustrated in the schematic below with the sample 
sizes in each group that were achieved. 
 
START Design Schematic: Original Design 
 
 
 
 
 
On May 15, 2015 the independent Data and Safety Monitoring Board (DSMB) for 
START determined that this question had been addressed. Immediate use of ART 
provided significant benefit over deferred ART for the primary composite endpoint of 
START and its two major components, serious AIDS and serious non-AIDS events over 
an average follow-up of 3 years.  The DSMB recommended offering ART to participants 
in the deferred arm who had not yet started ART.  They also recommended continued 
follow-up of study participants.  
 
START investigators and study participants were informed of these recommendations 
on May 27, 2015 and per the DSMB’s recommendation, participants in the deferred arm 
who had not started treatment were offered ART. 
 
Even though the findings from START unequivocally indicate that immediate ART has 
substantial benefits on major clinical outcomes compared to deferred ART, longer 
follow-up, as recommended by the DSMB, is warranted for several scientific and 
practical reasons.   
 
Early ART Group 
 
Initiate ART immediately 
following randomization 
 
 
N=2,325  
HIV-infected individuals who are ART-naïve with  
CD4+ count > 500 cells/mm3 
Deferred ART Group 
 
Defer ART until the CD4+ count 
declines to < 350 cells/mm3 or 
AIDS develops 
 
N=2,359  

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The general aim of long-term follow-up, formulated as two hypotheses stated below, is 
to determine whether the risk of major morbidity and mortality associated with deferral 
of ART is eliminated once ART is initiated or whether it persists due to the lower CD4+ 
cell count at ART initiation.   
 
This version of the protocol describes the rationale and the plan for continued follow-
up of START participants through 2021.  The major difference between this version of 
the protocol and Version 3.0 is that the data collection plan after 2017 has been 
greatly simplified, and beginning in 2018, as originally planned, antiretroviral treatment 
will be provided through local sources and not through a Central Drug Repository 
(CDR). 
 
Rationale for Extended Follow-up 
Follow-up through 2021 will provide 6 years of additional follow-up (9.5 years total 
from randomization) from January 2016 by which time 81% of participants in the 
deferred arm had initiated ART; by the end of 2016 93% of participants in the deferred 
ART group had initiated ART.  This is a large increase from the 48% of deferred arm 
participants taking ART in May 2015.  
 
Extended follow-up is important for several reasons: 
 
 To determine whether the harm resulting from deferral of ART can be eliminated 
for the primary and key secondary endpoints, overall and for key subgroups. 
 
 The START cohort is unique in many respects: 1) it is demographically and 
geographically diverse; 2) participants had a median CD4+ count of 651 
cells/mm3 at baseline; approximately 25% had counts > 800 cells/mm3; 3) 
approximately one-third of participants had a viral load < 5000 copies/mL at 
entry; and 4) the median time since diagnosis of HIV was one year.  
 
 Although most participants in the deferred arm have now started ART, the 
randomized allocation to immediate or deferred ART treatment led to a median 
difference in CD4+ cell counts of 180 cells/mm3 at the time of ART initiation at 
the end of 2016, substantial differences in exposure to ART (a median of 2.5 
years between ART initiation in the immediate and deferred groups), and 
consequently to large differences in viral load, CD4+ count, and markers of 
inflammation, coagulation, and vascular injury.  These differences, as well as 
differences in other factors, may impact treatment differences in clinical 
outcomes even after ART is initiated for participants in the deferred ART group. 
 
 Treatment for HIV is life-long and the median age of the cohort at study entry 
was 36 years.  The average three years of follow-up accrued so far may be 
insufficient to understand the full benefits of ART. It is important to more fully 
understand those benefits in order to inform calculations of cost-effectiveness of 
approaches for diagnosing people as rapidly as possible after infection. 
 

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 For key clinical outcomes such as cardiovascular disease, cancer and all-cause 
mortality, the number of participants with events were small, and with long-term 
follow-up the effects of immediate ART compared to deferred ART on these 
outcomes will be more precisely estimated. 
 
 The extended follow-up coupled with the experimental design of START allows 
new scientific questions which are clinically relevant to HIV positive participants 
and the people who are providing their care to be addressed in this unique 
cohort. 
 
Based on the initial findings of START, we have formulated two scientific hypotheses 
that will be addressed through follow-up of the study participants through 2021.  These 
hypotheses take advantage of the initial randomization and experimental design of 
START.  Importantly, no other study has the capability of addressing these questions.   
   
Hypothesis 1 (HIV RNA Hypothesis):  As a consequence of nearly all deferred arm 
participants initiating ART by the end of 2015 and the resulting similar HIV RNA levels 
after 2015 for the two treatment groups, the primary event rate in the two treatment 
groups will be similar between 2016 and 2021; the cumulative event rates in the two 
arms at the end of 2021 will remain significantly different from one another, reflecting 
the difference in accrued events when the study was unblinded, but the treatment 
difference will be substantially smaller than at the time of DSMB’s recommendation in 
May 2015.  
 
In terms of the treatment hazard ratio (HR), we hypothesize the true HR will be 1.0 
and the estimated HR for the time period between 2016 and 2021 will not differ 
significantly from 1.0; the average HR for the entire follow-up period from 
randomization through 2021, will be significantly less than 1.0 but much closer to 1.0 
than the HR of 0.43 reported following the DSMB recommendation. 
 
In other words, participants who were randomized to deferring ART until the CD4+ 
count decreased to 350 cells/mm3 have an increased risk of the primary endpoint 
during the deferral period, and this risk is nearly completely eliminated once ART is 
initiated.  
 
Hypothesis 2 (Nadir CD4+ Hypothesis): As a consequence of deferred arm 
participants initiating ART 2.5 years after the immediate ART group, the primary event 
rate for the deferred ART group will remain substantially higher than in the immediate 
ART group between 2016 and 2021; as a consequence, the cumulative event rates in 
the two arms at the end of 2021 will also remain substantially different from one 
another with only a modest movement of the overall average HR towards 1.0 from 
0.43. 
 
In other words, participants who were randomized to deferring ART to 350 cells/mm3 
have an increased risk of the primary endpoint during the deferral period that persists, 
albeit at lower levels, for 6 years after initiating ART.  This increased risk resulting from 

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deferred ART persists because of a number of factors including, the lower CD4+ cell 
count at which ART was initiated, lower CD4+ count levels during extended follow-up, 
increased exposure during the deferral period to activated inflammatory and 
coagulation pathways, and a reduced ability to normalize markers of inflammation, 
coagulation and vascular injury after ART is initiated.  If data are consistent with this 
hypothesis, we will estimate the rate with which the HR moves toward 1.0 over the 6 
years, if at all. 
 
Primary Endpoint of START 
The primary composite endpoint of START is the development of a serious AIDS 
event (“AIDS*”), a serious non-AIDS event (“non-AIDS”), or death from any cause.   
 
This endpoint will remain the primary focus of the extended follow-up planned.   
 
Serious AIDS events (or AIDS*) include most traditional opportunistic conditions but 
exclude non-fatal esophageal candidiasis and chronic Herpes simplex (see Appendix 
A for a complete list of conditions).  Non-fatal esophageal candidiasis and chronic 
Herpes simplex are not counted in the primary endpoint of serious AIDS events 
because they are more common than most other opportunistic events at higher CD4+ 
counts and usually do not cause significant limitations for people in whom they occur. 
 
In this protocol, the term “AIDS” (without an asterisk) denotes all opportunistic 
conditions, including non-fatal esophageal candidiasis and chronic Herpes simplex 
(see Appendix A).   
 
The following serious non-AIDS conditions are the components of the primary 
composite endpoint referred to as serious non-AIDS events, or “non-AIDS”:  
 
Cardiovascular disease (CVD) (myocardial infarction, stroke, coronary 
revascularization); 
 
End-stage renal disease (ESRD) (initiation of dialysis, renal transplantation); 
 
Decompensated liver disease; and  
 
Non-AIDS-defining cancers (excluding basal and squamous cell skin cancers). 
 
START Participants 
Participants enrolled in START were in reasonably good health, and in the clinician's 
opinion, able to adhere to the protocol (i.e., be willing to accept and adhere to the data 
collection schedule and assigned treatment strategy).  
 
Participants had to meet the following inclusion and exclusion criteria to be 
randomized: 
 
Inclusion Criteria 
 
Signed informed consent 

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 
HIV infection documented by a plasma HIV RNA viral load, rapid HIV test or any 
licensed1 ELISA test; and confirmed by another test using a different method 
including but not limited to a rapid HIV test, Western Blot, HIV culture, HIV antigen, 
or HIV pro-viral DNA at any time prior to study entry. 
 
Age ≥ 18 years (≥ 35 years after 4,000 participants were enrolled in July 2013) 
 
Karnofsky performance score ≥ 80 (an indication that the participant can perform 
normal activities) 
 
Perceived life expectancy of at least 6 months 
 
For women of child-bearing potential, willingness to use contraceptives as described 
in the product information of the ART drugs they are prescribed 
 
Two CD4+ cell counts > 500 cells/mm3 at least 2 weeks apart within 60 days before 
randomization 
 
Exclusion Criteria 
 
Any previous use of ART or IL-2 
 
Diagnosis of any clinical AIDS event before randomization (including esophageal 
candidiasis and chronic Herpes simplex infection) 
 
Presence of HIV progression such as oral thrush, unexplained weight loss, or 
unexplained fever at randomization 
 
Cardiovascular event (myocardial infarction, angioplasty, coronary-artery bypass 
grafting, stroke) within 6 months before randomization 
 
Non-AIDS-defining cancer, excluding basal and squamous cell skin cancer, within 6 
months before randomization 
 
Dialysis within 6 months before randomization 
 
Diagnosis of decompensated liver disease before randomization 
 
Current imprisonment, or compulsory detention (involuntary incarceration) for 
treatment of a psychiatric or physical illness 
 
Current pregnancy or breastfeeding (a negative serum or urine pregnancy test is 
required within 14 days before randomization for women of child-bearing potential) 
 
All HIV-positive participants in START are eligible to continue in extended follow-up. 
 
Data Collection Plan for Extended Follow-up 
In January 2016, the START protocol was amended as Version 3.0.  Version 3.0 
described plans to continue follow-up with existing funding through December 2017 and 
to seek funding for longer follow-up through December 2021. Study visits are required 
twice each year in Version 3.0.   ART was being provided through a CDR until the end 
                                            
 
1 The term “licensed” refers to an FDA-approved kit or, for sites located in countries other than the 
United States, a kit that has been certified or licensed by an oversight body within that country.  
Confirmation of the initial test result must use a test method that is different than the one used for the 
initial assessment. 

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of 2017 at which time, as originally planned, sites were required to transition all 
participants to a local ART supply.  
 
This version of the protocol (Version 4.0) describes plans for a much simplified follow-
up data collection plan beginning in 2018.  In person study visits will no longer be 
required. Data collection will occur once each year and focus on major clinical events. 
In addition, after 2017, the START trial no longer includes substudies.   ART is no 
longer provided through the study and the protocol does not specify ART regimens to 
be used.  Since follow-up data are collected retrospectively on an annual basis, serious 
and unexpected adverse reactions attributed to ART will no longer be collected in real 
time and reported to regulatory authorities by the sponsor.   Investigators will be 
reminded of their obligation to report to regulators per their countries’ requirements for 
reporting post-marketing adverse events considered related to ART. The occurrence of 
specific adverse outcomes (see below) will be collected on at least an annual basis as 
part of the trial data.  
 
The major clinical outcomes to be collected have been assessed since the beginning of 
the trial using similar methods, allowing the two treatment strategies to be compared for 
the outcomes below for three calendar periods: 1) from randomization to December 31, 
2015; 2) from January 1, 2016 to December 31, 2021;  and 3) cumulatively from 
randomization through December 2021. 
 
Primary Endpoint  
Time to AIDS*, non-AIDS, or death from any cause (first event) (see Appendix A) 
 
Major Secondary Endpoints  
 
AIDS* or death from AIDS 
 
Non-AIDS or death not attributable to AIDS 
 CVD (myocardial infarction, stroke, coronary revascularization) or death due to CVD 
 Cancer ( AIDS and non-AIDS malignancy, excluding basal and squamous cell skin 
cancers) 
 All-cause mortality 
 Tuberculosis 
 Serious bacterial infections 
 
Other Secondary Outcomes 
 
 
ESRD (initiation of dialysis, renal transplantation) 
 
Decompensated liver disease 
 
Non-AIDS malignancy, including basal and squamous cell skin cancers  
 
AIDS 
 
Unscheduled hospitalizations 

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2 Background and Rationale 
The START trial was designed to address the following question:  In HIV-1 
(subsequently referred to as HIV) infected asymptomatic participants with a CD4+ 
count greater than 500 cells/mm3, is immediate use of antiretroviral therapy (ART) 
superior to deferral of ART until the CD4+ count declines to 350 cells/mm3 or AIDS 
develops in terms of morbidity and mortality?  In this international randomized trial, 
participants were randomized in a 1:1 allocation ratio to the immediate (early) or 
deferred ART group.1  The design is illustrated in the schematic below with the sample 
sizes in each group that were achieved. 
 
START Design Schematic: Original Design 
 
 
 
 
 
On May 15, 2015 the independent Data and Safety Monitoring Board (DSMB) for 
START determined that this question had been addressed. Immediate use of ART 
provided significant benefit over deferred ART for the primary composite endpoint of 
START and its two major components, serious AIDS and serious non-AIDS events over 
an average follow-up of 3 years.   
 
Two months following the recommendation by the DSMB, the primary results of START 
were published.2  Key findings from the primary report of START are summarized 
below: 
 
 Over an average follow-up of 3 years, immediate use of ART provided significant 
benefit over deferred ART for the primary endpoint of START (HR=0.43; 95% CI: 
0.30-0.62); p<0.001) and each of its major components, serious AIDS (p<0.001) 
and serious non-AIDS events (p=0.04).  
 
Early ART Group 
 
Initiate ART immediately 
following randomization 
 
 
N=2,325  
HIV-infected individuals who are ART-naïve with  
CD4+ count > 500 cells/mm3 
Deferred ART Group 
 
Defer ART until the CD4+ count 
declines to < 350 cells/mm3 or 
AIDS develops 
 
N=2,359  

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 The magnitude of benefit of immediate ART as compared to deferred ART was 
greater for serious AIDS events (HR=0.28; 95% CI: 0.15-0.50) than for serious 
non-AIDS events (HR=0.61; 95% CI: 0.38-0.97). 
 
 While the overall rate of serious non-AIDS events was lower in the immediate 
compared to the deferred arm, the relative difference varied by type of event. The 
HR for non-AIDS cancer was 0.50 (95% CI: 0.22-1.11; p=0.09).  For 
cardiovascular disease, for which a similar number of participants (26) 
experienced an event as for non-AIDS cancer (27 participants) the HR was 0.84 
(95% CI: 0.39-1.81). 
 
 All-cause mortality rates favored the immediate ART group but the confidence 
interval was wide due to the small number of deaths (HR=0.58; 95% CI: 0.28-
1.17; p=0.13). 
 
 Symptomatic grade 4 events (potentially life-threatening events) and 
unscheduled hospitalization for reasons other than AIDS progression occurred at 
similar rates in the two treatment groups (HR= 1.01; 95% CI: 0.73-1.39; p=0.97 
and HR=0.91, 95% CI: 0.77-1.08; p=0.28, respectively).  The HR for a composite 
measure of clinical benefit that included the primary endpoint, grade 4 events, 
and unscheduled hospitalization, favored immediate ART and was 0.82; 95% CI: 
0.71-0.96; p=0.01). 
 
 During the follow-up period, the average CD4+ count was 194 cells/mm3 higher 
(95% CI: 185-203) in the immediate ART group compared to the deferred ART 
group. 
 
 In both treatment groups, once ART was initiated, a high percentage of 
participants (over 90%) achieved and maintained virologic suppression (viral load 
200 copies/mL or less). 
 
 In the deferred arm, 68 of 96 primary events (71%) occurred before ART was 
initiated.  Fifty-seven of the 96 events in the deferred arm occurred at CD4+ 
counts > 500 cells/mm3; 23 of the primary events occurred at counts > 650 
cells/mm3. 
 
Concurrent with the findings of START, findings from a trial of early ART that included 
participants with a median age of 35 years from the Ivory Coast (TEMPRANO) showed 
that immediate ART led to lower rates of severe illness after an average follow-up of 2.3 
years as compared to deferral of ART according to World Health Organization (WHO) 
criteria, which varied over follow-up, among those with CD4+ counts of at least 500 
cells/mm3 at study entry.3  These findings reinforced findings from START that early 
ART has benefits in populations across the world including Africa where the prevalence 
of HIV is highest.  Like START, follow-up in TEMPRANO was relatively short 
considering that ART treatment is life-long.  
  

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After START was initiated and prior to the interim findings of START becoming 
available, a large randomized clinical trial showed conclusively that lowering viral 
replication in the HIV-infected person substantially reduces heterosexual transmission.4  
Another recent study supports reduced transmission in both hetero- and homosexual 
relationships having condomless sex.5  
 
Taken together, the findings from these studies provide strong evidence for both an 
individual benefit to the person with HIV over a 2 to 3 year period and a public health 
benefit to early use of ART.  As a consequence of these studies guidelines across the 
world have changed.6,7,8 
 
Following the DSMB’s recommendation in May 2015, participants in the deferred arm 
who had not started treatment were offered ART.  At the time of the DSMB 
recommendation in May 2015, 48% had initiated ART. By the beginning of 2016, ART 
had been started for 81% of participants in the deferred ART group; by the end of 2016 
93% of participants in the deferred ART group had initiated ART.  Participants in the 
deferred ART group initiated ART a median (25th, 75th percentile) of 2.5 (1.6, 3.4) years 
after participants in the immediate ART group. Ninety-five percent of participants in the 
deferred ART group who started ART are currently virologically suppressed.   
 
The median CD4+ count at ART initiation for deferred arm participants by the end of 
2016 was 468 cell/mm3.  This CD4+ count is approximately 180 cells/mm3 lower than 
the median count at initiation in the immediate ART group.  In addition, the most recent 
follow-up CD4+ counts for immediate and deferred arm participants are 882 and 711 
cells/mm3, a difference of 172 cells/mm3 which is very similar to the difference in CD4+ 
counts at ART initiation for the two treatment groups. 
 
Recently, a panel of inflammatory, coagulation, and vascular injury biomarkers were 
measured at baseline and 8 months after randomization.9  Immediate ART reduced the 
level of these biomarkers compared to deferred ART, and D-dimer and interleukin-6 (IL-
6) increased in the deferred ART group. 
 
These data on inititation of ART in the deferred ART group, HIV RNA supppression 
after initiating ART, and CD4+ cell count and biomarker differences provide a strong 
foundation for testing the HIV RNA and Nadir CD4+ hypotheses.  
 
In January 2016, the START protocol was amended as Version 3.0.  Version 3.0 
described plans to continue follow-up with existing funding through December 2017 and 
to seek funding for longer follow-up through December 2021. Those plans have not 
changed; however, this version of the protocol describes plans for greatly simplified 
data collection beginning in 2018.  Currently participants who consented to Version 3.0 
are being seen twice each year.   ART is being provided through a Central Drug 
Repository (CDR) until the end of 2017.  By that time, all participants will have 
transitioned to local sources of ART. 
 

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Continued follow-up of START participants for morbidity and mortality is important 
because many individuals who become HIV positive will not initiate ART until their 
CD4+ cell count declines to less than 500 cells/mm3 because of delayed diagnosis or 
unavailability of ART.  Many individuals living with HIV are not aware of it.  The WHO 
estimates this percentage to be 40% worldwide;10 estimates for the U.S. and Europe 
are 13% and 15%, respectively.11,12  Further, late diagnoses are common in resource-
rich and –poor settings.13,14,15,16,17,18  A demonstration in a randomized trial of persistent 
poor prognosis with deferred ART will create a further impetus for individuals to seek 
HIV testing and treatment, and for health systems to more comprehensively ensure 
access to these services. 
 
Additionally, data from the extended follow-up of START participants will provide 
important insights into the pathophysiology of the impact of prior levels of HIV-induced 
immunodeficiency on risk of morbidity and mortality once HIV is controlled. 
 
It is critical to determine whether the risk of major morbidity and mortality associated 
with delayed initiation is completely eliminated once ART is initiated and HIV RNA 
levels are suppressed or whether it persists due to the delay in initiating ART.  No prior 
randomized trial has addressed this question.  START is the only trial that will ever 
settle this question.   
 
Observational studies have attempted to address this question. A cohort analysis 
published around the time of the START results found that mortality differences among 
different ART initiation strategies for participants with a CD4+ count > 350 cells/mm3 
were small and decreased over time;19 importantly, as they note, their estimates relied 
on the assumption of no unmeasured confounding. Another recent report based on a 
cohort study found that after surviving for 5 years of ART, the mortality of those who 
started ART with low baseline count converged to those with high baseline counts.20  
Other observational studies suggest residual excess risk of non-AIDS morbidity 
associated with lower nadir CD4+ counts, but their design makes them unable to 
demonstrate whether the associations are causal.21,22,23 
 
In addition, the long-term follow-up will provide more information on rates of specific 
non-AIDS conditions and all-cause mortality in this unique cohort of individuals most of 
whom will be treated with ART that provides long-term virologic suppression. 
 
In summary, this streamlined version of the protocol (Version 4.0) with a more focused, 
cost-effective data collection plan and with locally sourced ART, allowing for the 
elimination of sponsor-reported serious and unexpected adverse reactions attributed to 
ART will enable START to address an important scientific question at substantially 
reduced cost.  Sites will report serious and unexpected events to national and 
international regulatory authorities according to local post-marketing reporting 
requirements. 

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3 Methodology 
3.1  Study Design 
This version of the START protocol continues follow-up of the HIV-positive participants 
in START, using a reduced data collection schedule to optimize resources and thus 
allow for a longer follow-up period.  START is a multicenter, international, randomized 
trial that compares initiation of ART at a CD4+ cell count > 500 cells/mm3 (early ART) 
versus initiation of ART at a CD4+ cell count of < 350 cells/mm3 (deferred ART) for a 
composite outcome of AIDS*, non-AIDS, and death from any cause (see Appendix A).2  
From April 2009 through December 2013, eligible participants were randomized in a 1:1 
ratio to either the early ART group or the deferred ART group.  Randomization was 
stratified by clinical site.  A total of 4,684 HIV-positive participants were randomized 
(one randomized participant included in the primary result paper was later determined 
to be HIV-negative). Participants in the early ART arm commenced ART immediately 
following randomization.  Participants in the deferred ART group, the control arm, were 
to commence treatment when the CD4+ declines to < 350 cells/mm3 or if an AIDS-
defining diagnosis occurs.   
3.2  Extended Follow-up Objectives 
3.2.1 
Primary Objective and Hypotheses 
With extended follow-up of participants in START, the primary objective is to determine 
whether the benefit of early ART as compared to deferred ART in delaying the 
occurrence of a composite outcome consisting of AIDS*, non-AIDS, or death from any 
cause is maintained, increased or reduced. 
 
Two scientific hypotheses, both of which take advantage of the randomized design of 
START and the extended follow-up through 2021, have been formulated to address 
the primary objective.  These hypotheses are: 
   
Hypothesis 1 (HIV RNA Hypothesis):  As a consequence of nearly all deferred arm 
participants initiating ART by the end of 2015 and the resulting similar HIV RNA levels 
after 2015 for the two treatment groups, the primary event rate in the two treatment 
groups will be similar between 2016 and 2021; the cumulative event rates in the two 
arms at the end of follow-up in 2021 will remain significantly different from one 
another, but the treatment difference will be substantially smaller than at the time of 
DSMB’s recommendation in May 2015.  
 
In terms of the treatment hazard ratio (HR), we hypothesize the true HR will be 1.0 
and the estimated HR for the time period between 2016 and 2021 will not differ 
significantly from 1.0; the average HR for the entire follow-up period from 
randomization through 2021, will be significantly less than 1.0 but much closer to 1.0 
than the HR of 0.43 reported following the DSMB recommendation. 
 

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In other words, participants who were randomized to deferring ART until the CD4+ 
count decreased to 350 cells/mm3 have an increased risk of the primary endpoint 
during the deferral period, and this risk is nearly completely eliminated once ART is 
initiated.  
 
Hypothesis 2 (Nadir CD4+ Hypothesis): As a consequence of deferred arm 
participants initiating ART 2.5 years after the  immediate ART group,  the primary 
event rate for the deferred ART group will remain substantially higher than in the 
immediate ART group between 2016 and 2021; therefore, the cumulative event rates 
in the two arms at the end of follow-up in 2021 will also remain substantially different 
from one another with only a modest movement of the overall average HR towards 1.0 
from 0.43. 
 
In other words, participants who were randomized to deferring ART to 350 cells/mm3 
have an increased risk of the primary endpoint during the deferral period that persists, 
albeit at lower levels, for 6 years after initiating ART.  This increased risk persists 
resulting from deferred ART, is due to a number of factors including, the lower CD4+ 
cell count at which ART was initiated, lower CD4+ count levels during follow-up, 
increased exposure during the deferral period to activated inflammatory and 
coagulation pathways, and a reduced ability to normalize markers of inflammation, 
coagulation and vascular injury after ART is initiated. If data are consistent with this 
hypothesis, we will estimate the rate with which the HR moves toward 1.0 over the 6 
years, if at all. 
3.2.2 
Secondary Objectives 
As secondary objectives, we will evaluate these two hypotheses for major components 
of the START primary endpoint and other major outcomes between 2016 and 2021 
and using all of follow-up through 2021. The two hypotheses will also be evaluated for 
baseline-defined subgroups. 
 
a. To compare early ART to deferred ART for the following components of the primary 
composite outcome: 
 AIDS* or death from AIDS 
 Non-AIDS or death not attributable to AIDS 
 CVD (myocardial infarction, stroke, coronary revascularization) or death due to 
CVD 
 Cancer (AIDS and non-AIDS malignancy, excluding basal and squamous cell 
skin cancers) 
 All-cause mortality 
 Tuberculosis 
 Serious bacterial infections 
 
b. To compare early ART to deferred ART for the following other clinical outcomes: 
 ESRD (initiation of dialysis, renal transplantation) 
 Decompensated liver disease 
 Non-AIDS malignancy, including basal and squamous cell skin cancers 

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 
AIDS 
 Unscheduled hospitalizations 
 
c. To compare early ART with deferred ART for the primary composite outcome and 
other major clinical outcomes in subgroups defined by the following characteristics 
measured at baseline: 
 Age 
 Gender 
 Race/ethnicity 
 
Presence and levels of risk factors, including risk scores which are based on 
several risk factors, for serious non-AIDS and AIDS conditions in addition to age, 
gender and race/ethnicity (e.g., smoking, estimated GFR (eGFR), hepatitis co-
infection, diabetes mellitus, estimated CVD risk, lipids, blood pressure, presence 
of resting ECG abnormalities)  
 
Baseline CD4+ cell count 
 
Baseline CD8+ cell count 
 
Baseline HIV RNA level 
 
Baseline IL-6 level 
 
Baseline D-dimer level 
 
Duration of HIV infection, including those recently infected and those who are 
slow/non-progressors. 
 
Viral characteristics, including subtype, and evidence of transmitted drug 
resistance 
 
Host genetic traits 
 
Geographic region 
 
High versus low/moderate income countries 
 
Calendar date of enrollment 
3.2.3 
Other Objectives 
a. To compare the early and deferred ART groups for: 
 ART use over follow-up 
 HIV RNA levels over follow-up  
 CD4+ and CD8+ cell counts over follow-up 
 
b. To compare the early and deferred ART groups for maintained virologic suppression 
following the initiation of ART during follow-up according to: 
 Presence of ART drug resistance at baseline 
 Geographic setting with and without access to routine resistance testing 
 Viral characteristics, including subtype 
 
c. Among participants in both treatment groups, to study predictors, including genomic 
correlates, of the primary endpoint and its components 
 
d. To study the effects of time-updated HIV RNA, CD4+ and CD8+ cell count levels on 
risk of the primary endpoint and its components, and the extent to which changes in 

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these laboratory markers explain treatment differences in major clinical outcomes 
during the three calendar periods for which the immediate and deferred ART groups 
will be compared to address the HIV RNA and Nadir CD4+ hypotheses.  The three 
calendar periods are: 1) from randomization to December 31, 2015; 2) from January 
1, 2016 to December 31, 2021; and 3) cumulatively from randomization through 
2021. 
3.3  Primary Study Endpoint 
The primary composite endpoint, defined in Appendix A, remains the same as it has 
been throughout START and includes the following three major components: 
 AIDS* or death from AIDS  
 
Opportunistic events consistent with the 1993 CDC expanded surveillance definition 
plus additional events associated with immunosuppression in the patient population 
targeted for enrollment.  Esophageal candidiasis and chronic Herpes simplex 
infection will be counted as primary endpoints only if they result in death. 
 
 Non-AIDS 
o CVD:  myocardial infarction, stroke, coronary revascularization 
o ESRD:  initiation of dialysis, renal transplantation 
o Decompensated liver disease 
o Non-AIDS-defining cancers, excluding basal and squamous cell skin cancers.  
Basal and squamous cell skin cancer will be counted as a primary endpoint 
only if they result in death. 
 
 Death not attributable to AIDS, including death of unknown cause 
 
The primary outcome of START and each of the major components of the primary 
outcome will be evaluated as the time to the first occurrence of one of the above events.  
Other major endpoints are referred to in the Study Objectives (section 3.2). 
3.4  Statistical Considerations 
In this section, assumptions underlying the predicted HRs and 95% CIs cited for the 6 
year period from January 2016 to December 2021 and cumulatively from randomization 
through 2021 for the HIV RNA and Nadir CD4+ count hypotheses are given. 
 
Assumptions Underlying HIV RNA Hypothesis 
 
 In the immediate ART group, the rate of AIDS* does not change over time.  Rates 
of serious non-AIDS and all-cause mortality increase due to aging by 7.5% per 
year after December 31, 2016. 
 In the deferred ART group, as a consequence of the great majority of participants 
initiating ART, event rates for AIDS*, serious non-AIDS and all-cause mortality 
will be the same as rates in the immediate ART group between 2016 and 2021. 
   

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Assumptions Underlying Nadir CD4+ Count Hypothesis 
 
 In the immediate ART group, the rate of AIDS* does not change over time.  Rates 
of serious non-AIDS and all-cause mortality increase due to aging by 7.5% per 
year after December 31, 2016. 
 In the deferred ART group, the event rate for the primary endpoint between 2016 
and 2021 will be 75% higher than rate in the immediate ART group as a 
consequence of their lower nadir CD4+ count and continued CD4+ cell count 
difference between treatment groups, e.g., the CD4+ count difference between 
treatment groups at the latest follow-up visit is currently 172 cells/mm3.    
 
For both hypotheses, it is assumed that 90% of participants of the 4,684 HIV+ 
participants will be under follow-up on 1 January 2018.  It is also assumed that very 
few participants will experience both AIDS* and serious non-AIDS events, and that the 
lost-to-follow-up percent will be 1% per year after 2017. 
 
Considering these assumptions, we estimate 406 primary events will occur by 31 
December 2021 under the Nadir CD4+ hypothesis; 242 primary events are expected 
to occur between 2016 and 2021.  Under the HIV RNA hypothesis, 177 primary events 
are expected to occur between 2016 and 2021 and 341 events are predicted between 
randomization and 2021. Based on the assumptions above, the predicted HRs and 
95% confidence intervals (CIs) for the two hypotheses are given below.  
 
Hypothesis 
 HR 
(randomization 
through 31 
December 2015) 
HR (2016-2021; 6 
years) 
HR 
(randomization 
through 2021; 
9.5 years) 
# 1 (HIV RNA) 
0.47  
(95% CI: 0.34-0.65) 
1.00  
(95% CI: 0.74-1.36) 
0.70  
(95% CI: 0.56-0.87) 
# 2 (Nadir CD4+ ) 
0.57  
(95% CI:0.43-0.74) 
0.53  
(95% CI: 0.43-0.65) 
 
With 242 events, power is 0.98 during the calendar period January 2016 through 
December 2021 to detect a HR (Imm/Def) of 0.60; power is 0.79 to detect a HR of 
0.70, a difference that is more conservative than the projected HR of 0.57 under the 
Nadir CD4+ hypothesis. 
3.5  Participant Selection 
Participants enrolled in START were in reasonably good health, and in the clinician's 
opinion, able to adhere to the protocol (i.e., were willing to accept and adhere to the 
data collection schedule and the assigned treatment strategy).2,24  The inclusion and 
exclusion criteria used at study entry are given in the synopsis for reference.  
All HIV-positive participants in START who sign a consent for Version 3.0 (or Version 
4.0 if required by the local ethics committee) are eligible to continue in extended follow-
up with the exception of those who are involuntarily incarcerated.  Incarcerated 
participants may be re-consented to Version 4.0 upon release.   

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3.6  Study Plan 
Through May 26, 2015, the management of participants was guided by their assigned 
treatment strategy (see below).  On May 27, 2015 investigators and participants were 
informed that on May 15, 2015 the independent DSMB determined that the primary 
question of START had been addressed.  The DSMB recommended offering ART to 
participants in the deferred arm who had not yet started ART and continuing follow-up 
of all study participants.    
3.6.1 
Treatment Strategies 
For reference, this section describes the two treatment strategies in START through 
May 26, 2015.  Beginning on May 27, 2015, all participants in the deferred arm were 
offered ART. 
 
Before a participant was randomized, a potent combination ART regimen was pre-
specified by the study clinician.  The initial regimen used was to be from a list of 
regimens based on DHHS guidelines.  This list of regimens was regularly updated 
following changes in those guidelines.   
  
After randomization, participants in the two groups were to use potent combination ART 
as follows: 
a.   Participants assigned to the early ART group were to start the prespecified ART 
regimen as soon as possible. 
  
b.   Participants assigned to the deferred ART group were to defer ART until one of the 
following conditions occurs:  
    CD4+ cell count declines to < 350 cells/mm3 and is confirmed by a repeat CD4+  
 measurement within 4 weeks, or 
    AIDS develops, or 
    Conditions specified by local guidelines occur that indicate initiation of potent 
combination ART, e.g., symptoms indicative of HIV progression such as oral 
thrush, unexplained weight loss, or unexplained fever. 
  
The intent of the deferral strategy used in START was to initiate ART as soon as 
possible after the CD4+ count dropped below 350 cells/mm3.  The CD4+ count was 
monitored closely as it approached 350 cells/mm3. 
 
After discussion with their clinicians, participants in the deferred ART group who 
developed any of the conditions noted above were to start an ART regimen selected 
from the same list of regimens based on DHHS guidelines that regimens for the 
immediate ART group used.   
  
Women assigned to the deferred ART group who become pregnant before the CD4+ 
cell count declines to < 350 cells/mm3 were to be prescribed ART using a regimen in 
keeping with local treatment guidelines. 

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3.6.2 
Concomitant Medications 
There are no restrictions on concomitant medications for participants in either group.   
3.6.3 
Baseline Screening 
For reference, below we describe the data collected prior to randomization.  These data 
will be used to address many of the stated objectives of long-term follow-up. 
 
All consenting participants had the following information and measurements collected 
within 60 days before randomization unless otherwise noted.  All measurements were 
done locally unless otherwise noted. 
 
Demographics, including education 
 
Documentation of HIV infection 
 
CD4+ cell count and CD4%:  two measurements at least 2 weeks apart, with the 
earliest within 60 days before randomization 
 
Karnofsky score 
 
For women of child-bearing potential, a pregnancy test (serum or urine) done in the 
clinic must be documented to be negative within 14 days before randomization 
 
Targeted health history including date of first diagnosis of HIV infection, likely mode 
of HIV infection, history of non-AIDS events, pregnancy status, and history of 
fractures  
 
Brief clinical evaluation including weight, height, sitting blood pressure, pulse, and 
smoking status 
 
Nadir CD4+ cell count and CD4% and maximum HIV RNA level available in the 
medical record from any time in the past 
 
Up to three most recent (before the above baseline measurements) CD4+ cell 
counts, CD4%s, and HIV RNA measurements available in the medical record 
 
Findings from previous genotypic or other form of HIV resistance testing (such as 
virtual phenotype and/or phenotypic resistance testing), if performed and available 
Selected concomitant medications 
 
Quality of life assessment 
 
Use of alcohol and recreational drugs 
 
HIV transmission risk behavior assessment 
 
Health-care utilization 
 
HIV RNA measurement 
 
Additional laboratory assessments (participants should be asked to abstain from 
food, except water, for at least 8 hours prior to providing blood for glucose and lipid 
measurements): 
o Complete blood count (CBC):  hemoglobin, hematocrit, white blood cell count 
(WBC) with differential and platelets 
o CD8+ T-cell count and CD8% 
o Renal function:  serum creatinine to estimate GFR25 
o Liver function:  alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase, total bilirubin and albumin 
o Glucose 

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o Lipids:  total cholesterol, low density lipoprotein (LDL), high density lipoprotein 
(HDL), triglycerides 
o Dipstick urinalysis for measurement of protein 
 
Documentation of hepatitis B and C status:  hepatitis B surface antigen, core 
antibody and surface antibody; hepatitis C antibody and, if available, genotype and 
viral load.  Documented positive tests at any time in the past or documented 
negative tests in the 6 months before randomization may be used.   
 
In a subset of participants, a resting ECG (at sites with a study-provided ECG 
machine and a certified technician) 
 
ART regimen to be prescribed for the participant if randomized to the early group 
and whether the regimen would be obtained locally or through the INSIGHT CDR 
 
For consenting participants, stored plasma (sufficient for eight 1-mL transport tubes) 
for future HIV-related research (e.g., HIV resistance testing, CVD biomarkers)  
 
For consenting participants, stored urine (sufficient for six 1-mL transport tubes) for 
future HIV-related research  
 
In participants who were to be prescribed abacavir, HLA-B*5701 screening test results 
for abacavir hypersensitivity had to be available before prescription. 
 
In addition to the aforementioned data, the following laboratory measurements, which 
will also be used to address objectives of long-term follow-up have been made on 
stored baseline specimens: 
 IL-6, D-dimer, high sensitivity C-reactive protein (hsCRP), IL-27, serum amyloid 
A (SAA), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble 
vascular cell adhesion molecule-1 (sVCAM-1) were measured in all randomized 
participants who consented to the storage of blood for future research. 
 In a subsample of participants who reported recent infection and/or recent an 
HIV diagnosis, a Limiting Antigen-Avidity assay and a Johns Hopkins avidity 
modified Genetic Systems (GS) HIV-1/HIV-2 PLUS O enzyme immunoassay 
(EIA) were measured to identify participants with early HIV infection.26,27 
 In 2,549 START participants who consented to store DNA, a genome wide 
association study (GWAS) has been performed to investigate genetic 
determinants of immune function, ART toxicities, elevated biomarker levels, and 
AIDS and serious non-AIDS events. 
 Among 3,785 participants who consented to store specimens for future research 
with a baseline HIV RNA level > 1,000 copies/mL, next generation sequencing 
for HIV resistance was performed.   
3.6.4 
Participant Follow-up 
The planned follow-up is through December 2021. The extent of data collection and 
methods for data collection varied between Versions 1.0/2.0, Version 3.0 and Version 
4.0.  In Versions 1.0 and 2.0, participants were seen at routine follow-up visits which 
occurred at 1 and 4 months after randomization, and every 4 months thereafter.  
Beginning with Version 3.0, data collection visits occurred at 6 month intervals.  The 
table below summarizes follow-up data collection under Versions 1.0 and 2.0, Version 
3.0 and Version 4.0 of the START protocol.  

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Data/Samples 
Collected 
Versions 1.0 and 
2.0 
Version 3.0 
Version 4.0 
Primary endpoint 
and components 
X 
X 
X 
Basal and 
squamous cell 
skin cancers 
X 
X 
X 
Esophageal 
candidiasis and 
chronic Herpes 
Simplex infection 
X 
X 
X 
Bacterial 
pneumonia 
X 
X 
X 
Grade 4 events 
that do not lead to 
hospitalization 
X 
X 
 
Unscheduled 
hospitalizations 
X 
X 
X 
CD4+ and CD8+ 
counts 
X 
X 
X 
HIV RNA level 
X 
X 
X 
ART 
X 
X 
X 
Self-administered 
questionnaires: 
quality of life, 
health care 
utilization, alcohol 
and recreational 
drugs, HIV 
transmission risk 
behavior 
 
X 
 
 
Serious adverse 
events for 
regulatory 
authorities 
X 
X 
 
Complete blood 
count (other than 
CD4+ count), 
chemistries, 
lipids, urine 
dipstick 
X 
X 
 
Other targeted 
medical 
diagnoses, 
X 
X 
 

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including 
fractures 
Concomitant 
treatments  
X 
X 
 
Weight, blood 
pressure and 
smoking status 
X 
X 
 
Resting ECG 
(subsample) 
X 
X (completed in 
2016) 
 
Stored blood and 
urine 
X (every visit) 
X (annual visits only)  
Results of locally 
performed 
resistance tests 
X 
X 
 
Pregnancy 
outcomes 
X 
X 
 
Substudies: 
arterial elasticity, 
pulmonary, bone 
density, 
neurocognitive, 
site monitoring, 
informed consent, 
liver fibrosis, HIV-
1 reservoir 
X 
X (all substudies 
were completed in 
2016 except for liver 
fibrosis which will 
continue through 
December 2017) 
 
 
In Version 4.0, follow-up data collection will occur once each year.  The following 
information will be collected: 
 ART regimen currently prescribed 
 CD4+ cell counts and CD8+ cell counts measured since the last assessment, if 
available. 
 HIV RNA levels determined since the last assessment, if available. 
 Event documentation for serious AIDS, serious non-AIDS and deaths which 
constitute the START primary endpoint. 
 Event documentation for the following secondary outcomes: 
o Non-AIDS malignancy, including basal and squamous cell skin cancers 
o All AIDS events, including esophageal candidiasis and chronic Herpes 
Simplex 
o Bacterial pneumonia 
 Unscheduled hospitalizations, including an assessment of the severity of the 
condition that led to the hospitalization. 
 
For most participants these data will already exist as a consequence of routine care.  At 
some sites in order to collect these data, participants will be seen for a study visit.  
Whether the data exist already or are collected as part of a study visit, electronic case 
reports forms (eCRFs) will used to record the data at each site. 

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The INSIGHT Endpoint Review Committee (ERC) has established objective criteria for 
each event comprising the primary endpoint and for major secondary endpoints; these 
criteria are also found in the START Protocol Instructions Manual.  The ERC is 
responsible for reviewing each reported primary event to determine the level of 
diagnostic certainty.  Events which are judged as confirmed or probable will be included 
in the primary analysis. 
3.6.5 
Participant Relocation to a New Site 
If a participant relocates to an area without a START site where the participant could be 
transferred, data collection of items that are considered to be part of routine care (e.g., 
HIV RNA level, CD4+ cell count, clinical events) will continue if the participant gives 
permission.  The START Protocol Instructions Manual provides guidance on how to 
collect data for participants who relocate and/or transfer to another START clinical site.   
3.6.6 
Stored Samples and Future Research 
After 2017, no blood or urine specimens will be obtained for storage.  Specimens 
collected through December 2017 will be stored at a central specimen repository for use 
in HIV-related research concerning the effects of HIV and ART on AIDS and non-AIDS 
conditions.  Proposed research utilizing these specimens will be reviewed and approved 
by the INSIGHT Scientific Steering Committee.  Results of research tests on individual 
specimens will not be given to participants or their clinicians, but aggregate research 
results will be made available. 
4 Clinical Management Issues 
4.1 Antiretroviral Treatment 
Based on the results of START, all participants should be offered ART with a goal of 
continually suppressing HIV RNA levels.  Local guidelines which stipulate that once 
ART is started the goal should be viral suppression should be followed for clinical 
management. 
4.2 HIV Transmission Counseling 
All participants should receive counseling regarding prevention of HIV transmission to 
others as indicated. 
4.3  Study Withdrawal 
Participants may withdraw from the study at any time at their request and resume 
participation at any time upon re-consent.  A participant may be withdrawn if:  
 
S/he relocates and data can no longer be collected. 
 
S/he is imprisoned, or involuntarily incarcerated for medical reasons.  In this case, 
no data will be collected during the imprisonment or involuntary incarceration.  
However, once released from imprisonment or involuntary incarceration, an 
individual may resume participation upon re-consent. 

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 
The study is discontinued. 
 
All participants should otherwise be followed according to protocol.   
4.4   Co-enrollment in Other Studies 
Co-enrollment in other studies is permissible. 
5 Evaluation 
5.1 Data Analysis 
The primary analysis will be by intention to treat, comparing the early and deferred 
groups.  Time-to-event methods, including stratified log-rank tests, proportional 
hazards regression analysis, and Kaplan-Meier cumulative event curves, will be used 
to summarize the primary endpoint (i.e., time to the first event) and major secondary 
outcomes.28  Unless otherwise stated, analyses will be based on a Cox model with a 
single indicator for treatment group and with strata corresponding to geographic region 
(North America, South America, Europe, Australasia, and Africa). 
 
Analyses will be carried out for the following three calendar periods: 1) from 
randomization to December 31, 2015; 2) from January 1, 2016 to December 31, 2021; 
and 3) cumulatively from randomization through 2021.  These analyses will focus on the 
primary endpoint, serious AIDS events, serious non-AIDS events, all-cause mortality, 
CVD, non-AIDS cancer, and unscheduled hospitalizations.  
 
To assess whether treatment hazard ratios differ between the follow-up period prior to 
January 1, 2016 and afterwards, Cox models which include an interaction term with 
the calendar follow-up period will be used.  Similar analyses will use the cutoff of May 
27, 2015.  Cox models will also be used to assess the homogeneity of hazard ratios 
over the entire follow-up period, during the period between 2016 and 2021, and during 
the period before (May 27, 2015) and after investigators and participants were 
informed of the interim results. 
 
The randomized comparisons planned above will be supplemented with analyses that 
take into account the timing of ART use (viral suppression) in the deferred ART arm 
and consider ART use (viral suppression) and latest CD4+ count as time-updated 
covariates in order to determine the extent to which the treatment HR is explained by 
those factors.  
 
Subgroup analyses for the primary endpoint and major secondary outcomes will also 
be performed for the following three calendar time periods: 1) from randomization to 
December 31, 2015; 2) from January 1, 2016 to December 31, 2021; and 3) 
cumulatively from randomization through 2021. Subgroup analyses will be aimed at 
determining whether the treatment effect (immediate versus deferred) differs 
qualitatively across various baseline-defined subgroups.  Subgroup analyses will be 
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moderate/high income countries, the presence of risk factors, including risk scores, for 
serious non-AIDS and AIDS conditions, baseline CD4+ cell count, baseline HIV RNA 
level, baseline levels of IL-6 and D-dimer, duration of HIV infection at enrollment, viral 
characteristics, including subtype, and evidence of transmitted drug resistance, and 
calendar date of enrollment in order to assess the effect of different treatment patterns 
that may emerge. The consistency of the treatment difference across participating 
countries will also be assessed.  An overall test of heterogeneity will provide evidence 
of whether the magnitude of the treatment difference varies across baseline 
subgroups. 
 
HIV RNA levels, CD4+ and CD8+ cell counts will be compared for the early and 
deferred groups.  Likewise, discontinuation of ART in the early and deferred groups 
will be closely monitored.  Kaplan-Meier life-table methods will be used to estimate the 
cumulative percent of participants in the deferred group who initiate therapy after 
different periods of follow-up.  Follow-up levels of HIV RNA and CD4+ count will be 
summarized in a number of ways.  Follow-up time spent in various categories will be 
compared.  Longitudinal measurements of viral load and CD4+ cell count will be 
summarized using measured levels (or log transformed) and using repeated binary 
assessments (e.g., viral load below 50 copies/mL). 
 
Analyses which take into account use of ART by deferred arm participants will also be 
carried out for comparing the immediate and deferred ART groups for the time period 
between 2016 and 2021.  These analyses will be aimed at estimating the effect of 
initiating ART on the residual excess risk of the primary endpoint after taking into 
account the duration of ART after 2016.   
5.2 
Data Monitoring 
The trial will be conducted under the direction of the START study protocol team which 
includes representatives from the community, the major funder (NIAID), and from 
different scientific and administrative disciplines.  
 
During the extended follow-up the protocol team and other INSIGHT committees will 
closely monitor the data for completeness and quality. 
 
There are no planned interim analyses that would lead to earlier reporting of findings 
related to the two major hypotheses that will be addressed with extended follow-up.  
However, at least on an annual basis, the protocol leadership will review a report on 
data quality, the completeness of follow-up, and treatment differences for the primary 
and major secondary outcomes. 

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6 Protection of Human Subjects & Other Ethical 
Considerations 
6.1  Local Review of Protocol and Informed Consent 
Prior to the initiation of Version 4.0 of the protocol at each clinical research site, the 
protocol, and the participant Information materials will be submitted to and approved by 
the site’s IRB or IEC.  Likewise, any future amendments to the study protocol will be 
submitted and approved by each site’s IRB or IEC.   
6.2  Ethical Conduct of the Study  
The study will be conducted according to the Declaration of Helsinki in its current 
version; the requirements of Good Clinical Practice (GCP) as defined in Guidelines, EU 
Clinical Trials Directive (2001/20/EC and subsequent revisions), and EU GCP Directive 
(2005/28/EC and subsequent revisions); Human Subject Protection and Data Protection 
Acts; the US Office for Human Research Protections (OHRP); or with the local law and 
regulation, whichever affords greater protection of human subjects. 
6.3  Informed Consent of Study Participants  
All study participants must have signed all applicable approved informed consent forms  
prior to any study-related procedures.  The sponsor does not require an additional 
informed consent for Version 4.0 of the protocol if the participant consented to Version 
3.0.  Appendix D provides the Version 3.0 consent for reference, and a sample informed 
consent for Version 4.0 for those sites that may require it. 
6.4 
Confidentiality of Study Participants  
The confidentiality of all study participants will be protected in accordance with GCP 
Guidelines and national regulations.  
 

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7 Other Important Documents and Policies 
7.1  Reference Documents 
Study procedures are described in detail in the START Protocol Instructions Manual. 
7.2  Data Collection and Monitoring 
Study data will be collected on electronic case report forms (eCRFs) once each year 
for each participant.   Monitoring may be performed by staff from the INSIGHT 
International Coordinating Centers or Site Coordinating Centers or by contractors of 
the primary funder. 
 
At a minimum, all items referenced in the protocol as being relevant to the research 
study will be recorded in the participant's research record in accordance with standard 
procedures.  In addition, all items specifically required by the protocol will be recorded 
on eCRFs.  
7.3  Publications and Presentations 
Publications and presentations related to data obtained from the START study will 
adhere to the INSIGHT Publications and Presentations Policy on the INSIGHT website 
(see Appendix B) 
 

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APPENDIX A:    PRIMARY ENDPOINT DEFINITION 
 
The primary composite endpoint for START is non-fatal serious AIDS events (or 
“AIDS*”), non-fatal serious non-AIDS (or “non-AIDS”) events, and death from any 
cause.  It includes the following components: 
 
 
Fatal AIDS or non-fatal AIDS* events 
 
These include opportunistic events consistent with the 1993 CDC expanded 
surveillance definition plus additional events associated with immunosuppression 
in the participant population targeted for enrollment.  Esophageal candidiasis and 
chronic Herpes simplex infection will only be counted in the primary endpoint if 
fatal events. 
 
AIDS* events include:  
 Aspergillosis (invasive) 
 Bartonellosis 
 Candidiasis of the bronchi, trachea, or lungs 
 Invasive cervical cancer 
 Chagas disease (American trypanosomiasis) of the central nervous system 
(CNS) 
 Cytomegalovirus virus (CMV) disease (radiculomyelitis, meningoencephalitis, or 
other disease) 
 CMV retinitis 
 Extrapulmonary or disseminated coccidioidomycosis 
 Cryptosporidiosis with diarrhea > 1 month 
 Cryptococcosis, meningitis or extrapulmonary 
 HIV-related encephalopathy, including AIDS Dementia Complex 
 Disseminated Herpes zoster 
 Extrapulmonary or disseminated histoplasmosis 
 Isosporiasis with diarrhea > 1 month 
 Kaposi’s sarcoma, mucocutaneous or visceral 
 Leishmaniasis (visceral) 
 Hodgkin’s lymphoma 
 Non-Hodgkin’s lymphoma, all cell types 
 Primary lymphoma of the brain 
 Tuberculosis, pulmonary and/or extrapulmonary 
 Microsporidiosis with diarrhea > 1 month 
 Mycobacterium avium complex (MAC), disseminated 
 Other nontuberculous species or unidentified species of Mycobacterium, 
disseminated 
 Nocardiosis 
 Penicilliosis, disseminated 
 Extrapulmonary Pneumocystis jiroveci 
 Pneumocystis jiroveci pneumonia 
 Recurrent bacterial pneumonia (2 episodes within 12 months) 

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 Progressive multifocal leukoencephalopathy (PML) 
 Rhodococcus equi disease 
 Recurrent Salmonella septicemia (2 episodes within 12 months) 
 Toxoplasmosis of the brain 
 Wasting syndrome due to HIV 
 
AIDS events include: 
 All conditions defined as AIDS* above 
 Esophageal candidiasis 
 Chronic Herpes simplex 
 
 
Non-fatal serious non-AIDS events (“non-AIDS”) 
o Cardiovascular disease (CVD) (myocardial infarction, stroke, coronary 
revascularization) 
o End-stage renal disease (ESRD) (initiation of dialysis, renal transplantation) 
o Decompensated liver disease 
o Non-AIDS-defining cancers (excluding basal and squamous cell skin cancers) 
 
 
Deaths not attributable to AIDS 
 
The INSIGHT Endpoint Review Committee (ERC) has established objective criteria for 
each event and its level of diagnostic certainty.  These criteria are given in the START 
Protocol Instructions Manual.  The ERC is responsible for reviewing each reported 
event to determine the level of diagnostic certainty.  Events that are judged as 
confirmed or probable will be included in the primary analysis. 

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APPENDIX B:    REFERENCES ON INSIGHT WEBSITE 
  
The INSIGHT website (www.insight-trials.org) will maintain updated links to the 
following documents referenced in the START protocol and to other information 
pertinent to the study: 
 
 
The START Protocol Instructions Manual 
 
 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 1.0, December 2004 (or “DAIDS AE Grading Table”),  as applicable for 
START 
 
 
 
INSIGHT Publications and Presentations Policy 
 

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APPENDIX C:    LIST OF ACRONYMS 
 
ACSR 
AIDS Cancer Specimen Resource 
ADS 
Average Deficit Score 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome (see Appendix A) 
AIDS* 
Modified definition of AIDS (see Appendix A) 
ALT 
Alanine aminotransferase 
ANRS 
Agence Nationale de Recherches sur le SIDA et les Hépatites Virales  
ART 
Antiretroviral Therapy 
AST 
Aspartate aminotransferase 
AWP 
Average Wholesale Price 
BMBF 
Bundesministerium für Bildung und Forschung (German Ministry) 
BP  
Blood Pressure 
cART 
Combination Antiretroviral Therapy 
CASCADE 
Concerted Action on Seroconversion to AIDS and Death in Europe 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention (U.S.) 
CDR 
INSIGHT Central Drug Repository 
CES-D 
Center for Epidemiologic Studies Depression Scale 
CFR 
Code of Federal Regulations (U.S.) 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CPE 
CNS Penetration Score 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CVD 
Cardiovascular Disease 
D:A:D 
Data Collection for Adverse Events of Anti-HIV Drugs 
DAIDS 
The Division of AIDS, NIAID, NIH (U.S.) 
DC 
Drug Conservation (Arm in SMART Study) 
DHHS 
Department of Health and Human Services (U.S.) 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
EAE 
Expedited Adverse Event 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EMEA 
European Medicines Agency 
ERC 
Endpoint Review Committee 
ESPRIT 
Evaluation of Subcutaneous Pro-leukin in a Randomized International 
Trial 
ESRD 
End-stage Renal Disease 
EU 
European Union 
FDA 
Food and Drug Administration (U.S.) 
FIRST 
Flexible Initial Antiretrovirus Suppressive Therapies 

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GCP 
Good Clinical Practice 
GEE 
General Estimating Equations 
GFR 
Glomerular Filtration Rate 
GID 
Generated Identification Number 
HAART 
Highly Active Antiretroviral Therapy 
HBM 
Human Biological Material 
HBV  
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus Type 1 
HIVAN 
HIV-Associated Nephropathy 
HLA 
Human Leukocyte Antigen 
HR 
Hazard Ratio 
HVLT-R 
Hopkins Verbal Learning Test 
ICC 
International Coordinating Center (INSIGHT) 
IEC 
Institutional Ethics Committee 
IL-2 
Interleukin-2 
INSIGHT 
International Network for Strategic Initiatives in Global HIV Trials 
IRB 
Institutional Review Board 
LDL 
Low Density Lipoprotein 
MACS 
Multicenter AIDS Cohort Study 
mL 
Milliliter 
mm 
Millimeter 
NCI 
National Cancer Institute, NIH  (U.S.) 
NFL 
Neurofilament Protein 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH (U.S.) 
NIH 
National Institutes of Health (U.S.) 
NIMH 
National Institute of Mental Health, NIH (U.S.) 
NINDS 
National Institute of Neurological Disease and Stroke, NIH (U.S.) 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
Non-AIDS 
Serious Non-AIDS Conditions (see Appendix A) 
NRTI 
Nucleoside/Nucleotide Reverse Transcriptase Inhibitor 
OHRP 
Office for Human Research Protections (U.S.) 
PHI 
Primary HIV Infection 
PHS 
Public Health Service (U.S.) 
PI 
Protease Inhibitor 
PID 
Participant Identification Number 
PIM 
Protocol Instructions Manual 
QNPZ  
Quantitative Neurocognitive Performance Z Score 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDMC 
Statistical and Data Management Center (INSIGHT) 
SF-12 
Medical Outcomes Study Short-Form-12 Item Survey 
SMART 
Strategies for Management of Antiretroviral Therapy 
START 
Strategic Timing of Antiretroviral Treatment 

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SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TACC 
Tri-Service AIDS Commission, Department of Defense (U.S.) 
U.K. CHIC 
United Kingdom Collaborative HIV Cohort Study 
U.S. 
United States of America 
VS 
Viral Suppression (Arm in SMART Study) 
WAIS-III 
Wechsler Adult Intelligence Scale-III 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
 

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Appendix D:  Informed Consent Forms 
 
This appendix includes the sample informed consents for Version 3.0 and 4.0 of the 
START protocol.   
 
All START participants were asked to re-consent to Version 3.0, because at that time 
we were asking for participant consent to be followed until 2021, several more years 
than originally planned.  Participants who did not wish to continue follow-up under 
Version 3.0, with its reduced data collection schedule, withdrew from START.  Although 
sites must obtain appropriate IRB/EC approvals and registration with INSIGHT for 
Version 4.0 of START, the study sponsor is not requiring participants to re-consent in 
order to continue follow-up under Version 4.0.  The duration of follow-up under Version 
4.0 is the same as that to which participants consented for Version 3.0.  Data collection 
requirements have again been reduced, so we are not asking anything more from 
participants than what they have already consented to provide.  These changes can be 
communicated to participants in any way the site considers appropriate for its 
population, including verbal communication (documented in the participant’s record) at 
the participant’s next clinic visit.  A sample participant information sheet will be provided 
should sites wish to use it. 
 
As participants may move their care to another START site during follow-up or 
participants who have been lost to follow up and have yet to consent to version 3.0 
may return to clinic, a sample informed consent document for Version 4.0 of the 
protocol is also included in this appendix.  In addition, in some countries, individual 
sites’ IRBs/ECs may elect to require that participants re-consent to continue follow-up 
under Version 4.0.  In such cases, if participants decline re-consent they will be 
withdrawn from START. 
 
 

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START STUDY SAMPLE CONSENT FOR EXTENDED FOLLOW-UP 
(Version 3.0)  
 
University of Minnesota:  SPONSOR 
NIAID:  PRIMARY FUNDER 
 
Protocol Title: 
Strategic Timing of AntiRetroviral Treatment 
(START) 
 
A Multicenter Study of the 
International Network for Strategic Initiatives in Global HIV Trials 
(INSIGHT) 
 
Short Title of the Study:  START 
 
CONSENT FOR PARTICIPATING IN AN NIH-FUNDED RESEARCH TRIAL 
 
 
SITE LEADER:  ____________________________________ PHONE:  __________ 
 
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
REMOVED FROM THE SITE’S INFORMED CONSENT FOR SUBJECTS   
 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR:  PHONE: 
 
 
 
INTRODUCTION 
You are being asked to continue to participate in the START study through 2017, and 
possibly through 2021 if funding is available. This extended follow-up will provide 
important additional information on the long-term benefits and risk of taking HIV 
medicines. 
 
YOUR PARTICIPATION IS VOLUNTARY 
This consent form gives you information about the planned long-term follow-up of 
participants in the START study that will be discussed with you.  Once you understand 
OHRP Requirements to be read by the sites: 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL IRB REVIEW AND APPROVAL.  
INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL IRB WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH 
THE LANGUAGE INTENDED FOR LOCAL USE.  LOCAL IRBS ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  ANY DELETION OR 
SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY 
THE INVESTIGATOR, APPROVED BY THE LOCAL IRB, AND NOTED IN THE IRB MINUTES.  JUSTIFICATION AND IRB 
APPROVAL OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL COORDINATING CENTER..  SPONSOR-
APPROVED CHANGES IN THE PROTOCOL MUST BE APPROVED BY THE LOCAL IRB BEFORE USE UNLESS INTENDED 
FOR THE ELIMINATION OF APPARENT IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE SHARED WITH EXISTING 
SUBJECTS AT NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR TO INVOLVEMENT, OR AS THE LOCAL IRB MAY 
OTHERWISE ADDITIONALLY REQUIRE. 
 

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the reasons for extended follow-up, and if you agree to take part, you will be asked to 
sign this consent form. You will be given a copy to keep.  
 
Before you learn about the extended follow-up, it is important that you know the 
following: 
 
Your participation is entirely voluntary;  
 
You may decide not to take part or to withdraw from the planned follow-up at any 
time without losing the benefits of your routine medical care. 
 
START is being funded primarily by the National Institute of Allergy and Infectious 
Diseases (NIAID), U.S. National Institutes of Health (NIH), through a grant to the 
University of Minnesota, which is the lead institution in the INSIGHT group.  The 
University of Minnesota is the sponsor of this study.  This study is also being conducted 
with additional funding from Agence Nationale de Recherches sur le SIDA et les 
Hépatites Virales (ANRS, France); Australian National Health and Medical Research 
Council (NHMRC); Danish National Research Foundation; Medical Research Council 
(MRC, United Kingdom); National Heart, Lung, and Blood Institute (NHLBI); National 
Institute of Mental Health (NIMH); National Institute of Neurological Disorders and 
Stroke (NINDS); and Division of Clinical Research (NIAID).  Additional support is being 
provided by AbbVie Laboratories, Inc.; Bristol-Myers Squibb; Gilead Sciences, Inc.; 
GlaxoSmithKline, Inc.; Merck & Co., Inc, and Janssen Pharmaceuticals, Inc. 
 
WHY IS FOLLOW-UP CONTINUING THROUGH 2021? 
On May 15, 2015 the independent Data and Safety Monitoring Board (DSMB) for 
START determined that the primary study question had been answered. Beginning HIV 
medicines right away (the Early arm) was better than waiting to start HIV medicines (the 
Deferred arm) for the primary endpoint of START and its two major outcomes, serious 
AIDS illnesses and other non-AIDS serious medical illnesses.  The DSMB 
recommended offering HIV medicines to participants in the Deferred arm who had not 
yet started HIV medicines.  The DSMB also recommended continued follow-up of study 
participants.  
 
START investigators and study participants were told about these recommendations, 
and participants in the deferred arm who had not started treatment were offered HIV 
medicines. 
 
This consent describes the plan for continued follow-up of START participants through 
2021.  Currently, the START study has enough funding for follow-up through 2017. If 
the request for more funding to continue follow-up through 2021 is not successful, the 
follow-up and data collection described in this consent will end in 2017. 
 
The primary reason for continuing follow-up is to find out the differences in serious 
illnesses between the Early and Deferred HIV medicines groups.  Your continuing 
participation in START is very important to our ability to learn about these long-term 
effects, even if you are now taking HIV medicines. 
 

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HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
All HIV-positive participants randomized to START are being invited to be in the 
extended follow-up.   
 
HOW LONG WILL YOU BE IN THE STUDY? 
You will be in this study at least until the end of 2017.  We are asking you to consent to 
be followed through the end of 2021, because we plan to seek funding for follow-up 
through 2021.   
 
HOW WILL THE STUDY WORK? 
If you consent, we plan to see you at clinic visits for data collection twice each year 
(about every 6 months), instead of three times a year as before.  We will follow your 
regular HIV care and collect a little additional information from you, but not as much as 
in the past. 
 
At these visits, your study doctor or nurse will ask questions about your health and your 
HIV infection and will give you a short medical examination.  You will have about 5-10 
mL (about 1-2 tablespoons) of blood drawn.  This blood will be used to measure the 
amount of HIV in your blood, CD4+ cell count, and CD8+ cell count (another type of 
blood cell that is affected by HIV).   
 
Once each year, you will also have an extra 40-55 mL (3-4 tablespoons) of blood drawn 
to test how your kidneys and liver are working and to look at the amount of sugar and 
types of fats (called lipids) in your blood.  You will be asked to not eat anything for at 
least 8 hours before these tests for sugar and lipids, and to not drink anything except 
water during that time.  You will give a urine sample which will also be tested to see 
how your kidneys are working. 
 
These results will be shared with you when they are available.  You will be asked what 
medicines you are taking.   
 
 
 
 
 
 
 
At your annual visit in 2016, you will also have an electrocardiogram (ECG), a routine 
test that allows the doctor to look at the rhythm of your heart.  This involves lying on a 
table and having 10 small electrodes stuck to your skin for at least 5 minutes while the 
test is done.  This procedure does not usually hurt.  You will not have any more ECGs 
done in the study after 2016. 
 
Throughout the long-term follow-up of the study 
Site instruction: 
If your site will not be collecting study-specific ECGs please remove the text 
in italics in the next paragraph.  If your site will be doing ECGs, please 
change the text to not be in italics. 

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It is very important to let your study doctor or nurse know right away if you are sick or 
injured or in the hospital.  This is important for your safety, and also for the study to 
learn more about illnesses that happen to people with HIV who are treated early (or 
defer treatment) for their HIV infection.  Your study doctor or nurse will ask you for 
permission to get medical records from your other doctors or from the hospital (if you 
were in the hospital).  You will be asked to give permission for other doctors or hospitals 
to share this information with the study team. 
 
You should tell your study nurse or doctor before you take any other medicines or 
dietary supplements or enroll in other clinical trials.  This is important because some 
medicines should not be taken together.  Your study doctor or nurse will help figure out 
what medicines and supplements are safe for you to take. 
 
Your doctor may decide to see you more often than required for the study based on 
your needs. 
 
 
 
 
 
 
Stored specimens for future research 
If you have agreed to have blood and urine specimens stored, you will be asked to give 
a 15-30 ml sample of blood (about 1-2 tablespoons) and a urine sample once each 
year.  These samples will be stored in a safe and secure laboratory in the United States 
for use in future research related to HIV infection, its complications, and the immune 
system.   
 
We will also collect a 10-mL sample of blood (about 2 teaspoons) if you change HIV 
medicines because of the amount of HIV virus in your blood or because resistance 
mutations have been detected. You will be asked for this sample before you start taking 
your new HIV medicines.  This blood will be used sometime in the future to confirm 
whether your HIV virus had stopped responding to the HIV medicines you were taking.   
 
You and your doctor will not receive any results from tests done on these stored 
samples.  No tests of your genes (DNA) will be done on these samples.  These samples 
will not have any information on them that can identify you by name.  There is no time 
limit on how long your samples will be stored.  You can still be in the START study even 
if you do not want to have samples stored.   
 
HOW WILL YOU GET HIV MEDICINES? 
If you are already taking HIV medicines provided by the study, you will continue to 
receive them.  Likewise, if you begin to take HIV medicines, you may receive them from 
the study.  The study will be able to give you HIV medicines through 2017.  It is possible 
you will be able to get some or all HIV medicines from the study after 2017, but we do 
not know that yet.  Your study doctor or nurse will let you know at least 6 months ahead 
Site Instruction: 
Please remove the Stored specimens section that follows if your IRB 
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of time if the study will not be able to give you some or all HIV medicines anymore.  
They will help you arrange to get HIV medicines no longer provided by the study 
through your insurance or some other program.   
 
WHAT IF YOU MOVE? 
If you move or transfer your medical care to another doctor, the study staff would like to 
continue to collect information about your health.  If you give permission, your study 
doctor or nurse will contact your new doctor and ask him or her to provide information 
about your health.  The types of information your new doctor will be asked for are 
routine things, such as results of laboratory tests (for example, CD4+ cell count and 
viral load), what medicines you are taking, and whether you have been sick.  When you 
move, you will be asked by the study staff to give permission for your new doctor to 
share this information with the study team.  Your new doctor may also ask you to give 
permission. 
 
WHAT ARE THE RISKS AND/OR DISCOMFORTS OF THIS STUDY? 
This section describes risks or discomforts that you may have.  There may be other 
risks to you (or to your baby, if you are a woman and become pregnant while taking HIV 
medicines) that we have no way of knowing about right now.  If other risks or benefits 
are found during the study, your study doctor or nurse will let you know about them right 
away. 
 
Possible risks of taking HIV medicines 
The long-term risks of using HIV medicines are not clear, and as with all medicines, 
side effects can happen.  However, your risks are no greater than taking these 
medications and not being followed in START.   
 
It is also possible for the HIV virus to develop resistance to any anti-HIV drug.  Longer 
follow-up in START will help us know if beginning to treat HIV earlier or later will lead to 
resistance to more HIV medicines over time. 
 
It is possible that someone could inadvertently find out that you are infected with HIV if 
you are taking HIV medicines and someone in your household or at work notices you 
taking them. 
 
Risks of drug-drug interactions (where one medicine affects how another works) 
For your safety, you must tell your doctor or nurse about all medicines, including 
prescription, over-the-counter (non-prescription), herbal or alternative medicines, and 
dietary supplements you are taking.  This is because there may be serious side effects 
when other medicines are taken with HIV medicines.  Also, please let your nurse or 
doctor know before you enroll in any other studies while on this study. 
 
Risk of transmitting HIV 
Using HIV medicines such that your viral load is undetectable has been shown to 
substantially lower your ability to transmit HIV to other people, but this does not work 
100% of the time.  You should continue to use precautions to make sure you do not 

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infect someone else.  Your study doctor or nurse will tell you about how to protect 
yourself and other people. 
 
Risks of blood drawing 
The risks of having blood taken include pain, bleeding, bruising, lightheadedness, 
anxiousness, and in rare cases fainting or infection or a blood clot where the needle 
enters the body.  You may feel some anxiety while waiting for your test results to be 
available.  You will have blood tests like those in this study done as part of your usual 
care, even if you decide not to be in this study. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
By being in START you have already helped in improving the treatment of many people 
with HIV now and in the future.  What we learn from your continued follow-up will tell us 
more about benefits and risks of therapy.  If you stay in START, there could also be 
some direct benefit to you.  For example, by being in a research study you may find out 
about treatments, services, or other things that could help you live with your HIV 
infection sooner than you would if you were not in a research study.  
 
It is also possible that you may receive no benefit from being in this study.  What we 
learn from this study may help us to improve the treatment of other people who are 
infected with HIV. 
 
WHAT IF THERE ARE NEW FINDINGS? 
You will be told about any new information learned during the study that might cause 
you to change your mind about staying in the study.   
 
WHAT IF YOU DON’T WANT TO BE IN THE STUDY ANY LONGER? 
If you consent to long-term follow-up in the START study, you may decide to stop 
participating at any time.  Withdrawing from this study will not affect the benefits of your 
regular medical care.  However, if you are receiving HIV medicines from the study, you 
will not continue to be given HIV medicines from the study after you withdraw.  Your 
doctor or nurse will help you find another way to get HIV medicines. 
 
CAN YOUR STUDY PARTICIPATION BE STOPPED WITHOUT YOUR CONSENT? 
You may be taken off the entire study without your consent if: 
 
Your study doctor decides that continuing in the study would harm you; 
 
The study is cancelled by the sponsor (the University of Minnesota), the National 
Institute of Allergy and Infectious Diseases (NIAID), regulatory authorities in your 
country, or your site’s Institutional Review Board (IRB)/Ethics Committee(EC); 
 
You are in jail or prison; or 
 
Other administrative reasons, including a lack of funding for START study follow-up 
past 2017. 
 
WHAT ARE THE COSTS TO YOU? 
<Site should insert specific information about what HIV medicines will be provided for 
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for all other medicines, including HIV medicines not listed above and medicines needed 
to prevent or treat other illnesses.  We will provide all clinical and professional services, 
lab work, and other tests that are part of this study and not part of your regular care at 
no cost to you.  As stated above, the study may at some point no longer be able to give 
you some or all of your HIV medicines.  At that time, your study doctor or nurse will help 
you get your HIV medicines from another source. 
 
HOW IS YOUR PRIVACY PROTECTED?  
Researchers will take every reasonable step to keep your health information private 
and to prevent misuse of this information.  You will not be identified by name or any 
other way in any publication about this study.  You will be identified only by a number 
code, and personal information from your records will not be released without your 
written permission.  We will collect dates of your study visits and of hospitalizations 
and certain illnesses so that we can answer the study questions as accurately as 
possible.  We will use a 3-letter code given to you at the beginning of START as a 
check on the number code assigned to you to make sure all of your information stays 
together.   
 
[The following paragraph must be included at U.S. sites only] 
In addition to these efforts to keep your information private, the START study and its 
substudies are covered by a Certificate of Confidentiality from the U.S. Department of 
Health and Human Services.  This certificate means that researchers cannot be forced 
to give information collected as part of this study to people who are not involved with 
the study, such as the court system.  However, this certificate has limited protection 
rights.  You should know that it does not stop the doctor in charge of this study from 
taking appropriate steps to prevent serious harm to yourself or others. 
 
[The following paragraph must be included at international sites only] 
We will try to keep your personal information private, but we cannot guarantee 
complete confidentiality.  Your personal information may be released if required by 
law.  Any publication of this study will not use your name or identify you personally.   
 
Your medical and research records may be seen by the [insert the name of the site] 
ethics committee (institutional review board, IRB), the U.S. National Institutes of 
Health (NIH), the U.S. Office for Human Research Protections (OHRP), and the 
research staff and monitors, and their designees.  The research staff at [insert the 
name of the site] is required to make sure that people not involved with this study 
cannot see your research and medical records while collecting personal information 
about you.  They will keep your files in a locked cabinet in a safe place and will handle 
your personal information very carefully.  This will also help to protect your privacy. 
 
 
 
 
 
 
Site Instruction: 
If the information in the next paragraph is not correct for your 
country/site, please revise the information to inform the subject of the 
following:  1. what treatment will be provided to the subject; 2. who will 
pay for the treatment; 3. if there is any plan for compensation for 
research-related injury issues, such as lost wages, etc. 

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WHAT IF YOU ARE INJURED? 
If you are injured because of being in this study, [insert the name of the clinic] will give 
you immediate necessary treatment for your injuries.  The cost for this treatment will be 
charged to you or your insurance company.  You will then be told where you may 
receive additional treatment for injuries.   There is no program for monetary 
compensation.  This means that if you are hurt by being in the study, there is no money 
set aside to pay for treatment of injuries or other costs.  You do not give up any of your 
legal rights by signing this form. 
 
 
WHAT IF YOU HAVE PROBLEMS OR QUESTIONS? 
If you ever have questions about this study or in case of research-related injuries, you 
should contact [insert the name of the study doctor at your site] at [insert the telephone 
number].  If you have questions about research subject’s rights you can call [insert the 
name and title of the appropriate country- or site-specific person] at [insert the 
telephone number]. 
 

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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN EXTENDED FOLLOW-UP 
OF THE START STUDY 
 
If you have read the informed consent (or if you have had it explained to you) and 
understand the information, and you voluntarily agree to continue in START, please 
sign your name below. 
 
 
 
 
 
______________________________________________________ 
Participant’s name 
(typed or printed) 
 
 
____________________________________________________   _________ 
Participant’s signature   Date 
OR 
 
______________________________________________________ 
Participant’s legal guardian or representative name 
(typed or printed) 
 
 
____________________________________________________   _________ 
Legal guardian/representative’s signature  Date 
 
 
 
______________________________________________________ 
Witness’s name 
(typed or printed) 
 
 
____________________________________________________   _________ 
Witness’s signature    Date 
 
NOTE:  This consent form with the original signatures MUST be retained on file 
by the principal investigator.  A copy must be given to the participant.  A copy 
should be placed in the participant’s medical record. 
 
A witness to the participant’s signature is strongly encouraged. 
 

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SIGNATURE PAGE FOR CONSENT TO STORE BLOOD AND URINE SPECIMENS  
 
If you have read the information about stored specimens for future research in the 
informed consent (or if you have had it explained to you) and understand the 
information, please mark your choice in one of the boxes below and sign or initial as 
asked.  
 
You can still participate in extended follow-up of the START study even if you 
do not want to have samples stored. 
 
Please mark your choice: 
 
  YES.  I agree to have blood and urine samples collected and stored and used for 
future research.  Please sign below. 
 
  NO.  Do not collect and store samples.  Please put your initials and today’s date 
here  
              ____________________________    Do NOT sign below. 
 
 
______________________________________________________ 
Participant’s name (typed or printed) 
 
 
____________________________________________________   _________ 
Participant’s signature   Date 
OR 
 
______________________________________________________ 
Participant’s legal guardian or representative name (typed or printed) 
 
 
____________________________________________________   _________ 
Legal guardian/representative’s signature  Date 
 
 
NOTE:  This consent form with the original signatures MUST be retained on file 
by the principal investigator.  A copy must be given to the participant.  A copy 
should be placed in the participant’s medical record. 
Site Instruction: 
If your IRB/EC requires a separate consent document for specimen storage, 
do not use this signature page.  Instead, use the START STUDY SPECIMEN 
STORAGE (PLASMA AND URINE) SAMPLE CONSENT (Appendix A-2). 

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START STUDY SAMPLE CONSENT FOR EXTENDED 
FOLLOW-UP 
 (Version 4.0)  
 
 
University of Minnesota:  SPONSOR 
NIAID:  PRIMARY FUNDER 
 
Protocol Title: 
Strategic Timing of Anti-Retroviral Treatment 
(START) 
 
A Multicenter Study of the 
International Network for Strategic Initiatives in Global HIV Trials 
(INSIGHT) 
 
Short Title of the Study:  START 
 
CONSENT FOR PARTICIPATION IN AN NIH-FUNDED RESEARCH TRIAL 
 
 
SITE LEADER:  ____________________________________ PHONE:  __________ 
 
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
REMOVED FROM THE SITE’S INFORMED CONSENT FOR SUBJECTS 
 
 
 
 
 
 
 
 
 
 
Because you are a part of the START Study, we invite you to continue to be followed in 
START through 2021.  We hope this follow-up will give helpful additional information 
about the long-term effects of HIV medicines. 
 
It is up to you whether or not you want to continue.  Please ask questions and take as 
much time as you need to decide. 
 
OHRP Requirements to be read by the sites: 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL IRB REVIEW AND APPROVAL.  
INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL IRB WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE 
LANGUAGE INTENDED FOR LOCAL USE.  LOCAL IRBS ARE REQUIRED TO WEIGH THE UNIQUE RISKS, CONSTRAINTS, AND 
POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  ANY DELETION OR SUBSTANTIVE CHANGE OF 
INFORMATION CONCERNING RISKS OR ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED 
BY THE LOCAL IRB, AND NOTED IN THE IRB MINUTES.  JUSTIFICATION AND IRB APPROVAL OF SUCH CHANGES MUST BE 
FORWARDED TO THE INTERNATIONAL COORDINATING CENTER.  SPONSOR-APPROVED CHANGES IN THE PROTOCOL MUST 
BE APPROVED BY THE LOCAL IRB BEFORE USE UNLESS INTENDED FOR THE ELIMINATION OF APPARENT IMMEDIATE 
HAZARD.  NEW INFORMATION SHALL BE SHARED WITH EXISTING SUBJECTS AT NEXT ENCOUNTER, WITH ALL NEW 
SUBJECTS PRIOR TO INVOLVEMENT, OR AS THE LOCAL IRB MAY OTHERWISE ADDITIONALLY REQUIRE. 
 

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All of the people already in the START study are being asked to continue follow-up.    
 
WHAT WILL HAPPEN DURING THE EXTENDED FOLLOW-UP IN START? 
Starting on 01 January 2018, regular study visits are no longer required for START. Once a 
year the staff at your study site will collect information about any HIV medicines you are taking, 
any illnesses or hospitalizations you have had, and the results of CD4, CD8, and HIV viral load 
tests that you have had.  If you are seen at the site for your HIV care, the study staff will review 
your medical records to collect this information.  They may call you if they have questions.  
 
If you do not receive your regular heath care at the site, the research staff will contact you to 
see how you are doing and may ask you to come in for a study visit.  If you get your regular 
HIV care at a different clinic, the site staff will ask for your written permission to get the records 
from this clinic to review.   
 
WHAT ARE THE RISKS OF START? 
There are no risks associated with continuing your follow-up in START.  Your medical care and 
treatment will be decided by you and your regular doctor.  There are no specific study 
requirements to be followed.  All HIV medicines have some side effects.  There may also be 
long-term risks that we do not know about now.  This is true for anyone taking HIV medicines, 
whether or not you are in the START study.  Even if you are taking HIV medicines, you may 
still be able to give HIV to someone else.  Your doctor or nurse will tell you about how to 
protect yourself and other people. 
 
We will tell you if we learn about new risks or any other information that might be important to 
you. 
 
WHAT ARE THE BENEFITS OF CONTINUING IN START? 
Taking HIV medicines can help people with HIV infection.  However, we do not know all of the 
effects that taking them for a long time might have on your general health.  By continuing to 
follow people like you in the START study we will learn more about these effects. 
 
WHAT CHOICES DO YOU HAVE OTHER THAN CONTINUING IN START? 
You do not have to continue in START if you do not want to.  If you agree to continue, you can 
stop at any time.  If you choose not to continue or to stop, it will not affect your regular medical 
care.  
 
CAN YOUR PARTICIPATION IN START BE STOPPED EVEN IF YOU DON’T AGREE? 
The study doctor can take you out of START if you go to prison, or if the study is stopped by 
the study funder, sponsor, review committees (IRB/REC) or government authorities, or for 
other administrative reasons.   
 
WHO WILL BE ABLE TO SEE YOUR MEDICAL INFORMATION? 
We will protect the privacy of your medical information as much as legally possible, and 
release your records only with your written permission.  We will label your study records with a 
code number and three letters, and you will not be identified in any publications about this 
research.   However, your records may be seen by: 

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 
People in the US government agencies that fund or oversee this research, for example, the 
U.S. National Institutes of Health (NIH). 
 
Study monitors who make sure the study is being conducted correctly.  
 
Independent groups (IRBs or ethics committees) that make sure the study is ethically 
acceptable.   
 
 
[Include the following paragraph at US sites only] 
We have a Certificate of Confidentiality from the US Government.  This means that law 
enforcement officers, the courts, and others cannot force us to give them information 
about you. However, this does not prevent the study team from taking appropriate steps 
to prevent serious harm to you or to others.   
 
WHAT IF YOU ARE INJURED AS PART OF THE STUDY? 
We will provide treatment right away if you are hurt because of the research.  The costs may 
be charged to you or your insurance company.  We will give you information about where you 
can get additional treatment.  You do not give up any of your legal rights by signing this form. 
 
 
 
 
 
 
 
 
 
WHO CAN YOU TALK TO ABOUT THIS STUDY? 
Please contact (site PI and contact information) if you have any questions or concerns about 
this research study or contact (name and contact info) if you have concerns about your rights 
as a research participant or you are injured as part of this study.  
Site Instruction: 
If the information is not correct for your country/site, please revise the 
information to inform the subject of the following:  1. what treatment will be 
provided to the subject; 2. who will pay for the treatment; 3. if there is any plan 
for compensation for research-related injury issues, such as lost wages, etc. 

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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN START EXTENDED 
FOLLOW-UP 
 
If you have read the informed consent (or if you have had it explained to you) and 
understand the information, and you voluntarily agree to continue in this study, please 
sign your name below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________ 
Witness’s name 
(typed or printed) 
 
 
____________________________________________________   _________ 
Witness’s signature    Date 
 
NOTE:  This consent form with the original signatures MUST be kept on file by the 
principal investigator.  A copy must be given to the participant.  A copy should be 
placed in the participant’s medical record. 
 
A witness to the participant’s signature is strongly encouraged. 
 
 
 
______________________________________________________ 
Participant’s name 
(typed or printed) 
 
 
____________________________________________________   _________ 
Participant’s signature   Date 
OR 
 
______________________________________________________ 
Participant’s legal guardian or representative name 
(typed or printed) 
 
 
____________________________________________________   _________ 
Legal guardian/representative’s signature  Date 

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Reference-1 
REFERENCES 
                                            
 
1 Babiker AG, Emery S, Fätkenheuer G, et al.  Considerations in the rationale, design 
and methods of the Strategic Timing of AntiRetroviral Treatment (START) study.  Clin 
Trials 2013;10(1 Suppl):S5-S36. 
 
2 The INSIGHT START Study Group.  Initiation of antiretroviral therapy in early 
asymptomatic HIV infection. N Engl J Med 2015;373:795-807. 
  
3 The TEMPRANO ANRS 12136 Study Group.  A trial of early antiretrovirals and 
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4 Cohen MS, Chen YQ, McCauley M, et al.  Prevention of HIV-1 infection with early 
antiretroviral therapy.  N Engl J Med 2011;365:493-505. 
 
5 Rodger AJ, Cambiano V, Bruun T, et al.  Sexual activity without condoms and risk of 
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6 https://aidsinfo.nih.gov/news/1592/statement-from-adult-arv-guideline-panel---start-
and-temprano-trials, July 28, 2015. 
 
7 http://www.who.int/hiv/pub/arv/policy-brief-arv-2015/en/ (Accessed December 6, 
2015). 
 
8 http://www.bhiva.org/documents/Guidelines/Treatment/2015/2015-treatment-
guidelines.pdf (Accessed December 6, 2015) 
 
9 Baker JV, Sharma S, Grund B, et al.  The effect of ART on inflammation, coagulation 
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10 UNAIDS/AIDS estimates. http://www.who.int/hiv/data/en/ 
 
11 CDC. HIV Surveillance Supplemental Report, Monitoring selected national HIV 
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12 European Centre for Disease Prevention and Control.  The status of the HIV 
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13 Althoff KN, Gange SJ, Klein MB, et al. Late presentation of human immunodeficiency 
virus care in the United States and Canada.  CID 2010; 50:1512-1520. 
 
14 Hall HI, Tang T, Espinoza L.  Late diagnosis of HIV infection in metropolitan areas of 
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15 Mocroft A, Lundgren JD, Sabin ML, et al.  Risk factors and outcomes for late 
presentation for HIV-positive persons in Europe: results from the Collaboration of 
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16 European Centre for Disease Prevention and Control.  The status of the HIV 
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17 Drain PK, Losina E, Parker G, et al. Risk factors for late-stage HIV disease 
presentation at initial HIV diagnosis in Durban, South Africa. PLoS One 2013; 8: 
e55305. 
  
18 Lahuerta M, Ue F, Hoffman S, et al.  The problem of late ART presentation in Sub-
Saharan Africa: a transient aspect of scale-up or a long-term phenomenon?  J Health 
Care Poor Underserved 2013; 24: 359-383. 
 
19 The HIV-Causal Collaboration. Comparative effectiveness of immediate antiretroviral 
therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: 
observational cohort study. Lancet HIV 2015; 2: e335-e-345. 
 
20 May MT, Vehreschild J, Trickey A, et al.  Mortality according to CD4 count at start of 
combination antiretroviral therapy among HIV-infected patient followed for up to 15 
years after start of treatment: collaborative cohort study. CID 2016; 62: 1571-1577. 
  
21 Lang S, Mary-Krause M, Simon A, et al.  HIV replication and immune status are 
independent predictors of the risk of myocardial infarction in HIV-infected individuals.  
CID 2012; 55:600-607. 
  
22 Mocroft A, Lundgren J, Ross M, et al.  Development and validation of a risk score for 
chronic kidney disease in HIV infection using prospective cohort data from the D:A:D 
study.  PLoS Med 2015; 12:e1001809. 
  
23 Clifford GM, Franceschi S, Keiser O, et al.  Immunodeficiency and the risk of cervical 
intraepithelial neoplasia 2/3 and cervical cancer: a nested case-control study in the 
Swiss HIV cohort study. Int J Cancer 2016; 138:1732-1740. 
  
24 Sharma S, Babiker AG, Emery S, et al.  Demographic and HIV-specific characteristics 
of participants enrolled in the INSIGHT Strategic Timing of AntiRetroviral Treatment 
(START) trial.  HIV Medicine 2015;16(Suppl 1):30-36. 
 
25 National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney 
disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-S266. 
 

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26  Duong YT, Qiu M, De AK, et al.  Detection of recent HIV-1 infection using a new 
limiting-antigen avidity assay: potential for HIV-1 incidence estimates and avidity 
maturation studies.  PLoS One 2012; 7:e33328. 
 
27 Longosz AF, Morrison CS, Chen PL, et al.  Immune responses in Ugandan women 
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antibody avidity assay.  J Acquir Immune Defic Syndr 2014; 65:390-396. 
  
28 Kalbfleisch JD, Prentice RL.  The statistical analysis of failure time data.  2nd ed., New 
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