Strategic Timing of Antiretroviral Treatment

Background:

- Most guidelines agree that if the number of your CD4+ cells (cells in your blood which
help fight infection) drops below 350 cells/mm3, or if you have symptoms of AIDS, you
should start taking HIV medicines. There are randomized trials that support this
recommendation. (Randomized trials are usually considered the strongest form of evidence
to support treatment decisions. Other studies, like observational studies, provide
evidence too, but the evidence is often considered to be weaker than evidence from
randomized trials. A randomized trial gives the most certain information about how well
a treatment works because randomization makes sure each group is similar except for the
treatment they receive.) Some experts believe that HIV treatment should be started even
when the number of CD4+ cells is above 350 cells/mm3. For example, guidelines issued in
the US in December 2009 include a new recommendation for starting HIV medicines if your
CD4+ cell count is between 350 and 500 cells/mm3. However, this recommendation is based
on information from observational studies, not randomized trials. We are doing this
study to find out if the chances of getting a serious illness or of getting AIDS are
less if people start taking HIV medicines at a time when their CD4+ cell counts are
still fairly high, instead of waiting to take HIV medicines at a CD4+ count where there
is good evidence for starting medicines.

Objectives:

- To find out if the chance of developing a serious illness or of getting AIDS is less if
patients start taking HIV medicines at a time when their CD4+ cell count is still fairly
high, instead of waiting until the CD4+ count is at the level where there is good
evidence for starting medicines.

- To learn more about how a strategy of starting HIV medicines early might affect other
aspects of care, such as the chances of developing other illnesses or resistance to HIV
medicines, the frequency of doctor visits, the cost of medical care, and general health
and satisfaction.

Eligibility:

- Patients 18 years of age and older who are infected with HIV, have CD4+ cell counts of
greater than 500 cells/mm3, and who have never had antiretroviral therapy to treat HIV.

Design:

- Initial screening visits (2) to draw blood for CD4+ cell counts and provide a full
medical history

- Patients will be randomly split into two groups:

Early: Patients will begin receiving HIV medications from the start of the study.

Deferred: Patients will begin to take HIV medications when the CD4 drops below 350 cells/mm3,
or they develop AIDS or other symptoms of HIV infection.

- HIV medications for each patient will be determined by the study doctors.

- Evaluations during the treatment period:

- Physical examination, including vital signs and body weight checks, and pregnancy test
for women who can become pregnant.

- Questions about daily life, including sexual behaviors.

- Blood and urine tests.

- Heart tests with electrocardiogram.

- Patients will return for evaluations at 1 and 4 months after randomization, and every 4
months thereafter for the duration of the study.

Substudies will take advantage of the START randomization to compare outcomes in people
starting ART early vs. later.

The purpose of this randomized study is to determine whether immediate initiation of
antiretroviral treatment (ART) is superior to deferral of ART until the CD4+ declines below
350 cells/mm(3) in terms of morbidity and mortality in HIV-1 (subsequently referred to as
HIV) infected persons who are antiretroviral naive with a CD4+ count above 500 cells/mm(3).

The study will enroll an estimated 4,000 participants. Participants will be followed for at
least 3 years after enrollment, to a common closing date.

Substudies will take advantage of the START randomization to compare outcomes in people
starting ART early vs. later. These will measure outcomes that do not require the entire
sample size of START to determine whether early ART is related to a difference in these
outcomes over the course of the study.

INCLUSION CRITERIA:

- Signed informed consent

- HIV infection documented by a plasma HIV RNA viral load, rapid HIV test or any
licensed* 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 greater than or equal to 18 years

- Karnofsky performance score greater than or equal to 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 greater than 500 cells/mm(3) at least 2 weeks apart within 60
days before randomization

- 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.

EXCLUSION CRITERIA:

- Any previous use of ART or interleukin-2 (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

- 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)