Strategic Timing of Antiretroviral Treatment

Study Overview
=================
Brief Summary
-----------------
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 cluster-of-differentiation-4 (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.

Detailed Description
-----------------
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.

Official Title
-----------------
Strategic Timing of AntiRetroviral Treatment

Conditions
-----------------
HIV Infection

Intervention / Treatment
-----------------
* Drug: All licensed antiretroviral medications


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early ART<br>Initiate ART immediately following randomization | Drug: All licensed antiretroviral medications<br>* In both arms, participants may be prescribed any licensed antiretroviral medication, in accordance with national treatment guidelines. The nature of the intervention is the timing of when to begin treatment with these medications, as described in the two treatment arms.<br>|
| Active Comparator: Deferred ART<br>Defer ART until the CD4+ count declines to <350 cells/cu mm or AIDS develops | Drug: All licensed antiretroviral medications<br>* In both arms, participants may be prescribed any licensed antiretroviral medication, in accordance with national treatment guidelines. The nature of the intervention is the timing of when to begin treatment with these medications, as described in the two treatment arms.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Endpoint of AIDS, Serious Non-AIDS Diagnoses, and All-cause Mortality |  | 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AIDs or AIDs Related Death | participant count | 4.5 years | 
| Specific Non-AIDS Diagnoses |  | 4.5 years | 
| Death, All-cause Mortality | Count of participants | 4.5 years | 
| Quality of Life- Mean Change From Baseline in a Visual Analog Scale (VAS) for Perceived Current Health | Mean change from baseline of the VAS. This was a single data item where participants self-reported their perceived current state of health on a scale of 0-100 (0=worst possible and 100=best possible). | 4.5 years | 
| Transmission Risk Behavior Outcome 1 | Proportion of participants identifying as men who have sex with men (MSM) engaging in condomless sex with HIV serodifferent partners (CLS-D) at study month 12. Participant completed a self-reported questionnaire on transmission risk behavior during the past two months at the month 12 visit following randomization. | 12 months | 
| Change in Neurocognitive Function (in a Subset of Participants) | Mean change from baseline of the QNPZ-8 score. In the Neurology substudy of START, participants were administered a neuropsychological test battery of 8 tests (grooved peg board, finger tapping, Color Trails 1 and 2, Semantic Verbal Fluency, WAIS III Digit Symbol, HVLT-R Learning, HVLT-R Delayed Recall). Test scores were standardized to z-scores using baseline values as reference such that baseline values had a mean of 0 and standard deviation of 1. Test scores were standardized to z-scores using baseline values as reference such that baseline values had a mean of 0 and standard deviation of 1. Z-scores > 0 indicate improvement over baseline levels. The quantitative neuropsychological performance z-score (QNPZ-8) was the mean of the z-scores across the the 8 tests. Analyses were by intention-to-treat principles. | 4.5 years | 
| Large Artery Elasticity (in a Subset of Participants) | Mean change from baseline in large arterial elasticity. In the Arterial Elasticity substudy of START, participants had non-invasive measurements of radial artery blood pressure waveforms recorded at baseline, study months 4, 8, and 12, and then annually. Small arterial elasticity (SAE) and large arterial elasticity (LAE) were derived from analysis of the diastolic pulse waveform. Analyses were by intention-to-treat principles. | 4.5 years | 
| Rate of Lung Function Decline (in a Subset of Participants) Among | Rate of lung function decline (slope of forced expiratory volume (FEV1)) over follow-up among self-reported smokers at study entry. In the pulmonary substudy of START, participants had post-bronchodilator spirometry measures collected at baseline and annually. Analyses were by intention-to-treat principles. | 4.5 years | 
| Changes in Bone Mineral Density (in a Subset of Participants) Measure 1 | Mean percent change from baseline in bone mineral density at the spine. In the bone mineral density (BMD) substudy of START, participants underwent dual-enery x-ray absorptionmetry (DXA) to measure BMD at the spine and hip at baseline and annually. Analyses were by intention-to-treat principles. | 4.5 years | 
| Transmission Risk Behavior Outcome 2 | Percentage of participants identifying as hetrosexual engaging in condomless sex with HIV serodifferent partners (CLS-D) at study month 12. Participant completed a self-reported questionnaire on transmission risk behavior during the past two months at the month 12 visit following randomization. | 12 month visit | 
| Small Artery Elasticity (in a Subset of Participants) | Mean change from baseline in small arterial elasticity. In the Arterial Elasticity substudy of START, participants had non-invasive measurements of radial artery blood pressure waveforms recorded at baseline, study months 4, 8, and 12, and then annually. Small arterial elasticity (SAE) and large arterial elasticity (LAE) were derived from analysis of the diastolic pulse waveform. Analyses were by intention-to-treat principles. | 4.5 years | 
| Rate of Lung Function Decline (in a Subset of Participants) Among Non-smokers | Rate of lung function decline (slope of forced expiratory volume (FEV1)) over follow-up among self-reported non-smokers at study entry. In the pulmonary substudy of START, participants had post-bronchodilator spirometry measures collected at baseline and annually. Analyses were by intention-to-treat principles. | 4.5 years | 
| Changes in Bone Mineral Density (in a Subset of Participants) Measure 2 | Mean percent change from baseline in bone mineral density at the spine. In the bone mineral density (BMD) substudy of START, participants underwent dual-enery x-ray absorptionmetry (DXA) to measure BMD at the spine and hip at baseline and annually. Analyses were by intention-to-treat principles. | 4.5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, highly active antiretroviral therapy (HAART), CD4 Count, Early Intervention, HIV Infection, HIV Infections, treatment naive