Detailed results from the START study

Researchers in 35 countries across all continents collaborated to recruit 4,685 HIV-positive adults who were in good health for START. Upon entry to the study, all participants had CD4+ cell counts greater than 500 cells/mm³. Researchers randomly assigned participants to receive one of the following interventions:

• to start potent combination anti-HIV therapy (ART) immediately
• to defer initiation of ART until the CD4+ count fell to 350 cells/mm³ or until a serious illness developed

In this report we will refer to people in the first intervention as the immediate ART group and to people in the second intervention as the deferred ART group.

After an average time of three years in the study, researchers found that the following occurred among participants:

• immediate ART – 42 participants developed serious illness or died
• deferred ART – 96 participants developed serious illness or died

Clearly, the use of ART early in the course of HIV disease cuts the risk for developing serious AIDS-related illness by more than 50%.

Unexpectedly, nearly 70% of cases of AIDS and other serious outcomes that occurred in START participants did so in those who had more than 500 CD4+ cells/mm³. In high-income countries most of these unfavourable outcomes were related to cancer or cardiovascular disease. These and other results from the study appear below.

Study details

The average profile of participants at the start of the study was as follows:

• age – 36 years
• 73% men, 27% women
• length of time HIV positive – one year
• CD4+ count – 651 cells/mm³
• viral load – 13,000 copies/ml
• current smoker – 32%
• major ethno-racial groups: white – 45%, black – 30%, Latino – 14%, Asian – 8%

Common routes of HIV infection were as follows:

• men who had sex with men – 55%
• heterosexual sex – 38%
• contaminated blood products – 5%
• injecting street drugs – 1%

Researchers assigned 2,326 participants to receive immediate ART and 2,359 to deferred ART.

Results—Serious illness

Later in this report we provide details about the major clinical events (main illnesses) that occurred during START, but for now we summarize the results.

The distribution of major clinical events was as follows:

• immediate ART – 42 participants
• deferred ART – 96 participants

These differences between the two groups were statistically significant; that is, not likely due to chance alone.

Researchers found that there were two major benefits for participants who received immediate therapy as follows:

• a 72% reduction in the relative risk of serious AIDS-related events
• a 39% reduction in the relative risk of serious non-AIDS-related events; this was mostly due to a reduction in cancers unrelated to AIDS

The following specific major categories of illness that occurred during the study were more likely to happen to participants who deferred therapy:

Serious AIDS-related events

• Immediate ART group – 14 cases
• Deferred ART group – 50 cases

Serious non-AIDS-related events

• Immediate ART group – 29 cases
• Deferred ART group – 47 cases

Death from any cause

• Immediate ART group – 12 cases
• Deferred ART group – 21 cases

Tuberculosis

• Immediate ART group – six cases
• Deferred ART group – 20 cases

Kaposi’s sarcoma

• Immediate ART group – one case
• Deferred ART group – 11 cases

Lymphoma

• Immediate ART group – three cases
• Deferred ART group – 10 cases

Serious bacterial infections

• Immediate ART group – 14 cases
• Deferred ART group – 36 cases

Focus on cardiovascular disease

In this study, researchers defined cardiovascular disease as having one or more of the following:

• heart attack
• stroke
• interventions to widen or bypass clogged arteries; these blood vessels supply the heart with fresh oxygenated blood. These interventions generally take one of two forms: (1) A tiny tube is implanted within a blood vessel to keep it open. (2) Doctors can remove blood vessels from a person’s legs and implant them in the chest to bypass clogged arteries and to supply the heart with freshly oxygenated blood. These procedures that require surgery are called coronary revascularization.

In START, cardiovascular disease was relatively common as a major event.

Focus on cancers

Common AIDS-related cancers that occurred in START were as follows:

• Kaposi’s sarcoma (KS)
• lymphoma (Hodgkin’s and non-Hodgkin’s)

Cancers unrelated to AIDS that affected a broad range of organ-systems also occurred. However, none of these specific cancers was common.

AIDS-related events

Common AIDS-related events that occurred were as follows:

• TB
• KS
• lymphoma

Researchers found that there were differences in the distribution of AIDS-related events. For instance, most cases (62%) of TB occurred among people who lived in Africa. TB is relatively common in parts of this continent, so this distribution of TB in START should not be surprising.

In contrast, most cases of cancer (81%) and cardiovascular disease (73%) occurred in participants living in high-income countries.

KS is caused by a member of the herpes virus family called HHV-8 (human herpes virus-8). The growth of lymphomas can be triggered by infection with another member of the herpes virus family called EBV (Epstein-Barr virus). Both of these viruses are sexually transmitted and relatively common among men who have sex with men, particularly those living in high-income countries that participated in START. In general, these viruses do not normally cause serious problems unless a person’s immune system is weakened, in this case by HIV.

About adverse events

The term adverse event applies to certain poor outcomes that can occur in a clinical trial, including potential side effects and so on. Some of these events may not be related to the medicines or procedures used in a study.

In START, a total of 16 suspected serious adverse events occurred in 16 people. All 16 suspected serious adverse events might have been related to the study medicines. After investigators assessed the 16 cases they found that, in general, the majority of them were not apparently related to the use of anti-HIV drugs.

For the sake of argument, let’s say all 16 cases were somehow caused by exposure to anti-HIV medicines (highly unlikely). If we divide these 16 people by 3,421 (the total number of people who were taking ART), the result would be equivalent to less than half of one percent of participants. Therefore, it is safe to say that serious adverse events due to ART were rare in START. This should reassure both doctors and their patients.

There was no increased risk for serious adverse events in either study group (immediate or deferred ART).

An unexpected finding

Study researchers kept close track of participants’ CD4+ cell counts, particularly when serious illness developed. An unexpected finding from START was that the majority of serious illness (both AIDS-related and not) occurred when CD4+ counts were relatively high—500 cells/mm³ or greater.

With START, for the first time, high-quality data from a clinical trial have shown that HIV-positive people who have what was previously considered a relatively high CD4+ count (more than 500 cells) can and do develop serious illness.

Hospitalization and death

According to the START researchers, 12 people in the immediate ART group and 21 people in the deferred ART group died. This difference was not statistically significant.

The causes of death as supplied by the researchers are as follows:

Immediate ART – 12 deaths

• AIDS, ongoing active disease – one person
• cardiovascular disease – one person
• sudden death, cause unknown – two people
• cancer unrelated to AIDS – one person
• accident/violence – four people
• unknown – three people

Deferred ART – 21 deaths

• AIDS, ongoing active disease – four people
• cardiovascular disease – one person
• cancer unrelated to AIDS – one person
• chronic viral hepatitis – one person
• kidney failure – one person
• infection – one person
• type 2 diabetes – one person
• accident/violence – three people
• suicide – three people
• substance abuse – two people
• unknown – three people

A hole in the immune system

The findings from START reinforce the urgency of calls to begin ART shortly after HIV has been diagnosed. These findings also underscore the problem of using CD4+ count as a measure of overall health. For many years prior to START, researchers and doctors discouraged the initiation of ART when CD4+ counts were at or above the 500-cell mark. This practice arose because of at least two reasons, as follows:

1. Fifteen years ago, doctors lowered the CD4+ count threshold at which ART should be started to 200 cells/mm³ because the anti-HIV treatments then in use could cause serious side effects.
2. The possibility that AIDS-related life-threatening infections and cancers could occur in people with CD4+ counts of 500 cells/mm³ or greater seemed very unlikely.

That such complications can and did occur in START raises the following issue:

• CD4+ cell counts do not provide a highly accurate measure of the immune system’s strength. Indeed, the START results underscore the serious injury sustained by the immune system early in the course of HIV disease. START co-chair Jens Lundgren, MD, of the University of Copenhagen, summed up the immunological injury caused by HIV by stating that the results of START underscore the fact that “there is a hole in the immune system” that occurs early in the course of HIV disease and is not readily apparent when CD4+ counts are used to assess health.

Points to consider

Study researchers stated that the results of START “provide policy makers, clinicians and HIV-positive patients with the data to inform policies regarding the initiation of [ART].”

A growing international scientific and medical consensus suggests that doctors, nurses and important agencies are going to recommend that immediate treatment be offered to people who test positive for HIV. The U.S. Department of Health and Human Services (DHHS) has treatment guidelines that recommend the initiation of therapy regardless of CD4+ count. The World Health Organization (WHO) will release guidelines that make a similar recommendation. Updated treatment guidelines in the U.K. will also feature similar advice, having taken into account the results of START.

Many clinical trials in HIV medicine have a relatively small proportion of women. START pushed back against this trend by having a significant proportion of women enrolled—nearly 27%. Therefore, the findings from START also apply to women.

The benefit of starting ART early in the course of HIV disease is clear: a large and significant reduction in the risk of serious infections and cancers. For instance, among people who initiated immediate ART, there was a 72% reduction in their risk for developing serious AIDS-related infections and cancers. Immediate initiation of ART also led to a reduced relative risk of 39% for developing cancers unrelated to AIDS. This led START researchers to state that immediate initiation of ART has “broad positive effects” on health.

According to the START team, “most of the AIDS-related and non-AIDS-related infections occurred when patients had a high CD4+ cell count.” Furthermore, the researchers noted that “a substantial part of the beneficial effect of immediate treatment is due to changes induced by [ART] in [cells and/or proteins in the blood] other than CD4+ cells.” This underscores that there is still much to learn about the immune system and that even people with more than 500 CD4+ cells/mm³ are at risk for serious illness if they have not started ART.

What’s more, the researchers pointed out that even among people who took ART and whose viral load subsequently fell to less than 50 copies/ml, “the risk of AIDS was not zero.” They also stated that this finding means that “damage to the immune system may occur early in the course of HIV infection.” This provides a strong reason for starting ART as soon as possible after HIV infection has been diagnosed. It also underscores the need for scientists to study the immune system and find more accurate ways to assess its health.

In other studies, ART has been shown to reduce the amount of HIV in the blood and tremendously decrease the risk of transmitting HIV via sex. This finding from other studies is yet another compelling reason for HIV-positive people to consider starting ART as soon as possible after their diagnosis.

—Sean R. Hosein

REFERENCES:

1. Lundgren J, Babiker A, Gordin F, et al. The START study: design, conduct and main results. In: Program and abstracts of the 8^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2015. Abstract MOSY0302.
2. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infectious Diseases.  2014 Apr;14(4):281-90.