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CATIE News - Massive study called ART-CC examines causes of death among HAART users

11/05/2010 - The release of highly active antiretroviral therapy (HAART) in 1996 dramatically reduced deaths from AIDS-related infections among people who had access to these medicines and were able to adhere to and tolerate them. The power of HAART is so profound that researchers increasingly expect growing numbers of HIV-positive people to live near-normal life spans, particularly in high-income countries because of their social-welfare systems.

Despite this good news, there are some long-term issues that doctors and their patients must face, including these:

  • The immune system is only partially restored from HAART and as a result there is an increased risk of cancer.
  • The body continues to age, a process perhaps speeded-up by HIV.
  • The low-level production of HIV continues within the body and this helps keep the immune system in an activated state. Being constantly activated for many years negatively affects the immune system and likely the body's organs, slowly damaging them.
  • All of these factors may place some HIV-positive people at risk for health-related complications-cardiovascular disease, diabetes, thinning bones-as they age.

    Researchers in Canada, the United States and Western Europe have been collecting health-related information from HIV-positive people who began HAART between 1996 and 2006. The collection and analysis of this data is part of a project called ART-CC-the Antiretroviral Therapy-Cohort Collaboration. This project has enrolled nearly 40,000 HIV-positive people and serves as a powerful tool to help identify trends in health across high-income countries.

    The most recent analysis of the ART-CC appears in the May 15th, 2010 issue of the journal Clinical Infectious Diseases. This analysis has focused on causes of death among HAART users. Overall, there is good news: HIV-positive people are living longer. However, the ART-CC has also found disquieting trends: Previously uncommon causes of death have been increasing. Furthermore, the ART-CC has found that some HIV-positive people, particularly injection drug users (IDUs), have rates of death that are relatively high. The ART-CC is a valuable project and has performed a rigorous analysis that can help physicians, nurses, clinics, hospitals and health policy planners work to continue to save the lives of HIV-positive people.

    Study details

    The average profile of the 39,272 participants when they began HAART was as follows:

    • 27% females, 73% males
    • main risk groups were gay and bisexual men 36%; heterosexual 41%; IDUs 13%
    • 82% were 30 years or older
    • 53% had a CD4+ count of at least 200 cells
    • 47% had a viral load of at least 100,000 copies

    For the latest ART-CC analysis, participants were in this study for about four years.


    Over the course of the study, about 5% (1,876) of participants died. On average, HAART users who died had this profile:

    • age - 37 years
    • CD4+ count - about 110 cells

    Roughly half of the main causes of death were from AIDS-related complications, about a third of which were due to cancers.

    Deaths unrelated to AIDS were most commonly due to the following:

    • cancers unrelated to AIDS (12%) - these included cancers of the intestine, lips, lungs, mouth/throat and skin
    • infections unrelated to AIDS (8%)
    • cardiovascular diseases (8%) - half of these were due to heart attacks and nearly one-fifth to stroke
    • violence (8%) - these were evenly divided among three sources: suicide, substance abuse and murder/accidents
    • liver disease (7%) - half of these deaths were related to hepatitis infections

    Timing of deaths

    During the first year of HAART, 63% of deaths were due to AIDS; over time, this figure fell to 43%. Also, over the course of the study, deaths due to cancers unrelated to AIDS rose from 7% to just over 15%.

    In most cases, researchers were able to find factors(s) that likely caused a person's death. However, among 279 people who did not have a clear cause of death, two distinctive features stood out as follows:

    • being male
    • being an IDU

    Focus on drug users

    According to ART-CC, "rates of all specific causes of death except failure were higher in injection drug users." Furthermore, the study team found that the following causes of death were strongly associated with IDUs:

    • liver related
    • lung related
    • violence
    • infections

    Other key findings

    Having AIDS before initiating HAART was linked to subsequent death from any cause. Having a high viral load (more than 100,000 copies) before initiating HAART was linked to a higher rate of death from many causes, including cardiovascular and lung diseases.

    Influencing death rates-age

    In analysing the data, the ART-CC team found that certain factors were linked to particular causes of death as follows:

    • As the adults in the study aged, each decade of aging increased the relative risk of cancers unrelated to AIDS.
    • Similarly, each decade of aging significantly increased the relative risk of developing serious cardiovascular disease.
    • The risk of death from complications due to kidney disease was greatest in people who were more than 60 years old.

    Influencing death rates-gender

    Researchers compared death rates among men and women and found that women were:

    • less likely to die
    • less likely to die from cancers (related or not to AIDS)

    Trends in time

    There were clear trends within ART-CC revealing benefits from using HAART. For instance, the risk of dying from AIDS, non-AIDS infections or kidney failure decreased significantly the longer people took HAART.

    Aiming for perfection

    ART-CC is a cohort study. Such studies are good at finding associations but cannot clearly link cause and effect. Furthermore, cohort studies are bedeviled by confounding or channeling bias-issues that could lead to incorrect conclusions. As the research team understood these issues, ART-CC chose to not explore any possible associations between the use of specific anti-HIV drugs and the relative risk of death.

    It is possible that some categories of death were underestimated because of misclassification or insufficient information. For instance, the research team noted that some deaths classified as "heart-related" were likely due to severely abnormal heart rhythms brought about by overdoses of illicit substances.

    Some deaths, particularly in people with low CD4+ counts and multiple AIDS-related infections, could have been incorrectly assigned. But bear in mind that in such cases it can be very difficult to correctly assign a cause of death.

    ART-CC was unable to receive information about income, use of alcohol and tobacco, and high blood pressure. Any of these factors could have played a role in some of the deaths of participants.

    Yet, despite these potential drawbacks, and because the ART-CC researchers understood the limits of their study design, the results of their latest analysis are robust and so their findings will be very useful in years to come.

    Timing of treatment

    ART-CC has found that AIDS remains a relatively common cause of death "particularly early after initiation of treatment." This is probably because a large proportion of people in the study began HAART when their CD4+ counts were low-less than 200 copies, a level that places them at high risk for serious infections. HAART takes several months to suppress HIV, and the immune system takes several months to begin to repair itself. In the first months after starting HAART, therefore, the risk of developing lethal infections remains. This finding from ART-CC favours starting therapy at higher CD4+ cell counts.

    In ART-CC, researchers found an association between having a high viral load (more than 100,000 copies) and deaths due to infections, lung disease and cardiovascular disease. Having a low CD4+ cell count was not statistically linked to these specific outcomes. It is likely that a high level of HIV triggers inflammation that affects many organ systems, particularly the heart and blood vessels, and increases the risk of death from cardiovascular disease. Co-infections such as herpes, hepatitis and TB can also affect viral load.

    Social issues

    According to the study team, after AIDS, "social and lifestyle factors contributed to the next most frequent causes of death." In this regard they state that the most common cancer unrelated to AIDS was lung cancer, likely due to tobacco use. There were also many cases of heart infections, likely arising from the injection of illicit drugs. Social and lifestyle factors also contributed to deaths due to violence and liver-related diseases.

    A warning about the future

    One important finding from ART-CC is that increases in rates of death due to causes associated with aging suggest that "the process of aging will become a dominant factor in HIV-1 in the next decade."

    If gains in survival are to be maintained, ART-CC notes that "interventions to address risk factors for lifestyle-related causes of death, as well as monitoring for and care of diseases associated with old age, will be necessary."

    -Sean R. Hosein  


    •  Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clinical Infectious Diseases . 2010 May 15;50(10):1387-96.


    CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.

    From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at


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