What reduces survival 10 years after starting ART in North America and Europe?

In 1996 highly active antiretroviral therapy (HAART, now simply called ART) became widely available in North America and Western Europe. For the first time since the beginning of the AIDS pandemic, the immune systems of HIV-positive people became stronger and death rates began to fall.

It is important to find out what happened to people who began ART when it first emerged, as they began therapy with drugs that would be considered less effective and less tolerable than what is recommended for initial HIV therapy in 2016.

Researchers in Canada (British Columbia and southern Alberta), the U.S. and Western Europe pooled health-related information collected from about 13,000 HIV-positive people who began ART in the years 1996 to 1999. Participants in this analysis were alive for the first 10 years after starting ART.

Ten years later

The researchers found that 5% of participants died 10 or more years after starting ART. The most common causes of death in decreasing order of importance were cancers unrelated to AIDS, AIDS, cardiovascular disease and liver-related disease. Older people seemed particularly susceptible to death from cardiovascular disease. People who injected street drugs were at heightened risk of death from infections unrelated to AIDS and also from complications of liver disease. People who died from AIDS-related causes tended to have low CD4+ cell counts and detectable viral loads.

Study details

Data from participants were analysed in a project called ART-CC. Participants enrolled in this study were at least 16 years old when they began ART and had not previously taken anti-HIV drugs.

Participants started taking ART between 1996 and 1999. Researchers collected data up to July 31, 2013. The breakdown of participants by gender was 79% men and 21% women.

Results

In analysing data from 13,011 participants, researchers found that 656 had died at least 10 years after starting ART. The major factors associated with these deaths were as follows:

• older age (60 and up)
• low CD4+ cell counts (less than 100 cells/mm³)
• injecting street drugs
• a viral load greater than 1,000 copies/mL
• a diagnosis of AIDS

Estimating the risk of death

Researchers presented the following two scenarios whereby they calculated the subsequent five-year risk of death among participants aged 40 to 49 years after they had survived their first decade on ART:

• Participants who did not inject street drugs and whose CD4+ counts were greater than 500 cells/mm³ and whose viral loads were suppressed and who did not develop AIDS in the past decade had only a 2% chance of dying over the next five years.
• Participants who injected street drugs and who did not have a suppressed viral load and who had less than 100 CD4+ cells and who had AIDS during their first decade on ART had a 48% chance of dying over the next five years.

As a reference, researchers used the life expectancy of the average HIV-negative person in France around the same time. They used data from France as a comparison because a large fraction of HIV-positive people in ART-CC came from France. The average HIV-negative person from France had only a 1% chance of death over the subsequent five-year period.

Causes of death

It was possible to find a specific cause of death in medical records for 83% of participants in the present analysis. The most common causes of death were as follows:

• cancer unrelated to AIDS (or the liver)
• AIDS
• cardiovascular disease
• liver related

The researchers noted that among participants aged 60 and older, rates of death due to cardiovascular disease were “substantially higher” than in younger people. Causes of death unrelated to AIDS were also greater among older people.

People who injected street drugs and who died did so from infections unrelated to AIDS and from liver-related complications. These deaths were associated with low CD4+ counts and detectable viral loads.

Bear in mind

In this group of 13,011 participants 95% of whom survived their first decade on ART, it remains important to monitor HIV-related lab tests such as CD4+ cell count and viral load because poor results are linked to reduced survival.

Some populations of HIV-positive participants had substantially elevated rates of death compared to HIV-negative people of the same age.

The researchers found that older age was “strongly associated” with an increased risk of dying, particularly from causes unrelated to AIDS. The researchers therefore made the following statements:

• This association with age “suggests that provision of both preventive and therapeutic care in older [HIV-positive] patients treated for many years will become increasingly important as the number of patients aged 60 [and older] increases.”
• “The most common cause of death was non-AIDS-related cancer, implying a need for preventive and screening measures adapted for use with HIV-positive patients who have survived long-term treatment with ART to be incorporated into their routine health care.”

The researchers noted that the drugs available for treatment of HIV in the mid-to-late 1990s, while lifesaving, were less effective and relatively toxic compared to regimens available today in high-income countries. Therefore, they stated that the risk of death in “patients starting ART today can be expected to be lower than those found in our study.”

Substance use

The ART-CC researchers stated that people who inject street drugs need support for maintaining and improving their health and survival. At a minimum, such support would include opioid substitution and counselling, as well as screening for liver disease, including infection with hepatitis B and C viruses, and, when positive, treatment.

The researchers also noted that “alcohol misuse” might be another factor that unfavourably impacts the health of some people who use street drugs.

They also stated that people who smoke should be offered entry into smoking cessation programs.

Importantly, the researchers sought to underscore the drivers of addiction and substance use and noted that people who engage in such behaviours “may require interventions to address depression and social deprivation.”

—Sean R. Hosein

REFERENCE:

Trickey A, May MT, Vehreschild J, et al. Cause-specific mortality in HIV-positive patients who survived ten years after starting antiretroviral therapy. PLoS One. 2016 Aug 15;11(8):e0160460.