Scientists are gaining a better understanding of the risks and benefits of treatment interruptions in cure research.
By Heather Boerner
People living with HIV who underwent an analytical treatment interruption (ATI) in search of an HIV cure were four times more likely to be hospitalized for non-AIDS-defining illnesses, especially cancer, liver and kidney disease, in the years following the resumption of HIV treatment, according to an analysis published in the journal AIDS .
However, people who underwent an ATI were less likely to be hospitalized for cardiovascular events, non-AIDS-defining infections, or neuropsychiatric causes.
The study reports on the ongoing discussion between HIV researchers and people living with HIV about how to study functional approaches to HIV cure while protecting the health of those who volunteer to participate. Antiretroviral therapy keeps HIV under control as long as people are taking it, so interrupting treatment is necessary to see if a curative intervention works. During an ATI, viral load is monitored frequently, and antiretrovirals are restarted if it rises above a specific level.
Previous research found that closely monitored treatment interruptions were not associated with any increase in hospitalizations for non-AIDS-related conditions within the first three to four years after resuming treatment. Another study suggested that viral load recovery was just as rapid for people taking newer HIV medications as for those taking older-generation treatments. However, Lorna Leal, MD, PhD, of the Hospital Clínic of Barcelona, University of Barcelona, and her colleagues wanted to see what the long-term impact was.
Leal and colleagues observed 136 people with HIV who underwent an ATI in 10 cure studies in Barcelona between 1999 and 2018. As a control group, they also included 45 people who did not discontinue treatment. They then tracked hospital admissions from trial enrollment onward, looking for admissions for non-AIDS-defining illnesses. These included non-AIDS-defining cancers, neuropsychiatric conditions, heart disease, non-AIDS-defining infections, liver disease, and end-stage renal disease. People with hepatitis C were excluded from the analysis, and the researchers excluded all other medical conditions that could have resulted in hospital admission.
Nearly two out of three participants were gay men. The median age was 40 years, and they had been living with HIV for a median of 21 years at the time of analysis. They had received antiretroviral treatment for an average of 14 years and had an undetectable viral load for 12 of those years. The men were good candidates for analytical treatment discontinuation by modern standards, given that their lowest CD4 count was quite high (a median of 430) and their peak viral load was only 36,447, indicating that their HIV was detected early and they started treatment quickly. These numbers were similar in the control and treatment discontinuation arms.
When those who had undergone a treatment interruption restarted treatment, their CD4 count, at 470, was slightly higher than when they first started HIV care so many years ago, and their viral load was lower, at 24,642 copies.
During the following years, one in three participants (38%) were hospitalized for a non-AIDS-defining illness at least once, and five participants died. But when researchers compared those who underwent an ATI with those who did not, they found large differences. Nearly twice as many people who underwent an ATI experienced a health event: 43% versus 23%. When they isolated events that occurred only after treatment was resumed, the odds of future hospitalizations increased to 2.43, and this happened a median of only five years after treatment was restarted.
Hospitalizations for conditions such as non-AIDS-defining cancers were markedly more likely among people in the ATI group: 18 of the 19 such hospitalizations occurred among people who discontinued treatment. All seven hospitalizations for liver problems and all eight kidney-related hospitalizations occurred among people in the ATI group. However, more people who remained on treatment continued to experience cardiovascular events (39% in the control group compared with 29% in the ATI group) and non-AIDS-defining infections. Nearly half of the people in the control group were hospitalized for non-AIDS-defining infections, whereas these infections accounted for only a quarter of hospitalizations in the ATI group.
In the end, after adjusting for potential confounding factors such as age and sex, people who underwent ATI were four times more likely to be hospitalized at least once for non-AIDS-related events than their peers who did not.
Of course, a study of fewer than 200 participants in a hospital isn't the final word on the health effects of ATI, Leal and colleagues wrote. But it is important information for people considering participating in HIV cure trials. And it's important as researchers continue to design HIV cure studies. For example, a previous study found that once people's viral load reached 400 or more, their chances of having a cardiac event increased dramatically. That was in the short term. The study authors said this finding "is complementary" to the findings of the current study.
"In any case, further studies are needed to confirm our results," Leal and colleagues wrote. "If confirmed, these data could have a significant impact on functional cure clinical trials."