A small study from an HIV hospital that has been conducting experimental analytical treatment interruptions (ATIs) as part of research into achieving a functional cure for HIV infection has found that over a period of years, patients who had undergone ATIs had a higher risk of developing non-AIDS-related serious illnesses such as cancer, liver disease and kidney disease than a control group of patients who never interrupted their antiretroviral therapy (ART).
The study, by Dr Valèria Richart and colleagues from Barcelona University Hospital, included 146 patients who had taken part in ten studies involving ATIs and compared them to a similar group of 45 patients who had never had an ATI.
The study found that over a period of nearly 20 years, patients who had had an ATI were four times more likely to develop a serious non-AIDS-related event than ones who had not.
While the number of cardiovascular events and infectious diseases was actually slightly higher in the control group, the number of cancers were notably higher in the ATI group, as were liver disease and end-stage kidney failure.
Who was in the study
The average age of patients was just over 40 and 22% were women. They had been diagnosed with HIV for 21 years and had started ART initially 2.2 years after diagnosis. As would be expected, the time on ART was lower in the patients who had had ATIs (13 years) than the control group (16 years), though this was not a statistically significant difference. Similarly, their time with an undetectable viral load was slightly less, but not significantly so (11.5 years versus 12.2 years).
The lowest-ever median CD4 count was 430 and was the same in both groups, so these were not people who had experienced AIDS-defining immune suppression. The peak viral load in ATI patients was just over 41,000 compared with nearly 23,000 in the control group though this was again not significant.
People with hepatitis C were excluded. While people with chronic hepatitis B were not excluded, there were only three participants with the condition and they cannot explain the higher rate of liver disease in the ATI group.
The studies involving treatment interruption
The ten studies involving ATIs took place between 1999 and 2018, with follow-up to observe illnesses up to the end of 2019. Three were early studies of treatment interruption without additional medication, with results published between 1999 and 2003. Two published in 2003 and 2004 involved the early use of cytostatic drugs (hydroxyurea and mycophenolate) to see if they had an effect on ongoing HIV-infected cell replication.
The other five were therapeutic vaccine studies, four of single inoculations but one involving several vaccinations over 12 months, with results published between 2005 and 2020.
Duration of ATI and criteria for ending them varied widely between studies. In the early ones falling CD4 count was generally used as the criterion for restating; later ones used either viral load rising over a specific point or being detectable a specific number of times. Because of this, the early treatment-interruption studies tended to involve longer periods off ART, which may influence the results.
Results
Thirty-eight per cent of patients were hospitalised with a non-AIDS condition during the follow-up period, 53 (42%) in the ATI group and 10 (22%) in the control group. This was a statistically significant difference (p=0.015). The total number of clinical events (some patients had multiple events) was 85 in the ATI group and 23 in the control group.
After adjusting for the various criteria listed above (age, gender, clinical indicators etc) the odds of developing a non-AIDS related event were four times larger in ATI patients than controls.
The risk was similar whether the follow-up time over which the occurrence of the events was measured in the ATI patients from the time they started ART, or only from the time they resumed it after the ATI. The risk of events appeared roughly similar in the first six years from the start of ART or the end of the ATI, but then started to diverge.
There was no significant difference between patients who had had an ATI lasting over a year, and ones whose ATI had lasted less than a year, though as noted the studies involving longer ATIs tended to be earlier.
In terms of specific conditions, 21% of the non-AIDS-related conditions seen in the ATI group were non-AIDS-defining cancers (18 events) versus only 4% in the control group (just one event). No liver-related conditions or end-stage kidney disease were seen in the control group, but these respectively represented 8% and 9% of events in the ATI group.
Conversely, 29% of events (25 events) in the ATI group but 39% of events (nine events) in the control group involved cardiovascular disease, and 25% of events (21 events) in the ATI group and 48% of events (11 events) in the control group were infections. However, this has to be set against the overall higher proportion of events in the ARTI group.
Conclusions
This is a small study and in particular the control group was less than a third of the size of the ATI group. The ATI group was also very varied in terms of time off ART and resumption criteria, meaning that more systematic research on a larger group needs to be conducted. Nonetheless, this is the first study to compare what happens to patients who have had ATIs over a time period of nearly 20 years.
The authors conclude that this study should not be seen as indicating that studies involving ATIs should be stopped. But they do say that ATIs should be restricted to short periods (they suggest 16 weeks maximum) and that there should be careful selection of participants, close monitoring of viral loads, and strict resumption criteria.
Richart V et al. High rate of long-term clinical events after ART resumption in HIV-positive patients exposed to antiretroviral therapy interruption. AIDS, published ahead of print, 20 August 2021.