By Dr Jesper D Gunst, Dr Jesal Gohil, Dr Ole S Sogaard, Dr Sarah Fidler
Researchers from Denmark and The United Kingdom studied the effects of interrupting antiretroviral therapy (ART) in people who participated in clinical trials for HIV cure research and the frequency of people who were able to control HIV in the absence of ART after an intervention, known as “post treatment controllers”. Clinical trials are crucial in advancing medical research, but they must be ethical and safe. The team reviewed data from multiple past HIV cure clinical trials to try and improve the design of future clinical trials, but also to measure the frequency of natural post-treatment control, which occurs in people who didn’t receive an intervention but were able to naturally control HIV without ART.
How are HIV cure clinical trials conducted?
To see how effective the new treatment is, participants are often assigned to two groups – one group that receives the novel treatment and the other group that receives an inactive form of treatment/a “sugar pill”, known as the placebo group. Both groups then stop ART in what is called an Analytical Treatment Interruption (ATI). This period is used to measure how effective the treatment was at changing the size/quality of the HIV reservoir (a pool of dormant cells that contain viral DNA and the source of virus when ART is stopped) and a delay in viral rebound. ART interruption is therefore scientifically important, and virus levels are frequently checked during this period.
What did these researchers do?
In this study, the team collected data from 382 participants from 24 clinical trials that had placebo groups and ART interruption to study how quickly the virus re-emerges during ATI and how many people were post treatment controllers (<50 copies of HIV per mL in blood).
On average in these 382 participants, HIV took 16 days to rise above 50 copies/mL, 21 days to rise above 400 copies/mL, and 32 days to reach 10,000 copies/mL after stopping ART. After 12 weeks off ART, only 4% of participants had HIV levels <50 copies/mL and were called post-treatment controllers by the study team. They noted that when ART was started early (within 6 months of HIV acquisition), people were more likely to be able to control the virus without ART. 6% of the people who started ART early were able to control the virus, compared to only 1% among people who started ART later than 6 months of acquisition. This confirms what other HIV cure studies have also found – that early ART improves immunity and limits the HIV reservoir size, and so post-treatment controllers are more likely in this group.
What does this mean?
This study helped estimate the rate of post-treatment controllers in different cohorts (early or late ART) when calculated when virus might rebound in ATI and by how much. The researchers suggest that placebo groups in clinical trials with ART interruption should be considered carefully and may be unnecessary in some cases. An ethical question is raised about enrolling people in placebo groups where they do not receive the new treatment, and they have to undergo ART interruption. However, without the placebo group, it is difficult to conclude if any delay in viral rebound is truly the effect of the treatment tested, if it’s occurred by chance. Placebo groups are also important to provide other comparisons, such as how safe the new treatment is.
The researchers hope that the results will help inform future ATI studies: especially for the participants and sites about what to expect in terms of viral rebound and post-treatment control when pausing ART and no active intervention is given.
Read the full publication: Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies
Edited by Kiho Tanaka and Jillian Lau
