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ATIs in HIV Research
Analytical Treatment Interruptions: A Necessary Fact in HIV Cure Trials

Released: December 21, 2023

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Key Takeaways
  • Analytical treatment interruptions of ART are a common component of HIV cure-related trials because there is no perfect marker that can predict viral control after stopping ART.
  • In the context of a clinical trial, these treatment interruptions are safe, and viral replication is rapidly controlled when ART is resumed.
  • Thorough participant counseling on the risk for HIV transmission during treatment interruptions is needed; PrEP may be considered for sexual partners.

Antiretroviral therapy (ART) has significantly improved morbidity and mortality for people living with HIV; however, HIV cannot be cured, and lifelong treatment is required. HIV latency, with virus lying dormant in CD4 T-cells, is the primary barrier to achieving a cure.

The ultimate goal of interventions in HIV cure-related clinical trials is to allow someone to safely stop ART and maintain viral load at a low level. Ideally, that should be a viral load of <50 copies/mL; however, <200 copies/mL is also acceptable, given that clinical trials have demonstrated no sexual transmission of HIV at this threshold (ie, Undetectable=Untransmittable).

Currently, we do not have a biomarker for the HIV reservoir that can tell us whether someone can control viral replication after stopping treatment. Therefore, in most studies, the method used to test the efficacy of cure interventions is an analytical treatment interruption (ATI), which means temporarily stopping ART in a closely monitored setting while continuing observation of viral load. 

In some studies, a short period of viremia is permitted to allow the immune system to kick in and gain viral control. We have learned from some studies that if treatment is resumed too early, we will never know whether the person can maintain viral control after stopping treatment.

Approaches for ATIs
There are 2 major approaches for ATIs in HIV cure-related trials:

  1. Stop ART and wait until viral load becomes detectable—usually on 2 occasions—and then reinitiate treatment. Time to viral rebound is the primary outcome in most of these studies.
  2. Stop ART and allow virus to replicate for a short period up to a higher viral load. This method is used primarily in studies targeting the immune system, with the goal of boosting immune control rather than just reducing or eliminating the viral reservoir.

Parameters for Reinitiation of ART
There is no right or wrong approach to treatment interruption in these studies. However, expert panels have recommended some guardrails to ensure that a participant does not stay viremic for too long. It is recommended to monitor viral loads weekly for the first 12 weeks after cessation, as most individuals rebound during this time. Some investigators recommend reinitiation of ART with viral loads >1000 copies/mL over 4 weeks or with viral loads >100,000 copies/mL on 2 occasions.

CD4 counts also are closely monitored, and there are recommendations for reinitiation of ART should CD4 counts drop to <350 cells/mm3. CD4 drops are unusual, as high levels of replication are required. Measuring CD4 count is less sensitive than measuring viremia, as CD4 decline is often slow.

In addition to monitoring for viremia and CD4 count, we must ensure that patients do not develop acute retroviral syndrome during ATIs. Clinical signs and symptoms include malaise, fever, headache, lymphadenopathy, rash, sore throat, myalgia, weight loss, night sweats, or diarrhea. In these cases, reinitiation of ART is warranted.

Reducing Risk of HIV Transmission to Sexual Partners
It is critically important to prevent any transmission events in that short period of viremia. ATI is a challenging culture change for many healthcare professionals because we have been telling our patients for many years to stay on treatment, avoid missing doses, and maintain a viral load <50 copies/mL. Here, we are purposefully allowing a short period of virus replication.

We also have been heavily promoting the concept of U=U, which dictates that when the viral load is undetectable, HIV is untransmittable. When a person is participating in a cure study, this concept no longer applies. Therefore, thorough participant counseling is required so that they know that during this period, they are indeed at risk of transmitting HIV. In addition to counseling the participant, PrEP also is recommended for sexual partners. 

The Future of Viral Load Monitoring During ATIs
In the long term, we ideally would have a point-of-care, home-based test for viral load. This companion diagnostic is needed when we do not know the duration of viral control. This would give study participants and their providers a great deal more comfort that control of viral load is being maintained.

We were able to develop home-based tests for COVID-19, and it is feasible to do it for HIV viral loads. 

ART interruptions are not an easy endeavor, but they are short-lived. Researchers are working hard to find better predictors of viral control following cessation of ART or better measures of the size of the reservoir, as ATIs are difficult for participants and their providers.

Many studies have now shown that ATIs are safe, and when an individual resumes ART, viral load rapidly comes under control, and the reservoir returns to where it was prior to the interruption.

Your Thoughts?
Have you ever had to manage ART restarts after ATIs for people participating in HIV cure-related trials? What was your experience? Join the discussion by posting a comment below.