Antiretroviral therapy (ART) has significantly reduced the morbidity and mortality of patients infected with the human immunodeficiency virus (HIV) by suppressing replication of the virus. However, it is unable to completely eradicate the infection due to the persistence of HIV in the form of integrated proviral DNA in long-lived cells, such as memory CD4 T cells that act as an HIV reservoir. This HIV reservoir can persist during ART and cause viral rebound when treatment is stopped. Studies have shown that starting ART early in HIV infection can limit the size of the reservoir, delay viral rebound upon termination of ART, and improve chances of controlling viral load after treatment.
Several case report studies of HIV-infected infants given early ART showed long periods of remission, suggesting that interventions to enhance early ART in this unique population may yield better post-treatment viral control. However, assessing post-treatment control following new interventions requires interrupting ART, and therefore it is important to understand if treatment interruption (TI) affects the size of the HIV reservoir. A small number of studies in adults have shown that short TI may not cause a lasting increase in HIV-infected cell reservoirs. In contrast, a few studies of TI in infants showed persistent increase of HIV DNA levels, but the studies were small and in most cases did not include short TI. Therefore, to further understand the impact of short TI in infants, Dr. Dara Lehman together with members of the Overbaugh lab in the Human Biology Division, and their colleagues at the University of Washington and University of Nairobi, sought to further study the impact of treatment interruption in Kenyan infants that participated in the Optimizing Pediatric HIV-1 Treatment study (OPH).
The OPH study, originally published by some of the same authors in 2016 in the journal AIDS, was a randomized clinical trial to compare outcomes of children who were treated in the first year of life and randomized following 24 months of ART to a single treatment interruption versus continued treatment, and followed for 18 months. In this new study, the authors quantified HIV DNA levels in the reservoir before and after TI in the peripheral blood mononuclear cells (PBMCs) of Kenyan infants in the OPH study, and published their observations in Open Forum Infectious Diseases.
All seven children in the TI arm showed viral rebound after ~3 months of TI, and ART was restarted after a median of 106 days. HIV DNA levels were compared at randomization and again 18 months later, after all children had resumed ART for more than 15 months and had viral suppression. Children on continued ART had a fold change of 0.32, while those with TI had a median HIV DNA fold change of 1.04, suggesting that TI lessens the decay that occurs on continued ART. Furthermore, most children in the TI arm had similar HIV DNA levels before and after TI. This hints at the probability of reseeding of the reservoir during TI, which is followed by decay after ART resumes.
Despite a small sample size, Dr. Lehman and her team’s data greatly augmented previous studies on changes in HIV DNA levels following TI in children. Together, these studies highlight that increases in HIV DNA can be minimized or reversed by resuming rapid treatment. Dr. Lehman: “This study was performed in a very unique cohort of children which included a group with continued antiretroviral therapy and a group with a short treatment interruption. There are only a few studies that have looked at HIV DNA reservoir size following treatment interruption and very few with a continued arm for comparison.”
When asked about the clinical significance of interrupting treatment, Dr. Lehman explained: “Currently, substantial efforts and resources are being put towards finding a cure for HIV. However, the only way to test whether participants in these studies have truly been cured is to interrupt their treatment and see whether the virus rebounds. Thus, it is important to know how treatment interruption with viral rebound affects the size of the HIV reservoir, which is the major barrier to cure. Our data suggests that reservoir size is similar before and after short treatment interruption, which is good news and suggests that short treatment interruption during cure studies may not have a substantial impact.”
Longer TI may cause a sustained increase in reservoir size, as shown in other TI studies in perinatally infected infants. Taken together with this study, where the authors show that a short interruption of three months does not appear to have sustained impact on HIV DNA reservoir levels, these data strengthen the idea that frequent monitoring to reduce the amount of time the virus replicates during TI in cure trials is important.
Larger cohorts and longer follow-ups are needed to further evaluate treatment regiments that can reduce HIV DNA. Dr. Lehman’s team is well positioned to tackle the next step, as she revealed: “We recently received a grant to extend this study to look at HIV DNA reservoir dynamics in a larger cohort of children that started antiretroviral treatment in their first year of life and have now been in follow-up on treatment for up to 10 years. This is a very unique cohort, and our goal in these ongoing studies is to determine what immune factors influence the size of the reservoir in children on long-term antiretroviral therapy. Our hope is that these studies will inform interventions to improve reservoir control and long-term treatment outcomes in HIV-infected children.”
Pankau MD, Wamalwa D, Benki-Nugent S, Tapia K, Ngugi E, Langat A, Otieno V, Moraa H, Maleche-Obimbo E, Overbaugh J, John-Steward GC, Lehman DA. 2018. Decay of HIV DNA in the reservoir and the impact of short treatment interruption in Kenyan infants. Open Forum Infectious Diseases. doi:10.1093/ofid/ofx268
Funding was provided by the National Institutes of Health.
This study was a collaboration between the Fred Hutchinson Cancer Research Center, the University of Washington and the University of Nairobi.