On November 3rd, the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) announced the launch of the IMPAACT P1115 trial, which will investigate very early initiation of HIV treatment in newborns. Much of the impetus for the trial came from the Mississippi baby case, and although that has turned out to involve an extended, 27-month remission from HIV replication rather than a cure, there remains a rationale for evaluating the feasibility, benefits and risks of early treatment in perinatal HIV infection.
The news of the viral load rebound in the Mississippi case, which emerged this past summer, has led to some alterations to the P1115 protocol, including ongoing reviews of whether an interruption of antiretroviral therapy is justified when participants reach two years of age. Detailed information on the trial design is provided in an online Q&A document issued by NIAID and NICHD.
Clustered around the time of this news release were several other publications related to pediatric HIV cure research. In a brief but informative viewpoint piece in the Journal of the International AIDS Society Jintanat Ananworanich and Merlin Robb review the Mississippi case and two other reports of early-treated infants in whom HIV viral load rebounded rapidly after treatment interruption. One occurred in Canada and was described in a prior blog post; the researcher Jason Brophy also presented details at the International AIDS Conference in Melbourne in July (a webcast of Brophy’s talk is available on the conference website). The second was from Milan, Italy and reported in a letter to The Lancet in October.
Ananworanich and Robb outline some of the differences between these three cases that might underlie why an extensive period of remission occurred in one but not the others; these include higher baseline viral load (Milan) and evidence of low-level detectable HIV RNA after initial suppression (Canada). A third report from Ireland that was published recently is not mentioned in the review; this infant was treated from birth and had no detectable HIV-specific antibody responses or HIV DNA or RNA at age four, when treatment was interrupted. Viral load rebounded within seven days and climbed to over 100,000 copies before ART was successfully reinitiated. The authors of the case report note that, unlike in the Mississippi baby, the initial ART regimen was not fully suppressive (possibly due to an interaction between nevirapine and another needed medication) leading to an early viral load increase to over 3,000 copies while on treatment prior to an effective combination being instituted.
In discussing the outcome in this child, the researchers state: “This case unequivocally demonstrates that children on suppressive antiretroviral treatment from very early infancy can achieve a state of HIV persistence during which routine testing with standard HIV RNA and DNA assays can yield negative results. These may be falsely interpreted as absence of persistent replication-competent reservoirs. The prompt rebound in viremia emphasizes that the limitations in these markers to determine whether treatment should be stopped to assess viral remission. Cases such as this highlight the urgent need for more data and further research in this area.” Hopefully IMPAACT P1115 can help contribute to filling this knowledge gap.
Also in the realm of pediatric HIV cure research, last month in JAMA Pediatrics Deborah Persaud and colleagues published results from a study that was presented at CROI earlier this year (a webcast of the presentation is online). In a cross-sectional analysis, markers of HIV persistence were compared in three groups of perinatally infected adolescents that had achieved viral load suppression prior to one year of age, between one and five years, or after five years. Levels of both replication-competent virus and proviral DNA were significantly lower in the first group, and earlier control of viral load was also associated with an increased likelihood of indeterminate or negative HIV antibody test results (proportions were 86%, 19%, and 3%, respectively). A significant correlation was documented between low proviral DNA and seronegative or indeterminate HIV antibody tests. Although not considered cured, adolescents with low or undetectable HIV reservoirs may be candidates for clinical trials of interventions that aim to clear remaining latently infected cells.
Journal of the International AIDS Society 2014, 17:19859, Published 20 November 2014
Jintanat Ananworanich and Merlin L Robb
Lancet. 2014 Oct 4;384(9950):1320. doi: 10.1016/S0140-6736(14)61405-7.
Giacomet V, Trabattoni D, Zanchetta N, Biasin M, Gismondo M, Clerici M, Zuccotti G.
Pediatr Infect Dis J. 2014 Sep 23. [Epub ahead of print]
Butler KM, Gavin P, Coughlan S, Rochford A, Donagh SM, Cunningham O, Poulsom H, Watters S, Klein N.
Attention has focused on the possibility of cure for HIV infected infants if treated promptly following delivery. The 'Mississippi baby', who had very prolonged remission following ARV discontinuation, may represent a unique situation. We report an infant treated from birth, who seroreverted, remained virologically suppressed, and had undetectable HIV-1 RNA and DNA at four years of age, yet experienced virologic rebound within days of discontinuation of antiretroviral therapy.
JAMA Pediatr. Published online October 06, 2014. doi:10.1001/jamapediatrics.2014.1560
Deborah Persaud, MD; Kunjal Patel, DSc, MPH; Brad Karalius, MPH; Kaitlin Rainwater-Lovett, PhD, MPH; Carrie Ziemniak, MS; Angela Ellis, BS; Ya Hui Chen, BA; Douglas Richman, MD; George K. Siberry, MD, MPH; Russell B. Van Dyke, MD; Sandra Burchett, MD; George R. Seage III, DSc, MPH; Katherine Luzuriaga, MD; for the Pediatric HIV/AIDS Cohort Study
Importance: Combination antiretroviral therapy initiated within several weeks of human immunodeficiency virus (HIV) infection in adults limits proviral reservoirs that preclude HIV cure. Biomarkers of restricted proviral reservoirs may aid in the monitoring of HIV remission or cure.
Objectives: To quantify peripheral blood proviral reservoir size in perinatally HIV-infected (PHIV+) adolescents and to identify correlates of limited proviral reservoirs.
Design, Setting, and Participants: A cross-sectional study including 144 PHIV+ youths (median age, 14.3 years) enrolled in the United States–based Pediatric HIV/AIDS Cohort Study and receiving durable (median duration, 10.2 years) combination antiretroviral therapy, stratified by age at virologic control.
Main Outcomes and Measures: The primary end point was peripheral blood mononuclear cell (PBMC) proviral load after virologic control at different ages. Correlations between proviral load and markers of active HIV production (ie, HIV-specific antibodies, 2–long terminal repeat circles) and markers of immune activation and inflammation were also assessed.
Results: Proviral reservoir size was markedly reduced in the PHIV+ youth who achieved virologic control before 1 year of age (4.2 [interquartile range, 2.6-8.6] copies per 1 million PBMCs) compared with those who achieved virologic control at 1 to 5 years of age (19.4 [interquartile range, 5.5-99.8] copies per 1 million PBMCs) or after 5 years of age (70.7 [interquartile range, 23.2-209.4] copies per 1 million PBMCs; P < .001). A proviral burden of less than 10 copies per 1 million PBMCs in PHIV+ youth was measured in 11 (79%), 20 (40%), and 13 (18%) participants with virologic control before 1 year, at 1 to 5 years, and after 5 years of age, respectively (P < .001). Lower proviral load was associated with undetectable 2–long terminal repeat circles (P < .001) and HIV-negative or indeterminate serostatus (P < .001) but not with concentrations of soluble immune activation markers CD14 and CD163.
Conclusions and Relevance: Early effective combination antiretroviral therapy with prolonged virologic suppression after perinatal HIV infection leads to negligible peripheral blood proviral reservoirs in adolescence and is associated with negative or indeterminate HIV serostatus. These findings highlight the long-term effect of early effective control of HIV replication on biomarkers of HIV persistence in perinatal infection and the utility of HIV serostatus as a biomarker for small proviral reservoir size, although not necessarily for cure.