Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2025 Mar 1.
Published in final edited form as: Curr Opin HIV AIDS. 2024 Jan 12;19(2):79–86. doi: 10.1097/COH.0000000000000839

Age at ART initiation and proviral reservoir size in perinatal HIV-1 infection: Considerations for ART-free remission

Soumia Bekka 1, Kristen Kelly 1, Mareike Haaren 2, Adit Dhummakupt 3, Deborah Persaud 1,3
PMCID: PMC11715321  NIHMSID: NIHMS1971779  PMID: 38169427

Abstract

Purpose of Review:

Achieving ART-free remission without the need for lifelong antiretroviral treatment (ART) is a new objective in HIV-1 therapeutics. This review comprehensively examines the literature to evaluate whether the age at ART initiation in children with perinatal HIV-1 influences the size and decay of the HIV-1 reservoir. The insights gathered from this review serve to inform the field on the unique dynamics of HIV-1 reservoir size in perinatal HIV-1 infection as a function of age at ART initiation, as well as inform biomarker profiling and timing of ART-free remission strategies for children living with HIV-1 globally.

Recent findings.

Recent studies demonstrate that initiating very early effective ART in neonates is feasible and limits HIV-1 reservoir size. The clinical relevance of limiting the HIV-1 reservoir size in perinatal infection was recently demonstrated in the Tatelo Study, which investigated a treatment switch from ART to two broadly neutralizing antibodies (bNAbs) in very early treated children. Low proviral reservoir size was associated with sustained virologic control for 24 weeks on bNAbs,

Summary:

Immediate and early ART initiation for neonates and infants with perinatal HIV-1 is essential to restricting HIV-1 reservoir size that may enable ART-free remission.

Keywords: Perinatal HIV-1 reservoirs, very early ART, ART-free remission

Introduction

Children and adolescents living with perinatal HIV-1 remain an under-researched population in the field of HIV-1 reservoir dynamics (1). Of the 1.7 million children living with perinatal HIV-1 worldwide, only 52% are receiving lifesaving, effective combination antiretroviral treatment (2). Without ART, approximately one-third of children living with perinatal HIV-1 die within the first year of life (3,4) while 50% do not survive past the age of 2 (5). International guidelines now recommend that all individuals with a confirmed HIV-1 diagnosis should initiate ART immediately, irrespective of age, immunological, or clinical status (6). In the context of perinatal HIV-1, early initiation of ART within the 3 months following birth has been established as lifesaving standard of care in many settings (7,8). As in adults, the majority of children living with HIV-1 experience viral rebound within weeks of ART interruption, including those who previously achieved long-term viral suppression (1,9,10).

The effects of age at ART initiation on proviral reservoir size remain poorly understood. The most studied biomarker to approximate the reservoir size and dynamics in the context of perinatal HIV-1 infection is total concentrations of cell-associated HIV-1 DNA; multiple studies support that early ART leads to lower proviral loads later in childhood that are maintained through adolescence and adulthood (11–14). Understanding whether cell-associated HIV-1 DNA decay is influenced by age at ART initiation remains an area of great interest with regards to perinatal HIV-1 and potential for ART-free remission. Discerning differences of age at ART initiation is crucial for optimizing the design and delivery of effective remission and cure strategies. This report seeks to answer these questions through a systematic review of the literature on ART initiation and proviral reservoir size in perinatal HIV-1, including recent reports from very early treated neonates.

Systematic Review of Studies Measuring Total HIV-1 DNA in Perinatal HIV-1

26 studies selected (Fig. 1, Supp. Table 1) from a total of 4753 (Supp. Fig. 1) that reported on HIV-1 DNA copies per million (cpm) PBMCs at age of treatment initiation with a median cohort size of 12 (3–164) published between 2000–2023 were reviewed. Publications reporting total HIV-1 DNA were stratified by treatment timing: late treatment (ART initiated > 3 months of age; n=19); early treatment (ART initiated > 7 days to ≤ 3 months of age; n=13); and very early treatment (ART initiated ≤ 7 days of life; n=9). Search criteria and methods are further explained in the Supplemental Methods.

Figure 1:

Figure 1:

Open in a new tab

Venn diagram illustrating the intersection of the 26 papers examining total HIV-1 DNA in perinatal HIV-1, categorized by the timing of ART initiation—very early, early, and late. The diagram highlights the overlap and distinctions in studies focusing on these specific treatment initiation groups.

Abbreviations: HIV-1, human immunodeficiency virus-1; ART, antiretroviral treatment

In the 19 publications reporting on late treatment, ART was initiated at a median of 9.6 months, spanning 4–154.9 months of age with baseline HIV-1 DNA ranging from 2.9–4 log10 cpm PBMCs. The lowest total HIV-1 DNA reported following late ART was 1.3 log10 cpm PBMC at approximately 12.9 years of age (15,16) with a median age of ART initiation of 1.9 years (15) and 9 years (16). Zanchetta, et al. followed 14 children who initiated ART at a median age of 9 years with a baseline HIV-1 DNA of 2.9 log10 cpm PBMC (16). In contrast, at median 9.8 years of age, Brice, et al. found the median HIV-1 DNA was 2.6 log10 cpm PBMC in a cross-sectional study of 97 virologically suppressed children who initiated ART at a median 3.3 years of age (17). Overall, HIV-1 DNA varied greatly in late treated children and declined the least with increasing age and duration of ART (Fig. 2A, Fig. 3).

Figure 2:

Figure 2:

Open in a new tab

Median log10 HIV-1 DNA cpm PBMCs measurements since initiation of ART from the 26 studies reporting on (A) late, (B) early, and (C) very early ART initiation.

Abbreviations: HIV-1, human immunodeficiency virus-1; cpm, copies per million; PBMC, peripheral blood mononuclear cell; ART, antiretroviral treatment

Figure 3:

Figure 3:

Open in a new tab

Bubble plot illustrating median log10 HIV-1 DNA cpm PBMCs measurements across age in months from a total of 26 studies reporting on very early (orange), early (pink), or late (blue) ART initiation. This visual representation provides insights into the variations in HIV-1 DNA levels among different treatment initiation categories and age at measurement, with the bubble size reflecting sample size within the reported data.

Abbreviations: HIV, human immunodeficiency virus; cpm, copies per million; PBMC, peripheral blood mononuclear cell; ART, antiretroviral treatment

Of the 13 publications reporting on early ART initiation, ART was initiated at a median of 2 months, spanning 1.7–3 months of age with baseline DNA ranging from 3–3.4 log10 cpm PBMC (Fig. 2B, Fig. 3). The lowest median total HIV-1 DNA reported following early ART initiation was 0.6 log10 cpm PBMC at 12.6 years with a median ART initiation age of 2.4 months in one study (15). The Children with Early Antiretroviral Therapy (CHER) trial found early treatment with sustained long-term ART resulted in reduced levels of HIV-1 DNA when compared to children treated later and in those who underwent analytical treatment interruption (ATI) in the parent trial (7,11,17). Specifically, HIV-1 DNA was significantly higher in late treated group (median age of 6 months at ART initiation) with 3.4 log10 cpm PBMC versus the early treated group (median age of 1.7 months at ART initiation) with 2.5 log10 cpm PBMC after 84/96 weeks on ART (11). After ART reinitiation following ATI, there was no significant difference HIV-1 DNA between treatment initiation groups at 248 weeks on ART, indicating benefits of early treatment may be lost without continuous ART. In a follow up, Katusiime, et al investigated the proviral landscape of a small cohort of early and late-treated children from the CHER trial after 6–9 years of ART (18). Interestingly, genetically intact HIV-1 sequences were only identified in late treated children, suggesting early ART may lead to preferential deletion of intact proviruses.

Multiple studies directly compared HIV-1 DNA after early or late ART initiation (11,15,17–24). In a small cohort, Luzuriaga et al. compared HIV-1 DNA decay in infants who initiated ART between 0.5–2.6 months of age and to those treated between 12.3–14.5 years after established infection (19). HIV-1 DNA decayed below 1.1 log10 cpm PBMC by 14–17.7 years of age in the early treated group whereas HIV-1 DNA ranged from 1.8–2.5 log10 cpm PBMC by 19–23 years of age in the late treated group. This trend is further demonstrated across all studies analyzed (Fig. 3); while HIV-1 DNA continues to decline in both groups, early treated children reach and maintain lower HIV-1 DNA levels over time.

Uprety, et al. investigated the long-term decay dynamics of HIV-1 infected cells in children living with perinatal HIV-1 (21). Virologic suppression achieved by 1 year of age following early ART was associated with faster and greater decline in total HIV-1 DNA two years following virologic suppression though no significant difference in decay dynamics was observed between 2–14 years of ART. Despite this, early treated children achieved significantly lower HIV-1 DNA levels after 10 years of ART, reaching 1.0 log10 cpm PBMC in contrast to late treated children with 1.5 log10 cpm PBMC (21). Similarly, McManus et al. observed total HIV-1 DNA levels in early treated children trended lower than late treated children, though levels did not reach statistical significance (20).

In the 9 publications reporting on very early ART, treatment was initiated at a median of 32 hours, spanning 7 hours–6 days of life with baseline HIV-1 DNA ranging from 2.4–3-log10 cpm PBMCs. To date, only four clinical studies, the International Maternal Pediatric Adolescent AIDS Clinical Trial P1115 (IMPAACT P1115) ((25), Lancet HIV, in press), the Early Infant Treatment study (EIT) in Botswana (26,27), and Ucwaningo Lwabantwana study (14), and the Latency and Early Neonatal Provision of Antiretroviral Drugs study (LEOPARD) in South Africa, have specifically investigated the impact of very early ART initiation in neonates.

The EIT study enrolled 40 infants in Botswana who initiated ART at <7 days of age; only 38 children survived until week 24 (26). García-Broncano, et al. reported median total HIV-1 DNA to be 0.7 log10 cpm PBMC at a median age of 20.7 months for 10 of the 40 children who initiated ART at a median 7 hours after birth (26). This value is contrasted to a group of 10 control children with a median total HIV-1 DNA of 3.0 log10 cpm PBMC at a median age of 25.4 months who initiated ART at a median age of 4 months and a group of adults living with chronic HIV-1 with a median total HIV-1 DNA of 2.1 log10 cpm PBMC after a median of 16 years on ART. In a follow up with all 38 infants, Ajibola, et al. reported a median HIV-1 DNA of 1.9 log10 cpm PBMC by 84–96 weeks after ART initiation at a median of 2 days after birth (28). By week 96, 74% (28/38) were virologically suppressed (27,28).

In the Ucwaningo Lwabantwana study, Millar, et al. followed 164 South African neonates with in-utero HIV-1 who initiated ART at a median age of 6.5 days (14). 98/164 (60%) neonates achieved virologic suppression within 6 months of life. In the subgroup of 98 infants who achieved virologic suppression, 40/274 HIV-1 DNA measurements fell below the limit of detection (LOD) of 25 cpm PBMC in the first 3.5 years of life. In this cohort, male sex was correlated with smaller reservoir size, with male infants achieving HIV-1 DNA levels 0.5 1og10 cpm PBMC lower than female infants. In addition, lower baseline plasma viral load and higher baseline CD4+ T-cell percentage in the neonates garnered the strongest association with smaller reservoir size.

The LEOPARD study conducted in South Africa followed 63 neonates who initiated ART at median 2 days post-birth with baseline HIV-1 DNA of 3.2 1og10 cpm PBMC. After 48 weeks on ART, infants who initiated ART at <48 hrs and 49 hrs–14 days declined to a median 2.4 1og10 cpm PBMC while those who initiated ART >14 days of life maintained HIV-1 DNA levels of 3.2 1og10 cpm PBMC. This study found that smaller reservoir size in infants was associated with higher CD4+ T-cell percentage and viral load <100,000 copies/mL pre-ART (30).

In IMPAACT P1115 clinical trial, neonates in Cohort 1 initiated very early ART at a median age of 7.8 hours of life while neonates in Cohort 2 initiated very early ART at a median age of 32.8 hours of life ((25), Lancet HIV, in press(31)). 64% (7/11) infants in Cohort 1 and 71% (5/7) infants in Cohort 2 of infants who maintained virologic control through 108 weeks of age reached undetectable HIV-1 DNA levels in PBMCs with an assay LOD of 0.6 log10 cpm PBMCs (32). In line with sex differences observed in Millar, et al., in Cohort 1, female sex was associated with greater risk of virologic failure. Altogether, these studies have established that accelerated diagnosis and immediate ART initiation in neonates with perinatal HIV-1 is essential to restricting the reservoir size with the potential for enabling ART-free remission. These observations are exemplified when comparing the HIV-1 DNA trends over time in all studies analyzed (Fig. 2C, Fig. 3).

The studies analyzed were highly variable with respect to median ART initiation age, sample size, follow-up time of subgroups, and different HIV-1 DNA assays. Nevertheless, earlier ART initiation was associated with lower HIV-1 DNA over time in all studies (Fig. 2, Fig 3). Further, very early ART initiation has the potential to achieve exceedingly low levels of HIV-1 DNA, reaching concentrations below <0.6 log10 HIV-1 DNA cpm PBMC by two years of age. Thus, very early ART presents the opportunity for ART-free remission if immune-based therapies that control HIV-1 rebound off ART are identified.

Impact of HIV-1 DNA on ART-free Remission and Potential Cure Strategies in Perinatal HIV-1

Case studies on ART-free remission in perinatal HIV-1 infection with very early ART initiation such as the “Mississippi baby” and early, time-limited ART in the “French adolescent” and “South African boy” have demonstrated the potential for maintaining sustained virologic in the absence of ART in children (33–36). However, unexpected viral rebound, as evidenced by the case of the Mississippi baby (37), indicates that HIV-1 reservoirs are established early in the course of HIV-1 infection with sustained quiescence for over two years off ART. Combinations of interventions that restrict HIV-1 reservoirs as with very early ART initiation with immune-based therapies will likely be necessary to achieve lifelong ART-free remission.

One area of research currently under investigation has been the use of broadly neutralizing antibodies (bNAbs) in combination with ART. The Tatelo Study recently investigated the safety and efficacy of combination bNAbs, VRC01LS and 10–1074, in very early treated children with HIV-1. This study provides proof-of-concept of the potential for these bNAbs to be used for sustained virologic control (38,39). The Tatelo study focused on a subset of 25 children originally enrolled in the EIT study who initiated very early ART within 7 days post-birth. These children were administered dual bNAb monthly infusions for either 2 (n=6) or 8 months (n=19), followed by bNAb treatments continued in the absence of ART for up to 6 months (n=25). While 56% (14/25) experienced viral rebound within 4 weeks after ART discontinuation, 44% (11/25) maintained viremia below 400 copies of HIV-1 RNA/mL plasma for the 6-month timeframe. When evaluating biomarkers that correlated with successful bNAb response, the researchers identified that total HIV-1 DNA levels near birth was significantly lower in the children that responded successfully to bNAb treatment. Thus, the findings of the Tatelo study indicate that bNAbs may represent a potential treatment strategy for sustained virologic suppression in the setting of low proviral loads in the context of perinatal HIV-1.

Therapeutic approaches to reactivate and eliminate latent HIV-1 reservoirs to achieve HIV-1 remission are also under investigation in adults living with HIV (1). Recent studies (40–44) have emphasized the need for a comprehensive understanding of potential differences in reactivation based on characteristics including age, sex, and resource setting. Identification of virological and immunological biomarkers predictive of ART-free remission are also crucial to advancing the field of HIV-1 cure research for a diverse population (45). Perinatal HIV-1 offers a distinct opportunity to investigate the efficacy of HIV-1 remission interventions in relation to the timing of both transmission event, ART initiation and remission therapeutics.

Limitations of Total HIV-1 DNA Measurements

In the studies reviewed, the viral reservoir was largely quantified as total HIV-1 DNA cpm PBMC, a measurement that overestimates the size of the replication-competent HIV-1 reservoir due to an abundance of defective proviruses (46). Use of total HIV-1 DNA in PBMCs can provide a near maximal estimate of the concentration of HIV-1-infected cells in the circulation for which an overall estimate of infectious reservoir size can be derived.

The Quantitative Viral Outgrowth Assay (QVOA) is considered the gold standard for quantifying the induced replication-competent reservoir (45). However, this assay often requires higher blood volumes that cannot feasibly be extracted from pediatric populations living with HIV-1. Further, this assay may also require viable cells unattainable in some resource-constrained settings. The Intact Proviral DNA Assay (IPDA) allows for the differentiation between intact and defective genomes, increasing accuracy with minimal required blood volume. Studies in adults living with HIV-1 have demonstrated the heightened decay of cells harboring replication-competent intact proviruses and potentially replication-competent over those harboring defective proviruses (47,48). In both adult and pediatric populations, intact proviruses levels positively correlate with total HIV-1 cpm CD4+ T cells (47,49). The advent of newer multiplex HIV-1 DNA assays optimized for different HIV-1 subtypes will be instrumental for identifying the composition of the proviral pool capable of eliciting rebound after ATI.

Conclusion

This systematic review focused on understanding the impact of age at ART initiation on total concentrations of HIV-1-infected cells in PBMCs. Despite similar pre-ART baseline HIV-1 DNA levels, very early treatment results in lower levels of HIV-1 DNA in early childhood. More research is necessary to understand optimizing clearance and control of HIV-1 reservoirs in perinatal HIV-1 infection. The potential correlation of additional factors, such as sex differences, geographic region of residence, HIV-1 subtypes, with HIV-1 viral reservoir formation and stability should be further investigated.

Supplementary Material

coha_2023_12_14_persaud_coh190206_sdc1
coha_2023_12_14_persaud_coh190206_sdc2
coha_2023_12_14_persaud_coh190206_sdc2_excel

Key Points:

  1. Accelerated diagnosis and immediate ART initiation for infants with perinatal HIV-1 is essential to restricting the reservoir size in order to enable ART-free remission

  2. The clinical relevance of achieving low reservoir size in perinatal HIV-1 infection through early and very early ART is supported by the three pediatric cases of ART-free remission reported to date.

  3. Findings from the Tatelo Study support that low reservoir size achieved through very early ART of neonates may afford treatment switch to combination therapy with monthly infusions of two broadly neutralizing antibodies, which paves the way towards long-acting biologics for improved sustained virologic suppression in children.

Financial Support and Sponsorship

This research was supported by the National Institutes of Health (R01A1150412), IMPAACT subspecialty laboratory (5UMIAI106716), the PAVE collaboratory (UMIAI164566) and Johns Hopkins Center for AIDS Research (P30 AI094189).

Footnotes

Conflicts of Interest

All authors report no conflicts of interest.

References

  • 1.Deeks SG, Archin N, Cannon P, Collins S, Jones RB, de Jong MAWP, et al. Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021. Nat Med. 2021. Dec;27(12):2085–98. [DOI] [PubMed] [Google Scholar]
  • 2.Global HIV & AIDS statistics — Fact sheet [Internet]. [cited 2022 Nov 27]. Available from: https://www.unaids.org/en/resources/fact-sheet
  • 3.Brahmbhatt H, Kigozi G, Wabwire-Mangen F, Serwadda D, Lutalo T, Nalugoda F, et al. Mortality in HIV-infected and uninfected children of HIV-infected and uninfected mothers in rural Uganda. J Acquir Immune Defic Syndr. 2006. Apr 1;41(4):504–8. [DOI] [PubMed] [Google Scholar]
  • 4.Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004. Oct 2;364(9441):1236–43. [DOI] [PubMed] [Google Scholar]
  • 5.Global HIV Programme [Internet]. [cited 2023 Nov 16]. Available from: https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/treatment/treatment-and-care-in-children-and-adolescents
  • 6.Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy [Internet]. Geneva: World Health Organization; 2017. [cited 2023 Nov 16]. (WHO Guidelines Approved by the Guidelines Review Committee). Available from: http://www.ncbi.nlm.nih.gov/books/NBK475977/ [PubMed] [Google Scholar]
  • 7.Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008. Nov 20;359(21):2233–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Borkowsky W, Yogev R, Muresan P, McFarland E, Frenkel L, Fenton T, et al. Planned multiple exposures to autologous virus in HIV type 1-infected pediatric populations increases HIV-specific immunity and reduces HIV viremia. AIDS Res Hum Retroviruses. 2008. Mar;24(3):401–11. [DOI] [PubMed] [Google Scholar]
  • 9.Davey RT, Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A. 1999. Dec 21;96(26):15109–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Klein N, Sefe D, Mosconi I, Zanchetta M, Castro H, Jacobsen M, et al. The immunological and virological consequences of planned treatment interruptions in children with HIV infection. PLoS One. 2013;8(10):e76582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Payne H, Chan MK, Watters SA, Otwombe K, Hsiao NY, Babiker A, et al. Early ART-initiation and longer ART duration reduces HIV-1 proviral DNA levels in children from the CHER trial. AIDS Res Ther. 2021. Sep 29;18(1):63. * A sub-study of the children with HIV early antiretroviral therapy (CHER) trial comparing peripheral HIV-1 proviral DNA in children who received early but temporarily interrupted ART versus late but continuous ART. This study emphasized the correlation between early and sustained ART and lower levels of HIV-1 proviral DNA in children.
  • 12.Massanella M, Ignacio RAB, Lama JR, Pagliuzza A, Dasgupta S, Alfaro R, et al. Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study. The Lancet Microbe. 2021. May 1;2(5):e198–209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ananworanich J, Chomont N, Eller LA, Kroon E, Tovanabutra S, Bose M, et al. HIV DNA Set Point is Rapidly Established in Acute HIV Infection and Dramatically Reduced by Early ART. EBioMedicine. 2016. Sep 1;11:68–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Millar JR, Bengu N, Vieira VA, Adland E, Roider J, Muenchhoff M, et al. Early Initiation of Antiretroviral Therapy Following In Utero HIV Infection Is Associated With Low Viral Reservoirs but Other Factors Determine Viral Rebound. The Journal of Infectious Diseases. 2021. Dec 1;224(11):1925–34. ** This paper examined the impact of very early ART initiation on the viral reservoir in infants with in utero HIV-1 in Ucwaningo Lwabantwana, an observational study based in KwaZulu-Natal, South Africa. This is the first study to note sex differences in HIV-1 DNA levels in infants with in utero HIV-1 with female infants attaining higher HIV-1 DNA levels than their male counterparts.
  • 15.Persaud D, Patel K, Karalius B, Rainwater-Lovett K, Ziemniak C, Ellis A, et al. Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA Pediatr. 2014. Dec;168(12):1138–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Zanchetta M, Walker S, Burighel N, Bellanova D, Rampon O, Giaquinto C, et al. Long-term decay of the HIV-1 reservoir in HIV-1-infected children treated with highly active antiretroviral therapy. J Infect Dis. 2006. Jun 15;193(12):1718–27. [DOI] [PubMed] [Google Scholar]
  • 17.van Zyl GU, Bedison MA, van Rensburg AJ, Laughton B, Cotton MF, Mellors JW. Early Antiretroviral Therapy in South African Children Reduces HIV-1-Infected Cells and Cell-Associated HIV-1 RNA in Blood Mononuclear Cells. J Infect Dis. 2015. Jul 1;212(1):39–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Katusiime MG, Halvas EK, Wright I, Joseph K, Bale MJ, Kirby-McCullough B, et al. Intact HIV Proviruses Persist in Children Seven to Nine Years after Initiation of Antiretroviral Therapy in the First Year of Life. J Virol. 2020. Jan 31;94(4):e01519–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Luzuriaga K, Tabak B, Garber M, Chen YH, Ziemniak C, McManus MM, et al. HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment. J Infect Dis. 2014. Nov 15;210(10):1529–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.McManus M, Mick E, Hudson R, Mofenson LM, Sullivan JL, Somasundaran M, et al. Early Combination Antiretroviral Therapy Limits Exposure to HIV-1 Replication and Cell-Associated HIV-1 DNA Levels in Infants. PLoS One. 2016;11(4):e0154391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Uprety P, Patel K, Karalius B, Ziemniak C, Chen YH, Brummel SS, et al. Human Immunodeficiency Virus Type 1 DNA Decay Dynamics With Early, Long-term Virologic Control of Perinatal Infection. Clin Infect Dis. 2017. Jun 1;64(11):1471–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Tagarro A, Chan M, Zangari P, Ferns B, Foster C, De Rossi A, et al. Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children. J Acquir Immune Defic Syndr. 2018. Oct 1;79(2):269–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Bitnun A, Ransy DG, Brophy J, Kakkar F, Hawkes M, Samson L, et al. Clinical Correlates of Human Immunodeficiency Virus-1 (HIV-1) DNA and Inducible HIV-1 RNA Reservoirs in Peripheral Blood in Children With Perinatally Acquired HIV-1 Infection With Sustained Virologic Suppression for at Least 5 Years. Clin Infect Dis. 2020. Feb 14;70(5):859–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Avettand-Fenoel V, Lechenadec J, Diallo MS, Fillion M, Melard A, Samri A, et al. Initiating Antiretroviral Treatment Early in Infancy Has Long-term Benefits on the Human Immunodeficiency Virus Reservoir in Late Childhood and Adolescence. Clin Infect Dis. 2021. Dec 6;73(11):e4214–22. [DOI] [PubMed] [Google Scholar]
  • 25.Garcia-Broncano P, Maddali S, Einkauf KB, Jiang C, Gao C, Chevalier J, et al. Early antiretroviral therapy in neonates with HIV-1 infection restricts viral reservoir size and induces a distinct innate immune profile. Sci Transl Med. 2019. Nov 27;11(520):eaax7350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Ajibola G, Maswabi K, Hughes MD, Bennett K, Pretorius-Holme M, Capparelli EV, et al. Brief Report: Long-Term Clinical, Immunologic, and Virologic Outcomes Among Early-Treated Children With HIV in Botswana: A Nonrandomized Controlled Clinical Trial. J Acquir Immune Defic Syndr. 2023. Apr 15;92(5):393–8. ** This article reported on the nonrandomized controlled Early Infant Treatment (EIT) clinical trial in Botswana. Results in this article extend past the primary endpoint of 96 weeks and include complete viral reservoir evaluations for all 38 infants enrolled in the trial.
  • 27.Ajibola G, Garcia-Broncano P, Maswabi K, Bennett K, Hughes MD, Moyo S, et al. Viral Reservoir in Early-Treated Human Immunodeficiency Virus-Infected Children and Markers for Sustained Viral Suppression. Clin Infect Dis. 2021. Aug 16;73(4):e997–1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Kuhn L, Strehlau R, Shiau S, Patel F, Shen Y, Technau KG, et al. Early antiretroviral treatment of infants to attain HIV remission. EClinicalMedicine. 2020. Jan;18:100241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Kuhn L, Paximadis M, Da Costa Dias B, Shen Y, Mncube S, Strehlau R, et al. Predictors of Cell-Associated Human Immunodeficiency Virus (HIV)-1 DNA Over 1 Year in Very Early Treated Infants. Clin Infect Dis. 2022. Mar 23;74(6):1047–54. ** This study of very early treated infants in Johannesburg, South Africa reported on baseline neonatal characteristics correlated with lower reservoir size in the first year of life. This study found that the benefits of very early were still observed when ART was administered after 48 hours but within the first week of life.
  • 30. Persaud D Two-Year Virologic Outcomes of Very Early Art for Infants in the IMPAACT P1115 Study [Internet]. Oral presented at: Conference on Retroviruses and Opportunistic Infections; 2022. Feb 14. Available from: https://www.croiwebcasts.org/p/2022croi/croi/31 ** This presentation highlights the findings from IMPAACT P1115, a phase I/II, multi-center proof-of-concept study that assesses the potential of very early antiretroviral therapy (ART) for remission of in utero HIV-1 infection. This study demonstrates that very early treated infants who maintain virologic suppression can achieve restricted HIV-1 reservoirs by 2 years of age, which may enable ART-free remission.
  • 31.Powell L, Dhummakupt A, Siems L, Singh D, Le Duff Y, Uprety P, et al. Clinical Validation of a Quantitative HIV-1 DNA Droplet Digital PCR assay: Applications for Detecting Occult HIV-1 Infection and Monitoring Cell-associated HIV-1 Dynamics across Different Subtypes in HIV-1 Prevention and Cure Trials. J Clin Virol. 2021. Jun;139:104822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M, Chun TW, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013. Nov 7;369(19):1828–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Violari A, Cotton MF, Kuhn L, Schramm DB, Paximadis M, Loubser S, et al. A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation. Nat Commun. 2019. Jan 24;10(1):412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Frange P, Faye A, Avettand-Fenoël V, Bellaton E, Descamps D, Angin M, et al. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet HIV. 2016. Jan;3(1):e49–54. [DOI] [PubMed] [Google Scholar]
  • 35.Uprety P, Chadwick EG, Rainwater-Lovett K, Ziemniak C, Luzuriaga K, Capparelli EV, et al. Cell-Associated HIV-1 DNA and RNA Decay Dynamics During Early Combination Antiretroviral Therapy in HIV-1-Infected Infants. Clin Infect Dis. 2015. Dec 15;61(12):1862–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M, Rainwater-Lovett K, et al. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med. 2015. Feb 19;372(8):786–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Capparelli EV, Ajibola G, Maswabi K, Holme MP, Bennett K, Powis KM, et al. Safety and pharmacokinetics of intravenous 10–1074 and VRC01LS in young children. J Acquir Immune Defic Syndr. 2022. Oct 1;91(2):182–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Shapiro RL, Ajibola G, Maswabi K, Hughes M, Nelson BS, Niesar A, et al. Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana. Sci Transl Med. 2023. Jul 5;15(703):eadh0004. ** This proof-of-concept study showed the combinatory effects of broadly neutralizing antibodies and very early ART initiation in maintenance of viral suppression in infants with HIV-1 originally enrolled in the Early Infant Treatment (EIT) study. Virological and immunological characteristics associated with bNAb success were identified and provide insight for developing selection criteria for future bNAb studies in children living with HIV-1.
  • 39.Dhummakupt A, Rubens JH, Anderson T, Powell L, Nonyane BAS, Siems LV, et al. Differences in inducibility of the latent HIV reservoir in perinatal and adult infection. JCI Insight [Internet]. 2020. May 27 [cited 2022 Dec 18];5(4). Available from: https://insight.jci.org/articles/view/134105 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Amin O, Powers J, Bricker KM, Chahroudi A. Understanding Viral and Immune Interplay During Vertical Transmission of HIV: Implications for Cure. Front Immunol. 2021. Oct 21;12:757400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Scully EP, Gandhi M, Johnston R, Hoh R, Lockhart A, Dobrowolski C, et al. Sex-Based Differences in Human Immunodeficiency Virus Type 1 Reservoir Activity and Residual Immune Activation. J Infect Dis. 2019. Mar 15;219(7):1084–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Prodger JL, Capoferri AA, Yu K, Lai J, Reynolds SJ, Kasule J, et al. Reduced HIV-1 latent reservoir outgrowth and distinct immune correlates among women in Rakai, Uganda. JCI Insight. 2020. Jul 23;5(14):e139287, 139287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Falcinelli SD, Shook-Sa BE, Dewey MG, Sridhar S, Read J, Kirchherr J, et al. Impact of Biological Sex on Immune Activation and Frequency of the Latent HIV Reservoir During Suppressive Antiretroviral Therapy. J Infect Dis. 2020. Nov 9;222(11):1843–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Khetan P, Liu Y, Dhummakupt A, Persaud D. Advances in Pediatric HIV-1 Cure Therapies and Reservoir Assays. Viruses. 2022. Dec;14(12):2608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB, Capoferri AA, et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med. 2016. Sep;22(9):1043–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Gandhi RT, Cyktor JC, Bosch RJ, Mar H, Laird GM, Martin A, et al. Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy. J Infect Dis. 2020. Aug 21;223(2):225–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Peluso MJ, Bacchetti P, Ritter KD, Beg S, Lai J, Martin JN, et al. Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy. JCI Insight. 2020. Feb 27;5(4):e132997, 132997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Huang Y, Dhummakupt A, Khetan P, Nilles T, Zhou W, Mudvari P, et al. Immune activation and exhaustion marker expression on T-cell subsets in ART-treated adolescents and young adults with perinatal HIV-1 infection as correlates of viral persistence. Front Immunol. 2023. Mar 23;14:1007626. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

coha_2023_12_14_persaud_coh190206_sdc1
NIHMS1971779-supplement-coha_2023_12_14_persaud_coh190206_sdc1.docx (17.2KB, docx)
coha_2023_12_14_persaud_coh190206_sdc2
NIHMS1971779-supplement-coha_2023_12_14_persaud_coh190206_sdc2.doc (181.5KB, doc)
coha_2023_12_14_persaud_coh190206_sdc2_excel
NIHMS1971779-supplement-coha_2023_12_14_persaud_coh190206_sdc2_excel.xlsx (25.2KB, xlsx)

RESOURCES