HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study.

Autor:	Persaud D; Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: dpers@jhmi.edu., Bryson Y; University of California Los Angeles, Los Angeles, CA, USA., Nelson BS; Harvard T H Chan School of Public Health, Boston, MA, USA., Tierney C; Harvard T H Chan School of Public Health, Boston, MA, USA., Cotton MF; Stellenbosch University, Tygerberg, South Africa., Coletti A; FHI 360, Durham, NC, USA., Jao J; Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Spector SA; University of California San Diego School of Medicine, La Jolla, CA, USA., Mirochnick M; Boston University School of Medicine, Boston, MA, USA., Capparelli EV; University of California San Diego School of Medicine, La Jolla, CA, USA., Costello D; University of California Los Angeles, Los Angeles, CA, USA., Szewczyk J; Johns Hopkins University School of Medicine, Baltimore, MD, USA., Nicodimus N; University of Zimbabwe, Clinical Trials Research Centre, Harare, Zimbabwe., Stranix-Chibanda L; University of Zimbabwe, Clinical Trials Research Centre, Harare, Zimbabwe., Kekitiinwa AR; Baylor College of Medicine Children's Foundation, Kampala, Uganda., Korutaro V; Baylor College of Medicine Children's Foundation, Kampala, Uganda., Reding C; Frontier Science and Technology Research Foundation, Amherst, NY, USA., Carrington MN; Frederick National Laboratory for Cancer Research and Laboratory of Integrative Cancer Immunology National Cancer Institute, MD, USA., Majji S; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Yin DE; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Jean-Philippe P; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Chadwick EG; Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Jazyk:	angličtina
Zdroj:	The lancet. HIV [Lancet HIV] 2024 Jan; Vol. 11 (1), pp. e20-e30. Date of Electronic Publication: 2023 Dec 04.
DOI:	10.1016/S2352-3018(23)00236-9
Abstrakt:	Background: Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission. Methods: IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks' gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m 2 and lopinavir 300 mg/m 2 from 14 days of life and 42 weeks postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption. This study is registered with ClinicalTrials.gov, NCT02140255. Findings: Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17-49) in cohort 1 and 57% (28-78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31-89) in cohort 1 and five of seven (71%, 29-96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52-100) in cohort 1 and all seven (100%, 59-100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2. Interpretation: Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission. Funding: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health. Competing Interests: Declaration of interests MM receives research support from Gilead Sciences, ViiV Healthcare, and Merck. EVC serves as a consultant to Melinta Pharmaceuticals. EGC's spouse holds an equity interest in AbbVie. All other authors declare no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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