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1.
Lancet ; 397(10281): 1276-1292, 2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33812487

RESUMO

BACKGROUND: Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate. METHODS: This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14-28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14-18, 19-23, and 24-28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of -10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422. FINDINGS: Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0-5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per µL (308-624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of -10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (70 [33%] of 213; estimated difference -8·8% [95% CI -17·3 to -0·3], p=0·043) or the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (69 [33%] of 211; -8·6% [-17·1 to -0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (25 [12%] of 207; -6·3% [-11·8 to -0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (three [2%] of 202; p=0·050). INTERPRETATION: When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths. 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.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Tenofovir/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Alanina , Fármacos Anti-HIV/efeitos adversos , Quimioterapia Combinada , Emtricitabina/efeitos adversos , Feminino , Idade Gestacional , Infecções por HIV/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Piridonas/efeitos adversos , Tenofovir/efeitos adversos , Ultrassonografia Pré-Natal
2.
J Infect Dis ; 224(11): 1916-1924, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009371

RESUMO

BACKGROUND: Perinatal human immunodeficiency virus type 1 (HIV-1) continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). METHODS: An extended half-life bNAb, VRC01LS, was administered subcutaneously at 80 mg/dose after birth to HIV-1-exposed, nonbreastfed (cohort 1, n = 10) and breastfed (cohort 2, n = 11) infants. Cohort 2 received a second dose (100 mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. RESULTS: Local reactions (all grade ≤2) occurred in 67% and 20% after dose 1 and dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administered subcutaneously achieved a mean (standard deviation) plasma level of 222.3 (71.6) µg/mL by 24 hours and 44.0 (11.6) µg/mL at week 12, prior to dose 2. The preestablished target of ≥50 µg/mL was attained in 95% and 32% at weeks 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after 1 dose was significantly greater (P <.002) than after a VRC01 dose (20 mg/kg). No infants acquired HIV-1. CONCLUSIONS: VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with antiretrovirals to prevent infant HIV-1 transmission.


Assuntos
Antirretrovirais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Amplamente Neutralizantes/farmacologia , Anticorpos Anti-HIV , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Antirretrovirais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Amplamente Neutralizantes/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/efeitos adversos , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , HIV-1/patogenicidade , Meia-Vida , Humanos , Recém-Nascido , Masculino
3.
J Infect Dis ; 222(4): 628-636, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31681963

RESUMO

BACKGROUND: Although mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission. METHODS: A Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis. RESULTS: Forty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1-6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding. CONCLUSIONS: Subcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , África , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Amplamente Neutralizantes/efeitos adversos , Feminino , Anticorpos Anti-HIV/efeitos adversos , Infecções por HIV/sangue , Humanos , Recém-Nascido , Injeções Subcutâneas , Modelos Lineares , Masculino , Estados Unidos
4.
N Engl J Med ; 375(18): 1726-1737, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27806243

RESUMO

BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Zidovudina/uso terapêutico , Adulto , Negro ou Afro-Americano , Antirretrovirais/efeitos adversos , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Idade Gestacional , Infecções por HIV/etnologia , Infecções por HIV/transmissão , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Nevirapina/administração & dosagem , Assistência Perinatal , Gravidez , Resultado da Gravidez , Tenofovir/uso terapêutico , Adulto Jovem , Zidovudina/efeitos adversos
5.
Clin Infect Dis ; 67(11): 1712-1719, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29590326

RESUMO

Background: Herpes zoster (HZ) risk is increased in human immunodeficiency virus (HIV)-infected persons. Live attenuated zoster vaccine (ZV) reduces HZ incidence and severity in adults; safety and immunogenicity data in HIV-infected adults are limited. Methods: We conducted a randomized, double-blind, placebo-controlled trial in HIV-infected adults virally suppressed on antiretroviral therapy (ART). Participants, stratified by CD4+ count (200-349 or ≥350 cells/µL), were randomized 3:1 to receive ZV or placebo on day 0 and week 6. The primary endpoint was serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose. Immunogenicity (varicella zoster virus [VZV]-specific glycoprotein enzyme-linked immunosorbent assay and interferon-γ enzyme-linked immunospot assay responses) was assessed at 6 and 12 weeks postvaccination. Results: Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% [95% confidence interval {CI}, 2.9%-8.2%] vs 2.1% [95% CI, .3%-7.3%]; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%-47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%-20.6%) (P < .001). Week 12 median natural log VZV antibody titer was higher for ZV (6.30 [Q1, Q3, 5.64, 6.96]) vs placebo (5.48 [Q1, Q3, 4.63, 6.44]; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction-confirmed HZ occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related. Conclusions: Two doses of ZV in HIV-infected adults suppressed on ART with CD4+ counts ≥200 cells/µL were safe and immunogenic. Clinical Trials Registration: NCT00851786.


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/imunologia , Vacina contra Herpes Zoster/imunologia , Imunogenicidade da Vacina , Resposta Viral Sustentada , Adulto , Anticorpos Antivirais/sangue , Contagem de Linfócito CD4 , Método Duplo-Cego , ELISPOT , Feminino , Infecções por HIV/tratamento farmacológico , Herpesvirus Humano 3 , Humanos , Masculino , Pessoa de Meia-Idade
6.
N Engl J Med ; 366(25): 2380-9, 2012 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-22716976

RESUMO

BACKGROUND: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/prevenção & controle , HIV-1 , Lamivudina/uso terapêutico , Lopinavir/uso terapêutico , Zidovudina/uso terapêutico , Antirretrovirais/efeitos adversos , Contagem de Linfócito CD4 , Pré-Escolar , Quimioterapia Combinada/efeitos adversos , Feminino , Infecções por HIV/mortalidade , Humanos , Lactente , Estimativa de Kaplan-Meier , Lamivudina/efeitos adversos , Lopinavir/efeitos adversos , Masculino , Nevirapina/efeitos adversos , Nevirapina/uso terapêutico , RNA Viral/sangue , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , Zidovudina/efeitos adversos
7.
N Engl J Med ; 363(16): 1510-20, 2010 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-20942667

RESUMO

BACKGROUND: Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. METHODS: We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. RESULTS: A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. CONCLUSIONS: Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Nevirapina/administração & dosagem , Fármacos Anti-HIV/administração & dosagem , Pré-Escolar , Quimioterapia Combinada , Feminino , Infecções por HIV/mortalidade , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Estimativa de Kaplan-Meier , Lopinavir , Masculino , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Pirimidinonas/uso terapêutico , RNA Viral/sangue , Ritonavir/uso terapêutico , Falha de Tratamento
8.
Lancet HIV ; 10(6): e363-e374, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37167996

RESUMO

BACKGROUND: Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422. FINDINGS: Between Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per µL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups. INTERPRETATION: Safety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy. 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.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Gravidez , Criança , Feminino , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Tenofovir/efeitos adversos , Benzoxazinas/uso terapêutico , Emtricitabina/efeitos adversos , Adenina/uso terapêutico , RNA/uso terapêutico , Carga Viral
9.
Pediatr Infect Dis J ; 40(5): 446-452, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33464021

RESUMO

BACKGROUND: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. MATERIALS AND METHODS: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC0-12h) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. RESULTS: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) -3.4 (IQR -4.0, -3.0) and 27 non-SAM had median WHZ -1.0 (IQR -1.8, -0.1). No significant differences in mean AUC0-12h or CL/F were observed (P ≥ 0.09) except for lower 3TC AUC0-12h (GMR, 0.60; 95% CI, 0.4-1.0; P = 0.047) at week 12, higher ZDV AUC0-12h (GMR, 1.52; 1.2-2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). CONCLUSION: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.


Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Lamivudina/farmacocinética , Lopinavir/farmacocinética , Ritonavir/farmacocinética , Zidovudina/farmacocinética , África Subsaariana/epidemiologia , Fármacos Anti-HIV/sangue , Área Sob a Curva , Pré-Escolar , Cromatografia Líquida/instrumentação , Estudos de Coortes , Combinação de Medicamentos , Vias de Eliminação de Fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Infecções por HIV/complicações , Humanos , Lactente , Lamivudina/sangue , Lopinavir/sangue , Masculino , Segurança do Paciente , Ritonavir/sangue , Desnutrição Aguda Grave/complicações , Espectrometria de Massas em Tandem/instrumentação , Zidovudina/sangue
10.
Pediatr Infect Dis J ; 28(3): 215-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19209098

RESUMO

BACKGROUND: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). METHODS: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants > or =14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 microg/mL and area under the curve (AUC) <170 microg hr/mL. RESULTS: Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. CONCLUSIONS: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV , HIV-1/efeitos dos fármacos , Pirimidinonas , Ritonavir , Área Sob a Curva , Esquema de Medicação , Feminino , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , HIV-1/fisiologia , Humanos , Lactente , Lopinavir , Masculino , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Pirimidinonas/uso terapêutico , RNA Viral/sangue , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Resultado do Tratamento , Carga Viral
11.
J Pediatr Gastroenterol Nutr ; 49(2): 222-32, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19543114

RESUMO

OBJECTIVE: We tested the hypothesis that concentrated formula (CF) begun within the first 2 weeks of life increases growth in infants born to human immunodeficiency virus (HIV)-infected mothers. MATERIALS AND METHODS: HIV-exposed infants from the United States, the Bahamas, and Brazil were randomized in a double-blind, controlled trial to receive either a CF (87 kcal/100 mL [26 kcal/oz]) or a standard formula (SF; 67 kcal/100 mL [20 kcal/oz]) for 8 weeks. This article presents results for infants who were not determined to be HIV infected based on testing at 4 weeks. Primary outcomes were safety, tolerability, and growth in weight and length. RESULTS: Two thousand ninety-seven infants were enrolled, of whom 1998 were uninfected and had study formula dispensed. At weeks 4 and 8, uninfected infants receiving CF showed higher energy intake than those who were receiving SF (P < 0.001). By week 8, uninfected infants assigned to CF weighed more than infants receiving SF. There were no consistent differences in measures of tolerability, and rates of discontinuation or perceived formula intolerance were similar between treatment groups. CONCLUSIONS: A CF is well tolerated and results in increased weight gain compared with SF. Until the HIV status of an infant is reliably determined, early introduction of a CF in HIV-exposed children may have beneficial effects on growth. The role of early nutritional intervention remains to be determined for individuals living in countries with endemic malnutrition for whom formula feeding is a viable option.


Assuntos
Ingestão de Energia , Infecções por HIV , Fórmulas Infantis , Complicações Infecciosas na Gravidez , Aumento de Peso , Animais , Bahamas , Brasil , Método Duplo-Cego , Feminino , Infecções por HIV/transmissão , Humanos , Lactente , Fórmulas Infantis/química , Recém-Nascido , Leite , Gravidez , Estados Unidos
12.
J Acquir Immune Defic Syndr ; 81(4): 473-480, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241542

RESUMO

BACKGROUND: CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infected children younger than 36 months, but such data are lacking in those with tuberculosis (TB) coinfection. METHODS: Phase I, 24-week safety and pharmacokinetic (PK) study of EFV in HIV-infected children aged 3 to <36 months, with or without TB. CYP2B6 516 genotype classified children into extensive metabolizers (516 TT/GT) and poor metabolizers [(PMs), 516 TT]. EFV doses were 25%-33% higher in children with HIV/TB coinfection targeting EFV area under the curve (AUC) 35-180 µg × h/mL, with individual dose adjustment as necessary. Safety and virologic evaluations were performed every 4-8 weeks. RESULTS: Fourteen children from 2 African countries and India with HIV/TB enrolled, with 11 aged 3 to <24 months and 3 aged 24-36 months, 12 extensive metabolizers and 2 PMs. Median (Q1, Q3) EFV AUC was 92.87 (40.95, 160.81) µg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) µg × h/mL in children aged 24-36 months. AUC targets were met in 6/8 and 2/5 of the younger and older age groups, respectively. EFV clearance was reduced in PM's and older children. Pharmacokinetic modeling predicted adequate EFV concentrations if children younger than 24 months received TB-uninfected dosing. All 9 completing 24 weeks achieved viral suppression. Five/14 discontinued treatment early: 1 neutropenia, 3 nonadherence, and 1 with excessive EFV AUC. CONCLUSIONS: Genotype-directed dosing safely achieved therapeutic EFV concentrations and virologic suppression in HIV/TB-coinfected children younger than 24 months, but further study is needed to confirm appropriate dosing in those aged 24-36 months. This approach is most important for young children and currently a critical unmet need in TB-endemic countries.


Assuntos
Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Tuberculose/tratamento farmacológico , África , Alcinos , Pré-Escolar , Estudos de Coortes , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Feminino , Genótipo , Humanos , Índia , Lactente , Masculino , Estudos Prospectivos , Resultado do Tratamento
13.
AIDS ; 31(8): 1129-1136, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28323755

RESUMO

OBJECTIVES: To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. DESIGN: IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). METHODS: CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35-180 µg*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. RESULTS: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 µg*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. CONCLUSION: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.


Assuntos
Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Citocromo P-450 CYP2B6/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Alcinos , Pré-Escolar , Ciclopropanos , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
14.
AIDS Res Hum Retroviruses ; 32(7): 636-47, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26935044

RESUMO

Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.


Assuntos
Cloroquina/administração & dosagem , Infecções por HIV/imunologia , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Adolescente , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Adulto Jovem
15.
Pediatr Infect Dis J ; 21(7): 653-9, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12237598

RESUMO

BACKGROUND: Entry inhibitors, a new class of antiretroviral agents, interfere with the attachment, coreceptor interaction or fusion of HIV-1 with host target cells. The fusion inhibitor T-20 is the first in this new class, and the present study is the first to examine chronic s.c. administration of T-20 to HIV-1-infected children. METHODS: Fourteen children, 4 to 12 years of age, with incompletely suppressed HIV-1 were studied. The median plasma viral load at baseline was 26,866 copies/ml (4.4 log10), and the median CD4 count was 523 cells/mm3. T-20 was administered twice daily by s.c. injection at 30 or 60 mg per m2 of body surface area per dose. For 7 days T-20 was added to the patients' background antiretroviral regimens; at Day 7 each subject's background therapy was changed to a regimen that was predicted to be virologically active, while T-20 was continued. Results are presented for the first 24 weeks of chronic T-20 dosing. RESULTS: T-20 was generally well-tolerated. One child discontinued the drug because of aversion to injections, but no child discontinued because of adverse events. Eleven (79%) of 14 children had local injection site reactions at some time during the chronic T-20 dosing. Eleven of 14 subjects achieved the protocol-specified milestone of at least a 0.7-log10 reduction in plasma HIV-1 RNA by Day 7. In 10 subjects (71%) virologic suppression of 1.0 log10 or greater was achieved at 24 weeks; 6 subjects (43%) had viral loads <400 copies/ml and 3 (21%) had fewer than 50 copies/ml at 24 weeks. CONCLUSIONS: These results indicate that a 24-week regimen of twice daily s.c. dosing of T-20 in HIV-1-infected children is safe and tolerable and that it is associated with suppression of HIV-1 replication during 24 weeks of administration.


Assuntos
Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/administração & dosagem , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Infecções por HIV/diagnóstico , Infecções por HIV/mortalidade , Humanos , Injeções Subcutâneas , Assistência de Longa Duração , Masculino , Dose Máxima Tolerável , Probabilidade , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Método Simples-Cego , Taxa de Sobrevida , Resultado do Tratamento , Carga Viral
16.
J Acquir Immune Defic Syndr ; 66(4): 399-406, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24815851

RESUMO

BACKGROUND: Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease. METHODS: In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels ≤200 copies per milliliter for ≥6 months and CD4 lymphocyte counts <200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 µg/kg of palifermin on 3 consecutive days. RESULTS: The median change in the CD4 T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm] and the 20-µg/kg dose [11 (2, 32) cells/mm], the 40-µg/kg dose [12 (-2, 25) cells/mm], or the 60-µg/kg dose arm [8 (-13, 35) cells/mm] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants. CONCLUSIONS: Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Fator 7 de Crescimento de Fibroblastos/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1 , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fator 7 de Crescimento de Fibroblastos/administração & dosagem , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , Proteínas Recombinantes , Timo/efeitos dos fármacos , Carga Viral
17.
Vaccine ; 27(43): 6088-94, 2009 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-19450647

RESUMO

Targeting canarypox (CP)-HIV vaccine to dendritic cells (DCs) elicits anti-HIV-1 immune responses in vitro. We conducted a phase I/II clinical trial to evaluate whether adding DC to a CP-HIV vaccine improved virologic control during analytic treatment interruption (ATI) in HIV-1-infected subjects. Twenty-nine subjects on suppressive antiretroviral therapy were randomized to vaccination with autologous DCs infected with CP-HIV+keyhole limpet hemocyanin (KLH) (arm A, n=14) or CP-HIV+KLH alone (arm B, n=15). The mean viral load (VL) setpoint during ATI did not differ between subjects in arms A and B. A higher percentage of subjects in the DC group had a VL setpoint < 5,000 c/mL during ATI (4/13 or 31% in arm A compared with 0/13 in arm B, p=0.096), but virologic control was transient. Subjects in arm A had a greater increase in KLH lymphoproliferative response than subjects in arm B; however, summed ELISPOT responses to HIV-1 antigens did not differ by treatment arm. We conclude that a DC-CP-HIV vaccine is well-tolerated in HIV-1-infected patients, but does not lower VL setpoint during ATI compared with CP-HIV alone. New methods to enhance the immunogenicity and antiviral efficacy of DC-based vaccines for HIV-1 infection are needed.


Assuntos
Vacinas contra a AIDS/imunologia , Vírus da Varíola dos Canários/imunologia , Células Dendríticas/imunologia , Infecções por HIV/imunologia , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Proliferação de Células , Feminino , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral
18.
J Infect Dis ; 194(5): 623-32, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16897661

RESUMO

BACKGROUND: The ability to control human immunodeficiency virus (HIV) replication in vivo in the absence of antiretroviral therapy (ART) is a measure of the efficiency of antiviral immunity. In a study of patients with chronic, ART-suppressed HIV infection, AIDS Clinical Trials Group 5068 investigated the effects of immunization with an exogenous HIV vaccine and pulse exposure to the subject's unique viral epitopes, by means of structured treatment interruptions (STIs), on the dynamics of viral rebound during a subsequent analytical treatment interruption (ATI). METHODS: Ninety-seven subjects receiving stable ART with an HIV-1 RNA load <50 copies/mL and CD4(+) T lymphocyte count >400 cells/mm(3) were randomized to undergo continued ART, STIs, ALVAC-HIV vCP1452 immunization, or STIs and ALVAC-HIV vCP1452 immunization. RESULTS: Subjects in the 2 STI arms had a significantly longer median doubling time in the period of the initial rise of viral load, a significantly lower median peak viral load, a significantly lower median end-of-ATI viral load set point, and a greater proportion of subjects with an end-of-ATI viral load set point <1,000 copies/mL, compared with the subjects in the 2 arms without STIs. With an immunization schedule of 3 sets of 3 weekly injections, ALVAC-HIV vCP1452 did not affect viral load measures. CONCLUSIONS: In this randomized, controlled study of intermittent STI as a therapeutic autoimmunization strategy, evidence of enhanced immunologic control of HIV replication was demonstrated.


Assuntos
Vacinas contra a AIDS/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , HIV/fisiologia , Vacinas Virais/uso terapêutico , Replicação Viral/efeitos dos fármacos , Vacinas contra a AIDS/administração & dosagem , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , Fármacos Anti-HIV/administração & dosagem , Ensaios Clínicos como Assunto , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , HIV/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Grupos Raciais , Recidiva , Carga Viral , Vacinas Virais/administração & dosagem
19.
J Acquir Immune Defic Syndr ; 32(3): 281-6, 2003 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-12626887

RESUMO

Adult Clinical Trials Group Study 349 examined the immunology, virology, and safety of 40 mg/d prednisone as an adjunct to antiretroviral therapy in 24 HIV-infected subjects with >200 CD4+ T cells/mm in a randomized placebo-controlled trial. After 8 weeks, median lymphocyte and CD4+ cell numbers increased >40% above baseline values (p =.08). No effect was observed on markers of cell activation or apoptosis, although the proportion of CD28+ CD8+ T cells increased (p =.006). Prednisone inhibited monocyte TNFalpha production without affecting T-cell responses to antigens or mitogens. Two subjects assigned to prednisone were subsequently found to have asymptomatic osteonecrosis of the hip. Many questions remain regarding the role of activation-induced sequestration and apoptosis as causes of progressive CD4+ T-cell loss in AIDS. The potential role of corticosteroids as tools to examine this question will be limited by concerns regarding their toxicity; however, further studies of other agents to limit cellular activation in AIDS are warranted.


Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1 , Prednisolona/uso terapêutico , Adulto , Fármacos Anti-HIV/uso terapêutico , Apoptose , Antígenos CD28/análise , Contagem de Linfócito CD4 , Antígenos CD8/análise , Método Duplo-Cego , Quimioterapia Combinada , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Quadril/diagnóstico por imagem , Humanos , Contagem de Linfócitos , Osteonecrose/induzido quimicamente , Osteonecrose/diagnóstico por imagem , Prednisolona/efeitos adversos , Prednisolona/antagonistas & inibidores , RNA Viral/sangue , Radiografia , Linfócitos T/imunologia , Linfócitos T/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossíntese
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