RESUMO
BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).
Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1 , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Administração Oral , Adolescente , Alcinos/uso terapêutico , Antirretrovirais/efeitos adversos , Benzoxazinas/uso terapêutico , Criança , Pré-Escolar , Colesterol/sangue , Ciclopropanos/uso terapêutico , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Oxazinas/administração & dosagem , Oxazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Our understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are the predominant viruses seen in low- and middle-income countries (LMIC) in Africa and Asia. RESULTS: In this study, blood samples were obtained from well-suppressed ART-experienced HIV-1 patients monitored in Uganda (n = 62) or the U.S. (n = 50), with plasma HIV-1 loads < 50 copies/ml and CD4+ T-cell counts > 300 cells/ml. The peripheral HIV-1 reservoir, i.e., cell-associated HIV-1 RNA and proviral DNA, was characterized using our novel deep sequencing-based EDITS assay. Ugandan patients were slightly younger (median age 43 vs 49 years) and had slightly lower CD4+ counts (508 vs 772 cells/ml) than U.S. individuals. All Ugandan patients were infected with non-B HIV-1 subtypes (31% A1, 64% D, or 5% C), while all U.S. individuals were infected with subtype B viruses. Unexpectedly, we observed a significantly larger peripheral inducible HIV-1 reservoir in U.S. patients compared to Ugandan individuals (48 vs. 11 cell equivalents/million cells, p < 0.0001). This divergence in reservoir size was verified measuring proviral DNA (206 vs. 88 cell equivalents/million cells, p < 0.0001). However, the peripheral HIV-1 reservoir was more diverse in Ugandan than in U.S. individuals (8.6 vs. 4.7 p-distance, p < 0.0001). CONCLUSIONS: The smaller, but more diverse, peripheral HIV-1 reservoir in Ugandan patients might be associated with viral (e.g., non-B subtype with higher cytopathicity) and/or host (e.g., higher incidence of co-infections or co-morbidities leading to less clonal expansion) factors. This highlights the need to understand reservoir dynamics in diverse populations as part of ongoing efforts to find a functional cure for HIV-1 infection in LMICs.
Assuntos
Infecções por HIV , HIV-1 , Adulto , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos , HIV-1/genética , Humanos , Provírus/genética , Uganda/epidemiologia , Carga ViralRESUMO
This multicountry prospective study investigated whether persistent systemic inflammation, measured by 8 plasma biomarkers, in HIV-1-infected Africans during suppressive antiretroviral therapy (ART) (viral load <50 copies/mL), was associated with CD4+ T-cell recovery and viral rebound (>1000 copies/mL) during long-term treatment. On-ART sCD14 and C-reactive protein concentrations were inversely associated with subsequent CD4+ T-cell counts. Risk of viral rebound was increased for participants with higher on-ART CXCL10 concentrations and reduced for those with a greater sCD163 decline during the first year of ART. Persistent systemic inflammation predicted CD4+ T-cell recovery and viral rebound, warranting further mechanistic research in relation to clinical outcomes.
Assuntos
Fármacos Anti-HIV , Linfócitos T CD4-Positivos , Infecções por HIV , Soropositividade para HIV , Fármacos Anti-HIV/uso terapêutico , Biomarcadores , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , HIV-1 , Humanos , Inflamação/tratamento farmacológico , Estudos Prospectivos , Carga ViralRESUMO
OBJECTIVES: The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs. PATIENTS AND METHODS: HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells. RESULTS: HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug. CONCLUSIONS: Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.
Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Amidas , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis , Humanos , Mutação , Piperazinas , Piridonas/farmacologia , Raltegravir Potássico/farmacologia , Raltegravir Potássico/uso terapêuticoRESUMO
BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/administração & dosagem , Oxazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Adolescente , Peso Corporal , Criança , Pré-Escolar , Estudos de Coortes , Cálculos da Dosagem de Medicamento , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , RNA Viral/genética , África do Sul/epidemiologia , Tailândia/epidemiologia , Resultado do Tratamento , Uganda/epidemiologia , Carga Viral/efeitos dos fármacos , Organização Mundial da Saúde , Zimbábue/epidemiologiaRESUMO
BACKGROUND: Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs). METHODS: A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman's correlation coefficient was used to determine cross-resistance between INSTIs. RESULTS: INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT. CONCLUSIONS: In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance.
Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis , Humanos , Mutação , Oxazinas , Piperazinas/uso terapêutico , Piridonas , Raltegravir Potássico/farmacologia , Raltegravir Potássico/uso terapêutico , UgandaRESUMO
We evaluated immune biomarker profiles in human immunodeficiency virus (HIV)-infected adults (n = 398) from 5 African countries. Although all biomarkers decreased after antiretroviral therapy (ART) initiation, levels of C-X-C chemokine ligand 10 (CXCL10), lipopolysaccharide-binding protein, C-reactive protein, soluble CD163, and soluble scavenger receptor CD14 were significantly higher during ART than in an HIV-uninfected reference group (n = 90), indicating persistent monocyte/macrophage activation, inflammation, and microbial translocation. Before ART initiation, high HIV viral load was associated with elevated CXCL10 and tuberculosis coinfection was associated with elevated soluble CD14. High pre-ART levels of each biomarker strongly predicted residual immune activation during ART. Chemokine (C-C motif) ligand 2, lipopolysaccharide-binding protein, C-reactive protein, and interleukin 6 were differentially expressed between countries. Further research is needed on the clinical implications of residual immune dysregulation.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Proteína C-Reativa/análise , Proteínas de Transporte/sangue , Quimiocina CCL2/sangue , Quimiocina CXCL10/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Interleucina-6/sangue , Receptores de Lipopolissacarídeos/sangue , Glicoproteínas de Membrana/sangue , Receptores de Superfície Celular/sangue , Proteínas de Fase Aguda , Adulto , África Subsaariana , Biomarcadores/sangue , Contagem de Linfócito CD4 , Estudos de Coortes , Coinfecção/tratamento farmacológico , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Inflamação/sangue , Inflamação/imunologia , Masculino , Tuberculose/tratamento farmacológico , Carga Viral/efeitos dos fármacosRESUMO
The impact of variation in host genetics on replication of human immunodeficiency virus type 1 (HIV-1) in demographically diverse populations remains uncertain. In the current study, we performed a genome-wide screen for associations of single-nucleotide polymorphisms (SNPs) to viral load (VL) in antiretroviral therapy-naive participants (n = 2440) with varying demographics from the Strategic Timing of AntiRetroviral Treatment (START) trial. Associations were assessed using genotypic data generated by a customized SNP array, imputed HLA alleles, and multiple linear regression. Genome-wide significant associations between SNPs and VL were observed in the major histocompatibility complex class I region (MHC I), with effect sizes ranging between 0.14 and 0.39 log10 VL (copies/mL). Supporting the SNP findings, we identified several HLA alleles significantly associated with VL, extending prior observations that the (MHC I) is a major host determinant of HIV-1 control with shared genetic variants across diverse populations and underscoring the limitations of genome-wide association studies as being merely a screening tool.
Assuntos
Antirretrovirais/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Carga Viral/genética , Adulto , Alelos , Antirretrovirais/uso terapêutico , Feminino , Estudo de Associação Genômica Ampla , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Antígenos de Histocompatibilidade Classe I/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Tempo , Carga Viral/efeitos dos fármacos , Carga Viral/imunologiaRESUMO
BACKGROUND: As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of persons with human immunodeficiency virus (HIV) infection will experience treatment failure, and require second- or third-line ART. Data on second-line failure and development of protease inhibitor (PI) resistance in sub-Saharan Africa are scarce. METHODS: HIV-1-infected adults were included if they received >180 days of PI-based second-line ART. We assessed risk factors for having a detectable viral load (VL, ≥400 cps/mL) using Cox models. If VL was ≥1000 cps/mL, genotyping was performed. RESULTS: Of 227 included participants, 14.6%, 15.2% and 11.1% had VLs ≥400 cps/mL at 12, 24, and 36 months, respectively. Risk factors for a detectable VL were as follows: exposure to nonstandard nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based (hazard ratio, 7.10; 95% confidence interval, 3.40-14.83; P < .001) or PI-based (7.59; 3.02-19.07; P = .001) first-line regimen compared with zidovudine/lamivudine/NNRTI, PI resistance at switch (6.69; 2.49-17.98; P < .001), and suboptimal adherence (3.05; 1.71-5.42; P = .025). Among participants with VLs ≥1000 cps/mL, 22 of 32 (69%) harbored drug resistance mutation(s), and 7 of 32 (22%) harbored PI resistance. CONCLUSIONS: Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.
Assuntos
Antirretrovirais/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Adolescente , Adulto , África Subsaariana/epidemiologia , Feminino , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Estudos Prospectivos , Adulto JovemRESUMO
Most patients failing antiretroviral treatment in Uganda continue to fail their treatment regimen even if a dominant drug-resistant HIV-1 genotype is not detected. In a recent retrospective study, we observed that approximately 30% of HIV-infected individuals in the Joint Clinical Research Centre (Kampala, Uganda) experienced virologic failure with a susceptible HIV-1 genotype based on standard Sanger sequencing. Selection of minority drug-resistant HIV-1 variants (not detectable by Sanger sequencing) under antiretroviral therapy pressure can lead to a shift in the viral quasispecies distribution, becoming dominant members of the virus population and eventually causing treatment failure. Here, we used a novel HIV-1 genotyping assay based on deep sequencing (DeepGen) to quantify low-level drug-resistant HIV-1 variants in 33 patients failing a first-line antiretroviral treatment regimen in the absence of drug-resistant mutations, as screened by standard population-based Sanger sequencing. Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified low-frequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drug-resistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Adolescente , Adulto , Feminino , Genótipo , Infecções por HIV/genética , Humanos , Pessoa de Meia-Idade , Mutação/genética , RNA Viral/genética , Estudos Retrospectivos , Uganda , Adulto JovemRESUMO
OBJECTIVES: Limited availability of viral load (VL) monitoring in HIV treatment programmes in sub-Saharan Africa can delay switching to second-line ART, leading to the accumulation of drug resistance mutations (DRMs). The objective of this study was to evaluate the accumulation of resistance to reverse transcriptase inhibitors after continued virological failure on first-line ART, among adults and children in sub-Saharan Africa. METHODS: HIV-1-positive adults and children on an NNRTI-based first-line ART were included. Retrospective VL and, if VL ≥1000 copies/mL, pol genotypic testing was performed. Among participants with continued virological failure (≥2 VL ≥1000 copies/mL), drug resistance was evaluated. RESULTS: At first virological failure, DRM(s) were detected in 87% of participants: K103N (38.7%), G190A (21.8%), Y181C (20.2%), V106M (8.4%), K101E (8.4%), any E138 (7.6%) and V108I (7.6%) associated with NNRTIs, and M184V (69.7%), any thymidine analogue mutation (9.2%), K65R (5.9%) and K70R (5.0%) associated with NRTIs. New DRMs accumulated with an average rate of 1.45 (SD 2.07) DRM per year; 0.62 (SD 1.11) NNRTI DRMs and 0.84 (SD 1.38) NRTI DRMs per year, respectively. The predicted susceptibility declined significantly after continued virological failure for all reverse transcriptase inhibitors (all Pâ<â0.001). Acquired drug resistance patterns were similar in adults and children. CONCLUSIONS: Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adolescente , Adulto , África Subsaariana/epidemiologia , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Criança , Pré-Escolar , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/epidemiologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Mutação , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Falha de Tratamento , Carga Viral/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: After the scale-up of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in Africa, increasing numbers of patients have pretreatment drug resistance. METHODS: In a large multicountry cohort of patients starting standard first-line ART in six African countries, pol genotyping was retrospectively performed if viral load (VL) ≥1000 cps/mL. Pretreatment drug resistance was defined as a decreased susceptibility to ≥1 prescribed drug. We assessed the effect of pretreatment drug resistance on all-cause mortality, new AIDS events and switch to second-line ART due to presumed treatment failure, using Cox models. RESULTS: Among 2579 participants for whom a pretreatment genotype was available, 5.5% had pretreatment drug resistance. Pretreatment drug resistance was associated with an increased risk of regimen switch (adjusted hazard ratio [aHR] 3.80; 95% confidence interval [CI], 1.49-9.68; P = .005) but was not associated with mortality (aHR 0.75, 95% CI, .24-2.35; P = .617) or new AIDS events (aHR 1.06, 95% CI, .68-1.64; P = .807). During three years of follow up, 106 (4.1%) participants switched to second-line, of whom 18 (17.0%) switched with VL < 1000 cps/mL, 7 (6.6%) with VL ≥ 1000 cps/mL and no drug resistance mutations (DRMs), 46 (43.4%) with VL ≥ 1000 cps/mL and ≥1 DRMs; no HIV RNA data was available for 32 (30.2%) participants. CONCLUSIONS: Given rising pretreatment HIV drug resistance levels in sub-Saharan Africa, these findings underscore the need for expanded access to second-line ART. VL monitoring can improve the accuracy of failure detection and efficiency of switching practices.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adolescente , Adulto , África Subsaariana/epidemiologia , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade/normas , Contagem de Linfócito CD4 , Estudos de Coortes , Farmacorresistência Viral/genética , Feminino , Seguimentos , Genes pol , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/mortalidade , HIV-1/genética , Humanos , Masculino , Mutação , Modelos de Riscos Proporcionais , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: This study investigated the association of plasma microRNAs before and during antiretroviral therapy (ART) with poor CD4 + T-cell recovery during the first year of ART. DESIGN: MicroRNAs were retrospectively measured in stored plasma samples from people with HIV (PWH) in sub-Saharan Africa who were enrolled in a longitudinal multicountry cohort and who had plasma viral-load less than 50âcopies/ml after 12âmonths of ART. METHODS: First, the levels of 179 microRNAs were screened in a subset of participants from the lowest and highest tertiles of CD4 + T-cell recovery (ΔCD4) ( N â=â12 each). Next, 11 discordant microRNAs, were validated in 113 participants (lowest tertile ΔCD4: n â=â61, highest tertile ΔCD4: n â=â52). For discordant microRNAs in the validation, a pathway analysis was conducted. Lastly, we compared microRNA levels of PWH to HIV-negative controls. RESULTS: Poor CD4 + T-cell recovery was associated with higher levels of hsa-miR-199a-3p and hsa-miR-200c-3p before ART, and of hsa-miR-17-5p and hsa-miR-501-3p during ART. Signaling by VEGF and MET, and RNA polymerase II transcription pathways were identified as possible targets of hsa-miR-199a-3p, hsa-200c-3p, and hsa-miR-17-5p. Compared with HIV-negative controls, we observed lower hsa-miR-326, hsa-miR-497-5p, and hsa-miR-501-3p levels before and during ART in all PWH, and higher hsa-miR-199a-3p and hsa-miR-200c-3p levels before ART in all PWH, and during ART in PWH with poor CD4 + T-cell recovery only. CONCLUSION: These findings add to the understanding of pathways involved in persistent HIV-induced immune dysregulation during suppressive ART.
Assuntos
Infecções por HIV , HIV-1 , MicroRNAs , Humanos , HIV-1/genética , Estudos Retrospectivos , Infecções por HIV/tratamento farmacológico , MicroRNAs/genética , Linfócitos TRESUMO
Analytical treatment interruption (ATI) is widely acknowledged as an essential component of studies to advance our understanding of HIV cure, but discussion has largely been focused on adults. To address this gap, we reviewed evidence related to the safety and utility of ATI in paediatric populations. Three randomised ATI trials using CD4 T-cell and clinical criteria to guide restart of antiretroviral therapy (ART) have been conducted. These trials found low risks associated with ATI in children, including reassuring findings pertaining to neurocognitive outcomes. Similar to adults treated during acute infection, infants treated early in life have shifts in virological and immunological parameters that increase their likelihood of achieving ART-free viral control. Early ART limits the size and diversity of the viral reservoir and shapes effective innate and HIV-specific humoral and cellular responses. Several cases of durable ART-free viral control in early treated children have been reported. We recommend that, where appropriate for the study question and where adequate monitoring is available, ATI should be integrated into ART-free viral control research in children living with HIV. Paediatric participants have the greatest likelihood of benefiting and potentially the most years to prospectively realise those benefits. Excluding children from ATI trials limits the evidence base and delays access to interventions.
RESUMO
OBJECTIVE: In a multicountry prospective cohort of persons with HIV from six countries between 2007 and 2015, we evaluated long-term outcomes of first-line non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy (ART), and risk factors for loss-to-follow-up, mortality, virological failure, and incomplete CD4 + T-cell recovery. METHODS: We calculated cumulative incidence of lost-to-follow-up, death, virological failure (VLâ≥â1000âcps/ml) and incomplete CD4 + T-cell recovery (<500âcells/µl) at successive years, using Kaplan-Meier and Cox regression. RESULTS: Of 2735 participants, 58.0% were female, median age was 37 (interquartile range [IQR] 32-43) years, and median pre-ART CD4 + T-cell count was 135 (IQR 63-205)/µl. Total follow-up time was 7208 person-years (median 24.3âmonths, IQR 18.7-58.3). Deaths by any cause and loss to follow-up occurred mostly during the first year of ART (84%, 201/240 and 56%, 199/353, respectively). During their first 6 years of ART, 71% (95% confidence interval [CI] 69.0-73.7) were retained on first-line, and among those 90-93% sustained viral suppression (<1000âcps/ml); CD4 + T-cell recovery was incomplete in 60% (220/363) of participants. The risk factors associated with poor outcomes during long-term ART were: for loss-to-follow-up, recent VL ≥1000âcps/ml, recent CD4 + T-cell count ≤50âcells/µl, age <30âyears, being underweight; for mortality, recent CD4 + T-cell count ≤50âcells/µl; and, for virological failure, age <40âyears, recent CD4 + T-cell count ≤200âcells/µl, poor adherence, male sex, and low-level viremia. CONCLUSION: To achieve long-term ART success towards the UNAIDS targets, early ART initiation is crucial, coupled with careful monitoring and retention support, particularly in the first year of ART. Male and youth-centred care delivery models are needed to improve outcomes for those vulnerable groups.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Estudos Prospectivos , Resposta Viral Sustentada , Carga ViralRESUMO
BACKGROUND: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. METHODS: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127. FINDINGS: Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6-2·0) and median weight 8·1 kg (5·4-10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47-2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50-1·74]; p=0·83). No events were considered related to dolutegravir. INTERPRETATION: Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adulto , Fármacos Anti-HIV/efeitos adversos , Teorema de Bayes , Criança , Pré-Escolar , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lactente , Recém-Nascido , Oxazinas , Piperazinas , Inibidores de Proteases/uso terapêutico , Piridonas , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. METHODS: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0-24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014-002632-14), and the ISRCTN registry (ISRCTN91737921). FINDINGS: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4-17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08-2·11) for Ctrough, 1·23 (0·99-1·53) for AUC0-24 h, and 0·94 (0·76-1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30-40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. INTERPRETATION: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB. FUNDING: Penta Foundation, ViiV Healthcare, UK Medical Research Council.
Assuntos
Infecções por HIV , HIV-1 , Tuberculose , Adolescente , Criança , Pré-Escolar , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Humanos , Lactente , Masculino , Oxazinas , Piperazinas , Piridonas , Rifampina/efeitos adversos , Tuberculose/complicações , Tuberculose/tratamento farmacológico , UgandaRESUMO
OBJECTIVES: To characterize monocyte subsets and activation in persons living with HIV (PLWH) with tuberculosis coinfection. DESIGN: Cross-sectional study within a cohort of PLWH and HIV-uninfected participants at the Joint Clinical Research Centre in Kampala, Uganda. METHODS: Participants were at least 45 years old with at least one cardiovascular risk factor. PLWH had an HIV viral load 1000âcopies/ml or less on stable antiretroviral therapy prior to cohort entry. QuantiFERON-TB testing was performed to define latent tuberculosis infection (LTBI). Prior active TB was defined by self-report and verified by medical records. Blood was stained with monocyte subset markers (CD14+, CD16), CD62p, CD69, CX3CR1, HLA-DR, and tissue factor, and examined with flow cytometry. RESULTS: One hundred and twenty-five participants (83 PLWH and 42 without HIV) were included. Median CD4+ count was 582âcells/µl in PLWH. PLWH had a higher frequency of total monocytes (4.3% vs. 3.2%; Pâ<â0.001) and inflammatory monocyte subset (15.5% vs. 11.7%; Pâ=â0.016) compared with HIV-uninfected individuals. No differences in the frequency of monocyte subsets were observed by TB status. Among PLWH, prior active TB was associated with increased frequency of total monocytes compared with LTBI (5.1% vs. 3.7%; Pâ=â0.013). HLA-DR density on monocytes was three-fold higher in PLWH with LTBI or prior TB compared with PLWH without LTBI (Pâ=â0.002). In multivariate analysis, a higher monocyte HLA-DR density remained associated with LTBI or prior TB in PLWH (log-MFI; bâ=â1.17; Pâ<â0.001). CONCLUSION: Our findings indicate enhanced monocyte activation in PLWH with LTBI or prior active TB, which may contribute to the pathogenesis of noncommunicable diseases in HIV.
Assuntos
Coinfecção , Infecções por HIV , Tuberculose Latente , Tuberculose , Estudos Transversais , Infecções por HIV/complicações , Humanos , Tuberculose Latente/complicações , Pessoa de Meia-Idade , Monócitos , Uganda/epidemiologiaRESUMO
INTRODUCTION: To achieve viral suppression among more than 90% of people on antiretroviral therapy (ART), improved understanding is warranted of the modifiable causes of HIV viremic episodes. We assessed the relative contributions of drug-resistance, nonadherence and low-level viremia (LLV) (viral load 50-999âcps/ml) on viremic episodes in sub-Saharan Africa. METHODS: In a multicountry adult cohort initiating nonnucleoside reverse transcriptase inhibitor-based first-line ART, viremic episodes (viral load ≥1000 cps/ml) were classified as first, viral nonsuppression at 12 months; second, virological rebound at 24 months (after initial viral suppression at 12 months); third, failure to achieve viral resuppression at 24 months (after viremic episode at 12 months). We used adjusted odds ratios from multivariable logistic regression to estimate attributable fractions for each risk factor. RESULTS: Of 2737 cohort participants, 1935 had data on pretreatment drug resistance (PDR) and at least 1 viral load outcome. Viral nonsuppression episodes [173/1935 (8.9%)] were attributable to nonadherence in 30% (35% in men vs. 24% in women) and to PDR to nonnucleoside reverse transcriptase inhibitors in 10% (15% in women vs. 6% in men). Notably, at contemporary PDR prevalences of 10-25%, PDR would explain 13-30% of viral nonsuppression. Virological rebound episodes [96/1515 (6.3%)] were mostly attributable to LLV (29%) and nonadherence (14%), and only rarely to PDR (1.1%). Failures to achieve viral resuppression [66/81 (81.5%)] were mostly attributable to the presence of acquired drug resistance (34%) and only rarely to nonadherence (2.4%). CONCLUSION: Effective adherence interventions could substantially reduce viral nonsuppression (especially in men) and virological rebound (especially during LLV), but would have limited effect on improving viral resuppression. Alternative ART regimens could circumvent PDR and acquired resistance.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , Adesão à Medicação , Viremia/complicações , Adulto , África Subsaariana , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Carga ViralRESUMO
BACKGROUND: In Uganda, the HIV epidemic is now mature and generalized. Recently, there have been reports of resurgence in the incidence of HIV after several years of successful control. The causes for this resurgence are not clear but suspected to be driven by structural factors that influence large groups of people rather than individuals. The aim of this study was to describe the structural drivers of the HIV epidemic in high prevalence regions and inform the next generation of interventions. METHODOLOGY: We conducted a total of 35 focus group discussions in 11 districts in Uganda. Due to their high HIV prevalence, the districts had been selected to implement a donor supported program to scale up HIV prevention, care and treatment. Focus groups consisted of men and women including opinion leaders, civil servants including teachers, police officers, religious, political leaders, shop keepers, local residents and other ordinary persons from all walks of life. The qualitative data were transcribed and analyzed manually. Texts were coded using a coding scheme which was prepared ahead of time but emerging themes and codes were also allowed. RESULTS: Our data indicated there is persistence of several structural drivers and factors for HIV in rural Uganda. The structural drivers of HIV were divided into three categories: Gender issues, socio-cultural, and economic drivers. The specific drivers included several gender issues, stigma surrounding illness, traditional medical practices, urbanization, alcohol and substance abuse and poverty. New drivers arising from urbanization, easy access to mobile phone, internet and technological advancement have emerged. These drivers are intertwined within an existing culture, lifestyle and the mixture is influenced by modernization. CONCLUSION: The traditional structural drivers of HIV have persisted since the emergence of the HIV epidemic in Uganda and new ones have emerged. All these drivers may require combined structural interventions that are culturally and locally adapted in order to tackle the resurgence in incidence of HIV in Uganda.