RESUMO
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
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
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
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
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
In ART programs in sub-Saharan Africa, a growing proportion of HIV-infected persons initiating first-line antiretroviral therapy (ART) have a history of prior antiretroviral drug use (PAU). We assessed the effect of PAU on the risk of pre-treatment drug resistance (PDR) and virological failure (VF) in a multicountry cohort of HIV-infected adults initiated on a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART. Multivariate logistic regression was used to assess the associations between PAU, PDR and VF (defined as viral load ≥400 cps/mL). Causal mediation analysis was used to assess the proportion of the effect of PAU on VF that could be eliminated by intervening on PDR. Of 2737 participants, 122 (4.5%) had a history of PAU. Participants with PAU had a 7.2-fold (95% CI 4.4-11.7) risk of carrying PDR and a 3.1-fold (95% CI 1.6-6.1) increased risk of VF, compared to antiretroviral-naïve participants. Controlling for PDR would eliminate nearly half the effect of PAU on the risk of VF. Patients with a history of PAU are at increased risk of ART failure, which is to a large extent attributable to PDR. These findings support the recent WHO recommendations for use of differentiated, non-NNRTI-based empiric first-line therapy in patients with PAU.
Assuntos
Antirretrovirais/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Adulto , Antirretrovirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Mutação/genéticaRESUMO
OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART). DESIGN: Multicountry prospective cohort. METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4+ cell count thresholds (>200, >350 and >500âcells/µl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50âcopies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4+ strata. RESULTS: One thousand, five hundred and ninety-two participants were included; 60% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4+ cell count was 147âcells/µl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4+ cell counts less than 200âcells/µl, less than 350â cells/µl, and less than 500âcells/µl occurred in 7, 27, and 57% of participants, respectively. Compared with participants with CD4+ cell count greater than 500âcells/µl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4+ cell count less than 200, 200-349, and 350-499âcells/µl, respectively. All-cause mortality was highest in participants with CD4+ cell count less than 200âcells/µl, and comparable across the higher CD4+ strata. Older age, male sex, and lower pre-ART CD4+ cell count were strongly associated with suboptimal immune recovery. CONCLUSION: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4+ cell count.