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1.
J Clin Microbiol ; 58(9)2020 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-32522826

RESUMEN

HIV drug resistance (HIVDR) is a barrier to sustained virologic suppression in low- and middle-income countries (LMICs). Point mutation assays targeting priority drug resistance mutations (DRMs) are being evaluated to improve access to HIVDR testing. In a cross-sectional study (June 2018 to September 2019), we evaluated the diagnostic accuracy of a simple and rapid HIVDR assay (the pan-degenerate amplification and adaptation [PANDAA] assay targeting the mutations K65R, K103NS, M184VI, Y181C, and G190A) compared to Sanger sequencing and next-generation sequencing (NGS). Plasma samples from adolescents and young adults (aged 10 to 24 years) failing antiretroviral therapy (viral load, >1,000 copies/ml on 2 consecutive occasions 1 month apart) were analyzed. Sensitivity and specificity of the PANDAA assay were determined by a proprietary application designed by Aldatu Biosciences. Agreement between genotyping methods was evaluated using Cohen's kappa coefficient. One hundred fifty samples previously characterized by Sanger sequencing were evaluated using PANDAA. For all DRMs detected, PANDAA showed a sensitivity and specificity of 98% and 94%, respectively. For nucleotide reverse transcriptase inhibitor DRMs, sensitivity and specificity were 98% (95% confidence interval [CI], 92% to 100%) and 100% (94% to 100%), respectively. For non-nucleotide reverse transcriptase inhibitor DRMs, sensitivity and specificity were 100% (97% to 100%) and 76% (61% to 87%), respectively. PANDAA showed strong agreement with Sanger sequencing for K65R, K103NS, M184VI, and G190A (kappa > 0.85) and substantial agreement for Y181C (kappa = 0.720). Of the 21 false-positive samples genotyped by PANDAA, only 6 (29%) were identified as low-abundance variants by NGS. With the high sensitivity and specificity to detect major DRMs, PANDAA could represent a simple and rapid alternative HIVDR assay in LMICs.

2.
PLoS One ; 14(12): e0226276, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31826005

RESUMEN

BACKGROUND: Because tenofovir alafenamide (TAF) leads to significantly lower plasma tenofovir concentrations than tenofovir disoproxil fumarate (TDF) and is a stronger substrate for P-glycoprotein (P-gp) than TDF, TAF could lead to decreased central nervous system (CNS) tenofovir exposure than TDF. We aimed to determine if switching from TDF to TAF increases the risk of neuronal injury, by quantifying plasma levels of neurofilament light protein (NfL), a sensitive marker of neuronal injury in HIV CNS infection. METHODS: Plasma NfL concentration was measured at baseline, week 24, and week 84 in stored plasma samples from 416 participants (272 switching to elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF and 144 continuing E/C/F/TDF) enrolled in the randomized, active-controlled, multicenter, open-label, noninferiority Gilead GS-US-292-0109 trial. RESULTS: While plasma NfL levels in both groups were within the normal range, we found a small but significant decrease in the E/C/F/TAF arm after 84 weeks from a geometric mean of 9.3 to 8.8 pg/mL (5.4% decline, 95% CI 2.0-8.4, p = 0.002). This change was significantly different (p = 0.001) from that of the E/C/F/TDF arm, in which plasma NfL concentration changed from 9.7 pg/mL at baseline to 10.2 pg/mL at week 84 (5.8% increase, 95% CI -0.8-12.9, p = 0.085). This increase is in line with what could be expected in normal ageing. Plasma NfL concentrations significantly correlated with age. No correlation was found between plasma NfL and serum creatinine. CONCLUSIONS: We found no biomarker evidence of CNS injury when switching from TDF to TAF. It is unclear whether the small decrease in plasma NfL found after switch to TAF is of any clinical relevance, particularly with plasma NfL levels in both arms remaining within the limits found in HIV-negative controls. These results indicate that switching from TDF to TAF appears safe with regard to neuronal injury.


Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Proteínas de Neurofilamentos/sangre , Tenofovir/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/etiología , Creatinina/sangre , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tenofovir/efectos adversos
3.
J Acquir Immune Defic Syndr ; 82(3): 321-328, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31609930

RESUMEN

BACKGROUND: Bictegravir, coformulated with emtricitabine/tenofovir alafenamide as a fixed-dose combination (B/F/TAF), is recommended for treatment of HIV-1-infection. Multiple studies of B/F/TAF in treatment-naive and virologically suppressed cohorts have shown high efficacy and tolerability with no treatment-emergent resistance through 48 weeks. Participants in these studies have been predominantly men. We report 48-week results from a phase 3 study evaluating switching to B/F/TAF, specifically in a globally distributed trial population of women. METHODS: In this multicenter, randomized, open-label, active-controlled, noninferiority trial (ClinicalTrials.gov NCT02652624), women living with HIV who were virologically suppressed (HIV-1 RNA levels <50 copies/mL) on a regimen containing either TAF or tenofovir disoproxil fumarate were randomly assigned (1:1) to switch to B/F/TAF (50/200/25 mg) or stay on baseline regimen (SBR) once daily for 48 weeks. Primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (U.S. Food and Drug Administration snapshot algorithm); prespecified noninferiority margin was 4%. FINDINGS: We randomized 472 participants and treated 470 (234 B/F/TAF, 236 SBR). Switching to B/F/TAF was noninferior to SBR for the primary outcome, as 1.7% (4/234) vs 1.7% (4/236) had HIV-1 RNA ≥50 copies/mL at week 48 (difference 0.0%, 95.001% confidence interval: -2.9% to 2.9%). No individual receiving B/F/TAF developed treatment-emergent resistance. Both treatments were well-tolerated; no participant discontinued treatment because of an adverse event. INTERPRETATION: Fixed-dose combination B/F/TAF provides a safe and efficacious option for ongoing treatment of HIV in women. This study contributes important data on safety, tolerability, and outcomes of antiretroviral therapy among women living with HIV.


Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Adenina/administración & dosificación , Adenina/uso terapéutico , Adulto , Fármacos Anti-VIH/administración & dosificación , Recuento de Linfocito CD4 , Emtricitabina/administración & dosificación , Femenino , VIH-1 , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Tenofovir/uso terapéutico , Resultado del Tratamiento , Adulto Joven
4.
EClinicalMedicine ; 9: 26-34, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31143879

RESUMEN

Background: South Africa has the largest public antiretroviral therapy (ART) programme in the world. We assessed temporal trends in pretreatment HIV-1 drug resistance (PDR) in ART-naïve adults from South Africa. Methods: We included datasets from studies conducted between 2000 and 2016, with HIV-1 pol sequences from more than ten ART-naïve adults. We analysed sequences for the presence of 101 drug resistance mutations. We pooled sequences by sampling year and performed a sequence-level analysis using a generalized linear mixed model, including the dataset as a random effect. Findings: We identified 38 datasets, and retrieved 6880 HIV-1 pol sequences for analysis. The pooled annual prevalence of PDR remained below 5% until 2009, then increased to a peak of 11·9% (95% confidence interval (CI) 9·2-15·0) in 2015. The pooled annual prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) PDR remained below 5% until 2011, then increased to 10.0% (95% CI 8.4-11.8) by 2014. Between 2000 and 2016, there was a 1.18-fold (95% CI 1.13-1.23) annual increase in NNRTI PDR (p < 0.001), and a 1.10-fold (95% CI 1.05-1.16) annual increase in nucleoside reverse-transcriptase inhibitor PDR (p = 0.001). Interpretation: Increasing PDR in South Africa presents a threat to the efforts to end the HIV/AIDS epidemic. These findings support the recent decision to modify the standard first-line ART regimen, but also highlights the need for broader public health action to prevent the further emergence and transmission of drug-resistant HIV. Source of Funding: This research project was funded by the South African Medical Research Council (MRC) with funds from National Treasury under its Economic Competitiveness and Support Package. Disclaimer: The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of CDC.

5.
Open Forum Infect Dis ; 6(1): ofy333, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30648127

RESUMEN

Background: There are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) except CD4+ T-cell deficiency. At present, serum cryptococcal antigen (CrAg) screening of those with CD4 <100 cells/µL is used to identify persons at risk for HIV-associated CM. We determined if plasma antibody profiles could discriminate CrAg+ from CrAg- patients. Methods: We performed serological analyses of 237 HIV-infected asymptomatic Zimbabwean patients with CD4 <100 cells/µL; 125 CrAg- and CrAg+ but cerebrospinal fluid CrAg- by CrAg lateral flow assay. We measured plasma immunoglobulin M (IgM), immunoglobulin G (IgG) 1, and IgG2 concentrations by Luminex, and titers of Cryptococcus neoformans (Cn) glucuronoxylomannan (GXM) polysaccharide and naturally occurring Laminarin (natural Lam, a ß-(1-3)-glucan linked polysaccharide)-binding IgM and IgG by enzyme-linked immunosorbent assay. Results: GXM-IgG, -IgM, and -IgG2 levels were significantly higher in CrAg+ patients, whereas natural Lam-IgM and Lam-IgG were higher in CrAg- patients before and after adjustment for age, sex, and CD4 T-cell count, despite overlap of values. To address this variability and better discriminate the groups, we used Akaike Information Criteria to select variables that independently predicted CrAg+ status and included them in a receiver operating characteristic curve to predict CrAg status. By inclusion of CD4, GXM-IgG, GXM-IgM, and Lam-IgG, -IgG2, and -IgM, this model had an 80.4% probability (95% confidence interval, 0.75-0.86) of predicting CrAg+ status. Conclusions: Statistical models that include multiple serological variables may improve the identification of patients at risk for CM and inform new directions in research on the complex role that antibodies may play in resistance and susceptibility to CM.

6.
AIDS Res Hum Retroviruses ; 34(4): 337-342, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29368537

RESUMEN

We previously demonstrated superior efficacy and safety advantages in HIV-infected, virologically suppressed adults switched to a regimen containing tenofovir alafenamide (TAF) as compared with those remaining on a tenofovir disoproxil fumarate (TDF) regimen through week 48. We now report long-term data through week 96. In this randomized, active-controlled, multicenter, open-label, noninferiority trial (ClinicalTrials.gov No. NCT01815736), we randomized virologically suppressed (HIV-1 RNA <50 copies/ml) adults (2:1) to receive a once-daily, single-tablet regimen containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and TAF group or to continue one of four TDF-containing regimens (TDF group) for 96 weeks. We evaluated efficacy (HIV-1 RNA <50 copies/ml using the FDA snapshot algorithm) and prespecified bone and renal endpoints at week 96. We randomized and treated 1,436 participants in this study (TAF n = 959, TDF n = 477). At week 96, TAF was superior to TDF in virologic efficacy, with 93% on TAF and 89% on TDF having HIV-1 RNA <50 copies/ml (difference 3.7%, 95% confidence interval: 0.4%-7.0%). Improvements in hip and spine bone mineral density for those assigned to TAF versus TDF continued through week 96 (p < .001). Significant improvements in urine protein or albumin to creatinine ratios were also seen among those in the TAF group versus TDF through week 96 (p < .001). There were no cases of investigator-reported proximal renal tubulopathy in the TAF group as compared with one case in the TDF group. Switching to EVG/COBI/FTC/TAF (E/C/F/TAF) was associated with statistically significant efficacy and safety advantages over remaining on a standard-of-care TDF-based regimen.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacología , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Adenina/análogos & derivados , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Densidad Ósea/efectos de los fármacos , Cobicistat , Combinación de Medicamentos , Sustitución de Medicamentos , Emtricitabina , Humanos , Riñón/efectos de los fármacos , Quinolonas , ARN Viral/sangre , Tenofovir , Resultado del Tratamiento
7.
Trials ; 16: 276, 2015 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-26081985

RESUMEN

BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM. METHODOLOGY/DESIGN: This is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥ 18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400-800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat. TRIAL REGISTRATION: ISRCTN10248064. Date of Registration: 22 January 2014.


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Coinfección , Fluconazol/administración & dosificación , Meningitis Criptocócica/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Anfotericina B/efectos adversos , Antifúngicos/efectos adversos , Botswana , Protocolos Clínicos , Esquema de Medicación , Quimioterapia Combinada , Fluconazol/efectos adversos , Humanos , Meningitis Criptocócica/diagnóstico , Meningitis Criptocócica/microbiología , Meningitis Criptocócica/mortalidad , Proyectos de Investigación , Tanzanía , Factores de Tiempo , Resultado del Tratamiento
8.
Trop Med Int Health ; 20(7): 903-13, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25754063

RESUMEN

OBJECTIVE: To document the lived experiences of people with both poor mental health and suboptimal adherence to antiretroviral therapy in high HIV prevalence settings. METHODS: In-depth qualitative interviews were conducted with 47 (female = 31) HIV-positive adults who scored above the cut-point on a locally validated scale for common mental disorders (CMDs). Purposive sampling was used to recruit participants with evidence of poor adherence. Six additional key informant interviews (female = 6) were conducted with healthcare workers. Data were collected and analysed inductively by an interdisciplinary coding team. RESULTS: The major challenges faced by participants were stressors (poverty, stigma, marital problems) and symptoms of CMDs ('thinking too much', changes to appetite and sleep, 'burdened heart' and low energy levels). Thinking too much, which appears closely related to rumination, was the symptom with the greatest negative impact on adherence to antiretroviral therapy among HIV-positive adults with CMDs. In turn, thinking too much was commonly triggered by the stressors faced by people living with HIV/AIDS, especially poverty. Finally, participants desired private counselling, access to income-generating activities and family engagement in mental health care. CONCLUSIONS: Better understanding of the local expression of mental disorders and of underlying stressors can inform the development of culturally sensitive interventions to reduce CMDs and poor adherence to antiretroviral therapy.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/complicaciones , Cumplimiento de la Medicación , Trastornos Mentales/complicaciones , Estrés Psicológico , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Adulto , Cultura , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Necesidades y Demandas de Servicios de Salud , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Pobreza , Prevalencia , Estigma Social , Apoyo Social , Esposos , Estrés Psicológico/etiología , Pensamiento , Zimbabwe
9.
J Acquir Immune Defic Syndr ; 65 Suppl 1: S3-4, 2014 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-24321982

RESUMEN

The phenomenon of disproportionately large allocations of global health research resources to relatively limited components of the global health burden is widely acknowledged. Factors contributing to this are explored. The development of a national or regional research agenda is a critical step toward attempting to redress this imbalance. Key areas to be considered are a broad vision, dialogue, and commitment from those stakeholders comprising the "health research triangle": national policy makers and decision makers, key personnel in both health research and health care, and community representatives. The interdependent roles of human, material, and community resources are further examined.


Asunto(s)
Investigación Biomédica , Salud Global , Infecciones por VIH/prevención & control , Recursos en Salud , Investigación sobre Servicios de Salud , Humanos , Salud Pública , Asignación de Recursos
10.
AIDS ; 23(2): 189-93, 2009 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-19098488

RESUMEN

OBJECTIVES: The HIV-1 Nef protein selectively downregulates human leukocyte antigen (HLA)-A and HLA-B but not HLA-C molecules on the surface of infected cells. This allows HIV-infected cells to evade recognition by most cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. We investigated the recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope SFNCGGEFF (SF9) and its variant SFNCGGEFL (SL9) by T cells and NK receptors. DESIGN AND METHOD: Recognition of HIV-1 gp120 peptides (SF9 and SL9) by T-cell clones was measured by staining with HLA-Cw4-peptide tetrameric complexes and cytolytic assays using target cell pulsed with either peptides. KIR2DL1 binding to these two peptides was measured using surface plasmon resonance and tetramer staining of an NK cell line. RESULT: : CTLs could recognize SF9 better than the variant SL9, as shown by both tetramer staining and cytolytic assays. Intriguingly, an HLA-Cw4 tetramer folded with the 'escape' variant SL9 could bind to KIR2DL1 on NK cell lines with higher affinity than HLA-Cw4-SF9. The binding of KIR2DL1 to its ligand results in inhibition of NK cell function. Our results indicate that the HIV-1 gp120 variant peptide SL9 could potentially escape both from NK cell and CTL recognition by increasing its affinity for KIR2DL1 binding. CONCLUSION: These data suggest that HIV-1 can acquire mutations that are capable of escaping from both CTL and NK cell recognition, a phenomenon we have termed 'double escape'.


Asunto(s)
Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Antígenos HLA-C/inmunología , Células Asesinas Naturales/inmunología , Linfocitos T Citotóxicos/inmunología , Afinidad de Anticuerpos/inmunología , Reacciones Antígeno-Anticuerpo/inmunología , Línea Celular , Pruebas Inmunológicas de Citotoxicidad/métodos , Citotoxicidad Inmunológica/inmunología , VIH-1/genética , Humanos , Tolerancia Inmunológica , Receptores KIR2DL1/inmunología
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