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1.
AIDS ; 33(11): 1729-1737, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31361272

RESUMEN

OBJECTIVES: The integrase strand inhibitor dolutegravir (DTG) combined with tenofovir and lamivudine (TLD) is a single tablet regimen recommended for 1st, 2nd and 3rd-line public health antiretroviral therapy (ART). We determined drug resistance mutations (DRMs) and evaluated the predictive efficacy of a TLD containing regimen for viremic adolescents and young adults in Harare, Zimbabwe. METHODS: We sequenced plasma viral RNA from HIV-1-infected adolescents and young adults on 1st and 2nd-line ART with confirmed virologic failure (viral load >1000 copies/ml) and calculated total genotypic susceptibility scores to current 2nd, 3rd line and DTG regimens. RESULTS: A total of 160 participants were genotyped; 112 (70%) on 1st line and 48 (30%) on 2nd line, median (interquartile range) age 18 (15-19) and duration of ART (interquartile range) was 6 (4-8) years. Major DRMs were present in 94 and 67% of 1st and 2nd-line failures, respectively (P < 0.001). Dual class resistance to nucleotide reverse transcriptase inhibitors and nonnucleotide reverse transcriptase inhibitors was detected in 96 (60%) of 1st-line failures; protease inhibitor DRMs were detected in a minority (10%) of 2nd-line failures. A total genotypic susceptibility score of 2 or less may risk protease inhibitor or DTG monotherapy in 11 and 42% of 1st-line failures switching to 2nd-line protease inhibitor and TLD respectively. CONCLUSION: Among adolescents and young adults, current protease inhibitor-based 2nd-line therapies are poorly tolerated, more expensive and adherence is poor. In 1st-line failure, implementation of TLD for many adolescents and young adults on long-term ART may require additional active drug(s). Drug resistance surveillance and susceptibility scores may inform strategies for the implementation of TLD.


Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Adolescente , Estudios Transversales , Combinación de Medicamentos , Femenino , Genotipo , Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Lamivudine/uso terapéutico , Masculino , Cumplimiento de la Medicación , Oxazinas , Piperazinas , Piridonas , Tenofovir/uso terapéutico , Insuficiencia del Tratamiento , Carga Viral , Adulto Joven , Zimbabwe
2.
AIDS Behav ; 22(1): 86-101, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28063075

RESUMEN

Using a pilot trial design in an HIV care clinic in Zimbabwe, we randomised 32 adults with poor adherence to antiretroviral therapy and at least mild depression to either six sessions of Problem-Solving Therapy for adherence and depression (PST-AD) delivered by an adherence counsellor, or to Enhanced Usual Care (Control). Acceptability of PST-AD was high, as indicated by frequency of session attendance and through qualitative analyses of exit interviews. Fidelity was >80% for the first two sessions of PST-AD but fidelity to the adherence component of PST-AD dropped by session 4. Contamination occurred, in that seven patients in the control arm received one or two PST-AD sessions before follow-up assessment. Routine health records proved unreliable for measuring HIV viral load at follow-up. Barriers to measuring adherence electronically included device failure and participant perception of being helped by the research device. The study was not powered to detect clinical differences, however, promising change at 6-months follow-up was seen in electronic adherence, viral load suppression (PST-AD arm 9/12 suppressed; control arm 4/8 suppressed) and depression (Patient Health Questionnaire-4.7 points in PST-AD arm vs. control, adjusted p value = 0.01). Results inform and justify a future randomised controlled trial of task-shifted PST-AD.


Asunto(s)
Depresión/etiología , Depresión/terapia , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Cumplimiento de la Medicación/psicología , Aceptación de la Atención de Salud/psicología , Solución de Problemas , Adulto , Terapia Cognitivo-Conductual , Estudios de Factibilidad , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Admisión y Programación de Personal , Evaluación de Programas y Proyectos de Salud , Zimbabwe/epidemiología
4.
PLoS One ; 11(7): e0157546, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27388763

RESUMEN

INTRODUCTION: Enumeration of CD4+ T lymphocytes is important for pre-ART disease staging and screening for opportunistic infections, however access to CD4 testing in resource limited settings is poor. Point of care (POC) technologies can facilitate improved access to CD4 testing. We evaluated the analytical performance of a novel POC device the FACSPresto compared to the FACSCalibur as a reference standard and to the PIMA, a POC device in widespread use in sub-Saharan Africa. METHOD: Specimens were obtained from 253 HIV infected adults. Venous blood samples were analyzed on the FACSPresto and the FACSCalibur, in a subset of 41 samples additional analysis was done on the PIMA. RESULTS: The absolute CD4 count results obtained on the FACSPresto were comparable to those on the FACSCalibur with low absolute (9.5cells/µl) and relative bias (3.2%). Bias in CD4% values was also low (1.06%) with a relative bias of 4.9%. The sensitivity was lower at a CD4 count threshold of ≤350cells/µl compared with ≤500cells/µl (84.9% vs. 92.8%) resulting in a high upward misclassification rate at low CD4 counts. Specificity at thresholds of ≤350cells/µl and ≤500cells/µl were 96.6% and 96.8% respectively. The PIMA had a high absolute (-68.6cells/µl) and relative bias (-10.5%) when compared with the FACSCalibur. At thresholds of ≤350cells/µl and ≤500cells/µl the sensitivity was 100% and 95.5% respectively; specificity was 85.7% and 84.2% respectively. The coefficients of repeatability were 4.13%, 5.29% and 9.8% respectively. DISCUSSION: The analytic performance of the FACSPresto against the reference standard was very good with better agreement and precision than the PIMA. The FACSPresto had comparable sensitivity at a threshold of 500 cells/µl and better specificity than the PIMA. However the FACSPresto showed reduced sensitivity at low CD4 count thresholds. CONCLUSION: The FACSPresto can be reliably used as a POC device for enumerating absolute CD4 count and CD4% values.


Asunto(s)
Recuento de Linfocito CD4/métodos , Linfocitos T CD4-Positivos/virología , Separación Celular , Citometría de Flujo , Infecciones por VIH/virología , Sistemas de Atención de Punto , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
6.
Semin Neurol ; 34(1): 47-60, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24715488

RESUMEN

Cryptococcal meningitis remains one of the leading causes of morbidity and mortality among immunosuppressed individuals, particularly those with advanced acquired immunodeficiency syndrome. The greatest burden of disease is in sub-Saharan Africa and Asia where there is limited access to diagnostics and treatment for the disease. The authors review the available tools for diagnosing cryptococcal meningitis and review treatment for cryptococcal meningitis, highlighting the evidence behind current treatment guidelines.


Asunto(s)
VIH/patogenicidad , Meningitis Criptocócica/diagnóstico , Meningitis Criptocócica/terapia , Humanos
7.
Int J Infect Dis ; 17(10): e902-6, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23809198

RESUMEN

OBJECTIVE: To retrospectively investigate the outcomes of patients with AIDS-associated Kaposi sarcoma (AIDS-KS) after initiation of antiretroviral therapy (ART), under routine practice conditions, at a university-affiliated hospital in urban Zimbabwe. BACKGROUND: While studies from developed nations have demonstrated excellent outcomes for AIDS-KS patients treated with ART, few studies have examined the outcomes of African AIDS-KS patients after starting therapy. METHODS: A retrospective cohort of 124 AIDS patients initiating ART under routine practice conditions was studied. Thirty-one patients with AIDS-KS were matched 1:3 to 93 AIDS patients without KS (non-KS). The primary outcome was loss-to-care after initiation of therapy. Multivariate analysis was performed to identify significant predictors of loss-to-care. The percent change in weight at 6 months after starting ART was a secondary outcome. A sub-group analysis evaluated differences in pre-treatment variables between AIDS-KS patients retained-in-care compared to those lost-to-care. RESULTS: AIDS-KS patients had significantly greater 2-year proportional loss-to-care than matched non-KS AIDS patients (26.4% vs. 9.5%; p = 0.01) after initiation of ART. In multivariate analysis, the presence of KS (p = 0.02) was the only significant predictor of loss-to-care. AIDS-KS patients had significantly less weight gain after starting ART than non-KS AIDS patients (+3.4% vs. +6.4%; p = 0.03). AIDS-KS patients retained-in-care had significantly higher pre-treatment CD4+ lymphocyte counts than AIDS-KS patients lost-to-care (223 vs. 110 cells/mm(3); p = 0.04). CONCLUSIONS: In this retrospective study, AIDS-KS patients experienced significantly worse outcomes than matched non-KS AIDS patients after initiation of ART. AIDS-KS patients with higher pre-treatment CD4+ lymphocyte counts were more likely to be retained in care.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/administración & dosificación , Coinfección/tratamiento farmacológico , Sarcoma de Kaposi/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/mortalidad , Adulto , Coinfección/mortalidad , Coinfección/virología , Quimioterapia Combinada , Femenino , VIH-1 , Herpesvirus Humano 8 , Hospitales Universitarios , Humanos , Estimación de Kaplan-Meier , Lamivudine/administración & dosificación , Masculino , Análisis Multivariante , Nevirapina/administración & dosificación , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Sarcoma de Kaposi/etiología , Sarcoma de Kaposi/mortalidad , Estavudina/administración & dosificación , Resultado del Tratamiento , Población Urbana , Zimbabwe
8.
Clin Infect Dis ; 50(11): 1532-8, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20415574

RESUMEN

BACKGROUND. Cryptococcal meningitis (CM) remains a leading cause of acquired immunodeficiency syndrome-related death in sub-Saharan Africa. The timing of the initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV)-associated CM remains uncertain. The study aimed to determine the optimal timing for initiation of ART in HIV-positive individuals with CM. METHODS. A prospective, open-label, randomized clinical trial was conducted at a tertiary teaching hospital in Zimbabwe. Participants were aged > or = 18 years, were ART naive, had received a first CM diagnosis, and were randomized to receive early ART (within 72 h after CM diagnosis) or delayed ART (after 10 weeks of treatment with fluconazole alone). Participants received 800 mg of fluconazole per day. The ART regimen used was stavudine, lamivudine, and nevirapine given twice daily. The duration of follow-up was up to 3 years. The primary end point was all-cause mortality. RESULTS. Fifty-four participants were enrolled in the study (28 in the early ART arm and 26 in the delayed ART arm). The median CD4 cell count at enrollment was 37 cells/mm(3) (interquartile range, 17-69 cells/mm(3)). The 3-year mortality rate differed significantly between the early and delayed ART groups (88% vs 54%; P < .006); the overall 3-year mortality rate was 73%. The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (P = .031, by log-rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1-7.23). The study was terminated early by the data safety monitoring committee. CONCLUSIONS. In resource-limited settings where CM management may be suboptimal, when compared with a delay of 10 weeks after a CM diagnosis, early initiation of ART results in increased mortality. Trial registration. ClinicalTrials.gov identifier: NCT00830856.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Meningitis Criptocócica/tratamiento farmacológico , Adulto , Antifúngicos/administración & dosificación , Femenino , Fluconazol/administración & dosificación , Infecciones por VIH/mortalidad , Humanos , Masculino , Meningitis Criptocócica/mortalidad , Estudios Prospectivos , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Zimbabwe
9.
Eur J Immunol ; 40(4): 1036-41, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20104487

RESUMEN

HIV-specific CTL play an important role in the host control of HIV infection. HIV-nef may facilitate escape of HIV-infected cells from CTL recognition by selectively downregulating the expression of HLA-A and HLA-B molecules, while surface expression of HLA-C is unaffected. The HLA-C-restricted CTL responses have previously been largely ignored and poorly characterized. We examined the frequency, function, and phenotype of HLA-C-restricted CTL in ten antiretroviral therapy-naïve Caucasian and African individuals with chronic HIV-1 infection (for at least 8 years; CD4 cell counts in the range of 50-350) who carried the HLA-Cw04 allele. HLA-Cw04-restricted CTL that recognize a conserved epitope within HIV-1 envelope (aa 375-383 SF9) were analyzed using IFN-gamma ELISPOT assays and phenotypic analysis was carried out by flow cytometry. HLA-C-restricted CTL play an important role in the HIV-specific response, and can account for as much as 54% of the total response. HLA-C-restricted CTL are functionally and phenotypically identical to HLA-A- and HLA-B-restricted CTL. HLA-C-restricted CTL in chronic HIV infection are memory cells of an intermediate phenotype, characterized by high CD27 and low CD28 expression and lack of perforin production.


Asunto(s)
Antígenos VIH/inmunología , Infecciones por VIH/inmunología , VIH-1 , Antígenos HLA-C/inmunología , Memoria Inmunológica/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Grupo de Ascendencia Continental Africana/genética , Antígenos CD28/análisis , Recuento de Linfocito CD4 , Enfermedad Crónica , Estudios de Cohortes , Grupo de Ascendencia Continental Europea/genética , Citometría de Flujo , Infecciones por VIH/etnología , Antígenos HLA-C/genética , Humanos , Epítopos Inmunodominantes/inmunología , Inmunofenotipificación , Interferón gamma/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/análisis , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/fisiología
10.
AIDS ; 20(3): 462-4, 2006 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-16439884

RESUMEN

HLA-B5701 and its related allele B5703 have been shown to be strongly associated with slow HIV-1 disease progression. To elucidate the effect of these alleles fully on disease progression it is essential to identify key HIV-1 epitopes that are restricted by these alleles. Here we describe the identification of a novel HLA-B5701, B5703 restricted epitope within HIV-1 rev, which accounted for up to 25 and 40% of the total cytotoxic T-lymphocyte responses in two patients.


Asunto(s)
Epítopos de Linfocito T/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Antígenos HLA-B/inmunología , Linfocitos T Citotóxicos/inmunología , Enfermedad Aguda , Enfermedad Crónica , Progresión de la Enfermedad , Humanos , Inmunidad Celular
11.
Proc Natl Acad Sci U S A ; 100(15): 8856-61, 2003 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-12853576

RESUMEN

Ig-like transcript 4 (ILT4) (also known as leukocyte Ig-like receptor 2, CD85d, and LILRB2) is a cell surface receptor expressed mainly on myelomonocytic cells, whereas ILT2 (also known as leukocyte Ig-like receptor 1, CD85j, and LILRB1) is expressed on a wider range of immune cells including subsets of natural killer and T cells. Both ILTs contain immunoreceptor tyrosine-based inhibitory receptor motifs in their cytoplasmic tails that inhibit cellular responses by recruiting phosphatases such as SHP-1 (Src homology 2 domain containing tyrosine phosphatase 1). Although these ILTs have been shown to recognize a broad range of classical and nonclassical human MHC class I molecules (MHCIs), their precise binding properties remain controversial. We have used surface plasmon resonance to analyze the interaction of soluble forms of ILT4 and ILT2 with several MHCIs. Although the range of affinities measured was quite broad (Kd = 2-45 microM), some interesting differences were observed. ILT2 generally bound with a 2- to 3-fold higher affinity than ILT4 to the same MHCI. Furthermore, ILT2 and ILT4 bound to HLA-G with a 3- to 4-fold higher affinity than to classical MHCIs, suggesting that ILT/HLA-G recognition may play a dominant role in the regulation of natural killer, T, and myelomonocytic cell activation. Finally, we show that ILT2 and ILT4 effectively compete with CD8 for MHCI binding, raising the possibility that ILT2 modulates CD8+ T cell activation by blocking the CD8 binding as well as by recruiting inhibitory molecules through its immunoreceptor tyrosine-based inhibitory receptor motif.


Asunto(s)
Antígenos CD/metabolismo , Antígenos CD8/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Receptores Inmunológicos/metabolismo , Secuencia de Aminoácidos , Antígenos CD/química , Antígenos CD/genética , Secuencia de Bases , Sitios de Unión , Unión Competitiva , Linfocitos T CD8-positivos/inmunología , ADN Complementario/genética , Antígenos HLA/química , Antígenos HLA/genética , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Técnicas In Vitro , Células Asesinas Naturales/inmunología , Cinética , Receptor Leucocitario Tipo Inmunoglobulina B1 , Glicoproteínas de Membrana , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Receptores Inmunológicos/química , Receptores Inmunológicos/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Resonancia por Plasmón de Superficie
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