RESUMEN
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point, which may reduce infectivity and delay disease progression. METHODS: Randomized, placebo-controlled trial involving HIV-1-infected participants who received a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag vaccine or placebo. Sequence-based HLA typing was performed for all 110 participants who initiated analytic treatment interruption (ATI) to assess the role of HLA types previously associated with HIV prognosis. Plasma HIV-1 gag and pol RNA sequences were obtained during the ATI. Virologic endpoints and HLA groups were compared between treatment arms using the 2-sample rank sum test. A linear regression model was fitted to derive independent correlates of ATI week 16 plasma viral load (w16 PVL). RESULTS: Vaccinated participants with neutral HLA alleles had lower median w16 PVLs than did vaccinated participants with protective HLA alleles (P = .01) or placebo participants with neutral HLA alleles (P = .02). Factors independently associated with lower w16 PVL included lower pre-antiretroviral therapy PVL, greater Gag sequence divergence from the vaccine sequence, decreased proportion of HLA-associated polymorphisms in Gag, and randomization to the vaccine arm. CONCLUSIONS: Therapeutic vaccination with a rAd5-HIV gag vaccine was associated with lower ATI week 16 PVL even after controlling for viral and host genetic factors. CLINICAL TRIALS REGISTRATION: NCT00080106.
Asunto(s)
Vacunas contra el SIDA/administración & dosificación , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Inmunoterapia/métodos , Vacunación/métodos , Carga Viral , Adenoviridae/genética , Portadores de Fármacos/administración & dosificación , Vectores Genéticos , Antígenos HLA/genética , Humanos , Placebos/administración & dosificación , Plasma/virología , ARN Viral/sangre , Resultado del Tratamiento , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
The enhanced-sensitivity Trofile assay (TF-ES; Monogram Biosciences) was used to retest coreceptor tropism samples from 4 different cohorts of HIV-1-infected patients. Nine percent to 26% of patients with CCR5-tropic virus by the original Trofile assay had CXCR4-using virus by TF-ES. Lower CD4 cell counts were associated with CXCR4-using virus in all cohorts.
Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Receptores del VIH/metabolismo , Tropismo Viral , Virología/métodos , Acoplamiento Viral , Adulto , Humanos , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismoRESUMEN
Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-controlled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 microg/kg and a maximum tolerated dose of 30 microg/kg. Injection site reactions and transient elevations of liver function tests were the most notable side effects. Transient increases in plasma HIV-RNA levels were observed in 6 of 11 IL-7-treated patients. Recombinant hIL-7 induced CD4 and CD8 T cells to enter cell cycle; cell-cycle entry was also confirmed in antigen-specific CD8 T cells. Administration of rhIL-7 led to transient down-regulation of the IL-7 receptor alpha chain (CD127) in both CD4(+) and CD8(+) T cells. Single-dose rhIL-7 increased the numbers of circulating CD4(+) and CD8(+) T cells, predominantly of central memory phenotype. The frequency of CD4(+) T cells with a regulatory T-cell phenotype (CD25(high) CD127(low)) did not change after rhIL-7 administration. Thus, rhIL-7 has a biologic and toxicity profile suggesting a potential for therapeutic trials in HIV infection and other settings of lymphopenia. This clinical trial has been registered at http://www.clinicaltrials.gov under NCT0099671.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , VIH-1 , Interleucina-7/uso terapéutico , Subgrupos de Linfocitos T/efectos de los fármacos , Adulto , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ciclo Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Regulación hacia Abajo/efectos de los fármacos , Femenino , Infecciones por VIH/inmunología , Humanos , Memoria Inmunológica/efectos de los fármacos , Interleucina-7/administración & dosificación , Interleucina-7/efectos adversos , Interleucina-7/sangre , Interleucina-7/farmacología , Subunidad alfa del Receptor de Interleucina-7/biosíntesis , Subunidad alfa del Receptor de Interleucina-7/genética , Recuento de Linfocitos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Carga ViralRESUMEN
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-specific cellular immunity contributes to the control of HIV-1 replication. HIV-1-infected volunteers who were receiving antiretroviral therapy were given a replication-defective adenovirus type 5 HIV-1 gag vaccine in a randomized, blinded therapeutic vaccination study. METHODS: HIV-1-infected vaccine or placebo recipients underwent analytical treatment interruption (ATI) for 16 weeks. The log(10) HIV-1 RNA load at the ATI set point and the time-averaged area under the curve served as co-primary end points. Immune responses were measured by intracellular cytokine staining and carboxyfluorescein succinimidyl ester dye dilution. RESULTS: Vaccine benefit trends were seen for both primary end points, but they did not reach a prespecified significance level of P < or = 25. The estimated shifts in the time-averaged area under the curve and the ATI set point were 0.24 (P=.04, unadjusted) and 0.26 (P=.07, unadjusted) log(10) copies lower, respectively, in the vaccine arm than in the placebo arm. HIV-1 gag-specific CD4(+) cells producing interferon-gamma were an immunologic correlate of viral control. CONCLUSION: The vaccine was generally safe and well tolerated. Despite a trend favoring viral suppression among vaccine recipients, differences in HIV-1 RNA levels did not meet the prespecified level of significance. Induction of HIV-1 gag-specific CD4 cells correlated with control of viral replication in vivo. Future immunogenicity studies should require a substantially higher immunogenicity threshold before an ATI is contemplated.
Asunto(s)
Vacunas contra el SIDA , Adenoviridae/genética , Productos del Gen gag/metabolismo , Infecciones por VIH/prevención & control , VIH-1/inmunología , Vacunas de ADN , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Adenoviridae/metabolismo , Adulto , Linfocitos T CD4-Positivos/inmunología , Método Doble Ciego , Femenino , Productos del Gen gag/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Inmunización , Interferón gamma/biosíntesis , Masculino , Resultado del Tratamiento , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Vacunas de ADN/inmunología , Vacunas de ADN/uso terapéutico , Replicación ViralRESUMEN
BACKGROUND: Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized. METHODS: Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4(+), CD4(+) naive and memory, CD4(+) activation, CD8(+), CD8(+) activation, B, and natural killer cells among patients in different baseline CD4(+) strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113. RESULTS: Patients in the lower baseline CD4(+) strata did not achieve total CD4(+) cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4(+) cell count increases were similar. Ratios of CD4(+) naive-memory cell counts and CD4(+):CD8(+) cell counts remained significantly reduced in patients with lower baseline CD4(+) cell counts (Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico
, Síndrome de Inmunodeficiencia Adquirida/inmunología
, Terapia Antirretroviral Altamente Activa
, Subgrupos de Linfocitos T/inmunología
, Adulto
, Linfocitos B/inmunología
, Recuento de Linfocito CD4
, Relación CD4-CD8
, Femenino
, Humanos
, Células Asesinas Naturales/inmunología
, Masculino
, Persona de Mediana Edad
RESUMEN
T-regulatory cell (T-reg) frequency is increased in HIV infection and with aging. We evaluated the effect of age on total, memory and naïve T-reg percentages in untreated HIV infection. Older HIV(+) subjects had a total T-reg percent that is 2.8% (p=0.02) higher than among younger HIV(+), older HIV(-) and younger HIV(-) subjects. In HIV(+) subjects, the total T-reg percentage is inversely correlated with the lymphocyte proliferative responses to tetanus (r=-0.45, p=0.002) and Candida (r=-0.43, p=0.003) antigens. Similar correlations were seen between memory T-reg percentages and the lymphocyte proliferative response to tetanus and Candida in HIV(+) subjects. T-reg percentages did not correlate consistently with markers of immune activation. T-reg percentages are increased in the older HIV(+) population and may play a role in the accelerated disease progression seen in older HIV-infected persons.
Asunto(s)
Envejecimiento/inmunología , Infecciones por VIH/inmunología , VIH-1 , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Adulto , Recuento de Linfocito CD4 , Línea Celular Tumoral , Infecciones por VIH/fisiopatología , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: CD4+ T lymphocyte (CD4) counts and plasma human immunodeficiency virus (HIV) type 1 RNA concentrations predict clinical outcome in HIV-1 infection. Our objective was to assess the independent prognostic value for disease progression of soluble markers of immune system activation. METHODS: This retrospective marker-validation study utilized previously obtained clinical and laboratory data, including CD4+ cell counts, and made use of stored frozen serum samples to assay for levels of beta2-microglobulin, neopterin, endogenous interferon, triglycerides, interleukin-6, soluble tumor necrosis factor- alpha receptor II, and HIV-1 RNA, and to determine HIV genotypic reverse-transcriptase inhibitor resistance. The 152 patients who participated in this study represented a subsample of participants in AIDS Clinical Trials Group (ACTG) 116B/117, a randomized trial that demonstrated the clinical benefit of didanosine over zidovudine monotherapy in persons with advanced HIV-1 infection. Marker data were analyzed in relation to protocol-defined clinical disease progression, using Cox proportional hazards models. RESULTS: The median duration of follow-up was 344 days. Elevated baseline values for neopterin (P=.0009), endogenous interferon (P=.00039) and interleukin-6 (P=.0007) were each associated with greater subsequent risk of clinical disease progression. In a head-to-head comparison that was adjusted for CD4+ cell count (P=.0165) and HIV-1 RNA level (P=.1220), we found that elevated values for neopterin (P=.0002) and, to a lesser extent, endogenous interferon (P=.0053) were the strongest predictors of increased risk of clinical disease progression 6 months later. CONCLUSIONS: Soluble markers of immune activation add prognostic information to CD4 counts and viral load for risk of disease progression in advanced HIV-1 infection. The robust performance of neopterin, an inexpensive and reliably measured serum marker, supports its potential suitability for patient monitoring, particularly in resource-limited settings.
Asunto(s)
Infecciones por VIH/sangre , Neopterin/sangre , Fármacos Anti-VIH/uso terapéutico , Biomarcadores , Recuento de Linfocito CD4 , Didanosina/uso terapéutico , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Humanos , Interferones , Interleucina-6 , Masculino , Valor Predictivo de las Pruebas , Factores de Riesgo , Zidovudina/uso terapéuticoRESUMEN
OBJECTIVES: Interleukin (IL)-12 is a cytokine that stimulates T lymphocytes and natural killer cells to generate a Type 1 T-helper lymphocyte immune response. The primary objective of this study was to determine the safety and immunologic activity of repeated recombinant human IL-12 (rhIL-12) dosing in HIV-infected patients over a broad range of the HIV disease spectrum. DESIGN: A randomized, placebo-controlled, Phase 1 trial design was chosen to control for the effects of HIV disease alone on safety and immunologic measurements. METHODS: HIV-infected patients on antiretroviral therapy received rhIL-12 or placebo twice weekly for 4 weeks. Subjects were monitored for safety and changes in absolute lymphocyte subset number, serum interferon (IFN)gamma and neopterin levels, plasma HIV RNA level, peripheral blood mononuclear cell (PBMC)-inducible IFNgamma responses to mitogen, and PBMC proliferative responses to phytohemagglutinin, tetanus, Candida, Mycobacterium avium complex, streptokinase, and HIV p24 and gp160 antigens. RESULTS: rhIL-12 was well tolerated at doses up to 100 ng/kg in subjects enrolled with CD4 cell counts < 50 x 10(6) cells/l and at all doses in subjects with CD4 cell counts of 300 x 10(6)-500 x 10(6) cells/l. rhIL-12 resulted in dose-related increases in serum neopterin (particularly in subjects with baseline CD4 cell counts of 300-500 x 10(6) cells/l) but in no significant changes in other immunologic measurements or plasma HIV RNA levels. CONCLUSIONS: rhIL-12 dosed twice weekly at < or = 100 ng/kg was well tolerated in HIV-infected patients and resulted in dose-related increases in serum neopterin (possibly reflecting the effect of some degree of IFNgamma induction). However, there was no evidence of improvement in antigen-specific immune response.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Interleucina-12/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , División Celular , Método Doble Ciego , Humanos , Interferón gamma/sangre , Interleucina-12/efectos adversos , Recuento de Leucocitos , Linfocitos/inmunología , Persona de Mediana Edad , Neopterin/sangre , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéuticoRESUMEN
It is unclear why discordant immunologic and virologic responses occur during therapy for human immunodeficiency virus (HIV) infection. This study examined whether markers of immune activation and naive/memory lymphocyte subsets at study baseline could predict discordance between HIV type 1 (HIV-1) RNA and CD4+ lymphocyte responses at week 24 of antiretroviral therapy. Ten diverse, prospective antiretroviral studies with 1007 evaluable subjects were included. Subsets of subjects at increased risk for discordance were identified by recursive partitioning. The strongest predictor of more-favorable immunologic than virologic responses was a lower baseline CD4+ lymphocyte count. Weaker predictors in small subsets of subjects were fewer activated CD4+ lymphocytes and fewer CD8+ lymphocytes. Conversely, the strongest predictors of more-favorable virologic than immunologic responses were higher baseline CD4+ lymphocyte count and percentage. Additional predictors in some analyses were higher CD8+ lymphocyte count or percentage and lower HIV-1 RNA concentrations. Baseline markers of immune activation and naive/memory lymphocyte subsets had limited ability to predict subsequent discordance.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Recuento de Linfocito CD4 , Infecciones por VIH/inmunología , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Linfocitos T CD8-positivos , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Masculino , Estudios Retrospectivos , Carga ViralRESUMEN
Highly active antiretroviral therapy (HAART) of HIV disease is associated with effective virologic control, immune reconstitution, and clinical improvements. This study addresses the potential for improvements in lymphocyte phenotype and virologic responses of HIV-infected persons with extensive experience with dual nucleoside reverse transcriptase (NRTI) treatment and advanced HIV disease after a change to a potent antiretroviral therapy (NRTI + protease inhibitor). The majority of participants achieved virologic success. There was a median rise in CD4+ lymphocytes of 99 cells/mm(3) by 48 weeks, because of an increase in memory CD4+ cells at 4 and 16 weeks, followed by a later increase in naive CD4+ cells between weeks 16 and 48. The proportion of activated, DR+ CD38+ CD8+ lymphocytes decreased during the 48 weeks of follow-up. The immunologic findings (increased memory and naive T cells and reduced activation levels) were significantly improved in participants with persistent suppression of viral replication over the 48 weeks of the study. Baseline HIV RNA copy number was lower (median, 14,784 copies/ml) in persons who responded virologically than in those not suppressing viral replication (median, 49,454 copies/ml). CD4+ cell counts above the median (125/mm(3)) at time 0 for the participants, was the only baseline immunologic marker significantly associated with viral suppression at week 48. Participants older than 40 years of age demonstrated less immunologic recovery. The results of the study show that patients with extensive experience with NRTIs respond both virologically and immunologically during the first 48 weeks of therapy with a potent antiretroviral regimen.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Adulto , Anciano , Alquinos , Fármacos Anti-VIH/uso terapéutico , Antígenos CD/inmunología , Terapia Antirretroviral Altamente Activa , Benzoxazinas , Biomarcadores , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/citología , Ciclopropanos , Didanosina/uso terapéutico , Didesoxinucleósidos/uso terapéutico , Método Doble Ciego , Femenino , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/uso terapéutico , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Oxazinas/uso terapéutico , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Estavudina/uso terapéutico , Resultado del Tratamiento , Carga Viral , Zidovudina/uso terapéuticoRESUMEN
ACTG 266 was designed as a randomized study to evaluate two doses of the human monoclonal antibody directed against CMV gH (MSL-109) versus placebo, each in combination with standard antiviral therapy for the treatment of newly diagnosed Cytomegalovirus (CMV) retinitis in AIDS patients. A total of 82 subjects were enrolled and received either placebo (n = 28), or MSL-109 at 15 mg (n = 26) or 60 mg (n = 28) every 2 weeks until disease progression was diagnosed. The primary endpoint, disease progression, was determined by masked reading of retinal photographs taken every 4 weeks read by a single investigator. The median time to progression was 8.0, 8.3, and 12.1 weeks in the placebo, MSL-109 15mg and MSL-109 60 mg cohorts, respectively (P = 0.087, placebo versus 60 mg cohort). There were 22 deaths during the study period (9, 9, and 4 in the placebo, MSL-109 15 mg and MSL-109 60 mg cohorts, respectively (P = 0.0058, placebo versus 60 mg cohort)). MSL-109 was well tolerated with no significant adverse events attributable to study medication. The unexplained survival advantage in the higher dose cohort was discordant with the findings of the parallel Studies of Ocular Complications of AIDS Research Group (SOCA)-Monoclonal Anti-CMV Retinitis Trial (MACRT), which was prematurely halted because of increased mortality in subjects treated with high-dose MSL-109, recognizing that A266 enrolled subjects with newly diagnosed, whereas the MACRT enrolled subjects with relapsed, CMV retinitis.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/terapia , Anticuerpos Monoclonales/uso terapéutico , Antivirales/uso terapéutico , Retinitis por Citomegalovirus/terapia , Proteínas del Envoltorio Viral/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Antivirales/administración & dosificación , Citomegalovirus/efectos de los fármacos , Retinitis por Citomegalovirus/mortalidad , Retinitis por Citomegalovirus/virología , Método Doble Ciego , Quimioterapia Combinada , Femenino , Foscarnet/administración & dosificación , Foscarnet/uso terapéutico , Ganciclovir/administración & dosificación , Ganciclovir/uso terapéutico , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease. METHODS: In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels ≤200 copies per milliliter for ≥6 months and CD4 lymphocyte counts <200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 µg/kg of palifermin on 3 consecutive days. RESULTS: The median change in the CD4 T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm] and the 20-µg/kg dose [11 (2, 32) cells/mm], the 40-µg/kg dose [12 (-2, 25) cells/mm], or the 60-µg/kg dose arm [8 (-13, 35) cells/mm] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants. CONCLUSIONS: Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Factor 7 de Crecimiento de Fibroblastos/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Factor 7 de Crecimiento de Fibroblastos/administración & dosificación , Infecciones por VIH/inmunología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral , Proteínas Recombinantes , Timo/efectos de los fármacos , Carga ViralRESUMEN
BACKGROUND: The contribution of immune activation to accelerated HIV-disease progression in older individuals has not been delineated. METHODS: Prospective multicenter cohort of older (≥45 years) and younger (18-30 years) HIV-infected adults initiating 192 weeks of antiretroviral therapy (ART). Longitudinal models of CD4 cell restoration examined associations with age-group, thymic volume, immune activation, and viral load. RESULTS: Forty-five older and 45 younger adults (median age 50 and 26 years, respectively) were studied. Older patients had fewer naive CD4 cells (P<0.001) and higher HLA-DR/CD38 expression on CD4 (P=0.05) and CD8 cells (P=0.07) than younger patients at any time on ART. The rate of naive and total CD4 cell increase was similar between age groups, but older patients had a faster mean rate of B-cell increase (by +0.7 cells/week; P=0.01), to higher counts than healthy controls after 192 weeks (P=0.003). Naive CD4 increases from baseline were associated with immune activation reductions (as declines from baseline of %CD8 cells expressing HLA-DR/CD38; P<0.0001), but these increases were attenuated in older patients, or in those with small thymuses. A 15% reduction in activation was associated with naive gains of 29.9 and 6.2 cells/µl in younger, versus older patients, or with gains of 25.7, 23.4, and 2.1 cells/µl in patients with the largest, intermediate, and smallest thymuses, respectively (P<0.01 for interactions between activation reduction and age-group or thymic volume). CONCLUSION: Older patients had significant B-cell expansion, higher levels of immune activation markers, and significantly attenuated naive CD4 cell gains associated with activation reduction.
Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Adolescente , Adulto , Factores de Edad , Envejecimiento/inmunología , Fármacos Anti-VIH/uso terapéutico , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Quimioterapia Combinada , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Adulto JovenRESUMEN
BACKGROUND: HIV-specific cellular immune responses are associated with control of viremia and delayed disease progression. An effective therapeutic vaccine could mimic these effects and reduce the need for continued antiretroviral therapy. DermaVir, a topically administered plasmid DNA-nanomedicine expressing HIV (CladeB) virus-like particles consisting of 15 antigens, induces predominantly central memory T-cell responses. METHODS: Treated HIV-infected adults (HIV RNA <50 and CD4 >350) were randomized to placebo or escalating DermaVir doses (0.1 or 0.4 mg of plasmid DNA at weeks 1, 7, and 13 in the low- and intermediate-dose groups and 0.8 mg at weeks 0, 1, 6, 7, 12, and 13 in the high-dose group), n = 5-6 evaluable subjects per group. Immunogenicity was assessed by a 12-day cultured interferon-γ enzyme-linked immunosorbent spot assay at baseline and at weeks 9, 17, and 37 using 1 Tat/Rev and 3 overlapping Gag peptide pools (p17, p24, and p15). RESULTS: Groups were comparable at baseline. The study intervention was well tolerated, without dose-limiting toxicities. Most responses were highest at week 17 (4 weeks after last vaccination) when Gag p24 responses were significantly greater among intermediate-dose group compared with control subjects [median (IQR): 67,600 (5633-74,368) versus 1194 (9-1667)] net spot-forming units per million cells, P = 0.032. In the intermediate-dose group, there was also a marginal Gag p15 response increase from baseline to week 17 [2859 (1867-56,933), P = 0.06], and this change was significantly greater than in the placebo group [0 (-713 to 297), P = 0.016]. CONCLUSIONS: DermaVir administration was associated with a trend toward greater HIV-specific, predominantly central memory T-cell responses. The intermediate DermaVir dose tended to show the greatest immunogenicity, consistent with previous studies in different HIV-infected patient populations.
Asunto(s)
Vacunas contra el SIDA/inmunología , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Vacunas contra el SIDA/administración & dosificación , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Quimioterapia Combinada , Humanos , Esquemas de Inmunización , ARN Viral , Carga Viral , ViremiaRESUMEN
Nucleotide mixtures in human immunodeficiency virus type 1 (HIV-1) population sequences reflect sequence diversity. We evaluated gag and pol ambiguous nucleotide frequencies during an analytic treatment interruption (ATI) in an HIV-1 therapeutic vaccine study. The proportion of ambiguous nucleotides was significantly higher at ATI week 16 than at either the time of first detectable viremia (P < 0.001 gag and P = 0.03 reverse transcriptase) or preantiretroviral therapy (P = 0.007 gag). No significant differences were observed in the proportion of ambiguous nucleotides between those receiving vaccine and placebo. Increased HIV diversity during the ATI may represent a potentially higher barrier to success for a therapeutic as compared with a preventative vaccine targeting cell-mediated immunity.
Asunto(s)
Vacunas contra el SIDA/inmunología , Variación Genética , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/genética , Vacunas contra el SIDA/administración & dosificación , VIH-1/aislamiento & purificación , Humanos , Inmunoterapia/métodos , Datos de Secuencia Molecular , Placebos/administración & dosificación , Análisis de Secuencia de ADN , Privación de Tratamiento , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
BACKGROUND: In the placebo-controlled trial ACTG A5197, a trend favoring viral suppression was seen in the HIV-1-infected subjects who received a recombinant Ad5 HIV-1 gag vaccine. OBJECTIVE: To identify individuals with initial viral suppression (plasma HIV-1 RNA set point <3.0 log(10) copies/ml) during the analytic treatment interruption (ATI) and evaluate the durability and correlates of virologic control and characteristics of HIV sequence evolution. METHODS: HIV-1 gag and pol RNA were amplified and sequenced from plasma obtained during the ATI. Immune responses were measured by flow cytometric analysis and intracellular cytokine expression assays. Characteristics of those with and without initial viral suppression were compared using the Wilcoxon rank sum and Fisher's exact tests. RESULTS: Eleven out of 104 participants (10.6%) were classified as initial virologic suppressors, nine of whom had received the vaccine. Initial virologic suppressors had significantly less CD4+ cell decline by ATI week 16 as compared to non-suppressors (median 7 CD4+ cell gain vs. 247 CD4+ cell loss, Pâ=â0.04). However, of the ten initial virologic suppressors with a pVL at ATI week 49, only three maintained pVL <3.0 log(10) copies/ml. HIV-1 Gag-specific CD4+ interferon-γ responses were not associated with initial virologic suppression and no evidence of vaccine-driven HIV sequence evolution was detected. Participants with initial virologic suppression were found to have a lower percentage of CD4+ CTLA-4+ cells prior to treatment interruption, but a greater proportion of HIV-1 Gag-reactive CD4+ TNF-α+ cells expressing either CTLA-4 or PD-1. CONCLUSIONS: Among individuals participating in a rAd5 therapeutic HIV-1 gag vaccine trial, initial viral suppression was found in a subset of patients, but this response was not sustained. The association between CTLA-4 and PD-1 expression on CD4+ T cells and virologic outcome warrants further study in trials of other therapeutic vaccines in development. TRIAL REGISTRATION: ClinicalTrials.gov NCT00080106.
Asunto(s)
Vacunas contra el SIDA/uso terapéutico , VIH-1/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/citología , Antígeno CTLA-4/biosíntesis , Citocinas/biosíntesis , Femenino , Citometría de Flujo/métodos , Humanos , Sistema Inmunológico , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Placebos , Receptor de Muerte Celular Programada 1/biosíntesis , Reproducibilidad de los Resultados , Análisis de Secuencia de ADN , Resultado del Tratamiento , Vacunas Sintéticas/uso terapéuticoRESUMEN
The advent of highly active antiretroviral therapy in the treatment of HIV disease has substantially extended the lifespan of individuals infected with HIV resulting in a growing population of older HIV-infected individuals. The efficacy and safety of antiretroviral agents in the population are important concerns. There have been relatively few studies assessing antiretroviral pharmacokinetics in older patients. Thirty-seven subjects aged 18-30 years and 40 subjects aged 45-79 years, naive to antiretroviral therapy, received lopinavir/ritonavir (400/100) bid, emtricitibine 200 mg qd, and stavudine 40 mg bid. Trough lopinavir concentrations were available for 44 subjects, collected at 24, 36, and 96 weeks. At week 24, older age was associated with higher lopinavir trough concentrations, and a trend was observed toward older age being associated with higher lopinavir trough concentrations when all time points were evaluated. In the young cohort, among subjects with two or more measurements, there was a trend toward increasing intrasubject trough lopinavir concentrations over time. Using a nonlinear, mixed-effects population pharmacokinetic model, age was negatively associated with lopinavir clearance after adjusting for adherence. Adherence was assessed by patient self-reports; older patients missed fewer doses than younger patients (p = 0.02). No difference in grade 3-4 toxicities was observed between the two age group. Older patients have higher trough lopinavir concentrations and likely decreased lopinavir clearance. Age-related changes in the pharmacokinetics of antiretroviral drugs may be of increasing importance as the HIV-infected population ages and as older individuals comprise an increasing proportion of new diagnoses.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Inhibidores de la Proteasa del VIH/farmacocinética , Plasma/química , Pirimidinonas/farmacocinética , Adolescente , Adulto , Factores de Edad , Anciano , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/métodos , Femenino , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Humanos , Lopinavir , Masculino , Persona de Mediana Edad , Pirimidinonas/administración & dosificación , Pirimidinonas/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Pathogenesis studies show that naive CD4 cells are preferentially depleted in lymphoid tissues during HIV infection, and studies of advanced patients suggest levels of naive CD4 cells in blood correlate to total CD4 cells after starting antiretroviral therapy (ARV). We hypothesized that measuring naive CD4 cells in blood in people at earlier stages of disease would identify those at highest risk for poor CD4 reconstitution who may benefit from earlier initiation of ARV. METHODS AND FINDINGS: We identified 348 patients from multiple AIDS Clinical Trials Group studies who were ARV naive, had a CD4 count between 200 and 500 cells per microliter, a measure of pretreatment-naive CD4 percent, and serial follow-up measures of CD4 count and plasma HIV RNA after starting ARV. We used logistic regression to model the ability of naive CD4 percent to predict 100 and 200 CD4 cell increases after 24 months of therapy. After controlling for baseline viral load and demographic variables, baseline naive but not total CD4 cell count strongly predicted CD4 cell increases. Lower baseline naive CD4 percent was associated with greater time spent at lower CD4 T-cell counts after initiating ARV. CONCLUSIONS: Measurement of naive CD4 percent in patients can identify those least likely to reconstitute immunity, who may benefit from earlier ARV treatment.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/diagnóstico , Infecciones por VIH/inmunología , Adulto , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Pronóstico , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVES: To evaluate the association between baseline (BL) replication capacity (RC) (RCBL) and immunologic/virologic parameters (at BL and after 48 weeks on therapy) in HIV-1-infected subjects initiating antiretroviral therapy. METHODS: RCBL was determined using a modified Monogram PhenoSense HIV drug susceptibility assay on plasma HIV-1 from 321 treatment-naive subjects from AIDS Clinical Trials Group 384. Univariate and multivariable analyses were performed to determine the association of RCBL with BL and on-therapy virologic and immunologic outcomes. RESULTS: Higher RCBL was associated with lower baseline CD4 (CD4BL) (r = -0.23, P < 0.0001), higher baseline HIV-1 RNA (r = 0.25, P < 0.0001), higher CD4BL activation percent (r = 0.23, P < 0.0001), and lower CD4BL memory count (r = -0.21, P = 0.0002). In a multivariable model, week 48 CD4 increase (DeltaCD448) was associated with lower CD4BL memory count and higher CD4BL-naive percent (P = 0.004, P = 0.015, respectively). The interaction between CD4BL and RCBL was significant (P = 0.018), with a positive association between RCBL and DeltaCD448 in subjects with higher CD4BL and a negative association at lower absCD4BL. CONCLUSIONS: At baseline, higher RC was significantly associated with higher HIV-1 RNA, higher CD4 cell activation, lower CD4 cell count, and lower CD4 memory cell count. These factors may interact, directly or indirectly, to modify the extent to which CD4 recovery occurs in patients starting antiretroviral therapy at different CD4BL counts.
Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Carga Viral , Replicación Viral , Adulto , Anciano , Recuento de Linfocito CD4 , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The commonly used two-sample tests of equal area-under-the-curve (AUC), where AUC is based on the linear trapezoidal rule, may have poor properties when observations are missing, even if they are missing completely at random (MCAR). We propose two tests: one that has good properties when data are MCAR and another that has good properties when the data are missing at random (MAR), provided that the pattern of missingness is monotonic. In addition, we discuss other non-parametric tests of hypotheses that are similar, but not identical, to the hypothesis of equal AUCs, but that often have better statistical properties than do AUC tests and may be more scientifically appropriate for many settings.