RESUMO
BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV acquisition. To enable routine commissioning of PrEP in England, we aimed to establish population need, duration of need, PrEP uptake, and duration of use in attendees of sexual health services (SHS) in England. METHODS: The Impact Trial was a prospective, open-label, single-arm, multicentre trial conducted at 157 SHS across England between Oct 13, 2017, and July 12, 2020. Clinicians assessed HIV-negative attendees for their risk of HIV acquisition to identify those who were eligible to participate and receive either daily or event-based oral PrEP (tenofovir disoproxil maleate with emtricitabine), as appropriate. Eligible participants were aged 16 years or older, considered HIV-negative on the day of enrolment, and willing to adhere to the trial procedures. Non-trial attendees are mutually exclusive of trial participants and included SHS attendees who were not recruited to the Impact Trial at any point. They include HIV-negative individuals aged 16 years or older who attended a participating SHS at least once after recruitment at that SHS had begun and before Feb 29, 2020. The main outcomes assessed were PrEP need, uptake, and use, and HIV and sexually transmitted infection (STI) incidence. Data are presented up to Feb 29, 2020, before the introduction of COVID-19 control measures. The study is registered with ClinicalTrials.gov, NCT03253757. FINDINGS: In this analysis, we include 21â356 of 24â268 participants enrolled before Feb 29, 2020. 20â403 participants (95·5%) were men who have sex with men (MSM). Uptake of PrEP among SHS attendees clinically assessed and coded as eligible was 21â292 (57·1%) of 37â289. 18â400 trial participants had at least one post-enrolment visit and a median of 361 days of follow-up (IQR 143-638); 14â039 (75·9%) of these had enough PrEP prescribed to provide protection for 75% of their follow-up time. Among MSM, HIV incidence was 0·13 (95% CI 0·08-0·19) per 100 person-years in trial participants (27 seroconversions) and 0·95 (95% CI 0·88-1·03) per 100 person-years in non-trial attendees (587 seroconversions; proportionate reduction of 86·8%, 95% CI 80·2-91·6). 18â607 bacterial STIs were recorded (incidence 68·1 per 100 person-years in trial participants who were MSM). 4343 (24·4%) MSM participants were diagnosed with two or more STIs, accounting for 14â800 (79·5%) of all 18â607 diagnoses. INTERPRETATION: PrEP need was higher than initially estimated by an expert stakeholder group. The high proportion of follow-up time protected by PrEP suggests that the need for protection persisted throughout trial participation for most participants. HIV incidence among MSM trial participants was low. The large unmet need for PrEP suggests that greater provision is required to maximise the potential of a national programme. The high incidence of bacterial STIs among participants, concentrated within a subgroup of PrEP users, presents an opportunity for tailored STI control measures. FUNDING: NHS England.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Infecções Sexualmente Transmissíveis , Masculino , Humanos , Feminino , Homossexualidade Masculina , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por HIV/diagnóstico , Profilaxia Pré-Exposição/métodos , Fármacos Anti-HIV/uso terapêutico , Estudos Prospectivos , Avaliação da Tecnologia Biomédica , Infecções Sexualmente Transmissíveis/epidemiologia , Inglaterra/epidemiologiaRESUMO
BACKGROUND: In HIV-1-infected patients impaired IFN-γ responses to purified protein derivative (PPD) are associated with an increased risk of active tuberculosis. Tuberculosis antigen-specific cells are found in the T(H)1/T(H)17 subset of CD4 T cells, which support HIV-1 replication. Selective loss of T(H)1/T(H)17 cells in patients with HIV-1 infection might contribute to reduced tuberculosis-induced immune responses and an increased susceptibility to active tuberculosis. OBJECTIVES: We sought to investigate the association between T(H)1/T(H)17 cells and PPD-specific cytokine responses in HIV-1-infected patients. METHODS: A cross-sectional study was performed on healthy control subjects, HIV-1-infected patients receiving successful antiretroviral therapy (ART(+)), and ART-naive HIV-1-infected patients (ART(-)). All patients studied had evidence of BCG vaccination. Four discrete CD4 T-cell subsets were assessed by flow cytometry: T(H)1/T(H)17 cells (CXCR3(+)CCR6(+)CCR4(-)), T(H)1 cells (CXCR3(+)CCR6(-)CCR4(-)), T(H)17 cells (CXCR3(-)CCR6(+)CCR4(+)), and T(H)2 cells (CXCR3(-)CCR6(-)CCR4(+)). IFN-γ and IL-2 PPD-specific cytokine responses were assessed in PBMCs by using the enzyme-linked immunospot assay. RESULTS: Twenty-nine healthy control subjects, 34 ART(+) patients, and 26 ART(-) patients were recruited. The number and frequency of T(H)1/T(H)17 and T(H)1/T(H)17 CCR5(+) CD4 T cells were significantly reduced in HIV-1-infected patients. IFN-γ and IL-2 PPD responses were significantly lower in ART(-) patients and were partially reconstituted with successful ART. Loss of T(H)1/T(H)17 CCR5(+) cells was associated with reduced IFN-γ and IL-2 PPD responses. CONCLUSIONS: Selective loss of T(H)1/T(H)17 cells may be a risk factor for the development of active tuberculosis in patients with HIV-1 infection and might be a useful biomarker in the development of tuberculosis vaccines.
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Infecções Oportunistas Relacionadas com a AIDS/imunologia , HIV-1/imunologia , Interferon gama/imunologia , Interleucina-2/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tuberculina/imunologia , Tuberculose/imunologia , Adulto , Biomarcadores , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Th2/imunologiaRESUMO
CONTEXT: Therapies to decrease immune activation might be of benefit in slowing HIV disease progression. OBJECTIVE: To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/µL. INTERVENTION: Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models. RESULTS: There was no significant difference in CD8 cell activation between the 2 groups (-4.8% and -4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/µL vs -23 cells/µL at week 48; difference, -62 cells/µL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03). CONCLUSION: Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN30019040.
Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Hidroxicloroquina/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Adolescente , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
CCR5 antagonists may provide a well-tolerated switch option for patients experiencing tolerability or toxicity of their antiretroviral regimen. We analyzed stored samples from patients undergoing planned treatment interruptions for reasons other than virological failure, in order to analyze tropism evolution during fully suppressive antiretroviral therapy (ART). Two of 37 patients showed evidence of switching. Tropism switching after suppressive ART was uncommon in this cohort. Pretreatment human immunodeficiency virus (HIV) RNA tropism testing may help guide the switch to CCR5 antagonists in patients with undetectable HIV RNA.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Inibidores da Fusão de HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV/patogenicidade , Tropismo Viral , Adulto , Feminino , Humanos , Masculino , Gravidez , Suspensão de TratamentoRESUMO
Mechanisms underlying the lipodystrophy syndrome associated with antiretroviral therapy (ART) for HIV infection are not completely understood. We investigated the effect of ART on blood lipid concentrations in the fasting state and after consumption of a meal containing [1-13C]palmitic acid in HIV-positive men receiving nucleoside reverse transcriptase inhibitors (NRTI, n 7), NRTI combined with protease inhibitors (PI; NRTIPI, n 6), in HIV-positive but therapy-naïve men (noART, n 5) and in HIV-seronegative men (controls, n 6). HIV-positive subjects had higher fasting TAG concentrations and resting energy expenditure than controls. Subjects receiving NRTIPI therapy had higher fasting NEFA concentrations than the other groups. There were no significant differences in postprandial lipid metabolism between noART subjects and controls. NRTI therapy impaired hydrolysis of meal-derived TAG, most evidently when combined with PI (the NRTIPI group). Accumulation of 13C-label in the NEFA fraction was not different between groups. In the NRTIPI group, fasting and postprandial NEFA concentrations were significantly higher than other groups. Postprandial glucose and insulin responses in HIV-positive subjects did not differ from controls. These findings suggest that ART dyslipidaemia is associated with impaired postprandial TAG clearance, which is exacerbated by NRTIPI therapy. If dyslipidaemia is to be minimised in ART, the specific adverse effects of particular combinations during the fed state should be considered.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , HIV-1 , Hipertrigliceridemia/induzido quimicamente , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Glicemia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Infecções por HIV/sangue , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Humanos , Hidrólise/efeitos dos fármacos , Hipertrigliceridemia/sangue , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução/efeitos dos fármacos , Período Pós-Prandial/fisiologia , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Triglicerídeos/sangue , Adulto JovemRESUMO
We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4(+) T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Interleucina-2/análogos & derivados , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Citocinas/metabolismo , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Injeções Subcutâneas , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Interleucina-2/agonistas , Interleucina-2/farmacocinética , Contagem de Linfócitos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinéticaRESUMO
BACKGROUND: HIV-1 infection is known to have a detrimental impact on peripheral blood natural killer cell phenotype and function. Chronic HIV-1 also causes a substantial depletion of CD4+ T cells in the gastrointestinal tract and the blood. OBJECTIVE: To investigate the impact of chronic HIV-1 infection with on natural killer cell populations in the gastrointestinal tract and the effect of suppression of plasma viraemia with antiretroviral therapy. METHODS: Lymphocyte populations were extracted from the lamina propria of biopsies taken from the sigmoid colon of HIV-1-infected and uninfected individuals. The proportions of natural killer cell subsets were compared in viraemic (n = 15) and aviraemic HIV-1-positive, HAART-treated individuals (n = 27) and HIV-1 negative control individuals (n = 26) using flow cytometry on gated subsets. RESULTS: Natural killer cells are depleted in colonic biopsies from HIV-1-infected individuals with detectable plasma virus in comparison with HIV-1-negative individuals. A significant increase in the proportion of both natural killer and CD4+ T cells in the colonic lamina propria is observed in aviraemic individuals compared to viraemic individuals. CONCLUSIONS: Chronic HIV-1 infection results in depletion of both natural killer cells and CD4+ T cells in colonic tissue and antiretroviral therapy results in a recovery of these subsets in individuals with undetectable plasma viral load.
Assuntos
Colo Sigmoide , Infecções por HIV/imunologia , HIV-1 , Mucosa Intestinal/imunologia , Células Matadoras Naturais/imunologia , Mucosa/imunologia , Adulto , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , Humanos , Contagem de Linfócitos , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Carga Viral , Viremia/imunologiaRESUMO
OBJECTIVES: To determine if the expression of CD38 on CD8+ T-cells could be used as a marker of viral replication <50 copies/ml in peripheral blood. METHODS: In a cross-sectional study of patients attending a single HIV clinic in London, an ultra-sensitive HIV RNA viral load assay, with a limit of detection of 3 copies/ml, was used to determine HIV-1 replication in plasma in 70 patients who had sustained viral suppression <50 copies/ml by bDNA assays. Immune activation using the expression of CD38 on CD8+ T-cells was also assessed in patients on antiretroviral therapy (ART) with sustained viral suppression, individuals with persistent low-level viraemia <400 copies/ml and subjects failing ART (viral load >400 copies/mi). RESULTS: There was no significant difference in the percentage of CD8+CD38++ T-cells between patients with <50 copies or <3 copies/ml. Immune activation was significantly increased in patients with persistent low-level viraemia and in subjects failing ART. CD4+ T-cell counts in patients on long-term successful ART are inversely associated with CD8+ T-cell activation. CONCLUSIONS: T-cell activation in patients on long-term successful ART is not due to residual low-level viral replication in the blood compartment of HIV-1. CD8+ T-cell activation in this patient group appears to be associated with poor CD4+ T-cell recovery.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , ADP-Ribosil Ciclase 1/análise , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.
RESUMO
CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Adulto , Terapia Antirretroviral de Alta Atividade/normas , Monitoramento de Medicamentos , Farmacorresistência Viral , Feminino , HIV/efeitos dos fármacos , HIV/genética , Infecções por HIV/complicações , Infecções por HIV/imunologia , Hepatite B/complicações , Hepatite C/complicações , Humanos , Masculino , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Tuberculose/complicações , Carga ViralRESUMO
BACKGROUND: HIV-1 infection is characterized by increase in inhibitory receptors and loss of activating receptors on natural killer (NK) cells, resulting in loss of cell activity. Exceptionally, for an inhibitory receptor, the proportion of NK cells bearing CD94-NKG2A decreases during HIV-1 infection. It is not understood whether HIV-1 itself or other concomitant infections drive these changes. OBJECTIVES: To investigate the relationship between HIV-1 viraemia and changes in C-type lectin-like receptor expression in NK cells and to investigate the effect of highly active antiretroviral therapy (HAART) on these changes. METHODS: Three cohorts of patients were studied: (1) before, during and after treatment interruption in aviraemic and viraemic patients receiving HAART (n = 15); (2) HIV-1-positive treatment-naive individuals (n = 13); and (3) HIV-1-positive individuals receiving successful HAART for a minimum of 1 year without interruption (n = 11). Flow cytometry was used to study the expression of NKG2A before and after treatment interruption and to define expanded populations of NK cells in untreated and treated HIV-1-positive individuals. Assays were performed in vitro to assess the cytotoxicity of the expanded populations. RESULTS: Increases in plasma HIV-1 RNA during treatment interruption in aviraemic HAART-treated individuals did not influence the proportion of NK cells carrying the complex CD94-NKG2A. Loss of NKG2A NK cells corresponded to the dramatic expansion of a distinct population of cells expressing a functional activating CD94-NKG2C receptor with skewed expression of killer cell immunoglobulin-like receptor family and natural cytotoxicity receptors. CONCLUSION: Changes in the NK cell repertoire during HIV-1 infection were not a result of HIV-1 viraemia alone but resembled those associated with concomitant infections.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , HIV-1 , Células Matadoras Naturais/metabolismo , Lectinas Tipo C/metabolismo , Viremia/metabolismo , Anticorpos Antivirais/metabolismo , Estudos de Coortes , Citometria de Fluxo , Infecções por HIV/imunologia , Humanos , Lectinas Tipo C/antagonistas & inibidores , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Some patients with HIV/tuberculosis (TB) coinfection who are on anti-TB treatment and highly active antiretroviral therapy (HAART) will develop an exacerbation of symptoms, signs or radiological manifestations of TB that are not due to relapse or recurrence of their TB. The aetiology of these immune reconstitution inflammatory syndrome (IRIS) reactions is unknown but it is presumed that they occur, at least in part, as a consequence of HAART-related reconstitution of immunity. METHODS: Patients who were diagnosed with their first episode of definitive or presumed TB between January 2001 and July 2003 were identified from the Chelsea and Westminster TB/HIV database. The patients were classified into those who developed IRIS and those who did not using a set definition of the syndrome. Demographic, clinical and laboratory data relating to both HIV and TB were compared between the two groups. RESULTS: A total of 55 cases of TB were identified, of which 45 cases were confirmed on culture or gene probe and 10 were presumed cases. Fourteen cases (25.5%) developed IRIS with a median (range) duration of 2.53 (0.53-14.97) months. The median baseline CD4 [interquartile range (IQR)] for the IRIS group was significantly lower at 80 (33-117) cells/mm3 (P = 0.05) than the non-IRIS group at 139 (77-284) cells/mm3. A significantly greater proportion of patients in the IRIS group [11/14 (78.60%), P = 0.011] had baseline CD4 < 100cells/mm3 compared with the non-IRIS group [16/41 (39.0%)]. There was no significant difference between the two groups when comparing the log10 baseline viral load (VL). Eight (57.0%) patients in the IRIS group had disseminated TB at baseline compared with seven (17.0%) in the non-IRIS group (P = 0.006). In those who had a detectable VL at baseline, the median fold change (IQR) in CD4 from baseline to 3 months was significantly higher in the IRIS group patients, 1.5 (0.6-5.6), compared with 0.7 (-0.2 to 1.0) for those in the non-IRIS group (P = 0.046). CONCLUSIONS: Patients who develop IRIS are more likely to present with disseminated TB, have a CD4 count < 100 cells/mm3 and have a prompt rise in CD4 count in the initial 3 months of HAART.
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Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/imunologia , Tuberculose/imunologia , Adulto , Antituberculosos/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Imunidade/efeitos dos fármacos , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Síndrome , Fatores de Tempo , Tuberculose/complicações , Tuberculose/tratamento farmacológicoRESUMO
BACKGROUND: In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddl). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddl- and non-ddl-containing regimens in the presence or absence of the M184V mutation. METHODS: Data from an observational cohort study of all HIV-1 patients who had phenotypic resistance testing following the emergence of virological failure to an existing highly active antiretroviral therapy (HAART) regimen were analysed. A total of 586 patients entered the study and were followed-up over 48 weeks; 281 (48%) were switched to ddl-containing HAART, of whom 105 had the M184V mutation at baseline. Virological efficacy of combination therapy was studied by reference to average area under the curve of viral load (VL) response and the proportion of patients attaining an undetectable VL (<400 copies/ml). Baseline characteristics and univariate analysis of changes in VL were compared using the Wilcoxon rank sum test. Multivariate analyses were performed using the Van Elteren test. Additional variables included the number of baseline nucleoside reverse transcriptase inhibitor mutations and the number of active antiretroviral drugs given to each group as compared by 'real phenotype' resistance test results. RESULTS: Amongst patients on ddl-containing HAART, median fold changes in phenotypic susceptibility to ddl were greater in patients with the M184V mutation (fold changes of 2.2 vs 1.2, P<0.001). Nonetheless, the median change in VL and percentage of patients attaining an undetectable VL were similar in those taking ddl, irrespective of whether the M184V mutation was present at baseline. In the group of patients with the M184V mutation at baseline, the virological outcome was significantly better in those treated with ddl-containing HAART than in those on HAART without ddl (P<0.05). CONCLUSIONS: While the M184V did increase the fold resistance of HIV to ddl, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug.
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Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/genética , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Estudos de Coortes , Didanosina/farmacologia , Farmacorresistência Viral , Quimioterapia Combinada , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Mutação , Inibidores da Transcriptase Reversa/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVES: Many questionnaires on adherence to antiretroviral therapy are in use, but the validity of patients' responses has not been tested. The Medication Adherence Self-Report Inventory (MASRI) has been developed and tested for its validity against objective measures and treatment outcome. DESIGN: Prospective study comparing questionnaire responses with MEMS TrackCap (MC, a medication event monitoring system), pill count (PC) and plasma HIV viraemia in a publicly funded specialist HIV clinic. PARTICIPANTS: Patients self-medicating antiretroviral therapy who were not cognitively impaired and were able to read and understand English. RESULTS: Mean adherence by MC of the 78 subjects was 92.9% (SE, 1.8%) and by PC 96.8% (SE, 1.4%). Agreement between MC and responses to items about doses missed 1, 2 or 3 days ago was low (kappa = 0.23 (P < 0.03), 0.44 (P < 0.001) and 0.28 (P < 0.01) respectively). This improved when these responses were summated (kappa = 0.46;P < 0.001) and was similar to that for recall of non-adherence over the preceding 2 weeks (kappa = 0.54; P < 0.001). Mean self-reported adherence by visual analogue scale (VAS) over the preceding month was 93.3% (SE, 1.2%). This was strongly associated with both MC (r = 0.63; P < 0.001) and PC (r = 0.75; P < 0.001). On multivariate analysis, the strongest association between a MASRI item and MC was for the VAS. Both the 2 week recall and VAS items were inversely associated with viral load (P = 0.01). There was no association between dose timing (measured MC or questionnaire) or 3 day self-report and viral load. CONCLUSIONS: The MASRI provides a means of measuring patient adherence that is valid when compared with objective measures.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/psicologia , Inibidores da Protease de HIV/uso terapêutico , Cooperação do Paciente/estatística & dados numéricos , Inibidores da Transcriptase Reversa/uso terapêutico , Autoadministração/estatística & dados numéricos , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Relação Dose-Resposta a Droga , Esquema de Medicação , Processamento Eletrônico de Dados , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , Humanos , Modelos Lineares , Masculino , Cooperação do Paciente/psicologia , Estudos Prospectivos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/farmacologia , Autoadministração/psicologia , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Carga Viral , ViremiaRESUMO
OBJECTIVE: To measure the effects of combined chemotherapy and highly active antiretroviral therapy (HAART) on immune cell counts and plasma HIV-1 RNA loads in patients with AIDS-related lymphoma (ARL) to determine the implications for opportunistic infection prophylaxis and medium-term immune function. DESIGN AND METHODS: Peripheral blood total lymphocyte count, CD4 T-cell count, CD8 T-cell count, CD19 B-cell count, CD16/CD56 natural killer cell count and plasma HIV-1 RNA load were prospectively measured at ARL diagnosis, at 1 and 3 months during and 1, 3 and 6 months after chemotherapy in twenty patients receiving HAART. RESULTS: Significant declines in T-helper cell (CD4) count, natural killer cell (CD16/CD56) and B lymphocyte count (CD19 cells) occurred during the first 3 months of chemotherapy. There was no significant alteration in the T-cytotoxic cell (CD8) count, CD4 percentage or HIV-1 RNA load during the study period. The T-helper cell and natural killer cell counts recovered to pre-treatment levels within 1 month of finishing chemotherapy. The recovery of B-cells was slower with pre-treatment levels only being achieved after 3 months. The recovery of CD4 T-cell count following completion of chemotherapy was more rapid than described for ARL patients who were not receiving concomitant HAART. CONCLUSIONS: By combining chemotherapy with HAART, immune function is better maintained in the medium term. The CD4 T-cell count falls by 50% during chemotherapy and this will help to identify patients who require opportunistic infection prophylaxis during chemotherapy.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/imunologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/imunologia , Linfoma Relacionado a AIDS/imunologia , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade , Linfócitos B/citologia , Biomarcadores , Contagem de Linfócito CD4 , Antígeno CD56 , Linfócitos T CD8-Positivos/citologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Células Matadoras Naturais/citologia , Contagem de Linfócitos , Linfoma Relacionado a AIDS/complicações , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de IgG , Carga ViralRESUMO
The combination of intermittent subcutaneous IL-2 and highly active antiretroviral therapy in individuals infected with HIV-1 has been shown to have a beneficial quantitative effect on the CD4 T cell count. We observed IL-2-associated viral load 'blips' inducing HIV-1-specific lymphoproliferative responses at 24 weeks in such individuals. This immunotherapeutic approach, utilizing autologous virus as autovaccination, may be a viable, safer alternative to structured treatment interruption and potentially more efficacious than therapeutic vaccines.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , HIV-1 , Imunoterapia Ativa/métodos , Interleucina-2/uso terapêutico , Contagem de Linfócito CD4 , Infecções por HIV/imunologia , Humanos , Interleucina-2/imunologia , Carga ViralRESUMO
OBJECTIVE: To evaluate the prevalence, outcome and possible risk factors for hyperlactataemia and lactic acidosis in HIV-positive persons receiving antiretroviral therapy. METHODS: Cross-sectional and longitudinal data from a prospectively collected clinical database. Associations with antiretroviral regimen, clinical and laboratory parameters were assessed using univariate and multivariate Cox's proportional hazards model. RESULTS: Patients naive to therapy and patients on current therapy for a minimum of 4 months were assessed. Median lactate was 1.1 mol/l in 253 untreated individuals and 1.4 mmol/l in 1239 patients stable on therapy for at least 4 months. At least two on-therapy samples were available for 750 of the 1239 individuals, taken a median 92 days apart. Lactate measurement showed a low positive predictive value of 38.9% but a high negative predictive value (98%) for normal values. Lactate was elevated > or = 2.4 mmol/l in 102 individuals on at least one occasion. In the multivariate Cox's proportional hazards model, no demographic characteristics were associated with hyperlactataemia. Didanosine-containing regimens doubled the relative hazard of hyperlactataemia compared with those sparing didanosine. Abacavir-containing regimens reduced the hazard of hyperlactataemia. Choice of thymidine analogue did not influence risk. Hyperlactataemia was associated with acid-base disturbance. Use of didanosine and female sex were over-represented amongst nine patients with severe hyperlactataemia (> 5 mmol/l) or lactic acidosis. CONCLUSIONS: Screening of lactate is of limited use in asymptomatic individuals on antiretroviral therapy. Raised lactate represents part of a spectrum of lactate and acid-base disturbance that infrequently includes lactic acidosis. Didanosine appears associated with an increased risk of hyperlactataemia.
Assuntos
Acidose Láctica/induzido quimicamente , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Ácido Láctico/sangue , Acidose Láctica/sangue , Acidose Láctica/economia , Adulto , Estudos Transversais , Didanosina/efeitos adversos , Didesoxinucleosídeos/uso terapêutico , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Humanos , Estudos Longitudinais , Masculino , Análise Multivariada , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Fatores Sexuais , Timidina/análogos & derivados , Timidina/uso terapêuticoRESUMO
OBJECTIVE: To determine the pharmacokinetics of saquinavir hard-gel capsules/ritonavir/atazanavir co-administered once daily at 1600/100/300 mg in HIV-infected individuals. METHODS: Eighteen patients receiving saquinavir/ritonavir switched to 1600/100 mg once daily a minimum of 3 days before the study. On study day 1, levels of saquinavir and ritonavir were determined over 24 h. Atazanavir (300 mg once daily) was then added to the regimen. On day 11, a pharmacokinetic analysis was performed. Atazanavir was discontinued on day 32. Drug concentrations were measured by high-pressure liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir and ritonavir pharmacokinetic parameters, with and without atazanavir. A safety analysis was performed at screening, days 1, 11, 32 and follow-up. RESULTS: After the addition of atazanavir, statistically significant increases in saquinavir trough plasma concentration (Ctrough GMR, 95% CI 2.12, 1.72-3.50), maximum plasma concentration (Cmax 1.42, 1.24-1.94), area under the plasma concentration-time curve from 0-24 h (AUC0-24 1.60, 1.35-2.43) and ritonavir Cmax (1.58, 1.32-2.08), AUC0-24 (1.41, 1.22-1.74) were observed. The pharmacokinetics of atazanavir compared with those obtained in patients receiving atazanavir/ritonavir without saquinavir. Four patients developed scleral icterus and two jaundice. Total and unconjugated bilirubin increased approximately fivefold during atazanavir therapy. CONCLUSION: The addition of atazanavir to saquinavir/ritonavir increased saquinavir Ctrough, Cmax and AUC0-24 by 112, 42 and 60%. Ritonavir Cmax and AUCo-24 increased by 34 and 41%. The regimen was well tolerated, with no significant change in laboratory parameters, except for the occurrence of hyperbilirubinemia.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Oligopeptídeos/uso terapêutico , Piridinas/uso terapêutico , Ritonavir/uso terapêutico , Saquinavir/uso terapêutico , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Sulfato de Atazanavir , Esquema de Medicação , Monitoramento de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Géis , Infecções por HIV/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ritonavir/farmacocinética , Saquinavir/farmacocinéticaRESUMO
BACKGROUND: Guidelines recommend both protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens for initial therapy in HIV-positive individuals whilst clinical trial data comparing treatment options remain limited. OBJECTIVE: To assess whether drug selection (PI versus NNRTI) in antiretroviral-naive patients is related to virological response at 6 months within a clinical cohort. DESIGN: Databases from two large clinics were used to identify all treatment-naive patients initiating highly active antiretroviral therapy (PI/ two PI or NNRTI). Statistical models determined the likelihood of suppressing HIV viral load < 500 copies/ml, the risk of treatment failure by 6 months, and factors associated with treatment success. RESULTS: Of 1109 potentially eligible patients 888 met study criteria and were included; 484 were prescribed a PI (40% indinavir, 41% nelfinavir) and 404 were prescribed NNRTI (40% efavirenz, 60% nevirapine). Three treatment arms were compared: efavirenz versus nevirapine versus PI. After stratification by year and centre and adjustment for baseline variables, only treatment group and baseline viral load remained significantly associated with virological suppression at 6 months. Patients on efavirenz were significantly more likely to achieve an undetectable viral load than those on PI or nevirapine. The relative hazard for nevirapine was 0.77 (95% confidence interval, 0.61-0.96, P = 0.02) and that for PI was 0.74 (95% confidence interval, 0.58-0.94, P = 0.01). Efavirenz also performed better in the analysis of treatment failure at 6 months. CONCLUSION: Although observational cohort data may be susceptible to significant bias, this study suggests a better initial virological response for efavirenz compared to either nevirapine or the PI. Clinical trial data is required to confirm these findings.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral , Adulto , Idoso , Alcinos , Benzoxazinas , Estudos de Coortes , Ciclopropanos , Esquema de Medicação , Feminino , HIV-1/fisiologia , Humanos , Indinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nelfinavir/uso terapêutico , Nevirapina/uso terapêutico , Oxazinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , RNA Viral/sangue , Resultado do TratamentoRESUMO
OBJECTIVES: To determine the prevalence and prognostic significance of intermittent viraemia (IV) in patients who attained an undetectable viral load (VL) < 400 copies/ml within 6 months on highly active antiretroviral therapy (HAART). METHODS: Retrospective analysis of viral load rebound > or = 400 copies/ml and CD4 cell counts rise for 765 patients followed for > or = 12 months following initial VL undetectability, comparing the 226 (29.5%) who maintained an undetectable VL for > 1 year from initiation of HAART and 122 (15.9%) who had one or more episodes of IV. Genotypic resistance was evaluated at the time of the first episode of IV > or = 2000 copies/ml. RESULTS: Patients with IV had a threefold higher rate of sustained virological rebound [hazards ratio (HR), 3.15; 95% confidence interval (CI), 1.72-5.77; P < 0.001). For patients with and without IV, the Kaplan-Meier estimates at 24 and 36 months after initiation of HAART were 19.3% (95% CI, 8.9-21.5) versus 7.7% (95% CI, 4.5-13.0) and 31.6% (95% CI, 21.8-44.2) versus 12.9% (95% CI, 7.5-21.5), respectively (P < 0.001). The median CD4 cell count rise at 18 and 24 months was significantly lower in those with IV than in those without: 138 [interquartile range (IQR), 58-221] versus 224 x 10(6) cells/l (IQR, 119-357) (P = 0.0001) and 200 (IQR, 89-294) versus 260 x 10(6) cells/l (IQR, 125-384) (P = 0.003), respectively. In a subgroup of 16 patients, genotypic resistance mutations were found in the reverse transcriptase gene for five (31%) and in the protease gene in one. A probable contributing factor/event was identified for most patients with IV, such as poor adherence (42.6%), intercurrent infection (26.2%) or drug interaction (6.8%). CONCLUSIONS: Patients with IV > 400 copies/ml are three times more likely to experience sustained viral rebound and to have an impaired CD4 cell rise relative to those who maintain undetectable VL. This supports the adoption of a more pro-active approach to treatment intensification and the need for caution with structured treatment interruptions.