RESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1-5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. METHODS: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. RESULTS: The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. CONCLUSION: Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.
Assuntos
Antineoplásicos Imunológicos , Melanoma , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Soroepidemiológicos , Qualidade de Vida , Antineoplásicos Imunológicos/uso terapêutico , Austrália/epidemiologia , Melanoma/tratamento farmacológico , Estudos RetrospectivosRESUMO
A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient-year, P < 0·0001); the rate of all infections was 4·38/patient-year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3-4·1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.
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Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Feminino , Seguimentos , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/farmacocinética , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVES: PEPDar compared the tolerability and safety of ritonavir-boosted darunavir (DRV/r)-based post-exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The primary endpoint was the early discontinuation rate among the per-protocol population. METHODS: PEPDar was an open-label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty-two private or university HIV clinics in Germany participated. Subjects were ≥ 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative. RESULTS: A total of 324 subjects were screened, the per-protocol population was 305, and 273 subjects completed the study. One hundred and fifty-five subjects received DRV/r-based PEP and 150 subjects received ritonavir-boosted lopinavir (LPV/r)-based PEP for 28-30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow-up. CONCLUSIONS: Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.
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Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Darunavir/administração & dosagem , Darunavir/efeitos adversos , Profilaxia Pós-Exposição/métodos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Adulto , Feminino , Alemanha , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento , Suspensão de TratamentoRESUMO
Numerous virus-specific, class I-restricted cytotoxic T lymphocyte (CTL) epitopes have been identified, yet little information is available regarding the specificity of the CTL response in persons of the same human histocompatibility leukocyte antigen (HLA) type. In this study, the human immunodeficiency virus (HIV) 1 envelope-specific CTL response was evaluated in five HLA-B14-positive persons. CTL responses specific for a previously described nine-amino acid epitope in gp41 (aa 584-592, ERYLKDQQL) could be identified in all subjects, and CTL clones specific for this epitope could be isolated from four persons. Despite heterogeneous T cell receptor usage, the fine specificity of the clones was similar, as defined by recognition of alanine-substituted peptides as well as peptides representing natural HIV-1 sequence variants. Correlation with in vivo virus sequences revealed that the dominant species in two of the subjects represented poorly recognized variants, with a K-->Q substitution at amino acid 588, whereas no variants were observed in the other two subjects. Although clonal type-specific responses to these dominant variants could be identified, the magnitude of these responses remained small, and the dominant CTL response was directed at the minor in vivo variant. These studies indicate that despite similar epitope-specific immunologic pressure in persons of the same HLA type, the in vivo quasispecies may differ, and that the major in vivo immune response to a given CTL epitope can be directed at a minor variant.
Assuntos
Proteína gp41 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-B/imunologia , Fragmentos de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos , Antígenos Virais/genética , Antígenos Virais/imunologia , Sequência de Bases , Células Clonais , Variação Genética , Proteína gp41 do Envelope de HIV/genética , HIV-1/genética , Antígeno HLA-B14 , Teste de Histocompatibilidade , Humanos , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Masculino , Dados de Sequência Molecular , Fragmentos de Peptídeos/genética , Análise de Sequência de DNA , Homologia de Sequência , Especificidade da Espécie , Linfócitos T Citotóxicos/citologiaRESUMO
This manuscript is communicated by the German AIDS Society (DAIG) (www.daignet.de). It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V.).
Assuntos
Infecções por HIV/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/virologia , Alemanha , HumanosRESUMO
OBJECTIVE: As its central basis for research, the Competence Network for HIV/AIDS (KompNet) established a nationwide cohort study on HIV-positive patients being in medical care in Germany. In this paper, we describe the epidemiological composition, and clinical as well as treatment characteristics of the KompNet cohort over time. METHODS: The KompNet cohort is an open, retrospective and prospective, multi-center, disease-specific and nationwide cohort study that started gathering data in June 2004. Semiannually, follow up visits of the patients are documented, covering a wide range of clinical and sociodemographic data. At enrollment and three years afterwards, an EDTA-sample is taken; a serum-sample is taken at every follow up. RESULTS: As of 20.10.2008, a total of 15,541 patients were enrolled by 44 documenting sites. In September 2007, the cohort size was reduced to ten outpatient clinics and fifteen private practitioners, covering a total of 9,410 patients. The documentation of these patients comprised 24,117 years of follow up-time since enrollment (mean: 2.6 years), 62,862 person years inclusive data documented retrospectively on course of HIV-infection and antiretroviral therapy (ART, mean: 6.7 years). Due to the short period of recruitment till now, rates of death (0.3%-0.8%) and losses to follow up (1.1%-5.5%) were low. 84.9% of patients were men. Main risk of transmission was sex between men (MSM: 62.9%). Mean age was 45 years. About two third of patients were classified as CDC-stage B or C. Therapy regimens of currently treated patients complied with recent guidelines. Trends of mean CD4 cell count/microl regarding the initial therapy and concerning the population under treatment reflected the developments and the changing standards of antiretroviral therapy over time. CONCLUSION: The KompNet cohort covers about a quarter of all patients estimated as being under treatment in Germany. Its composition can be accounted approximately representative for the situation of clinical care and treatment in the scope of HIV/AIDS in Germany. Therefore, it is an important instrument for measuring the course of HIV/AIDS, the reality of use of antiretroviral therapy and its clinical and psychosocial outcomes in Germany.
Assuntos
Infecções por HIV/epidemiologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Seguimentos , Alemanha/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos RetrospectivosRESUMO
This case study describes a 44-year-old, chronically non-adherent, HIV-infected male with relapsing, life threatening toxoplasmic encephalitis (TE) and other recurring opportunistic infections. Non-adherence resulted in critical illness, suppressed CD4 lymphocyte count and elevated viral load. In order to bypass the patient's complete psychological aversion to taking medication, and after exhausting various psychological interventions, a percutaneous endoscopic gastronomy (PEG) tube was inserted for delivery of indispensable medication. During the 15-month follow-up the patient was adherent, exhibiting a consistently undetectable viral load, high CD4 count and a remission of the opportunistic infections. This is an interesting case study demonstrating life-saving and long-term benefit of PEG in an exceptional setting, which has implications for future research and treatment of non-adherent HIV-infected patients.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Gastrostomia/instrumentação , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Recusa do Paciente ao Tratamento/psicologia , Administração Cutânea , Adulto , Contagem de Linfócito CD4 , Estado Terminal , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Masculino , Toxoplasmose Cerebral/tratamento farmacológico , Resultado do Tratamento , Carga ViralRESUMO
To investigate Candida epidemiology and immunologic correlates of protection in HIV-1 infected patients, we analyzed oral Candida colonization in correlation to the Candida-specific T-cell response measured by g-IFN ELISPOT using different Candida (C.) albicans strains. In 16/46 patients (13 asymptomatic, 3 with oral thrush), but in 0/28 controls, Candida (13 C. albicans, 1 C. lusitaniae, 1 C. krusei, 1 C. parapsilosis) was isolated. Candida specific T-cells were detected more frequently in controls (20/28) than in HIV-1+ subjects (16/46, p= 0.03). We observed a significant association of higher CD4 cell numbers with both detection of Candida specific T-cells and lack of oral Candida colonization, but there was no significant correlation of oral Candida colonization to the detection of Candida specific T-cells, viral load or antiretroviral therapy. Thus, local mucosal immunity seems to be more important in the pathogenesis of Candida colonization than circulating Candida specific T-cells. The pathogenic C. albicans strain K24122 was less frequently recognized by patients (6/46) than the laboratory adapted strain SC5314 (14/46, p= 0.03), whereas a similar recognition of both strains was observed in healthy controls. This indicates an impaired Candida-specific T-cell repertoire in HIV+ patients that could increase the risk of immune evasion by C. albicans.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Linfócitos T CD4-Positivos/imunologia , Candida albicans/fisiologia , Candidíase Bucal/microbiologia , Orofaringe/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Contagem de Linfócito CD4 , Candidíase Bucal/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunidade nas Mucosas , Interferon gama/metabolismo , Masculino , Carga ViralAssuntos
Antibacterianos/uso terapêutico , Doenças do Sistema Nervoso/etiologia , Uveíte/tratamento farmacológico , Uveíte/etiologia , Baixa Visão/etiologia , Doença de Whipple/complicações , Doença de Whipple/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/diagnóstico , Resultado do Tratamento , Baixa Visão/diagnóstico , Redução de Peso , Doença de Whipple/tratamento farmacológicoRESUMO
BACKGROUND: Studies in HIV-1 infected long-term non-progressors could demonstrate a strong HIV-1-specific CTL response, but it is difficult to prove that this strong CTL response actually is the cause of the efficient control of HIV-1 and not the consequence of low HIV-1 replication in these patients. OBJECTIVE: Studies of HIV-1-specific immunity and viral replication in patients undergoing immunosuppressive therapy provide important opportunities to understand the role of HIV-1-specific T-cells. RESULTS: In this report we describe an HLA B27 positive patient with normal CD4 counts and a low viral load of 200 copies/ml without antiretroviral therapy who exhibited a very strong HIV-1-specific CTL response. He had to be treated with steroids, NSAIDS and hydroxchloroquine because of a severe inflammatory reactive arthritis triggered by an acute Chlamydia trachomatis infection. Analysis of HIV-1 specific T-cells by gamma-IFN-ELISPOT revealed a high frequency of HIV-1 gag-specific CTL both in blood and synovial fluid, whereas gag-specific CD4-cells could be detected only in the peripheral blood. Further analysis revealed that the gag-specific T-cells were predominantly targeting the HLA B27-restricted CTL epitope KRWIILGLNK (KK10). Immunosuppressive therapy by prednisone was associated with a moderate increase of HIV-1 viremia and a decrease both in the number and in the gamma-IFN production of KK10-specific CTL indicating that inhibition of CTL function contributed to the increase of viral load. CONCLUSIONS: This study is suggesting that HIV-1 specific CTL play an important role in the control of HIV-1, at least in this patient. Inhibition of CTL function by immunosuppressive therapy with prednisone may enhance viral replication. In addition, we could demonstrate for the first time the migration of HIV-1 specific T-cells into the synovial fluid.
Assuntos
Artrite Reativa/complicações , Infecções por Chlamydia/complicações , Infecções por HIV/complicações , Imunossupressores/efeitos adversos , Linfócitos T Citotóxicos/imunologia , Adulto , Artrite Reativa/tratamento farmacológico , Infecções por Chlamydia/tratamento farmacológico , Chlamydia trachomatis , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Masculino , Carga ViralRESUMO
A 39 year old patient with HIV-1 infection, who was asymptomatic without antiretroviral therapy (HAART) for ten years, developed severe encephalopathy. Despite therapy with a four drug antiretroviral combination regimen including two protease-inhibitors (PI), plasma viral load could not be suppressed sufficiently with persistence of low level viremia of 3.08-3.40 log copies/ml, even after addition of two other antiretroviral drugs. On therapy the patient showed improvement of clinical symptoms, however with severe persisting cognitive deficits. Repeated parallel measurements of viral load showed a far higher viremia in the cerebrospinal fluid than in the plasma. Resistance testing provided no evidence of relevant PI-mutations and analysis of protease inhibitor levels demonstrated good plasma levels. 17 months after start of HAART, the patient developed a cerebral Non-Hodgkin lymphoma, leading to his death despite radiation therapy. There has been a dramatic reduction in the prevalence of HIV-1 associated CNS events in the post-HAART era. Nevertheless, subgroups of patients are infected with neurotropic viral variants which could cause progressive neurological pathology as they can not be reached sufficiently by the available drugs. These patients require the development of new drugs that achieve a better penetration into the brain.
Assuntos
Complexo AIDS Demência/complicações , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Neoplasias Encefálicas/etiologia , Linfoma Relacionado a AIDS/etiologia , Linfoma não Hodgkin/etiologia , Complexo AIDS Demência/tratamento farmacológico , Adulto , Encéfalo/patologia , Encéfalo/virologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Evolução Fatal , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Linfoma Relacionado a AIDS/patologia , Linfoma Relacionado a AIDS/radioterapia , Linfoma não Hodgkin/radioterapia , Imageamento por Ressonância Magnética , Masculino , Replicação Viral/efeitos dos fármacos , Replicação Viral/fisiologiaRESUMO
OBJECTIVE: The reverse transcriptase (RT) M184V mutation within the HLA-A2-restricted HIV-1 cytotoxic T lymphocyte (CTL) epitope VL9 (VIYQYMDDL; RT 179-187) not only induces drug escape against lamivudine but also abolished recognition by a CTL clone derived from a long-term non-progressor. To test whether the variant VL9 epitope containing the M184V mutation represents a new CTL epitope, we studied recognition of this epitope in a cohort of HLA-A2-positive HIV-1-infected patients. METHODS: Peripheral blood mononuclear cells isolated from 28 HIV-1-infected patients were stimulated with the peptide VIYQYVDDL, containing the M1 84V mutation. Outgrowing cell lines were tested for specific recognition in a standard chromium-release assay. RESULTS: In one subject, a CTL line could be isolated recognizing the peptide VIYQYVDDL in conjunction with HLA-A2. The CTL clone also recognized the M1841 mutation, but it failed to recognize the wild-type epitope VIYQYMDDL. CONCLUSION: CTL can specifically recognize lamivudine-resistant HIV-1 variants. Therefore, the cellular immune response could have an important influence on the control of drug-resistant virus. Furthermore, this demonstrates that the immune system can generate new CTL specificities even in patients with advanced disease, as the M184V HIV variants emerges only after drug treatment. Specific immunotherapy against this epitope might be helpful in delaying or preventing lamivudine resistance.
Assuntos
HIV-1/efeitos dos fármacos , HIV-1/imunologia , Lamivudina/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Linfócitos T Citotóxicos/imunologia , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Linhagem Celular , Citotoxicidade Imunológica , Resistência Microbiana a Medicamentos , Quimioterapia Combinada , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , Transcriptase Reversa do HIV/genética , HIV-1/genética , Antígeno HLA-A2/imunologia , Humanos , Ativação Linfocitária , Masculino , Mutação , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
BACKGROUND: Resistance against protease inhibitors (PI) can either be analysed genotypically or phenotypically. However, the interpretation of genotypic data is difficult, particularly for PI, because of the unknown contributions of several mutations to resistance and cross-resistance. OBJECTIVE: Development of an algorithm to predict PI phenotype from genotypic data. METHODS: Recombinant viruses containing patient-derived protease genes were analysed for sensitivity to indinavir, saquinavir, ritonavir and nelfinavir. Drug resistance-associated mutations were determined by direct sequencing. geno- and phenotypic data were compared for 119 samples from 97 HIV-1 infected patients. RESULTS: Samples with one or two mutations in the gene for the protease were phenotypically sensitive in 74.3%, whereas 83.6% of samples with five or more mutations were resistant against all PI tested. Some mutations (361, 63P, 71V/T, 771) were frequent both in sensitive and resistant samples, whereas others (241, 30N, 461/L, 48V, 54V, 82A/F/T/S, 84V, 90M) were predominantly present in resistant samples. Therefore, the presence or absence of a single drug resistance-associated mutation predicted phenotypic PI resistance with high sensitivity (96.5-100%) but low specificity (13.3-57.4%). A more specific algorithm was obtained by taking into account the total number of drug resistance-associated mutations in the gene for the protease and restricting these to certain key positions for the PI. The algorithm was subsequently validated by analysis of 72 independent samples. CONCLUSION: With an optimized algorithm, phenotypic PI resistance can be predicted by viral genotype with good sensitivity (89.1-93.0%) and specificity (82.6-93.3%). The reliability and relevance of this algorithm should be further evaluated in clinical practice.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Algoritmos , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/virologia , Bases de Dados Factuais , Resistência Microbiana a Medicamentos/genética , Genótipo , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , Dados de Sequência Molecular , Fenótipo , Mutação Puntual , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To compare antiretroviral efficacy, safety and tolerance of three dosing regimens of the novel nucleoside reverse transcriptase inhibitor, abacavir (1592U89) over 24 weeks and its efficacy in open-label combination with zidovudine and lamivudine. DESIGN: Sixty HIV-1-infected antiretroviral therapy naive subjects (entry criteria; CD4+ cell count > or = 100 cells/mm(3), plasma HIV-1 RNA > or = 30 000 copies/ml), randomized into 20 subjects per cohort received 100, 300 or 600 mg abacavir twice daily. Subjects successfully completing 24 weeks' randomized therapy could switch to open label therapy (abacavir, zidovudine, lamivudine at 300, 300 and 150 mg twice daily, respectively) for a further 24 weeks of studly, as could subjects meeting one or more switch criteria. METHODS: Subjects were assessed for antiretroviral activity by measuring changes in plasma HIV-1 RNA load and CD4+ cell counts. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: At week 4, subjects receiving 300 or 600 mg abacavir twice daily had greater reductions in plasma HIV-1 RNA (median changes -1.55 and -1.61 log10) copies/ml, respectively); differences (P = 0.007 and P < or = 0.001, respectively) than subjects receiving 100 mg abacavir twice daily (median change, -0.63 log10 copies/ml). Differences between the 300 and 600 mg twice daily groups were not clinically or statistically significant. At 24 weeks, analysis showed a median change in plasma HIV-1 RNA of -0.70 and -1.30 log10 copies/ml in the 300 and 600 mg twice daily groups, respectively. During the open label phase in which zidovudine/lamivudine was added to 300 mg abacavir twice daily, a further median reduction in plasma HIV-1 RNA of 1.74 log10 copies/ml was seen. At 48 weeks pooled data from all abacavir-treated subjects showed a sustained reduction in plasma HIV-1 RNA of 2.8 log10) copies/ml; 65% and 43% of subjects had < or = 400 and < or = 50 HIV-1 RNA copies/ml, respectively, and a further median increase of 111 CD4+ cells/mm3 were seen. Abacavir was generally well tolerated with few clinically significant adverse events. Two subjects (3.3%) developed hypersensitivity reactions to abacavir. There were no differences between the groups with regard to serious adverse events. CONCLUSIONS: In terms of antiretroviral therapy naive subjects, treatment with 300 or 600 mg abacavir twice daily was statistically superior to a 100 mg twice daily dose at 4 weeks. Combinations therapy containing abacavir-zidovudine-lamivudine was a highly effective antiretroviral regimen, resulting in substantial reductions in plasma HIV-1 RNA which may be comparable to combinations containing protease inhibitors. Abacavir was generally tolerated.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Didesoxinucleosídeos/administração & dosagem , HIV-1 , Lamivudina/administração & dosagem , Zidovudina/administração & dosagem , Síndrome da Imunodeficiência Adquirida/sangue , Fármacos Anti-HIV/efeitos adversos , Estudos de Coortes , Didesoxinucleosídeos/efeitos adversos , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , RNA Viral/sangue , Fatores de Tempo , Carga ViralRESUMO
OBJECTIVE: To study the prevalence of multiple dideoxynucleoside (ddN)-resistant (MddNR) HIV-1 in European patients under treatment with multiple ddN analogues, and to characterize MddNR strains genotypically and phenotypically. DESIGN AND METHODS: Blood samples from patients after > or = 6 months of treatment with multiple ddN were screened for the MddNR mutation Q151M. After confirmation of MddNR in 15 patients from five European countries, genotypic resistance was evaluated by DNA sequencing of the reverse transcriptase (RT) gene. Phenotypic resistance was measured by the recombinant virus assay. Results were compared with the clinical evolution of the patients. RESULTS: The prevalence of MddNR strains in European patients treated with multiple ddN analogues was 3.5%. Viruses typically contained amino acid substitutions V75F, F77L, F116Y and Q151M in the RT gene. A new mutation, S68G, was frequently associated with MddNR. Phenotypically, viruses displayed high-level resistance to zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), stavudine (d4T) and partial resistance to lamivudine (3TC) once multiple mutations were present. Under in-vivo treatment pressure, some MddNR strains additionally developed resistance to protease inhibitors or non-nucleoside RT inhibitors (NNRTI). Clinically, most patients had advanced HIV disease with low CD4 cell counts, high viral loads and a rapid progression, but two patients harbouring MddNR virus responded well to dual protease inhibitor associations. CONCLUSIONS: MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.
Assuntos
Fármacos Anti-HIV/farmacologia , Didesoxinucleosídeos/farmacologia , Resistência a Múltiplos Medicamentos/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Sequência de Aminoácidos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/uso terapêutico , Quimioterapia Combinada , Europa (Continente) , Infecções por HIV/tratamento farmacológico , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Dados de Sequência Molecular , Fenótipo , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
Since the introduction of PRimed IN Situ labeling (PRINS) as a rapid and extremely sensitive alternative method to conventional fluorescence in situ hybridization (FISH), its application in clinical cytogenetics has been limited to the detection of highly repeated sequences, such as centromeric and telomeric regions. In the original PRINS method, unlabeled oligonucleotide probes are annealed to their repeated complementary target sequences in fixed human metaphase chromosomes on a slide. The probes serve as primers for subsequent in situ chain elongation with Taq DNA polymerase and labeled nucleotides. In contrast to conventional PCR, cyclic in situ amplification of the chromosomal target DNA with paired primers remained both difficult and strictly limited to highly repeated sequences, since the maintenance of constant reaction conditions on the slide during temperature and pressure shifts presents a major problem. We developed a new system for in situ PCR that allows the amplification of target sequences analogous to PCR in the test tube. We applied this method successfully for the detection of highly repeated sequences, for the detection of low copy repeats, and in one case, for the detection of a single-copy DNA sequence. The significance of this development for further in situ PCR applications will be discussed.
Assuntos
Cromossomos Humanos/genética , Metáfase/genética , Marcação in Situ com Primers/métodos , Apolipoproteínas A/genética , Primers do DNA , Distrofina/genética , Feminino , Dosagem de Genes , Humanos , Masculino , Distrofias Musculares/genética , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido Nucleico/genéticaRESUMO
CD8-positive cytotoxic T cells (CTLs) are activated by recognition of peptide bound to MHC class I molecules on target cells. This human leukocyte antigen-restricted process induces not only lysis of target cells but also secretion of lymphokines by the CTLs, including TNF-alpha, TNF-beta, and IFN-gamma. In this study we show that activation of HIV-1-specific CTL clones by their cognate peptide epitopes induces HIV-1 replication in the chronically HIV-1-infected T-cell line ACH-2. The HIV-1-inducing activity correlates with increased levels of TNF-alpha produced by these CTLs, and can be inhibited by anti-TNF-alpha antibodies, indicating that the effect is mediated by this cytokine. These studies suggest that activation of CTL in vivo could lead to enhanced viral replication. Although HIV-1-specific CTLs may serve as a host defense to inhibit virus replication, the induction of TNF-alpha production by these cells may facilitate viral replication in infected bystander cells, contributing to viral persistence and disease pathogenesis.
Assuntos
HIV-1/fisiologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T/microbiologia , Replicação Viral , Linhagem Celular , Células Clonais , Humanos , Ativação Linfocitária , Linfócitos T Citotóxicos/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
In order to analyse whether drug sensitivity testing would be beneficial for clinical decision-making in heavily pretreated patients, we retrospectively studied viral genotype and phenotypic drug resistance in 12 HIV-1-infected patients, each of them with a history of failing at least one therapeutic regimen including one or two protease inhibitors (PIs). The salvage therapy included nelfinavir as new PI in all cases. Four patients showed a sustained and five patients a transient viral load decrease. Three patients failed to show a significant decline of plasma HIV-1 RNA. In the baseline samples of these cases, resistance against all components of their combination therapy could be detected, whereas at least one antiretroviral drug was still active in the cases with transient treatment response. All patients with sustained therapy response harboured viruses that were either fully sensitive or resistant to only one of the drugs administered. In our study, phenotypic drug resistance was predictive for the success of antiretroviral salvage regimens.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Nelfinavir/uso terapêutico , Terapia de Salvação , Sequência de Aminoácidos , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Resistência Microbiana a Medicamentos/genética , Genótipo , Infecções por HIV/virologia , Protease de HIV/genética , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/farmacologia , HIV-1/genética , Humanos , Dados de Sequência Molecular , Nelfinavir/farmacocinética , Nelfinavir/farmacologia , Fenótipo , RNA Viral/sangue , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Carga ViralRESUMO
The introduction of potent combinations of antiviral drugs is a major breakthrough in the treatment of HIV. We investigated the long-term virologic outcome and the development of resistance after initiating highly active antiretroviral therapy (HAART) in drug-naive patients in daily clinical practice. Twenty-five treatment-naive HIV-1 patients were started on HAART. Fifteen patients responded with a drop in viral load below the limit of detection during 35.5 (interquartile range: 7) months of therapy. In 6 of 10 patients with virologic failure, virus with resistance-related mutations against the received drugs emerged. Compared with responders (R), nonresponding (NR) patients were in a later disease stage at therapy start (p = 0.0089) with lower CD4 cell counts at baseline (p = 0.040), and a lower proportion of nonresponders showed protease inhibitor (PI) levels above C(min) (p = 0.049). More NR patients showed secondary PI mutations at baseline (p = 0.079), and the CCR2-64I coreceptor polymorphism was absent among NR patients, compared with 38.5% of R patients displaying CCR2-64I (p = 0.053), although the differences were not significant. In conclusion, starting HAART in antiretroviral drug-naive HIV-infected patients followed in daily clinical practice prevented viral breakthrough for up to 44 months in 60% of the patients. Virologic failure was associated with the development of resistance-related mutations, a later stage of disease at start of therapy and lower PI drug levels.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , HIV-1 , Síndrome da Imunodeficiência Adquirida/genética , Síndrome da Imunodeficiência Adquirida/imunologia , Contagem de Linfócito CD4 , Feminino , Genótipo , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , Humanos , Masculino , Mutação , Polimorfismo Genético , Receptores CCR2 , Receptores CCR5/genética , Receptores de Quimiocinas/genética , Fatores de TempoRESUMO
Some individuals in well-defined cohorts have now been infected with HIV-1 for well over a decade and yet remain clinically asymptomatic with normal CD4 counts. To determine immunologic and virologic parameters in these individuals, we examined 10 persons from the San Francisco City Clinic with firmly documented infection of 11-15 years duration who had maintained stable CD4 counts above 500 cells/microliters. Our results indicate that long-term nonprogressors are a heterogeneous group with respect to viral load and HIV-1-specific immune responses, and that progression can occur even after 15 years of stable infection. However, in a subset of persons with the lowest viral loads and persistent nonprogressive infection, we detected strong CTL responses, whereas neutralizing antibody studies revealed weak to undetectable titers against a panel of 10 primary isolates. This study demonstrates that a vigorous in vivo activated HIV-1-specific CTL response can be part of the host immune response in stable nonprogressive HIV-1 infection, and that circulating activated CTL can be detected in the setting of an extremely low viral load. These results also indicate that long-term nonprogressing HIV-1 infection does not require the presence of broadly cross-reactive neutralizing antibodies.