RESUMO
Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Repetição Terminal Longa de HIV , HIV-1/genética , Sequência de Bases , Contagem de Linfócito CD4/efeitos dos fármacos , Primers do DNA , Quimioterapia Combinada , Infecções por HIV/imunologia , HIV-1/fisiologia , Humanos , Linfócitos/imunologia , RNA Viral/sangue , Valores de Referência , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral , Replicação ViralRESUMO
Recent studies of subjects infected with human immunodeficiency virus (HIV-1) have produced conflicting results about the extent of reconstitution possible in the CD4+ lymphocyte repertoire after highly active antiretroviral therapy (HAART). The effect of HAART on the incidence of opportunistic infections will probably depend on reconstitution of antigen-specific CD4+ lymphocyte responses to important pathogens, including cytomegalovirus (CMV), the leading cause of blindness in AIDS. Several studies have demonstrated an important role for CD4+ lymphocytes in controlling CMV replication in vitro and in clinical studies. It is now possible to quantitate antigen-specific CD4+ lymphocyte responses by flow cytometry. Using this method, we studied CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 with and without a history of active CMV-associated end organ disease (EOD), and in those with quiescent CMV EOD after ganciclovir therapy and HAART. The presence of active CMV-associated EOD strongly correlated with loss of CMV-specific lymphocyte responses (P = 0.0004). In contrast, patients with no history of CMV-associated EOD and most patients with quiescent EOD after HAART demonstrated strong CMV-specific CD4+ lymphocyte responses. These data indicate that the loss of CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 who have active CMV EOD may be restored after ganciclovir therapy and HAART, which provides evidence for functional immune reconstitution to an important pathogen.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Retinite por Citomegalovirus/tratamento farmacológico , Retinite por Citomegalovirus/imunologia , Ganciclovir/uso terapêutico , HIV-1 , Contagem de Linfócito CD4/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Células Cultivadas , Estudos de Coortes , Citometria de Fluxo , Humanos , Estudos Longitudinais , Ativação LinfocitáriaRESUMO
By studying changes in the clonal composition of HIV-1 populations during the first weeks of zidovudine (ZDV) treatment before the development of ZDV resistance-conferring mutations, we demonstrated previously a selective inhibition of nonsyncytium-inducing (NSI) HIV-1, even when present as coexisting population in individuals also harboring syncytium-inducing (SI) HIV-1. In this study, we observed the opposite in individuals receiving didanosine (ddI) treatment. In these individuals (n = 7) a median -0.98 log change (range -1.55-0.08) in infectious cellular SI load was observed, whereas the coexisting NSI load was only minimally affected (median -0.15 log, range -1.27-0.50; P = 0.03). The virus phenotype-dependent treatment responses were independent of the clonal composition of HIV-1 populations at baseline. Individuals treated with a combination of ZDV and ddI revealed an equal decline of both NSI and SI infectious cellular load (n = 4; NSI: median -1.55 log, range -2.19 to -1.45; SI: median -1.47 log, range -1.81 to -0.86; P = 0.56). To test the hypothesis that the previously reported optimal activation of ZDV and ddI in activated and resting T cells, respectively, in combination with the differential T cell tropism of NSI and SI HIV-1 is the basis for the observed virus phenotype specific efficacy of nucleoside analogs, we studied the effect of treatment with a protease inhibitor that does not require intracellular activation. Individuals receiving ritonavir (n = 4) indeed showed equal declines in NSI and SI infectious cellular load (NSI: median -2.37 log, range -2.59 to -2.16; SI: median -2.82 log, range -3.14 to -2.50; P = 0.25). Our data suggest HIV-1 phenotype as an additional parameter in the design of optimal treatment regimens.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Zidovudina/uso terapêutico , Animais , Contagem de Linfócito CD4/efeitos dos fármacos , Fusão Celular/efeitos dos fármacos , Didanosina/farmacologia , Células Gigantes/efeitos dos fármacos , Inibidores da Protease de HIV/uso terapêutico , Humanos , Camundongos , RNA Viral/sangue , Ritonavir/uso terapêutico , Zidovudina/farmacologiaRESUMO
Effective therapeutic interventions and clinical care of adults infected with HIV-1 require an understanding of factors that influence time of response to antiretroviral therapy. We have studied a cohort of 118 HIV-1-infected subjects naive to antiretroviral therapy and have correlated the time of response to treatment with a series of virological and immunological measures, including levels of viral load in blood and lymph node, percent of CD4 T cells in lymph nodes, and CD4 T-cell count in blood at study entry. Suppression of viremia below the limit of detection, 50 HIV-1 RNA copies/mL of plasma, served as a benchmark for a successful virological response. We employed these correlations to predict the length of treatment required to attain a virological response in each patient. Baseline plasma viremia emerged as the factor most tightly correlated with the duration of treatment required, allowing us to estimate the required time as a function of this one measure.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , RNA Viral/sangue , Carga Viral , Viremia/tratamento farmacológico , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Carbamatos , Estudos de Coortes , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/farmacologia , Didesoxinucleosídeos/uso terapêutico , Furanos , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Linfonodos/virologia , Nelfinavir/administração & dosagem , Nelfinavir/farmacologia , Nelfinavir/uso terapêutico , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Saquinavir/administração & dosagem , Saquinavir/farmacologia , Saquinavir/uso terapêutico , Estavudina/administração & dosagem , Estavudina/farmacologia , Estavudina/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Fatores de Tempo , Zidovudina/administração & dosagem , Zidovudina/farmacologia , Zidovudina/uso terapêuticoRESUMO
PURPOSE: To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures. METHODS: Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six). RESULTS: ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months. CONCLUSION: Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Didanosina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Fármacos Anti-HIV/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Contagem de Linfócito CD4/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Didanosina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Filgrastim , HIV/isolamento & purificação , Proteína do Núcleo p24 do HIV/análise , Humanos , Linfoma Relacionado a AIDS/mortalidade , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Proteínas Recombinantes , Taxa de Sobrevida , ViremiaRESUMO
The CD45RA and CD45RO isoforms of the leukocyte common antigen identify functionally distinct CD4+ T cell subsets: CD4+/CD45RA+ cells which represent a more 'naive' stage of T cell compartment and CD4+/CD45RO+ 'memory' cells. Phenotypic and functional abnormalities in T cell compartment have been frequently reported in patients with hairy cell leukemia (HCL) and, in more recent studies, a significant reduction in the absolute number of CD4+ lymphocytes bearing the CD45RO antigen has also been recorded. In our study we evaluated the CD45RA and CD45RO expression on CD4+ T cells by three-color staining in flow cytometry in 38 HCL patients, 19 untreated and 19 previously treated with 2-chlorodeoxyadenosine (2-CdA), administered at a daily dose of 0.1 mg/kg c.i. for 7 days. In HCL untreated patients, the proportion and the absolute number of CD4+/CD45RA+ and of CD4+/CD45RO+ T cell subsets were similar to normal controls. In contrast, HCL patients at 3-5 years by the end of treatment with 2-CdA, together with a reduction in the absolute number of CD4+ T cells, showed a persistent and significant decrease in the proportion and absolute number of CD4+/CD45RA+ cells as compared with both untreated HCL patients and normal controls (41 +/- 16% vs 57 +/- 14% and vs 65 +/- 7%) (P = 0.01 and 0.0001) and (0.201 +/- 0.137 x 10(9)/l vs 0.549 +/- 0.238 x 10(9)/l and vs 0.696 +/- 0.078 x 10(9)/l) (P = 0.00009 and P = 0.00001). In addition, together with the reduction of CD4+/CD45RA+ cells, we recorded a concomitant increase in the proportion of the CD4+/CD45RO+ cells as compared to untreated HCL patients and normal controls (62 +/- 16% vs 47 +/- 15% and vs 42 +/- 12%) (P = 0.08 and 0.02). These findings may suggest that CD4+/CD45RA+ cells are more sensitive than CD4+/CD45RO+ to the toxic effect of 2-CdA.
Assuntos
Antineoplásicos/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Cladribina/administração & dosagem , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/imunologia , Adulto , Idoso , Contagem de Linfócito CD4/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Leucemia de Células Pilosas/patologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Pessoa de Meia-Idade , Gravidez , Fatores de TempoRESUMO
Retinoids have anti-tumor activity in several malignant and premalignant conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have anti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients with mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were treated with all-trans retinoic acid (tRA). Poor tolerance was observed at the initial starting dose of 150 mg/m2, and thus subsequent patients were treated using a weekly dose escalation, starting with 45 mg/m2 (given daily, in subdivided doses), to the target dose of 150 mg/m2 (given daily in three subdivided doses). Nearly half (46%) of the patients had extensive mucocutaneous disease with over 25 lesions. No patient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm3 or greater (strata I); and 17 had under 200/mm3 CD4 lymphocytes (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m2; there was no significant difference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vomiting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to therapy was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three responders had baseline CD4 lymphocyte counts < 200/mm3. Three additional patients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease stabilization of 16 weeks or greater. In evaluable patients, the median time to disease progression was 22 weeks and the overall median survival in all patients was 27.3 months. No significant changes in CD4 lymphocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in soluble IL-2 receptor levels while on tRA (p = 0.037). We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Tretinoína/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Contagem de Linfócito CD4/efeitos dos fármacos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Receptores de Interleucina-2/efeitos dos fármacos , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia , Análise de Sobrevida , Resultado do Tratamento , Tretinoína/administração & dosagem , Tretinoína/efeitos adversosRESUMO
The fluorescence-activated cell sorter (FACS) was utilized to phenotype lymphocyte compartments in children receiving intensive chemotherapy for acute lymphoblastic leukemia (ALL). Sixteen patients (eight males and eight females) of diverse ages, risks of relapse, and within weeks 7-53 of maintenance/continuation chemotherapy treatment were arbitrarily selected for study. All 16 patients had profound B cell lymphopenia. In contrast, T cell numbers were often normal or marginally low, and accounted for up to 98% of the lymphocyte populations. No abnormality in T cell phenotypes could be demonstrated. Due to the highly skewed B/T lymphocyte ratios in these ALL patients, the absolute white blood cell counts and lymphocyte percentages were not predictive of the underlying B cell lymphopenia. Patients were also tested for serum immunoglobulin levels and most had abnormally low IgG and IgM. None of four patients immunized with the 1996-1997 influenza virus vaccine seroconverted to at least two vaccine antigens as compared to 10 of 10 healthy, age-matched controls. In total, these data highlight for the first time the profound abnormality of the B/T lymphocyte ratio in patients during treatment for ALL, and argue for consideration of B cell-targeted immunotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/imunologia , Subpopulações de Linfócitos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Linfócitos B/efeitos dos fármacos , Contagem de Linfócito CD4/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Linfócitos T/efeitos dos fármacosRESUMO
Until recently, treatment for human immunodeficiency virus type 1 (HIV-1) infection was limited to the use of nucleoside inhibitors of the viral enzyme reverse transcriptase. While these agents initially offered promise, they have only modest antiviral activity and the benefits of treatment are limited by the emergence of drug resistance and dose-limiting toxic effects. Development of more potent drugs that target different stages of the virus life cycle has thus been aggressively pursued. Efforts to develop inhibitors of HIV-1 protease have yielded a potent new class of compounds that suppress HIV-1 replication to an extent far greater than was previously attainable. Four protease inhibitors, saquinavir mesylate, ritonavir, nelfinavir, and indinavir sulfate, have been approved by the Food and Drug Administration. Other agents are undergoing active investigation. The purpose of this article is to review the currently available data on those agents that have been approved for clinical use.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , Animais , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Contagem de Linfócito CD4/efeitos dos fármacos , Ensaios Clínicos como Assunto , Interações Medicamentosas , Resistência a Medicamentos , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Indinavir/farmacologia , Isoquinolinas/farmacologia , Nelfinavir , RNA Viral/efeitos dos fármacos , Ritonavir/farmacologia , Saquinavir/farmacologia , Ácidos Sulfônicos/farmacologiaRESUMO
OBJECTIVES: To determine the efficacy of the non-nucleoside reverse transcriptase inhibitor atevirdine in the treatment of AIDS dementia complex (ADC). DESIGN: Open label pilot study. METHODS: Ten patients with ADC (stage 1 or 2) who were intolerant to zidovudine or dideoxyinosine, or in whom the antiretrovirals had failed to prevent further decline in CD4 cell levels, were entered into the study. Atevirdine, 1800 mg daily in three divided doses, was given over a 12-week period. Patients were assessed neurologically and neuropsychologically every 4 weeks. Cerebrospinal fluid analysis was performed at entry and at weeks 4 and 12. Technetium-99 exametazine single photon emission computed tomographic cerebral perfusion scans and magnetic resonance imaging brain scans were performed at weeks 0 and 12. RESULTS: Five patients completed the 12 week protocol. Four of these five responded to atevirdine, as judged by quantified neurological and neuropsychological assessments. Atevirdine was well tolerated apart from the development of rash, anxiety, intermittent diarrhoea and fatigue. CONCLUSIONS: These preliminary results suggest that atevirdine is efficacious in the treatment of ADC. Larger blinded studies of this class of drug in the treatment of ADC are required.
Assuntos
Complexo AIDS Demência/tratamento farmacológico , Antivirais/uso terapêutico , HIV-1 , Piperazinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Biomarcadores , Biopterinas/análogos & derivados , Biopterinas/líquido cefalorraquidiano , Contagem de Linfócito CD4/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Neopterina , Projetos Piloto , Piperazinas/líquido cefalorraquidiano , Microglobulina beta-2/líquido cefalorraquidianoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of zidovudine (ZDV) and lymphoblastoid interferon (IFN)-alpha combination therapy compared with ZDV monotherapy in HIV-infected subjects with CD4+ cell counts between 150 and 500 x 10(6)/l. DESIGN: Open, randomized controlled trial with subjects stratified by the Centers for Disease Control and Prevention (CDC) 1986 classification of HIV disease (group II/III or IV). The study was amended to a sequential design in February 1992 to allow interim analyses to be conducted. SETTING: Outpatient clinics in 45 hospitals in Europe, Australia and Canada. PARTICIPANTS: A total of 402 previously untreated subjects with symptomatic HIV infection (CDC group IV) and CD4+ count 150-500 x 10(6)/l or asymptomatic HIV infection (CDC group II/III) with CD4+ count 150-350 x 10(6)/l. INTERVENTIONS: ZDV 250 mg twice daily with or without 3 MU subcutaneous injections of lymphoblastoid IFN-alpha three times per week. MAIN OUTCOME MEASURES: Time to development of a study endpoint defined as: progression from CDC group II/III to group IV, group IV non-AIDS to AIDS, or group IV AIDS to a second AIDS-defining condition; also CD4+ count to < 50 x 10(6)/l on two occasions at least 1 month apart or HIV-related death irrespective of CDC group on entry. RESULTS: There was no reduction in the rate of disease progression for patients receiving ZDV plus IFN-alpha compared with patients receiving ZDV alone. No major differences between the groups were seen for CD4+ counts or percentages, or p24 antigenaemia. In a subset of 70 patients, a similar proportion from both dose groups showed evidence of ZDV resistance after 48 weeks of treatment. More adverse experiences were seen in the ZDV/IFN-alpha group. CONCLUSIONS: Combination therapy with low dose lymphoblastoid IFN-alpha and ZDV revealed no clinical benefit compared with ZDV monotherapy.
Assuntos
Contagem de Linfócito CD4/efeitos dos fármacos , Infecções por HIV/terapia , Interferon-alfa/administração & dosagem , Zidovudina/administração & dosagem , Adolescente , Adulto , Idoso , Terapia Combinada , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Proteína do Núcleo p24 do HIV/sangue , Infecções por HIV/imunologia , Humanos , Injeções Subcutâneas , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Zidovudina/efeitos adversosRESUMO
OBJECTIVE: We have previously shown that drugs that decrease intracellular cAMP levels increase/restore the proliferative and cytotoxic capacity of T cells from HIV-seropositive subjects in vitro. Buspirone, a serotonin receptor agonist, indirectly decreases intracellular cAMP levels in T cells and has the same increasing/restoring effect on T-cell proliferation in lymphocytes from HIV-seropositive subjects in vitro. DESIGN: Buspirone was given as a single high dose to six HIV-seropositive subjects, or as continuous medication with increasing dosage over 6 weeks to nine HIV-seropositive subjects, with CD4 T-cell counts of 150-300 x 10(6)/l. RESULTS: Significant increases in CD4 T cells, CD4 percentage and CD4/CD8 ratio were found 1 week after a single high dose of buspirone was administered. With continuous administration, a significant increase in CD4 T cells was observed after 1 and 4 weeks. Serum HIV RNA showed a significant decrease 1 h after a single dose of buspirone was administered. With continuous administration of buspirone, plasma HIV RNA first increased within the first 2 weeks of treatment and then decreased towards and below baseline concurrently with a significant decrease in CD8T cells. The proliferative T-cell response to poke weed mitogen and membrane expression of IL-2R increased significantly during continuous treatment with a significant decrease in expression of HLA-DR on CD8+ T cells. Development of "flu-like' symptoms, so severe that two patients withdrew from the study and two patients ceased medication before time, was a clinical indication of modulation of the immune system by buspirone. CONCLUSION: The study shows that buspirone modulates the immune system and leads to changes in the CD4 and CD8 T-cell numbers, functional capacity, cell maturation and viral load.
Assuntos
Buspirona/uso terapêutico , Contagem de Linfócito CD4/efeitos dos fármacos , Soropositividade para HIV/imunologia , Adulto , Biopterinas/análogos & derivados , Biopterinas/sangue , Relação CD4-CD8/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Citometria de Fluxo , Soropositividade para HIV/tratamento farmacológico , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neopterina , RNA Viral/análise , Receptores de Interleucina-2/sangue , Microglobulina beta-2/análiseRESUMO
OBJECTIVES: To determine predictors of clinical relapse of cytomegalovirus (CMV) end-organ disease in a cohort of 17 HIV-infected patients with healed and treated CMV retinitis (CMVR) who responded to HAART with an increase in CD4 cell counts to above 70 cells/mm3 and discontinued CMV maintenance therapy (MT). DESIGN: Seventeen patients were monitored for reactivation of retinitis. The CD4 cell counts, HIV RNA and peripheral blood mononuclear cell (PBMC) lymphoproliferative assays to CMV at 3 month intervals were compared between patients with and without reactivation of CMVR. Positive lymphoproliferative responses were defined as a stimulation index of 3 or greater. RESULTS: Five out of 17 (29%) patients experienced a recurrence of CMVR a mean of 14.5 months after stopping CMV MT and between 8 days and 10 months after CD4 cell counts fell below 50 cells/mm3. Median CD4 cell counts and plasma HIV RNA at reactivation were 37 cells/mm3 and 5.3 log10 copies/ml. Three patients recurred at a previously active site of the retina, one had contralateral CMVR, and one a recurrence of retinitis and pancreatitis simultaneously. Mean lymphoproliferative responses to CMV were 2.4 in patients with reactivation versus 21.0 stimulation index (SI) in patients without reactivation (P= 0.01). A model incorporating four variables (CD4 cell counts and HIV RNA at maintenance discontinuation, highest CD4 cell count, nadir HIV RNA and median lymphoproliferative responses) identified correctly 88% of patients with and without reactivation. CONCLUSION: CMV disease recurs after virological and immunological failure of HAART if CD4 cell counts drop below 50. In this situation, anti-CMV agents should be resumed before clinical reactivation ensues, because of the risk of contralateral retinal involvement and systemic disease.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Retinite por Citomegalovirus/tratamento farmacológico , HIV , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Contagem de Linfócito CD4/efeitos dos fármacos , Estudos de Coortes , Citomegalovirus/efeitos dos fármacos , Retinite por Citomegalovirus/prevenção & controle , Feminino , HIV/efeitos dos fármacos , HIV/genética , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/sangue , Recidiva , Fatores de Risco , Linfócitos T/imunologia , Falha de Tratamento , Carga ViralRESUMO
INTRODUCTION: This article reports a meta-analysis focused on the efficacy of zalcitabine and zidovudine alone or in combination as reported by three AIDS Clinical Trial Group trials. We analyzed the log CD4 count (LCD4) response to therapy up to 1 year after the beginning of therapy. One of the purposes of this article was to illustrate a meta-analysis method that permits pooling of original data from trials with different designs. METHODS: To effectively eliminate obvious differences due to design, we first estimated complete (1 year) individual LCD4 versus time curves using a sophisticated smoothing technique. Then several summary descriptors were computed from the completed LCD4 curves. Those descriptors were corrected for baseline covariate differences, and the corrected values were then related to measures of drug exposure. RESULTS: Significant baseline covariates were LCD4 baseline count and AIDS-related complex or AIDS diagnosis. The predictor, corrected for baseline covariates, that correlated best with drug exposure was intensity, the initial rate of rise of LCD4, estimated as the slope of LCD4 between pretreatment and peak LCD4. CONCLUSION: Using intensity as a single response measure, we found weak evidence for synergism of zalcitabine and zidovudine: combination therapy increased response by 20% over that expected from a purely additive interaction.
Assuntos
Complexo Relacionado com a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Fármacos Anti-HIV/farmacologia , Contagem de Linfócito CD4/efeitos dos fármacos , Zalcitabina/farmacologia , Zidovudina/farmacologia , Complexo Relacionado com a AIDS/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Quimioterapia Combinada , Humanos , Análise de Regressão , Fatores de Tempo , Zalcitabina/administração & dosagem , Zidovudina/administração & dosagemRESUMO
Clenoliximab (IDEC-151) is a macaque-human chimeric monoclonal antibody (immunoglobulin G4) specific for the CD4 molecule on the surface of T lymphocytes. It is being studied in patients with rheumatoid arthritis in which T cell activation orchestrates inflammation and tissue damage. In this initial study in humans, the pharmacokinetics and pharmacodynamics of clenoliximab were investigated after single intravenous infusion. Blood was collected up to 12 weeks after dose administration to measure clenoliximab concentration, CD4+ T-cell count, CD4 antigen coating, and CD4 cell surface density. Clenoliximab displayed nonlinear pharmacokinetic behavior and caused an 80% reduction in CD4 density for up to 3 weeks, without depleting T cells. A pharmacokinetic-pharmacodynamic model was developed that described the relationship between antibody concentration, antigen coating, and the observed decreases in CD4 cell surface density. This was used to anticipate the effects of clenoliximab in untested regimens and optimize the design of future clinical trials.
Assuntos
Anticorpos Monoclonais/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Adulto , Anticorpos Monoclonais/farmacocinética , Antirreumáticos/farmacocinética , Artrite Reumatoide/imunologia , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/metabolismo , Contagem de Linfócito CD4/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly increases saquinavir bioavailability. In this study we assessed the safety and antiretroviral efficacy of the combination of these two compounds in patients pretreated and receiving continued treatment with zidovudine and lamivudine who were protease inhibitor naive and who had a CD4 cell counts below 200/mm3. METHODS: In this 48-week pilot study, all patients received 600 mg ritonavir and 400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was continued without a change in previous doses. Viral load, CD4 cell count, and the emergence of resistance to the two protease inhibitors were evaluated repeatedly up to week 48. RESULTS: Sixteen patients were included in the study. Previous nucleoside analog treatment duration was 48+/-22 months (mean +/- SD). Two patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose had to be reduced in 10 other patients because of side effects. Between inclusion and week 48, plasma viremia varied from 4.87+/-0.43 to 3.00+/-1.29 log10 copies/mL and CD4 cell counts ranged from 98+/-61 to 250+/-139/mm3. Ten patients (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50 copies/mL. A single key mutation that conferred ritonavir resistance I84V and V82A/V developed in two patients. A mutation at codon 54 developed in another patient. These mutations were associated with repeated cessations of antiretroviral treatment. No lipodystrophy was observed. CONCLUSION: Ritonavir and saquinavir in combination are quite well tolerated and induce a high and sustained antiretroviral efficacy. A four-drug combination that includes these two protease inhibitors should be considered as a first line of treatment in patients with low CD4 cell counts.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Saquinavir/uso terapêutico , Zidovudina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/diagnóstico , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Contagem de Linfócito CD4/efeitos dos fármacos , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Esquema de Medicação , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Genótipo , Inibidores da Protease de HIV/efeitos adversos , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Projetos Piloto , Reação em Cadeia da Polimerase , Inibidores da Transcriptase Reversa/efeitos adversos , Ritonavir/efeitos adversos , Saquinavir/efeitos adversos , Índice de Gravidade de Doença , Fatores de Tempo , Carga Viral , Zidovudina/efeitos adversosRESUMO
OBJECTIVE: The goals of this study were to determine whether fluoxetine is superior to placebo in treating HIV-seropositive patients with major depression or dysthymia or both, whether severity of immunosuppression is associated with treatment response, and whether fluoxetine treatment is associated with change in immune status as measured by CD4 cell count. METHOD: A double-blind, randomized, placebo-controlled 8-week trial of fluoxetine was conducted in a university-affiliated research outpatient clinic. The fluoxetine-placebo randomization was 2:1. All patients were offered 4 months of additional open treatment. Main outcome measures included the Clinical Global Impression, Hamilton Depression Rating Scale, and CD4 cell count. RESULTS: Of 120 patients randomly assigned to fluoxetine or placebo, 87 completed 8 weeks of treatment. In the total group, 51% had AIDS. All but three were men, 35% were nonwhite, and 6% had intravenous drug use as a risk factor. In an intention-to-treat analysis, 57% of fluoxetine patients and 41% of placebo patients were responders. Among patients who completed the study, 74% responded to fluoxetine and 47% to placebo; this difference was statistically significant. Severity of immunosuppression was not related to antidepressant response, attrition, or side effects, and fluoxetine treatment was not associated with change in CD4 cell count. CONCLUSIONS: Fluoxetine is an effective antidepressant in the context of HIV illness. However, both placebo response and attrition were substantial, suggesting both that nonspecific factors may be more salient and that yet another medication (i.e., an antidepressant) may be less acceptable among patients with serious medical illness already requiring multiple concomitant medications.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Transtorno Depressivo/tratamento farmacológico , Fluoxetina/uso terapêutico , Soropositividade para HIV/complicações , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/psicologia , Adulto , Contagem de Linfócito CD4/efeitos dos fármacos , Transtorno Depressivo/etiologia , Método Duplo-Cego , Análise Fatorial , Feminino , Soropositividade para HIV/imunologia , Soropositividade para HIV/psicologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Placebos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVES: To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. DESIGN: Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). PATIENTS: Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/microL (range 2 to 2290 cells/microL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. RESULTS: As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. CONCLUSIONS: Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.
Assuntos
Infecções por HIV/tratamento farmacológico , Estavudina/uso terapêutico , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Peso Corporal , Contagem de Linfócito CD4/efeitos dos fármacos , Criança , Pré-Escolar , Progressão da Doença , Feminino , Crescimento , Proteína do Núcleo p24 do HIV/sangue , Infecções por HIV/classificação , Humanos , Lactente , Masculino , Estavudina/administração & dosagem , Estavudina/efeitos adversos , Estavudina/sangue , Estavudina/farmacocinética , Taxa de Sobrevida , Zidovudina/administração & dosagem , Zidovudina/uso terapêuticoRESUMO
OBJECTIVES: To obtain preliminary information on the pharmacokinetic properties, tolerance, safety, and antiviral activity of combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus (HIV) infection. METHODS: Eight children (median age, 6.6 years; range, 2.8 to 12 years) with advanced HIV disease (median CD4 + lymphocyte count at baseline, 42 cells/ microL; range, 8 to 553 cells/microL) were treated with stavudine (2 mg/kg per day in two divided doses) and didanosine (180 mg/m2 per day in two divided doses) for 24 weeks. Seven children had histories of prior zidovudine therapy. All children had received stavudine alone for 19 to 33 months before the addition of didanosine to the treatment regimen. Children were assessed clinically and with laboratory studies at baseline, weekly through week 4 of combination therapy, and every 4 weeks thereafter. RESULTS: Analysis of stavudine and didanosine plasma half-life values, clearances, and area under the plasma concentration-versus-time curves revealed no obvious clinical pharmacokinetic interaction between the drugs through study week 12. Combination therapy was well tolerated, and there were no drug-associated clinical or laboratory adverse events. Signs and symptoms of peripheral neuropathy were not observed. All three children with baseline CD4 + lymphocyte counts greater than 50 cells/muL had greater than 20% increases in their counts within the first 12 weeks of therapy; CD4 + lymphocyte count increases were not observed in the other children. Plasma HIV RNA concentrations showed median declines of 0.88 log10 (range, -3.41 log10 to 0.31 log10) and 0.30 log10 (range, -0.63 log10 to 0.89 log10) at study weeks 12 and 24, respectively. CONCLUSIONS: Combination therapy with stavudine and didanosine was well tolerated and safe in this small group of children with advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable effect of therapy on virus load. These findings should be confirmed, and the regimen's clinical efficacy should be examined, in controlled studies of HIV-infected children with less-advanced disease.
Assuntos
Antivirais/uso terapêutico , Didanosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , RNA Viral/sangue , Estavudina/uso terapêutico , Antivirais/farmacocinética , Contagem de Linfócito CD4/efeitos dos fármacos , Criança , Pré-Escolar , Didanosina/farmacocinética , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , Humanos , Masculino , Projetos Piloto , Estavudina/farmacocinéticaRESUMO
The introduction of high-purity factor VIII (FVIII) concentrates in the treatment of patients with hemophilia A has raised the issue that the use of these products may change on the immune system of the recipients. There is now clear evidence that high-purity concentrates, particularly those produced by immune-affinity chromatography or recombinant DNA technology, slow the fall in CD4 cells that occurs in HIV seropositive patients. It remains to be demonstrated that this biological effect results in clinical benefits and that the occurrence of AIDS is slowed or delayed by the use of high-purity concentrates. On the other hand, concern has been expressed about the possibility that high-purity products might render patients with hemophilia less immunotolerant, facilitating the onset of FVIII antibodies. Follow-up studies of previously untreated hemophiliacs infused for the first time with recombinant FVIII products have ignited this concern, because approximately one fourth of severe hemophiliacs developed inhibitors. However, most of the inhibitors were transient, so that ultimately they had little influence on the efficacy of replacement therapy. It was subsequently realized that inhibitors develop with high frequency even in hemophiliacs treated with less pure, plasma-derived products, provided testing is prospective and as frequent as for studies of recombinant FVIII. On the whole, these data have provided new insights on the natural history of inhibitor development in previously untreated hemophiliacs, showing that low-titer, short-lasting inhibitors develop more frequently than previously recognized.