RESUMO
OBJECTIVE: Immunotherapy of tuberculosis (TB) to shorten treatment duration represents an unmet medical need. Orally delivered, tableted TB vaccine (V7) containing heat-killed Mycobacterium vaccae (NCTC 11659) has been demonstrated in prior clinical studies to be safe and fast-acting immune adjunct. METHODS: The outcome of Phase III trial of V7 containing 10 µg of hydrolyzed M. vaccae was evaluated in 152 patients randomized at 2:1 ratio: V7 (Nâ¯=â¯100), placebo (Nâ¯=â¯52). Both arms received conventional 1st or 2nd line TB drugs co-administered with daily pill of V7 or placebo. RESULTS: After one month mycobacterial clearance was observed in 68% (P < 0.0001) and 23.1% (Pâ¯=â¯0.04) of patients on V7 and placebo. Stratified conversion rates in V7 recipients with drug-sensitive and multidrug-resistant TB were 86.7% and 55.6% vs 27.2% and 15% in placebo. Patients on V7 gained on average 2.4 kg (P < 0.0001) vs 0.3 kg (Pâ¯=â¯0.18) in placebo. Improvements in hemoglobin levels, erythrocyte sedimentation rate and leukocyte counts were significantly better than in controls. Liver function tests revealed that V7 can prevent chemotherapy-induced hepatic damage. CONCLUSION: Oral M. vaccae is safe, can overcome TB-associated weight loss and inflammation, reduce hepatotoxicity of TB drugs, improve sputum conversion three-fold OR 3.15; 95%CI (2.3,4.6), and cut treatment length by at least six-fold. Longer follow-up studies might be needed to further substantiate our findings (Clinicaltrials.gov: NCT01977768).
RESUMO
BACKGROUND: An increasing number of studies is now devoted to immunotherapy of cancer. We evaluated the clinical benefit of hepcortespenlisimut-L (Hepko-V5 [formerly known as V5])-an oral therapeutic vaccine designated by the United States Food and Drug Administration (FDA) as an orphan drug for treatment of hepatocellular carcinoma (HCC). V5 was initially developed by us in 2002 to treat hepatitis B or C viral infections and liver cirrhosis. METHODS: The outcome of open-label Phase II trial of daily dose of V5 pill was analyzed retrospectively. Over a period of 5 years, 75 patients with advanced HCC were enrolled, consisting of 29 (38.7%) females and 46 (61.3%) males with a median age of 60 years (mean 61.6±8.1 years). Out of these, 23 (30.7%) had hepatitis B and 34 (45.3%) had hepatitis C infections, including 9 (12%) with dual infection, 4 (5.3%) negative for both viruses, and 5 (6.7%) without established viral diagnosis. Most patients (94.7%) had underlying liver cirrhosis of varying severity. RESULTS: After a median of 2 months of treatment, 50 out of 75 patients had experienced a decline in serum levels of the tumor marker, alpha-fetoprotein (AFP) (66.7%; P=0.006 by Wilcoxon signed rank test). Baseline median AFP levels were 245.2 IU/mL (mean 4,233; range 7.2-92,407; 95% confidence interval [CI] 1,186-7,280) and post-treatment values were 102.3 IU/mL (mean 2,539; range 0.9-54,478; 95% CI 503-4,575). The decrease in AFP was correlated either with tumor clearance or regression on computed tomography scans. The median overall survival time could not be established since 68 out of 75 (90.7%) patients were still alive after median follow-up of 12 months (mean 15±9.7; range 7-59; 95% CI 12.8-17.2). The first patient in this study received immunotherapy 5 years ago and still remains in complete remission. None of the patients experienced any serious adverse effects or toxicity. CONCLUSION: The results indicate that hepcortespenlismut-L is a safe, effective, and fast-acting immunomodulatory intervention for HCC. The Phase III, randomized, double-blind, placebo-controlled trial is now initiated at the Mongolian National Cancer Center to confirm these promising findings.
RESUMO
AIM: Safer and shorter antituberculosis treatment (ATT) regimens represent the unmet medical need. PATIENTS & METHODS: The patients were randomly assigned into two arms: the first (n = 137) received once-daily sublingual honey lozenge formulated with botanical immunomodulator Immunoxel and the second (n = 132) received placebo lozenges along with conventional ATT. Immunoxel and placebo arms were demographically similar: 102 versus 106 had drug-susceptible TB; 28 versus 20 multidrug-resistant TB (MDR-TB); 7 versus 7 extensively drug-resistant TB (XDR-TB); and 22 versus 20 TB-HIV. The primary end point was sputum smear conversion. RESULTS: After 1 month 87 out 132 (65.9%) of Immunoxel recipients became sputum smear negative, whereas 32 out of 127 (25.2%) in placebo group had converted (p < 0.0001). Sputum clearance produced by Immunoxel was equally effective across all forms of TB. In the immunotherapy arm the average weight gain was 2 kg, but placebo recipients gained only 0.6 kg. Immunoxel reduced TB-associated inflammation as evidenced by defervescence and normalization of elevated leukocyte counts and erythrocyte sedimentation rate. No adverse effects were seen at any time. The liver function tests indicate that ATT-caused hepatotoxicity was counteracted by Immunoxel. These results are in agreement with prior 20 trials of Immunoxel conducted over the past 17 years. CONCLUSION: Immunoxel is affordable, safe, effective, fast-acting, commercially available immunotherapeutic intervention to supplement conventional TB chemotherapy. Clinicaltrials.gov ID: NCT01061593.
Assuntos
Antituberculosos/uso terapêutico , Misturas Complexas/uso terapêutico , Infecções por HIV/terapia , Mel , Imunoterapia/métodos , Tuberculose Resistente a Múltiplos Medicamentos/terapia , Tuberculose Pulmonar/terapia , Administração Sublingual , Adulto , Método Duplo-Cego , Feminino , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Masculino , Efeito Placebo , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/complicações , Tuberculose Resistente a Múltiplos Medicamentos/imunologia , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/imunologiaRESUMO
AIM: A 1-month Phase II trial was conducted in 41 patients with pulmonary TB who were randomized into treatment (n = 20) and placebo (n = 21) arms to investigate the safety and efficacy of an orally-administered therapeutic TB vaccine (V7) containing 10 µg heat-killed Mycobacterium vaccae provided by Immodulon Therapeutics Ltd (London, UK). MATERIALS & METHODS: Both arms received conventional anti-TB therapy administered along with a daily pill of V7 or placebo. The subject population had four categories of TB: drug-sensitive TB; retreated TB; drug-resistant TB; and TB with HIV distributed in V7 and placebo arms at 9:4:7:6 and 14:1:6:8 ratios, respectively. RESULTS: The mycobacterial clearance in sputum smears was observed in 72.2% (p < 0.0001) and 19% (p = 0.03) of patients on V7 and placebo, respectively. The average weight accrual among V7 recipients was 2.6 kg (p = 0.002) versus -0.2 kg (p = 0.69) in the control group. Except reduction in fever and increased lymphocyte counts, the changes in other secondary end points, such as hemoglobin, erythrocyte sedimentation rate and leukocyte counts, were not statistically different, although the proportion of patients responding favorably to V7 was invariably higher compared with placebo (p = 0.002). In control patients, no difference from baseline levels was noted except decreased hemoglobin content (p = 0.02). CONCLUSION: Oral M. vaccae was safe and has potential as an adjunct immunotherapy, targeting mucosal immunity, to improve efficacy and shorten treatment duration of TB chemotherapy.
Assuntos
Vacinas Bacterianas , HIV/imunologia , Mycobacterium/imunologia , Preparações Farmacêuticas/administração & dosagem , Tuberculose Pulmonar/prevenção & controle , Administração Oral , Adulto , Carga Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana , Feminino , Infecções por HIV/complicações , Temperatura Alta , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Resultado do Tratamento , Tuberculose Pulmonar/complicações , Vacinas de Produtos InativadosRESUMO
One-month Phase II trial was conducted in 43 sputum smear-positive patients with pulmonary tuberculosis randomized into treatment (n = 22) and placebo (n = 21) arms to investigate the safety and efficacy of an orally-administered therapeutic TB vaccine (V7) containing 10 µg of heat-killed Mycobacterium vaccae provided by Longcom company. Immunotherapy and control groups comprised 8 newly diagnosed (1stDx TB; 18.6%), 6 re-treated (RTB; 14%), and 29 multidrug-resistant (MDR-TB; 67.4%) cases distributed at 5:4:13 and 3:2:16 ratios, respectively. Both arms received conventional TB drugs administered under directly observed therapy. The average weight gain in V7 arm was modest, but statistically significant (0.6 kg; p = 0.004), while placebo patients lost 0.1 kg (p = 0.77). Except defervescence and increased lymphocyte percentage, other secondary endpoints such as erythrocyte sedimentation rate (ESR), leukocyte counts and hemoglobin content were not significantly affected. In control patients only one secondary endpoint, ESR, has improved. After one month mycobacterial clearance in sputum smears was observed in 31.8% (p = 0.03) and 9.5% (p = 0.83) of patients on V7 and placebo. However, the difference between outcomes in two arms was below significance threshold (p = 0.07). Thus, larger population of patients with prolonged follow-up is required to support these preliminary findings.
Assuntos
Imunoterapia/métodos , Mycobacterium/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/terapia , Administração Oral , Adulto , Antituberculosos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Escarro/microbiologia , Resultado do Tratamento , Vacinas contra a Tuberculose/efeitos adversos , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologiaRESUMO
AIM: To evaluate the effect of an adjunct immunotherapy in randomized double-blind, placebo-controlled Phase IIb trial involving 123 TB patients. METHODS: Patients were randomly allocated into two arms: one (n = 62) received a once-daily pill of V-5 Immunitor™ (V5) and the other (control; n= 61) received placebo for 30 days in addition to first- or second-line TB drugs administered under directly observed therapy. The subjects in V5 and placebo arms had first-diagnosed, relapsed, treatment-failed and multidrug-resistant TB at ratios of 17:21:11:13 and 20:19:14:8, respectively; among them, ten and seven had HIV coinfection, respectively. RESULTS: After 1 month, 55 out of 62 patients (88.7%) became sputum smear-negative in the V5 arm (p < 0.0001), whereas in the placebo group, nine out of 61 (14.8%) had converted. The conversion rate among V5 recipients was similar, regardless of whether TB was drug-sensitive, drug-resistant or with HIV. V5 downregulated TB-associated inflammation, as shown by the normalization of elevated leukocyte counts (8.7 vs 6.3 × 10 (9)/l; p < 0.0001) and decreased erythrocyte sedimentation rate (22.8 vs 12.6 mm/h; p < 0.0001), whereas among placebo recipients, changes were smaller (8.9 vs 8.2 × 10 (9)/l and 25.1 vs 19.9 mm/h). Thirty three (54.1%) placebo patients gained on average 0.8 kg (p = 0.0002); by contrast, 57 (91.9%) out of 62 patients in the V5 group gained a mean weight of 2.9 kg (p < 0.0001). No adverse side effects or reactivation of TB were seen at any time. CONCLUSION: V5 is safe and effective as an immune adjunct to chemotherapy for TB and can potentially reduce the treatment duration down to 1 month.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/terapia , Vacinas contra Citomegalovirus/uso terapêutico , Vacinas contra Hepatite B/uso terapêutico , Imunoterapia/métodos , Tuberculose Resistente a Múltiplos Medicamentos/terapia , Tuberculose Pulmonar/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Falha de Tratamento , Ucrânia , Adulto JovemRESUMO
TB is typically caused by Mycobacterium tuberculosis, a symbiotic bacterium present in one-third of the world's population. There any many factors triggering overt clinical disease in a small proportion of humans. In our view the major role in the process is played by the host's immune response, especially self-directed, destructive inflammation. Conventional chemotherapy produces bactericidal or bacteriostatic effects, but immunopathological changes can only be corrected by immunotherapy. Various attempts have been made to identify the optimal immune intervention. Some have shown promising effects, but many have failed. It is commonly believed that the field started in 1890: the year Robert Koch announced his tuberculin therapy. In the Pên Ts'ao Kang Mu, classical Chinese materia medica, published during Ming dynasty, Li Shi Chen (1518-1593) recommended, as a remedy for hemoptysis, to collect from the sputum " blood lumps, roast them till they are black, and take then them as a powder". In retrospect, this is perhaps the earliest recorded reference relating to immunotherapy of TB with heat-killed mycobacteria. Modern science is obviously geared toward more palatable approach, but without hindsight from often disdained empirical evidence no progress can be made. The clinical experience from various trial and error processes is briefly discussed in this review.
Assuntos
Imunoterapia/métodos , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Ensaios Clínicos como Assunto , Humanos , Tolerância Imunológica , Fatores Imunológicos/uso terapêutico , Resultado do Tratamento , Tuberculina/imunologia , Tuberculina/uso terapêutico , Tuberculose/microbiologia , Tuberculose/fisiopatologia , Tuberculose/terapia , Vacinas contra a Tuberculose/uso terapêuticoRESUMO
Immunoxel (Dzherelo) is a water-alcohol extract of medicinal plants used in Ukraine as an adjunct immunotherapy to TB and HIV therapy. Four types of solid sublingual formulations of Immunoxel were made: sugar dragées, sugar-coated pills, gelatin pastilles and dried-honey lozenges. They were administered once-daily along with TB drugs. After 1 month, 84.1% of TB patients became sputum-negative with rates in individual groups of 89.5, 70, 76.9 and 100%, respectively. The conversion rate was independent of bodyweight, age, gender, differences in chemotherapy regimens or whether subjects had newly diagnosed TB, re-treated TB, multidrug-resistant TB or TB with HIV coinfection. Patients experienced earlier clinical improvement, faster defervescence, weight gain, a higher hemoglobin content and reduced inflammation as evidenced by lower leukocyte counts and erythrocyte sedimentation rate. By contrast, in the placebo group, only 19% of patients had converted. These findings imply that mucosal delivery of solid Immunoxel is equivalent to the original liquid formula given per os twice-daily for 2-4 months.
Assuntos
Imunoterapia/métodos , Fitoterapia/métodos , Preparações de Plantas/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/terapia , Administração Sublingual , Adulto , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Tuberculose Resistente a Múltiplos Medicamentos/sangue , Tuberculose Resistente a Múltiplos Medicamentos/complicações , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , UcrâniaRESUMO
Placebo-controlled, randomized, phase 2b trial was conducted in 34 adults comprising 18 first-diagnosed (52.9%), 6 relapsed (17.6%), and 10 MDR-TB (29.4%) cases to investigate the safety and efficacy of an oral immune adjunct (V5). The immunotherapy (N = 24) and placebo (N = 10) arms received once-daily tablet of V5 or placebo for one month in addition to conventional anti-TB therapy (ATT) administered under directly observed therapy (DOT).The enlarged liver, total bilirubin, erythrocyte sedimentation rate, lymphocyte and leukocyte counts improved significantly in V5 recipients (P = 0.002; 0.03; 8.3E-007; 2.8E-005; and 0.002) but remained statistically unchanged in the placebo group (P = 0.68; 0.96; 0.61; 0.91; and 0.43 respectively). The changes in hemoglobin and ALT levels in both treatment arms were not significant. The body weight increased in all V5-treated patients by an average 3.5 ± 1.8 kg (P = 2.3E-009), while 6 out of 10 patients on placebo gained mean 0.9 ± 0.9 kg (P = 0.01). Mycobacterial clearance in sputum smears was observed in 78.3% and 0% of patients on V5 and placebo (P = 0.009). The conversion rate in V5-receiving subjects with MDR-TB (87.5%) seemed to be higher than in first-diagnosed TB (61.5%) but the difference was not significant (P = 0.62). Scoring of sputum bacillary load (range 3-0) at baseline and post-treatment revealed score reduction in 23 out of 24 (95.8%) V5 recipients (from mean/median 2.2/3 to 0.3/0; P = 6E-010) but only in 1 out of 10 (10%) patients on placebo (1.9/1.5 vs. 1.8/1; P = 0.34). No adverse effects or TB reactivation were seen at any time during follow-up. V5 is safe as an immune adjunct to chemotherapeutic management of TB and can shorten substantially the duration of treatment.
RESUMO
This Phase IIb, placebo-controlled study involved 55 TB patients treated with anti-TB therapy. They were divided into two groups, matched by age, gender, baseline bodyweight and clinical manifestations: one group (n = 27) received a once-daily V-5 Immunitor (V5) immunotherapy pill and the other (n = 28) received placebo. Only one (3.7%) and three (10.7%) subjects in V5 and placebo arms, respectively had first-diagnosed, drug-sensitive TB; the remaining patients had re-treated TB, multidrug-resistant TB or HIV-TB coinfection. After 1 month, 26 out of 27 patients (96.3%) became sputum smear negative in the V5 group (p < 0.0000001), whereas seven out of 28 (25%) in the placebo group had converted (p = 0.005). V5 contributed to the downregulation of TB-associated inflammation, as shown by normalization of high leukocyte counts, erythrocyte sedimentation rate and faster defervescence than controls. Patients in both arms experienced an increase in the levels of hemoglobin corresponding to 128.9 ± 17.6 versus 133.1 ± 14.7 g/l (p = 0.03) and 112.6 ± 14 versus 117 ± 11.7 g/l (p = 0.03) in V5 and placebo arms, respectively. In total, 19 out of 28 placebo patients (67.9%) gained, on average, 1.07 kg (59.1 ± 10 vs 60.1 ± 10.4 kg; p = 0.003). By contrast, all patients in the V5 group gained weight with mean 3.4 kg (59.7 ± 8 vs 63.1 ± 9 kg; p = 5.7E-007). Clinical symptoms improved among all patients in V5 arm, while 28.6% of patients on placebo reported satisfactory results (p = 0.007). No adverse or side effects attributable to V5 were seen at any time. Further studies are needed to gauge the extent of the benefits of V5 as safe and effective adjunct immunotherapy for TB.
Assuntos
Farmacorresistência Bacteriana Múltipla , Infecções por HIV/complicações , Imunoterapia , Tuberculose/tratamento farmacológico , Administração Oral , Adulto , Antituberculosos/administração & dosagem , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Tuberculose/complicaçõesRESUMO
BACKGROUND: Chronic inflammations, atherosclerosis and obesity, are major risk factors for cardiovascular diseases. Immune modulation of the inflammatory response has shown promise in animal models of atherogenesis and metabolic disease. Tableted dietary supplement, V-6, containing pooled antigens derived from pig adipose tissue has been administered daily to 12 volunteers for 2 months. RESULTS: No significant changes were observed in liver ALT and AST enzymes, i.e., 28 vs 23.8 IU and 22.6 vs 24.8 IU, with p=0.07 and p=0.49, respectively. Creatinine decreased; 0.88 vs 0.84 mg/dL (p=0.05) while BUN moved upward; 14.5 vs 17.5 mg/dL (p=0.01), but both values remained within normal range. Blood glucose remained within normal range; 96.1 vs 101.1 mg/dL (p=0.04). Complete blood cell analysis has not revealed any change except slight increase in hemoglobin; 13.13 to 13.96 g/dL (p=0.0002); hematocrit and red blood cells count 40.3 to 42.3% (p=0.02) and 5.15 to 5.35x10(6) cells/mm3 (p=0.03) respectively. Blood pressure systolic and diastolic values were not affected, i.e., 116.1 vs 116.3 (p=0.12) and 76.8 vs 76.6 (p=0.99). Body weight and body mass index (BMI) remained same; 66.4 vs 66.3 kg (p=0.47) and 25.7 vs 25.6 kg/m2 (p=0.2). Body fat deposit indices, such as abdomen; mid-arm; and thigh circumferences declined by 3.5 cm (p=0.008); 1.2 cm (p=0.004); and 3.0 cm (p=0.0007) respectively. The total cholesterol and LDL levels did not change; 195.5 vs 195.1 (-0.2%; p=0.8) and 113.4 vs 120.3 (6.1%; p=0.08) respectively. Triglycerides have been reduced but not statistically significant; 168.1 vs 118 mg/dL (-29.8%; p=0.2). In contrast, HDL content had risen by 29.7% from 39.4 to 51.1 mg/dL in all 12 patients (p=0.000003). TG/HDL ratio--a marker of insulin resistance--was reduced from 4.78 to 2.56 (-46.5%; p=0.04). CONCLUSIONS: These results demonstrate that V-6 is safe and has a potential as an anti-atherogenic and overweight/obesity immune intervention.
Assuntos
Tecido Adiposo/metabolismo , Extratos de Tecidos/administração & dosagem , Vacinas/administração & dosagem , Viroses/prevenção & controle , Administração Oral , Adulto , Idoso , Animais , Pressão Sanguínea , Índice de Massa Corporal , Suplementos Nutricionais , Eritrócitos/citologia , Feminino , Seguimentos , Hematócrito , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Suínos , Triglicerídeos/metabolismoRESUMO
Modulation of the inflammatory response through vaccination has shown promise in animal models of atherogenesis and obesity-main risk factors for cardiovascular diseases. Tableted preparation, V-6, containing pooled antigens derived from pig adipose tissue was administered per os daily to 13 volunteers for 3 months. Total cholesterol and LDL levels have not changed from the baseline value; 193.4 vs 191.8 (p=0.75) and 113.8 vs 117.2 (p=0.18), respectively. Triglyceride levels declined by 26.1% from 163 to 120.5mg/dL (p=0.29). HDL increased by 25.9% from 38.6 to 48.5mg/dL (p=0.000002) in 12 out 13 patients. Despite negligible effect of V6 on weight and body mass index, i.e., 67.87 vs 66.58 kg (-1.9%; p=0.46) and 26.25 vs 25.75 kg/m(2) (-1.9%; p=0.35), statistically significant reduction in waist (-7.6%; p=0.002), mid-arm (-3.3%; p=0.049), and thigh (-7.6%; p=0.0003) circumferences were observed. Blood pressure systolic and diastolic values were not affected, i.e., 115.6 vs 121 (p=0.2) and 77.1 vs 83 (p=0.55). No changes were observed in liver ALT and AST enzymes. Creatinine decreased; 0.877 vs 0.842 mg/dL (p=0.02), while BUN has shown slight increase; 14.8 vs 16.1mg/dL (p=0.03) but within normal range. Fasting blood sugar levels were also within normal range, i.e., 94.8 vs 98.8 (p=0.04). Complete blood cell analysis has not revealed any change except slight decrease in hemoglobin 13.25-13.19 g/dL (p=0.0004), but its amount per red blood cell (MCH) increased from 25.62 up to 26.42 picograms/cell (p=0.000003). The average red blood cell size (MCV) increased from 78.5 to 80.0 fl (p=0.00009) but hemoglobin concentration relative to size of the cell (MCHC) has not changed (p=0.2). Hematocrit and red blood cells count decreased slightly, but within normal range 40.7-40.2% (p=0.02) and 5.22-5.05 x 10(6)cells/mm(3) (p=0.002). The number of platelets moved upward, 2.471 vs 2.921 x 10(5)per mm(3) (p=0.009). The white blood cells count and percent of leukocytes and neutrophils were not affected. Pro-inflammatory eosinophils declined from 4.0% down to 2.4% (p=0.29). These results show that V6 is safe and holds a promise as an anti-atherogenic and overweight/obesity immune intervention.
Assuntos
Tecido Adiposo/imunologia , Antígenos/administração & dosagem , Aterosclerose/prevenção & controle , Imunização/métodos , Obesidade/prevenção & controle , Vacinas/administração & dosagem , Administração Oral , Adulto , Idoso , Animais , Antígenos/efeitos adversos , Aterosclerose/imunologia , Fenômenos Fisiológicos Sanguíneos , Pressão Sanguínea/fisiologia , Colesterol/sangue , Feminino , Experimentação Humana , Humanos , Rim/fisiologia , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Fígado/fisiologia , Masculino , Pessoa de Meia-Idade , Obesidade/imunologia , Triglicerídeos/sangue , Vacinas/efeitos adversos , Adulto JovemRESUMO
Franciscan missionary Giovanni Di Plano Carpini traveled in 1245 to a country named Yeke Tartar, to visit a certain man called Genghis Khan. His journey's report narrated peculiar dietary habits of the locals: "they eat anything, even lice". Little that Carpini knew, he had actually documented the earliest known to us record of oral vaccination against blood-borne infections - an approach that is still used occasionally in the present-day Mongolia for therapy of hepatitis. Currently, efforts aimed at developing therapeutic hepatitis vaccines have switched to more palatable path, but we may still benefit from the insight of medieval Mongols. This review provides an update on development of hepatitis B and C vaccines as related to immunotherapy of hepatitis. Immune therapy is a fast-moving field but the results so far failed to pitch woo. Current trends in research on therapeutic vaccine candidates and liver immunology are discussed. We subscribe to the idea that viral hepatitis is essentially an autoimmune disease generating immune-mediated liver damage. Therapeutic vaccines need to be designed in such a way that self-destructive immunity of the host is targeted not the virus, which is not cytopathic.
Assuntos
Vacinas contra Hepatite B/uso terapêutico , Hepatite B/tratamento farmacológico , Hepatite C/tratamento farmacológico , Vacinas Virais/uso terapêutico , Administração Oral , Animais , Antivirais/uso terapêutico , Células Dendríticas/imunologia , Hepatite B/imunologia , Hepatite B/prevenção & controle , Hepatite C/imunologia , Hepatite C/prevenção & controle , Humanos , Vacinas Virais/administração & dosagemRESUMO
It is extremely rare when HIV seropositive adult patients experience spontaneous loss of antibodies, that is, seroreversion. The disappearance of HIV antibodies was occasionally attributed to iatrogenic intervention-serodeconversion. Such interventions include: HAART; oral interferon; Chinese herbal remedies; and therapeutic AIDS vaccines derived from pooled blood. Oral therapeutic, alloimmune AIDS vaccine, V-1 Immunitor (V1), was administered to 60000 HIV-positive Thai patients. The administration of V1 resulted in serodeconversion among 23 individuals. The patient group consisted of 9 females (39%) and 14 males (61%) including two 2-year-old boys. The age range was 2-58 years with mean/median 29/29.3 years. Patients were tested seropositive for HIV at least once before being enrolled on V1. The duration of treatment until discovery of seronegative status ranged between 2 weeks and 15 months with average/median 7.2/8 months. Time to seronegativity was correlated with baseline disease stage (R = 0.62; P = .002). The seronegative status was positively associated with V1-induced undetectable or low viral load (R = 0.65; P = .0008). The odds ratio analysis comparing the outcome of our study with published surveys of diagnostic accuracy of laboratory tests suggested that the probability of HIV antibody testing error was remote (P < .000001). The possible causes responsible for this unusual phenomenon are discussed.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/terapia , Anticorpos Anti-HIV/sangue , Vacinas contra a AIDS/efeitos adversos , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Síndrome da Imunodeficiência Adquirida/virologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não Paramétricas , Tailândia , Carga Viral , Adulto JovemRESUMO
We evaluated whether V-5 Immunitor (V5)--tableted therapeutic bivalent vaccine comprising heat-inactivated HCV antigens from pooled blood of HBV- and HCV-infected donors - may produce clinical benefit through induction of oral tolerance and reduction of immune-mediated liver injury. Once daily dose of V5 was administered per os to 10 patients with chronic hepatitis C in an open-label study that lasted 1 month. Every patient who entered the study had elevated liver enzyme levels, which at the end of study have decreased in 100% of analyzed patients. The reduction was highly significant, from 157.7+/-73.4 to 49.9+/-43.8 U/L (P=0.0013) and 147.0+/-79.2 to 58.7+/-56.6 U/L (P=0.0132), for ALT and AST, respectively. The AST/ALT ratio has improved from 0.93 to 1.18 (P=0.00058) indicating the reversion of progression to cirrhosis. None of intent-to-treat patients who were anti-HCV antibody positive at study entry, became negative after 1 month on V5 (P=0.998). All patients, except one, reported complete recuperation from hepatitis C-associated clinical symptoms present at baseline (P=0.0016) with Mantel Haenszel's odds ratio 9.4 (P=0.0021) at 95% confidence interval: 2.7Assuntos
Vacinas contra Citomegalovirus/administração & dosagem
, Vacinas contra Citomegalovirus/uso terapêutico
, Vacinas contra Hepatite B/administração & dosagem
, Vacinas contra Hepatite B/uso terapêutico
, Hepatite C Crônica/tratamento farmacológico
, Hepatite C Crônica/imunologia
, Vacinas contra Hepatite Viral/administração & dosagem
, Vacinas contra Hepatite Viral/uso terapêutico
, Administração Oral
, Adolescente
, Adulto
, Alanina Transaminase/sangue
, Aspartato Aminotransferases/sangue
, Vacinas contra Citomegalovirus/efeitos adversos
, Feminino
, Vacinas contra Hepatite B/efeitos adversos
, Anticorpos Anti-Hepatite C/sangue
, Hepatite C Crônica/fisiopatologia
, Humanos
, Testes de Função Hepática
, Masculino
, Pessoa de Meia-Idade
, Vacinas contra Hepatite Viral/efeitos adversos
RESUMO
As early as 900 years ago, the Bedouins of the Negev desert were reported to kill a rabid dog, roast its liver and feed it to a dog-bitten person for three to five days according to the size and number of bites [1] . In sixteenth century China, physicians routinely prescribed pills made from the fleas collected from sick cows, which purportedly prevented smallpox. One may dismiss the wisdom of the Bedouins or Chinese but the Nobel laureate, Charles Richet, demonstrated in 1900 that feeding raw meat can cure tuberculous dogs - an approach he termed zomotherapy. Despite historical clues indicating the feasibility of oral vaccination, this particular field is notoriously infamous for the abundance of dead-end leads. Today, most commercial vaccines are delivered by injection, which has the principal limitation that recipients do not like needles. In the last few years, there has been a sharp increase in interest in needle-free vaccine delivery; new data emerges almost daily in the literature. So far, there are very few licensed oral vaccines, but many more vaccine candidates are in development. Vaccines delivered orally have the potential to take immunization to a fundamentally new level. In this review, the authors summarize the recent progress in the area of oral vaccines.
Assuntos
Trato Gastrointestinal/imunologia , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Vacinas de Plantas Comestíveis/administração & dosagem , Vacinas de Produtos Inativados/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Administração Oral , Animais , Química Farmacêutica , Portadores de Fármacos , Composição de Medicamentos , Humanos , Tolerância Imunológica , Imunidade nas Mucosas , Vacinação/tendências , Vacinas Atenuadas/química , Vacinas Atenuadas/imunologia , Vacinas de Plantas Comestíveis/química , Vacinas de Plantas Comestíveis/imunologia , Vacinas de Produtos Inativados/química , Vacinas de Produtos Inativados/imunologiaRESUMO
Death, rather than surrogate markers, is a single and most straightforward clinical endpoint, defining unequivocally the merit of a therapeutic intervention. As there is still neither a cure for AIDS nor a vaccine to prevent HIV infection, an AIDS diagnosis remains associated with a death sentence. V-1 Immunitor (V1) is an experimental, oral, therapeutic AIDS vaccine licensed as a dietary supplement. As part of a charity program V1 has been offered at Wat Phra Baht Nam Phu--a Buddhist hospice for end-stage AIDS patients. Out of 117 approached individuals, 53 decided to take V1 and 64 declined the treatment. Patients in both groups did not differ in age, gender, or severity of disease. All patients were in WHO terminal stage 4 at study entry and had received similar palliative care. None of the patients had received conventional antiviral drugs. At 9 weeks the last two patients in the non-V1 group died. In contrast, 56.6% (30/53) in the V1 group remained alive. Kaplan-Meier survival analysis showed that median short-term survival time for non-treated and treated patients was 4 and 10 weeks, respectively. The difference was statistically significant by Wilcoxon signed rank test (P=0.000089). Patients who remained alive were followed until the last patient died at 142 weeks. Based on the main outcome, i.e. time to death, patients on V1 had a 15.8 times longer life expectancy than the control group (P<0.000001). Observed results are encouraging and V1 needs to be tested in controlled clinical trials as a life-saving immunotherapy.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Síndrome da Imunodeficiência Adquirida/terapia , Imunoterapia Ativa , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/patologia , Feminino , Seguimentos , Humanos , Masculino , Cuidados Paliativos , Análise de Sobrevida , TailândiaRESUMO
The development of prophylactic AIDS vaccines and immunotherapeutic approaches such as therapeutic AIDS vaccines would greatly benefit from acquired experience in reproductive immunology field relating to pregnancy and infertility. Certain immune and pathological aspects of HIV infection are closely related to problems faced by obstetricians, embryologists, gynecologists, and andrologists. This review attempts to bring together the recent advances in AIDS field with progress made in the physiology and pathology of reproduction in humans. The insight gained in reproductive biology research, particularly in the area of immunotherapy of recurrent spontaneous abortions, can help to develop better strategies for the treatment and prevention of HIV infection.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Infecções por HIV/terapia , Imunoterapia Ativa , Infertilidade Feminina/terapia , Aborto Habitual/terapia , Feminino , Humanos , GravidezRESUMO
BACKGROUND: V-1 Immunitor (V1) is an oral AIDS vaccine containing heat- and chemically-inactivated viral antigens derived from pooled blood of HIV-positive donors. V1 has a pending status as an investigational drug but is currently marketed as a dietary supplement. Earlier published, uncontrolled studies of V1 demonstrated body weight gain, increase in T-lymphocyte numbers, decrease in viral load, and improved survival of end-stage AIDS patients. OBJECTIVES AND STUDY DESIGN: In order to substantiate prior observations we have undertaken a placebo-controlled phase II clinical trial involving 47 antiviral therapy naive, asymptomatic individuals who had over 350 mm(3) CD4 T-cells (mean/median 538/480) at study entry. Both placebo and treatment arms were identical demographically and by every clinical parameter measured at baseline. RESULTS AND CONCLUSIONS: At the end of 6-month follow-up 29 volunteers who received V1 b.i.d. had gained on average 43 CD4 T-cells (540 versus 583). This gain was statistically significant (p=0.01) while changes in T-cell numbers in placebo group failed to reach the significance threshold (p=0.33). The clinical potential of V1 is further supported by an elevation in CD4/CD8 ratio among V1 recipients and decline in CD4/CD8 ratio in patients on placebo (0.575 versus 0.524; p=0.02). The average weight gain among patients on V1 was 1.8 kg while placebo group lost 0.5 kg. These results suggest that V1 may delay or reverse the disease progression without any concurrent toxicity and support our prior open-label studies indicating that V1 confers clinical benefit. A phase III clinical study is required to confirm these findings and to allow us to seek license for V1 as a therapeutic AIDS vaccine.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Infecções por HIV/terapia , Administração Oral , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , PlacebosRESUMO
A considerable progress has been made in recent years in the field of drug development against HIV. However, the current cost of AIDS drugs is the main obstacle that prevents their use in developing countries, where 95% of HIV-infected patients reside. The average yearly price of AIDS therapy and related health care of affected patients in the USA runs as high as $22,000 - an amount that corresponds to the combined income of as many as one hundred individuals in developing countries. Even in the USA, patients without medical insurance cannot afford the costly therapy. From the beginning it was clear that the most feasible and economic means of finding a solution is to identify anti-HIV drugs among already available and preferably over-the-counter pharmaceuticals, which have historically been used for unrelated clinical purposes. This review summarizes the development and discovery of affordable and potentially promising AIDS drugs. The anti-HIV activity of drugs and immunomodulating substances such as warfarin, cimetidine, levamisole, acetaminophen, gramicidin, and V-1 immunitor are described and discussed in relation to their clinical application. These compounds may be used in a cocktail drug combination.