• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Prediction method of anemia in treatments with direct-acting antivirals. The present invention relates to a method based on a logistic regression model for predicting or predicting the risk of anemia in an individual before and after initiating the early treatment of Hepatitis C with ribavirin, computer-implemented methods and uses . (Machine-translation by Google Translate, not legally binding)
    公开号:ES2680396A1
    申请号:ES201730241
    申请日:2017-02-23
    公开日:2018-09-06
    发明作者:Emilio MOLINA CUADRADO
    申请人:Servicio Andaluz de Salud；
    IPC主号:
    专利说明:

    image 1
    image2
    image3 DESCRIPTION
    Anemia prediction method in treatments with direct-acting antivirals FIELD OF THE INVENTION
    The present invention is within the field of biomedicine and biotechnology, and refers to a method based on a logistic regression model to predict or predict the risk of suffering from an individual's anemia before and once treatment is initiated early. of Hepatitis C with ribavirin. BACKGROUND OF THE INVENTION
    Hepatitis C virus is one of the leading causative agents of chronic liver disease worldwide1. The long-term impact of the Hepatitis C virus infection is very variable, being able to go from a disease with minimal histological changes to cases in which a wide fibrosis and cirrhosis develops with or without hepatocellular carcinoma. The number of chronically infected people worldwide is estimated at about 160 million people2. The clinical management of patients with liver disease associated with the hepatitis C virus has advanced considerably in the last two decades, thanks to a better knowledge of the pathophysiology of the disease and the development of new diagnostic techniques and therapeutic alternatives.
    Until 2011, the combination of pegylated interferon and ribavirin (PR) for 24 or 48 weeks was the standard of treatment for patients with chronic hepatitis C3. With this regimen, patients infected with hepatitis C virus genotype 1 obtained sustained viral response rates (SVR) of between 40-50% and up to 80% for genotype 2. Genotypes 3, 4, 5 and 6 obtained intermediate SVR rates4.
    In 2011 boceprevir and telaprevir, both protease inhibitors, were approved for the treatment of hepatitis C virus genotype 1. These two drugs were the first direct-acting antiviral drugs (ADF) and both had to be administered in combination with PR5-7 . However, the profile of side effects of this combination and the cost for SVR in patients with advanced liver fibrosis is such that they are no longer recommended as there are other more effective combinations and with better tolerance.
    image4
    image5
    image6
    Several treatments were approved in 2014 for the treatment of hepatitis C. Sofosbuvir, an inhibitor of pangenotypic RNA polymerase. Dasabuvir, an RNA polymerase inhibitor used against hepatitis C virus genotype 1. Simeprevir and Paritaprevir, second generation protease inhibitors active against genotypes 1 and 4 of the virus. Daclatasvir, Ledipasvir, pangenotypic NS5A inhibitors and Ombistavir, NS5A inhibitor used against genotypes 1 and 4.
    All these therapeutic advances that have made the combinations of these new drugs together with PR have practically fallen out of favor in favor of interferon-free combinations. However, the use of ribavirin is still indicated on many occasions, such as in patients with genotype 1a treated with ombistavir / paritaprevir / ritonavir plus dasabuvir and patients with genotype 4 treated with ombistavir / paritaprevir / ritonavir, but it is mostly in cirrhotic patients where its use is recommended associated with the basic treatment indicated 8.
    The most important side effect associated with ribavirin is anemia. A number of factors that increase the risk of anemia during the treatment of hepatitis C with PR are known. Damage to renal function and a drop in hemoglobin> 1.5g / dl in week two has been shown to predict the risk of anemia9. Another study conducted with telaprevir and PR showed that female gender, age> 50 years, body mass index <23kg / m2 and interleukin genotype 28B CC were all risk factors for anemia10.
    However, the incidence of anemia, understood as hemoglobin <10mg / dl at any time during treatment, varies between 20-31% in the case of patients treated with interferon PR11, 12, 38% with telaprevir plus PR13 and 50 % with boceprevir plus PR12. On the other hand, in clinical trials conducted with sofosbuvir / ledipasvir and ombistavir / paritaprevir / ritonavir plus dasabuvir, the incidence of anemia has been 10% in the case of sofosbuvir / ledipasvir14 and between 7.5% and 10.5% in the case of ombistavir / paritaprevir / ritonavir plus dasabuvir depending on the duration of 12 or 24 weeks respectively15. These incidents have therefore occurred, either in treatments combined with pegylated interferon, with durations of 48 weeks longer than 12-24 weeks of current treatments8 or in clinical trials conducted in patients with stricter conditions of inclusion.14, 15 .
    image7
    image8
    image9
    It seems therefore necessary to conduct a study to assess the incidence of anemia and establish what are the predictive factors of anemia in these new circumstances such as the combination of ribavirin with the new ADAs in associations that last 1224 weeks and in real practice situations. BRIEF DESCRIPTION OF THE INVENTION
    A first aspect of the invention relates to the use of the glomerular filtration rate and hemoglobin concentration markers in the logistic regression model of formula (I):
    Probability = 1 / (1 + e- (21,583-0,098 * (CKD-EPI) -2,006 * (Duration W) -0,915 * (Basal Hb))
    Formula (I)
    where Duration W (duration of treatment) is a dichotomous variable that can be equal to 1 (12 weeks) or equal to 0 (> 12 weeks),
    to predict or predict the risk of an individual suffering from anemia before treatment of Hepatitis C with direct-acting antivirals (ADD).
    A preferred embodiment of this aspect of the invention relates to the use of the markers glomerular filtration rate, baseline hemoglobin concentration and the percentage of hemoglobin change from week 0 to 2 in the logistic regression models of formula (II):
    Probability = 1 / (1 + e- (30,447-0,111 * (CKD-EPI) -2,942 * (Duration W) -1,753 * (Basal Hb) + 0.628 * (Hb change% W2))
    Formula (II)
    where Duration W (duration of treatment) is a dichotomous variable that can be equal to 1 (12 weeks) or equal to 0 (> 12 weeks),
    to predict or predict the risk of an individual suffering from anemia after starting the treatment of Hepatitis C with direct-acting antivirals (ADD).
    In another preferred embodiment of this aspect of the invention, ADDs are selected from the list consisting of nucleosides and nucleotides excluding reverse transcriptase inhibitors, cyclic amines, phosphonic acid derivatives, protease inhibitors, nucleosides and nucleotides inhibitors. reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, neuraminidase inhibitors, antivirals for the treatment of HIV infections, other antivirals or any combination thereof. In a more preferred embodiment, the ADDs are nucleosides and nucleotides excluding reverse transcriptase inhibitors. In an even more preferred embodiment, the use of the nucleoside and nucleotide markers excluding reverse transcriptase inhibitors is ribavirin.
    image10
    In another preferred embodiment, the markers of this first aspect of the invention are used to predict or predict the risk of an individual suffering from anemia after treatment of Hepatitis C with Rivabirin and, optionally, together with other direct-acting antivirals. More preferably, hepatitis C treatment is performed with Rivabirin and other direct-acting antivirals (ADD).
    A second aspect of the invention relates to a method of obtaining useful data, hereafter the first method of the invention, to predict or predict the risk of an individual suffering from anemia before treatment of Hepatitis C with ribavirin, which understands:
    a) quantify the markers glomerular filtration rate (CKD-EPI) and basal hemoglobin concentration (Basal Hb) as defined in the first aspect of the invention in an isolated biological sample of an individual, and
    b) apply the logistic regression model of formula (I):
    Probability = 1 / (1 + e- (21,583-0,098 * (CKD-EPI) -2,006 * (Duration W) -0,915 * (Basal Hb))
    In a preferred embodiment, the first method of the invention is a method for predicting or forecasting the risk of an individual suffering from anemia before treatment of Hepatitis C with ribavirin, which comprises steps (a) and (b) of the first method. of the invention, and also comprises:
    c) assign the individual to the group of individuals who will suffer from anemia when it has a probability of at least 50%.
    A third aspect of the invention relates to a method of obtaining useful data, hereafter referred to as the second method of the invention, to predict or predict the risk of an individual suffering from anemia after starting treatment of Hepatitis C with ribavirin. , which includes:
    image11
    image12
    image13
    a) quantify the markers glomerular filtration rate (CKD-EPI), baseline hemoglobin concentration (Basal Hb) and hemoglobin change percentage from week 0 to 2 (HB Change% W2) as defined in the first aspect of the invention in an isolated biological sample of an individual, and
    b) apply the logistic regression model of formula (II):
    Probability = 1 / (1 + e- (30,447-0,111 * (CKD-EPI) -2,942 * (Duration W) -1,753 * (Basal Hb) + 0.628 * (Hb Change% W2))
    In a preferred embodiment, the second method of the invention is a method for predicting
    or predict the risk of an individual suffering from anemia after starting treatment of Hepatitis C with ribavirin, which comprises steps (a) and (b) of the second method of the invention, and also includes:
    c) assign the individual to the group of individuals who will suffer from anemia when it has a probability of at least 50%.
    A fourth aspect of the invention relates to a computer program comprising program instructions to make a computer carry out the process according to any of the methods described in the present invention.
    A fifth aspect of the invention relates to a computer-readable storage medium comprising program instructions capable of having a computer perform the steps of any of the methods described in the present invention.
    A sixth aspect of the invention relates to a transmissible signal comprising program instructions capable of having a computer perform the steps of any of the methods described in the present invention.
    DESCRIPTION OF THE FIGURES
    Figure 1. Time to develop anemia (Hb <10g / dl).
    Figure 2. Change in hemoglobin concentration during treatment.
    Figure 3. Compared change in hemoglobin concentration (g / dl) from week 0 to
    12.
    Figure 4. Result of the bivariate logistic regression analysis.
    image14
    image15
    image16 DETAILED DESCRIPTION OF THE INVENTION
    The authors of the present invention describe the use of a method based on a logistic regression model to predict or predict the risk of an individual suffering from anemia in response to the treatment of Hepatitis C with ribavirin, before and during treatment.
    The present invention greatly helps to improve the safety in the use of ribavirin in the context of the new direct-acting antiviral drugs by forecasting those patients who are most at risk of anemia (which is the main side effect of ribavirin). This allows prior to treatment to identify patients who would be candidates for other treatment options "without ribavirin" or to perform a readjustment of treatment once treatment has begun.
    USE OF MARKERS
    Therefore, a first aspect of the invention relates to the use of the glomerular filtration rate and hemoglobin concentration markers in the logistic regression model of formula (I):
    Probability = 1 / (1 + e- (21,583-0,098 * (CKD-EPI) -2,006 * (Duration W) -0,915 * (Basal Hb))
    Formula (I)
    where Duration W (duration of treatment) is a dichotomous variable that can be equal to 1 (12 weeks) or equal to 0 (> 12 weeks),
    to predict or predict the risk of an individual suffering from anemia before treatment of Hepatitis C with direct-acting antivirals (ADD).
    A preferred embodiment of this aspect of the invention relates to the use of the markers glomerular filtration rate, baseline hemoglobin concentration and the percentage of hemoglobin change from week 0 to 2 in the logistic regression models of formula (II):
    Probability = 1 / (1 + e- (30,447-0,111 * (CKD-EPI) -2,942 * (Duration W) -1,753 * (Basal Hb) + 0.628 * (Hb change% W2))
    Formula (II) where Duration W (duration of treatment) is a dichotomous variable that can be equal to 1 (12 weeks) or equal to 0 (> 12 weeks),
    image17
    image18
    image19
    to predict or predict the risk of suffering from anemia of an individual after starting the treatment of Hepatitis C with direct-acting antivirals (ADD). Preferably once treatment of Hepatitis C with direct-acting antiviral drugs (ADD) is initiated early
    In another preferred embodiment of this aspect of the invention, ADDs are selected from the list consisting of nucleosides and nucleotides excluding reverse transcriptase inhibitors, cyclic amines, phosphonic acid derivatives, protease inhibitors, nucleosides and nucleotides inhibitors. reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, neuraminidase inhibitors, antivirals for the treatment of HIV infections, other antivirals or any combination thereof. In a more preferred embodiment, the ADDs are nucleosides and nucleotides excluding reverse transcriptase inhibitors. In an even more preferred embodiment, the use of the nucleoside and nucleotide markers excluding reverse transcriptase inhibitors is ribavirin.
    In another preferred embodiment, the markers of this first aspect of the invention are used to predict or predict the risk of an individual suffering from anemia after treatment of Hepatitis C with rivabirin and, optionally, together with other direct-acting antivirals. More preferably, hepatitis C treatment is performed with rivabirin and other direct-acting antivirals (ADD).
    The term “logistic regression model, logistic model, logit model, or maximum entropy classifier” refers to a type of regression analysis used to predict the outcome of a categorical variable (a variable that can adopt a limited number of categories) depending on the independent or predictive variables. It is useful for modeling the probability of an event occurring as a function of other factors. In the present invention it is necessary to differentiate the "logistic regression pretreatment model", which uses formula I, and the "logistic regression model intratreatment", which uses formula II.
    The term "marker, biomarker or biological marker" is used to designate that substance used as an indicator of a biological state. It should be able to be measured objectively and evaluated as an indicator of a normal biological process, pathogenic state or response to a pharmacological treatment. More specifically, in the present invention, the markers glomerular filtration rate, baseline hemoglobin concentration (Basal Hb) and percent hemoglobin change from week 0 to 2 (HB Change% W2) are quantified. The determination of the markers can be done by any means known to the person skilled in the art.
    image20
    image21
    image22
    More specifically, the term "glomerular filtration rate or glomerular filtration rate" refers to the volume of fluid filtered per unit of time from the renal glomerular capillaries into the Bowman capsule. It is usually measured in milliliters per minute (ml / min). There are different techniques to calculate or estimate the glomerular filtration rate, these techniques in general make use of an endogenous or added substance that filters almost completely at the glomerular level and that is then almost not reabsorbed or excreted at the tubular level. In the clinic, this index is usually used to measure renal function at the glomerulus level. To calculate it, the formula GFR CKD-EPI (Glomerular Filtration Rate by the Chronic Kidney Disease Epidemiology Collaboration), known by the person skilled in the art, has been used in the present invention, which has the variables age , sex, race and baseline creatinine, and measured in ml / min.
    More specifically, the term "hemoglobin (Hb)" refers to the characteristic red-colored blood protein that carries oxygen from the respiratory organs to the tissues. It is usually measured in grams per deciliter (g / dl). In the clinic, a decrease in hemoglobin values below normal is very common and a characteristic symptom of anemias, repeated hemorrhages and leukemia. In the present invention, the determination of basal hemoglobin (Basal Hb or Basal Hb) is carried out in the case of the pre-treatment and intra-treatment logistic regression model, and the determination of hemoglobin change percentage from week 0 to 2 or at Two weeks of treatment (Hb change% W2) in the intra-treatment logistic regression model.
    In the present invention, "Duration W" (present in formulas I and II of the logistic regression model) is understood as the duration of treatment with ribavirin. This is a dichotomous variable that can be equal to 1 (12 weeks) or equal to 0 (> 12 weeks). The duration of treatment with ribavirin may be equal to or greater than 12 weeks. Preferably the duration of treatment can be between 12 and 24 weeks.
    In the present invention, "prognosis" is understood as the expected evolution of a disease and refers to the assessment of the probability according to which a subject suffers from a disease as well as the assessment of its onset, stage of development, evolution, or its regression, and / or the prognosis of the course of the disease in the future.
    image23
    image24
    image25
    The term "anemia" as described in the present invention refers to a low concentration of hemoglobin in the blood. It is detected by a laboratory test in which a lower than normal level of hemoglobin in the blood is discovered. It can be accompanied by other altered parameters, such as a decrease in the number of red blood cells, or a decrease in hematocrit, but it is not correct to define it as a decrease in the number of red blood cells, since these blood cells can vary considerably in size, sometimes the number of blood cells Red is normal and nevertheless there is anemia.
    The term "Hepatitis C" as described in the present invention, is a liver disease caused by the virus of the same name; This virus can cause an infection, both acute and chronic, the severity of which varies between a mild illness that lasts a few weeks, and a serious disease for life. Hepatitis C virus (HCV) is transmitted through the blood, and the most common causes of infection are unsafe injection practices, inappropriate sterilization of medical equipment, and the transfusion of blood and unprocessed blood products. Worldwide there are between 130 and 150 million people with chronic hepatitis C virus infection. A considerable number of those people with chronic infection will develop cirrhosis or liver cancer. Approximately 700,000 people die each year from liver diseases related to hepatitis C. Antiviral agents can cure more than 90% of cases of hepatitis C virus infection, reducing the risk of death from liver cancer and cirrhosis. , but access to diagnosis and treatment is limited.
    The term "direct-acting antivirals (ADD)" refers to one of the therapeutic groups of systemic antivirals, which in the present invention are used for the treatment of Hepatitis C. Nucleosides and nucleotides are of primary importance. , excluding reverse transcriptase inhibitors, and even more ribavirin. Preferably reference is made to ribavirin in combination with other ADDs.
    An "individual" or "subject", as used herein, refers to a mammal, human or non-human, under observation, and more preferably a human being. The individual can be anyone, an individual predisposed to a disease (for example PCa) or an individual suffering from said disease.
    METHODS OF THE INVENTION
    Prediction of the risk of anemia before treatment with ribavirin
    image26
    image27
    image28
    A second aspect of the invention relates to a method of obtaining useful data, hereafter the first method of the invention, to predict or predict the risk of an individual suffering from anemia before treatment of Hepatitis C with ribavirin, which understands:
    a) quantify the markers glomerular filtration rate (CKD-EPI) and basal hemoglobin concentration (Basal Hb) as defined in the first aspect of the invention in an isolated biological sample of an individual, preferably blood, and
    b) apply the logistic regression model of formula (I):
    Probability = 1 / (1 + e- (21,583-0,098 * (CKD-EPI) -2,006 * (Duration W) -0,915 * (Basal Hb))
    In a preferred embodiment, the first method of the invention is a method of predicting or predicting the risk of an individual suffering from anemia before treatment of Hepatitis C with ribavirin, which comprises steps (a) and (b) of the first method. of the invention, and also comprises:
    c) assign the individual to the group of individuals who will suffer from anemia when it has a probability of at least 50%.
    Prediction of the risk of anemia before treatment with ribavirin
    A third aspect of the invention relates to a method of obtaining useful data, hereafter referred to as the second method of the invention, to predict or predict the risk of an individual suffering from anemia once treatment of Hepatitis C with ribavirin has begun. , which includes:
    a) quantify the markers glomerular filtration rate (CKD-EPI), baseline hemoglobin concentration (Basal Hb) and hemoglobin change percentage from week 0 to 2 (HB Change% W2) as defined in the first aspect of the invention in an isolated biological sample of an individual, preferably blood, and
    b) apply the logistic regression model of formula (II):
    Probability = 1 / (1 + e- (30,447-0,111 * (CKD-EPI) -2,942 * (Duration W) -1,753 * (Basal Hb) + 0.628 * (Hb Change% W2))
    image29
    image30
    image31
    Preferably, the second method of the invention is to predict or predict the risk of an individual suffering from anemia once the treatment of Hepatitis C with ribavirin is initiated early.
    In a preferred embodiment, the second method of the invention is a method for predicting
    or to predict the risk of an individual suffering from anemia after starting the treatment of Hepatitis C with ribavirin, which comprises steps (a) and (b) of the second method of the invention, and also includes:
    c) assign the individual to the group of individuals who will suffer from anemia when it has a probability of at least 50%.
    The term "quantify" as used in the description refers to, but is not limited to, the determination of the absolute or relative amount of markers, their concentration in blood, as well as any other value or parameter related to the same or that may be derived from them. Said values or parameters comprise signal intensity values obtained from any of the physical or chemical properties of said expression products obtained by direct measurement. Additionally, said values
    or parameters include all those obtained by indirect measurement, for example, any of the measurement systems described elsewhere in this document. Steps a) and / or b) of the methods described above can be fully or partially automated, for example, by means of a robotic sensor device for quantification in step a) or the application of the logistic regression model in step b).
    A "biological sample" as defined herein is a small part of a subject, representative of the whole and may be a biopsy or a sample of body fluid. Biopsies are small pieces of tissue and can be fresh, frozen or fixed, as fixed with formalin and embedded in paraffin (formalin-fixed and paraffin embedded FFPE). Samples of body fluids may be blood, plasma, serum, urine, sputum, cerebrospinal fluid, milk or ductal fluid samples and may also be fresh, frozen or fixed. Samples can be surgically removed, by extraction, that is, with hypodermic or other needles, by microdissection or laser capture. The sample must contain any biological material suitable for detecting the desired marker, biomarker or biomarkers / s, therefore, said sample must advantageously comprise material from the subject's cells. Therefore, in a particular embodiment, the biological sample isolated from step a) is a sample of body fluid, preferably blood.
    image32
    image33
    image34
    METHODS IMPLEMENTED BY COMPUTER
    A fourth aspect of the invention relates to a computer program comprising program instructions to make a computer carry out the process according to any of the methods described in the present invention.
    In particular, the invention encompasses computer programs arranged on or within a carrier. The carrier can be any entity or device capable of supporting the program. When the program is incorporated into a signal that can be directly transported by a cable or other device or medium, the carrier may be constituted by said cable or other device or means. As a variant, the carrier could be an integrated circuit in which the program is included, the integrated circuit being adapted to execute, or to be used in the execution of the corresponding processes.
    For example, the programs could be incorporated into a storage medium, such as a ROM, a CD ROM or a semiconductor ROM, a USB memory, or a magnetic recording medium, for example, a floppy disk or a disk Lasted. Alternatively, the programs could be supported on a transmissible carrier signal. For example, it could be an electrical or optical signal that could be transported through an electrical or optical cable, by radio or by any other means.
    A fifth aspect of the invention relates to a computer-readable storage medium comprising program instructions capable of having a computer perform the steps of any of the methods described in the present invention.
    A sixth aspect of the invention relates to a transmissible signal comprising program instructions capable of having a computer perform the steps of any of the methods described in the present invention.
    Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.
    image35 EXAMPLES OF THE INVENTION
    In this work, a tool was applied that greatly helps to improve the safety in the use of ribavirin in the context of the new direct-acting antivirals. When predicting those patients who are most at risk of anemia (which is the main side effect of ribavirin). This allows prior to treatment to identify patients who would be candidates for other treatment options "without ribavirin" or to perform a readjustment of treatment once treatment has begun.
    A study of a retrospective cohort of patients treated with ribavirin and ADF in a third level hospital was performed. Since it has been a retrospective observational study, ethical aspects have been related to the confidentiality of information. The database was completely anonymous, each participant identified with a numerical code and the personal data to which each code was assigned were kept in a separate file that had high-level security measures. The study was approved by the independent ethical committee of the institution in compliance with the principles of the Helsinki declaration.
    Example 1. Materials and Methods
    Patients
    A total of 152 patients were included in the study. Patients older than 18 years, weighing between 40 and 125 kg, a viral load> 10,000 IU / ml (TaqMan v2.0; Roche Diagnostics) 16 and genotypes 1, 2, 3 and 4 were included. Our sample also included they included patients with renal insufficiency, decompensated cirrhosis, hepatitis B virus infection as well as human immunodeficiency. The baseline characteristics of the patients can be seen in Table 1.
    image36
    image37
    image38
    Table 1. Baseline characteristics of the patients.
    n = 152
    Age, average age (interval) 54.73 (8.60)
    Sex, man, n (%) 119 (78.30)
    FibroScan score, average kPa (DS) 17.60 (9.99)
    Fibrosis
    Non-cirrhotic, n (%) 57 (37.50)
    F1 5 (3.30)
    F2 17 (11.20)
    F3 35 (23.00)
    Cirrhotic, n (%)
    F4 95 (62.50)
    GFR CKD-EPI, mean, ml / min (DS) 98 (16.81)
    HCV RNA x106 medium, copies / ml (DS) 2.79 (3.5)
    Platelets, x103 average, units / µl (DS) 157.99 (83.77)
    Albumine, media, g / dl (DS) 4.11 (0.50)
    ALT, mean, U / l (DS) 83.11 (52.08)
    Weight> 75kg, n (%) 73 (48.00)
    image39
    image40
    image41
    Naive n (%) Treatment duration 12 weeks /> 12 weeks, n (%) Mean baseline hemoglobin g / dL (DS) 86 (56.60) 128/24 (84.20 / 15.80) 14.93 (1.62)
    HCV genotype, n (%)
    one 102 (67.10)
    2 5 (3.30)
    3 24 (15.80)
    4 21 (13.80)
    Treatment associated with ribavirin n (%)
    Sofosbuvir-Ledipasvir 59 (38.80)
    Ombistavir-Paritaprevir-Ritonavir-Dasabuvir 31 (20.40)
    Sofosbuvir-Simeprevir 17 (11.20)
    Sofosbuvir-Daclatasvir 18 (11.80)
    Sofosbuvir 5 (3.30)
    Sofosbuvir-PegInterferon 10 (6.60)
    Simeprevir-Peginterferon 3 (2.00)
    Ombistavir-Paritaprevir-Ritonavir 9 (5.90)
    Abbreviations: ALT, Alanin Aminotransferase; IC, Confidence Interval; GFR CKD-EPI, Glomerular Filtration Rate for Chronic Kidney Disease Epidemiology Collaboration; HCV, hepatitis C virus; DS, Standard deviation.
    Study regime
    The treatments used were all the recommended combinations for the different genotypes, associated with a daily dose of ribavirin depending on weight, 1000mg for patients under 75 kg and 1200mg for patients with 75 kg or more8. For the management of anemia, the dose of ribavirin was reduced to 800mg if hemoglobin levels fell below 10g / dl and was discontinued when hemoglobin dropped to less than 8.5g / dl17.
    image42
    image43
    image44
    Study variables
    The monitoring of serum hemoglobin was carried out following clinical practice in our center, that is: before starting treatment and at 4, 8, 12 in patients with 12-week treatment, extending to 16, 20 and 24 weeks for patients. patients with 24-week treatment. Patients with anemia (hemoglobin <10g / dl) and the week of occurrence of the event were also registered. Likewise, the maximum decrease produced in the hemoglobin of the patients during the entire treatment, the change of hemoglobin from baseline to week 4 was measured and finally an estimation of what the hemoglobin would be made at two weeks of the study, to calculate the percentage of hemoglobin decrease from week 0 to 2 and use it as an early predictor of the onset of anemia in the logistic regression model. For this, what was done was to calculate the average hemoglobin decrease between week 0 and week 4 and subtract it from baseline hemoglobin. The baseline characteristics of the registered patients were: sex, age, type of treatment, genotype, FibroScan® score, degree of fibrosis, viral load, dose, weight, estimation of glomerular filtration according to Glomerular Filtration Rate by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Alanine Aminotransferase (ALT), albumin, platelets, duration of treatment and if the patient was naive.
    Statistic analysis
    To achieve an accuracy of 5.00% in the estimation of a proportion by means of a normal asymptotic confidence interval at 95.00% bilateral, assuming that the proportion would be 10.00%, it was calculated that it would be necessary to include 139 experimental units in the study to which 10% was added in anticipation of any loss of information. To compare the baseline characteristics of patients with anemia and without anemia, the Student and U Mann-Whitney tests for continuous variables and the Chi-square test for categorical variables were performed. The p value of statistical significance was ≤ 0.05. To verify the difference in hemoglobin values at weeks 0, 4, 8, and 12, an analysis of variance (ANOVA) was performed for paired means. An univariable logistic regression analysis was initially performed and subsequently multivariable to assess the association between possible predictors and the occurrence of anemia. The characteristics initially included in the bivariate analysis were: sex, age, FibroScan score, whether cirrhotic or not, viral load, dose, CKD-EPI, ALT, albumin, treatment duration 12 vs> 12 weeks, baseline hemoglobin and Estimated percent decrease in hemoglobin from week 0 to week 2.
    image45
    image46
    image47
    In the model of forced entry of multivariate logistic regression, the variables were introduced if the Chi-square test was significant in the bivariate analysis for a significance level of ≤ 0.1. On the other hand, the variables were removed from the model if the Wald Chi-square test was not significant for a significance level of ≤ 0.05. The odds ratio and 95% confidence interval (95% CI) were calculated from the factors that were significantly predict the risk of anemia.
    In parallel, two models were developed with the variables that significantly predicted the risk of anemia. A model to predict anemia before starting treatment and another model to detect early the risk of anemia once started. Finally, the results predicted by the models were compared with the results actually observed in our patients to calculate the positive predictive value and the negative predictive value. The positive predictive value was defined as the percentage of patients in whom the model predicted that they would have anemia and actually had it. The positive predictive value was defined as the percentage of patients in whom the model predicted that they would not have anemia and that they did not really suffer anemia.
    Example 2. Results
    Anemia
    23 patients suffered anemia during the study period (15.10%). Of these in four (2.63%) hemoglobin was <8.5g / dl. The baseline characteristics compared between the population that developed anemia and those not shown in Table 2. It shows that the characteristics in which there were significant differences were: age (p≤ 0001), sex (p ≤ 0 , 01) estimated glomerular filtration rate (p ≤ 0.001), platelet count, (p ≤ 0.05), albumin (p ≤ 0.01), treatment duration greater than 12 weeks (p ≤ 0.05) and hemoglobin baseline (p ≤ 0.001). Although there were no significant differences in the proportion of cirrhotic patients, it should be noted that no patient with F1 or F2 fibrosis had anemia.
    image48
    Table 2. Baseline characteristics compared
    Parameters Patients with Hb> 10g / dL (n = 129)Patients with Hb <10g / dL (n = 23)p-value
    Age, mean age (SD) 53.75 (7.64)60.22 (11.44)p≤0.001a
    Sex, man, n (%) 107 (82.90)12 (52.20)p≤0.01b
    FibroScan, average score (DS) 17.20 (17.20)19.88 (19.89)nsc
    Cirrhotic, n (%) 78 (60.05)17 (73.90)nsb
    GFR CKD-EPI, mean, ml / min (DS) 99.92 (11.03)73.05 (24.33)p≤0.001a
    HCV RNA x106 average, copies / ml (DS) Platelets, average, x 103 unit / µL (DS) 2.87 (3.70) 164.64 (86.10) 4.16 (0.47)2.32 (2.46) 120.69 (57.57) 3.85 (0.59)nsc p≤0.05a p≤0.01a
    Albumine, media, g / dl (DS) 83.48 (52.70)81.04 (49.52)nsc
    ALT, mean, U / L (DS) 66 (51.20)7 (30.40)nsb
    Weight> 75kg, n (%) 73 (56.60%)13 (56.50)nsb
    Naive, n (%) Duration of treatment> 12 weeks, n (%) 16 (20.40) 15.29 (1.35)8 (34.80) 12.88 (1.45)p≤0.05b p≤0.001a
    Basal hemoglobin average g / dl
    (DS)
    a: Student test, b: Chi-square test, c: Mann-Whitney U test.
    Abbreviations: ALT, Alanin Aminotransferase; IC, Confidence Interval; GFR CKD-EPI, Glomerular Filtration Rate for Chronic Kidney Disease Epidemiology Collaboration; HCV, hepatitis C virus; ns, not significant DS, Standard deviation.
    image49
    image50
    image51
    Anemia appeared mostly in the first month of treatment (9 cases) (Figure 1). The average decrease in hemoglobin during treatment was 2.67 95% CI (2.45-2.90). The average hemoglobin at weeks 0, 4, 8, 12, 16, 20, 24 can be seen in Figure 2, the ANOVA performed from week 0 to week 12 showed a statistically significant difference in the hemoglobin means (p ≤ 0.001 ). This figure shows how this difference occurred mostly from week 0 to week 4 and then softened and even stabilized in the following weeks. Figure 3 shows that the difference is statistically significant between each group of patients (anemia vs. non-anemia) for each week (p <0.001). The slope in the decrease of hemoglobin from week 0 to week 4 was more pronounced in patients with anemia than in patients without anemia and then had a similar behavior from this week.
    Bivariate logistic regression analysis
    The results of this analysis are shown in Figure 4. It is observed that female sex, age, estimated glomerular filtration rate, albumin, duration of treatment, baseline hemoglobin and percent hemoglobin decrease from week 0 to week 2 were factors associated with the occurrence of anemia during treatment with ribavirin. (p <0.05). The rest did not show a statistically significant association. Stresses that although being cirrhotic did not prove to be associated with the onset of anemia, none of the F1 and F2 patients (n = 22) had anemia. On the other hand, of the 115 patients with CKD-EPI> 90ml / min, only 4.30% had anemia showing a protective effect (OR, 0.05; IC95, 0.02-0.14).
    Multivariate logistic regression analysis
    The final multivariate analysis identified 4 predictive factors: the estimated glomerular filtration rate, baseline hemoglobin, treatment duration 12 weeks and the percentage decrease in hemoglobin from week 0 to week 2 (p≤0.05). In contrast, albumin and dose were not shown to be associated with the onset of anemia (Table 3).
    image52
    image53
    image54
    Anemia prediction pretreatment model
    Based on the results obtained in Table 3, the regression coefficients of the baseline variables of the patients were used to construct a predictive pretreatment model whose formula is:
    Probability = 1 / (1 + e- (21,583-0,098 * (CKD-EPI) -2,006 * (Duration W) -0,915 * (Basal Hb)),
    R2 Nagelkerker = 0.64.
    Subsequently, the predicted results were compared with those observed to calculate the predictive values, obtaining a positive predictive value of 86.60% and a negative predictive value of 92.70%. The Hosmer-Lemeshow test indicates that the proposed model has been adjusted to the observed (p = 0.784) and that the discrimination capacity of the model is good since the Area under the ROC curve has been 0.942 (0.904-0.981 ).
    Intratratramiene model of anemia predition
    Based on the results obtained in Table 3, the regression coefficients of the baseline variables and the percentage of hemoglobin decrease estimated in week 2 were used to construct an intra-treatment predictive model. The reason for using this estimated variable was that during the study it was observed that in week 4 there had been 9 of the 23 cases of anemia, so it was decided to use an early variable that allows implementing measures before the event appears. The formula of the model is:
    Probability = 1 / (1 + e- (30,447-0,111 * (CKD-EPI) -2,942 * (Duration W) -1,753 * (Basal Hb) + 0.628 * (Hb Change% W2)),
    R2 Nagelkerker = 0.80.
    Subsequently, the predicted results were compared with those observed to calculate the predictive values, obtaining a positive predictive value of 90.48% and a negative predictive value of 96.95%. The Hosmer-Lemeshow test indicates that the proposed model has been adjusted to what was observed (p = 0.613) and that the discrimination capacity of the model is good since the Area under the ROC curve has been 0.978 95% CI (0 , 9551,000).
    image55
    image56
    image57
    Table 3. Multivariate logistic regression analysis result (Ribaviririn-induced anemia)
    image58
    a: Wald Chi-square test
    5 Abbreviations: CI Confidence interval; ns, not significant; OR, Odds ratio; CR, regression coefficient
    Example 3. Discussion
    In this study, the characteristics of the analyzed patients have been of real practice to
    10 difference from other studies with interferon in which conditions were more stringent, excluding patients with decompensated cirrhosis, renal failure, hepatitis B virus infection or human immunodeficiency.5, 7, 9. However, in this study Cirrhotic patients have been included mostly. In addition, in this study 25% of patients had mild-moderate renal impairment and included coinfected patients. Despite these
    15 more flexible criteria for inclusion in the study the percentage of patients with anemia (15.10%), has been lower than when the PR combination was used 48 weeks (20-30) 11, 12 and significantly lower than the combinations of telaprevir and boceprevir with PR (30-50%) 12, 13 on the contrary has been higher than in clinical trials conducted with sofosbuvir / ledipasvir (10%) 14 and ombistavir / paritaprevir / ritonavir plus dasabuvir (7.5-10, 5%) 15. The cause of this lower incidence when compared to combinations that carry interferon, telaprevir and boceprevir, is that on the one hand all these treatments enhance the risk of anemia caused by ribavirin and on the other hand the shorter duration of exposure to ribavirin It is likely that he has favored this lower incidence of anemia. On the contrary, the higher incidence of anemia in our study with respect to clinical trials with sofosbuvir / ledipasvir and and ombistavir / paritaprevir / ritonavir plus dasabuvir could be due, on the one hand, to 8.60% of our patients who were treated with combinations that included interferon of which one had anemia, this is a limitation of our work, on the other hand although we have not found the renal function of the patients in the studies with sofosbuvir / ledipasvir and ombistavir / paritaprevir / ritonavir plus dasabuvir could be that The fact that our study includes 25% of patients with mild-moderate renal impairment has influenced this slight higher incidence.
    image59
    image60
    image61
    As for the kinetics in the decrease in hemoglobin, the behavior in our study has been similar to that observed in studies conducted with PR, in which it was observed that the greatest decrease in hemoglobin occurred in the first 4 weeks and then stabilized9 , 11. This behavior has also coincided when patients have been stratified based on whether they have suffered anemia or not. So the decrease between week 0 and 4 has been more pronounced among patients with anemia than in patients without anemia11.
    From the bivariate analysis, it can be deduced that variables such as FibroScan score, viral load, ALT, or being cirrhotic have not been associated with anemia. Still, it should be noted that no patient with grades of F1 or F2 fibrosis has had anemia. We have also found that a CKD-EPI value> 90ml / min was associated with a lower risk of anemia.
    The results of the multivariate regression analysis have shown that baseline hemoglobin is associated with the risk of anemia as in the works of Zeuzem et al13 and Reau et al9. In addition, we have also found that glomerular filtration is also associated with the risk of anemia as in the work of Reau et al9. However, this variable does not fall within the variables analyzed in other studies carried out in this field11-13, 18. Finally, this multivariate analysis showed that the treatment duration of 12 weeks is also a factor that reduces the risk of anemia. This indicator had not been studied before, perhaps because the treatments performed with PR or with PR plus boceprevir or telaprevir had a duration of approximately 48 weeks.
    image62
    image63
    image64
    The sex and age variables that were significant in the bivariate analysis were not included in the multivariate analysis. This result could suggest that it disagrees with the results obtained in other studies in which the sex and age variables did predict the risk of anemia.13, 18. The reason for not including them was that these variables are used to calculate the CKD-EPI. that the inclusion of these variables in the multivariate analysis could generate collinearity biases. Our result is similar to the result of Reau et al9, in which, like us, we took into account glomerular filtration and in which the sex and age variables were significant in the bivariate analysis but not in the multivariate analysis and in turn explains why in In studies where glomerular filtration has not been analyzed as a possible predictor of anemia, the variables sex and age are statistically significant in the multivariate analysis.13, 18
    Finally, we find ourselves in a context in which ribavirin continues to have a role as a complementary treatment, although not as decisive as in previous decades. This allows us, before starting treatment, that we can consider other options that do not include ribavirin or the choice of the same alternative with extensions of 12 to 24 weeks8. Similarly, it allows us to anticipate the onset of anemia by reducing the dose or changing treatment durations, without the need to use erythropoietins that are also associated with adverse effects such as neoplasms, thrombotic events or hypertension19, 20.
    Within this new framework for the use of ribavirin, our study has allowed us to develop two models of anemia prediction. A pretreatment model and an intratreatment model to reduce the risk of anemia. The strategy we suggest to reduce the risk of anemia would be the following: first use the pretreatment predictive model so that if the model predicts the onset of anemia (positive predictive value of 86.6%), alternatives without ribavirin are sought. The application of this model when the predicted results have been compared with those observed would have avoided 5 of the 9 episodes of anemia that occur in week 4 and 3 of the 4 episodes of anemia that occurred with values <8.5g / dl. For patients in whom the pretreatment model predicts low risk of anemia (negative predictive value of 92.70%), the next step could be to start the combination with ribavirin and use the early predictive intratreatment model (positive predictive value of 90, 48%), to reduce the dose of ribavirin
    or even change the duration of treatments from 12 to 24 weeks before anemia appears. The application of this model when comparing the expected and observed results shows that the model predicts all patients with anemia before week 4 and all patients with anemia <8.5g / dl. Both models used together are an easy and useful tool to improve the safety in the use of ribavirin.
    image65
    Therefore, from this data we can extract that:
    one.  The incidence of anemia in these conditions of real practice has been lower than when ribavirin is associated with interferon, boceprevir and telaprevir, but somewhat higher than when compared to the results obtained in clinical trials.
    2.  The decrease in hemoglobin is mainly observed in the first four weeks.
    3.  The variables that have been shown to significantly predict the risk of anemia have been baseline hemoglobin, glomerular filtration, duration of treatment 12 weeks and percentage decrease in hemoglobin from week 0 to 2.
    Four.  This analysis has allowed the development of a tool that identifies patients at risk of anemia, improving the safety of the use of ribavirin.
    Example 4. Implementation of the logistic regression model
    As an example of the application of this logistic regression model to predict or predict the risk of suffering from an individual's anemia in the treatment of Hepatitis C with ribavirin, in an explanatory and non-limiting manner, the clinical case of a patient with White race with Hepatitis C genotype 1st degree of Fibrosis F2 to which it is decided to apply this logistic regression model before the choice of therapy. The patient is a 50-year-old male, whose baseline Hemoglobin (Hb) is 15g / dl, the indicated duration of treatment is 12 weeks and the baseline serum creatinine is 0.8mg / dl. In this way, the imputs of the pretreatment model would be:
    Basal Hb = 15g / dl
    Duration = 12 weeks (dichotomous variable 0/1. In this case the imput would be 1)
    CKD-EPI: According to age, sex, race and baseline creatinine (50 years, male, Caucasian, 0.8) = 104.16ml / min
    image66
    image67
    image68
    The calculated probability of anemia is 12% therefore <50% and the logistic regression model indicates that it is low risk and therefore would be a candidate to start treatment, in this case, with Ombistavir / Paritaprevir / Ritonavir 2 tablets in the breakfast + Dasabuvir 1 tablet / 12h in combination with ribavirin 3 tablets / 12h. The predictive pretreatment model has a negative predictive value of 92.7%, that is, it predicts that the patient is low risk, the model is successful 92.7% of the time.
    In this same patient, at two weeks, an intra-treatment logistic regression model is applied, in which a Hb determination is made again. The patient in this case has an Hb of 12g / dL. In other words, a decrease of 3g / dL (the baseline was 15g / dL), which represents a decrease in Hb of 20%.
    In this way, the imputs of the intratreatment model would be:
    Basal Hb = 15g / dl
    Duration = 12 weeks (dichotomous variable 0/1. In this case the imput would be 1)
    CKD-EPI: According to age, sex, race and baseline creatinine (50 years, male, Caucasian, 0.8) = 104.16ml / min
    % Decrease Hb week 0-2 = 20%
    In this case, the intra-treatment model detects that the patient has an 87% chance of having anemia (> 50%) and indicates that the patient is at risk of anemia.
    The greatest risk of anemia is at 4 weeks of treatment with ribavirin, so that, with the result obtained, in week two it could either lower the dose of ribavirin to 2 tablets / 12h or withdraw ribavirin and extend The duration of treatment at 24 weeks only with Ombistavir / Paritaprevir / Ritonavir 2 tablets at breakfast + Dasabuvir 1 tablet / 12h as indicated by the guidelines and thus anticipate the onset of anemia. The positive predictive value of this intratreatment model is 90.48%, that is, if the model predicts that the patient is at risk of anemia, it is correct 90.48% of the time.
    image69
    image70
    image71 REFERENCES
    one. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011; 17 (2): 107-115.
    2. World Health Organization Hepatitis C. Available at http://www.who.int/mediacentre/factsheets/fs164/en/ Last accessed 3 Agost. 2016.
    3. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 55 (2): 245-264.
    Four. Antaki N, Craxi A, Kamal S et al. The neglected hepatitis C virus genotypes 4, 5 and
    6: an international consensus report. Liver Int 2010; 30 (3): 342-355.
    5. Jacobson IM, McHutchison JG, Dusheiko G et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364 (25): 2405-2416.
    6. Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364 (25): 2417-2428.
    7. Poordad F, McCone J, Jr., Bacon BR et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364 (13): 1195-1206.
    8. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2016; http: //dx.doi.org/10.1016/j.jhep.2016.09.001.
    9. Reau N, Hadziyannis SJ, Messinger D, Fried MW, Jensen DM. Early predictors of anemia in patients with hepatitis C genotype 1 treated with peginterferon alfa-2a (40KD) plus ribavirin. Am J Gastroenterol 2008; 103 (8): 1981-1988.
    10. Suzuki F, Suzuki Y, Akuta N et al. Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir. Hepatology 2011; 53 (2): 415-421.
    eleven. Nomura H, Tanimoto H, Kajiwara E et al. Factors contributing to ribavirin-induced anemia. J Gastroenterol Hepatol 2004; 19 (11): 1312-1317.
    12. Sulkowski MS, Poordad F, Manns MP et al. Anemia during treatment with peginterferon Alfa-2b / ribavirin and boceprevir: Analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial. Hepatology 2013; 57 (3): 974-984.
    13. Zeuzem S, DeMasi R, Baldini A et al. Risk factors predictive of anemia development during telaprevir plus peginterferon / ribavirin therapy in treatment-experienced patients. J Hepatol 2014; 60 (6): 1112-1117.
    image72
    image73
    image74
    14. Afdhal N, Zeuzem S, Kwo P et al. Ledipasvir and sofosbuvir for untreated HCV 5 genotype 1 infection. N Engl J Med 2014; 370 (20): 1889-1898.
    fifteen. Poordad F, Hezode C, Trinh R et al. ABT-450 / r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370 (21): 1973-1982.
    16. Barbeau JM, Goforth J, Caliendo AM, Nolte FS. Performance characteristics of a
    quantitative TaqMan hepatitis C virus RNA analyte-specific reagent. J Clin Microbiol 10 2004; 42 (8): 3739-3746.
    17. Hadziyannis SJ, Sette H, Jr., Morgan TR et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140 (5): 346-355.
    18. Snoeck E, Wade JR, Duff F, Lamb M, Jorga K. Predicting sustained virological
    15 response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin. Br J Clin Pharmacol 2006; 62 (6): 699-709.
    19. Lindahl K, Stahle L, Bruchfeld A, Schvarcz R. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 2005; 41 (2): 275-279.
    20 20. McHutchison JG, Lawitz EJ, Shiffman ML et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361 (6): 580-593.
    权利要求:
    Claims (13)
    [1]
    image 1
    image2
    image3
    1. Use of the markers glomerular filtration rate and hemoglobin concentration in the logistic regression model of formula (I):
    Probability = 1 / (1 + e- (21,583-0,098 * (CKD-EPI) -2,006 * (Duration W) -0,915 * (Basal Hb))
    Formula (I)
    where Duration W (duration of treatment) is a dichotomous variable that can be equal to 1 (12 weeks) or equal to 0 (> 12 weeks),
    to predict or predict, before treatment, the risk of an individual suffering from anemia before treatment of Hepatitis C with direct-acting antiviral drugs (ADD).
    [2]
    2. Use of the markers glomerular filtration rate and basal hemoglobin concentration according to claim 1, and additionally the hemoglobin change percentage from week 0 to 2, in the logistic regression model of formula (II):
    Probability = 1 / (1 + e- (30,447-0,111 * (CKD-EPI) -2,942 * (Duration W) -1,753 * (Basal Hb) + 0.628 * (Hb change% W2))
    Formula (II)
    where Duration W (duration of treatment) is a dichotomous variable that can be equal to 1 (12 weeks) or equal to 0 (> 12 weeks),
    To predict or predict, the risk of an individual suffering from anemia after starting the treatment of Hepatitis C with direct-acting antiviral drugs (ADD).
    [3]
    3. The use of the markers according to any of claims 1-2, wherein the ADDs are selected from the list consisting of nucleosides and nucleotides excluding reverse transcriptase inhibitors, cyclic amines, phosphonic acid derivatives, protease inhibitors, nucleosides and nucleotides reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, neuraminidase inhibitors, antivirals for the treatment of HIV infections, other antivirals or any combination thereof.
    [4]
    Four. The use of the markers according to any of claims 1-3, wherein the ADDs are nucleosides and nucleotides excluding reverse transcriptase inhibitors.
    [5]
    5. The use of the markers according to claim 4, wherein the nucleosides and nucleotides excluding reverse transcriptase inhibitors is ribavirin.
    [6]
    6. The use of the markers according to any of claims 1-5, to predict
    29
    image4
    or predict the risk of suffering from an individual's anemia to the treatment of Hepatitis C with ribavirin, associated with other direct-acting antivirals (ADD).
    [7]
    7. A method of obtaining useful data to predict or predict, before treatment, the risk of an individual suffering from anemia as a result of Hepatitis C treatment with ribavirin, which comprises:
    a) quantifying the markers glomerular filtration rate and baseline hemoglobin concentration, as defined in claim 1, in an isolated biological sample of an individual, and
    b) apply the logistic regression model of formula (I):
    Probability = 1 / (1 + e- (21,583-0,098 * (CKD-EPI) -2,006 * (Duration W) -0,915 * (Basal Hb))
    [8]
    8. A method for predicting or forecasting, before treatment, the risk of an individual suffering from anemia as a result of the treatment of Hepatitis C with ribavirin, which comprises steps (a) and (b) according to the preceding claim, and further comprises:
    c) assign the individual to the group of individuals who will suffer from anemia when it has a probability of at least 50%.
    [9]
    9. A method of obtaining useful data to predict or predict, once treatment has begun, the risk of an individual suffering from anemia as a result of Hepatitis C treatment with ribavirin, which includes:
    a) quantify the markers glomerular filtration rate, baseline hemoglobin concentration and hemoglobin change percentage from week 0 to 2 (HB Change% W2) as defined in claim 2, in an isolated biological sample of an individual , Y
    b) apply the logistic regression model of formula (II):
    30
    image5
    image6
    image7
    Probability = 1 / (1 + e- (30,447-0,111 * (CKD-EPI) -2,942 * (Duration W) -1,753 * (Basal Hb) + 0.628 * (Hb Change% W2))
    [10]
    10. A method of predicting or forecasting, once treatment has begun, the risk of an individual suffering from anemia as a result of the treatment of Hepatitis C with ribavirin, comprising steps (a) and (b) according to the preceding claim, Y
    5 also includes:
    c) Assign the individual to the group of individuals who will suffer from anemia when it has a probability of at least 50%.
    [11]
    11. A computer program comprising program instructions to do
    for a computer to implement the method as described in any one of claims 7–10.
    [12]
    12. A computer-readable storage medium comprising program instructions capable of having a computer perform the steps of any of the methods described in any of claims 7–
    [10]
    10.
    13. A transmissible signal comprising program instructions capable of having a computer perform the steps of any of the methods described in any of claims 7-10.
    31
    类似技术:
    公开号 | 公开日 | 专利标题
    Kim et al.2012|The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis
    Martinez et al.2011|Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C
    El Raziky et al.2013|The effect of peginterferon alpha-2a vs. peginterferon alpha-2b in treatment of naive chronic HCV genotype-4 patients: a single centre Egyptian study
    Brown et al.2012|Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs
    Hofmann et al.2011|Risk of kidney cancer and chronic kidney disease in relation to hepatitis C virus infection: a nationwide register-based cohort study in Sweden
    Wang et al.2019|Albumin-Bilirubin | as an accurate and simple prognostic score for chronic hepatitis B-related liver cirrhosis
    Fung et al.2010|Hepatitis B virus DNA and hepatitis B surface antigen levels in chronic hepatitis B
    Kurosaki et al.2012|Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C
    Festa et al.2014|Acute fulminant hepatitis E virus genotype 3e infection: description of the first case in Europe
    Gonzalez et al.2016|Virologic cure of hepatitis C: impact on hepatic fibrosis and patient outcomes
    Hou et al.2015|Long-term telbivudine treatment results in resolution of liver inflammation and fibrosis in patients with chronic hepatitis B
    Tag-Adeen et al.2017|Impact of hepatitis C virus genotype-4 eradication following direct acting antivirals on liver stiffness measurement
    Kondo et al.2017|Daclatasvir and asunaprevir for genotype 1b chronic hepatitis C patients with chronic kidney disease
    Sayyar et al.2019|Platelet count increases after viral elimination in chronic HCV, independent of the presence or absence of cirrhosis
    Wu et al.2019|HEV‐LFS: A novel scoring model for patients with hepatitis E virus‐related liver failure
    Maesaka et al.2021|Clinical course of hepatitis C virus‐positive patients with decompensated liver cirrhosis in the era of direct‐acting antiviral treatment
    Kobeisy et al.2012|Clinical significance of elevated alpha-foetoprotein | in patients with chronic hepatitis C without hepatocellular carcinoma in upper EGYPT
    Loo et al.2019|Real-world observational experience with direct-acting antivirals for hepatitis C: baseline resistance, efficacy, and need for long-term surveillance
    ES2680396B1|2019-06-19|Prediction method of anemia in treatments with direct-acting antivirals
    Van Tong et al.2018|Interferon-stimulated gene 20 kDa protein serum levels and clinical outcome of hepatitis B virus-related liver diseases
    Park et al.2015|Serum gamma-glutamyltransferase levels predict clinical outcomes in hemodialysis patients
    Assmar et al.2016|Combined evaluation of AFP, CA15-3, CA125, CA19-9, and CEA tumor markers in patients with hepatitis B and C
    Hsu et al.2021|Hepatitis C virus eradication decreases the risks of liver cirrhosis and cirrhosis‐related complications |
    Bassyouni et al.2020|Possible Association of Elevated Plasma Levels of Growth Arrest-Specific Protein 6 and the Soluble Form of Tyrosine Kinase Receptor Axl with Low Hepatitis C Viral Load in Patients with Type 2 Diabetes Mellitus
    Fontana et al.2004|Controversies in the management of hepatitis C patients with advanced fibrosis and cirrhosis
    同族专利:
    公开号 | 公开日
    ES2680396B1|2019-06-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2018-09-06| BA2A| Patent application published|Ref document number: 2680396 Country of ref document: ES Kind code of ref document: A1 Effective date: 20180906 |
    2019-06-19| FG2A| Definitive protection|Ref document number: 2680396 Country of ref document: ES Kind code of ref document: B1 Effective date: 20190619 |
    2021-10-04| FD2A| Announcement of lapse in spain|Effective date: 20211004 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201730241A|ES2680396B1|2017-02-23|2017-02-23|Prediction method of anemia in treatments with direct-acting antivirals|ES201730241A| ES2680396B1|2017-02-23|2017-02-23|Prediction method of anemia in treatments with direct-acting antivirals|
    [返回顶部]