Interferon Alpha-2b Combination Research Articles

Possibility of using a combination of interferon alpha-2b and a complex immunoglobulin drug for infectious diseases in children

Possibility of using a combination of interferon alpha-2b and a complex immunoglobulin drug for infectious diseases in children

Keratopathy in Patients with Adenoviral Keratoconjunctivitis: Evaluation of the Effectiveness of Modern Interferon Preparations

It is considered, that one of the main directions of treatment of adenovirus conjunctivitis is the appointment of interferon alpha-2b in combination with diphenhydramine, which until recently was provided by the only original drug. In 2020, the first generic drug, Interferon-Oftalmo, would be registered in Russia.The purpose: to evaluate and compare the efficacy, safety and tolerability of treatment of patients with keratopathy against the background of adenovirus keratoconjunctivitis with Interferon-Oftalmo and Oftalmoferon.Material and methods. The comparative analysis included completed cases of treatment of 51 patients (102 eyes) aged 18–75 years with clinical signs of keratopathy against the background of epidemic adenoviral keratoconjunctivitis. Patients of the first group (n = 27, 54 eyes) on the background of tear replacement therapy received eight instillations of the drug Interferon-Ophthalmo, the second (n = 24, 48 eyes) received Oftalmoferon. The observation period was 15 days. Treatment efficacy was assessed based on a quantitative analysis of the dynamics of clinical symptoms of inflammation and the state of the cornea, the severity of subjective manifestations of ocular surface xerosis using the ocular surface damage index (OSDI), as well as the stability of the tear film. Safety and tolerability were also evaluated.Results. Against the background of complex therapy, which included the instillation of Interferon-Ophthalmo or Oftalmoferon, all patients showed comparable dynamics in the relief of the inflammatory process and keratopathy. This was expressed in a statistically significant decrease in the severity of foreign body sensation, lacrimation, itching, eyelid edema, conjunctival edema and hyperemia, follicular reaction, conjunctival hemorrhages, punctate keratopathy, subepithelial infiltrates in the cornea. In both groups, there was a steady downward trend in OSDI against the background of an increase in the stability of the tear film and an increase in maximally corrected visual acuity. The safety and tolerability profile of the drugs was assessed as comparably favorable.Conclusion. The inclusion of the drug Interferon-Oftalmo in the complex therapy of adenoviral epidemic keratoconjunctivitis allows us to expect a comparable effect on the course of the disease compared to the original drug Oftalmoferon.

Anti-Lethal Therapy of COVID-19 for Home Health Outpatient Therapy

The article presents the rationale for a new therapeutic strategy for treatment of patients with COVID-19, based on the combined use of biologic response modifiers and drugs targeting etiology and pathophysiology of the novel coronavirus infection, excluding disadvantages of polypharmacy, and providing a high clinical effect. This approach has been predominantly used in home health outpatient treatment of 324 patients with COVID-19 of variable severity using the biologic response modifiers “double drug cocktail” made of recombinant human interleukin-2 and recombinant human interferon alpha-2b in combination with alimemazine, nimesulide, rivaroxaban and antibiotic therapy (co-amoxiclav, or ceftriaxone) if secondary bacterial pneumonia was diagnosed. The results obtained indicate a dramatic improvement in the condition of patients, even with a severe COVID-19, which made possible to avoid artificial ventilation and prevent deaths.

Efficacy and safety of interferon alfa-2b in combination with vitamins C and E in treatment and prevention of neonatal congenital pneumonia

The article presents the results of analysis of works published over 25 years on the effectiveness and safety of interferon alpha-2b in combination with vitamins C and E for the treatment and prevention of congenital pneumonia. The purpose of the work is to summarize and evaluate the results of studies on the effectiveness and safety of the drug based on interferon alpha-2b in combination with ascorbic acid and alpha-tocopherol acetate in complex therapy and for the prevention of congenital pneumonia. Materials and methods . The analysis of available publications was carried out in accordance with the purpose. Selected studies that present the characteristics of the compared groups that received different therapies, conducted a qualitative analysis of the results and statistical processing of data. Results . We selected four researches out of more than a hundred publications, which provided data on the formation and characteristics of the compared groups, and a detailed analysis of the results obtained using statistical methods was carried. The efficacy and safety of interferon-based alpha-2b in combination with vitamins C and E were studied for the treatment of congenital pneumonia in 3 studies. The drug was evaluated of preventive effect in one study. Conclusions . The addition of a combination drug based on interferon alpha-2b in combination with vitamins C and E (Viferon ® ) leads to a significant reduction in the duration of symptoms, the period of hospitalization, the need for a ventilator, and the duration of isolation of pathogens to the treatment regimen for congenital pneumonia. Interferon therapy provides prevention of complications and repeated episodes of infectious diseases. The use of Viferon ® in pregnant women helps to reduce the risk of congenital pneumonia and improve the health indicators of newborns.

Severe persistent canine oral papillomatosis a multimodal approach including interferon alpha-2B, CPV-1 autologous vaccine, CO2 laser ablation and aggressive cryotherapy

A 3-year-old, 29.5 kg female, spayed, labrador retriever cross with a 5-month history of severe, persistent papillomas affecting the oral mucous membranes was successfully treated using a multimodal approach that...

Возможности терапии комбинированным препаратом интерферона альфа-2b с лоратадином при лечении обострений хронической обструктивной болезни легких

Возможности терапии комбинированным препаратом интерферона альфа-2b с лоратадином при лечении обострений хронической обструктивной болезни легких

End treatment response and sustained viral response in hepatitis C virus genotype 3 among Pakistani population

BACKGROUND AND OBJECTIVESThis study aimed to determine the end treatment response (ETR) and sustained viral response (SVR) to interferon (IFN) and ribavirin in hepatitis C virus (HCV) genotype 3 in the Pakistani population.DESIGN AND SETTINGSThis is an interventional study conducted from January 2010 to December 2012 in Lyari General Hospital and Abbasi Shaheed Hospital, Karachi, outpatients department.METHODSAll patients with chronic hepatitis C genotype 3 infections were included. Patients with decompensated chronic liver disease, or having coexisting hepatitis B virus/human immunodeficiency virus were excluded. All patients received IFN alpha, 3 million international units (MIU), subcutaneously 3 times weekly and ribavirin >800 mg/d for a period of 6 months. Outcome parameters included ETR (negative polymerase chain reaction [PCR] at the end of therapy), SVR (negative PCR both at the end of treatment and 6 months later), and relapse (PCR negative at the end of treatment but positive 6 months later) were determined.RESULTSA total of 1170 patients were included with a female to male ratio of 1.64:1 and a mean age of 31.6 (8.4) years. Among 1170 patients, 985 completed the therapy as per the protocol, 119 were defaulted (treatment abandoned before completion), and 66 had to stop treatment due to side effects. ETR was 74.1%, SVR was 98%, relapse rate was 1.5%, and 10.1% were nonresponders. SVR was seen only in patients who had achieved an ETR (n=867). SVR was achieved in 848 patients (out of 867) (98%), relapse was seen in 13 (1.5%), and 6 (0.7%) patients lost follow-up after stopping treatment. Patients achieving ETR and SVR had a mean serum alanine aminotransferase of 71.3 (57.1) and 71.0 (56.5), respectively, which is approximately twice the upper normal limit.CONCLUSIONThe conventional IFN and ribavirin therapy in genotype 3 chronic HCV-infected patients gives an ETR and SVR of 74.1% and 98%, respectively.

A study of best positive predictors for sustained virologic response to interferon alpha plus ribavirin therapy in naive chronic hepatitis C patients.

BackgroundThe aim of this study was to determine the rate of sustained virological response (SVR) and various factors associated with response rates in chronic hepatitis C infected patients treated with interferon alpha and ribavirin combination therapy.MethodsA retrospective review of patients data collected at this Centre from 2001 to 2007 was performed. Out of 731 consecutive patients 400 patients that fulfilled the study criteria were evaluated and subsequently treated with a combination of interferon alpha 2b (3 MU subcutaneously three injections weekly) and ribavirin (800–1200 mg orally daily). Treatment were administered for either 24 weeks or 48 weeks and patients were followed for an additional 6 months thereafter. End of the treatment response (ETR), SVR and side effects were recorded.ResultsOut of 400 patients, 394 completed the entire treatment course and six patients discontinued treatment at month 2. Over 67% responded at the end of treatment and 16% suffered relapse. Among all treated patients, 47.6% males and 56.7% females had sustained viral response with a total combined sustained viral response rate of 50.5%. Rapid response was seen in 46.5% patients. In a multivariate logistic regression analysis, slow virological responders (adjusted OR 2.6 [95% CI 1.9–3.7]), HCV genotype 1&4 (adjusted OR 2.4 [95% CI 1.7–3.5]), pre-treatment viral load > 0.2 MIU/mL (adjusted OR 2.2 [95% CI 1.8–4.2]), Panjabi ethnic group (adjusted OR 1.6 [95% CI 1.0–3.2]) and Age > 40 years (adjusted OR 1.5 [95% CI 0.9–2.4]) were independent risk factors for non response. Side effects were usual and tolerable and only 1.5% discontinued the treatment.ConclusionThe best positive predictor for SVR in this country are: rapid virologic response, HCV genotype 2 & 3, age < 40 years, ethnic race Pashtoons and pre-treatment viral load < 0.2 million IU/mL.

Efficacy and Safety of In-Asia-manufactured Interferon alpha-2b in Combination with Ribavirin for Therapy of Naïve Chronic Hepatitis C Patients: A Multicenter, Prospective, Open-Label Trial

Background : An open-label, multi center and non-comparative study was conducted to evaluate the efficacy and safety of a more affordable in-Asia-manufactured interferon a-2b product in combination with ribavirin to treat naive chronic hepatitis C patients. Method : Thirty chronic naive hepatitis C patients were treated with in-Asia-manufactured interferon a-2b subcutaneously 3 MIU thrice weekly and ribavirin 800-1,200 mg daily for 48 weeks. Follow-up was done until 24 weeks after the end of treatment. Efficacy was assessed by examining serologic and biochemical parameters at pre and post-treatment. Safety was assessed by evaluating clinical symptoms and laboratory parameters. Results : The virological response and sustained virological response rates of all Hepatitis C Virus (HCV) genotypes were 83.3% and 76.7% respectively. Post-treatment, 80% patients had significant alanine transaminase (ALT) decreased into normal level and remained normal in 76.7% patients at 24th week follow up period. At that time, the ALT level and sustained virological response were lower in HCV genotypes 1 and 4 than in non-1 and non-4 genotypes. The most frequent adverse event was flu-like syndrome. Conclusion : The efficacy and safety study on combination therapy of in-Asia-manufactured interferon a-2b and ribavirin has shown a good result based on the current standard of interferon alpha and ribavirin combination therapy. Keywords : interferons, combination drug therapy, chronic hepatitis C, treatment efficacy, safety

Clinical trial: comparison of weekly once versus twice half‐dose weekly administration of pegylated interferon alpha 2b in combination with ribavirin for the treatment of HCV‐1 positive patients with chronic hepatitis C

Pegylated interferon (PEG-IFN) alpha2b is currently used as a once weekly injection in combination with ribavirin for the treatment of chronic hepatitis C. To test whether twice half-dose weekly administration may improve the virological response in difficult-to-treat hepatitis C virus-1 patients. Thirty patients were treated with 1.5 microg/kg of PEG-IFN alpha2b given once weekly for 48 weeks (group A) and were compared with 30 patients treated with the same dose of PEG-IFN alpha2b divided in twice weekly doses of 0.75 microg/kg for the initial 4 weeks (group B). All patients were hepatitis C virus-1 positive and received weight-based ribavirin (800-1400 mg/daily). Weekly twice half-dose administration of PEG-IFN alpha2b for the first 4 weeks was associated with lower rates of biochemical and virological response at all time points compared with a once weekly schedule, and with significantly higher rates of in-therapy breakthrough leading to significantly lower rates of end of therapy response (week 48). The rate of sustained virological response was of 56.7% in group A and 36.7% in group B. Weekly twice half-dose administration of PEG-IFN alpha2b is not superior to the standard once weekly schedule, and might be less efficacious.

Recombinant interferon α-2b and coenzyme Q10 as a postsurgical adjuvant therapy for melanoma: a 3-year trial with recombinant interferon-α and 5-year follow-up

Early surgical intervention remains the most successful therapy for melanoma. Despite better outcomes observed in soft tissue and lymph node metastases, the results of pharmacological therapies are still disappointing. Currently, there is no standard adjuvant therapy for melanoma. Low concentrations of coenzyme Q10 have been demonstrated in melanoma cell lines and in sera of melanoma patients. These data and the results of clinical trials of patients with other advanced cancers prompted this study of the long-term administration of an optimized dose of recombinant interferon alpha-2b and coenzyme Q10 to patients with stage I and II melanoma. A 3-year trial envisaging uninterrupted treatment with low-dose recombinant interferon alpha-2b (9 000 000 000 IU weekly) administered twice daily and coenzyme Q10 (400 mg/day) was conducted in patients with stage I and II melanoma (American Joint Committee on Cancer criteria 2002) and surgically removed lesions. Treatment efficacy was evaluated as incidence of recurrences at 5 years. All patients completed the treatment and the follow-up. Significantly different rates of disease progression were observed in the interferon+coenzyme Q10 and the interferon group for both stages. No patient withdrew from the study owing to side effects. Long-term administration of an optimized dose of recombinant interferon alpha-2b in combination with coenzyme Q10 seemed to induce significantly decreased rates of recurrence and had negligible adverse effects. A survival study could not be undertaken owing to the small patient sample and the short duration of follow-up.

Factors Influencing Treatment Efficacy of 24-Week Combination Therapy with Interferon α-2b Plus Ribavirin for Chronic Hepatitis C

The efficacy of a combination therapy of interferon (IFN) alpha-2b plus ribavirin (RBV) in chronic hepatitis C, and the factors contributing to efficacy, were investigated. One hundred eighty-six cases were enrolled in this study and treated with a combination of IFN alpha-2b plus RBV. IFN alpha-2b was administered at 6-10 mega-units daily for 2-4 weeks and three times per week for 20-22 weeks, in combination with oral intake of RBV at 600 or 800 mg for 24 weeks. Rates of sustained virological response (SVR) were 34.9% in serogroup 1 (SG1) and 82.5% in SG2. SVR rates in cases with both drugs discontinued, reduced, and unchanged were 4.2%, 40%, and 42.7% in SG1 and 42.9%, 76.9%, and 91.9%, in SG2. In terms of the total RBV dose per kilogram body weight, SVR rates were 14.3% and 46.2% with <1600 mg, 36.2% and 91.7% with 1600-2000 mg, and 62.1% and 95% with > or =2000 mg in SG1 and SG2, respectively. Total doses of RBV per body weight and negative HCV RNA at 8 weeks were the significant factors contributing to SVR in SG1 cases. These results indicate that it was critical to tailor the doses of RBV and IFN to the individual. To improve the rate of SVR, it is necessary to make efforts, where possible, not to discontinue drug use or reduce the drug dose.

Valor de la respuesta virológica precoz como factor predictivo de respuesta virológica sostenida al tratamiento con interferón α-2b y ribavirina en pacientes con hepatitis crónica C con o sin coinfección por el VIH

The most effective currently available therapy for chronic hepatitis C virus infection is the combination of interferon alpha-2b plus ribavirin both, in patients with human immunodeficiency virus (HIV) coinfection and in patients without coinfection. In an attempt to avoid morbidity and health costs we searched for an indicator of early virologic response (EVR). We evaluated the EVR efficiency at 4 and 12-weeks after the initiation of antiviral combination therapy. A total of consecutive 127 patients with chronic hepatitis C virus infection treated with combination therapy for 12 months in genotypes 1 and 4 and for 6 months in genotypes 2 and 3, were studied, 62 HIV-coinfected and 65 non-coinfected. They were evaluated for sustained virologic response and EVR at 4 and 12-weeks to initial therapy. Sustained virologic response was greater in the non-coinfected group than coinfected group; these differences were significant for genotypes 1 and 4. In both groups EVR had a 100% predictive negative value at 12-weeks after the initiation of therapy in genotypes 1 and 4, however came down in 79% at 4-weeks. The EVR at 12-weeks after the initiation of therapy has a 100% predictive negative value in coinfected and non-coinfected patients. Patient adherence to prescribed antiviral therapy is a predictive value of response.

Improvement in quality of life measures in patients with refractory hepatitis C, responding to re-treatment with Pegylated interferon alpha -2b and ribavirin.

BackgroundIn this paper, we report the health related quality of life (HRQOL) data from patients with hepatitis C viral infection (HCV) who were refractory to prior therapy and had re-treatment with a combination of Pegylated interferon alpha-2b and ribavirin. We hypothesized that the HRQOL will improve in those patients who attain sustained viral response similar to naïve patients undergoing treatment for HCV.MethodsHRQOL data was obtained from 152 patients enrolled into a randomized study for re-treatment of HCV refractory to prior therapy with interferon alpha-2b in combination with ribavirin. The treatment protocol was for 48 weeks and had a high and low dose arm. The HRQOL data was collected at baseline, weeks 24 and 48 of treatment, and at 24 week follow-up after treatment. A repeated measures statistical model was used for comparing the HRQOL domain scores between the responders and non-responders and the treatment groups. The responders and non-responders were also compared to the age and sex adjusted national mean scores.ResultsTwenty-five of the 152 (17%) patients achieved a sustained viral response. At baseline, HRQOL is lower in HCV patients compared to national norms. The norm based HRQOL domain scores for the different domains of the SF-36 instrument were as follows: physical functioning = 47.13, role-physical = 46.87, bodily pain = 48.00, general health = 44.01, vitality = 45.39, social functioning = 47.05, role-emotional = 48.88, mental health = 48.76, physical component score 43.26 and mental component score = 46.17. The scores decreased during therapy in those who would be responders and non-responders, but the pattern of change was different. During the treatment, the HRQOL domain scores of responders decrease notably in the domain of vitality. At week 48 vitality scores were worst in responders. 5 of the 8 domain scores were lower compared to baseline in non-responders. At 24 weeks post treatment follow up, HRQOL in those refractory patients who respond to re-treatment tended to be better than the national average in the domains of vitality (p = .06), social functioning (p = .06) and role-emotional (p = .03) while the non-responders improved their scores in domains of physical function and bodily pain.ConclusionWe conclude that patients who are to be responders and non-responders behave differently in terms of the HRQOL domain scores when re-treated with a combination of interferon alpha 2b and ribavirin. The responders sustained a significant decrease in the domain score of vitality while 5 of the 8 domain scores decrease in non-responders at the end of treatment. At the end of follow up, in responders, the HRQOL score tended to be better than the national average notably in the domains of role-emotional, vitality and social functioning. On the other hand, in non-responders, the domain scores of physical function improve, while that of role-emotional worsened.

The Effect of Ribavirin on Bone Density in Patients with Chronic Hepatitis C Treated with Interferon-Ribavirin Therapy

The objective of this study was to investigate the effects of ribavirin on bone mineral metabolism in patients with chronic hepatitis C who had been treated with interferon and ribavirin. Twenty patients (3 female, 17 male) with chronic hepatitis C were enrolled. Age range was 6 to 15 years (mean+/-SD, 11.15+/- 2.3 years). Thirteen patients received combined interferon alpha-2b and ribavirin therapy (Group 1), and 7 patients received only interferon alpha-2b (Group 2). Both groups were treated for 12 months. Bone mineral density, z-scores and biochemical bone markers were evaluated in both groups before and after treatment. There were no significant differences between the groups in age or gender. Mean lumbar vertebral bone mineral density and mean z-scores in groups 1 and 2 before and after treatment were not significantly different. In both groups, serum and urinary biochemical values and bone markers were all normal and there were no differences between the pretreatment and post-treatment values. Contrary to studies in adults, we did not find any ribavirin-dependent changes related to bone mineral metabolism in our pediatric study groups. Further studies are needed to obtain more detailed information about the effects of ribavirin on bone mineral density.

Results of a Phase II Trial Testing Interferon Alpha 2b and Cytarabine in Children with Chronic Myelogenous Leukemia.

Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.

447 Liver histology in chronic hepatitis B patients after 1 year of treatment with pegylated interferon alpha-2B in combination with lamivudine or placebo

447 Liver histology in chronic hepatitis B patients after 1 year of treatment with pegylated interferon alpha-2B in combination with lamivudine or placebo

Sexual Transmission of Hepatitis C and Early Intervention

The major risk factors for the transmission of hepatitis C virus (HCV) have been sharing needles for intravenous drug use (IDU) and receiving blood and blood products; however, recent findings suggest that HCV is being increasingly sexually transmitted, particularly among HIV-positive men who engage in high-risk, unprotected sexual behaviors with other men. Sixteen HIV-positive patients were diagnosed with sexually acquired HCV infection at a leading London HIV outpatient treatment center during 2002. All 16 patients were homosexual males with no history of IDU who had been involved in high-risk, unprotected sexual behaviors, which included active and passive anal intercourse, fisting, rimming, and oral sex. Six patients (37.5%) in the cohort spontaneously cleared HCV infection and consequently tested negative for HCV RNA. The remaining 10 patients were all started on HCV treatment, which consisted of pegylated interferon alpha-2b in combination with ribavirin. Three patients (43%) have achieved a significant reduction in HCV RNA after 12 to 24 weeks of HCV treatment. The earlier HCV seroconversion is detected and treated, the better the chance of achieving viral eradication.

Successful treatment of hepatitis C after kidney transplantation with combined interferon alpha-2b and ribavirin

The management of acute hepatitis C virus (HCV) infection after renal transplantation (RT) remains controversial, due to the potential risk of interferon-induced graft dysfunction. There is little experience with combined interferon and ribavirin therapy in this group of patients. We treated four consenting RT recipients who developed acute de novo HCV infection with a combination of interferon-alpha 2b and ribavirin. After 48 weeks’ treatment, sustained virologic and biochemical remission were achieved in three patients infected with HCV genotypes 1a, 2, and 6a, respectively. The median time from treatment onset to ALT normalization was 8 weeks. The fourth patient was a non-responder infected with genotype 1b. Dose-dependent hemolysis was the most frequent side-effect. No patient developed allograft dysfunction. Our experience indicates that the judicious use of combined interferon and ribavirin can be considered in selected RT recipients with severe acute hepatitis C infection.

Efficacy of pegylated interferon alpha-2B in combination with ribavirin in patients with chronic hepatitis C non-responders to a previous treatment

Efficacy of pegylated interferon alpha-2B in combination with ribavirin in patients with chronic hepatitis C non-responders to a previous treatment