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BACKGROUND: Models for predicting hepatitis B e antigen (HBeAg) seroconversion in patients with HBeAg-positive chronic hepatitis B (CHB) after nucleos(t)ide analog treatment are rare. AIM: To establish a simple scoring model based on a response-guided therapy (RGT) strategy for predicting HBeAg seroconversion and hepatitis B surface antigen (HBsAg) clearance. METHODS: In this study, 75 previously treated patients with HBeAg-positive CHB underwent a 52-week peginterferon-alfa (PEG-IFNα) treatment and a 24-wk follow-up. Logistic regression analysis was used to assess parameters at baseline, week 12, and week 24 to predict HBeAg seroconversion at 24 wk post-treatment. The two best predictors at each time point were used to establish a prediction model for PEG-IFNα therapy efficacy. Parameters at each time point that met the corresponding optimal cutoff thresholds were scored as 1 or 0. RESULTS: The two most meaningful predictors were HBsAg ≤ 1000 IU/mL and HBeAg ≤ 3 S/CO at baseline, HBsAg ≤ 600 IU/mL and HBeAg ≤ 3 S/CO at week 12, and HBsAg ≤ 300 IU/mL and HBeAg ≤ 2 S/CO at week 24. With a total score of 0 vs 2 at baseline, week 12, and week 24, the response rates were 23.8%, 15.2%, and 11.1% vs 81.8%, 80.0%, and 82.4%, respectively, and the HBsAg clearance rates were 2.4%, 3.0%, and 0.0%, vs 54.5%, 40.0%, and 41.2%, respectively. CONCLUSION: We successfully established a predictive model and diagnosis-treatment process using the RGT strategy to predict HBeAg and HBsAg seroconversion in patients with HBeAg-positive CHB undergoing PEG-IFNα therapy.

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PURPOSE OF REVIEW: Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis, with no FDA-approved therapy. Progress in the development of effective HDV treatments is accelerating. This review highlights how mathematical modeling is improving understanding of HDV-HBsAg-host dynamics during antiviral therapy and generating insights into the efficacy and modes of action (MOA) of new antiviral agents. RECENT FINDINGS: Clinical trials with pegylated-interferon-λ, bulevertide, nucleic acid polymers, and/or lonafarnib against various steps of the HDV-life cycle have revealed new viral-kinetic patterns that were not observed under standard treatment with pegylated-interferon-α. Modeling indicated that the half-lives of circulating HDV and HBsAg are ~ 1.7 d and ~ 1.3 d, respectively, estimated the relative response of HDV and HBsAg during different antiviral therapies, and provided insights into the efficacy and MOA of drugs in development for treating HDV, which can inform response-guided therapy to individualize treatment duration. Mathematical modeling of HDV and HBsAg kinetics provides a window into the HDV virus lifecycle, HDV-HBsAg-host dynamics during antiviral therapy, and the MOA of new drugs for HDV.

Asunto(s)

Hepatitis D , Virus de la Hepatitis Delta , Humanos , Virus de la Hepatitis Delta/fisiología , Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B/farmacología , Antígenos de Superficie de la Hepatitis B/uso terapéutico , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Hepatitis D/tratamiento farmacológico , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico

RESUMEN

Radiation therapy (RT) has long been fundamental for the curative treatment of breast cancer. While substantial progress has been made in the anatomical and technological precision of RT delivery, and some approaches to de-escalate or omit RT based on clinicopathologic features have been successful, there remain substantial opportunities to refine individualised RT based on tumour biology. A major area of clinical and research interest is to ascertain the individualised risk of loco-regional recurrence to direct treatment decisions regarding escalation and de-escalation of RT. Patient-tailored treatment with RT is considerably lagging behind compared with the massive progress made in the field of personalised medicine that currently mainly applies to decisions on the use of systemic therapy or targeted agents. Herein we review select literature surrounding the use of tumour genomic biomarkers and biomarkers of the immune system, including tumour infiltrating lymphocytes (TILs), within the management of breast cancer, specifically as they relate to progress in moving toward analytically validated and clinically tested biomarkers utilized in RT.

Asunto(s)

Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor , Pronóstico , Biomarcadores de Tumor/genética , Genómica

RESUMEN

PURPOSE: Neoadjuvant endocrine therapy (NET) is a treatment option for estrogen receptor-positive (ER+) postmenopausal early breast cancer (EBC). This phase III trial evaluated the prognosis of EBC patients treated with/without chemotherapy (CT) following NET. METHODS: ER+/HER2-, T1c-2, and clinically node-negative EBC patients were enrolled in 2008-2013 and treated with endocrine therapy (ET) in weeks 24-28. All patients, excluding those with progressive disease (PD) during NET or ≥ 4 positive lymph nodes after surgery, were randomized to ET for 4.5-5 years with/without CT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant DFS (DDFS), overall survival (OS), and DFS/DDFS/OS according to clinical response to NET. RESULTS: Of 904 patients, 669 were randomized to CT+ET (n = 333) or ET alone (n = 336). The median follow-up was 7.8 years. DFS (CT+ET, 47 events; ET alone, 70 events) and DDFS did not reach the planned numbers of events. Eight-year DFS/DDFS rates were 86%/93% and 83%/92%, respectively. DFS was significantly better in CT+ET than ET alone in subgroups aged < 60 years (P = 0.016), T2 (P = 0.013), or Ki67 > 20% (P = 0.026). Progesterone receptor and histological grade were predictive markers for clinical responses to NET. CONCLUSION: NET may be used as standard treatment for patients with ER+EBC. Although it is difficult to decide whether to administer adjuvant CT based solely on the effect of NET, the response to NET may help to inform this decision. TRIAL REGISTRATION: This study was registered at the UMIN Clinical Trials Registry under UMIN000001090 (registered 20 March 2008).

Asunto(s)

Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Receptores de Estrógenos , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pronóstico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Receptor ErbB-2

RESUMEN

Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods: Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28. Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels. Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment. Funding: Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).

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Hepatitis C is a blood-borne virus that causes thousands of deaths from liver cirrhosis and liver cancer each year. Antiviral therapies can cure most cases of infection in 12 weeks. Unfortunately, treatment is expensive, and sticking with the regimen for 12 weeks can be difficult. It may be especially challenging for unhoused people or those who use injection drugs and who have high rates of hepatitis C infection. Shorter durations of therapy may make it more accessible, especially for high-risk populations. But studies of shorter antiviral treatment durations have yet to produce high enough cure rates. Finding ways to identify patients who would benefit from shorter therapy is a key goal of the World Health Organization. Potential characteristics that may predict a faster treatment response include low virus levels before initiating treatment, patient genetics, drug resistance mutations in the virus, and higher drug levels in the patient's blood during treatment. For example, previous research showed that a rapid decrease in virus levels in a patient's blood two days after starting antiviral therapy with three drugs predicted patient cures after three weeks of treatment. To test if high cure rates could be achieved in just four weeks of treatment, Flower et al. enrolled 52 patients with hepatitis C in a study to receive the most widely accessible dual antiviral treatment (sofosbuvir and daclatasvir). Participants received four or eight weeks of treatment, depending on the amount of viral RNA in their blood after two days of treatment. The results indicate that a rapid decrease in virus levels in the blood does not adequately predict cure rates with four weeks of two-drug combination therapy. However, eight weeks may be highly effective, regardless of viral levels early in treatment. Thirty-four individuals with low virus levels on the second day of treatment received four weeks of therapy, which cured 21 or 62% of them. All seventeen individuals with higher viral levels on day two were cured after eight weeks of treatment. Twelve weeks of retreatment was sufficient to cure the 13 individuals who did not achieve cure with four weeks of therapy. Even patients with drug resistance genes after the first round of therapy responded to a longer second round. Flower et al. show that patient genetics, virus subtype, drug levels in the patient's blood, and viral drug resistance genes before therapy, were not associated with patient cures after four weeks of treatment. Given that retreatment is safe and effective, larger studies are now needed to determine whether eight weeks of therapy with sofosbuvir and daclatasvir may be enough to cure patients with mild liver disease. More studies are also necessary to identify patients that may benefit from shorter therapy durations. Finding ways to shorten antiviral therapy for hepatitis C could help make treatment more accessible and reduce therapy costs for both individuals and governments.

Asunto(s)

Hepatitis C Crónica , Hepatitis C , Adulto , Humanos , Sofosbuvir/uso terapéutico , Antivirales , Proyectos Piloto , Hepatitis C Crónica/tratamiento farmacológico , Quimioterapia Combinada , Resultado del Tratamiento , Hepacivirus/genética , Genotipo , Ribavirina/uso terapéutico , Interleucinas/genética

RESUMEN

Shortening duration of direct-acting antiviral therapy for chronic hepatitis C could provide cost savings, reduce medication exposure, and foster adherence and treatment completion in special populations. The current analysis indicates that measuring hepatitis C virus at baseline and on days 7 and 14 of therapy can identify patients for shortening therapy duration.

RESUMEN

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

Asunto(s)

Neoplasias de la Mama , Terapia Neoadyuvante , Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Ciclofosfamida , Epirrubicina , Femenino , Fluorouracilo , Estudios de Seguimiento , Humanos , Terapia Neoadyuvante/efectos adversos , Pronóstico , Puntaje de Propensión , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Taxoides/uso terapéutico , Trastuzumab

RESUMEN

BACKGROUND: Genotype 6 is the most genetically diverse lineage of hepatitis C virus, and it predominates in Vietnam. It can be treated with sofosbuvir with daclatasvir (SOF/DCV), the least expensive treatment combination globally. In regional guidelines, longer treatment durations of SOF/DCV (24 weeks) are recommended for cirrhotic individuals, compared with other pangenotypic regimens (12 weeks), based on sparse data. Early on-treatment virological response may offer means of reducing length and cost of therapy in patients with liver fibrosis. METHODS: In this prospective trial in Vietnam, genotype 6-infected adults with advanced liver fibrosis or compensated cirrhosis were treated with SOF/DCV. Day 14 viral load was used to guide duration of therapy: participants with viral load <500 IU/mL at day 14 were treated with 12 weeks of SOF/DCV and those ≥500 IU/mL received 24 weeks. Primary endpoint was sustained virological response (SVR). RESULTS: Of 41 individuals with advanced fibrosis or compensated cirrhosis who commenced treatment, 51% had genotype 6a and 34% had 6e. The remainder had 6h, 6k, 6l, or 6o. One hundred percent had viral load <500 IU/mL by day 14, meaning that all received 12 weeks of SOF/DCV. One hundred percent achieved SVR12 despite a high frequency of putative NS5A inhibitor resistance-associated substitutions at baseline. CONCLUSIONS: Prescribing 12 weeks of SOF/DCV results in excellent cure rates in this population. These data support the removal of costly genotyping in countries where genotype 3 prevalence is <5%, in keeping with World Health Organization guidelines. NS5A resistance-associated mutations in isolation do not affect efficacy of SOF/DCV therapy. Wider evaluation of response-guided therapy is warranted.

RESUMEN

BACKGROUND: RNA detection in plasma/stool is the gold-standard for diagnosis of hepatitis E virus (HEV) infection. The impact of viral extraction methods on HEV RNA detection is poorly investigated. METHODS: We determined the limit of detection of the RealStar HEV RT-PCR V2.0 Kit (altona Diagnostics, RS) utilizing 3 RNA extraction methods (COBAS® AmpliPrep Total Nucleic Acid Isolation Kit, TNAi Roche; MagNA Pure 96 DNA, Viral NA SV Kit, MgP; QIAamp Viral RNA mini Kit Qiagen; VRK) in plasma and stool. The most sensitive method was evaluated in a total of 307 longitudinal samples of patients with HEV infection (acute = 18/chronic = 36) and compared to results with the former diagnostic standard of our centre (TNAi/FastTrack Diagnostic; FTD). RESULTS: The plasma-LOD was 49, 94 and 329 IU/mL for extraction with MgP, VRK and TNAi respectively. In stool, the LOD was 21 IU/mL, 528 IU/mL and indefinable for extraction with TNAi, VRK and MgP respectively. Utilizing longitudinal patient plasma samples, MgP/RS revealed 56 HEV RNA-positive samples in 158 negative samples as determined by TNAi/FTD. In stool, from 37 HEV negative samples (TNAi/FTD), 15 were positive with TNAi/RS. At end of treatment, 8 out of 27 chronically infected patients were RNA positive with MgP/RS, while classified negative with TNAi/FTD. A relapse occurred in 3 of these patients. CONCLUSION: Different methods for RNA extraction and quantification have a significant, compartment-specific impact on the sensitivity of HEV detection. Knowledge about the favourable combinations of extraction and quantification has important implications for diagnosis and patients receiving antiviral therapy.

Asunto(s)

Virus de la Hepatitis E , Hepatitis E , Heces , Hepatitis E/diagnóstico , Virus de la Hepatitis E/genética , Humanos , Reacción en Cadena de la Polimerasa , ARN Viral , Sensibilidad y Especificidad

RESUMEN

We recently showed in a proof-of-concept study that real-time modeling-based response-guided therapy can shorten hepatitis C virus treatment duration with sofosbuvir-velpatasvir, elbasvir-grazoprevir, and sofosbuvir-ledipasvir without compromising efficacy, confirming our retrospective modeling reports in >200 patients. However, retrospective modeling of pibrentasvir-glecaprevir (P/G) treatment has yet to be evaluated. In the current study, modeling hepatitis C virus kinetics in 44 cirrhotic and noncirrhotic patients predicts that P/G treatment might have been reduced to 4, 6, and 7 weeks in 16%, 34%, and 14% of patients, respectively. These results support the further evaluation of a modeling-based response-guided therapy approach using P/G.

Asunto(s)

Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Quinoxalinas/administración & dosificación , Sulfonamidas/administración & dosificación , Anciano , Anciano de 80 o más Años , Amidas/administración & dosificación , Carbamatos/administración & dosificación , Ciclopropanos/administración & dosificación , Esquema de Medicación , Combinación de Medicamentos , Quimioterapia Combinada , Duración de la Terapia , Femenino , Fluorenos/administración & dosificación , Humanos , Cinética , Masculino , Persona de Mediana Edad , Modelos Teóricos , ARN Viral/sangre , Estudios Retrospectivos , Sofosbuvir/administración & dosificación , Respuesta Virológica Sostenida , Factores de Tiempo

RESUMEN

BACKGROUND: Response-guided hepatitis C therapy was standard with interferon-based regimens but is not used for direct-acting antivirals (DAAs). Week 4 viral kinetics may predict sustained virological response (SVR) with DAAs, but it is unclear whether extending therapy in slow responders affects outcomes. OBJECTIVES: The primary objective was to compare SVR rates between traditional and extended duration groups. Secondary objectives were to compare SVR rates among subgroups and to determine factors associated with SVR. METHODS: This institutional review board-approved, retrospective, single-center study identified patients with chronic hepatitis C virus (HCV) infection with detectable week 4 HCV RNA who were treated with DAAs. Patients were excluded for early discontinuation, treatment regimen not recommended first-line, or missing HCV RNA labs. Patients were stratified into traditional and extended duration groups. The primary end point was SVR. Secondary end points included factors associated with SVR and rationale for extension of therapy duration. RESULTS: A total of 363 patients were included; 58 (16%) received extended therapy. Patients were primarily genotype 1a (70%) and treatment naïve (80%). More than half had advanced fibrosis or cirrhosis. SVR12 rates were 100% in the extended duration group and 96.7% in the traditional duration group (P = 0.37). There were no associations with SVR and prespecified patient-specific factors. Sample size was limited. CONCLUSION AND RELEVANCE: Based on these findings, a recommendation for extension of therapy cannot be made for patients with detectable HCV RNA at week 4 of treatment at this time. Cost analyses may help guide recommendations to re-treat rare failures versus extend therapy in all slow responders.

Asunto(s)

Antivirales/uso terapéutico , Duración de la Terapia , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Respuesta Virológica Sostenida , Adulto , Antivirales/administración & dosificación , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento

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Background: As hepatitis C virus (HCV) treatment continues to evolve, there is an ongoing need to understand and optimize real-world disease management. The primary objective of the SIMPLE study was to describe the real-life management of genotype 1 (G1) HCV in Canada treated with boceprevir + pegylated interferon and ribavirin therapy. Methods: This was an observational, prospective cohort, multicentre, non-interventional study of patients with G1 HCV. A single cohort of adult patients were to be managed as per standard of care (SoC) and treated with 4 weeks of PegRBV dual therapy, followed by boceprevir + PegRBV for 24-44 weeks, with 24-weeks follow-up. Treatment compliance, health care resource utilization (HCRU), HCV viral load, and hematological adverse event (AE) data were collected. Results: This study enrolled 159 patients. All investigators were well educated on the Canadian consensus guidelines for HCV management but only a minority of patients were treated according to treatment guidelines. Viral response was achieved by >50% of patients by week 8 of therapy and in 50%-60% of tested patients during follow-up. An average of 17.9 HCRU visits were reported during the study period. The most commonly used resources were nursing visits for routine follow-up. Conclusions: Results from this real-world study suggest that most patients were not treated according to the product monograph. Further studies are required to determine how oral treatments fit into this paradigm and how these findings extrapolate to the current treatment model. This study can serve as a benchmark for future real-world treatment including heath care utilization analyses.

RESUMEN

BACKGROUND: A direct-acting antiviral (DAA) era in hepatitis C virus (HCV) treatment is fast approaching; unfortunately, the availability and affordability of DAAs in Asia-Pacific areas vary, making it difficult to develop universal HCV practice guidelines appropriate for the all Asian populations. This study aimed to evaluate the real-world cost-effectiveness of IFN-based therapy according to the current strategies with PegIFN/RBV for "easy-to-treat" to provide a reference for application of future DAA development for IFN-eligible, treatment naïve HCV patients. METHODS: A total of 1032 chronic hepatitis C treatment-naïve patients who corresponded to response-guided therapy (RGT) guidelines of PegIFN/RBV regimens were linked to the entire population of expenditures and order in the National Health Insurance Research Database of Taiwan. The average total cost per SVR achieved was calculated as the summation of the total cost for all treated patients/number of SVR cases. RESULTS: Current RGT suggested 24 weeks of PegIFN/RBV for G1 naïve patients with baseline LVL and RVR at treatment week 4 achieved an average treatment cost per SVR of $5090 ± 2400. This was of superior cost-effectiveness compared with those other subgroups of G1 patients. In terms of G2 patients, according to current RGT of 16 weeks of treatment duration, PegIFN/RBV treatment with RVR achieved was of a very competitive cost per SVR ($3237 ± 488). CONCLUSION: For a naïve patient in the new DAA era, the PegIFN/RBV treatment might be conserved for those with all favorable risk parameters, considering the treatment duration and cost per SVR, in the resource-constrained countries.

Asunto(s)

Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferones/uso terapéutico , Anciano , Anciano de 80 o más Años , Análisis Costo-Beneficio , Femenino , Costos de la Atención en Salud , Hepatitis C Crónica/genética , Humanos , Interferón alfa-2/uso terapéutico , Interferón-alfa/uso terapéutico , Interleucinas/genética , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Polimorfismo de Nucleótido Simple , Proteínas Recombinantes/uso terapéutico

RESUMEN

We aimed to determine whether the HCV viral load after four weeks of treatment (W4VL) with direct-acting antiviral agents (DAAs) predicts sustained virologic response (SVR) in a real-world clinical setting. We identified 21 095 patients who initiated DAA-based antiviral treatment in the national Veterans Affairs (VA) healthcare system from 01/01/2014 to 06/30/2015. Week 4 viral load was categorized as undetectable, detectable below quantification (DBQ), detectable above quantification (DAQ) with viral load ≤42 IU/mL and DAQ with viral load >42 IU/mL. Week 4 viral load was undetectable in 36.1%, detectable below quantification in 45.6%, DAQ ≤42 in 9.3%, DAQ >42 in 9.1%. Detectable above quantification was much more common and undetectable week 4 viral load much less common when tested with the Abbott RealTime HCV assay vs the Roche COBAS AmpliPrep/COBAS TaqMan Version 2 assay. Compared to patients with undetectable week 4 viral load (SVR=93.5%), those with detectable below quantification (SVR=91.8%, adjusted odds ratio [AOR] 0.79, P-value=.001), DAQ ≤42 (SVR=90.0%, AOR 0.63, P-value<.001) and DAQ >42 (SVR=86.2%, AOR 0.52, P-value<.001) had progressively lower likelihood of achieving SVR after adjusting for baseline characteristics and treatment duration. Among genotype 1-infected patients who were potentially eligible for 8-week sofosbuvir/ledipasvir monotherapy, we did not find evidence that treatment for 12 weeks instead of 8 weeks was associated with higher SVR, even among those with detectable above quantification. In summary, DBQ and DAQ W4VL are very common in real-world practice, contrary to what was reported in clinical trials, and strongly predict reduced SVR across genotypes and clinically relevant patient subgroups. Whether and how week 4 viral load results should influence treatment decisions requires further study.

Asunto(s)

Antivirales/uso terapéutico , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , ARN Viral , Carga Viral , Antivirales/administración & dosificación , Antivirales/efectos adversos , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C/epidemiología , Hospitales de Veteranos , Humanos , Oportunidad Relativa , Vigilancia de la Población , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

On-treatment hepatitis C virus (HCV) RNA has been used to predict response to interferon (IFN)-based therapy. The concept of response-guided treatment (RGT) was established to determine optimal treatment duration and to early identify patients not responding to futile therapies. RGT helped to improve sustained virologic response (SVR) rates and lower the rates of adverse effects. RGT was of particular importance for telaprevir- and boceprevir-based triple therapies. RGT strategies are dependent on highly sensitive and reproducible HCV RNA quantification. However, different HCV RNA assays are used in routine clinical practice and these differ significantly in their performance characteristics. The development of IFN-free therapies has fundamentally changed the role of on-treatment HCV RNA for SVR prediction. Given the high efficacy and excellent tolerability of IFN-free regimens, the interest in treatment individualization has decreased. However, shorter treatment durations may still be desirable, particularly with respect to the high costs of current IFN-free direct-acting antiviral agents (DAAs). Moreover, some difficult-to-treat patients remain, e.g., those infected with HCV genotype 3 in whom the current standard of care may not always be sufficient to achieve SVR, especially in treatment-experienced patients with cirrhosis. Here, a RGT extension may be feasible. However, current data on the predictive value of on-treatment HCV RNA are limited and have shown conflicting results. As more potent DAAs become available, the role of response prediction may diminish further. Currently, shorter treatment duration is only based on baseline HCV RNA whereas no RGT strategy is recommended for any of the approved DAA regimens available.

Asunto(s)

Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Algoritmos , Antivirales/uso terapéutico , Quimioterapia Combinada , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Interferones/uso terapéutico , Límite de Detección , Medicina de Precisión/estadística & datos numéricos , Medicina de Precisión/tendencias , Valor Predictivo de las Pruebas , ARN Viral/sangre , ARN Viral/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Respuesta Virológica Sostenida , Virología/métodos

RESUMEN

BACKGROUND AND AIMS: Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS: In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS: Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS: On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.

Asunto(s)

Antivirales/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Sofosbuvir/administración & dosificación , Adulto , Anciano , Antivirales/efectos adversos , Carbamatos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Humanos , Imidazoles/efectos adversos , Cirrosis Hepática/sangre , Cirrosis Hepática/etiología , Masculino , Persona de Mediana Edad , Pirrolidinas , ARN Viral/sangre , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Factores de Tiempo , Estados Unidos , Valina/análogos & derivados , Carga Viral , Adulto Joven

RESUMEN

BACKGROUND: Historically, chronic hepatitis C virus (HCV) treatment was response-guided. Clinical trials with sofosbuvir indicated on-treatment virologic response was not predictive of sustained virologic response (SVR) and hence response-guided therapy (RGT) was abandoned. The purpose of this study is to examine the association between on-treatment 4-week HCV RNA and SVR in patients treated in real-world practice. METHODS: The study is a retrospective analysis of consecutive patients started on treatment with a sofosbuvir-containing regimen, January 1, 2014 through August 20, 2014, for HCV genotype 1-6 infection. Patients were treated by HCV specialists at 6 centers in the Project ECHO (Extension for Community Healthcare Outcomes) HCV Collaborative or in the community by primary care clinicians mentored by HCV specialists through Project ECHO. Patients were included if they were over 18 years, had evidence of chronic HCV, and were started on a sofosbuvir-containing regimen. The aspartate aminotransferase:platelet ratio index (APRI) was used to estimate fibrosis. The main outcome measures were 4-week HCV RNA and SVR. RESULTS: Overall SVR was 82.5 %. At week 4, HCV RNA was detected in 27.4 % of patients. Stepwise multivariable logistic-regression analyses identified APRI > 1.0, male sex, genotype 3, and detectable on treatment 4-week HCV RNA as independent predictors of failure to achieve SVR. CONCLUSIONS: In a real-world setting, a significant proportion of sofosbuvir treated patients have detectable on-treatment 4-week HCV RNA. Detectable on-treatment 4-week HCV RNA is associated with virologic failure. More data are needed to formulate guidance for RGT with newly available HCV therapies.

Asunto(s)

Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Sofosbuvir/administración & dosificación , Anciano , Femenino , Hepacivirus/genética , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/genética , Estudios Retrospectivos , Factores de Riesgo , Respuesta Virológica Sostenida , Resultado del Tratamiento , Carga Viral/efectos de los fármacos

RESUMEN

OBJECTIVE: To determine compliance and improvement in sustained viral response (SVR) by following response guided therapy (RGT) plan of interferon and ribavirin, for genotype 3 in chronic hepatitis C. METHODS: Patients with chronic hepatitis C genotype 3, who were eligible for interferon-ribavirin therapy and consented for RGT, were included. Those with no rapid viral response (RVR), having coarse echotexture of liver or undergoing re-treatment, were advised 48 week treatment whereas, rest had 24 week standard therapy. PCR for HCV RNA checked 6 months after discontinuing treatment, was the primary end point of study. RESULTS: Of 154 patients, included in the study with mean age of 39.9 (±10.84) and male to female ratio 1.4/1 (94/60), majority of patients, 136 (88.4%) were treatment naïve whereas, 18 (11.6%) were being retreated. On ultrasound, 63 (40.9%) patients had coarse liver and 33 (21.4%) had splenomegaly. RVR was achieved in 99 (64.3%) patients. Overall 66(42.8%) patients merited extended duration of therapy as per RGT plan but only 22 (33%) were compliant. Treatment related side effects were the dominant reason for declining RGT in 33 (75%) patients. SVR was noted in 111 (72.1%) patients. Those patients with extended therapy (RGT), had SVR 90.9% (20/22), although, better but statistically not significant than those who stopped therapy at 6 months 77.2% (34/44) (p value 0.11). CONCLUSION: Response guided therapy plan did not improve SVR to pegylatedinterferon and ribavirin therapy in patients with genotype 3 and it has low patient compliance due to treatment related side effects.

RESUMEN

AIM: To examined the efficacy and safety of treatment with boceprevir, PEGylated-interferon and ribavirin (PR) in hepatitis C virus genotype 1 (HCVGT1) PR treatment-failures in Asia. METHODS: The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures. Participating physicians were invited to contribute data from their patients: baseline characteristics, on-treatment responses, sustained virological response at week 12 (SVR12), and safety were collected and analysed. Multivariate analysis was performed to determine predictors of response. RESULTS: 150 patients were enrolled from Australia, Malaysia, Singapore and Thailand (Asians = 86, Caucasians = 63). Overall SVR12 was 61% (Asians = 59.3%, Caucasians = 63.5%). SVR12 was higher in relapsers (78%) compared with non-responders (34%). On-treatment responses predicted SVR, with undetectable HCVRNA at week 4, 8 and 12 leading to SVR12s of 100%, 87%, and 82% respectively, and detectable HCVRNA at week 4, 8 and 12, leading to SVR12s of 58%, 22% and 6% respectively. Asian patients were similar to Caucasian patients with regards to on-treatment responses. Patients with cirrhosis (n = 69) also behaved in the same manner with regards to on-treatment responses. Those with the IL28B CC genotype (80%) had higher SVRs than those with the CT/TT (56%) genotype (P = 0.010). Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR. Serious adverse events occurred in 18.6%: sepsis (2%), decompensation (2.7%) and blood transfusion (14%). Discontinuations occurred in 30.7%, with 18.6% fulfilling stopping rules. CONCLUSION: Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80% if they have good on-treatment responses; however, discontinuations occurred in 30% because of virological failure or adverse events.

Asunto(s)

Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Prolina/análogos & derivados , Antivirales/efectos adversos , Asia/epidemiología , Pueblo Asiatico , Australia/epidemiología , Biomarcadores/sangre , Distribución de Chi-Cuadrado , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/etnología , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etnología , Cirrosis Hepática/virología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polietilenglicoles/uso terapéutico , Prolina/efectos adversos , Prolina/uso terapéutico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , ARN Viral/sangre , Proteínas Recombinantes/uso terapéutico , Recurrencia , Ribavirina/uso terapéutico , Factores de Tiempo , Insuficiencia del Tratamiento , Carga Viral , Población Blanca

RESUMEN

BACKGROUND: Response-guided therapy (RGT) is a treatment model that bases adjustments to therapeutic regimens on individualized patient physiologic response. This approach is applied to patients with chronic hepatitis C virus (HCV) infection who are treated with a triple therapy regimen of boceprevir or telaprevir in combination with pegylated interferon and ribavirin. As RGT expands in other pharmacologic regimens, including the treatment of breast cancer and acute myeloid leukemia, a measurement of how this approach is applied in clinical practice is important to determine whether the benefits of RGT are being optimized. OBJECTIVE: To measure adherence to the RGT guidelines and to the treatment futility rules based on the drug labeling information for boceprevir and for telaprevir in the treatment of patients with chronic HCV infection. METHODS: A retrospective observational cohort study was conducted using the large Humana research database, which includes pharmacy, medical, and laboratory claims, as well as enrollment data for more than 1.5 million fully insured commercial members, 1.9 million Medicare Advantage members, and 2.4 million Medicare Part D members from all 50 states. The study population included patients aged ≥18 years to <90 years who were fully insured with commercial or Medicare Advantage coverage. A pharmacy claim for boceprevir or telaprevir was used to identify patients receiving triple therapy for HCV infection. Medical, pharmacy, and laboratory claims were reviewed from the date of the first boceprevir or telaprevir pharmacy claim between May 2011 and February 2012 through a 32-week follow-up period, during which patients were required to have continuous health plan enrollment eligibility. This time period allowed for the occurrences of required HCV RNA laboratory monitoring and the assessment of treatment patterns. The use of RGT for boceprevir and telaprevir includes the monitoring of HCV RNA levels at routine intervals to determine how to proceed with therapy. Adherence to HCV RNA monitoring was measured as the proportion of eligible patients who had an HCV RNA assay at each of the recommended time intervals. According to futility rules, patients with greater-than-expected HCV RNA levels are deemed to be nonresponders and should discontinue therapy. Adherence to futility rules was measured as the proportion of patients who stopped therapy among all patients who had an HCV RNA result, which indicated treatment futility at each monitoring interval. RESULTS: A total of 326 patients (65 in the boceprevir group; 261 in the telaprevir group) were eligible for the HCV RNA monitoring analysis, and 134 patients (20 receiving boceprevir and 114 receiving telaprevir) were eligible for the futility rules analysis. There were 1203 HCV RNA assays during the follow-up period. The percentage of patients who were adherent to HCV RNA monitoring during the entire treatment period was 29.2% in the boceprevir group and 32.2% in the telaprevir group. In both treatment groups, adherence to HCV RNA monitoring was highest at the first recommended time interval, followed by a downward trend in the second and third time intervals. Approximately 15% of 134 eligible patients met the futility rules for stopping therapy based on HCV RNA assay results, and 55% of those patients stopped the therapy in accordance with the treatment futility rules. CONCLUSION: The implementation of RGT was suboptimal in this population of patients with chronic HCV infection; adherence to HCV RNA monitoring guidelines was less than 33%, and adherence to treatment futility rules was less than 50%. Managed care pharmacists should identify strategies to increase the adoption of RGT, which may, in turn, improve patient care and reduce unnecessary expenditures.