Ledipasvir-sofosbuvir in Adolescents With Chronic Hepatitis C and Hematological Malignancies Undergoing Chemotherapy.

OBJECTIVES: In children with hematological malignancies, chronic hepatitis C virus (HCV) infection has been associated with more rapid liver disease progression and higher risk of malignancy relapse due to chemotherapy interruption. We evaluated the safety and efficacy of ledipasvir-sofosbuvir for 12weeks in these patients. METHODS: In a phase 2, open-label study, at one site in Egypt, patients ages 12-<18years with chronic HCV genotype 1 or 4 infection undergoing maintenance chemotherapy for hematological malignancies received ledipasvir-sofosbuvir (90 mg/400 mg) once daily for 12weeks. The efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). Safety was assessed by the incidence of adverse events and clinical and laboratory data, including HCV flares defined as alanine aminotransferase >3-fold increase from Day 1 and HCV RNA elevation >1 × log10 from Day 1. RESULTS: Of the 19 adolescents enrolled and treated, median age was 14 years (range 12-17), 84% (16/19) were male, and all had HCV genotype 4 and were HCV treatment naive. All patients completed treatment and achieved SVR12 (19/19, 100%, 95% confidence interval, 82-100). Common adverse events were pyrexia (5/19, 26%), diarrhea (4/19, 21%), and headache (4/19, 21%). Three patients experienced serious adverse events of pneumonia (two patients), and osteoarthritis and diarrhea (one patient); none were considered related to study drug. No patient experienced HCV flares. CONCLUSIONS: Ledipasvir-sofosbuvir was well-tolerated and efficacious in adolescents with chronic HCV genotype 4 and leukemia undergoing maintenance chemotherapy. These data support the use of this interferon and ribavirin-free regimen in adolescents with hematological malignancies.

Planning and prioritizing direct-acting antivirals treatment for HCV patients in countries with limited resources: Lessons from the Egyptian experience.

BACKGROUND AND AIMS: The introduction of direct-acting antivirals for hepatitis C virus (HCV) in Egypt led to massive treatment uptake, with Egypt's national HCV treatment program becoming the largest in the world. The aim of this paper is to present the Egyptian experience in planning and prioritizing mass treatment for patients with HCV, highlighting the difficulties and limitations of the program, as a guide for other countries of similarly limited resources. METHODS: Baseline data of 337,042 patients, treated between October 2014 to March 2016 in specialized viral hepatitis treatment centers, were grouped into three equal time intervals of six months each. Patients were treated with different combinations of direct-acting antivirals, with or without ribavirin and pegylated interferon. Baseline data, percentage of patients with known outcome, and sustained virological response at week 12 (SVR12) were analyzed for the three cohorts. The outcomes of 94,258 patients treated in the subsequent two months are also included. RESULTS: For cohort-1, treatment was prioritized for patients with advanced fibrosis (F3-F4 fibrosis, liver stiffness ≥9.5 kPa, or Fibrosis-4 ≥3.25). Starting cohort-2, all stages of fibrosis were included (F0-F4). The prioritization strategy in the initial phase caused delays in enrollment and massive backlogs. Cohort-1 patients were significantly older, and more had advanced fibrosis compared to subsequent cohorts. The percentage of patients with known SVR12 results were low initially, and increased with each cohort, as several methods to capture patient results were adopted. Sofosbuvir-ribavirin therapy for 24 weeks had the lowest SVR12 rate (82.7%); while other therapies were associated with SVR12 rates between 94% and 98%. CONCLUSION: Prioritization based on fibrosis stage was not effective and enrollment increased greatly only after including all stages of fibrosis. The availability of generic drugs reduced costs, and helped massively increase uptake of the program. Post-treatment follow-up was initially very low, and although this has increased, further improvement is still needed. LAY SUMMARY: We are presenting the largest national program for HCV treatment in the world. We clearly demonstrate that hepatitis C can be cured efficiently in large scale real-life programs. This is a clear statement that global HCV eradication is foreseeable, providing a model for other countries with limited resources and prevalent HCV. Moreover, the availability of generic products has influenced the success of this program.

Real life Egyptian experience of efficacy and safety of Simeprevir/Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients.

BACKGROUND & AIMS: Major changes have emerged during the last few years in the therapy of chronic HCV. Several direct acting antiviral agents have been developed showing potent activity with higher rates of sustained virological response, even in difficult-to-treat patients. This study explores real life experience concerning efficacy, safety and possible predictors of response for the first cohort of Egyptian patients with chronic HCV genotype IV treated with Sofosbuvir/Simprevir combination therapy. METHODS: This real life study recruited the first (6211) chronic HCV genotype IV Egyptian patients, who received antiviral therapy in viral hepatitis specialized treatment centres affiliated to the National committee for control of viral hepatitis. All enrolled patients received 12 weeks course of daily combination of sofosbuvir (400 mg) and simeprevir (150 mg). Patients were closely monitored for treatment safety and efficacy. RESULTS: Overall sustained virological response 12 rate was 94.0% while the end of treatment response rate was 97.6%. sustained virological response 12 rates in easy and difficult-to-treat groups were 96% and 93% respectively. Univariate and multivariate logistic regression analysis revealed significant association of low albumin (<3.5), cirrhosis and Fib-4 score (>3.25) with treatment failure. Fatal adverse events occurred in 23/6211 cases (0.37%) due to liver cell failure adverse events or SAEs leading to treatment discontinuation occurred in 97 patients (1.6%). CONCLUSION: Sofosbuvir/Simeprevir combination is an effective and well tolerated regimen for patients with chronic HCV genotype IV.

Lipid profile and hepatic steatosis in hepatitis C infected egyptian survivors of childhood cancer.

BACKGOUND/AIM: Studies associating chronic hepatitis C virus (HCV) infection with lipid profile and hepatic steatosis in children and adolescents are scarce. This study investigated lipid profile abnormalities and hepatic steatosis among HCV-infected Egyptian children and adolescents who survived leukemia and lymphoma and evaluated impact on response to antiviral therapy. SUBJECTS AND METHODS: Thirty-six leukemia/lymphoma cured children and adolescents (mean age: 12.47 ± 3.56 years) with chronic HCV infection and 30 healthy controls (mean age: 11.64 ± 3.96 years) were enrolled in this prospective study. Serum lipid profile and abdominal ultrasonography were done for all patients and controls. Guided liver biopsy with histopathological examination was done for 32 (88.9%) patients eligible for antiviral therapy. RESULTS: Total cholesterol, LDL-cholesterol, and apolipoprotein B (apo-B) in patients were significantly lower than in the control group (P ≤ .01, ≤ .01, and ≤ .05, respectively). Among those who underwent liver biopsy (n = 32), macrovesicular hepatic steatosis associated with chronic hepatitis C was documented in 10 children (31.3%). Body mass index was significantly higher (P ≤ .05) and apo-B was significantly lower in steatotic (P ≤ .05) than non-steatotic HCV-infected children. Liver span by ultrasound, alanine aminotransferase (ALT), and apo-B were independent predictors for hepatic steatosis (P < .001, <.001, and <.05, respectively). A significantly worse response to interferon alpha 2-b plus ribavrin treatment for HCV was reported among children with steatosis (P < .001). CONCLUSIONS: The study showed low serum lipids in HCV-infected children with cured leukemia/lymphoma. Hepatic steatosis was found in a significant proportion of patients and was associated with a poor response to antiviral treatment.

Challenge of managing hepatitis B virus and hepatitis C virus infections in resource-limited settings.

The global burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and coinfection represents a major public health concern, particularly in resource-limited settings. Elimination of HCV by 2030 has become foreseeable, with effective direct-acting antiviral oral therapies and the availability of affordable generics in low-and-middle-income countries (LMICs). However, access to oral nucleos(t)ide therapy for HBV remains critical and is limited outside the existing global HIV program platforms despite affordable prices. Prevention of mother-to-child transmission of HBV through scaling up of birth dose implementation in LMICs is essential to achieve the 2030 elimination goal. Most individuals living with HBV and/or HCV in resource-limited settings are unaware of their infection, and with improved access to medications, the most significant barrier remains access to affordable diagnostics and preventive strategies. The coronavirus disease 2019 pandemic interrupted hepatitis elimination programs, albeit offered opportunities for improved diagnostic capacities and raised political awareness of the critical need for strengthening health care services and universal health coverage. This review underpins the HBV and HCV management challenges in resource-limited settings, highlighting the current status and suggested future elimination strategies in some of these countries. Global efforts should continue to improve awareness and political commitment. Financial resources should be secured to access and implement comprehensive strategies for diagnosis and linkage to care in resource-constrained settings to fulfill the 2030 elimination goal.

Egyptian revalidation of non-invasive parameters for predicting esophageal varices in cirrhotic patients: A retrospective study.

BACKGROUND AND STUDY AIMS: In resource-limited countries, non-invasive tests for assessing liver fibrosis are a potential alternative to costly endoscopic screening for esophageal varices. We aimed to validate several non-invasive parameters for predicting the presence of varices. PATIENTS AND METHODS: Between September 2006 and August 2017, a total of 46,014 patients who underwent upper gastrointestinal endoscopy as one of the perquisites for receiving hepatitis C virus (HCV) therapy were enrolled and divided into group I (without varices) and group II (with varices). Non-invasive parameters of fibrosis, namely Lok index, Bonacini score, liver stiffness, FIB-4, Baveno, and extended Baveno criteria, were validated. RESULTS: Lok index, Bonacini score, liver stiffness, and FIB-4 had areas under the receiver operating characteristic curve (AUCs) of >0.6 (all P < 0.01 for the null hypothesis that the AUC was 0.5) for determination of the presence/absence of varices, with cutoff values of 0.80, 6.5, 21.9 kPa, and 2.94, and sensitivities of 74%, 74%, 66%, and 83%, respectively. The expanded Baveno VI criteria performed better than the Baveno VI criteria (spared endoscopy rate 81% versus 63%). CONCLUSION: The use of non-invasive methods is of limited value in predicting esophageal varices. The limited accuracy of ≤60% may delay the use of appropriate primary prophylaxis against variceal bleeding in a large proportion of cirrhotic patients.

The outcome of re-treatment of relapsed hepatitis C virus infection in a resource-limited setting.

The aim of this study was to compare efficacy and safety of different combination regimens in re-treatment of HCV in the setting of inaccessibility of resistance testing. This real-life prospective study included 86 chronic HCV infected patients who experienced failure of treatment treated at Faculty of Medicine Ain shams Research Institute (MASRI) since 2018. 64% of the patients were males, with median age 50.2 years. They were re-treated using 1 of 3 proposed regimens of DAA combinations. One group received PAR/OMB/SOF/RBV for 12 weeks, another group received SOF/DAC/SIM/RBV for 12 weeks and a third received SOF/DAC/RBV for 24 weeks. Response to different regimens was assessed by comparing sustained virologic response (SVR) of each. Monitoring the occurrence of adverse events was performed. SVR was achieved in all but 3 patients (96.5% SVR), one in the SOF/DAC/SIM/RBV group and two in the SOF/DAC/RBV group. The group receiving RBV had more anaemia and hyperbilirubinemia. The first treatment regimen used was a significant predictor to SVR achievement. This study presents alternative treatment regimens for re-treatment of HCV patients in areas with limited resources in the case of non-availability of other regimens as velpatasvir, voxilaprevir, grazoprevir, elbasvir.

Global prevalence of hepatitis C virus in children in 2018: a modelling study.

BACKGROUND: Hepatitis C virus (HCV) prevalence estimates for adults and high-risk groups have been widely published, but the disease burden in children is poorly understood. Direct-acting antiviral drugs, which are considered to be highly effective curative therapies for HCV, are now approved for paediatric patients as young as 3 years. Reliable prevalence estimates for this population are needed to inform scale-up of treatment and national strategies. This analysis combines past modelling and epidemiological work in 104 countries and territories to estimate global HCV prevalence in children in 2018. METHODS: In this modelling study, a comprehensive literature review for articles published between Jan 1, 2000, and March 31, 2019, was used to determine historical HCV prevalence estimates in children in all 249 countries and territories of the world. We identified published HCV prevalence estimates for children aged 0-18 years who are not at high risk of HCV infection in 39 countries and territories and inputted them into dynamic Markov disease-burden models to estimate viraemic HCV prevalence in 2018. For 25 of them, which had complete data, available information on HCV prevalence in children was used to build regression models to predict paediatric prevalence in an additional 65 countries and territories that had country-specific or territory-specific data about predictors only. Regression models were created for each 5-year paediatric age cohort from 0 to 19 years, considering several predictor variables. The data and forecasts from the 104 countries and territories for which data were available were used to calculate HCV prevalence by Global Burden of Disease region, which was then applied to the remaining 145 countries and territories to generate a global estimate. FINDINGS: The global estimate for viraemic prevalence in the paediatric population aged 0-18 years was 0·13% (95% uncertainty interval 0·08-0·16), corresponding to 3·26 million (2·07-3·90) children with HCV in 2018. HCV prevalence increased with age in all countries and territories. HCV prevalence in women of childbearing age was the strongest predictor of HCV prevalence in children aged 0-4 years (p<0·0001). Prevalence of HCV in adults was significantly associated with HCV prevalence in children aged 5-19 years (p<0·0001), and the proportion of HCV infections in people who inject drugs was significantly associated with HCV prevalence in children aged 15-19 years (p=0·036). INTERPRETATION: Most studies on HCV prevalence in children focus on high-risk groups and highly endemic geographic areas. Our analysis provides global prevalence estimates of HCV in the paediatric population. Treatment in paediatric patients requires different clinical and population health management optimisation than in adults. Because of this heterogeneity, country-specific or territory-specific and age-specific HCV prevalence estimates can help countries and territories to improve national HCV elimination strategies. FUNDING: Gilead Sciences, John C Martin Foundation, and private donors.

Liver stiffness measurements and FIB-4 are predictors of response to sofosbuvir-based treatment regimens in 7256 chronic HCV patients.

Objectives: To assess the role of baseline liver stiffness (LS) by Transient elastography (TE) and FIB-4 in the prediction of virological response to sofosbuvir - based regimens in chronic HCV patients.Methods: A retrospective, multicenter study including 7256 chronic HCV patients who received different sofosbuvir-based regimens. Baseline demographic and laboratory data were recorded. TE was performed with FIB-4 calculation at baseline.Results: Sustained virological response at week 12 post-treatment (SVR12) was 91.4%. Pretreatment TE values and FIB-4 were significantly lower among sustained responders (17.8 ± 11.5 kPa, 2.66 ± 1.98, respectively) versus relapsers (24.5 ± 13.9 kPa, 4.02 ± 3.3, respectively). Best cutoff levels for LS by TE and FIB-4 score for prediction of failure to treatment response were 16.7 kPa and 2.4, respectively. Among different treatment protocol, patients with FIB-4 > 2.4, TE values >16.7 kPa are more prone to treatment failure except when using SOF/SIM treatment regimens.Conclusion: Baseline LS by TE and FIB-4 score may be useful for predicting treatment outcome in the new era of DAAs and could be integrated into pretreatment assessment of chronic HCV patients for better optimization of patient management.

Assessment of puberty in relation to L-carnitine and hormonal replacement therapy in beta-thalassemic patients.

OBJECTIVE: To investigate puberty in a group of thalassemic patients with delayed or arrested pubertal development and to compare the effects of hormonal and L-carnitine therapy on puberty in those patients. PATIENTS: Thirty-two -thalassemic patients with arrested or failure of puberty were enrolled for 1 year in this study. METHOD: Clinical pubertal assessment and laboratory investigations were done for all patients at the beginning, 6 months later clinical pubertal assessment was done. Patients were divided into two groups (16 each): first group received L-carnitine therapy, while the second group received hormonal therapy. Pubertal and laboratory assessment were done 6 months after hormonal and L-carnitine therapy. RESULTS: Failure of puberty was confirmed in 71.4% of boys and 33.3% of girls, while arrested puberty was observed in 28.6% of boys and 66.7% of girls. All girls had amenorrhea, primary amenorrhea in 88.9% and secondary amenorrhea in 11.1%. Menses occurred in 20% of female patients after L-carnitine therapy and in 37.5% of them after hormonal therapy. Improvement of pubertal staging was observed in 50% of males after L-carnitine therapy compared to 75% of them after hormonal therapy. While improvement of pubertal staging was seen in 90% of females after L-carnitine therapy compared to 100% of females after hormonal treatment. However, these results showed no significant difference between both groups. CONCLUSION: Delayed puberty in beta-thalassemia major is either due to failure of gonads or failure of the whole hypothalamic pituitary gonadal axis. L-carnitine as well as hormonal replacement therapy had a positive effect on puberty in the thalassemic patients. Further studies are needed to clarify the role of L-carnitine on puberty in these patients.

ADAMTS13 Levels in Young Patients With ß-Thalassemia Major: Relation to Hepatitis C Virus Infection, Liver Cirrhosis, and Iron Overload.

UNLABELLED: We measured levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in 50 children and adolescents with ß-thalassemia major (25 without hepatitis C virus [HCV] infection and 25 with HCV infection) compared to 25 healthy controls and assessed their relation to iron overload, HCV infection, and liver cirrhosis. Hematological and coagulation profiles, serum ferritin, and von Willebrand factor antigen were assessed. Levels of ADAMTS13 were significantly lower in ß-thalassemia major with and without HCV infection compared to healthy controls, with a more significant reduction in levels among patients with HCV (P < .001). HCV-positive patients with thalassemia having liver cirrhosis had the lowest ADAMTS13 levels than those without cirrhosis (P = .012) or HCV-negative patients with thalassemia (P < .001). Levels of ADAMTS13 were positively correlated with platelet count while inversely correlated with partial thromboplastin time, serum ferritin, and VWF: Ag (P < .05). CONCLUSION: Patients with ß-thalassemia major infected with HCV have low ADAMTS13 levels, and a marked reduction was observed among patients with liver cirrhosis and, therefore, may be liable to thromboembolic manifestations.

Overwhelming postsplenectomy infection: is quality of patient knowledge enough for prevention?

BACKGROUND/OBJECTIVE: Fulminant, potentially life-threatening infection represents a major long-term risk after splenectomy. This study examines the impact of patient's knowledge and compliance on the prevention of overwhelming postsplenectomy infection (OPSI). METHODS: A Total of 318 splenectomized patients (median age: 18 years (10-26 years); M : F, 187 : 131) were enrolled in this study. A questionnaire was administered to assess the degree of knowledge and patient compliance and their role in the prevention of postsplenectomy risks; while identifying the group of health-care providers most successful in conveying information. RESULTS: The 318 patients had been splenectomized and followed up through a 17-year period. OPSI occurred among 5.7% (n=18) of patients. Of these, 56% occurred within the first 6 months and 44% in the following 10 years post splenectomy. Three patients died of OPSI, two during the first 6 months and one 2 years later. Of the followed up patients, 44.8% (n=142) had good knowledge of the risks of splenectomy and their prevention, 30.4% (n=96) had fair knowledge and 24.8% (n=79) had poor knowledge. Patients displaying greatest knowledge had a prevalence of OPSI of 1.4% compared to 16.5% among those with poor knowledge (P<0.001). In all, 60% of patients with good knowledge got their information principally from their tending hematologist. Among patients on regular and irregular prophylactic oral penicillin, OPSI occurred in 2.7 and 10% respectively (P<0.01). The incidence of OPSI also decreased from 7.3 to 3.2% after routine administration of pneumococcal vaccine (P<0.05). CONCLUSION: Although good knowledge, prophylactic penicillin and pneumococcal vaccination have remarkably reduced OPSI, it was not enough for complete prevention. The use of lifelong antibiotic prophylaxis remains of disputed value since no OPSI was recorded more than 10 years post splenectomy.

Efficacy and safety of pegylated interferon in children and adolescents infected with chronic hepatitis C: a preliminary study.

This study researches the efficacy and safety of pegylated interferon alpha-2a (pegIFNα-2a) in Egyptian children and adolescents diagnosed with hepatitis C virus. Thirty patients were enrolled to receive pegIFN once a week with ribavirin twice daily for 12 weeks; viral load and experienced adverse effects were then assessed. Of the 30 patients, 16 (53.33%) were cleared from the virus, showing early virologic response (EVR). Three patients (10%) showed a 2-log reduction by week 12, with an overall early response rate of 63.33%. Three patients who showed EVR after 4 weeks relapsed by week 12. Levels of serum alanine aminotransferase (ALT) normalized at week 12. Adverse events included fever, myalgia, headache, flu-like symptoms, fatigue, anemia, and leucopenia; 63.33% of the patients showed significant reduction in their body weight. Although the patients showed a reduction in average body mass index, this reduction was not significant. Hemoglobin values decreased within the first 2 weeks and then stabilized but not back to baseline. A significant reduction in the level of absolute neutrophil count (ANC) was observed by the 4th week and started to improve by the 12th week. Of the recruited patients, 29.4% were subjected to IFN dose reduction. None of the patients with neutropenia developed serious infection or sepsis. The authors concluded that pegIFN plus ribavirin therapy is promising when tested on Egyptian children.