This document summarizes key factors related to drug rechallenge following drug-induced liver injury (DILI). It finds that nearly 50 drugs are associated with positive rechallenge, defined as ALT levels 3-5x upper limits of normal. Drugs that cause mitochondrial impairment or immunoallergic injury in vitro have higher positive rechallenge rates, as do those with a daily dose over 50mg. Personal factors like genetics and environment also influence outcomes. Drugs associated with DILI in clinical trials tend to have higher ALT elevations than placebos. While rechallenge carries risks, it may be considered for critical medications if alternatives are unavailable and patients can be closely monitored. More data is still needed to better understand outcomes and identify re
"Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury, Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD"
Context—Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide, and have been linked to acute interstitial nephritis. Less is known about the relationship between PPI use and chronic kidney disease (CKD).
Objective—To quantify the association between PPI use and incident CKD in a population based cohort.
In total, 144,032 participants in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m2 were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analysed from May 2015 to October 2015.
Proton Pump Inhibitors and Risk of Acute and Chronic Kidney Disease: A Retros...KhalafAlGhamdi
This document summarizes a study presented at a nephrology journal club that examined the association between proton pump inhibitor (PPI) use and the risk of acute kidney injury (AKI) and chronic kidney disease (CKD) using a large health insurance database. The study found that PPI use was associated with a 4-fold higher risk of AKI and a 20% higher risk of CKD compared to non-users. While the results strengthen evidence of this association, limitations include potential residual confounding and inability to account for over-the-counter medication use. The conclusion calls for provider education and deprescribing initiatives to reduce PPI overuse and potential kidney risks.
Risk factors of chronic liver disease amongst patients receiving care in a Ga...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
Sydney Sexual Health Centre Journal Club presentation by Cherie Desreaux on the British Medical Journal and the Medical Journal of Australia editions published between November 2015 and March 2016.
The Sydney Sexual Health Centre Journal Club allows our team to stay up-to-date with what is being published in the field of sexual health. Staff members take turns to read, review and share the contents of an allocated journal. Journal Club encourages knowledge sharing and discussion about topics raised.
This randomized controlled trial compared the efficacy of pentoxifylline and prednisolone in treating severe alcoholic hepatitis. 68 patients were divided into two groups - one received pentoxifylline and the other received prednisolone for 4 weeks, followed by a tapering dose of prednisolone over 7 weeks. More patients died in the prednisolone group (12 patients) compared to the pentoxifylline group (5 patients) by 3 months. Patients receiving prednisolone also had more life-threatening complications like hepatorenal syndrome and gastrointestinal bleeding. The study suggests pentoxifylline is superior to prednisolone for treating severe alcoholic hepatitis due to its reduced mortality and renopro
This study analyzed clinical outcomes of treated and untreated patients with hepatitis C virus (HCV) infection in two cohorts. It found that HCV patients who did not respond to interferon-alpha based treatment had a significantly increased risk of developing cirrhosis compared to untreated patients, even after adjusting for factors like fibrosis stage and psychosocial risks. Specifically, treatment nonresponders had a 2.35 times higher hazard of cirrhosis in the Veterans Affairs cohort and a 5.9 times higher hazard in the University Hospital cohort compared to untreated patients. However, the overall survival of nonresponders was not significantly different than untreated patients. This suggests that while interferon-alpha treatment failure may accelerate liver fibrosis, it does not necessarily impact overall
This document summarizes an expert panel discussion on innovative antiretroviral therapy (ART) paradigms. The panel discussed whether positive results from two-drug and long-acting injectable regimens in clinical trials will translate to long-term efficacy and safety. They also considered the potential risks of resistance emerging with two-drug regimens and the impact of missed doses with long-acting injectables. The panel agreed that maintaining cold storage requirements for long-acting injectables may pose challenges for implementation in low- and middle-income countries but that qualitative research found patients highly satisfied with the convenience of long-acting ART.
"Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury, Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD"
Context—Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide, and have been linked to acute interstitial nephritis. Less is known about the relationship between PPI use and chronic kidney disease (CKD).
Objective—To quantify the association between PPI use and incident CKD in a population based cohort.
In total, 144,032 participants in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m2 were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analysed from May 2015 to October 2015.
Proton Pump Inhibitors and Risk of Acute and Chronic Kidney Disease: A Retros...KhalafAlGhamdi
This document summarizes a study presented at a nephrology journal club that examined the association between proton pump inhibitor (PPI) use and the risk of acute kidney injury (AKI) and chronic kidney disease (CKD) using a large health insurance database. The study found that PPI use was associated with a 4-fold higher risk of AKI and a 20% higher risk of CKD compared to non-users. While the results strengthen evidence of this association, limitations include potential residual confounding and inability to account for over-the-counter medication use. The conclusion calls for provider education and deprescribing initiatives to reduce PPI overuse and potential kidney risks.
Risk factors of chronic liver disease amongst patients receiving care in a Ga...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
Sydney Sexual Health Centre Journal Club presentation by Cherie Desreaux on the British Medical Journal and the Medical Journal of Australia editions published between November 2015 and March 2016.
The Sydney Sexual Health Centre Journal Club allows our team to stay up-to-date with what is being published in the field of sexual health. Staff members take turns to read, review and share the contents of an allocated journal. Journal Club encourages knowledge sharing and discussion about topics raised.
This randomized controlled trial compared the efficacy of pentoxifylline and prednisolone in treating severe alcoholic hepatitis. 68 patients were divided into two groups - one received pentoxifylline and the other received prednisolone for 4 weeks, followed by a tapering dose of prednisolone over 7 weeks. More patients died in the prednisolone group (12 patients) compared to the pentoxifylline group (5 patients) by 3 months. Patients receiving prednisolone also had more life-threatening complications like hepatorenal syndrome and gastrointestinal bleeding. The study suggests pentoxifylline is superior to prednisolone for treating severe alcoholic hepatitis due to its reduced mortality and renopro
This study analyzed clinical outcomes of treated and untreated patients with hepatitis C virus (HCV) infection in two cohorts. It found that HCV patients who did not respond to interferon-alpha based treatment had a significantly increased risk of developing cirrhosis compared to untreated patients, even after adjusting for factors like fibrosis stage and psychosocial risks. Specifically, treatment nonresponders had a 2.35 times higher hazard of cirrhosis in the Veterans Affairs cohort and a 5.9 times higher hazard in the University Hospital cohort compared to untreated patients. However, the overall survival of nonresponders was not significantly different than untreated patients. This suggests that while interferon-alpha treatment failure may accelerate liver fibrosis, it does not necessarily impact overall
This document summarizes an expert panel discussion on innovative antiretroviral therapy (ART) paradigms. The panel discussed whether positive results from two-drug and long-acting injectable regimens in clinical trials will translate to long-term efficacy and safety. They also considered the potential risks of resistance emerging with two-drug regimens and the impact of missed doses with long-acting injectables. The panel agreed that maintaining cold storage requirements for long-acting injectables may pose challenges for implementation in low- and middle-income countries but that qualitative research found patients highly satisfied with the convenience of long-acting ART.
Современное лечение ВИЧ : лечение возрастных пациентов.2017/Contemporary Management of HIV. Management of Aging Patients.2017
In this downloadable slideset, Edgar Turner Overton, MD, and Program Director Joseph J. Eron, Jr., MD, review key data on managing aging patients with HIV.
Source: Contemporary Management of HIV
Date Posted: 4/24/2017
This study analyzed serious non-AIDS events (SNAs) among HIV-infected adults in Latin America. The researchers identified 130 patients with SNA events out of 6007 patients in the cohort, representing an incidence rate of 0.86 events per 100 person-years. Risk factors like hepatitis B/C coinfection, diabetes, and alcohol abuse were associated with SNA events. Lower CD4 cell counts prior to and at the index date were significantly associated with SNA events occurring, even in patients receiving antiretroviral treatment. The study found HIV-associated immune deficiency increased the risk of SNA events.
Аллопуринол и прогрессирование ХБП и кардиоваскулярные события. РКИ / Allopur...hivlifeinfo
Allopurinol and Progression of CKD and Cardiovascular Events- Long-term Follow-up of a Randomized Clinical Trial.Am J Kidney Dis. 2015 Apr
Background:Asymptomatic hyperuricemia increases renal and cardiovascular (CV) risk. We previously
conducted a 2-year, single-blind, randomized, controlled trial of allopurinol treatment that showed improved
estimated glomerular filtration rate and reduced CV risk.
Study Design:Post hoc analysis of a long-term follow-up after completion of the 2-year trial.
Setting & Participants:113 participants (57 in the allopurinol group and 56 in the control group) initially
followed up for 2 years and 107 participants followed up to 5 additional years.
Intervention: Continuation of allopurinol treatment, 100 mg/d, or standard treatment.
Outcome:Renal event (defined as starting dialysis therapy and/or doubling serum creatinine and/or$50%
decrease in estimated estimated glomerular filtration rate) and CV events (defined as myocardial infarction,
coronary revascularization or angina pectoris, congestive heart failure, cerebrovascular disease, and peripheral vascular disease).
Results:During initial follow-up, there were 2 renal and 7 CV events in the allopurinol group compared with
6 renal and 15 CV events in the control group. In the long-term follow-up period, 12 of 56 participants taking
allopurinol stopped treatment and 10 of 51 control participants received allopurinol. During long-term follow-up,
an additional 7 and 9 participants in the allopurinol group experienced a renal or CV event, respectively, and an
additional 18 and 8 participants in the control group experienced a renal or CV event, respectively. Thus,
during the initial and long-term follow-up (median, 84 months), 9 patients in the allopurinol group had a
renal event compared with 24 patients in the control group (HR, 0.32; 95% CI, 0.15-0.69; P50.004;
adjusted for age, sex, baseline kidney function, uric acid level, and renin-angiotensin-aldosterone system
blockers). Overall, 16 patients treated with allopurinol experienced CV events compared with 23 in the
control group (HR, 0.43; 95% CI, 0.21-0.88;P50.02; adjusted for age, sex, and baseline kidney function).
Limitations:Small sample size, single center, not double blind, post hoc follow-up and analysis.
Conclusions: Long-term treatment with allopurinol may slow the rate of progression of kidney disease and
reduce CV risk.
Contemporary Management of HIV.How Common Comorbidities Affect ART Management...hivlifeinfo
In this downloadable slideset, expert faculty review key data and offer important guidance on managing HIV treatment in patients with frequently encountered comorbidities, including cardiovascular disease, osteopenia, and HCV coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 2.27 MB
Date posted: 2/12/2018
1. This document provides guidelines for the diagnosis, management, and treatment of hepatitis C virus (HCV) infection based on a formal review of recent literature and expert consensus.
2. It recommends screening high-risk groups for HCV infection, including current and former injection drug users, those with HIV, and prior blood transfusion recipients.
3. It also provides guidance on counseling HCV-infected individuals, including advising them to avoid behaviors that may spread the virus and informing them that properly performed tattooing and piercing pose a very low risk of transmission.
HIV Alert:ART Considerations for Aging Patients.2018hivlifeinfo
In this downloadable slideset, Eric S. Daar, MD, and David A. Wohl, MD, provide expert recommendations for older patients with HIV, both in terms of ART selection and general management.
Format: Microsoft PowerPoint (.ppt)
File size: 545 KB
Date posted: 2/12/2018
Dexamethasone is a corticosteroid that has shown promise in improving outcomes for patients with bacterial meningitis. However, previous studies have found conflicting results on whether it benefits all patients or only certain subgroups. This study conducted a meta-analysis of individual patient data from 5 randomized controlled trials involving 2029 patients to identify which patients are most likely to benefit from dexamethasone treatment. The analysis found that dexamethasone did not significantly reduce death rates or neurological disability overall. It also did not provide significant benefits within any prespecified subgroups based on factors like causative organism, pre-treatment with antibiotics, HIV status, or age. The only benefit seen was a reduction in hearing loss among survivors.
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Conte...hivlifeinfo
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Contemporary Management of HIV. Managing HIV in Viral Hepatitis Coinfection.2016
In this downloadable slideset, David L. Wyles, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for ART management in patients with HIV and viral hepatitis coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 1.85 MB
Современное лечение ВИЧ: лечение ВИЧ у женщин.2017/Contemporary Management of...hivlifeinfo
In this downloadable slideset, Kathleen E. Squires, MD, and Program Director Joseph J. Eron, Jr., MD, review key data and optimal strategies in caring for HIV-infected women, including ART safety and efficacy in women, reproductive health management, ART and pregnancy, and preventing HIV infection in women.
Format: Microsoft PowerPoint (.ppt)
File size: 1.59 MB
Date posted: 4/25/2017
The Prevalence of Hcv Infection among Renal Failure Patients Before Starting ...CrimsonpublishersMedical
HCV infection is common and associated with significant morbidity and mortality among heamodialysis (HD) patients [1]. Heamodialysis is a trusted intermediate procedure for management of chronic kidney disease (CKD) patients. As such CKD is an immunedeficient state, hence blood borne viral infection particularly HCV pose great risk to patients treated by heamodialysis [2]. A high prevalence of HCV infection in heamodialysis patients has been reported in heamodialysis units since the introduction of heamodialysis therapy. Risk factors such as the number of blood transfusions or duration on heamodialysis. The prevalence of HCV infection in patients undergoing dialysis is greater than that in the general population, suggesting that patients on dialysis may be at higher risk of acquiring HCV infection.
This document summarizes considerations for clinicians in diagnosing acute interstitial nephritis (AIN). AIN is a common cause of acute kidney injury, particularly among hospitalized patients. It can be difficult to differentiate AIN from other causes of kidney injury based on clinical history, exams, and tests alone. No single test is diagnostic of AIN. While urine tests may provide some clues, kidney biopsy is often needed for a definitive diagnosis and to guide management. The document reviews the etiology, presentation, and utility of commonly ordered urine tests in evaluating for AIN.
This document summarizes updates to the 2009 American Association for the Study of Liver Diseases (AASLD) Practice Guidelines for the management of chronic hepatitis B. Key changes include:
1) Tenofovir is now recommended as a first-line oral antiviral treatment based on its superior efficacy compared to adefovir in clinical trials. Adefovir is now recommended as a second-line treatment.
2) Entecavir is no longer recommended for patients co-infected with HBV and HIV due to data on its anti-HIV activity.
3) Screening recommendations were expanded to include persons born in intermediate endemic areas and those receiving cancer chemotherapy or long-term immunosuppression based on
1) The study evaluated converting 210 stable liver transplant recipients from twice-daily tacrolimus to a once-daily prolonged-release formulation on a 1 mg to 1 mg basis.
2) Seven patients (3.3%) withdrew from the conversion due to side effects. Liver enzymes increased mildly in some patients but renal function and uric acid levels improved.
3) Seven additional patients (3.4%) experienced suspected acute rejection after converting, though three cases were attributed to non-adherence. Most patients reported more social/travel flexibility with once-daily dosing.
This document is the February 2015 issue of the UTSW Internal Medicine Journal Watch. It contains summaries of recent articles across various specialties, including endocrinology, rheumatology, health care improvement, general internal medicine, nephrology, infectious diseases, hepatology, and cardiology. There is also an EKG challenge case. The endocrinology section highlights updates to diabetes screening and treatment guidelines from the American Diabetes Association, including changes to blood glucose and blood pressure targets. The health care improvement section discusses a study finding that some health plans are using adverse drug tiering to discourage enrollment by patients with high-cost conditions like HIV.
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусной супрессией и ...hivlifeinfo
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусной супрессией и у пациентов с вирусологической неудачей. /Contemporary Management of HIV. Modifying Antiretroviral Therapy in Virologically Suppressed Patients and Those With Treatment Failure.2016
In this downloadable slideset, W. David Hardy, MD, and Program Director Eric S. Daar, MD review key data and optimal approaches for modifying ART in patients who are virologically suppressed or have experienced treatment failure.
Format: Microsoft PowerPoint (.ppt)
File size: 2.07 MB
This study examined risk factors for post-transplant erythrocytosis (PTE) in 235 kidney transplant recipients. The results showed that being male significantly increased the risk of developing PTE. Patients with polycystic kidney disease or glomerulonephritis also had a higher risk. While smoking was associated with PTE, further analysis revealed this was likely due to the relationship between smoking and male sex rather than a direct effect. The study did not find significant relationships between PTE and other factors like hypertension, diabetes, transplant organ source, or immunosuppressant regimen.
Integrating Recent Data When Selecting First-line Antiretroviral Therapy.2015...Hivlife Info
Joseph J. Eron Jr., MD
W. David Hardy, MD
Paul E. Sax, MD
How do leading experts select first-line antiretroviral therapy for their HIV-infected patients?
Review these downloadable slides for key clinical trial data and the latest DHHS recommendations for first-line antiretroviral therapy.
Comparison of Infection Episodes in CKD Patients with or without Hemodialysis...ijtsrd
This study compared infection episodes in chronic kidney disease (CKD) patients with and without hemodialysis. A cross-sectional study of 56 CKD patients found that those undergoing hemodialysis had higher rates of chills, increased white blood cell count, and elevated erythrocyte sedimentation rate compared to non-hemodialysis patients. The study concluded that CKD patients on long-term hemodialysis were more prone to developing infections than those not on hemodialysis, likely due to factors such as catheter insertion for hemodialysis. Better infection prevention strategies are needed for CKD patients undergoing hemodialysis.
1. The document discusses managing Hepatitis C infection in unique populations such as children, pregnant women, and those with comorbidities. It provides guidelines for testing, monitoring, and treatment of acute and chronic HCV infection in these groups.
2. Rates of mother-to-child transmission of HCV are approximately 5% but can be higher in women with HIV coinfection or higher viral loads. Children born to HCV-infected mothers should be tested after 18 months of age.
3. For children under 12, the only approved treatment is 24-48 weeks of pegylated interferon and ribavirin depending on genotype. For adolescents 12 and older, direct-acting antiviral regimens are
The Cleveland Clinic Gastrointestinal symptoms in cancer patients with.pdfJaveriana Cali
Gastrointestinal (GI) symptoms are common and detrimental to quality of life in advanced cancer patients. Nausea, vomiting, and diarrhea are prevalent, often caused by medication side effects or the underlying disease. Effective management of GI symptoms requires thorough assessment, evidence-based approaches, and monitoring of both clinical measures and patient-reported outcomes. New drugs and complementary therapies show promise in both symptom management and prevention.
Современное лечение ВИЧ : лечение возрастных пациентов.2017/Contemporary Management of HIV. Management of Aging Patients.2017
In this downloadable slideset, Edgar Turner Overton, MD, and Program Director Joseph J. Eron, Jr., MD, review key data on managing aging patients with HIV.
Source: Contemporary Management of HIV
Date Posted: 4/24/2017
This study analyzed serious non-AIDS events (SNAs) among HIV-infected adults in Latin America. The researchers identified 130 patients with SNA events out of 6007 patients in the cohort, representing an incidence rate of 0.86 events per 100 person-years. Risk factors like hepatitis B/C coinfection, diabetes, and alcohol abuse were associated with SNA events. Lower CD4 cell counts prior to and at the index date were significantly associated with SNA events occurring, even in patients receiving antiretroviral treatment. The study found HIV-associated immune deficiency increased the risk of SNA events.
Аллопуринол и прогрессирование ХБП и кардиоваскулярные события. РКИ / Allopur...hivlifeinfo
Allopurinol and Progression of CKD and Cardiovascular Events- Long-term Follow-up of a Randomized Clinical Trial.Am J Kidney Dis. 2015 Apr
Background:Asymptomatic hyperuricemia increases renal and cardiovascular (CV) risk. We previously
conducted a 2-year, single-blind, randomized, controlled trial of allopurinol treatment that showed improved
estimated glomerular filtration rate and reduced CV risk.
Study Design:Post hoc analysis of a long-term follow-up after completion of the 2-year trial.
Setting & Participants:113 participants (57 in the allopurinol group and 56 in the control group) initially
followed up for 2 years and 107 participants followed up to 5 additional years.
Intervention: Continuation of allopurinol treatment, 100 mg/d, or standard treatment.
Outcome:Renal event (defined as starting dialysis therapy and/or doubling serum creatinine and/or$50%
decrease in estimated estimated glomerular filtration rate) and CV events (defined as myocardial infarction,
coronary revascularization or angina pectoris, congestive heart failure, cerebrovascular disease, and peripheral vascular disease).
Results:During initial follow-up, there were 2 renal and 7 CV events in the allopurinol group compared with
6 renal and 15 CV events in the control group. In the long-term follow-up period, 12 of 56 participants taking
allopurinol stopped treatment and 10 of 51 control participants received allopurinol. During long-term follow-up,
an additional 7 and 9 participants in the allopurinol group experienced a renal or CV event, respectively, and an
additional 18 and 8 participants in the control group experienced a renal or CV event, respectively. Thus,
during the initial and long-term follow-up (median, 84 months), 9 patients in the allopurinol group had a
renal event compared with 24 patients in the control group (HR, 0.32; 95% CI, 0.15-0.69; P50.004;
adjusted for age, sex, baseline kidney function, uric acid level, and renin-angiotensin-aldosterone system
blockers). Overall, 16 patients treated with allopurinol experienced CV events compared with 23 in the
control group (HR, 0.43; 95% CI, 0.21-0.88;P50.02; adjusted for age, sex, and baseline kidney function).
Limitations:Small sample size, single center, not double blind, post hoc follow-up and analysis.
Conclusions: Long-term treatment with allopurinol may slow the rate of progression of kidney disease and
reduce CV risk.
Contemporary Management of HIV.How Common Comorbidities Affect ART Management...hivlifeinfo
In this downloadable slideset, expert faculty review key data and offer important guidance on managing HIV treatment in patients with frequently encountered comorbidities, including cardiovascular disease, osteopenia, and HCV coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 2.27 MB
Date posted: 2/12/2018
1. This document provides guidelines for the diagnosis, management, and treatment of hepatitis C virus (HCV) infection based on a formal review of recent literature and expert consensus.
2. It recommends screening high-risk groups for HCV infection, including current and former injection drug users, those with HIV, and prior blood transfusion recipients.
3. It also provides guidance on counseling HCV-infected individuals, including advising them to avoid behaviors that may spread the virus and informing them that properly performed tattooing and piercing pose a very low risk of transmission.
HIV Alert:ART Considerations for Aging Patients.2018hivlifeinfo
In this downloadable slideset, Eric S. Daar, MD, and David A. Wohl, MD, provide expert recommendations for older patients with HIV, both in terms of ART selection and general management.
Format: Microsoft PowerPoint (.ppt)
File size: 545 KB
Date posted: 2/12/2018
Dexamethasone is a corticosteroid that has shown promise in improving outcomes for patients with bacterial meningitis. However, previous studies have found conflicting results on whether it benefits all patients or only certain subgroups. This study conducted a meta-analysis of individual patient data from 5 randomized controlled trials involving 2029 patients to identify which patients are most likely to benefit from dexamethasone treatment. The analysis found that dexamethasone did not significantly reduce death rates or neurological disability overall. It also did not provide significant benefits within any prespecified subgroups based on factors like causative organism, pre-treatment with antibiotics, HIV status, or age. The only benefit seen was a reduction in hearing loss among survivors.
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Conte...hivlifeinfo
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Contemporary Management of HIV. Managing HIV in Viral Hepatitis Coinfection.2016
In this downloadable slideset, David L. Wyles, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for ART management in patients with HIV and viral hepatitis coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 1.85 MB
Современное лечение ВИЧ: лечение ВИЧ у женщин.2017/Contemporary Management of...hivlifeinfo
In this downloadable slideset, Kathleen E. Squires, MD, and Program Director Joseph J. Eron, Jr., MD, review key data and optimal strategies in caring for HIV-infected women, including ART safety and efficacy in women, reproductive health management, ART and pregnancy, and preventing HIV infection in women.
Format: Microsoft PowerPoint (.ppt)
File size: 1.59 MB
Date posted: 4/25/2017
The Prevalence of Hcv Infection among Renal Failure Patients Before Starting ...CrimsonpublishersMedical
HCV infection is common and associated with significant morbidity and mortality among heamodialysis (HD) patients [1]. Heamodialysis is a trusted intermediate procedure for management of chronic kidney disease (CKD) patients. As such CKD is an immunedeficient state, hence blood borne viral infection particularly HCV pose great risk to patients treated by heamodialysis [2]. A high prevalence of HCV infection in heamodialysis patients has been reported in heamodialysis units since the introduction of heamodialysis therapy. Risk factors such as the number of blood transfusions or duration on heamodialysis. The prevalence of HCV infection in patients undergoing dialysis is greater than that in the general population, suggesting that patients on dialysis may be at higher risk of acquiring HCV infection.
This document summarizes considerations for clinicians in diagnosing acute interstitial nephritis (AIN). AIN is a common cause of acute kidney injury, particularly among hospitalized patients. It can be difficult to differentiate AIN from other causes of kidney injury based on clinical history, exams, and tests alone. No single test is diagnostic of AIN. While urine tests may provide some clues, kidney biopsy is often needed for a definitive diagnosis and to guide management. The document reviews the etiology, presentation, and utility of commonly ordered urine tests in evaluating for AIN.
This document summarizes updates to the 2009 American Association for the Study of Liver Diseases (AASLD) Practice Guidelines for the management of chronic hepatitis B. Key changes include:
1) Tenofovir is now recommended as a first-line oral antiviral treatment based on its superior efficacy compared to adefovir in clinical trials. Adefovir is now recommended as a second-line treatment.
2) Entecavir is no longer recommended for patients co-infected with HBV and HIV due to data on its anti-HIV activity.
3) Screening recommendations were expanded to include persons born in intermediate endemic areas and those receiving cancer chemotherapy or long-term immunosuppression based on
1) The study evaluated converting 210 stable liver transplant recipients from twice-daily tacrolimus to a once-daily prolonged-release formulation on a 1 mg to 1 mg basis.
2) Seven patients (3.3%) withdrew from the conversion due to side effects. Liver enzymes increased mildly in some patients but renal function and uric acid levels improved.
3) Seven additional patients (3.4%) experienced suspected acute rejection after converting, though three cases were attributed to non-adherence. Most patients reported more social/travel flexibility with once-daily dosing.
This document is the February 2015 issue of the UTSW Internal Medicine Journal Watch. It contains summaries of recent articles across various specialties, including endocrinology, rheumatology, health care improvement, general internal medicine, nephrology, infectious diseases, hepatology, and cardiology. There is also an EKG challenge case. The endocrinology section highlights updates to diabetes screening and treatment guidelines from the American Diabetes Association, including changes to blood glucose and blood pressure targets. The health care improvement section discusses a study finding that some health plans are using adverse drug tiering to discourage enrollment by patients with high-cost conditions like HIV.
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусной супрессией и ...hivlifeinfo
Современное лечение ВИЧ: модификация АРТ у пациентов с вирусной супрессией и у пациентов с вирусологической неудачей. /Contemporary Management of HIV. Modifying Antiretroviral Therapy in Virologically Suppressed Patients and Those With Treatment Failure.2016
In this downloadable slideset, W. David Hardy, MD, and Program Director Eric S. Daar, MD review key data and optimal approaches for modifying ART in patients who are virologically suppressed or have experienced treatment failure.
Format: Microsoft PowerPoint (.ppt)
File size: 2.07 MB
This study examined risk factors for post-transplant erythrocytosis (PTE) in 235 kidney transplant recipients. The results showed that being male significantly increased the risk of developing PTE. Patients with polycystic kidney disease or glomerulonephritis also had a higher risk. While smoking was associated with PTE, further analysis revealed this was likely due to the relationship between smoking and male sex rather than a direct effect. The study did not find significant relationships between PTE and other factors like hypertension, diabetes, transplant organ source, or immunosuppressant regimen.
Integrating Recent Data When Selecting First-line Antiretroviral Therapy.2015...Hivlife Info
Joseph J. Eron Jr., MD
W. David Hardy, MD
Paul E. Sax, MD
How do leading experts select first-line antiretroviral therapy for their HIV-infected patients?
Review these downloadable slides for key clinical trial data and the latest DHHS recommendations for first-line antiretroviral therapy.
Comparison of Infection Episodes in CKD Patients with or without Hemodialysis...ijtsrd
This study compared infection episodes in chronic kidney disease (CKD) patients with and without hemodialysis. A cross-sectional study of 56 CKD patients found that those undergoing hemodialysis had higher rates of chills, increased white blood cell count, and elevated erythrocyte sedimentation rate compared to non-hemodialysis patients. The study concluded that CKD patients on long-term hemodialysis were more prone to developing infections than those not on hemodialysis, likely due to factors such as catheter insertion for hemodialysis. Better infection prevention strategies are needed for CKD patients undergoing hemodialysis.
1. The document discusses managing Hepatitis C infection in unique populations such as children, pregnant women, and those with comorbidities. It provides guidelines for testing, monitoring, and treatment of acute and chronic HCV infection in these groups.
2. Rates of mother-to-child transmission of HCV are approximately 5% but can be higher in women with HIV coinfection or higher viral loads. Children born to HCV-infected mothers should be tested after 18 months of age.
3. For children under 12, the only approved treatment is 24-48 weeks of pegylated interferon and ribavirin depending on genotype. For adolescents 12 and older, direct-acting antiviral regimens are
The Cleveland Clinic Gastrointestinal symptoms in cancer patients with.pdfJaveriana Cali
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Polypharmacy appropriate and inappropriate based on risk and benefit assessment case study, negative consequences of polypharmacy, deprescribing tools,
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usage these medications itself has adverse effect on liver and kidneys causes hepatotoxicity and nephrotoxicity or organs
specific toxicity.
This document summarizes the results of a randomized, prospective, open-label clinical trial evaluating the efficacy and safety of Sulfad tablets for the management of non-alcoholic steatohepatitis (NASH) patients. The trial involved 100 patients taking Sulfad tablets for 3 months. Significant improvements were seen in liver enzymes and lipid profiles after 1, 2, and 3 months of treatment. No major safety issues were reported. The study concluded that Sulfad tablets were well-tolerated and effective for the management of NASH patients.
efficacy and safety of Sulfad tablets in the management of NASH
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Dra. Margaret Redfield. Congreso ACC 2013, Estados Unidos. RELAX: Inhibidor de la fosfodiesterasa-5 no mostró beneficio en la insuficiencia cardiaca con función ventricular preservada. Encuentre más presentaciones de este congreso en la página oficial de SOLACI: www.solaci.org/
ASCO Guideline managmente of immune related advers eventsyeseniahuerta8
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Antihyperglycemic effects of short term resveratrol supplementation in type 2...zanet1
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3) In contrast, the placebo group had slightly increased fasting glucose and LDL compared to baseline. Liver and kidney function markers were unchanged with resveratrol treatment.
Type A and Type B adverse drug reactions can both cause liver injury. Type A reactions are intrinsic and dose-dependent, such as acetaminophen toxicity. Type B reactions are idiosyncratic and result from unpredictable factors in susceptible individuals. Risk factors for Type B reactions include medications that produce toxic metabolites, pre-existing liver disease, concomitant medications, age, and genetics. Resources like LiverTox help clinicians identify and manage drug-induced liver injury.
Thesis_PhD_Improving medication safety in the elderlyHA VO THI
The document discusses medication safety issues for elderly patients, noting that physiological changes with aging increase their risk of adverse drug reactions and interactions from polypharmacy. Polypharmacy, defined as using multiple medications, is common in elderly patients due to multiple chronic conditions but can increase problems with adherence and side effects. Improving medication safety for elderly patients requires addressing polypharmacy issues through individualized treatment reviews that consider life expectancy, treatment goals and targets.
Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. Get For More Info Visit Us http://www.jcehapatology.com
This study analyzed data from over 1,400 patients hospitalized for hepatorenal syndrome (HRS) in Japan between 2010-2019 using a national inpatient database. The results showed that 65.5% of patients died or underwent liver transplantation. Patients in this group had more advanced liver disease, were more likely to be male, and had higher rates of complications like hepatocellular carcinoma and spontaneous bacterial peritonitis. Over half of all patients received albumin therapy, while noradrenaline and dopamine were used as vasoconstrictors, with dopamine being more common than noradrenaline in clinical practice despite guidelines recommending noradrenaline. Mortality from HRS in Japan remains high.
This document discusses how complementary and alternative medicines (CAMs) are increasingly being used by patients and can impact cardiopulmonary bypass. It presents two case studies of patients taking specific CAMs (Sovaldi/Ribavirin and Saw Palmetto) who experienced bleeding issues during bypass surgery. The document advocates for perfusionists to be aware of CAMs patients are taking and create discontinuation plans in advance to improve outcomes and decrease blood product usage and costs.
This document discusses inappropriate prescribing in hospitalized elderly patients. It defines inappropriate prescribing as using medications that significantly increase the risk of adverse drug events when safer alternatives exist. Inappropriate prescribing is common in the elderly and associated with increased morbidity, mortality and healthcare costs. Risk factors in hospitals include advanced age, polypharmacy due to multiple comorbidities, and transitions of care involving multiple providers. The document reviews validated tools to evaluate inappropriate prescribing, including Beers Criteria, IPET, STOPP and MAI. It concludes inappropriate prescribing in hospitals is an important public health problem given the aging population.
Sunitinib for the pancreatic neuroendocrine tumors, Moh'd sharshirMoh'd sharshir
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Sometimes it is difficult & even problem to deal with patient with refractory LN, so we are in need for expert perspectives as a guide to treat those cases.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
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Breast cancer: Post menopausal endocrine therapyDr. Sumit KUMAR
Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
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PGx Analysis in VarSeq: A User’s PerspectiveGolden Helix
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The skin is the largest organ and its health plays a vital role among the other sense organs. The skin concerns like acne breakout, psoriasis, or anything similar along the lines, finding a qualified and experienced dermatologist becomes paramount.
Nutritional deficiency Disorder are problems in india.
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Discover the benefits of homeopathic medicine for irregular periods with our guide on 5 common remedies. Learn how these natural treatments can help regulate menstrual cycles and improve overall menstrual health.
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Computer in pharmaceutical research and development-Mpharm(Pharmaceutics)MuskanShingari
Statistics- Statistics is the science of collecting, organizing, presenting, analyzing and interpreting numerical data to assist in making more effective decisions.
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1. HEP-16-2338: Drug Rechallenge Following Drug-Induced Liver Injury
Christine M. Hunt, MD MPH1,2
Julie I. Papay, PharmD,3
Vid Stanulovic, MD,4,5
Arie Regev, MD6
1
Department of Medicine, Duke University Medical Center, Durham, NC
2
Durham Veterans Administration Medical Center, Durham, NC; email:
Christine.Hunt@va.gov
3
Global Patient Safety, UCB BioSciences, Research Triangle Park, NC; email:
Julie.Papay@ucb.com
4
Accelsiors Clinical Research Organization and Consultancy, Budapest, Hungary; email:
Vid.Stanulovic@gmail.com
5
Semmelweis University School of Pharmacy, Budapest, Hungary
6
Global Patient Safety, Eli Lilly and Company, Indianapolis, IN; email:
REGEV_ARIE@LILLY.COM
Correspondence to: Christine M. Hunt, M.D., M.P.H.
Adjunct Associate Professor of Medicine, Duke University
00550 Hospital South
Durham, NC 27710
Email: Christine.Hunt@va.gov
Phone: 919-389-9617
FAX: 919-416-5839
Conflict of Interest Statement: Christine M. Hunt has received consultancy fees from
Otsuka and Furiex. Julie I. Papay was employed at UCB Biosciences during manuscript
preparation. Vid Stanulovic is employed at Accelsiors Clinical Research Organization and
Consultancy, Budapest, Hungary. Arie Regev is employed at Eli Lilly and Company. The
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/hep.29152
This article is protected by copyright. All rights reserved.
2. 2
views expressed in this paper are those of the authors and do not necessarily represent the
policies or position of, nor imply endorsement from, the FDA, Department of Veterans Affairs,
or U.S. Government.
Sponsor: None (there was no external funding source).
Word Count: 2900
Key Words: hepatotoxicity, immunoallergic, mitochondrial dysfunction, toxicity assessment,
benefit: risk assessment
Prior Data Postings:
1) Data was shared at the March 23 2016 FDA : Critical Path Institute Drug-Induced Liver
Injury Conference XVI in Hyattsville MD. Conference proceedings are posted at AASLD.org
2) Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug
rechallenge after drug‐induced liver injury: A systematic review. Hepatol 2010;52:2216-2222.
Abbreviations: bile salt export pump (BSEP); drug-induced liver injury (DILI); IC50:
concentration of an inhibitor which reduces the rate of an enzymatic reaction by 50%;
Institutional Review Board (IRB); times upper limits of normal (xULN)
Authors’ contributions (all authors can attest to the intellectual content of the paper):
Christine M. Hunt: FDA meeting speaker and discussant, drafted and prepared manuscript
Julie I. Papay: FDA meeting speaker and discussant, manuscript preparation and review
Vid Stanulovic: FDA meeting speaker and discussant, manuscript review
Arie Regev: FDA meeting co-chair and discussant, manuscript review
Page 2 of 33
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Hepatology
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3. 3
Abstract (254 words)
Drug induced hepatocellular injury is identified internationally by ALT 5x upper limits normal
(ULN) appearing within 3 months of drug initiation, after alternative causes are excluded.
Upon withdrawing the suspect drug, ALT generally decreases by 50% or more. With drug
readministration, a positive rechallenge has recently been defined by an ALT 3-5xULN or
greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver
injury (DILI): antimicrobials, central nervous system, cardiovascular and oncology
therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk
factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials,
immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors
interact with personal genetic, immune, and metabolic factors to influence positive
rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is
associated with up to 13% mortality in prospective series of all prescribed drugs. In recent
oncology trials, standardized systems enable safer drug rechallenge with weekly liver
chemistry monitoring during the high risk period and exclusion of patients with
hypersensitivity. Yet, high positive rechallenge rates with other innovative therapeutics
suggest caution with rechallenge of high risk drugs.
Conclusion: For critical medicines, drug rechallenge may be appropriate, when no safer
alternatives are available, the objective benefit exceeds the risk, and patients are fully
informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To
better understand rechallenge outcomes and identify key risk factors for positive rechallenge,
additional data is needed from controlled clinical trials, prospective registries, and large
healthcare databases.
Page 3 of 33
Hepatology
Hepatology
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4. 4
Introduction
Drug-induced liver injury (DILI) remains a key cause of death from acute liver failure.(1),(2)
In a prospective US registry, 3% of those with drug-induced liver injury progressed to liver-
related death, 4% to liver transplant, and 17% of patients developed chronic liver injury (3).
Up to 5% of patients with drug-induced liver injury also suffer Stevens-Johnson
Syndrome/Toxic Epidermal Necrolysis, with 36% mortality (attributed to anti-epileptic,
antimicrobial, and antiretroviral drugs).(4)
DILI is a common cause of hepatic injury identified by liver chemistry elevations, temporally
related to the initiation and cessation of the suspect drug.(5-8) Serious DILI is most
commonly hepatocellular and is the focus of this review. Hepatocellular DILI is characterized
by predominant ALT elevations of 5 times upper limits normal (xULN) (5, 7), appearing within
90 days of suspect drug initiation, which decrease by half or more within one month of drug
cessation.(5, 6, 8) DILI is further affirmed by excluding other causes (e.g. viral hepatitis,
biliary obstruction, alcoholic hepatitis, or hypotension), reports of suspect drug hepatotoxicity,
and liver injury recurrence upon rechallenge (or readministration) of the suspect drug – which
has traditionally been strongly discouraged (Figure 1).(5, 6, 9) DILI may be misidentified in
clinical practice, with nearly half of DILI reports not representing DILI on expert review.(10)
Designed for clinicians, internationally agreed scoring systems identify the likelihood of DILI
as highly probable, probable, possible, unlikely or excluded – by tallying DILI findings.(5, 6, 8)
Following DILI, most patients fully recover when the suspect medication is stopped. When
liver chemistries normalize with drug cessation, this “positive dechallenge” suggests liver
injury resolution and may implicate the suspect drug in the initial liver injury (Figure 1).(5)
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Hepatology
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5. 5
Following a positive dechallenge, patients receiving benefit from a critical or life-saving
medicine may be considered for drug rechallenge. Increasingly, drug rechallenge has been
incorporated into controlled clinical trials of critical therapeutics. Recent prospective clinical
studies examining hundreds of rechallenge events currently define a positive drug
rechallenge as an ALT 3-5xULN or greater, which generally occurs much more rapidly than
the initial drug-induced liver injury(11-13). This new definition of positive rechallenge has
largely replaced an earlier historic definition of ALT doubling for hepatocellular injury,
empirically defined in 77 cases, which has not been further substantiated (9).
High Risks in Drug Rechallenge
In comparison to the initial DILI, drug rechallenge is associated with even greater risks. For
example, among those rechallenged with halothane within one month of halothane re-
exposure, nearly half died (Figure 2).(14) This resulted in the markedly decreased use of
halothane and a heightened awareness of drug rechallenge-related liver injury. DILI and drug
rechallenge of all prescribed drugs have been prospectively recorded and analyzed in the
Spanish DILI registry for more than 20 years. In this series, 13% of patients exhibiting a
positive drug rechallenge after predominantly hepatocellular DILI either died or underwent
liver transplantation.(15) These positive rechallenge events were also associated with
frequent hospitalization (52%), jaundice (64%), and hypersensitivity (39%).(15) Similarly, in a
retrospective study of 88 positive drug rechallenge events, the highest risk events occurred in
those with severe hepatocellular injury with jaundice, in whom two (2%) died.(16) Further,
most positive rechallenge events occur more rapidly than the initial DILI: a) in less than half
Page 5 of 33
Hepatology
Hepatology
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6. 6
the time in the prospective study,(15) and b) within one week of rechallenge in nearly half of
those reported retrospectively.(16) There’s very limited published data on negative
rechallenge,(17) suggesting a bias to reporting positive rechallenge. Most drug rechallenge
events are inadvertent (e.g. patients self-medicating months or years after DILI)(16). Hence,
by accurately identifying DILI and communicating with the patient their need to avoid suspect
drug readministration, inadvertent drug rechallenge may be preventable.
A Small Minority of Drugs Account for Most Positive Rechallenge Events
Among the hundreds of drugs associated with hepatotoxicity, 48 drugs have more than 50
published cases each of DILI.(18) These drugs include antimicrobials, central nervous
system (e.g. anti-seizure), cardiovascular and oncology therapeutics.(18) In this high risk
subgroup, more than 90% are associated with at least one fatal liver injury and one positive
rechallenge.(18) In Phase II and III studies, drugs associated with DILI exhibit a higher
incidence of ALT > 3xULN in treated versus placebo groups, particularly when the daily dose
exceeds 50 mg.(19) In contrast, drugs with fewer DILI reports are associated with
progressively lower fatality and positive rechallenge rates.(18) When a similarly low incidence
of ALT elevations in treated versus placebo groups is observed during clinical trials, liver
safety is likely.(19) This suggests that drug characteristics influence the risk of DILI, fatality,
and positive rechallenge, including reactive metabolites, bile salt export pump (BSEP)
inhibition, and mitochondrial impairment.(15, 20, 21) Timely information on a drug’s
association with mitochondrial impairment can be obtained through online search (i.e. drug
name AND mitochondrial impairment). Among drugs withdrawn from the market or labeled
with a black box warning, 38% result in mitochondrial impairment and most inhibit the bile
Page 6 of 33
Hepatology
Hepatology
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7. 7
salt export pump.(21) An earlier systematic review of drugs with at least 10 well-documented
rechallenge events revealed that the highest rate of positive rechallenge (and fatality) is
observed in drugs associated with: 1) immunoallergic injury and mitochondrial impairment
(with positive rechallenge rates of up to 11% to 51%), 2) hepatocellular injury, and 3) high
daily drug dose (>50 mg).(7, 20, 22) A list of 46 drugs with ten or more events of DILI and at
least one positive rechallenge is provided in Supplementary Table 1. Among these drugs, 40
(87%) have a daily dose range >50 mg (observed in 40% of the most commonly prescribed
US drugs) (22) and half exhibit mitochondrial impairment in vitro.
In summary, in diverse medications, a drug’s mechanism of liver injury, high daily dose, and
clinical profile of injury inform rechallenge risk.
Personal and Environmental Risk Factors Affect Liver Injury
In addition to drug-specific factors, susceptibility to DILI varies by patient. For example,
children with mitochondrial polymorphisms/disorders are highly susceptible to drug-induced
acute liver failure and fatality. (23-25) Further, drug metabolism and immune response are
influenced by concomitant medications, inflammation, and genetics.(26, 27) More than a
dozen HLA markers are associated with an increased risk of DILI, which varies from less
than 2-fold for isoniazid to a more than an 80-fold increase with flucloxacillin.(28) However, in
contrast to the 100% positive predictive value of HLA-B*5701 carriage for abacavir
hypersensitivity,(29) positive predictive values are generally low for DILI HLA markers,
suggesting the importance of other factors.(28)
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Hepatology
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8. 8
Drugs with Fatal or Frequent Positive Rechallenge
Through salient examples, we can examine drugs associated with fatal or frequent positive
rechallenge. Halothane is associated with DILI with jaundice resulting in nearly 50 percent
mortality with rechallenge. Halothane is oxidized to a trifluoroacetyl halide, which forms
protein adducts.(30) Immunoallergic injury occurs rapidly with halothane rechallenge, with
fever, rash, eosinophilia, halothane adduct and auto-antibodies, and an associated HLA A-11
marker.(31) Further, by inhibiting mitochondrial complex I and II,(32) fatty acid and pyruvate
oxidation,(33) halothane impairs mitochondrial function, resulting in critical cellular energy
loss (as mitochondria provide 90% percent of cellular ATP).(34) Mitochondria can
regenerate, yet require one to several weeks for regeneration (34) – leaving the hepatocyte
vulnerable to a “second hit”. Patients rechallenged with halothane within the first month after
halothane liver injury exhibit the highest fatality rate (Figure 2), with nearly half of patients
receiving halothane rechallenge resulting in death.(14) This one month period aligns with the
time required for mitochondrial regeneration, suggesting mitochondrial impairment
contributes to immunoallergic injury in halothane positive rechallenge.
A more contemporary oral drug associated with frequent positive rechallenge (Figure 3),
lapatinib is a dual tyrosine kinase inhibitor effective in breast cancer. Lapatinib is metabolized
in the liver to an electrophilic quinone imine which both generates oxidative stress, resulting
in mitochondrial dysfunction, and forms protein adducts, contributing to immunoallergic
injury.(35) Patients carrying HLA-DQA1*02:01 and HLA-DRB1*07:01 are particularly
susceptible to lapatinib-induced liver injury (odds ratio, 14.0),(36) and account for the majority
Page 8 of 33
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Hepatology
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9. 9
of affected patients. Lapatinib metabolites also inhibit BSEP, blocking bile acid efflux from the
hepatocyte and causing cytotoxicity. While primarily liver metabolized, lapatinib exhibits high
inter-subject variability in its metabolism and fecal elimination, and interacts with multiple
drugs (37) – likely further affecting liver injury. The microbiome also affects drug metabolism
(38) and lipopolysaccharide can affect immune tolerance (39) – further modulating liver
injury. Thus, drug, host, and environmental factors interact to determine an individual’s
response to drug rechallenge – which ranges from asymptomatic adaptation without
apparent liver injury to rapid, severe, and even fatal liver injury.
Drug characteristics influence drug-induced liver injury and positive rechallenge
Specific features identify drugs associated with high rates of DILI and positive rechallenge:
daily dose exceeding 50 mg,(7, 19, 22) predominant hepatic metabolism,(7) hepatocellular
injury, and evidence of immunoallergic injury (40) or mitochondrial impairment in vitro.(41,
42) Hepatotoxicity is evident in most drugs with preclinical testing exhibiting: reactive
metabolites, marked metabolism-dependent CYP inhibition (with >5-fold change in IC50),
covalent protein binding (> 200 pmol eq/mg protein), reactive oxygen species, glutathione
adduct formation, lipophilicity (logP>3), BSEP inhibition, cellular ATP depletion, mitochondrial
toxicity, or cytotoxicity.(21, 43-45) Modeling these preclinical tests in human hepatocyte
culture, the FDA’s National Center for Toxicologic Research has identified two factors most
predictive of serious clinical hepatotoxicity: 1) increases in oxidative stress and 2) decreases
in cellular ATP (i.e. mitochondrial dysfunction).(44) Mirroring these findings, immunoallergic
injury from reactive metabolites and mitochondrial dysfunction were associated with the
highest rates of clinically important positive rechallenge injury(20). Searched through
Page 9 of 33
Hepatology
Hepatology
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10. 10
PubMed, Google Scholar, FDA.gov and cross-referencing (2010-2016), recent data from
drugs with 10 or more rechallenge events was incorporated with that of an earlier systematic
review to highlight key drug characteristics in a “heat map” fashion (Figure 3). When
compared to drugs with few or no positive rechallenge reports, drugs associated with positive
rechallenge exhibit both immunoallergic (i.e. hypersensitivity, reactive metabolite, and HLA
marker) and mitochondrial injury.
Emphasizing the risks of drug rechallenge, the FDA DILI clinical trial guidance advises
caution (46). Yet, innovative therapeutics efficacious in inhibiting targeted cancer pathways
continue to exhibit hepatotoxicity.(47) Hence, in patients with DILI exhibiting efficacy,
prospective oncology trials are increasingly examining drug rechallenge, using selective
criteria (Table 1)(11). With the rigorous monitoring of prospective clinical trials, we can better
evaluate the efficacy and safety outcomes of drug rechallenge of critical medications(48).
Drug Rechallenge in Controlled Clinical Trials
With early evidence of efficacy and liver injury, pazopanib controlled trials adapted protocols
to enable drug rechallenge with attentive follow-up. Pazopanib is a tyrosine kinase inhibitor
effective in the treatment of renal cell carcinoma and soft tissue sarcoma. During clinical
trials, ALT > 8xULN affected 5% of patients receiving pazopanib.(11) In over 2000 patients in
Phase II and III studies, 103 patients developing pazopanib-induced liver injury were
rechallenged if they derived clinical benefit from pazopanib, exhibited a positive dechallenge
(with ALT’s decreasing to <2.5xULN), and had no evidence of hypersensitivity.(11) Patients
were monitored with weekly liver chemistries for 2 months,(49) and most received an initially
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11. 11
reduced dose of pazopanib.(49) Among the 103 patients, 62 (60%) displayed a negative
rechallenge (or adaptation), 2 (2%) had incomplete follow-up, and 39 (38%) exhibited a
positive rechallenge with ALT > 3xULN. In the 39 patients with a positive rechallenge, 31/39
(79%) exhibited an ALT < 8xULN and 8/39 (21%) developed an ALT > 8 to 20xULN at a
median of nine days. No patients developed severe liver injury with positive rechallenge. Risk
factors for pazopanib-induced liver injury included older age,(11) concomitant simvastatin
treatment,(49) and carriage of HLA-B*57:01, present in only 10% of patients with ALT >
5xULN.(50) These data support the safety of pazopanib rechallenge with close
monitoring.(49) With pazopanib rechallenge after an event of likely pazopanib-induced liver
injury, most patients exhibit adaptation to liver injury, rather than recurrence.
Critical to public health globally, tuberculosis medications are associated with high rates of
DILI. Two prospective controlled clinical trials evaluated the safety of rechallenging patients
with active tuberculosis following positive dechallenge, many of whom had severe
symptomatic hepatitis or jaundice on initial isoniazid, rifampin, and pyrazinamide
treatment.(12, 13) In 220 patients rechallenged with isoniazid, rifampin, with or without
pyrazinamide or ethambutol, most patients exhibited a negative rechallenge, or clinical
adaptation.(12, 13) From 0-24% of patients experienced nonfatal positive rechallenge (with
negative rechallenge observed when pyrazinamide was excluded). The initial DILI severity
did not increase the risk of positive rechallenge. No difference in rechallenge rates was
observed when all drugs were restarted simultaneously or sequentially.(12) Mechanisms
contributing to positive rechallenge with tuberculosis medications include: isoniazid’s
reactive metabolite, an HLA DQB1*0201 marker associated with liver injury (odds ratio,
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12. 12
1.9)(51), hypersensitivity, and mitochondrial impairment (52). Patients experiencing liver
injury exhibited increased Th17 cells, anti-isoniazid and anti-CYP P450 antibodies,
hypoalbuminemia, older age, female gender and alcohol use (51, 53).
In contrast to the predominantly negative rechallenge observed with tuberculosis medications
or pazopanib, 55% of patients exhibited a positive rechallenge with lapatinib or tolvaptan in
small retrospective clinical trial reviews (Figure 3)(54, 55). These two compounds are
associated with immunoallergic injury (with HLA marker carriage substantively increasing risk
of lapatinib liver injury), mitochondrial impairment,(35, 56) and BSEP inhibition.(37, 57)
Tolvaptan is a vasopressin V2-receptor antagonist indicated for hyponatremia and evaluated
for autosomal dominant polycystic kidney disease (ADPKD).(55) In ADPKD clinical trials,
ALT >3xULN was reported in 4% of tolvaptan-treated and 1% of those receiving placebo,
with 3 serious events of tolvaptan-induced liver injury (which resolved with treatment
cessation).(55) DILI developed after 3 to 18 months of tolvaptan administration, progressed
for 1 month after treatment cessation, and resolved in a median of 1.5 months.(55) In total,
20 patients were rechallenged with tolvaptan. Nine rechallenged patients exhibited
adaptation, with ALT < 3xULN. Eleven (55%) patients exhibited rapid positive rechallenge
(e.g. ALT 10xULN) prompting tolvaptan cessation, with ALT normalizing in 1 to 4 months.(55)
With immunoallergic injury appearing likely, studies are reportedly underway to search for a
possible HLA marker of tolvaptan-induced liver injury.(55)
Drug rechallenge of critical medications
In prospective national registry studies of all drugs, drug rechallenge was associated with
13% mortality (or liver transplantation), and substantive comorbidity.(15) Hence, drug
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13. 13
rechallenge should generally be avoided. With innovative drugs targeting cancer or other
critical pathways associated with DILI in development, prospective controlled Phase II/III
clinical trial data on drug rechallenge can inform the safety of targeted therapeutics(48) and
may enable safe rechallenge in clinical practice.(58) In earlier described oncology clinical
trials, drug rechallenge was safely performed in patients deriving a clinical benefit, without
evidence of hypersensitivity, in whom ALT decreased to <2.5xULN prior to rechallenge with a
reduced dose of the suspect drug, and whom completed 2 months of weekly liver chemistry
monitoring.(11) Additional prospective rechallenge data of diverse drugs is needed to better
inform outcomes. These data can be obtained in large healthcare databases, clinicians
reporting rechallenge results to FDA MedWatch,(59) and in prospective national DILI
registries.
In a patient with a likely initial DILI event,(5, 6) a critical medicine providing valuable patient
benefits may be considered for drug rechallenge after DILI if: a) continued treatment is
necessary and there are no safer therapeutic alternatives; b) the patient is receiving a
compelling benefit which exceeds the risk of rechallenge; c) in shared decision making, the
benefits and risks of drug rechallenge are discussed fully with the patient to assure a clear
understanding and informed consent, d) the patient agrees to immediately alert their provider
if hepatitis symptoms arise (e.g. fatigue, nausea, abdominal pain, anorexia, or jaundice) and
adhere to close clinical follow-up (e.g., liver chemistries at one week or less), and e) an
Institutional Review Board (IRB) Chair discussion may be helpful (Table 1). Rechallenge
results are then recorded in the medical record and communicated to the FDA or other health
authorities.(59) While drug desensitization may be used prior to rechallenge,(60) this
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14. 14
approach may be infeasible for a critical medication requiring a specified therapeutic
exposure threshold or when resistance may develop with subtherapeutic dosing. Dose
reductions have been successfully used in prospective rechallenge studies,(11, 13) yet data
is limited. For patients exhibiting a positive rechallenge and liver failure with mild hepatic
encephalopathy, N-acetylcysteine administration has proven beneficial in a controlled clinical
trial.(27) No other agents have proven efficacious in DILI.
Conclusions
Our broad review reveals that a minority of drugs, administered at daily doses >50 mg,
associated with an increased ALT incidence in clinical trials, immunoallergic injury, and
mitochondrial impairment in vitro, are responsible for the highest rates of DILI and positive
rechallenge. A patient’s immune response, genetics, co-medications, and other factors also
influence positive rechallenge. With up to 13% mortality of drug rechallenge following DILI in
prospective series of all prescribed drugs, drug rechallenge should generally be avoided.
Large controlled studies have demonstrated that drug rechallenge of critical medicines can
be safely performed, using standardized safety algorithms and weekly liver chemistry
monitoring during the high risk period.(11) However, high positive rechallenge rates and
clinically significant liver injury in other recent trials (54, 55) suggest the need for controlled,
cautious rechallenge of high risk drugs. Drug rechallenge can be appropriate for critical
medicines, when no safer alternatives are available and the patient’s objective benefit
exceeds their risk. Patients must be involved in shared decision making, alert providers to
hepatitis symptoms and adhere to close follow-up. Due to the high potential risk of drug
rechallenge, IRB discussion may be appropriate. When DILI affects a critical medication,
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15. 15
controlled clinical trial assessment of drug rechallenge may afford adequate safety data to
inform clinical practice. Further data from clinical trials, prospective DILI registries, and large
healthcare datasets can inform rechallenge outcomes and identify key risk factors for positive
rechallenge.
Acknowledgements
The authors wish to acknowledge the informed, insightful discussions of participants at the
FDA: Critical Path Institute Drug-Induced Liver Injury Conference XVI on March 23-24, 2016.
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16. 16
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24. Figure Legends
Figure 1. Hepatocellular drug-induced liver injury and rechallenge definitions
Hepatocellular drug-induced liver injury is identified by ALT >5xULN observed within 90
days of suspect drug challenge (or initiation), for which non-drug diagnoses are
excluded.(5,6) With dechallenge, or cessation of the suspect drug, most patients fully
recover from liver injury. When the suspect drug is then rechallenged or readministered
after a drug-induced liver injury event, a positive rechallenge is defined by an ALT >3-
5xULN, while a negative rechallenge remains below this threshold.(8)
Figure 2. High mortality with halothane rechallenge within 4 weeks
In two case series, those rechallenged with halothane anesthetic within one month of
halothane-associated liver injury, nearly half died.(12) Most deaths were observed
when halothane was rechallenged within one month of the original liver injury.
Figure 3. Nonclinical and clinical characteristics of drugs associated or not
associated with drug-induced liver injury and positive rechallenge
In the far left column, drugs are profiled in descending order of positive rechallenge
rates, with the top nine medium gray rows depicting drugs with at least ten published
rechallenge events, the next five light gray rows include drugs associated with non-
serious drug-induced liver injury and low or absent rechallenge, and the bottom 3 white
rows portray drugs which are not associated with either drug-induced liver injury nor
positive rechallenge. The columns to the right of the drug names are profiled in a “heat
map” fashion to reveal drug characteristics: red indicates “severe or fatal”, orange
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25. represents “marked”, yellow profiles “mild to moderate”, green reports “absent,” and
white indicates “no data”. When compared to drugs with few or no positive rechallenge
reports, drugs associated with positive rechallenge exhibit notable immunoallergic (i.e.
hypersensitivity, reactive metabolite, and HLA marker) and mitochondrial injury, with a
modest increase in bile salt export pump inhibition.
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26. Challenge
Drug induced hepatocellular injury with ALT > 5xULN within 90 days of suspect drug initiation
Dechallenge
Recovery from injury with drug discontinuation (e.g. ALT < 2.5xULN)
Rechallenge
Suspect drug readministered
Negative
ALT unchanged or < 3xULN
Positive
ALT > 3-5xULN
Figure 1.
• Exclude viral hepatitis, biliary obstruction, alcoholic hepatitis, hypotension
• Examine suspect drug information, published reports of hepatotoxicity
• Assess concomitant medications for hepatotoxicity
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27. High mortality with halothane rechallenge within 4 weeksFigure 2.
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29. Table 1. Considerations for drug rechallenge after drug-induced liver injury
1. Evaluate role of suspect drug in initial drug-induced liver injury
• Confirm drug-induced liver injury(6) and exclude alternative diagnoses(5, 7)
2. Examine alternatives
• Is treatment continuation necessary?
• Are there safer therapeutic alternatives?
3. Review suspect drug information for increased risk of positive rechallenge
• Higher incidence of ALT elevations in suspect drug vs control groups in
clinical trials
• Reports of hypersensitivity (fever, rash, eosinophilia), HLA marker associated
with liver injury
• Mitochondrial regeneration following injury requires 1 to several weeks
• Reports of suspect drug-induced liver injury with jaundice (i.e. serious liver
injury)
• Severe or fatal liver injury or rechallenge reports in product label or
publications
4. Evaluate drug’s clinical benefit and risks in patient being considered for
rechallenge
• Is the patient receiving a compelling benefit which exceeds the risk of
rechallenge?
• Has the patient exhibited hypersensitivity or drug-specific HLA markers,
putting them at high risk of positive drug rechallenge (i.e. rechallenge to be
avoided)?
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30. • Has the patient experienced jaundice, coagulopathy, or encephalopathy (i.e.
signs of liver failure) with the initial suspect drug-induced liver injury (i.e.
rechallenge to be avoided)?
• Should a reduced dose be administered (or is this inappropriate, due to
subtherapeutic exposure or possible resistance limiting clinical benefit)?
5. Is rechallenge appropriate in this patient?
• Have the benefits and risks of drug rechallenge been discussed fully with the
patient in shared decision making to assure a clear understanding and
informed consent?
• Can the patient promptly report hepatitis symptoms and adhere to the
required clinical follow-up?
• Has rechallenge been discussed with the IRB or Ethics Committee?
6. Report results of rechallenge
• Record results in the medical record and report to the FDA or health
authorities
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31. Supplementary Table 1. Drugs associated with ten or more events of drug-
induced liver injury and at least one positive drug rechallenge event
Allopurinol1
Interferon-alpha/Peginterferon Sulindac1,2
Amiodarone1,2
Interferon-beta Tacrine1,2
Androgenic steroids (n=10)1
Isoniazid1,2
Tolvaptan1,2
Atorvastatin1,2
Ketoconazole1,2
Valproate1,2
Auranofin/Gold products (n=3) Lamivudine/Didanosine/Stavudine/Zidovudine1,2
Azathioprine/Mercaptopurine1,2
Lapatinib1,2
Carbamazepine1,2
Methyldopa1
Chlorpromazine1
Minocycline1,2
Clavulanate with Amoxicillin1
Nevirapine1
Dantrolene1
Nimesulide1
Diclofenac1,2
Nitrofurantoin1,2
Didanosine1,2
Pazopanib1,2
Disulfiram1,2
Phenytoin/Fosphenytoin1
Erythromycin1,2
Propylthiouracil1,2
Estrogens (n=9)/Progestins (n=12) Pyrazinamide1
Flucloxacillin1
Quinidine1
Flutamide Rifampin1,2
Halothane2
Simvastatin2
Hydralazine1
Sulfamethoxazole with Trimethoprim1
Ibuprofen1,2
Sulfasalazine1,2
Infliximab1
Sulfonamides (n=5)1
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32. 1
daily drug dose range > 50 mg 2
mitochondrial toxicity in vitro
[References: 11-13, 15-18, 20, 21, 42-44, 52-56]
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Hepatology
Hepatology
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