Karen Blum

ROME – Tumor necrosis factor–alpha (TNF-alpha) inhibitors are well established as a treatment for psoriatic arthritis patients, but efficacy can vary greatly within that population. New work from Canadian researchers demonstrates that the global DNA methylation pattern differs between TNF-alpha–inhibitor responders and secondary failures, which could help explain the variability in medication success rates.

“Although TNF inhibitors [TNFi] work very well in certain individuals with psoriatic arthritis [PsA], up to 40% of individuals receiving this treatment fail to achieve a therapeutic response, and 20%-50% of individuals who have an initial response to treatment become refractory weeks or months after receiving therapy.” lead study author Darren O’Rielly, Ph.D., said at the European Congress of Rheumatology.

The preliminary study findings eventually could lead to the identification of biomarkers that would indicate patients who are not good candidates for TNFi medications, said Dr. O’Rielly of Memorial University, St. John’s, Nfld.

Given recent advances in epigenetics and that the epigenetic signature is affected by environmental factors, the investigators set out to determine if methylation alterations could help explain why PsA patients respond or fail with TNFi. The researchers performed genome-wide DNA methylation profiling on blood samples from 41 PsA patients, using machinery that measures about 480,000 CpG sites per sample and covers 96% of RefSeq genes. A total of 21 patients were considered TNFi responders, of whom 13 were treated with etanercept and 8 with adalimumab; median follow-up duration was 18 months. Twenty patients were considered secondary TNFi failures, of whom 15 were treated with etanercept and 5 with adalimumab; median follow-up duration was 36 months.

Dr. O’Rielly, a senior research scientist at Memorial and director of the Molecular Genetics Laboratory at Eastern Health in St. John’s, and his associates measured the methylation level at CpG sites using a genome-wide approach and selected regions of interest based on functional relevance to TNF-mediated signaling pathways with methylation level differences of 5% or greater and an adjusted P-value less than .05.

After quality-control filtering, investigators evaluated 384,599 CpG sites for TNFi responders and 368,863 CpG sites for TNFi failures. Researchers found 72 CpG sites of interest in the TNFi responder group and 91 CpG sites of interest in the TNFi failure group. Top candidate genes for TNFi responders included TRAPPC9 (which functions as an activator of NF-kB), CCR6 (which regulates the migration and recruitment of dendritic and T cells), and PSORS1C3 (psoriasis susceptibility 1 candidate 3), while top candidate genes for TNFi secondary failures included CD70 (an encoded protein that is a ligand for TNFRSF27/CD27) and TNFRSF1B (a member of the TNF receptor ‘superfamily’ that mediates most of the metabolic effects of TNF-alpha).

“We are very encouraged by these findings,” Dr. O’Rielly said. “We were a little surprised that several of our best candidate genes, such as TNFRSF1B and CD70, appear to play a role in TNF-alpha signaling, and that their methylation change occurs in a gene region that is consistent with a possible functional effect. We were expecting to find some methylation changes in genes but not necessarily in pathways with a direct connection with TNF-alpha–mediated signaling.”

The group plans to confirm these findings for the best candidate genes using other methylation-specific polymerase chain reaction technology, he said, and will investigate additional CpG sites adjacent to the region of interest, including promoters and enhancers, in the best candidate genes to better characterize the full extent of methylation changes in these regions. They also would like to replicate the findings in a prospective, independent cohort.

Dr. O’Rielly reported no relevant financial conflicts.

ROME – Tumor necrosis factor–alpha (TNF-alpha) inhibitors are well established as a treatment for psoriatic arthritis patients, but efficacy can vary greatly within that population. New work from Canadian researchers demonstrates that the global DNA methylation pattern differs between TNF-alpha–inhibitor responders and secondary failures, which could help explain the variability in medication success rates.

“Although TNF inhibitors [TNFi] work very well in certain individuals with psoriatic arthritis [PsA], up to 40% of individuals receiving this treatment fail to achieve a therapeutic response, and 20%-50% of individuals who have an initial response to treatment become refractory weeks or months after receiving therapy.” lead study author Darren O’Rielly, Ph.D., said at the European Congress of Rheumatology.

The preliminary study findings eventually could lead to the identification of biomarkers that would indicate patients who are not good candidates for TNFi medications, said Dr. O’Rielly of Memorial University, St. John’s, Nfld.

Given recent advances in epigenetics and that the epigenetic signature is affected by environmental factors, the investigators set out to determine if methylation alterations could help explain why PsA patients respond or fail with TNFi. The researchers performed genome-wide DNA methylation profiling on blood samples from 41 PsA patients, using machinery that measures about 480,000 CpG sites per sample and covers 96% of RefSeq genes. A total of 21 patients were considered TNFi responders, of whom 13 were treated with etanercept and 8 with adalimumab; median follow-up duration was 18 months. Twenty patients were considered secondary TNFi failures, of whom 15 were treated with etanercept and 5 with adalimumab; median follow-up duration was 36 months.

Dr. O’Rielly, a senior research scientist at Memorial and director of the Molecular Genetics Laboratory at Eastern Health in St. John’s, and his associates measured the methylation level at CpG sites using a genome-wide approach and selected regions of interest based on functional relevance to TNF-mediated signaling pathways with methylation level differences of 5% or greater and an adjusted P-value less than .05.

After quality-control filtering, investigators evaluated 384,599 CpG sites for TNFi responders and 368,863 CpG sites for TNFi failures. Researchers found 72 CpG sites of interest in the TNFi responder group and 91 CpG sites of interest in the TNFi failure group. Top candidate genes for TNFi responders included TRAPPC9 (which functions as an activator of NF-kB), CCR6 (which regulates the migration and recruitment of dendritic and T cells), and PSORS1C3 (psoriasis susceptibility 1 candidate 3), while top candidate genes for TNFi secondary failures included CD70 (an encoded protein that is a ligand for TNFRSF27/CD27) and TNFRSF1B (a member of the TNF receptor ‘superfamily’ that mediates most of the metabolic effects of TNF-alpha).

“We are very encouraged by these findings,” Dr. O’Rielly said. “We were a little surprised that several of our best candidate genes, such as TNFRSF1B and CD70, appear to play a role in TNF-alpha signaling, and that their methylation change occurs in a gene region that is consistent with a possible functional effect. We were expecting to find some methylation changes in genes but not necessarily in pathways with a direct connection with TNF-alpha–mediated signaling.”

The group plans to confirm these findings for the best candidate genes using other methylation-specific polymerase chain reaction technology, he said, and will investigate additional CpG sites adjacent to the region of interest, including promoters and enhancers, in the best candidate genes to better characterize the full extent of methylation changes in these regions. They also would like to replicate the findings in a prospective, independent cohort.

Dr. O’Rielly reported no relevant financial conflicts.

ROME – Tumor necrosis factor–alpha (TNF-alpha) inhibitors are well established as a treatment for psoriatic arthritis patients, but efficacy can vary greatly within that population. New work from Canadian researchers demonstrates that the global DNA methylation pattern differs between TNF-alpha–inhibitor responders and secondary failures, which could help explain the variability in medication success rates.

“Although TNF inhibitors [TNFi] work very well in certain individuals with psoriatic arthritis [PsA], up to 40% of individuals receiving this treatment fail to achieve a therapeutic response, and 20%-50% of individuals who have an initial response to treatment become refractory weeks or months after receiving therapy.” lead study author Darren O’Rielly, Ph.D., said at the European Congress of Rheumatology.

The preliminary study findings eventually could lead to the identification of biomarkers that would indicate patients who are not good candidates for TNFi medications, said Dr. O’Rielly of Memorial University, St. John’s, Nfld.

Given recent advances in epigenetics and that the epigenetic signature is affected by environmental factors, the investigators set out to determine if methylation alterations could help explain why PsA patients respond or fail with TNFi. The researchers performed genome-wide DNA methylation profiling on blood samples from 41 PsA patients, using machinery that measures about 480,000 CpG sites per sample and covers 96% of RefSeq genes. A total of 21 patients were considered TNFi responders, of whom 13 were treated with etanercept and 8 with adalimumab; median follow-up duration was 18 months. Twenty patients were considered secondary TNFi failures, of whom 15 were treated with etanercept and 5 with adalimumab; median follow-up duration was 36 months.

Dr. O’Rielly, a senior research scientist at Memorial and director of the Molecular Genetics Laboratory at Eastern Health in St. John’s, and his associates measured the methylation level at CpG sites using a genome-wide approach and selected regions of interest based on functional relevance to TNF-mediated signaling pathways with methylation level differences of 5% or greater and an adjusted P-value less than .05.

After quality-control filtering, investigators evaluated 384,599 CpG sites for TNFi responders and 368,863 CpG sites for TNFi failures. Researchers found 72 CpG sites of interest in the TNFi responder group and 91 CpG sites of interest in the TNFi failure group. Top candidate genes for TNFi responders included TRAPPC9 (which functions as an activator of NF-kB), CCR6 (which regulates the migration and recruitment of dendritic and T cells), and PSORS1C3 (psoriasis susceptibility 1 candidate 3), while top candidate genes for TNFi secondary failures included CD70 (an encoded protein that is a ligand for TNFRSF27/CD27) and TNFRSF1B (a member of the TNF receptor ‘superfamily’ that mediates most of the metabolic effects of TNF-alpha).

“We are very encouraged by these findings,” Dr. O’Rielly said. “We were a little surprised that several of our best candidate genes, such as TNFRSF1B and CD70, appear to play a role in TNF-alpha signaling, and that their methylation change occurs in a gene region that is consistent with a possible functional effect. We were expecting to find some methylation changes in genes but not necessarily in pathways with a direct connection with TNF-alpha–mediated signaling.”

The group plans to confirm these findings for the best candidate genes using other methylation-specific polymerase chain reaction technology, he said, and will investigate additional CpG sites adjacent to the region of interest, including promoters and enhancers, in the best candidate genes to better characterize the full extent of methylation changes in these regions. They also would like to replicate the findings in a prospective, independent cohort.

Dr. O’Rielly reported no relevant financial conflicts.

Celiac disease is not uncommon, affecting about 1% of the population in the United States and around the world, but the biggest barrier to patients receiving treatment is practitioners’ failure to recognize the condition, said Dr. Peter H.R. Green, director of the celiac disease center at Columbia University, New York.

There’s a very low rate of diagnosis in the United States, compared with other countries, according to Dr. Green. Only about 18% of U.S. patients with celiac are properly diagnosed. Physicians need to be more aware of the condition as it is on the rise. The incidence of celiac disease has increased four- to fivefold over the past 50 years, he said.

“Patients, when they get diagnosed, have often had a long history” of symptoms, Dr. Green said at Digestive Diseases: New Advances. “They say, ‘Why didn’t my doctor think of this? I’ve been complaining so long,’ etc.”

The main symptoms of celiac disease are diarrhea or bloating, iron-deficiency anemia, osteoporosis, fatigue, hypothyroidism, and/or weight loss. “The host of presentations is very great, which is one of the factors that may be contributing to the low rate of diagnosis. Almost anyone you could think of could have celiac disease based on these symptoms,” he said.

Once a physician considers celiac disease as a possible diagnosis, the rest is easy, he said. The most definitive blood test is an anti-tissue transglutaminase IgA, which is available through most laboratories. If the test results show antibodies toward gluten, or if it’s inconclusive, it should be followed up by an intestinal biopsy to confirm the diagnosis. From there, patients could start a gluten-free diet.

Although biopsy rates have been increasing, as recently as 2009 only 51% of individuals undergoing upper endoscopy with signs and symptoms of celiac disease had had a small-bowel biopsy, judging from findings from one of his recent studies, Dr. Green reported. Patients who are less likely to have a biopsy are nonwhite or male or have weight loss as the presenting symptom. More recent studies indicate that several biopsies should be taken, including four to six from the descending duodenum and two from the duodenal bulb, the portion closest to the stomach.

Once diagnosed, patients should be managed in a center that specializes in celiac disease and should be referred to a knowledgeable dietitian to learn what to avoid and what to eat. “People will just eat the same stuff because they think it’s safe,” Dr. Green said.

Antibody levels should be checked again 6 and 12 months after starting a gluten-free diet to ensure that antibodies normalize. Levels of iron, folate, and B₁₂ also should be checked, he said, as well as bone density and thyroid function. In addition, patients should be encouraged to follow up with their physician at least annually. Whether patients need a follow-up biopsy remains controversial. “We think they do, but maybe in 2-3 years, when you can assess the effects of the diet,” he said.

Some patients have true celiac, while others may have a wheat allergy or just a gluten sensitivity. There has been an increased interest in gluten-free diets not just among those affected with celiac disease but by people who think it will help with weight loss or by those who think it’s healthy. “In fact, a gluten-free diet is not healthy,” Dr. Green said. “It’s low in fiber, low in B vitamins, high in heavy metals, and there is some concern about toxins in corn.” Patients should make sure to have a blood test for celiac disease before embarking on a gluten-free diet. Some patients studied who did not have celiac had diagnoses such as bacterial overgrowth in the small intestine; intolerance to fructose, lactose, or other foods; and microscopic colitis.

Risk factors for developing celiac disease include being born via cesarean section, taking proton pump inhibitors or antibiotics, or having a history of GI infections such as rotavirus or campylobacter, although it’s unclear why the disorder can occur at any age, he said at the meeting, which was held by Global Academy for Medical Education and Rutgers, the State University of New Jersey. Global Academy and this news organization are owned by the same company.

Dr. Green reported no relevant financial disclosures.

Celiac disease is not uncommon, affecting about 1% of the population in the United States and around the world, but the biggest barrier to patients receiving treatment is practitioners’ failure to recognize the condition, said Dr. Peter H.R. Green, director of the celiac disease center at Columbia University, New York.

There’s a very low rate of diagnosis in the United States, compared with other countries, according to Dr. Green. Only about 18% of U.S. patients with celiac are properly diagnosed. Physicians need to be more aware of the condition as it is on the rise. The incidence of celiac disease has increased four- to fivefold over the past 50 years, he said.

“Patients, when they get diagnosed, have often had a long history” of symptoms, Dr. Green said at Digestive Diseases: New Advances. “They say, ‘Why didn’t my doctor think of this? I’ve been complaining so long,’ etc.”

The main symptoms of celiac disease are diarrhea or bloating, iron-deficiency anemia, osteoporosis, fatigue, hypothyroidism, and/or weight loss. “The host of presentations is very great, which is one of the factors that may be contributing to the low rate of diagnosis. Almost anyone you could think of could have celiac disease based on these symptoms,” he said.

Once a physician considers celiac disease as a possible diagnosis, the rest is easy, he said. The most definitive blood test is an anti-tissue transglutaminase IgA, which is available through most laboratories. If the test results show antibodies toward gluten, or if it’s inconclusive, it should be followed up by an intestinal biopsy to confirm the diagnosis. From there, patients could start a gluten-free diet.

Although biopsy rates have been increasing, as recently as 2009 only 51% of individuals undergoing upper endoscopy with signs and symptoms of celiac disease had had a small-bowel biopsy, judging from findings from one of his recent studies, Dr. Green reported. Patients who are less likely to have a biopsy are nonwhite or male or have weight loss as the presenting symptom. More recent studies indicate that several biopsies should be taken, including four to six from the descending duodenum and two from the duodenal bulb, the portion closest to the stomach.

Once diagnosed, patients should be managed in a center that specializes in celiac disease and should be referred to a knowledgeable dietitian to learn what to avoid and what to eat. “People will just eat the same stuff because they think it’s safe,” Dr. Green said.

Antibody levels should be checked again 6 and 12 months after starting a gluten-free diet to ensure that antibodies normalize. Levels of iron, folate, and B₁₂ also should be checked, he said, as well as bone density and thyroid function. In addition, patients should be encouraged to follow up with their physician at least annually. Whether patients need a follow-up biopsy remains controversial. “We think they do, but maybe in 2-3 years, when you can assess the effects of the diet,” he said.

Some patients have true celiac, while others may have a wheat allergy or just a gluten sensitivity. There has been an increased interest in gluten-free diets not just among those affected with celiac disease but by people who think it will help with weight loss or by those who think it’s healthy. “In fact, a gluten-free diet is not healthy,” Dr. Green said. “It’s low in fiber, low in B vitamins, high in heavy metals, and there is some concern about toxins in corn.” Patients should make sure to have a blood test for celiac disease before embarking on a gluten-free diet. Some patients studied who did not have celiac had diagnoses such as bacterial overgrowth in the small intestine; intolerance to fructose, lactose, or other foods; and microscopic colitis.

Risk factors for developing celiac disease include being born via cesarean section, taking proton pump inhibitors or antibiotics, or having a history of GI infections such as rotavirus or campylobacter, although it’s unclear why the disorder can occur at any age, he said at the meeting, which was held by Global Academy for Medical Education and Rutgers, the State University of New Jersey. Global Academy and this news organization are owned by the same company.

Dr. Green reported no relevant financial disclosures.

Celiac disease is not uncommon, affecting about 1% of the population in the United States and around the world, but the biggest barrier to patients receiving treatment is practitioners’ failure to recognize the condition, said Dr. Peter H.R. Green, director of the celiac disease center at Columbia University, New York.

There’s a very low rate of diagnosis in the United States, compared with other countries, according to Dr. Green. Only about 18% of U.S. patients with celiac are properly diagnosed. Physicians need to be more aware of the condition as it is on the rise. The incidence of celiac disease has increased four- to fivefold over the past 50 years, he said.

“Patients, when they get diagnosed, have often had a long history” of symptoms, Dr. Green said at Digestive Diseases: New Advances. “They say, ‘Why didn’t my doctor think of this? I’ve been complaining so long,’ etc.”

The main symptoms of celiac disease are diarrhea or bloating, iron-deficiency anemia, osteoporosis, fatigue, hypothyroidism, and/or weight loss. “The host of presentations is very great, which is one of the factors that may be contributing to the low rate of diagnosis. Almost anyone you could think of could have celiac disease based on these symptoms,” he said.

Once a physician considers celiac disease as a possible diagnosis, the rest is easy, he said. The most definitive blood test is an anti-tissue transglutaminase IgA, which is available through most laboratories. If the test results show antibodies toward gluten, or if it’s inconclusive, it should be followed up by an intestinal biopsy to confirm the diagnosis. From there, patients could start a gluten-free diet.

Although biopsy rates have been increasing, as recently as 2009 only 51% of individuals undergoing upper endoscopy with signs and symptoms of celiac disease had had a small-bowel biopsy, judging from findings from one of his recent studies, Dr. Green reported. Patients who are less likely to have a biopsy are nonwhite or male or have weight loss as the presenting symptom. More recent studies indicate that several biopsies should be taken, including four to six from the descending duodenum and two from the duodenal bulb, the portion closest to the stomach.

Once diagnosed, patients should be managed in a center that specializes in celiac disease and should be referred to a knowledgeable dietitian to learn what to avoid and what to eat. “People will just eat the same stuff because they think it’s safe,” Dr. Green said.

Antibody levels should be checked again 6 and 12 months after starting a gluten-free diet to ensure that antibodies normalize. Levels of iron, folate, and B₁₂ also should be checked, he said, as well as bone density and thyroid function. In addition, patients should be encouraged to follow up with their physician at least annually. Whether patients need a follow-up biopsy remains controversial. “We think they do, but maybe in 2-3 years, when you can assess the effects of the diet,” he said.

Some patients have true celiac, while others may have a wheat allergy or just a gluten sensitivity. There has been an increased interest in gluten-free diets not just among those affected with celiac disease but by people who think it will help with weight loss or by those who think it’s healthy. “In fact, a gluten-free diet is not healthy,” Dr. Green said. “It’s low in fiber, low in B vitamins, high in heavy metals, and there is some concern about toxins in corn.” Patients should make sure to have a blood test for celiac disease before embarking on a gluten-free diet. Some patients studied who did not have celiac had diagnoses such as bacterial overgrowth in the small intestine; intolerance to fructose, lactose, or other foods; and microscopic colitis.

Risk factors for developing celiac disease include being born via cesarean section, taking proton pump inhibitors or antibiotics, or having a history of GI infections such as rotavirus or campylobacter, although it’s unclear why the disorder can occur at any age, he said at the meeting, which was held by Global Academy for Medical Education and Rutgers, the State University of New Jersey. Global Academy and this news organization are owned by the same company.

Dr. Green reported no relevant financial disclosures.

Patients with Barrett’s esophagus, a condition in which cells lining the esophagus are replaced by the type of cells that normally line the intestine, need to be monitored carefully to prevent the development of esophageal cancer, a gastroenterologist expert in the condition said here at Digestive Diseases: New Advances. The condition can occur following exposure to stomach acids and bile from gastroesophageal reflux disease (GERD).

“The reason we worry about Barrett’s is because it’s a major risk factor for developing esophageal adenocarcinoma, and that’s a tumor that has been experiencing an enormous increase in frequency over the past few decades,” said Dr. Stuart Spechler, chief of gastroenterology for the VA North Texas Healthcare System and co-director of the Esophageal Diseases Center at the University of Texas Southwestern Medical Center in Dallas.

The incidence of esophageal adenocarcinoma increased more than sevenfold over 33 years, going from 3.6 per million in 1973 to 25.6 per million in 2006. Barrett’s esophagus affects about 5.6% of U.S. adults, he noted.

Endoscopic screening for Barrett’s esophagus is recommended for patients with multiple risk factors for esophageal cancer, including chronic GERD (having GERD for more than 5 years), hiatal hernia, age of at least 50 years, male gender, white race, and an elevated body mass index, especially if there’s an intra-abdominal body fat distribution, Dr. Spechler said.

Barrett’s esophagus traditionally is treated with proton pump inhibitors because of their ability to decrease gastric acid production and acid reflux and heal reflux esophagitis. “We also recommend that these patients have regular endoscopic surveillance to look for precancerous changes,” most notably dysplasia, he said. If no dysplasia is found, patients should receive a repeat endoscopy every 3-5 years. Patients with high-grade dysplasia should be treated with endoscopic eradication therapy. The risk of developing cancer in patients with high-grade dysplasia is about 6% per year, he said, which is “sufficient to warrant intervention.”

For patients with visible mucosal irregularities, endoscopic mucosal resection can determine how far the neoplasms have spread, Dr. Spechler said.

For those neoplasms confined to the mucosa, like high-grade dysplasia, radiofrequency ablation can be used to burn the abnormal mucosa away. As the esophagus heals, normal cells grow back. The procedure is safe and effective and has been shown to prevent neoplastic progression at 1 year, he said – the most serious complication is esophageal stricture (N. Engl. J. Med. 2009;360:2277-88). Radiofrequency ablation also can be considered in patients with low-grade dysplasia, and even for highly selected patients with nondysplastic Barrett’s esophagus deemed to be at increased risk for progression to high-grade dysplasia or cancer.

“We do worry about Barrett’s esophagus recurring after endoscopic eradication, and there is a rate of recurrence, but this newer treatment seems to be very effective, at least in the short term, for preventing progression to cancer,” he said.

More advanced cancers can be treated by surgery and chemotherapy or radiation therapy.

Overall, “this is a condition that’s increasing in frequency, and we do worry about it, but as long as you are treating patients, screening for Barrett’s esophagus, and following them regularly with surveillance, the prognosis for any individual patient is really excellent,” he said at the meeting, which was held by Global Academy for Medical Education and Rutgers, the State University of New Jersey. Global Academy and this news organization are owned by the same company.

Dr. Spechler has served a consultant for Takeda Pharmaceuticals and is currently a consultant for Interpace Diagnostics.

Patients with Barrett’s esophagus, a condition in which cells lining the esophagus are replaced by the type of cells that normally line the intestine, need to be monitored carefully to prevent the development of esophageal cancer, a gastroenterologist expert in the condition said here at Digestive Diseases: New Advances. The condition can occur following exposure to stomach acids and bile from gastroesophageal reflux disease (GERD).

“The reason we worry about Barrett’s is because it’s a major risk factor for developing esophageal adenocarcinoma, and that’s a tumor that has been experiencing an enormous increase in frequency over the past few decades,” said Dr. Stuart Spechler, chief of gastroenterology for the VA North Texas Healthcare System and co-director of the Esophageal Diseases Center at the University of Texas Southwestern Medical Center in Dallas.

The incidence of esophageal adenocarcinoma increased more than sevenfold over 33 years, going from 3.6 per million in 1973 to 25.6 per million in 2006. Barrett’s esophagus affects about 5.6% of U.S. adults, he noted.

Endoscopic screening for Barrett’s esophagus is recommended for patients with multiple risk factors for esophageal cancer, including chronic GERD (having GERD for more than 5 years), hiatal hernia, age of at least 50 years, male gender, white race, and an elevated body mass index, especially if there’s an intra-abdominal body fat distribution, Dr. Spechler said.

Barrett’s esophagus traditionally is treated with proton pump inhibitors because of their ability to decrease gastric acid production and acid reflux and heal reflux esophagitis. “We also recommend that these patients have regular endoscopic surveillance to look for precancerous changes,” most notably dysplasia, he said. If no dysplasia is found, patients should receive a repeat endoscopy every 3-5 years. Patients with high-grade dysplasia should be treated with endoscopic eradication therapy. The risk of developing cancer in patients with high-grade dysplasia is about 6% per year, he said, which is “sufficient to warrant intervention.”

For patients with visible mucosal irregularities, endoscopic mucosal resection can determine how far the neoplasms have spread, Dr. Spechler said.

For those neoplasms confined to the mucosa, like high-grade dysplasia, radiofrequency ablation can be used to burn the abnormal mucosa away. As the esophagus heals, normal cells grow back. The procedure is safe and effective and has been shown to prevent neoplastic progression at 1 year, he said – the most serious complication is esophageal stricture (N. Engl. J. Med. 2009;360:2277-88). Radiofrequency ablation also can be considered in patients with low-grade dysplasia, and even for highly selected patients with nondysplastic Barrett’s esophagus deemed to be at increased risk for progression to high-grade dysplasia or cancer.

“We do worry about Barrett’s esophagus recurring after endoscopic eradication, and there is a rate of recurrence, but this newer treatment seems to be very effective, at least in the short term, for preventing progression to cancer,” he said.

More advanced cancers can be treated by surgery and chemotherapy or radiation therapy.

Overall, “this is a condition that’s increasing in frequency, and we do worry about it, but as long as you are treating patients, screening for Barrett’s esophagus, and following them regularly with surveillance, the prognosis for any individual patient is really excellent,” he said at the meeting, which was held by Global Academy for Medical Education and Rutgers, the State University of New Jersey. Global Academy and this news organization are owned by the same company.

Dr. Spechler has served a consultant for Takeda Pharmaceuticals and is currently a consultant for Interpace Diagnostics.

Patients with Barrett’s esophagus, a condition in which cells lining the esophagus are replaced by the type of cells that normally line the intestine, need to be monitored carefully to prevent the development of esophageal cancer, a gastroenterologist expert in the condition said here at Digestive Diseases: New Advances. The condition can occur following exposure to stomach acids and bile from gastroesophageal reflux disease (GERD).

“The reason we worry about Barrett’s is because it’s a major risk factor for developing esophageal adenocarcinoma, and that’s a tumor that has been experiencing an enormous increase in frequency over the past few decades,” said Dr. Stuart Spechler, chief of gastroenterology for the VA North Texas Healthcare System and co-director of the Esophageal Diseases Center at the University of Texas Southwestern Medical Center in Dallas.

The incidence of esophageal adenocarcinoma increased more than sevenfold over 33 years, going from 3.6 per million in 1973 to 25.6 per million in 2006. Barrett’s esophagus affects about 5.6% of U.S. adults, he noted.

Endoscopic screening for Barrett’s esophagus is recommended for patients with multiple risk factors for esophageal cancer, including chronic GERD (having GERD for more than 5 years), hiatal hernia, age of at least 50 years, male gender, white race, and an elevated body mass index, especially if there’s an intra-abdominal body fat distribution, Dr. Spechler said.

Barrett’s esophagus traditionally is treated with proton pump inhibitors because of their ability to decrease gastric acid production and acid reflux and heal reflux esophagitis. “We also recommend that these patients have regular endoscopic surveillance to look for precancerous changes,” most notably dysplasia, he said. If no dysplasia is found, patients should receive a repeat endoscopy every 3-5 years. Patients with high-grade dysplasia should be treated with endoscopic eradication therapy. The risk of developing cancer in patients with high-grade dysplasia is about 6% per year, he said, which is “sufficient to warrant intervention.”

For patients with visible mucosal irregularities, endoscopic mucosal resection can determine how far the neoplasms have spread, Dr. Spechler said.

For those neoplasms confined to the mucosa, like high-grade dysplasia, radiofrequency ablation can be used to burn the abnormal mucosa away. As the esophagus heals, normal cells grow back. The procedure is safe and effective and has been shown to prevent neoplastic progression at 1 year, he said – the most serious complication is esophageal stricture (N. Engl. J. Med. 2009;360:2277-88). Radiofrequency ablation also can be considered in patients with low-grade dysplasia, and even for highly selected patients with nondysplastic Barrett’s esophagus deemed to be at increased risk for progression to high-grade dysplasia or cancer.

“We do worry about Barrett’s esophagus recurring after endoscopic eradication, and there is a rate of recurrence, but this newer treatment seems to be very effective, at least in the short term, for preventing progression to cancer,” he said.

More advanced cancers can be treated by surgery and chemotherapy or radiation therapy.

Overall, “this is a condition that’s increasing in frequency, and we do worry about it, but as long as you are treating patients, screening for Barrett’s esophagus, and following them regularly with surveillance, the prognosis for any individual patient is really excellent,” he said at the meeting, which was held by Global Academy for Medical Education and Rutgers, the State University of New Jersey. Global Academy and this news organization are owned by the same company.

Dr. Spechler has served a consultant for Takeda Pharmaceuticals and is currently a consultant for Interpace Diagnostics.

ROME – Patients with systemic sclerosis have a distinct colonic microbiota, compared with healthy individuals, which could contribute to their immune dysfunction and symptoms, according to a new study.

As with chronic inflammatory states such as inflammatory bowel disease, systemic sclerosis (SSc) patients had decreased commensal gut bacteria such as Bacteroides and Faecalibacterium, and increased pathogenic genera such as Enterobacteriales and Fusobacterium, in the cecum and sigmoid, compared with healthy controls.

In addition, SSc patients had increased sigmoid and cecum Bifidobacterium, which is typically found in lower abundance in inflammatory bowel disease. Additional taxa alterations also were observed. These differences had never been described in scleroderma before, according to lead study author Dr. Elizabeth Volkmann, a rheumatologist and clinical instructor at the University of California, Los Angeles.

“Gastrointestinal tract dysfunction affects 90% of systemic sclerosis patients and is a leading cause of morbidity and mortality in these patients,” Dr. Volkmann said in an interview. “Symptoms such as constipation and fecal incontinence are among the most disruptive physical problems for SSc patients, and we really don’t know the cause of them at this point.”

Dr. Volkmann and her colleagues studied 17 patients with SSc: Eighty-eight percent were women, the median age was 52 years, and the median disease duration was nearly 7 years. They compared these patients to age- and gender-matched healthy controls. The SSc patients had a mean total score of 0.7 on the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire, indicating moderate symptom severity.

At baseline, the patients underwent a colonoscopy. Researchers obtained cecum and sigmoid mucosal lavage samples for analysis; they used 16S sequencing to determine the microbiota and the Greengenes database to determine operational taxonomic units, in addition to other tests. Patients also completed the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire to assess gastrointestinal symptom severity at the time of colonoscopy, she said at the European Congress of Rheumatology.

“We found significant and profound differences in the microbial composition” between SSc patients and controls, Dr. Volkmann said. “Even with our small sample size, there were still statistically significant differences, including [in SSc patients] a decrease in normal, healthy bacteria and an increase in more pathogenic bacteria that in other disease states cause inflammation.”

Comparisons between SSc patients and healthy controls demonstrated numerous differences in the microbial communities in both the cecum and sigmoid, including a much higher abundance of the species Erwinia and Trabulsiella in patients with the most severe symptoms.

“This suggests not only are there differences in the microbiota composition between SSc patients and healthy controls, but these differences may contribute to clinical symptoms,” Dr. Volkmann said.

The SSc patients had a mean total score of 0.7 on the GIT 2.0, indicating moderate symptom severity. They also had moderate severity on the distension, constipation, emotional well-being, and social functioning domains on the GIT 2.0, and mild symptom severity on the diarrhea and fecal soilage domains.

Replacing healthy bacteria through probiotic supplements may be a potential therapy, she said. However, some SSc patients had an increase in Lactobacillus and Bifidobacterium, which normally are decreased in patients with inflammation, she said. Probiotic therapy should be used to target only species that are decreased, and many commercial probiotics are rich in Lactobacillus and Bifidobacterium.

One potential hypothesis for why some SSc patients had higher levels of Lactobacillus and Bifidobacterium may be because most were using a probiotic, she said. However, they asked patients to stop using a probiotic 3 weeks before their colonoscopy.

Her group is continuing studies in this population to evaluate microbiome changes over the course of a year.

Dr. Volkmann did not report any relevant financial disclosures.

ROME – Patients with systemic sclerosis have a distinct colonic microbiota, compared with healthy individuals, which could contribute to their immune dysfunction and symptoms, according to a new study.

As with chronic inflammatory states such as inflammatory bowel disease, systemic sclerosis (SSc) patients had decreased commensal gut bacteria such as Bacteroides and Faecalibacterium, and increased pathogenic genera such as Enterobacteriales and Fusobacterium, in the cecum and sigmoid, compared with healthy controls.

In addition, SSc patients had increased sigmoid and cecum Bifidobacterium, which is typically found in lower abundance in inflammatory bowel disease. Additional taxa alterations also were observed. These differences had never been described in scleroderma before, according to lead study author Dr. Elizabeth Volkmann, a rheumatologist and clinical instructor at the University of California, Los Angeles.

“Gastrointestinal tract dysfunction affects 90% of systemic sclerosis patients and is a leading cause of morbidity and mortality in these patients,” Dr. Volkmann said in an interview. “Symptoms such as constipation and fecal incontinence are among the most disruptive physical problems for SSc patients, and we really don’t know the cause of them at this point.”

Dr. Volkmann and her colleagues studied 17 patients with SSc: Eighty-eight percent were women, the median age was 52 years, and the median disease duration was nearly 7 years. They compared these patients to age- and gender-matched healthy controls. The SSc patients had a mean total score of 0.7 on the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire, indicating moderate symptom severity.

At baseline, the patients underwent a colonoscopy. Researchers obtained cecum and sigmoid mucosal lavage samples for analysis; they used 16S sequencing to determine the microbiota and the Greengenes database to determine operational taxonomic units, in addition to other tests. Patients also completed the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire to assess gastrointestinal symptom severity at the time of colonoscopy, she said at the European Congress of Rheumatology.

“We found significant and profound differences in the microbial composition” between SSc patients and controls, Dr. Volkmann said. “Even with our small sample size, there were still statistically significant differences, including [in SSc patients] a decrease in normal, healthy bacteria and an increase in more pathogenic bacteria that in other disease states cause inflammation.”

Comparisons between SSc patients and healthy controls demonstrated numerous differences in the microbial communities in both the cecum and sigmoid, including a much higher abundance of the species Erwinia and Trabulsiella in patients with the most severe symptoms.

“This suggests not only are there differences in the microbiota composition between SSc patients and healthy controls, but these differences may contribute to clinical symptoms,” Dr. Volkmann said.

The SSc patients had a mean total score of 0.7 on the GIT 2.0, indicating moderate symptom severity. They also had moderate severity on the distension, constipation, emotional well-being, and social functioning domains on the GIT 2.0, and mild symptom severity on the diarrhea and fecal soilage domains.

Replacing healthy bacteria through probiotic supplements may be a potential therapy, she said. However, some SSc patients had an increase in Lactobacillus and Bifidobacterium, which normally are decreased in patients with inflammation, she said. Probiotic therapy should be used to target only species that are decreased, and many commercial probiotics are rich in Lactobacillus and Bifidobacterium.

One potential hypothesis for why some SSc patients had higher levels of Lactobacillus and Bifidobacterium may be because most were using a probiotic, she said. However, they asked patients to stop using a probiotic 3 weeks before their colonoscopy.

Her group is continuing studies in this population to evaluate microbiome changes over the course of a year.

Dr. Volkmann did not report any relevant financial disclosures.

ROME – Patients with systemic sclerosis have a distinct colonic microbiota, compared with healthy individuals, which could contribute to their immune dysfunction and symptoms, according to a new study.

As with chronic inflammatory states such as inflammatory bowel disease, systemic sclerosis (SSc) patients had decreased commensal gut bacteria such as Bacteroides and Faecalibacterium, and increased pathogenic genera such as Enterobacteriales and Fusobacterium, in the cecum and sigmoid, compared with healthy controls.

In addition, SSc patients had increased sigmoid and cecum Bifidobacterium, which is typically found in lower abundance in inflammatory bowel disease. Additional taxa alterations also were observed. These differences had never been described in scleroderma before, according to lead study author Dr. Elizabeth Volkmann, a rheumatologist and clinical instructor at the University of California, Los Angeles.

“Gastrointestinal tract dysfunction affects 90% of systemic sclerosis patients and is a leading cause of morbidity and mortality in these patients,” Dr. Volkmann said in an interview. “Symptoms such as constipation and fecal incontinence are among the most disruptive physical problems for SSc patients, and we really don’t know the cause of them at this point.”

Dr. Volkmann and her colleagues studied 17 patients with SSc: Eighty-eight percent were women, the median age was 52 years, and the median disease duration was nearly 7 years. They compared these patients to age- and gender-matched healthy controls. The SSc patients had a mean total score of 0.7 on the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire, indicating moderate symptom severity.

At baseline, the patients underwent a colonoscopy. Researchers obtained cecum and sigmoid mucosal lavage samples for analysis; they used 16S sequencing to determine the microbiota and the Greengenes database to determine operational taxonomic units, in addition to other tests. Patients also completed the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire to assess gastrointestinal symptom severity at the time of colonoscopy, she said at the European Congress of Rheumatology.

“We found significant and profound differences in the microbial composition” between SSc patients and controls, Dr. Volkmann said. “Even with our small sample size, there were still statistically significant differences, including [in SSc patients] a decrease in normal, healthy bacteria and an increase in more pathogenic bacteria that in other disease states cause inflammation.”

Comparisons between SSc patients and healthy controls demonstrated numerous differences in the microbial communities in both the cecum and sigmoid, including a much higher abundance of the species Erwinia and Trabulsiella in patients with the most severe symptoms.

“This suggests not only are there differences in the microbiota composition between SSc patients and healthy controls, but these differences may contribute to clinical symptoms,” Dr. Volkmann said.

The SSc patients had a mean total score of 0.7 on the GIT 2.0, indicating moderate symptom severity. They also had moderate severity on the distension, constipation, emotional well-being, and social functioning domains on the GIT 2.0, and mild symptom severity on the diarrhea and fecal soilage domains.

Replacing healthy bacteria through probiotic supplements may be a potential therapy, she said. However, some SSc patients had an increase in Lactobacillus and Bifidobacterium, which normally are decreased in patients with inflammation, she said. Probiotic therapy should be used to target only species that are decreased, and many commercial probiotics are rich in Lactobacillus and Bifidobacterium.

One potential hypothesis for why some SSc patients had higher levels of Lactobacillus and Bifidobacterium may be because most were using a probiotic, she said. However, they asked patients to stop using a probiotic 3 weeks before their colonoscopy.

Her group is continuing studies in this population to evaluate microbiome changes over the course of a year.

Dr. Volkmann did not report any relevant financial disclosures.

Sofosbuvir plus GS-5816 appears to be a promising treatment regimen for treatment-naive patients with chronic genotype 1-6 hepatitis C virus infection without cirrhosis, according to a randomized, open-label study.

The work, led by Dr. Tram T. Tran, medical director of liver transplantation at Cedars-Sinai Medical Center in Los Angeles, found the drug combination achieved sustained viral response to treatment (SVR) rates of 77%-90% after 8 weeks and 91%-100% after 12 weeks.

Investigators enrolled 377 patients with genotype 1-6 HCV infection without cirrhosis in the study. Forty-seven percent were genotype 1; 33% were genotype 2; 14% were genotype 3; 4% were genotype 4; less than 1% were genotype 5; and 2% were genotype 6.

During the first part of the study, 154 patients were randomized to receive either sofosbuvir (SOF) and 25 mg of GS-5816, or SOF and 100 mg of GS-5816, for 12 weeks. In the second part, 223 patients with genotype 1 and 2 hepatitis C without cirrhosis who had not received prior treatment were randomized to one of the following four treatments for 8 weeks: SOF and 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF and 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. SOF was dosed at 400 mg; ribavirin was administered as 1,000 mg-1,200 mg in a divided daily dose.

SVR rates at 12 weeks in the first part of the study, with 12 weeks of treatment, were 96% using the 25-mg dose of GS-5816 and 100% with the 100-mg dose in patients with genotype 1 HCV infection, Dr. Tran said at the annual meeting of the American Association for the Study of Liver Diseases. For patients with genotype 2, SVR rates at 12 weeks were 91% and 100% with the 25-mg and 100-mg doses, respectively. SVR rates at 12 weeks for the other genotypes ranged from 86% to 100%.

In the second part of this study that reduced treatment duration to 8 weeks and added ribavirin to some treatment arms, SVR rates at 12 weeks ranged from 81% to 90% for patients with genotype 1 infection and from 77% to 88% for patients with genotype 2 infection.

The most frequently reported adverse events were fatigue, headache,and nausea, occurring in more than 10% of patients. One patient discontinued treatment because of abdominal pain.

“SVR rates were lower and relapse rates increased in patients with genotype 1 or 2 infection when treated for 8 weeks instead of 12 weeks,” Dr. Tran said.
A coformulated, fixed dose of 400 mg SOF and 100 mg of GS-5816 is now in a phase 3 clinical trial, she said.

Sofosbuvir plus GS-5816 appears to be a promising treatment regimen for treatment-naive patients with chronic genotype 1-6 hepatitis C virus infection without cirrhosis, according to a randomized, open-label study.

The work, led by Dr. Tram T. Tran, medical director of liver transplantation at Cedars-Sinai Medical Center in Los Angeles, found the drug combination achieved sustained viral response to treatment (SVR) rates of 77%-90% after 8 weeks and 91%-100% after 12 weeks.

Investigators enrolled 377 patients with genotype 1-6 HCV infection without cirrhosis in the study. Forty-seven percent were genotype 1; 33% were genotype 2; 14% were genotype 3; 4% were genotype 4; less than 1% were genotype 5; and 2% were genotype 6.

During the first part of the study, 154 patients were randomized to receive either sofosbuvir (SOF) and 25 mg of GS-5816, or SOF and 100 mg of GS-5816, for 12 weeks. In the second part, 223 patients with genotype 1 and 2 hepatitis C without cirrhosis who had not received prior treatment were randomized to one of the following four treatments for 8 weeks: SOF and 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF and 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. SOF was dosed at 400 mg; ribavirin was administered as 1,000 mg-1,200 mg in a divided daily dose.

SVR rates at 12 weeks in the first part of the study, with 12 weeks of treatment, were 96% using the 25-mg dose of GS-5816 and 100% with the 100-mg dose in patients with genotype 1 HCV infection, Dr. Tran said at the annual meeting of the American Association for the Study of Liver Diseases. For patients with genotype 2, SVR rates at 12 weeks were 91% and 100% with the 25-mg and 100-mg doses, respectively. SVR rates at 12 weeks for the other genotypes ranged from 86% to 100%.

In the second part of this study that reduced treatment duration to 8 weeks and added ribavirin to some treatment arms, SVR rates at 12 weeks ranged from 81% to 90% for patients with genotype 1 infection and from 77% to 88% for patients with genotype 2 infection.

The most frequently reported adverse events were fatigue, headache,and nausea, occurring in more than 10% of patients. One patient discontinued treatment because of abdominal pain.

“SVR rates were lower and relapse rates increased in patients with genotype 1 or 2 infection when treated for 8 weeks instead of 12 weeks,” Dr. Tran said.
A coformulated, fixed dose of 400 mg SOF and 100 mg of GS-5816 is now in a phase 3 clinical trial, she said.

Sofosbuvir plus GS-5816 appears to be a promising treatment regimen for treatment-naive patients with chronic genotype 1-6 hepatitis C virus infection without cirrhosis, according to a randomized, open-label study.

The work, led by Dr. Tram T. Tran, medical director of liver transplantation at Cedars-Sinai Medical Center in Los Angeles, found the drug combination achieved sustained viral response to treatment (SVR) rates of 77%-90% after 8 weeks and 91%-100% after 12 weeks.

Investigators enrolled 377 patients with genotype 1-6 HCV infection without cirrhosis in the study. Forty-seven percent were genotype 1; 33% were genotype 2; 14% were genotype 3; 4% were genotype 4; less than 1% were genotype 5; and 2% were genotype 6.

During the first part of the study, 154 patients were randomized to receive either sofosbuvir (SOF) and 25 mg of GS-5816, or SOF and 100 mg of GS-5816, for 12 weeks. In the second part, 223 patients with genotype 1 and 2 hepatitis C without cirrhosis who had not received prior treatment were randomized to one of the following four treatments for 8 weeks: SOF and 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF and 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. SOF was dosed at 400 mg; ribavirin was administered as 1,000 mg-1,200 mg in a divided daily dose.

SVR rates at 12 weeks in the first part of the study, with 12 weeks of treatment, were 96% using the 25-mg dose of GS-5816 and 100% with the 100-mg dose in patients with genotype 1 HCV infection, Dr. Tran said at the annual meeting of the American Association for the Study of Liver Diseases. For patients with genotype 2, SVR rates at 12 weeks were 91% and 100% with the 25-mg and 100-mg doses, respectively. SVR rates at 12 weeks for the other genotypes ranged from 86% to 100%.

In the second part of this study that reduced treatment duration to 8 weeks and added ribavirin to some treatment arms, SVR rates at 12 weeks ranged from 81% to 90% for patients with genotype 1 infection and from 77% to 88% for patients with genotype 2 infection.

The most frequently reported adverse events were fatigue, headache,and nausea, occurring in more than 10% of patients. One patient discontinued treatment because of abdominal pain.

“SVR rates were lower and relapse rates increased in patients with genotype 1 or 2 infection when treated for 8 weeks instead of 12 weeks,” Dr. Tran said.
A coformulated, fixed dose of 400 mg SOF and 100 mg of GS-5816 is now in a phase 3 clinical trial, she said.

Sofosbuvir plus GS-5816 appears to be a promising treatment regimen for treatment-naive patients with chronic genotype 1-6 hepatitis C virus infection without cirrhosis, according to a randomized, open-label study.

The work, led by Dr. Tram T. Tran, medical director of liver transplantation at Cedars-Sinai Medical Center in Los Angeles, found the drug combination achieved sustained viral response to treatment (SVR) rates of 77%-90% after 8 weeks and 91%-100% after 12 weeks.

Investigators enrolled 377 patients with genotype 1-6 HCV infection without cirrhosis in the study. Forty-seven percent were genotype 1; 33% were genotype 2; 14% were genotype 3; 4% were genotype 4; less than 1% were genotype 5; and 2% were genotype 6.

During the first part of the study, 154 patients were randomized to receive either sofosbuvir (SOF) and 25 mg of GS-5816, or SOF and 100 mg of GS-5816, for 12 weeks. In the second part, 223 patients with genotype 1 and 2 hepatitis C without cirrhosis who had not received prior treatment were randomized to one of the following four treatments for 8 weeks: SOF and 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF and 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. SOF was dosed at 400 mg; ribavirin was administered as 1,000 mg-1,200 mg in a divided daily dose.

SVR rates at 12 weeks in the first part of the study, with 12 weeks of treatment, were 96% using the 25-mg dose of GS-5816 and 100% with the 100-mg dose in patients with genotype 1 HCV infection, Dr. Tran said at the annual meeting of the American Association for the Study of Liver Diseases. For patients with genotype 2, SVR rates at 12 weeks were 91% and 100% with the 25-mg and 100-mg doses, respectively. SVR rates at 12 weeks for the other genotypes ranged from 86% to 100%.

In the second part of this study that reduced treatment duration to 8 weeks and added ribavirin to some treatment arms, SVR rates at 12 weeks ranged from 81% to 90% for patients with genotype 1 infection and from 77% to 88% for patients with genotype 2 infection.

The most frequently reported adverse events were fatigue, headache,and nausea, occurring in more than 10% of patients. One patient discontinued treatment because of abdominal pain.

“SVR rates were lower and relapse rates increased in patients with genotype 1 or 2 infection when treated for 8 weeks instead of 12 weeks,” Dr. Tran said.
A coformulated, fixed dose of 400 mg SOF and 100 mg of GS-5816 is now in a phase 3 clinical trial, she said.

Sofosbuvir plus GS-5816 appears to be a promising treatment regimen for treatment-naive patients with chronic genotype 1-6 hepatitis C virus infection without cirrhosis, according to a randomized, open-label study.

The work, led by Dr. Tram T. Tran, medical director of liver transplantation at Cedars-Sinai Medical Center in Los Angeles, found the drug combination achieved sustained viral response to treatment (SVR) rates of 77%-90% after 8 weeks and 91%-100% after 12 weeks.

Investigators enrolled 377 patients with genotype 1-6 HCV infection without cirrhosis in the study. Forty-seven percent were genotype 1; 33% were genotype 2; 14% were genotype 3; 4% were genotype 4; less than 1% were genotype 5; and 2% were genotype 6.

During the first part of the study, 154 patients were randomized to receive either sofosbuvir (SOF) and 25 mg of GS-5816, or SOF and 100 mg of GS-5816, for 12 weeks. In the second part, 223 patients with genotype 1 and 2 hepatitis C without cirrhosis who had not received prior treatment were randomized to one of the following four treatments for 8 weeks: SOF and 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF and 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. SOF was dosed at 400 mg; ribavirin was administered as 1,000 mg-1,200 mg in a divided daily dose.

SVR rates at 12 weeks in the first part of the study, with 12 weeks of treatment, were 96% using the 25-mg dose of GS-5816 and 100% with the 100-mg dose in patients with genotype 1 HCV infection, Dr. Tran said at the annual meeting of the American Association for the Study of Liver Diseases. For patients with genotype 2, SVR rates at 12 weeks were 91% and 100% with the 25-mg and 100-mg doses, respectively. SVR rates at 12 weeks for the other genotypes ranged from 86% to 100%.

In the second part of this study that reduced treatment duration to 8 weeks and added ribavirin to some treatment arms, SVR rates at 12 weeks ranged from 81% to 90% for patients with genotype 1 infection and from 77% to 88% for patients with genotype 2 infection.

The most frequently reported adverse events were fatigue, headache,and nausea, occurring in more than 10% of patients. One patient discontinued treatment because of abdominal pain.

“SVR rates were lower and relapse rates increased in patients with genotype 1 or 2 infection when treated for 8 weeks instead of 12 weeks,” Dr. Tran said.
A coformulated, fixed dose of 400 mg SOF and 100 mg of GS-5816 is now in a phase 3 clinical trial, she said.

Sofosbuvir plus GS-5816 appears to be a promising treatment regimen for treatment-naive patients with chronic genotype 1-6 hepatitis C virus infection without cirrhosis, according to a randomized, open-label study.

The work, led by Dr. Tram T. Tran, medical director of liver transplantation at Cedars-Sinai Medical Center in Los Angeles, found the drug combination achieved sustained viral response to treatment (SVR) rates of 77%-90% after 8 weeks and 91%-100% after 12 weeks.

Investigators enrolled 377 patients with genotype 1-6 HCV infection without cirrhosis in the study. Forty-seven percent were genotype 1; 33% were genotype 2; 14% were genotype 3; 4% were genotype 4; less than 1% were genotype 5; and 2% were genotype 6.

During the first part of the study, 154 patients were randomized to receive either sofosbuvir (SOF) and 25 mg of GS-5816, or SOF and 100 mg of GS-5816, for 12 weeks. In the second part, 223 patients with genotype 1 and 2 hepatitis C without cirrhosis who had not received prior treatment were randomized to one of the following four treatments for 8 weeks: SOF and 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF and 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. SOF was dosed at 400 mg; ribavirin was administered as 1,000 mg-1,200 mg in a divided daily dose.

SVR rates at 12 weeks in the first part of the study, with 12 weeks of treatment, were 96% using the 25-mg dose of GS-5816 and 100% with the 100-mg dose in patients with genotype 1 HCV infection, Dr. Tran said at the annual meeting of the American Association for the Study of Liver Diseases. For patients with genotype 2, SVR rates at 12 weeks were 91% and 100% with the 25-mg and 100-mg doses, respectively. SVR rates at 12 weeks for the other genotypes ranged from 86% to 100%.

In the second part of this study that reduced treatment duration to 8 weeks and added ribavirin to some treatment arms, SVR rates at 12 weeks ranged from 81% to 90% for patients with genotype 1 infection and from 77% to 88% for patients with genotype 2 infection.

The most frequently reported adverse events were fatigue, headache,and nausea, occurring in more than 10% of patients. One patient discontinued treatment because of abdominal pain.

“SVR rates were lower and relapse rates increased in patients with genotype 1 or 2 infection when treated for 8 weeks instead of 12 weeks,” Dr. Tran said.
A coformulated, fixed dose of 400 mg SOF and 100 mg of GS-5816 is now in a phase 3 clinical trial, she said.

A combination drug regimen of sofosbuvir plus the investigational medication GS-5816 yielded high rates of sustained viral response to treatment among patients with genotype 3 hepatitis C virus infection without cirrhosis, according to new research.

Study results, taken from the phase II ELECTRON2 study, showed the combination of drugs with or without ribavirin led to SVR rates of 88% to 100% after 12 weeks. Previous work had shown the drug combination to be effective in 12 weeks across all genotypes 1-6.

Investigators led by Dr. Edward J. Gane, professor of medicine at the University of Auckland, New Zealand, and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital, randomized 104 treatment-naive patients to receive one of four drug regimens: sofosbuvir (SOF) plus 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF plus 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. Most participants were male, white, and had IL28B non-CC genotype. Two patients did not complete the study.

Adverse events, which were more common in the ribavirin arm, were generally mild, the authors said. Grade 3/4 laboratory abnormalities were infrequent and consistent with the ribavirin safety profile.

“These data support further development of SOF in combination with GS-5816 but without ribavirin for the treatment of chronic HCV,” the authors said at the annual meeting of the American Association for the Study of Liver Diseases.

The trial was sponsored by Gilead Sciences, manufacturer of the drugs. Dr. Gane has served on an advisory board for and has received speaking fees from the company. All but one coauthor either is employed by Gilead or has received speaking fees from the company.

[email protected]

A combination drug regimen of sofosbuvir plus the investigational medication GS-5816 yielded high rates of sustained viral response to treatment among patients with genotype 3 hepatitis C virus infection without cirrhosis, according to new research.

Study results, taken from the phase II ELECTRON2 study, showed the combination of drugs with or without ribavirin led to SVR rates of 88% to 100% after 12 weeks. Previous work had shown the drug combination to be effective in 12 weeks across all genotypes 1-6.

Investigators led by Dr. Edward J. Gane, professor of medicine at the University of Auckland, New Zealand, and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital, randomized 104 treatment-naive patients to receive one of four drug regimens: sofosbuvir (SOF) plus 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF plus 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. Most participants were male, white, and had IL28B non-CC genotype. Two patients did not complete the study.

Adverse events, which were more common in the ribavirin arm, were generally mild, the authors said. Grade 3/4 laboratory abnormalities were infrequent and consistent with the ribavirin safety profile.

“These data support further development of SOF in combination with GS-5816 but without ribavirin for the treatment of chronic HCV,” the authors said at the annual meeting of the American Association for the Study of Liver Diseases.

The trial was sponsored by Gilead Sciences, manufacturer of the drugs. Dr. Gane has served on an advisory board for and has received speaking fees from the company. All but one coauthor either is employed by Gilead or has received speaking fees from the company.

[email protected]

A combination drug regimen of sofosbuvir plus the investigational medication GS-5816 yielded high rates of sustained viral response to treatment among patients with genotype 3 hepatitis C virus infection without cirrhosis, according to new research.

Study results, taken from the phase II ELECTRON2 study, showed the combination of drugs with or without ribavirin led to SVR rates of 88% to 100% after 12 weeks. Previous work had shown the drug combination to be effective in 12 weeks across all genotypes 1-6.

Investigators led by Dr. Edward J. Gane, professor of medicine at the University of Auckland, New Zealand, and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital, randomized 104 treatment-naive patients to receive one of four drug regimens: sofosbuvir (SOF) plus 25 mg of GS-5816; SOF, 25 mg of GS-5816, and ribavirin; SOF plus 100 mg of GS-5816; or SOF, 100 mg of GS-5816, and ribavirin. Most participants were male, white, and had IL28B non-CC genotype. Two patients did not complete the study.

Adverse events, which were more common in the ribavirin arm, were generally mild, the authors said. Grade 3/4 laboratory abnormalities were infrequent and consistent with the ribavirin safety profile.

“These data support further development of SOF in combination with GS-5816 but without ribavirin for the treatment of chronic HCV,” the authors said at the annual meeting of the American Association for the Study of Liver Diseases.

The trial was sponsored by Gilead Sciences, manufacturer of the drugs. Dr. Gane has served on an advisory board for and has received speaking fees from the company. All but one coauthor either is employed by Gilead or has received speaking fees from the company.

[email protected]

Viral suppression of hepatitis C virus–infected patients improved neural health as measured by magnetic resonance spectroscopy, according to findings from a new study.

Treatment led to an increase in the n-acetyl aspartate/creatine ratio in patients’ basal ganglia, according to Dr. Nezam H. Afdhal of Beth Israel Deaconess Medical Center, Boston.

Dr. Afdhal and his associates studied 14 treatment-naive HCV patients participating in the ION-1 trial. For 12 weeks, seven patients received combination ledipasvir/sofosbuvir; the other seven received the same combination plus ribavirin (RBV). All patients achieved sustained viral response (SVR) to treatment. Researchers used MR spectroscopy to evaluate signals from choline, creatine (Cr), n-acetyl aspartate (NAA), and myoinisitol. “MR spectroscopy showed an increase in the basal ganglia NAA/Cr ratio at week 4 that became significant at SVR (P = .0134) and more apparent in the RBV-free group,” Dr. Afdhal said at the annual meeting of the American Association for the Study of Liver Diseases.

“At week 12 post treatment, the NAA/Cr ratio in left basal ganglia increased in the RBV-free arm (P = .0156) and remained unchanged in the RBV-containing arm (P > .05),” he reported. After 12 weeks post treatment, some changes in the metabolite in the left basal ganglia shown by MR spectroscopy correlated with changes in the emotional function domain of a quality-of-life questionnaire and in the mental health scale of SF-36.

“Changes in the metabolite pattern captured by MR [spectroscopy] also may be associated with changes in patient reported outcomes related to mental health,” the authors said. “The role of HCV on neurocognition is undergoing further study in a double-blind placebo-controlled trial.”

The ION-1 trial was sponsored by Gilead Sciences, manufacturer of ledipasvir/sofosbuvir. Dr. Afdhal reported financial relationships with Gilead, Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Pharmasett, and Abbott.

Viral suppression of hepatitis C virus–infected patients improved neural health as measured by magnetic resonance spectroscopy, according to findings from a new study.

Treatment led to an increase in the n-acetyl aspartate/creatine ratio in patients’ basal ganglia, according to Dr. Nezam H. Afdhal of Beth Israel Deaconess Medical Center, Boston.

Dr. Afdhal and his associates studied 14 treatment-naive HCV patients participating in the ION-1 trial. For 12 weeks, seven patients received combination ledipasvir/sofosbuvir; the other seven received the same combination plus ribavirin (RBV). All patients achieved sustained viral response (SVR) to treatment. Researchers used MR spectroscopy to evaluate signals from choline, creatine (Cr), n-acetyl aspartate (NAA), and myoinisitol. “MR spectroscopy showed an increase in the basal ganglia NAA/Cr ratio at week 4 that became significant at SVR (P = .0134) and more apparent in the RBV-free group,” Dr. Afdhal said at the annual meeting of the American Association for the Study of Liver Diseases.

“At week 12 post treatment, the NAA/Cr ratio in left basal ganglia increased in the RBV-free arm (P = .0156) and remained unchanged in the RBV-containing arm (P > .05),” he reported. After 12 weeks post treatment, some changes in the metabolite in the left basal ganglia shown by MR spectroscopy correlated with changes in the emotional function domain of a quality-of-life questionnaire and in the mental health scale of SF-36.

“Changes in the metabolite pattern captured by MR [spectroscopy] also may be associated with changes in patient reported outcomes related to mental health,” the authors said. “The role of HCV on neurocognition is undergoing further study in a double-blind placebo-controlled trial.”

The ION-1 trial was sponsored by Gilead Sciences, manufacturer of ledipasvir/sofosbuvir. Dr. Afdhal reported financial relationships with Gilead, Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Pharmasett, and Abbott.

Viral suppression of hepatitis C virus–infected patients improved neural health as measured by magnetic resonance spectroscopy, according to findings from a new study.

Treatment led to an increase in the n-acetyl aspartate/creatine ratio in patients’ basal ganglia, according to Dr. Nezam H. Afdhal of Beth Israel Deaconess Medical Center, Boston.

Dr. Afdhal and his associates studied 14 treatment-naive HCV patients participating in the ION-1 trial. For 12 weeks, seven patients received combination ledipasvir/sofosbuvir; the other seven received the same combination plus ribavirin (RBV). All patients achieved sustained viral response (SVR) to treatment. Researchers used MR spectroscopy to evaluate signals from choline, creatine (Cr), n-acetyl aspartate (NAA), and myoinisitol. “MR spectroscopy showed an increase in the basal ganglia NAA/Cr ratio at week 4 that became significant at SVR (P = .0134) and more apparent in the RBV-free group,” Dr. Afdhal said at the annual meeting of the American Association for the Study of Liver Diseases.

“At week 12 post treatment, the NAA/Cr ratio in left basal ganglia increased in the RBV-free arm (P = .0156) and remained unchanged in the RBV-containing arm (P > .05),” he reported. After 12 weeks post treatment, some changes in the metabolite in the left basal ganglia shown by MR spectroscopy correlated with changes in the emotional function domain of a quality-of-life questionnaire and in the mental health scale of SF-36.

“Changes in the metabolite pattern captured by MR [spectroscopy] also may be associated with changes in patient reported outcomes related to mental health,” the authors said. “The role of HCV on neurocognition is undergoing further study in a double-blind placebo-controlled trial.”

The ION-1 trial was sponsored by Gilead Sciences, manufacturer of ledipasvir/sofosbuvir. Dr. Afdhal reported financial relationships with Gilead, Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Pharmasett, and Abbott.

FROM THE LIVER MEETING 2014
A combined formula of ABT-450 with ritonavir, ombitasvir, and dasabuvir, given with ribavirin, yielded high rates of sustained viral response at 12 weeks among patients with hepatitis C virus genotype 1 and cirrhosis, according to work presented at the annual meeting of the American Association for the Study of Liver Diseases.

The regimen worked well in a “broad range of subgroups, including patients with evidence of impaired hepatic synthetic function and/or evidence of portal hypertension,” according to the study, led by Dr. Michael W. Fried, professor of medicine and director of the liver center at the University of North Carolina, Chapel Hill.

Investigators analyzed results from 380 patients randomly assigned to the therapy – coformulated ABT-450/r/ombitasvir+dasabuvir with ribavirin – for either 12 weeks or 24 weeks in the phase III TURQUOISE-II trial. They used sustained viral response to treatment at 12 weeks (SVR12) as the primary outcome measure.

Overall, SVR12 rates were 91.8% for patients taking the drug regimen for 12 weeks, and 96.5% for those taking it for 24 weeks. SVR12 rates did not differ substantially by sex, age, body mass index, or HCV RNA levels. SVR rates ranged from 83.3% at 12 weeks to 96.2% at 24 weeks in patients with platelet counts < 90 × 10⁹/L, and from 84% at 12 weeks to 88.9% at 24 weeks in patients with serum albumin < 35 g/L.
[email protected]

FROM THE LIVER MEETING 2014
A combined formula of ABT-450 with ritonavir, ombitasvir, and dasabuvir, given with ribavirin, yielded high rates of sustained viral response at 12 weeks among patients with hepatitis C virus genotype 1 and cirrhosis, according to work presented at the annual meeting of the American Association for the Study of Liver Diseases.

The regimen worked well in a “broad range of subgroups, including patients with evidence of impaired hepatic synthetic function and/or evidence of portal hypertension,” according to the study, led by Dr. Michael W. Fried, professor of medicine and director of the liver center at the University of North Carolina, Chapel Hill.

Investigators analyzed results from 380 patients randomly assigned to the therapy – coformulated ABT-450/r/ombitasvir+dasabuvir with ribavirin – for either 12 weeks or 24 weeks in the phase III TURQUOISE-II trial. They used sustained viral response to treatment at 12 weeks (SVR12) as the primary outcome measure.

Overall, SVR12 rates were 91.8% for patients taking the drug regimen for 12 weeks, and 96.5% for those taking it for 24 weeks. SVR12 rates did not differ substantially by sex, age, body mass index, or HCV RNA levels. SVR rates ranged from 83.3% at 12 weeks to 96.2% at 24 weeks in patients with platelet counts < 90 × 10⁹/L, and from 84% at 12 weeks to 88.9% at 24 weeks in patients with serum albumin < 35 g/L.
[email protected]

FROM THE LIVER MEETING 2014
A combined formula of ABT-450 with ritonavir, ombitasvir, and dasabuvir, given with ribavirin, yielded high rates of sustained viral response at 12 weeks among patients with hepatitis C virus genotype 1 and cirrhosis, according to work presented at the annual meeting of the American Association for the Study of Liver Diseases.

The regimen worked well in a “broad range of subgroups, including patients with evidence of impaired hepatic synthetic function and/or evidence of portal hypertension,” according to the study, led by Dr. Michael W. Fried, professor of medicine and director of the liver center at the University of North Carolina, Chapel Hill.

Investigators analyzed results from 380 patients randomly assigned to the therapy – coformulated ABT-450/r/ombitasvir+dasabuvir with ribavirin – for either 12 weeks or 24 weeks in the phase III TURQUOISE-II trial. They used sustained viral response to treatment at 12 weeks (SVR12) as the primary outcome measure.

Overall, SVR12 rates were 91.8% for patients taking the drug regimen for 12 weeks, and 96.5% for those taking it for 24 weeks. SVR12 rates did not differ substantially by sex, age, body mass index, or HCV RNA levels. SVR rates ranged from 83.3% at 12 weeks to 96.2% at 24 weeks in patients with platelet counts < 90 × 10⁹/L, and from 84% at 12 weeks to 88.9% at 24 weeks in patients with serum albumin < 35 g/L.
[email protected]

Patients with chronic hepatitis C genotype 1 infection who relapse after sofosbuvir plus ribavirin may be successfully retreated with sofosbuvir plus ledipasvir, a new study demonstrated.

During the study, investigators approached patients treated with sofosbuvir plus ribavirin for 24 weeks in the National Institute of Allergy and Infectious Diseases (NIAID) SPARE study who relapsed after treatment. The participants, mostly black men with an interleukin-28B non-CC genotype, were offered retreatment with sofosbuvir plus ledipasvir for 12 weeks in the ongoing, phase IIa, open-label NIAID SYNERGY study. Fourteen enrolled. The medication was a single daily tablet of 400 mg of sofosbuvir and 90 mg of ledipasvir.

All patients achieved sustained viral response to treatment (SVR12), including seven who had advanced liver disease and one with a detectable NS5B S282T mutation, according to work directed by Dr. Anu Osinusi of Gilead Sciences, manufacturer of the combination drug. Most adverse events, including loose stool, constipation, headache, myalgia, nasal congestion, and pruritic rash, were mild.

The research suggests that patients who have viral relapse after sofosbuvir/ribavirin “can be successfully retreated with sofosbuvir/ledipasvir for 12 weeks,” the authors wrote. “The low incidence of adverse events, low pill burden, short treatment duration, and high efficacy demonstrated in this group and other populations make this drug combination attractive in a real-world setting.”

The study was supported by NIAID, the National Institutes of Health, the National Cancer Institute, and Gilead Sciences (manufacturer of sofosbuvir/ledipasvir). Two authors are employed by Gilead; two others disclosed other company-sponsored findings during the study period.

Patients with chronic hepatitis C genotype 1 infection who relapse after sofosbuvir plus ribavirin may be successfully retreated with sofosbuvir plus ledipasvir, a new study demonstrated.

During the study, investigators approached patients treated with sofosbuvir plus ribavirin for 24 weeks in the National Institute of Allergy and Infectious Diseases (NIAID) SPARE study who relapsed after treatment. The participants, mostly black men with an interleukin-28B non-CC genotype, were offered retreatment with sofosbuvir plus ledipasvir for 12 weeks in the ongoing, phase IIa, open-label NIAID SYNERGY study. Fourteen enrolled. The medication was a single daily tablet of 400 mg of sofosbuvir and 90 mg of ledipasvir.

All patients achieved sustained viral response to treatment (SVR12), including seven who had advanced liver disease and one with a detectable NS5B S282T mutation, according to work directed by Dr. Anu Osinusi of Gilead Sciences, manufacturer of the combination drug. Most adverse events, including loose stool, constipation, headache, myalgia, nasal congestion, and pruritic rash, were mild.

The research suggests that patients who have viral relapse after sofosbuvir/ribavirin “can be successfully retreated with sofosbuvir/ledipasvir for 12 weeks,” the authors wrote. “The low incidence of adverse events, low pill burden, short treatment duration, and high efficacy demonstrated in this group and other populations make this drug combination attractive in a real-world setting.”

The study was supported by NIAID, the National Institutes of Health, the National Cancer Institute, and Gilead Sciences (manufacturer of sofosbuvir/ledipasvir). Two authors are employed by Gilead; two others disclosed other company-sponsored findings during the study period.

Patients with chronic hepatitis C genotype 1 infection who relapse after sofosbuvir plus ribavirin may be successfully retreated with sofosbuvir plus ledipasvir, a new study demonstrated.

During the study, investigators approached patients treated with sofosbuvir plus ribavirin for 24 weeks in the National Institute of Allergy and Infectious Diseases (NIAID) SPARE study who relapsed after treatment. The participants, mostly black men with an interleukin-28B non-CC genotype, were offered retreatment with sofosbuvir plus ledipasvir for 12 weeks in the ongoing, phase IIa, open-label NIAID SYNERGY study. Fourteen enrolled. The medication was a single daily tablet of 400 mg of sofosbuvir and 90 mg of ledipasvir.

All patients achieved sustained viral response to treatment (SVR12), including seven who had advanced liver disease and one with a detectable NS5B S282T mutation, according to work directed by Dr. Anu Osinusi of Gilead Sciences, manufacturer of the combination drug. Most adverse events, including loose stool, constipation, headache, myalgia, nasal congestion, and pruritic rash, were mild.

The research suggests that patients who have viral relapse after sofosbuvir/ribavirin “can be successfully retreated with sofosbuvir/ledipasvir for 12 weeks,” the authors wrote. “The low incidence of adverse events, low pill burden, short treatment duration, and high efficacy demonstrated in this group and other populations make this drug combination attractive in a real-world setting.”

The study was supported by NIAID, the National Institutes of Health, the National Cancer Institute, and Gilead Sciences (manufacturer of sofosbuvir/ledipasvir). Two authors are employed by Gilead; two others disclosed other company-sponsored findings during the study period.