ACG Annual Meeting

SAN DIEGO – Electrical stimulation therapy of the lower esophageal sphincter is effective for treating refractory gastroesophageal reflux disease, according to interim results from a trial presented at the annual meeting of the American College of Gastroenterology.

A total of 32 patients underwent implantation of a pair of electrodes in the muscular layer of the gastroesophageal junction. The electrodes were connected to a pulse generator in the abdomen that delivered intermittent stimulation.

Six months later, the patients had a sustained, more than one-half reduction from baseline in exposure of the esophagus to acid and a two-thirds reduction in symptoms, reported first author Dr. Edy E. Soffer at the meeting.

Additionally, whereas most of the patients had been taking proton pump inhibitors (PPIs) at baseline, only about 1 in 10 were doing so at 6 months. None experienced any device-related adverse events.

The findings support the effectiveness and safety of electrical stimulation therapy in this population, according to Dr. Soffer, who is a professor in the gastroenterology division, Keck School of Medicine, University of Southern California, Los Angeles.

"Currently, there are ongoing studies, and there will be future sham-controlled studies that should clarify further the role of this intervention in the treatment of GERD [gastroesophageal reflux disease] and its mechanism of action," he noted.

Session attendee Dr. Marcelo Vela of the Baylor Clinic, Houston, noted that earlier studies have shown that this therapy increases basal pressure of the lower esophageal sphincter (LES). "Because the main mechanism for reflux is transient LES relaxations [TLESRs], particularly with small hernias as in your patients, do you have any data on TLESRs?" he asked.

"No, LES pressure was not an endpoint in these studies," Dr. Soffer replied. "Initially, we thought that this [basal pressure] is the main mechanism; as we are learning more, it is probably not going to be the main mechanism. We are looking at others, including TLESRs. ... We don’t have data yet."

Dr. Joel Richter, of the University of South Florida, Tampa, wondered whether patients experienced any of the oft-feared complications of antireflux surgery, such as bloating, diarrhea, and dysphagia.

"There were only two cases of dysphagia, and they basically resolved on their own," Dr. Soffer replied. "We didn’t see any of the symptoms that you see with postsurgical therapy. ... The intervention really should not result in the symptoms that come after standard surgical care."

Dr. Richter also requested more information on hiatal hernia repairs undertaken in some patients. "If you had a hernia repair, how do you know what part of the success was related to the hernia repair versus the stimulation?" he asked.

Thirteen patients had a hernia repair, with technique left up to the treating physician, Dr. Soffer replied. "We will look separately, when we complete that phase, at those that had the hernia repair versus those that did not."

"Was there a bit of a trend toward any improvement depending on your hernia size?" Dr. Richard McCallam of Texas Tech University in El Paso asked, while also noting that patients with hernias measuring 3 cm or more were excluded.

There were too few patients to assess trends, according to Dr. Soffer. "We tried not to take patients who had particularly severe disease at the beginning," he added. "The 3-cm hernia repair will be the one perhaps that will need to be looked at more carefully. This is a more sustained hernia situation as compared to the 1- and 2-cm [ones]."

The investigators enrolled GERD patients in the study who had a GERD health-related quality of life score of 20 or higher when not taking PPIs, and who had at least a partial response to these agents. They were required to have a basal LES end-expiratory pressure of at least 5 mm Hg, and to have a pH below 4.0 for more than 5% of the time on 24-hour esophageal pH monitoring.

The patients’ mean age was 50 years, and 18 of them were male, according to Dr. Soffer.

The main results showed a sustained reduction in esophageal acid exposure; the percentage of time at pH less than 4.0 was 10.3% at baseline, compared with 3.7% at 3 months (P less than .01), and 4.6% at 6 months (P less than .01).

There was also a sustained improvement in symptoms as assessed from GERD health-related quality of life; the score was 15 at baseline on PPIs and 31 at baseline off PPIs. These figures compared with a score of 4 at 3 months and 5 at 6 months.

Large proportions of patients met criteria for successful treatment at 6 months: 65% had control of esophageal acid exposure (either normalization or a greater than one-half reduction), 86% had control of GERD symptoms compared with level without medical therapy (a greater than 50% improvement versus baseline level not on PPIs), and 76% had control of GERD symptoms compared with level with medical therapy (any improvement of symptoms versus baseline level on PPIs).

Quality of life as assessed with the Short Form-12 showed improvement at 6 months in physical health scores compared with those measured at baseline while off PPIs.

Patients also had significant reductions from the level at baseline off PPIs at both 3 and 6 months in the median percentages of daily diary days with heartburn and with regurgitation symptoms.

Analyses of daytime versus nighttime symptoms are still ongoing, according to Dr. Soffer.

Stimulation therapy was also associated with a dramatic reduction in PPI use. Whereas only 10% of patients did not use any of these agents at baseline, 89% were not using any at 6 months.

There were just two serious adverse events: a procedure-related trocar perforation of the small bowel during laparoscopy (the stimulation device was prophylactically removed and there was resolution after surgical repair) and atrioventricular nodal reentrant tachycardia unrelated to the device or procedure.

There were no device-related serious adverse events. There were 35 nonserious events possibly or probably related to the device or procedure.

Dr. Soffer is a consultant for and shareholder in EndoStim*. The study was supported by EndoStim.

*Correction, 2/4/2014: An earlier version of the story misstated Dr. Soffer's conflicts of interest.

SAN DIEGO – Electrical stimulation therapy of the lower esophageal sphincter is effective for treating refractory gastroesophageal reflux disease, according to interim results from a trial presented at the annual meeting of the American College of Gastroenterology.

A total of 32 patients underwent implantation of a pair of electrodes in the muscular layer of the gastroesophageal junction. The electrodes were connected to a pulse generator in the abdomen that delivered intermittent stimulation.

Six months later, the patients had a sustained, more than one-half reduction from baseline in exposure of the esophagus to acid and a two-thirds reduction in symptoms, reported first author Dr. Edy E. Soffer at the meeting.

Additionally, whereas most of the patients had been taking proton pump inhibitors (PPIs) at baseline, only about 1 in 10 were doing so at 6 months. None experienced any device-related adverse events.

The findings support the effectiveness and safety of electrical stimulation therapy in this population, according to Dr. Soffer, who is a professor in the gastroenterology division, Keck School of Medicine, University of Southern California, Los Angeles.

"Currently, there are ongoing studies, and there will be future sham-controlled studies that should clarify further the role of this intervention in the treatment of GERD [gastroesophageal reflux disease] and its mechanism of action," he noted.

Session attendee Dr. Marcelo Vela of the Baylor Clinic, Houston, noted that earlier studies have shown that this therapy increases basal pressure of the lower esophageal sphincter (LES). "Because the main mechanism for reflux is transient LES relaxations [TLESRs], particularly with small hernias as in your patients, do you have any data on TLESRs?" he asked.

"No, LES pressure was not an endpoint in these studies," Dr. Soffer replied. "Initially, we thought that this [basal pressure] is the main mechanism; as we are learning more, it is probably not going to be the main mechanism. We are looking at others, including TLESRs. ... We don’t have data yet."

Dr. Joel Richter, of the University of South Florida, Tampa, wondered whether patients experienced any of the oft-feared complications of antireflux surgery, such as bloating, diarrhea, and dysphagia.

"There were only two cases of dysphagia, and they basically resolved on their own," Dr. Soffer replied. "We didn’t see any of the symptoms that you see with postsurgical therapy. ... The intervention really should not result in the symptoms that come after standard surgical care."

Dr. Richter also requested more information on hiatal hernia repairs undertaken in some patients. "If you had a hernia repair, how do you know what part of the success was related to the hernia repair versus the stimulation?" he asked.

Thirteen patients had a hernia repair, with technique left up to the treating physician, Dr. Soffer replied. "We will look separately, when we complete that phase, at those that had the hernia repair versus those that did not."

"Was there a bit of a trend toward any improvement depending on your hernia size?" Dr. Richard McCallam of Texas Tech University in El Paso asked, while also noting that patients with hernias measuring 3 cm or more were excluded.

There were too few patients to assess trends, according to Dr. Soffer. "We tried not to take patients who had particularly severe disease at the beginning," he added. "The 3-cm hernia repair will be the one perhaps that will need to be looked at more carefully. This is a more sustained hernia situation as compared to the 1- and 2-cm [ones]."

The investigators enrolled GERD patients in the study who had a GERD health-related quality of life score of 20 or higher when not taking PPIs, and who had at least a partial response to these agents. They were required to have a basal LES end-expiratory pressure of at least 5 mm Hg, and to have a pH below 4.0 for more than 5% of the time on 24-hour esophageal pH monitoring.

The patients’ mean age was 50 years, and 18 of them were male, according to Dr. Soffer.

The main results showed a sustained reduction in esophageal acid exposure; the percentage of time at pH less than 4.0 was 10.3% at baseline, compared with 3.7% at 3 months (P less than .01), and 4.6% at 6 months (P less than .01).

There was also a sustained improvement in symptoms as assessed from GERD health-related quality of life; the score was 15 at baseline on PPIs and 31 at baseline off PPIs. These figures compared with a score of 4 at 3 months and 5 at 6 months.

Large proportions of patients met criteria for successful treatment at 6 months: 65% had control of esophageal acid exposure (either normalization or a greater than one-half reduction), 86% had control of GERD symptoms compared with level without medical therapy (a greater than 50% improvement versus baseline level not on PPIs), and 76% had control of GERD symptoms compared with level with medical therapy (any improvement of symptoms versus baseline level on PPIs).

Quality of life as assessed with the Short Form-12 showed improvement at 6 months in physical health scores compared with those measured at baseline while off PPIs.

Patients also had significant reductions from the level at baseline off PPIs at both 3 and 6 months in the median percentages of daily diary days with heartburn and with regurgitation symptoms.

Analyses of daytime versus nighttime symptoms are still ongoing, according to Dr. Soffer.

Stimulation therapy was also associated with a dramatic reduction in PPI use. Whereas only 10% of patients did not use any of these agents at baseline, 89% were not using any at 6 months.

There were just two serious adverse events: a procedure-related trocar perforation of the small bowel during laparoscopy (the stimulation device was prophylactically removed and there was resolution after surgical repair) and atrioventricular nodal reentrant tachycardia unrelated to the device or procedure.

There were no device-related serious adverse events. There were 35 nonserious events possibly or probably related to the device or procedure.

Dr. Soffer is a consultant for and shareholder in EndoStim*. The study was supported by EndoStim.

*Correction, 2/4/2014: An earlier version of the story misstated Dr. Soffer's conflicts of interest.

SAN DIEGO – Electrical stimulation therapy of the lower esophageal sphincter is effective for treating refractory gastroesophageal reflux disease, according to interim results from a trial presented at the annual meeting of the American College of Gastroenterology.

A total of 32 patients underwent implantation of a pair of electrodes in the muscular layer of the gastroesophageal junction. The electrodes were connected to a pulse generator in the abdomen that delivered intermittent stimulation.

Six months later, the patients had a sustained, more than one-half reduction from baseline in exposure of the esophagus to acid and a two-thirds reduction in symptoms, reported first author Dr. Edy E. Soffer at the meeting.

Additionally, whereas most of the patients had been taking proton pump inhibitors (PPIs) at baseline, only about 1 in 10 were doing so at 6 months. None experienced any device-related adverse events.

The findings support the effectiveness and safety of electrical stimulation therapy in this population, according to Dr. Soffer, who is a professor in the gastroenterology division, Keck School of Medicine, University of Southern California, Los Angeles.

"Currently, there are ongoing studies, and there will be future sham-controlled studies that should clarify further the role of this intervention in the treatment of GERD [gastroesophageal reflux disease] and its mechanism of action," he noted.

Session attendee Dr. Marcelo Vela of the Baylor Clinic, Houston, noted that earlier studies have shown that this therapy increases basal pressure of the lower esophageal sphincter (LES). "Because the main mechanism for reflux is transient LES relaxations [TLESRs], particularly with small hernias as in your patients, do you have any data on TLESRs?" he asked.

"No, LES pressure was not an endpoint in these studies," Dr. Soffer replied. "Initially, we thought that this [basal pressure] is the main mechanism; as we are learning more, it is probably not going to be the main mechanism. We are looking at others, including TLESRs. ... We don’t have data yet."

Dr. Joel Richter, of the University of South Florida, Tampa, wondered whether patients experienced any of the oft-feared complications of antireflux surgery, such as bloating, diarrhea, and dysphagia.

"There were only two cases of dysphagia, and they basically resolved on their own," Dr. Soffer replied. "We didn’t see any of the symptoms that you see with postsurgical therapy. ... The intervention really should not result in the symptoms that come after standard surgical care."

Dr. Richter also requested more information on hiatal hernia repairs undertaken in some patients. "If you had a hernia repair, how do you know what part of the success was related to the hernia repair versus the stimulation?" he asked.

Thirteen patients had a hernia repair, with technique left up to the treating physician, Dr. Soffer replied. "We will look separately, when we complete that phase, at those that had the hernia repair versus those that did not."

"Was there a bit of a trend toward any improvement depending on your hernia size?" Dr. Richard McCallam of Texas Tech University in El Paso asked, while also noting that patients with hernias measuring 3 cm or more were excluded.

There were too few patients to assess trends, according to Dr. Soffer. "We tried not to take patients who had particularly severe disease at the beginning," he added. "The 3-cm hernia repair will be the one perhaps that will need to be looked at more carefully. This is a more sustained hernia situation as compared to the 1- and 2-cm [ones]."

The investigators enrolled GERD patients in the study who had a GERD health-related quality of life score of 20 or higher when not taking PPIs, and who had at least a partial response to these agents. They were required to have a basal LES end-expiratory pressure of at least 5 mm Hg, and to have a pH below 4.0 for more than 5% of the time on 24-hour esophageal pH monitoring.

The patients’ mean age was 50 years, and 18 of them were male, according to Dr. Soffer.

The main results showed a sustained reduction in esophageal acid exposure; the percentage of time at pH less than 4.0 was 10.3% at baseline, compared with 3.7% at 3 months (P less than .01), and 4.6% at 6 months (P less than .01).

There was also a sustained improvement in symptoms as assessed from GERD health-related quality of life; the score was 15 at baseline on PPIs and 31 at baseline off PPIs. These figures compared with a score of 4 at 3 months and 5 at 6 months.

Large proportions of patients met criteria for successful treatment at 6 months: 65% had control of esophageal acid exposure (either normalization or a greater than one-half reduction), 86% had control of GERD symptoms compared with level without medical therapy (a greater than 50% improvement versus baseline level not on PPIs), and 76% had control of GERD symptoms compared with level with medical therapy (any improvement of symptoms versus baseline level on PPIs).

Quality of life as assessed with the Short Form-12 showed improvement at 6 months in physical health scores compared with those measured at baseline while off PPIs.

Patients also had significant reductions from the level at baseline off PPIs at both 3 and 6 months in the median percentages of daily diary days with heartburn and with regurgitation symptoms.

Analyses of daytime versus nighttime symptoms are still ongoing, according to Dr. Soffer.

Stimulation therapy was also associated with a dramatic reduction in PPI use. Whereas only 10% of patients did not use any of these agents at baseline, 89% were not using any at 6 months.

There were just two serious adverse events: a procedure-related trocar perforation of the small bowel during laparoscopy (the stimulation device was prophylactically removed and there was resolution after surgical repair) and atrioventricular nodal reentrant tachycardia unrelated to the device or procedure.

There were no device-related serious adverse events. There were 35 nonserious events possibly or probably related to the device or procedure.

Dr. Soffer is a consultant for and shareholder in EndoStim*. The study was supported by EndoStim.

*Correction, 2/4/2014: An earlier version of the story misstated Dr. Soffer's conflicts of interest.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Current thiopurine use is an independent risk factor for nonmelanoma skin cancer in patients with ulcerative colitis, according to a study reported at the annual meeting of the American College of Gastroenterology.

In the retrospective cohort study of more than 14,000 U.S. veterans with ulcerative colitis, current users of thiopurines were more than twice as likely as never users to receive a diagnosis of squamous or basal cell skin cancer. The excess risk, however, disappeared after stopping thiopurines.

"It is crucial to educate physicians and patients about the risk of nonmelanoma skin cancer and possible preventive measures," asserted Dr. Ali Abbas, an internal medicine resident at * University of Florida, Gainesville.

Session comoderator Dr. Stephen B. Hanauer of the University of Chicago noted, "The current quality measures in [inflammatory bowel disease] include a number of measures related to biologic therapy – immunization/vaccination, [tuberculosis] testing, etc. ... Do you believe that yearly skin examination should be added? Is there enough evidence that this should be added to the quality indicators?"

"I think now we have enough evidence to recommend regular skin examination for those on long-term thiopurines," Dr. Abbas replied, while adding that the reversibility of risk after stopping remains controversial.

Dr. Hanauer further noted that number of health care visits also predicted nonmelanoma skin cancer risk. "I would suspect that, while patients are on thiopurines, they are getting more intensive visits, so can you dissociate those factors?"

Multivariate analyses took into account the number of visits, according to Dr. Abbas. "Even after exclusion of this confounding effect, we had a two times increase of the risk," he said. "If you compare our hazard ratio with previously reported hazard ratios, it’s lower – most of them reported were 4 to 5. So I am assuming that we kind of excluded the effect of the detection bias and we present a more independent effect of thiopurines on risk of nonmelanoma skin cancer."

"Do you know what the lag time would be then from exposure to the development of a nonmelanoma? So is it biologically plausible to understand that this would be reversible in patients who stop therapy?" asked Dr. David T. Rubin, codirector of the inflammatory bowel disease center at the University of Chicago, the other session comoderator.

The investigators did not calculate lag time, Dr. Abbas replied. "The biological origin is just the interaction between the UV [ultraviolet] radiation on the skin and the damage that the thiopurine causes to the DNA will prevent the repair. So from a biological point of view, I think it’s understandable to conclude that, once the insult to the DNA or the repair mechanism is gone, the UV radiation effect will also be low."

"Well, I think there is another biologic plausibility," Dr. Hanauer suggested, "which is the potential for viral infections such as [human papillomavirus] contributing to skin cancers, and the known effect of thiopurines on viruses. So certainly, UV is a very strong association, but we are also familiar with individuals who have skin warts."

"You do need to understand lag time between exposure and subsequent neoplasia before you conclude that when you are off therapy, you don’t need screening anymore," Dr. Rubin said.

Upcoming analyses will stratify patients according to the location of skin cancer, for example, looking at anogenital skin cancers separately, Dr. Abbas replied.

In the study, the investigators reviewed pharmacy benefits records for 14,527 veterans with an ulcerative colitis diagnosis who were seen in the Veterans Affairs health care system between 2001 and 2011.

They were 59 years old on average at baseline; 94% were male and 77% were white. Their median follow-up was 8.1 years, according to Dr. Abbas.

Overall, 23% of the patients used thiopurines, for a median of 1.6 years during follow-up, and the median duration of follow-up after stopping these medications was 3.6 years. The median duration of follow-up among thiopurine-unexposed patients was 6.7 years.

Main results showed that the incidence of nonmelanoma skin cancer was 3.7 per 1,000 person-years among unexposed patients, 8.4 per 1,000 person-years during thiopurine use, and 3.0 per 1,000 person-years after stopping thiopurines.

In a multivariate model, patients had a significantly higher risk of nonmelanoma skin cancer while taking thiopurines when compared with never-users (hazard ratio, 2.1). There also was a nonsignificant trend toward reduced risk after stopping, as compared with never users (0.7).

Other factors associated with higher risk included older age, male sex, white race/ethnicity, living in zones with high UV exposure, and more frequent use of the VA health care system.

In stratified analyses, the incidence of nonmelanoma skin cancer during thiopurine use increased with patient age from younger than 40 years to 40-65 years to older than 65 years (0.6, 9.1, and 12.2 per 1,000 person-years); was greater among patients living in high-UV zones versus low- or medium-UV zones (10.3 vs. 6.0 per 1,000 person-years); and increased with number of VA visits annually from fewer than six, to 6-12, and then more than 12 (1.2, 9.4, and 12.3 per 1,000 person-years).

Finally, the rate rose with the cumulative duration of exposure to thiopurines. It increased steadily during the first 2 years of use, stabilized through the fourth year of use, and rose sharply in the fifth year of use to 13.6 per 1,000 person-years.

Dr. Abbas disclosed no relevant conflicts of interest.

*Correction 12/10/13: A previous version of this article incorrectly reported Dr. Ali Abbas' university affiliation. This version has been updated.

SAN DIEGO – Current thiopurine use is an independent risk factor for nonmelanoma skin cancer in patients with ulcerative colitis, according to a study reported at the annual meeting of the American College of Gastroenterology.

In the retrospective cohort study of more than 14,000 U.S. veterans with ulcerative colitis, current users of thiopurines were more than twice as likely as never users to receive a diagnosis of squamous or basal cell skin cancer. The excess risk, however, disappeared after stopping thiopurines.

"It is crucial to educate physicians and patients about the risk of nonmelanoma skin cancer and possible preventive measures," asserted Dr. Ali Abbas, an internal medicine resident at * University of Florida, Gainesville.

Session comoderator Dr. Stephen B. Hanauer of the University of Chicago noted, "The current quality measures in [inflammatory bowel disease] include a number of measures related to biologic therapy – immunization/vaccination, [tuberculosis] testing, etc. ... Do you believe that yearly skin examination should be added? Is there enough evidence that this should be added to the quality indicators?"

"I think now we have enough evidence to recommend regular skin examination for those on long-term thiopurines," Dr. Abbas replied, while adding that the reversibility of risk after stopping remains controversial.

Dr. Hanauer further noted that number of health care visits also predicted nonmelanoma skin cancer risk. "I would suspect that, while patients are on thiopurines, they are getting more intensive visits, so can you dissociate those factors?"

Multivariate analyses took into account the number of visits, according to Dr. Abbas. "Even after exclusion of this confounding effect, we had a two times increase of the risk," he said. "If you compare our hazard ratio with previously reported hazard ratios, it’s lower – most of them reported were 4 to 5. So I am assuming that we kind of excluded the effect of the detection bias and we present a more independent effect of thiopurines on risk of nonmelanoma skin cancer."

"Do you know what the lag time would be then from exposure to the development of a nonmelanoma? So is it biologically plausible to understand that this would be reversible in patients who stop therapy?" asked Dr. David T. Rubin, codirector of the inflammatory bowel disease center at the University of Chicago, the other session comoderator.

The investigators did not calculate lag time, Dr. Abbas replied. "The biological origin is just the interaction between the UV [ultraviolet] radiation on the skin and the damage that the thiopurine causes to the DNA will prevent the repair. So from a biological point of view, I think it’s understandable to conclude that, once the insult to the DNA or the repair mechanism is gone, the UV radiation effect will also be low."

"Well, I think there is another biologic plausibility," Dr. Hanauer suggested, "which is the potential for viral infections such as [human papillomavirus] contributing to skin cancers, and the known effect of thiopurines on viruses. So certainly, UV is a very strong association, but we are also familiar with individuals who have skin warts."

"You do need to understand lag time between exposure and subsequent neoplasia before you conclude that when you are off therapy, you don’t need screening anymore," Dr. Rubin said.

Upcoming analyses will stratify patients according to the location of skin cancer, for example, looking at anogenital skin cancers separately, Dr. Abbas replied.

In the study, the investigators reviewed pharmacy benefits records for 14,527 veterans with an ulcerative colitis diagnosis who were seen in the Veterans Affairs health care system between 2001 and 2011.

They were 59 years old on average at baseline; 94% were male and 77% were white. Their median follow-up was 8.1 years, according to Dr. Abbas.

Overall, 23% of the patients used thiopurines, for a median of 1.6 years during follow-up, and the median duration of follow-up after stopping these medications was 3.6 years. The median duration of follow-up among thiopurine-unexposed patients was 6.7 years.

Main results showed that the incidence of nonmelanoma skin cancer was 3.7 per 1,000 person-years among unexposed patients, 8.4 per 1,000 person-years during thiopurine use, and 3.0 per 1,000 person-years after stopping thiopurines.

In a multivariate model, patients had a significantly higher risk of nonmelanoma skin cancer while taking thiopurines when compared with never-users (hazard ratio, 2.1). There also was a nonsignificant trend toward reduced risk after stopping, as compared with never users (0.7).

Other factors associated with higher risk included older age, male sex, white race/ethnicity, living in zones with high UV exposure, and more frequent use of the VA health care system.

In stratified analyses, the incidence of nonmelanoma skin cancer during thiopurine use increased with patient age from younger than 40 years to 40-65 years to older than 65 years (0.6, 9.1, and 12.2 per 1,000 person-years); was greater among patients living in high-UV zones versus low- or medium-UV zones (10.3 vs. 6.0 per 1,000 person-years); and increased with number of VA visits annually from fewer than six, to 6-12, and then more than 12 (1.2, 9.4, and 12.3 per 1,000 person-years).

Finally, the rate rose with the cumulative duration of exposure to thiopurines. It increased steadily during the first 2 years of use, stabilized through the fourth year of use, and rose sharply in the fifth year of use to 13.6 per 1,000 person-years.

Dr. Abbas disclosed no relevant conflicts of interest.

*Correction 12/10/13: A previous version of this article incorrectly reported Dr. Ali Abbas' university affiliation. This version has been updated.

SAN DIEGO – Current thiopurine use is an independent risk factor for nonmelanoma skin cancer in patients with ulcerative colitis, according to a study reported at the annual meeting of the American College of Gastroenterology.

In the retrospective cohort study of more than 14,000 U.S. veterans with ulcerative colitis, current users of thiopurines were more than twice as likely as never users to receive a diagnosis of squamous or basal cell skin cancer. The excess risk, however, disappeared after stopping thiopurines.

"It is crucial to educate physicians and patients about the risk of nonmelanoma skin cancer and possible preventive measures," asserted Dr. Ali Abbas, an internal medicine resident at * University of Florida, Gainesville.

Session comoderator Dr. Stephen B. Hanauer of the University of Chicago noted, "The current quality measures in [inflammatory bowel disease] include a number of measures related to biologic therapy – immunization/vaccination, [tuberculosis] testing, etc. ... Do you believe that yearly skin examination should be added? Is there enough evidence that this should be added to the quality indicators?"

"I think now we have enough evidence to recommend regular skin examination for those on long-term thiopurines," Dr. Abbas replied, while adding that the reversibility of risk after stopping remains controversial.

Dr. Hanauer further noted that number of health care visits also predicted nonmelanoma skin cancer risk. "I would suspect that, while patients are on thiopurines, they are getting more intensive visits, so can you dissociate those factors?"

Multivariate analyses took into account the number of visits, according to Dr. Abbas. "Even after exclusion of this confounding effect, we had a two times increase of the risk," he said. "If you compare our hazard ratio with previously reported hazard ratios, it’s lower – most of them reported were 4 to 5. So I am assuming that we kind of excluded the effect of the detection bias and we present a more independent effect of thiopurines on risk of nonmelanoma skin cancer."

"Do you know what the lag time would be then from exposure to the development of a nonmelanoma? So is it biologically plausible to understand that this would be reversible in patients who stop therapy?" asked Dr. David T. Rubin, codirector of the inflammatory bowel disease center at the University of Chicago, the other session comoderator.

The investigators did not calculate lag time, Dr. Abbas replied. "The biological origin is just the interaction between the UV [ultraviolet] radiation on the skin and the damage that the thiopurine causes to the DNA will prevent the repair. So from a biological point of view, I think it’s understandable to conclude that, once the insult to the DNA or the repair mechanism is gone, the UV radiation effect will also be low."

"Well, I think there is another biologic plausibility," Dr. Hanauer suggested, "which is the potential for viral infections such as [human papillomavirus] contributing to skin cancers, and the known effect of thiopurines on viruses. So certainly, UV is a very strong association, but we are also familiar with individuals who have skin warts."

"You do need to understand lag time between exposure and subsequent neoplasia before you conclude that when you are off therapy, you don’t need screening anymore," Dr. Rubin said.

Upcoming analyses will stratify patients according to the location of skin cancer, for example, looking at anogenital skin cancers separately, Dr. Abbas replied.

In the study, the investigators reviewed pharmacy benefits records for 14,527 veterans with an ulcerative colitis diagnosis who were seen in the Veterans Affairs health care system between 2001 and 2011.

They were 59 years old on average at baseline; 94% were male and 77% were white. Their median follow-up was 8.1 years, according to Dr. Abbas.

Overall, 23% of the patients used thiopurines, for a median of 1.6 years during follow-up, and the median duration of follow-up after stopping these medications was 3.6 years. The median duration of follow-up among thiopurine-unexposed patients was 6.7 years.

Main results showed that the incidence of nonmelanoma skin cancer was 3.7 per 1,000 person-years among unexposed patients, 8.4 per 1,000 person-years during thiopurine use, and 3.0 per 1,000 person-years after stopping thiopurines.

In a multivariate model, patients had a significantly higher risk of nonmelanoma skin cancer while taking thiopurines when compared with never-users (hazard ratio, 2.1). There also was a nonsignificant trend toward reduced risk after stopping, as compared with never users (0.7).

Other factors associated with higher risk included older age, male sex, white race/ethnicity, living in zones with high UV exposure, and more frequent use of the VA health care system.

In stratified analyses, the incidence of nonmelanoma skin cancer during thiopurine use increased with patient age from younger than 40 years to 40-65 years to older than 65 years (0.6, 9.1, and 12.2 per 1,000 person-years); was greater among patients living in high-UV zones versus low- or medium-UV zones (10.3 vs. 6.0 per 1,000 person-years); and increased with number of VA visits annually from fewer than six, to 6-12, and then more than 12 (1.2, 9.4, and 12.3 per 1,000 person-years).

Finally, the rate rose with the cumulative duration of exposure to thiopurines. It increased steadily during the first 2 years of use, stabilized through the fourth year of use, and rose sharply in the fifth year of use to 13.6 per 1,000 person-years.

Dr. Abbas disclosed no relevant conflicts of interest.

*Correction 12/10/13: A previous version of this article incorrectly reported Dr. Ali Abbas' university affiliation. This version has been updated.

SAN DIEGO – An optimized colonoscopy method dramatically reduces colorectal cancer diagnoses and deaths, finds a study reported at the annual meeting of the American College of Gastroenterology.

Dr. Sudha Xirasagar of the University of South Carolina in Columbia, reported the experience of the Community Endoscopy Group in using an optimized colonoscopy protocol that includes enhanced efforts, through staffing and protocol modifications, to ensure adequate bowel preparation and polyp identification and removal.

With a follow-up of nearly 5 years, the rate of colorectal cancer in the more than 16,000 patients screened was reduced by 83% and the rate of colorectal cancer mortality was reduced by 89%, relative to what was expected based on data for the general population.

"This study documents the highest-ever colorectal cancer incidence reduction and mortality reduction in a community-based colonoscopy series," Dr. Xirasagar noted.

"Excellent colorectal cancer prevention can be achieved by implementing a protocol that focuses primarily on quality. Colorectal cancer is a preventable disease for 80%-90% of the U.S. population," she maintained.

A session attendee noted that withdrawal time is an important quality indicator in colonoscopy and asked whether she had any data on that measure.

"The total procedure time in the lowest quartile of time was 17 minutes, and the withdrawal time within that was 4.8 minutes," Dr. Xirasagar replied. "Whereas the highest quartile of total time was about 28 minutes."

Giving some background to the study, she noted, "In theory, colonoscopy should prevent 80%-90% of colorectal cancers if we assume that polyps growing over 10-20 years cause colorectal cancer. In reality, as we know, colonoscopy in community-based practice has not lived up to its promise."

Her group set out to prevent all colorectal cancers, with a viewpoint that quality is the most importance endoscopy practice driver, according to Dr. Xirasagar.

They developed a unique colonoscopy protocol that 57 of 59 their group endoscopists use. It entails a personal phone call with prep instructions 2 days before the procedure; administration of propofol sedation by nurse anesthetists; use of two individuals to separately guide the endoscope shaft and head; slow insertion and circumferential withdrawal, with polyp search and removal during both phases; viewing of the video screen and active participation by all of three or four people in the endoscopy room; and referral of patients with large, vascular, or invasive polyps for surgical excision.

Analyses were based on 16,315 patients aged 30-89 years who underwent optimized colonoscopy screening between 2001 and 2008 and had a complete procedure, did not have colorectal cancer at a prior or their first colonoscopy, did not have surgery for a polyp or mass at their first colonoscopy, and did not have polyps measuring 3 cm or more that were sessile or flat.

The patients’ outcomes were ascertained by linking their records to those of a state cancer registry and a vital records registry.

On average, the patients were 58 years old at baseline; 53% were female and 49% were black, according to Dr. Xirasagar, who disclosed no conflicts of interest related to the research. Colonoscopy identified adenomas in 31% of the patients and advanced adenomas in 5%.

After a mean follow-up of 4.8 years, the total number of colorectal cancers expected was 104 based on data for the South Carolina general population, but the total number observed was just 18.

The difference translated to a standardized incidence ratio of 0.17, corresponding to an 83% reduction in incidence with optimized colonoscopy.

Dr. Xirasagar noted that there was considerable background screening going on in the general population during the study period, with 32% of eligible patients undergoing colonoscopy alone. "So one way of thinking is that 104 represents an underestimate of the expected cases in the screening-naive population," she said.

In additional findings, 36 colorectal cancer deaths were expected in the optimized colonoscopy cohort, but only 4 were observed.

This difference translated to a standardized mortality ratio of 0.11, corresponding to an 89% reduction in deaths from this disease with optimized colonoscopy.

The 18 interval colorectal cancers diagnosed in the optimized colonoscopy cohort were roughly equally divided between black and white patients, according to Dr. Xirasagar. Nine were diagnosed at surveillance colonoscopy, half were in the right colon, and three had metastasized at the time of diagnosis.

During the same study period, the observed and expected incidences of lung cancer – used as a control – did not differ significantly in the optimized colonoscopy cohort.

"One of the points this makes is that our study cohort was no more or no less healthy than the general population," she said.

SAN DIEGO – An optimized colonoscopy method dramatically reduces colorectal cancer diagnoses and deaths, finds a study reported at the annual meeting of the American College of Gastroenterology.

Dr. Sudha Xirasagar of the University of South Carolina in Columbia, reported the experience of the Community Endoscopy Group in using an optimized colonoscopy protocol that includes enhanced efforts, through staffing and protocol modifications, to ensure adequate bowel preparation and polyp identification and removal.

With a follow-up of nearly 5 years, the rate of colorectal cancer in the more than 16,000 patients screened was reduced by 83% and the rate of colorectal cancer mortality was reduced by 89%, relative to what was expected based on data for the general population.

"This study documents the highest-ever colorectal cancer incidence reduction and mortality reduction in a community-based colonoscopy series," Dr. Xirasagar noted.

"Excellent colorectal cancer prevention can be achieved by implementing a protocol that focuses primarily on quality. Colorectal cancer is a preventable disease for 80%-90% of the U.S. population," she maintained.

A session attendee noted that withdrawal time is an important quality indicator in colonoscopy and asked whether she had any data on that measure.

"The total procedure time in the lowest quartile of time was 17 minutes, and the withdrawal time within that was 4.8 minutes," Dr. Xirasagar replied. "Whereas the highest quartile of total time was about 28 minutes."

Giving some background to the study, she noted, "In theory, colonoscopy should prevent 80%-90% of colorectal cancers if we assume that polyps growing over 10-20 years cause colorectal cancer. In reality, as we know, colonoscopy in community-based practice has not lived up to its promise."

Her group set out to prevent all colorectal cancers, with a viewpoint that quality is the most importance endoscopy practice driver, according to Dr. Xirasagar.

They developed a unique colonoscopy protocol that 57 of 59 their group endoscopists use. It entails a personal phone call with prep instructions 2 days before the procedure; administration of propofol sedation by nurse anesthetists; use of two individuals to separately guide the endoscope shaft and head; slow insertion and circumferential withdrawal, with polyp search and removal during both phases; viewing of the video screen and active participation by all of three or four people in the endoscopy room; and referral of patients with large, vascular, or invasive polyps for surgical excision.

Analyses were based on 16,315 patients aged 30-89 years who underwent optimized colonoscopy screening between 2001 and 2008 and had a complete procedure, did not have colorectal cancer at a prior or their first colonoscopy, did not have surgery for a polyp or mass at their first colonoscopy, and did not have polyps measuring 3 cm or more that were sessile or flat.

The patients’ outcomes were ascertained by linking their records to those of a state cancer registry and a vital records registry.

On average, the patients were 58 years old at baseline; 53% were female and 49% were black, according to Dr. Xirasagar, who disclosed no conflicts of interest related to the research. Colonoscopy identified adenomas in 31% of the patients and advanced adenomas in 5%.

After a mean follow-up of 4.8 years, the total number of colorectal cancers expected was 104 based on data for the South Carolina general population, but the total number observed was just 18.

The difference translated to a standardized incidence ratio of 0.17, corresponding to an 83% reduction in incidence with optimized colonoscopy.

Dr. Xirasagar noted that there was considerable background screening going on in the general population during the study period, with 32% of eligible patients undergoing colonoscopy alone. "So one way of thinking is that 104 represents an underestimate of the expected cases in the screening-naive population," she said.

In additional findings, 36 colorectal cancer deaths were expected in the optimized colonoscopy cohort, but only 4 were observed.

This difference translated to a standardized mortality ratio of 0.11, corresponding to an 89% reduction in deaths from this disease with optimized colonoscopy.

The 18 interval colorectal cancers diagnosed in the optimized colonoscopy cohort were roughly equally divided between black and white patients, according to Dr. Xirasagar. Nine were diagnosed at surveillance colonoscopy, half were in the right colon, and three had metastasized at the time of diagnosis.

During the same study period, the observed and expected incidences of lung cancer – used as a control – did not differ significantly in the optimized colonoscopy cohort.

"One of the points this makes is that our study cohort was no more or no less healthy than the general population," she said.

SAN DIEGO – An optimized colonoscopy method dramatically reduces colorectal cancer diagnoses and deaths, finds a study reported at the annual meeting of the American College of Gastroenterology.

Dr. Sudha Xirasagar of the University of South Carolina in Columbia, reported the experience of the Community Endoscopy Group in using an optimized colonoscopy protocol that includes enhanced efforts, through staffing and protocol modifications, to ensure adequate bowel preparation and polyp identification and removal.

With a follow-up of nearly 5 years, the rate of colorectal cancer in the more than 16,000 patients screened was reduced by 83% and the rate of colorectal cancer mortality was reduced by 89%, relative to what was expected based on data for the general population.

"This study documents the highest-ever colorectal cancer incidence reduction and mortality reduction in a community-based colonoscopy series," Dr. Xirasagar noted.

"Excellent colorectal cancer prevention can be achieved by implementing a protocol that focuses primarily on quality. Colorectal cancer is a preventable disease for 80%-90% of the U.S. population," she maintained.

A session attendee noted that withdrawal time is an important quality indicator in colonoscopy and asked whether she had any data on that measure.

"The total procedure time in the lowest quartile of time was 17 minutes, and the withdrawal time within that was 4.8 minutes," Dr. Xirasagar replied. "Whereas the highest quartile of total time was about 28 minutes."

Giving some background to the study, she noted, "In theory, colonoscopy should prevent 80%-90% of colorectal cancers if we assume that polyps growing over 10-20 years cause colorectal cancer. In reality, as we know, colonoscopy in community-based practice has not lived up to its promise."

Her group set out to prevent all colorectal cancers, with a viewpoint that quality is the most importance endoscopy practice driver, according to Dr. Xirasagar.

They developed a unique colonoscopy protocol that 57 of 59 their group endoscopists use. It entails a personal phone call with prep instructions 2 days before the procedure; administration of propofol sedation by nurse anesthetists; use of two individuals to separately guide the endoscope shaft and head; slow insertion and circumferential withdrawal, with polyp search and removal during both phases; viewing of the video screen and active participation by all of three or four people in the endoscopy room; and referral of patients with large, vascular, or invasive polyps for surgical excision.

Analyses were based on 16,315 patients aged 30-89 years who underwent optimized colonoscopy screening between 2001 and 2008 and had a complete procedure, did not have colorectal cancer at a prior or their first colonoscopy, did not have surgery for a polyp or mass at their first colonoscopy, and did not have polyps measuring 3 cm or more that were sessile or flat.

The patients’ outcomes were ascertained by linking their records to those of a state cancer registry and a vital records registry.

On average, the patients were 58 years old at baseline; 53% were female and 49% were black, according to Dr. Xirasagar, who disclosed no conflicts of interest related to the research. Colonoscopy identified adenomas in 31% of the patients and advanced adenomas in 5%.

After a mean follow-up of 4.8 years, the total number of colorectal cancers expected was 104 based on data for the South Carolina general population, but the total number observed was just 18.

The difference translated to a standardized incidence ratio of 0.17, corresponding to an 83% reduction in incidence with optimized colonoscopy.

Dr. Xirasagar noted that there was considerable background screening going on in the general population during the study period, with 32% of eligible patients undergoing colonoscopy alone. "So one way of thinking is that 104 represents an underestimate of the expected cases in the screening-naive population," she said.

In additional findings, 36 colorectal cancer deaths were expected in the optimized colonoscopy cohort, but only 4 were observed.

This difference translated to a standardized mortality ratio of 0.11, corresponding to an 89% reduction in deaths from this disease with optimized colonoscopy.

The 18 interval colorectal cancers diagnosed in the optimized colonoscopy cohort were roughly equally divided between black and white patients, according to Dr. Xirasagar. Nine were diagnosed at surveillance colonoscopy, half were in the right colon, and three had metastasized at the time of diagnosis.

During the same study period, the observed and expected incidences of lung cancer – used as a control – did not differ significantly in the optimized colonoscopy cohort.

"One of the points this makes is that our study cohort was no more or no less healthy than the general population," she said.

SAN DIEGO – Fecal microbiota transplantation is effective and safe for treating Clostridium difficile infection in immunocompromised patients, according to a retrospective study of 66 patients treated in the United States and Canada.

The final cure rate after one or two fecal microbiota transplantation (FMT) procedures was 89%, first author Dr. Chioma Ihunnah reported at the annual meeting of the American College of Gastroenterology.

There were no infectious complications, but about 10% of patients with inflammatory bowel disease (IBD) had a flare. One patient with severe C. difficile infection died as a result of aspiration during the procedure, but there were no deaths directly related to the fecal microbiota.

"This series demonstrates the effective use of fecal microbiota transplantation for C. diff infection in immunocompromised patients. The rate of cure observed in this study is similar to rates observed in similar studies of immunocompetent patients," said Dr. Ihunnah, a second-year resident in internal medicine at Brown University in Providence, R.I.

"Prospective studies of FMT in immunocompromised patients are needed to confirm efficacy and safety in this population. Additionally, the creation of a national registry for monitoring short- and long-term adverse events after FMT would better provide understanding of patient characteristics that may ultimately correlate with safety and efficacy of FMT," she added.

Session attendee Dr. Samir Shah, also of Brown University, said, "I am curious. There are no guidelines for what we do with our IBD patients with C. diff as far as their medicine. Did you have any protocols to continue medicines or stop medicines, or was it center specific?"

Continuation of antibiotics appeared largely center specific, although analyses are still ongoing, Dr. Ihunnah replied. "The IBD-specific medications were continued, to our knowledge. It was limited to what [data] the centers sent us, but to our knowledge, they were all continued."

In a related press briefing, Dr. Colleen R. Kelly, a study coauthor and a clinical assistant professor at Brown, said that although FMT generally appears to be safe, there have been concerns that complications are underreported.

"We focused on immunocompromised patients because our feeling was that if anybody was going to have a problem with getting an infection or another problem from FMT, that it would be this particular group of patients," she explained, as feces are rich in microorganisms. "There were some worries that some of these very severely immunocompromised patients could get sepsis or could get very ill. And that doesn’t seem to be the case."

The patient who died had a severe C. difficile infection and experienced aspiration during sedation for FMT via colonoscopy. "It maybe brings up the idea that in sicker patients, to just carefully look at the route of administration that you choose to administer FMT and use the least invasive, safest route possible," she said.

The future appears bright for improvements in FMT, such as delivery by pill and tailoring of the material administered, according to Dr. Kelly.

"We won’t be using whole stool a few years from now," she predicted. "There are people who are looking very hard at finding what is the active ingredient, what are the key species, one or more bacteria, that we need to restore this diversity to the flora ... There are companies working on it right now, and with this kind of evidence behind it, to develop a pill that could potentially be used to treat millions of people rather than the 130 people I’ve been able to treat over the last 5 years by conventional means. I really look forward to all of these blends and formulations that are coming around the corner."

Press briefing moderator Dr. Michael E. Cox, of Mercy Medical Center in Baltimore, noted that his center has experienced some failures of FMT that appeared to occur when patients resumed antibiotic therapy. "Do you counsel your patients not to go on antibiotics for a set period of time?" he asked.

Patients receive a lot of counseling tailored at reducing inappropriate use of antibiotics and, when antibiotics are absolutely needed, those that are less likely to trigger a recurrence are selected, Dr. Kelly said. But recurrences of C. difficile infection have been rare in their experience. "I do have them take probiotics during future courses of antibiotics. There is a little bit of data that that can be protective," she noted.

Dr. Kelly cautioned against rushing to use FMT to treat conditions such as IBD, irritable bowel syndrome, and autism. "There are all these diseases where there is thought to be intestinal dysbiosis, and there is this real hope that fecal transplant is going to cure it all. And I just really throw up a big caution that we are not there with any of these other conditions at this point. And to treat those conditions with fecal transplant outside of a clinical trial, really, I don’t think, is right," she maintained.

"That probably bears repeating," commented press briefing discussant Dr. Brian E. Lacy, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H. "So if somebody came to you and said, right now, what do you think are the best indications for FMT, what would your answer be?"

"Recurrent C. difficile infection or refractory C. difficile infection – people who aren’t getting better on antibiotics," Dr. Kelly replied.

"Some would say severe C. difficile infection, but that’s another place where I’d probably say there is a yellow light of caution, because in my experience, we have treated very few patients with severe C. diff infection. They don’t appear to do as well," she continued. "They are also much more complicated; they are very sick, patients in the intensive care unit with toxic megacolon. The standard of care in these patients in 2013 is a surgical colectomy."

In the study, the investigators reviewed data collected from 16 centers performing FMT for recurrent, refractory, severe, or complicated C. difficile infection.

Analyses were restricted to immunocompromised patients who underwent the procedure and had at least 12 weeks of follow-up. Overall, 92% of the patients were adults, with a mean age of 53 years (range, 20-82 years). Sixty-two percent of the patients were men.

The reason for immunocompromise was use of immunosuppressive medications for IBD in 48% of patients, receipt of a solid organ transplant in 21%, a chronic medical condition and/or use of other immunosuppressive medication in 18%, cancer or its treatment in 9%, and HIV/AIDS in 3%.

The C. difficile infection was recurrent in 54% of cases, refractory in 12%, and severe or complicated in 34%.

The large majority of the patients (78%) underwent their FMT procedure in the outpatient setting. On average, the mean follow-up was 12 months (range, 3-51 months).

The results showed that 52 patients did not have any recurrence of C. difficile infection within 12 weeks of FMT, reported Dr. Ihunnah. Nine of the patients who had a recurrence underwent a second FMT, and seven of them did not have any additional recurrences. The final cure rate was therefore 89%.

Overall, nine patients (14%) had a serious adverse event within 12 weeks of their FMT: There were seven unplanned hospitalizations (most commonly due to a flare of IBD) and two deaths (one due to worsening of preexisting pneumonia unrelated to FMT and the one due to aspiration).

Nonserious adverse events included two cases of self-limited diarrhea in which no pathogen was identified, four cases of mild abdominal discomfort, one case of minor mucosal tear, and two cases of colectomy among patients with ulcerative colitis performed more than 100 days after FMT.

Dr. Ihunnah and Dr. Kelly disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation is effective and safe for treating Clostridium difficile infection in immunocompromised patients, according to a retrospective study of 66 patients treated in the United States and Canada.

The final cure rate after one or two fecal microbiota transplantation (FMT) procedures was 89%, first author Dr. Chioma Ihunnah reported at the annual meeting of the American College of Gastroenterology.

There were no infectious complications, but about 10% of patients with inflammatory bowel disease (IBD) had a flare. One patient with severe C. difficile infection died as a result of aspiration during the procedure, but there were no deaths directly related to the fecal microbiota.

"This series demonstrates the effective use of fecal microbiota transplantation for C. diff infection in immunocompromised patients. The rate of cure observed in this study is similar to rates observed in similar studies of immunocompetent patients," said Dr. Ihunnah, a second-year resident in internal medicine at Brown University in Providence, R.I.

"Prospective studies of FMT in immunocompromised patients are needed to confirm efficacy and safety in this population. Additionally, the creation of a national registry for monitoring short- and long-term adverse events after FMT would better provide understanding of patient characteristics that may ultimately correlate with safety and efficacy of FMT," she added.

Session attendee Dr. Samir Shah, also of Brown University, said, "I am curious. There are no guidelines for what we do with our IBD patients with C. diff as far as their medicine. Did you have any protocols to continue medicines or stop medicines, or was it center specific?"

Continuation of antibiotics appeared largely center specific, although analyses are still ongoing, Dr. Ihunnah replied. "The IBD-specific medications were continued, to our knowledge. It was limited to what [data] the centers sent us, but to our knowledge, they were all continued."

In a related press briefing, Dr. Colleen R. Kelly, a study coauthor and a clinical assistant professor at Brown, said that although FMT generally appears to be safe, there have been concerns that complications are underreported.

"We focused on immunocompromised patients because our feeling was that if anybody was going to have a problem with getting an infection or another problem from FMT, that it would be this particular group of patients," she explained, as feces are rich in microorganisms. "There were some worries that some of these very severely immunocompromised patients could get sepsis or could get very ill. And that doesn’t seem to be the case."

The patient who died had a severe C. difficile infection and experienced aspiration during sedation for FMT via colonoscopy. "It maybe brings up the idea that in sicker patients, to just carefully look at the route of administration that you choose to administer FMT and use the least invasive, safest route possible," she said.

The future appears bright for improvements in FMT, such as delivery by pill and tailoring of the material administered, according to Dr. Kelly.

"We won’t be using whole stool a few years from now," she predicted. "There are people who are looking very hard at finding what is the active ingredient, what are the key species, one or more bacteria, that we need to restore this diversity to the flora ... There are companies working on it right now, and with this kind of evidence behind it, to develop a pill that could potentially be used to treat millions of people rather than the 130 people I’ve been able to treat over the last 5 years by conventional means. I really look forward to all of these blends and formulations that are coming around the corner."

Press briefing moderator Dr. Michael E. Cox, of Mercy Medical Center in Baltimore, noted that his center has experienced some failures of FMT that appeared to occur when patients resumed antibiotic therapy. "Do you counsel your patients not to go on antibiotics for a set period of time?" he asked.

Patients receive a lot of counseling tailored at reducing inappropriate use of antibiotics and, when antibiotics are absolutely needed, those that are less likely to trigger a recurrence are selected, Dr. Kelly said. But recurrences of C. difficile infection have been rare in their experience. "I do have them take probiotics during future courses of antibiotics. There is a little bit of data that that can be protective," she noted.

Dr. Kelly cautioned against rushing to use FMT to treat conditions such as IBD, irritable bowel syndrome, and autism. "There are all these diseases where there is thought to be intestinal dysbiosis, and there is this real hope that fecal transplant is going to cure it all. And I just really throw up a big caution that we are not there with any of these other conditions at this point. And to treat those conditions with fecal transplant outside of a clinical trial, really, I don’t think, is right," she maintained.

"That probably bears repeating," commented press briefing discussant Dr. Brian E. Lacy, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H. "So if somebody came to you and said, right now, what do you think are the best indications for FMT, what would your answer be?"

"Recurrent C. difficile infection or refractory C. difficile infection – people who aren’t getting better on antibiotics," Dr. Kelly replied.

"Some would say severe C. difficile infection, but that’s another place where I’d probably say there is a yellow light of caution, because in my experience, we have treated very few patients with severe C. diff infection. They don’t appear to do as well," she continued. "They are also much more complicated; they are very sick, patients in the intensive care unit with toxic megacolon. The standard of care in these patients in 2013 is a surgical colectomy."

In the study, the investigators reviewed data collected from 16 centers performing FMT for recurrent, refractory, severe, or complicated C. difficile infection.

Analyses were restricted to immunocompromised patients who underwent the procedure and had at least 12 weeks of follow-up. Overall, 92% of the patients were adults, with a mean age of 53 years (range, 20-82 years). Sixty-two percent of the patients were men.

The reason for immunocompromise was use of immunosuppressive medications for IBD in 48% of patients, receipt of a solid organ transplant in 21%, a chronic medical condition and/or use of other immunosuppressive medication in 18%, cancer or its treatment in 9%, and HIV/AIDS in 3%.

The C. difficile infection was recurrent in 54% of cases, refractory in 12%, and severe or complicated in 34%.

The large majority of the patients (78%) underwent their FMT procedure in the outpatient setting. On average, the mean follow-up was 12 months (range, 3-51 months).

The results showed that 52 patients did not have any recurrence of C. difficile infection within 12 weeks of FMT, reported Dr. Ihunnah. Nine of the patients who had a recurrence underwent a second FMT, and seven of them did not have any additional recurrences. The final cure rate was therefore 89%.

Overall, nine patients (14%) had a serious adverse event within 12 weeks of their FMT: There were seven unplanned hospitalizations (most commonly due to a flare of IBD) and two deaths (one due to worsening of preexisting pneumonia unrelated to FMT and the one due to aspiration).

Nonserious adverse events included two cases of self-limited diarrhea in which no pathogen was identified, four cases of mild abdominal discomfort, one case of minor mucosal tear, and two cases of colectomy among patients with ulcerative colitis performed more than 100 days after FMT.

Dr. Ihunnah and Dr. Kelly disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation is effective and safe for treating Clostridium difficile infection in immunocompromised patients, according to a retrospective study of 66 patients treated in the United States and Canada.

The final cure rate after one or two fecal microbiota transplantation (FMT) procedures was 89%, first author Dr. Chioma Ihunnah reported at the annual meeting of the American College of Gastroenterology.

There were no infectious complications, but about 10% of patients with inflammatory bowel disease (IBD) had a flare. One patient with severe C. difficile infection died as a result of aspiration during the procedure, but there were no deaths directly related to the fecal microbiota.

"This series demonstrates the effective use of fecal microbiota transplantation for C. diff infection in immunocompromised patients. The rate of cure observed in this study is similar to rates observed in similar studies of immunocompetent patients," said Dr. Ihunnah, a second-year resident in internal medicine at Brown University in Providence, R.I.

"Prospective studies of FMT in immunocompromised patients are needed to confirm efficacy and safety in this population. Additionally, the creation of a national registry for monitoring short- and long-term adverse events after FMT would better provide understanding of patient characteristics that may ultimately correlate with safety and efficacy of FMT," she added.

Session attendee Dr. Samir Shah, also of Brown University, said, "I am curious. There are no guidelines for what we do with our IBD patients with C. diff as far as their medicine. Did you have any protocols to continue medicines or stop medicines, or was it center specific?"

Continuation of antibiotics appeared largely center specific, although analyses are still ongoing, Dr. Ihunnah replied. "The IBD-specific medications were continued, to our knowledge. It was limited to what [data] the centers sent us, but to our knowledge, they were all continued."

In a related press briefing, Dr. Colleen R. Kelly, a study coauthor and a clinical assistant professor at Brown, said that although FMT generally appears to be safe, there have been concerns that complications are underreported.

"We focused on immunocompromised patients because our feeling was that if anybody was going to have a problem with getting an infection or another problem from FMT, that it would be this particular group of patients," she explained, as feces are rich in microorganisms. "There were some worries that some of these very severely immunocompromised patients could get sepsis or could get very ill. And that doesn’t seem to be the case."

The patient who died had a severe C. difficile infection and experienced aspiration during sedation for FMT via colonoscopy. "It maybe brings up the idea that in sicker patients, to just carefully look at the route of administration that you choose to administer FMT and use the least invasive, safest route possible," she said.

The future appears bright for improvements in FMT, such as delivery by pill and tailoring of the material administered, according to Dr. Kelly.

"We won’t be using whole stool a few years from now," she predicted. "There are people who are looking very hard at finding what is the active ingredient, what are the key species, one or more bacteria, that we need to restore this diversity to the flora ... There are companies working on it right now, and with this kind of evidence behind it, to develop a pill that could potentially be used to treat millions of people rather than the 130 people I’ve been able to treat over the last 5 years by conventional means. I really look forward to all of these blends and formulations that are coming around the corner."

Press briefing moderator Dr. Michael E. Cox, of Mercy Medical Center in Baltimore, noted that his center has experienced some failures of FMT that appeared to occur when patients resumed antibiotic therapy. "Do you counsel your patients not to go on antibiotics for a set period of time?" he asked.

Patients receive a lot of counseling tailored at reducing inappropriate use of antibiotics and, when antibiotics are absolutely needed, those that are less likely to trigger a recurrence are selected, Dr. Kelly said. But recurrences of C. difficile infection have been rare in their experience. "I do have them take probiotics during future courses of antibiotics. There is a little bit of data that that can be protective," she noted.

Dr. Kelly cautioned against rushing to use FMT to treat conditions such as IBD, irritable bowel syndrome, and autism. "There are all these diseases where there is thought to be intestinal dysbiosis, and there is this real hope that fecal transplant is going to cure it all. And I just really throw up a big caution that we are not there with any of these other conditions at this point. And to treat those conditions with fecal transplant outside of a clinical trial, really, I don’t think, is right," she maintained.

"That probably bears repeating," commented press briefing discussant Dr. Brian E. Lacy, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H. "So if somebody came to you and said, right now, what do you think are the best indications for FMT, what would your answer be?"

"Recurrent C. difficile infection or refractory C. difficile infection – people who aren’t getting better on antibiotics," Dr. Kelly replied.

"Some would say severe C. difficile infection, but that’s another place where I’d probably say there is a yellow light of caution, because in my experience, we have treated very few patients with severe C. diff infection. They don’t appear to do as well," she continued. "They are also much more complicated; they are very sick, patients in the intensive care unit with toxic megacolon. The standard of care in these patients in 2013 is a surgical colectomy."

In the study, the investigators reviewed data collected from 16 centers performing FMT for recurrent, refractory, severe, or complicated C. difficile infection.

Analyses were restricted to immunocompromised patients who underwent the procedure and had at least 12 weeks of follow-up. Overall, 92% of the patients were adults, with a mean age of 53 years (range, 20-82 years). Sixty-two percent of the patients were men.

The reason for immunocompromise was use of immunosuppressive medications for IBD in 48% of patients, receipt of a solid organ transplant in 21%, a chronic medical condition and/or use of other immunosuppressive medication in 18%, cancer or its treatment in 9%, and HIV/AIDS in 3%.

The C. difficile infection was recurrent in 54% of cases, refractory in 12%, and severe or complicated in 34%.

The large majority of the patients (78%) underwent their FMT procedure in the outpatient setting. On average, the mean follow-up was 12 months (range, 3-51 months).

The results showed that 52 patients did not have any recurrence of C. difficile infection within 12 weeks of FMT, reported Dr. Ihunnah. Nine of the patients who had a recurrence underwent a second FMT, and seven of them did not have any additional recurrences. The final cure rate was therefore 89%.

Overall, nine patients (14%) had a serious adverse event within 12 weeks of their FMT: There were seven unplanned hospitalizations (most commonly due to a flare of IBD) and two deaths (one due to worsening of preexisting pneumonia unrelated to FMT and the one due to aspiration).

Nonserious adverse events included two cases of self-limited diarrhea in which no pathogen was identified, four cases of mild abdominal discomfort, one case of minor mucosal tear, and two cases of colectomy among patients with ulcerative colitis performed more than 100 days after FMT.

Dr. Ihunnah and Dr. Kelly disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – Fecal microbiota transplantation by colonoscopy is cost-effective when used as the initial treatment for recurrent Clostridium difficile infection, new data show.

A team led by Dr. Gauree Konijeti, a gastroenterology fellow at Massachusetts General Hospital in Boston, constructed decision analytic models of various treatment strategies in a hypothetical cohort of patients with a first, mild to moderate recurrence of C. difficile infection.

Relative to vancomycin, fecal microbiota transplantation (FMT) delivered by colonoscopy had an incremental cost-effectiveness ratio (ICER) of about $38,000 per quality-adjusted life-year gained, placing it well within the conventional willingness-to-pay threshold of $50,000, she reported at the annual meeting of the American College of Gastroenterology.

Additionally, FMT colonoscopy was more effective and less costly than both metronidazole (Flagyl) and fidaxomicin (Dificid).

However, FMT using other modes of delivery – either enema or duodenal infusion through esophagogastroduodenoscopy – was not cost-effective because of its relatively lower cure rates.

"A strategy consisting of first-line treatment with FMT colonoscopy for an initial recurrence of C. difficile appeared cost-effective at conventional willingness-to-pay thresholds," Dr. Konijeti commented.

"Guidelines should consider earlier use of FMT in the treatment of C. difficile infection, and future studies should incorporate FMT for comparative effectiveness," she recommended.

A session attendee asked, "What are your thoughts on the future of noncolonoscopic delivery methods?"

"One is if we can increase the infusion cure rates for enema and duodenal infusion, or even nasogastric infusion, those would be cost-effective. Right now they are on the order of 81%, compared to colonoscopic delivery, which is closer to the 93%-95% range," Dr. Konijeti replied.

"The other thought is that there has been a study of a fecal transplant pill that was recently presented at ID Week, where they used fresh donor feces from related donors and encapsulated a concentrated form of bacteria into these pills, and then gave about 20 pills to patients in a case series. They showed about a 100% efficacy rate, with only one recurrence in the setting of antibiotics," she said. "So I think we are in an era where we have the opportunity to deliver FMT via a variety of strategies, but we need to find more standardized ways of doing it and then optimize the efficacy."

Giving some background to the research, Dr. Konijeti noted that C. difficile infection has become increasingly challenging to manage. Emergence of the 027 strain has led to lower cure rates and higher rates of resistance. Today, up to one-third of patients have a recurrence after an initial infection, and up to two-thirds of that group go on to have yet more recurrences.

"FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence," she commented.

The investigators studied four competing treatment strategies – vancomycin, metronidazole, fidaxomicin, and FMT – for treatment of a first, mild to moderate recurrence of C. difficile infection in a hypothetical cohort of patients having a median age of 65 years.

The models used various subsequent treatments in the event of a second and third recurrence, and the time horizon was 6 months. A key assumption was that payers would be willing to pay up to $50,000 per quality-adjusted life-year gained.

Base-case results showed that FMT colonoscopy was the most cost-effective strategy relative to vancomycin, with an ICER of $38,382 per quality-adjusted life-year gained, and was much more effective than both metronidazole and fidaxomicin.

However, in sensitivity analyses, FMT delivered by duodenal infusion or enema was not superior to other strategies.

Additional analyses tinkering with various model components showed that FMT colonoscopy was the most cost-effective strategy as long as its cure rate exceeded 93.8%, its cost was less than $2,324, or the probability of a post-treatment recurrence was less than 10%.

When the investigators explored thresholds for other treatment strategies, they found vancomycin would be the most cost-effective if its post-treatment recurrence rate were less than 33.9% (vs. 35.5% in the base case); fidaxomicin if its cost dropped to less than $1,539 (vs. $2,800 in the base case); and FMT by duodenal infusion or enema if the cure rate with one-time infusion hit 89.4% and 88.8%, respectively (vs. 81.3% and 81.5%).

Finally, when analyses assumed that FMT was not available, vancomycin was the most cost-effective strategy.

Dr. Konijeti disclosed no relevant conflicts of interest.

SAN DIEGO – A negative screening colonoscopy dramatically reduces the subsequent risk of colorectal cancer, according to a systematic review and meta-analysis of 18 studies presented at the annual meeting of the American College of Gastroenterology.

In the analysis, average-risk individuals whose colonoscopy showed neither cancer nor polyps had an incidence rate of colorectal cancer (CRC) of 0.58 per 1,000 person-years, corresponding to an estimated 10-year risk of just 0.58%, reported first author Dr. Larissa L. Fujii, a physician with the Mayo Clinic in Scottsdale, Ariz.

Compared with the expected risk for the general population based on surveillance data, these individuals were 57% less likely to receive a CRC diagnosis.

"Our findings support the effectiveness of colonoscopy as a screening and risk-stratification tool, and can be used to help educate patients who come in asking about their risk of colorectal cancer after having a negative colonoscopy," she commented.

Session comoderator Dr. Michael B. Wallace of the Mayo Clinic, Jacksonville, Fla., noted that a recent study found a higher incidence of CRC after a colonoscopy with polypectomy, at about 1.5 per 1,000 person-years of follow-up (Gut 2013 June 21 [Epub ahead of print]). "Do you think that your study might underestimate [the rate] because of follow-up? Was that a limitation in these patients?"

Adequacy of follow-up was included when assessing the studies’ methodologic quality, Dr. Fujii replied. "The incidence was lower in the higher-methodological-quality studies, so I would say that we are probably not underestimating. In fact, we might still be overestimating the risk based off of the population and the quality subgroup analyses."

Dr. Wallace also noted that there was a much lower CRC rate after negative colonoscopy for studies conducted in hospital settings as compared with those conducted in population settings. "Which do you think might be more accurate in terms of the rate?" he asked.

"I do think, because the population probably captured more colorectal cancers, that might be more indicative of what the actual incidence rate is," Dr. Fujii said.

Session attendee Dr. Douglas Robertson of the Geisel School of Medicine at Dartmouth, Hanover, N.H., said, "We like to think we are doing better colonoscopy over time. So can you see any differences as you look at newer studies versus older studies?"

The investigators have not yet assessed temporal trends, but identifying any might be difficult because only a single study was conducted before 2000, according to Dr. Fujii.

"I guess the subtext here is, is 10 years the right interval" for repeating colonoscopy after a negative result? Dr. Robertson further asked. "So you have thought a lot about this. What do you think – is a 57% reduction enough to stick with the 10-year interval?"

"I do like to think that this does support the 10-year recommendation – repeat the colonoscopy after 10 years rather than doing what many people might do, which is 5 years for average-risk patients, because the incidence is lower than what we would expect for the general population," Dr. Fujii replied.

In the study, the investigators searched for cohort studies and randomized controlled trials of average-risk patients undergoing screening colonoscopy. Studies were included if they had a mean follow-up duration exceeding 1 year.

All of the 18 studies meeting inclusion criteria were cohort studies, according to Dr. Fujii.

Thirteen studies each were conducted in hospital-based settings and in Western countries. The patients included in the studies had a weighted mean age of 72.5 years, and the weighted mean percentage of males was 41%.

The mean duration of follow-up was 5 years (range, 2-12 years). During follow-up, nearly 7,000 colorectal cancers were diagnosed.

Main results showed that the pooled incidence of CRC after a negative colonoscopy was 0.058% per year.

In subgroup analyses, the rate was significantly lower in studies conducted in hospital- versus population-based settings (0.08 vs. 0.96 per 1,000 person-years) and in studies conducted in Eastern versus Western countries (0.05 vs. 0.66). The rate also differed significantly according to whether studies were of high, moderate, or low quality (0.01, 0.88, and 0.38, respectively).

However, there was no significant difference according to whether the physician performing the colonoscopy was a gastroenterologist or some other specialist.

The estimated 5- and 10-year risks of CRC after a negative colonoscopy were 0.29% and 0.58%, respectively. These values compared with the expected rates of 0.6% and 1.5% for the general population according to Surveillance, Epidemiology, and End Results (SEER) data.

The difference amounted to more than halving of the rate of CRC after a negative colonoscopy relative to the general population (rate ratio, 0.43).

Dr. Fujii disclosed no relevant conflicts of interest.

SAN DIEGO – A negative screening colonoscopy dramatically reduces the subsequent risk of colorectal cancer, according to a systematic review and meta-analysis of 18 studies presented at the annual meeting of the American College of Gastroenterology.

In the analysis, average-risk individuals whose colonoscopy showed neither cancer nor polyps had an incidence rate of colorectal cancer (CRC) of 0.58 per 1,000 person-years, corresponding to an estimated 10-year risk of just 0.58%, reported first author Dr. Larissa L. Fujii, a physician with the Mayo Clinic in Scottsdale, Ariz.

Compared with the expected risk for the general population based on surveillance data, these individuals were 57% less likely to receive a CRC diagnosis.

"Our findings support the effectiveness of colonoscopy as a screening and risk-stratification tool, and can be used to help educate patients who come in asking about their risk of colorectal cancer after having a negative colonoscopy," she commented.

Session comoderator Dr. Michael B. Wallace of the Mayo Clinic, Jacksonville, Fla., noted that a recent study found a higher incidence of CRC after a colonoscopy with polypectomy, at about 1.5 per 1,000 person-years of follow-up (Gut 2013 June 21 [Epub ahead of print]). "Do you think that your study might underestimate [the rate] because of follow-up? Was that a limitation in these patients?"

Adequacy of follow-up was included when assessing the studies’ methodologic quality, Dr. Fujii replied. "The incidence was lower in the higher-methodological-quality studies, so I would say that we are probably not underestimating. In fact, we might still be overestimating the risk based off of the population and the quality subgroup analyses."

Dr. Wallace also noted that there was a much lower CRC rate after negative colonoscopy for studies conducted in hospital settings as compared with those conducted in population settings. "Which do you think might be more accurate in terms of the rate?" he asked.

"I do think, because the population probably captured more colorectal cancers, that might be more indicative of what the actual incidence rate is," Dr. Fujii said.

Session attendee Dr. Douglas Robertson of the Geisel School of Medicine at Dartmouth, Hanover, N.H., said, "We like to think we are doing better colonoscopy over time. So can you see any differences as you look at newer studies versus older studies?"

The investigators have not yet assessed temporal trends, but identifying any might be difficult because only a single study was conducted before 2000, according to Dr. Fujii.

"I guess the subtext here is, is 10 years the right interval" for repeating colonoscopy after a negative result? Dr. Robertson further asked. "So you have thought a lot about this. What do you think – is a 57% reduction enough to stick with the 10-year interval?"

"I do like to think that this does support the 10-year recommendation – repeat the colonoscopy after 10 years rather than doing what many people might do, which is 5 years for average-risk patients, because the incidence is lower than what we would expect for the general population," Dr. Fujii replied.

In the study, the investigators searched for cohort studies and randomized controlled trials of average-risk patients undergoing screening colonoscopy. Studies were included if they had a mean follow-up duration exceeding 1 year.

All of the 18 studies meeting inclusion criteria were cohort studies, according to Dr. Fujii.

Thirteen studies each were conducted in hospital-based settings and in Western countries. The patients included in the studies had a weighted mean age of 72.5 years, and the weighted mean percentage of males was 41%.

The mean duration of follow-up was 5 years (range, 2-12 years). During follow-up, nearly 7,000 colorectal cancers were diagnosed.

Main results showed that the pooled incidence of CRC after a negative colonoscopy was 0.058% per year.

In subgroup analyses, the rate was significantly lower in studies conducted in hospital- versus population-based settings (0.08 vs. 0.96 per 1,000 person-years) and in studies conducted in Eastern versus Western countries (0.05 vs. 0.66). The rate also differed significantly according to whether studies were of high, moderate, or low quality (0.01, 0.88, and 0.38, respectively).

However, there was no significant difference according to whether the physician performing the colonoscopy was a gastroenterologist or some other specialist.

The estimated 5- and 10-year risks of CRC after a negative colonoscopy were 0.29% and 0.58%, respectively. These values compared with the expected rates of 0.6% and 1.5% for the general population according to Surveillance, Epidemiology, and End Results (SEER) data.

The difference amounted to more than halving of the rate of CRC after a negative colonoscopy relative to the general population (rate ratio, 0.43).

Dr. Fujii disclosed no relevant conflicts of interest.

SAN DIEGO – A negative screening colonoscopy dramatically reduces the subsequent risk of colorectal cancer, according to a systematic review and meta-analysis of 18 studies presented at the annual meeting of the American College of Gastroenterology.

In the analysis, average-risk individuals whose colonoscopy showed neither cancer nor polyps had an incidence rate of colorectal cancer (CRC) of 0.58 per 1,000 person-years, corresponding to an estimated 10-year risk of just 0.58%, reported first author Dr. Larissa L. Fujii, a physician with the Mayo Clinic in Scottsdale, Ariz.

Compared with the expected risk for the general population based on surveillance data, these individuals were 57% less likely to receive a CRC diagnosis.

"Our findings support the effectiveness of colonoscopy as a screening and risk-stratification tool, and can be used to help educate patients who come in asking about their risk of colorectal cancer after having a negative colonoscopy," she commented.

Session comoderator Dr. Michael B. Wallace of the Mayo Clinic, Jacksonville, Fla., noted that a recent study found a higher incidence of CRC after a colonoscopy with polypectomy, at about 1.5 per 1,000 person-years of follow-up (Gut 2013 June 21 [Epub ahead of print]). "Do you think that your study might underestimate [the rate] because of follow-up? Was that a limitation in these patients?"

Adequacy of follow-up was included when assessing the studies’ methodologic quality, Dr. Fujii replied. "The incidence was lower in the higher-methodological-quality studies, so I would say that we are probably not underestimating. In fact, we might still be overestimating the risk based off of the population and the quality subgroup analyses."

Dr. Wallace also noted that there was a much lower CRC rate after negative colonoscopy for studies conducted in hospital settings as compared with those conducted in population settings. "Which do you think might be more accurate in terms of the rate?" he asked.

"I do think, because the population probably captured more colorectal cancers, that might be more indicative of what the actual incidence rate is," Dr. Fujii said.

Session attendee Dr. Douglas Robertson of the Geisel School of Medicine at Dartmouth, Hanover, N.H., said, "We like to think we are doing better colonoscopy over time. So can you see any differences as you look at newer studies versus older studies?"

The investigators have not yet assessed temporal trends, but identifying any might be difficult because only a single study was conducted before 2000, according to Dr. Fujii.

"I guess the subtext here is, is 10 years the right interval" for repeating colonoscopy after a negative result? Dr. Robertson further asked. "So you have thought a lot about this. What do you think – is a 57% reduction enough to stick with the 10-year interval?"

"I do like to think that this does support the 10-year recommendation – repeat the colonoscopy after 10 years rather than doing what many people might do, which is 5 years for average-risk patients, because the incidence is lower than what we would expect for the general population," Dr. Fujii replied.

In the study, the investigators searched for cohort studies and randomized controlled trials of average-risk patients undergoing screening colonoscopy. Studies were included if they had a mean follow-up duration exceeding 1 year.

All of the 18 studies meeting inclusion criteria were cohort studies, according to Dr. Fujii.

Thirteen studies each were conducted in hospital-based settings and in Western countries. The patients included in the studies had a weighted mean age of 72.5 years, and the weighted mean percentage of males was 41%.

The mean duration of follow-up was 5 years (range, 2-12 years). During follow-up, nearly 7,000 colorectal cancers were diagnosed.

Main results showed that the pooled incidence of CRC after a negative colonoscopy was 0.058% per year.

In subgroup analyses, the rate was significantly lower in studies conducted in hospital- versus population-based settings (0.08 vs. 0.96 per 1,000 person-years) and in studies conducted in Eastern versus Western countries (0.05 vs. 0.66). The rate also differed significantly according to whether studies were of high, moderate, or low quality (0.01, 0.88, and 0.38, respectively).

However, there was no significant difference according to whether the physician performing the colonoscopy was a gastroenterologist or some other specialist.

The estimated 5- and 10-year risks of CRC after a negative colonoscopy were 0.29% and 0.58%, respectively. These values compared with the expected rates of 0.6% and 1.5% for the general population according to Surveillance, Epidemiology, and End Results (SEER) data.

The difference amounted to more than halving of the rate of CRC after a negative colonoscopy relative to the general population (rate ratio, 0.43).

Dr. Fujii disclosed no relevant conflicts of interest.

SAN DIEGO – A blood test for antibodies to vinculin, a protein involved in nerve cell migration, may allow objective diagnosis of irritable bowel syndrome, a condition historically diagnosed clinically, after a thorough workup excludes other possibilities.

Investigators led by Dr. Mark Pimentel, director of the GI Motility Program at the Cedars-Sinai Medical Center in Los Angeles, performed a multicenter validation study of the test among patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), and healthy individuals.

Study results, reported at the annual meeting of the American College of Gastroenterology, showed that the anti-vinculin antibody test had a positive predictive value of at least 90% for distinguishing IBS from IBD.

And when analyses also took into account antibodies to cytolethal distending toxin B (CdtB) – a toxin produced by bacteria commonly associated with food poisoning – the positive predictive value was at least 94%.

"Elevated anti-vinculin antibodies are specific for IBS compared to IBD, and an increase in anti-vinculin antibodies with respect to anti-CdtB increases that specificity," Dr. Pimentel said, summing up the findings. "This may be the first serum diagnostic biomarker that can discriminate IBS from IBD, and it would help avoid unnecessary tests."

Additionally, the findings lend support to a pathogenic mechanism for postinfectious IBS suggested by a rodent model, whereby bacterial gastroenteritis gives rise to autoimmunity against vinculin in the digestive tract.

The assay may be useful in IBD research too, he noted. "One of the problems with IBD studies is those patients who don’t respond to therapies, and maybe they have IBS and they don’t have IBD. Maybe this test could be used to screen those patients out before the study begins."

A session attendee expressed reservations about the study, noting that some analyses compared IBS patients with healthy individuals, and that positive predictive values may not be the best statistic given the composition of the study population.

"We don’t need a test to tell us someone that has no symptoms versus someone that does. So this is the start of your validation, not the end of it," he said. "If you apply this to the population right now, I’ve done some calculations, your positive predictive value would be about 20%. So it’s not that great in clinical practice. ... I’m sure you will develop this more and it will get better, but right now, I don’t think this is ready for prime time."

"First, you can use a likelihood ratio, which accounts for the volumes of patients. ... Our likelihood ratio is between 3 and 4, which I hope gives you more confidence in it," Dr. Pimentel replied. "The second thing is that the patients who arrive in a doctor’s office are not healthy: They are going to have IBD or IBS or something else if they have diarrhea in the clinic."

In a related press briefing, Dr. Brian E. Lacy, of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., commented, "This is an incredibly important topic, when we are talking about prevalence rates of IBS – a conservative rate is 12% to 15% – and when you are talking about spending $20 billion to $30 billion a year diagnosing and treating IBS."

"For many patients, IBS is a diagnosis of exclusion; they undergo a battery of unnecessary tests which are usually fruitless because this is a functional bowel disorder," he added. "To possibly have a diagnostic test – a blood test – that could confidently make the diagnosis of IBS to me would be incredibly important. And I think for the community primary care providers, family practice doctors, who are not confident at diagnosing IBS, to have somebody say, ‘This is a great test, and we can not only make the diagnosis, but exclude or maybe improve our ability to exclude the patients with IBD,’ that would be incredibly important."

The test may also have implications for treatment, according to Dr. Pimentel. "Another question is, could this antibody test predict who will respond to antibiotics, or does it predict bacterial overgrowth or other treatable aspects of IBS?" he explained.

Finally, such a test would help validate IBS as a legitimate medical condition. "IBS is a very, very difficult illness because nobody understands it, and it kind of gets the short end of the stick because it is viewed as a lifestyle disorder instead of a legitimate disease," he commented. "So what I’d like to do in my career is to make IBS a real disease, not just a syndrome as it’s been for at least the last 2 decades."

Press briefing moderator Dr. Michael E. Cox of the Mercy Medical Center in Baltimore, said, "The $64,000 question is, when would this possibly be ready for prime time?"

"We are validating this antibody every day," Dr. Pimentel replied, although as yet, no companies are collaborating in developing the assay. "When it will be ready for prime time, I’m not sure."

In the study, the investigators assayed serum samples from 162 prospectively identified patients who met Rome III criteria for IBS, 30 patients with active IBD who were not receiving biologic agents, and 26 consecutive healthy individuals.

Across groups, about 70% of patients were female, with no significant differences in the sex and age distributions.

Results showed that the anti-vinculin antibody optical density (OD) reading was higher in patients with IBS than in patients with IBD (P less than .01) and healthy individuals (P less than .01), reported Dr. Pimentel.

Meanwhile, the anti-CdtB antibody OD reading was higher in the patients with IBD than in the patients with IBS (P = .02).

For distinguishing IBS from IBD, an anti-vinculin antibody OD reading exceeding 0.8 had a sensitivity of 43%, a specificity of 73%, and a positive predictive value of 90%.

There is a good rationale for simultaneously looking at anti-CdtB and anti-vinculin, according to Dr. Pimentel: In the model of postinfectious IBS, anti-vinculin antibodies persist over time, whereas anti-CdtB antibodies decline.

And indeed, in the study, the difference between the two OD readings (anti-vinculin minus anti-CdtB) was higher in the patients with IBS than in both the patients with IBD (P less than .0001) and the healthy individuals (P less than .001).

For distinguishing IBS from IBD, a difference exceeding 0.2 had a sensitivity of 41%, a specificity of 88%, and a positive predictive value of 94%.

A confounding issue is that about 10% of patients with IBD also have IBS, Dr. Pimentel noted. But a model taking this into account showed high positive predictive values for an anti-vinculin antibody OD reading exceeding 0.8 (92%) and for a difference between the OD readings of anti-vinculin and anti-CdtB exceeding 0.2 (97%).

Dr. Pimentel disclosed no relevant conflicts of interest.

SAN DIEGO – A blood test for antibodies to vinculin, a protein involved in nerve cell migration, may allow objective diagnosis of irritable bowel syndrome, a condition historically diagnosed clinically, after a thorough workup excludes other possibilities.

Investigators led by Dr. Mark Pimentel, director of the GI Motility Program at the Cedars-Sinai Medical Center in Los Angeles, performed a multicenter validation study of the test among patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), and healthy individuals.

Study results, reported at the annual meeting of the American College of Gastroenterology, showed that the anti-vinculin antibody test had a positive predictive value of at least 90% for distinguishing IBS from IBD.

And when analyses also took into account antibodies to cytolethal distending toxin B (CdtB) – a toxin produced by bacteria commonly associated with food poisoning – the positive predictive value was at least 94%.

"Elevated anti-vinculin antibodies are specific for IBS compared to IBD, and an increase in anti-vinculin antibodies with respect to anti-CdtB increases that specificity," Dr. Pimentel said, summing up the findings. "This may be the first serum diagnostic biomarker that can discriminate IBS from IBD, and it would help avoid unnecessary tests."

Additionally, the findings lend support to a pathogenic mechanism for postinfectious IBS suggested by a rodent model, whereby bacterial gastroenteritis gives rise to autoimmunity against vinculin in the digestive tract.

The assay may be useful in IBD research too, he noted. "One of the problems with IBD studies is those patients who don’t respond to therapies, and maybe they have IBS and they don’t have IBD. Maybe this test could be used to screen those patients out before the study begins."

A session attendee expressed reservations about the study, noting that some analyses compared IBS patients with healthy individuals, and that positive predictive values may not be the best statistic given the composition of the study population.

"We don’t need a test to tell us someone that has no symptoms versus someone that does. So this is the start of your validation, not the end of it," he said. "If you apply this to the population right now, I’ve done some calculations, your positive predictive value would be about 20%. So it’s not that great in clinical practice. ... I’m sure you will develop this more and it will get better, but right now, I don’t think this is ready for prime time."

"First, you can use a likelihood ratio, which accounts for the volumes of patients. ... Our likelihood ratio is between 3 and 4, which I hope gives you more confidence in it," Dr. Pimentel replied. "The second thing is that the patients who arrive in a doctor’s office are not healthy: They are going to have IBD or IBS or something else if they have diarrhea in the clinic."

In a related press briefing, Dr. Brian E. Lacy, of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., commented, "This is an incredibly important topic, when we are talking about prevalence rates of IBS – a conservative rate is 12% to 15% – and when you are talking about spending $20 billion to $30 billion a year diagnosing and treating IBS."

"For many patients, IBS is a diagnosis of exclusion; they undergo a battery of unnecessary tests which are usually fruitless because this is a functional bowel disorder," he added. "To possibly have a diagnostic test – a blood test – that could confidently make the diagnosis of IBS to me would be incredibly important. And I think for the community primary care providers, family practice doctors, who are not confident at diagnosing IBS, to have somebody say, ‘This is a great test, and we can not only make the diagnosis, but exclude or maybe improve our ability to exclude the patients with IBD,’ that would be incredibly important."

The test may also have implications for treatment, according to Dr. Pimentel. "Another question is, could this antibody test predict who will respond to antibiotics, or does it predict bacterial overgrowth or other treatable aspects of IBS?" he explained.

Finally, such a test would help validate IBS as a legitimate medical condition. "IBS is a very, very difficult illness because nobody understands it, and it kind of gets the short end of the stick because it is viewed as a lifestyle disorder instead of a legitimate disease," he commented. "So what I’d like to do in my career is to make IBS a real disease, not just a syndrome as it’s been for at least the last 2 decades."

Press briefing moderator Dr. Michael E. Cox of the Mercy Medical Center in Baltimore, said, "The $64,000 question is, when would this possibly be ready for prime time?"

"We are validating this antibody every day," Dr. Pimentel replied, although as yet, no companies are collaborating in developing the assay. "When it will be ready for prime time, I’m not sure."

In the study, the investigators assayed serum samples from 162 prospectively identified patients who met Rome III criteria for IBS, 30 patients with active IBD who were not receiving biologic agents, and 26 consecutive healthy individuals.

Across groups, about 70% of patients were female, with no significant differences in the sex and age distributions.

Results showed that the anti-vinculin antibody optical density (OD) reading was higher in patients with IBS than in patients with IBD (P less than .01) and healthy individuals (P less than .01), reported Dr. Pimentel.

Meanwhile, the anti-CdtB antibody OD reading was higher in the patients with IBD than in the patients with IBS (P = .02).

For distinguishing IBS from IBD, an anti-vinculin antibody OD reading exceeding 0.8 had a sensitivity of 43%, a specificity of 73%, and a positive predictive value of 90%.

There is a good rationale for simultaneously looking at anti-CdtB and anti-vinculin, according to Dr. Pimentel: In the model of postinfectious IBS, anti-vinculin antibodies persist over time, whereas anti-CdtB antibodies decline.

And indeed, in the study, the difference between the two OD readings (anti-vinculin minus anti-CdtB) was higher in the patients with IBS than in both the patients with IBD (P less than .0001) and the healthy individuals (P less than .001).

For distinguishing IBS from IBD, a difference exceeding 0.2 had a sensitivity of 41%, a specificity of 88%, and a positive predictive value of 94%.

A confounding issue is that about 10% of patients with IBD also have IBS, Dr. Pimentel noted. But a model taking this into account showed high positive predictive values for an anti-vinculin antibody OD reading exceeding 0.8 (92%) and for a difference between the OD readings of anti-vinculin and anti-CdtB exceeding 0.2 (97%).

Dr. Pimentel disclosed no relevant conflicts of interest.

SAN DIEGO – A blood test for antibodies to vinculin, a protein involved in nerve cell migration, may allow objective diagnosis of irritable bowel syndrome, a condition historically diagnosed clinically, after a thorough workup excludes other possibilities.

Investigators led by Dr. Mark Pimentel, director of the GI Motility Program at the Cedars-Sinai Medical Center in Los Angeles, performed a multicenter validation study of the test among patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), and healthy individuals.

Study results, reported at the annual meeting of the American College of Gastroenterology, showed that the anti-vinculin antibody test had a positive predictive value of at least 90% for distinguishing IBS from IBD.

And when analyses also took into account antibodies to cytolethal distending toxin B (CdtB) – a toxin produced by bacteria commonly associated with food poisoning – the positive predictive value was at least 94%.

"Elevated anti-vinculin antibodies are specific for IBS compared to IBD, and an increase in anti-vinculin antibodies with respect to anti-CdtB increases that specificity," Dr. Pimentel said, summing up the findings. "This may be the first serum diagnostic biomarker that can discriminate IBS from IBD, and it would help avoid unnecessary tests."

Additionally, the findings lend support to a pathogenic mechanism for postinfectious IBS suggested by a rodent model, whereby bacterial gastroenteritis gives rise to autoimmunity against vinculin in the digestive tract.

The assay may be useful in IBD research too, he noted. "One of the problems with IBD studies is those patients who don’t respond to therapies, and maybe they have IBS and they don’t have IBD. Maybe this test could be used to screen those patients out before the study begins."

A session attendee expressed reservations about the study, noting that some analyses compared IBS patients with healthy individuals, and that positive predictive values may not be the best statistic given the composition of the study population.

"We don’t need a test to tell us someone that has no symptoms versus someone that does. So this is the start of your validation, not the end of it," he said. "If you apply this to the population right now, I’ve done some calculations, your positive predictive value would be about 20%. So it’s not that great in clinical practice. ... I’m sure you will develop this more and it will get better, but right now, I don’t think this is ready for prime time."

"First, you can use a likelihood ratio, which accounts for the volumes of patients. ... Our likelihood ratio is between 3 and 4, which I hope gives you more confidence in it," Dr. Pimentel replied. "The second thing is that the patients who arrive in a doctor’s office are not healthy: They are going to have IBD or IBS or something else if they have diarrhea in the clinic."

In a related press briefing, Dr. Brian E. Lacy, of the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., commented, "This is an incredibly important topic, when we are talking about prevalence rates of IBS – a conservative rate is 12% to 15% – and when you are talking about spending $20 billion to $30 billion a year diagnosing and treating IBS."

"For many patients, IBS is a diagnosis of exclusion; they undergo a battery of unnecessary tests which are usually fruitless because this is a functional bowel disorder," he added. "To possibly have a diagnostic test – a blood test – that could confidently make the diagnosis of IBS to me would be incredibly important. And I think for the community primary care providers, family practice doctors, who are not confident at diagnosing IBS, to have somebody say, ‘This is a great test, and we can not only make the diagnosis, but exclude or maybe improve our ability to exclude the patients with IBD,’ that would be incredibly important."

The test may also have implications for treatment, according to Dr. Pimentel. "Another question is, could this antibody test predict who will respond to antibiotics, or does it predict bacterial overgrowth or other treatable aspects of IBS?" he explained.

Finally, such a test would help validate IBS as a legitimate medical condition. "IBS is a very, very difficult illness because nobody understands it, and it kind of gets the short end of the stick because it is viewed as a lifestyle disorder instead of a legitimate disease," he commented. "So what I’d like to do in my career is to make IBS a real disease, not just a syndrome as it’s been for at least the last 2 decades."

Press briefing moderator Dr. Michael E. Cox of the Mercy Medical Center in Baltimore, said, "The $64,000 question is, when would this possibly be ready for prime time?"

"We are validating this antibody every day," Dr. Pimentel replied, although as yet, no companies are collaborating in developing the assay. "When it will be ready for prime time, I’m not sure."

In the study, the investigators assayed serum samples from 162 prospectively identified patients who met Rome III criteria for IBS, 30 patients with active IBD who were not receiving biologic agents, and 26 consecutive healthy individuals.

Across groups, about 70% of patients were female, with no significant differences in the sex and age distributions.

Results showed that the anti-vinculin antibody optical density (OD) reading was higher in patients with IBS than in patients with IBD (P less than .01) and healthy individuals (P less than .01), reported Dr. Pimentel.

Meanwhile, the anti-CdtB antibody OD reading was higher in the patients with IBD than in the patients with IBS (P = .02).

For distinguishing IBS from IBD, an anti-vinculin antibody OD reading exceeding 0.8 had a sensitivity of 43%, a specificity of 73%, and a positive predictive value of 90%.

There is a good rationale for simultaneously looking at anti-CdtB and anti-vinculin, according to Dr. Pimentel: In the model of postinfectious IBS, anti-vinculin antibodies persist over time, whereas anti-CdtB antibodies decline.

And indeed, in the study, the difference between the two OD readings (anti-vinculin minus anti-CdtB) was higher in the patients with IBS than in both the patients with IBD (P less than .0001) and the healthy individuals (P less than .001).

For distinguishing IBS from IBD, a difference exceeding 0.2 had a sensitivity of 41%, a specificity of 88%, and a positive predictive value of 94%.

A confounding issue is that about 10% of patients with IBD also have IBS, Dr. Pimentel noted. But a model taking this into account showed high positive predictive values for an anti-vinculin antibody OD reading exceeding 0.8 (92%) and for a difference between the OD readings of anti-vinculin and anti-CdtB exceeding 0.2 (97%).

Dr. Pimentel disclosed no relevant conflicts of interest.

SAN DIEGO – The mortality-reducing benefit of colorectal cancer screening persists long term, according to an updated analysis of the randomized Minnesota Fecal Occult Blood Trial.

Investigators led by Dr. Aasma Shaukat, a gastroenterologist with the University of Minnesota, Minneapolis, analyzed data for more than 46,000 participants aged 50-80 years who were assigned to screening with the fecal occult blood test (FOBT) or no screening.

After the first 18 years, the cumulative colorectal cancer mortality rate was reduced by one-third with annual screening and by one-fifth with biennial screening as compared with no screening, according to initially reported results (J. Natl. Cancer Inst. 1999;91:434-7).

The updated results, now after 30 years of follow-up – the longest of any such trial to date – showed that the reductions in risk with screening were essentially unchanged, Dr. Shaukat reported at the annual meeting of the American College of Gastroenterology.

"Screening for colon cancer using fecal occult blood testing consistently reduces colorectal cancer mortality..., and this effect is sustained through 30 years of follow-up," she commented. "This suggests the effect of polypectomy, because [if] fecal occult blood testing [detected only] early cancers, most of the benefit would be seen in the first 8-10 years. The sustained benefit suggests that these individuals underwent removal of polyps that would have turned into cancer and resulted in a death at 30 years."

In additional trial findings, the benefit of screening appeared to be greater for men than women and greater for those who began screening after the age of 60 years.

Session attendee Dr. Samir Gupta, of the University of California, San Diego, asked, "After the initial 10 or 15 years of protocolized screening, is it possible that screening was going on in the control group" and that might explain the lesser benefit in younger individuals, as they would have had more time to be screened.

"During the trial, through 1998, the screening in the control group was less than 5%, so there wasn’t much screening going on in the control group," Dr. Shaukat replied. However, "after the trial ended, we don’t have information on people’s screening behavior. And screening became popular, particularly in the last two decades. So there is a possibility that a large number of people that were in the control group underwent screening, and that’s diluting the effects that we would have otherwise seen."

She offered a few possible additional reasons for the smaller benefit in the younger group. "One is that group doesn’t have a higher risk of colon cancer and of dying from colon cancer, and hence, we are just not seeing the effect of screening," she said. "The second is that perhaps fecal occult blood testing is fairly insensitive in that age group; that’s something that needs to be explored further."

Session comoderator Dr. Jonathan A. Leighton of the Mayo Clinic in Scottsdale, Ariz., asked, "Why do you think there was that benefit in men over women?"

"That’s something that’s actually been shown in several natural history and modeling studies," Dr. Shaukat replied. "Men have a higher incidence of colon cancer and they have a higher risk of dying from colon cancer compared to women. So it bears to reason that we would see a larger effect of screening among men compared to women." That said, subgroup analyses should be considered hypothesis generating and require confirmation, she acknowledged.

Dr. Carol Burke of the Cleveland Clinic, who also attended the session, asked whether the screening benefit would have been even greater in analyses restricted to adherent patients.

"Compliance-adjusted estimates ... are a lot larger, to the magnitude of about a 40% reduction in colorectal cancer mortality," Dr. Shaukat replied.

"What effect do you think FIT [fecal immunochemical test] would have on the magnitude [of benefit] – similar for FIT or better because of adherence?" Dr. Burke further queried.

"These fecal occult blood tests were rehydrated, so their sensitivity is comparable to modern-day FIT. So we expect FIT to do the same if not better," Dr. Shaukat replied.

In the trial, 46,551 participants in the Minnesota Colon Cancer Control Study were assigned to annual or biennial screening or no screening between 1976 and 1992. Those with positive FOBT results underwent colonoscopy with polypectomy if needed. All groups had annual follow-up thereafter through 1998.

Adherence to screening was high in the trial, with 90% of participants in the screening groups completing at least one FOBT, and no difference between men and women, according to Dr. Shaukat.

At each screening, 10% of participants had positive results, and 83% of this subset overall underwent colonoscopy. The complication rate from colonoscopy was low, at less than 0.1%.

In the updated analysis, 71% of trial participants had died as ascertained from the National Death Index.

In intention-to-treat analyses, the risk of colorectal cancer mortality was a significant 32% lower in the group screened annually (relative risk, 0.68) and 22% lower in the group screened biennially (RR, 0.78) as compared with the nonscreened group, according to data reported at the meeting and recently published (N. Engl. J. Med. 2013;369:1106-14).

"We don’t know what happened after 1998," Dr. Shaukat reminded attendees. "At best, the effects that we are seeing might be dilute, and if truly the control group had remained unscreened, we would have seen perhaps larger differences."

The absolute cumulative colorectal cancer mortality rates were 0.02 with annual screening, 0.02 with biennial screening, and 0.03 with no screening. "This separation [in curves] started at about 13 years of follow-up and persisted through 30 years of follow-up," she pointed out.

All-cause mortality was statistically indistinguishable between groups, although the trial was underpowered to assess this outcome.

In subgroup analyses, there was a near-significant interaction of screening with sex (P = .06), whereby the benefit was greater among men (RR, 0.62) than among women (RR, 0.83).

Additionally, among men, there was a significant interaction with age (P = .04), whereby screening was most beneficial among those 60-69 years old at baseline (RR, 0.46). The benefit among women appeared to be restricted to those who started screening at age 60 or later.

"We don’t have information on the incidence of colon cancer, and hence we can’t comment on right- versus left-sided colon cancer mortality," Dr. Shaukat noted.

Dr. Shaukat disclosed no conflicts of interest.

SAN DIEGO – The mortality-reducing benefit of colorectal cancer screening persists long term, according to an updated analysis of the randomized Minnesota Fecal Occult Blood Trial.

Investigators led by Dr. Aasma Shaukat, a gastroenterologist with the University of Minnesota, Minneapolis, analyzed data for more than 46,000 participants aged 50-80 years who were assigned to screening with the fecal occult blood test (FOBT) or no screening.

After the first 18 years, the cumulative colorectal cancer mortality rate was reduced by one-third with annual screening and by one-fifth with biennial screening as compared with no screening, according to initially reported results (J. Natl. Cancer Inst. 1999;91:434-7).

The updated results, now after 30 years of follow-up – the longest of any such trial to date – showed that the reductions in risk with screening were essentially unchanged, Dr. Shaukat reported at the annual meeting of the American College of Gastroenterology.

"Screening for colon cancer using fecal occult blood testing consistently reduces colorectal cancer mortality..., and this effect is sustained through 30 years of follow-up," she commented. "This suggests the effect of polypectomy, because [if] fecal occult blood testing [detected only] early cancers, most of the benefit would be seen in the first 8-10 years. The sustained benefit suggests that these individuals underwent removal of polyps that would have turned into cancer and resulted in a death at 30 years."

In additional trial findings, the benefit of screening appeared to be greater for men than women and greater for those who began screening after the age of 60 years.

Session attendee Dr. Samir Gupta, of the University of California, San Diego, asked, "After the initial 10 or 15 years of protocolized screening, is it possible that screening was going on in the control group" and that might explain the lesser benefit in younger individuals, as they would have had more time to be screened.

"During the trial, through 1998, the screening in the control group was less than 5%, so there wasn’t much screening going on in the control group," Dr. Shaukat replied. However, "after the trial ended, we don’t have information on people’s screening behavior. And screening became popular, particularly in the last two decades. So there is a possibility that a large number of people that were in the control group underwent screening, and that’s diluting the effects that we would have otherwise seen."

She offered a few possible additional reasons for the smaller benefit in the younger group. "One is that group doesn’t have a higher risk of colon cancer and of dying from colon cancer, and hence, we are just not seeing the effect of screening," she said. "The second is that perhaps fecal occult blood testing is fairly insensitive in that age group; that’s something that needs to be explored further."

Session comoderator Dr. Jonathan A. Leighton of the Mayo Clinic in Scottsdale, Ariz., asked, "Why do you think there was that benefit in men over women?"

"That’s something that’s actually been shown in several natural history and modeling studies," Dr. Shaukat replied. "Men have a higher incidence of colon cancer and they have a higher risk of dying from colon cancer compared to women. So it bears to reason that we would see a larger effect of screening among men compared to women." That said, subgroup analyses should be considered hypothesis generating and require confirmation, she acknowledged.

Dr. Carol Burke of the Cleveland Clinic, who also attended the session, asked whether the screening benefit would have been even greater in analyses restricted to adherent patients.

"Compliance-adjusted estimates ... are a lot larger, to the magnitude of about a 40% reduction in colorectal cancer mortality," Dr. Shaukat replied.

"What effect do you think FIT [fecal immunochemical test] would have on the magnitude [of benefit] – similar for FIT or better because of adherence?" Dr. Burke further queried.

"These fecal occult blood tests were rehydrated, so their sensitivity is comparable to modern-day FIT. So we expect FIT to do the same if not better," Dr. Shaukat replied.

In the trial, 46,551 participants in the Minnesota Colon Cancer Control Study were assigned to annual or biennial screening or no screening between 1976 and 1992. Those with positive FOBT results underwent colonoscopy with polypectomy if needed. All groups had annual follow-up thereafter through 1998.

Adherence to screening was high in the trial, with 90% of participants in the screening groups completing at least one FOBT, and no difference between men and women, according to Dr. Shaukat.

At each screening, 10% of participants had positive results, and 83% of this subset overall underwent colonoscopy. The complication rate from colonoscopy was low, at less than 0.1%.

In the updated analysis, 71% of trial participants had died as ascertained from the National Death Index.

In intention-to-treat analyses, the risk of colorectal cancer mortality was a significant 32% lower in the group screened annually (relative risk, 0.68) and 22% lower in the group screened biennially (RR, 0.78) as compared with the nonscreened group, according to data reported at the meeting and recently published (N. Engl. J. Med. 2013;369:1106-14).

"We don’t know what happened after 1998," Dr. Shaukat reminded attendees. "At best, the effects that we are seeing might be dilute, and if truly the control group had remained unscreened, we would have seen perhaps larger differences."

The absolute cumulative colorectal cancer mortality rates were 0.02 with annual screening, 0.02 with biennial screening, and 0.03 with no screening. "This separation [in curves] started at about 13 years of follow-up and persisted through 30 years of follow-up," she pointed out.

All-cause mortality was statistically indistinguishable between groups, although the trial was underpowered to assess this outcome.

In subgroup analyses, there was a near-significant interaction of screening with sex (P = .06), whereby the benefit was greater among men (RR, 0.62) than among women (RR, 0.83).

Additionally, among men, there was a significant interaction with age (P = .04), whereby screening was most beneficial among those 60-69 years old at baseline (RR, 0.46). The benefit among women appeared to be restricted to those who started screening at age 60 or later.

"We don’t have information on the incidence of colon cancer, and hence we can’t comment on right- versus left-sided colon cancer mortality," Dr. Shaukat noted.

Dr. Shaukat disclosed no conflicts of interest.

SAN DIEGO – The mortality-reducing benefit of colorectal cancer screening persists long term, according to an updated analysis of the randomized Minnesota Fecal Occult Blood Trial.

Investigators led by Dr. Aasma Shaukat, a gastroenterologist with the University of Minnesota, Minneapolis, analyzed data for more than 46,000 participants aged 50-80 years who were assigned to screening with the fecal occult blood test (FOBT) or no screening.

After the first 18 years, the cumulative colorectal cancer mortality rate was reduced by one-third with annual screening and by one-fifth with biennial screening as compared with no screening, according to initially reported results (J. Natl. Cancer Inst. 1999;91:434-7).

The updated results, now after 30 years of follow-up – the longest of any such trial to date – showed that the reductions in risk with screening were essentially unchanged, Dr. Shaukat reported at the annual meeting of the American College of Gastroenterology.

"Screening for colon cancer using fecal occult blood testing consistently reduces colorectal cancer mortality..., and this effect is sustained through 30 years of follow-up," she commented. "This suggests the effect of polypectomy, because [if] fecal occult blood testing [detected only] early cancers, most of the benefit would be seen in the first 8-10 years. The sustained benefit suggests that these individuals underwent removal of polyps that would have turned into cancer and resulted in a death at 30 years."

In additional trial findings, the benefit of screening appeared to be greater for men than women and greater for those who began screening after the age of 60 years.

Session attendee Dr. Samir Gupta, of the University of California, San Diego, asked, "After the initial 10 or 15 years of protocolized screening, is it possible that screening was going on in the control group" and that might explain the lesser benefit in younger individuals, as they would have had more time to be screened.

"During the trial, through 1998, the screening in the control group was less than 5%, so there wasn’t much screening going on in the control group," Dr. Shaukat replied. However, "after the trial ended, we don’t have information on people’s screening behavior. And screening became popular, particularly in the last two decades. So there is a possibility that a large number of people that were in the control group underwent screening, and that’s diluting the effects that we would have otherwise seen."

She offered a few possible additional reasons for the smaller benefit in the younger group. "One is that group doesn’t have a higher risk of colon cancer and of dying from colon cancer, and hence, we are just not seeing the effect of screening," she said. "The second is that perhaps fecal occult blood testing is fairly insensitive in that age group; that’s something that needs to be explored further."

Session comoderator Dr. Jonathan A. Leighton of the Mayo Clinic in Scottsdale, Ariz., asked, "Why do you think there was that benefit in men over women?"

"That’s something that’s actually been shown in several natural history and modeling studies," Dr. Shaukat replied. "Men have a higher incidence of colon cancer and they have a higher risk of dying from colon cancer compared to women. So it bears to reason that we would see a larger effect of screening among men compared to women." That said, subgroup analyses should be considered hypothesis generating and require confirmation, she acknowledged.

Dr. Carol Burke of the Cleveland Clinic, who also attended the session, asked whether the screening benefit would have been even greater in analyses restricted to adherent patients.

"Compliance-adjusted estimates ... are a lot larger, to the magnitude of about a 40% reduction in colorectal cancer mortality," Dr. Shaukat replied.

"What effect do you think FIT [fecal immunochemical test] would have on the magnitude [of benefit] – similar for FIT or better because of adherence?" Dr. Burke further queried.

"These fecal occult blood tests were rehydrated, so their sensitivity is comparable to modern-day FIT. So we expect FIT to do the same if not better," Dr. Shaukat replied.

In the trial, 46,551 participants in the Minnesota Colon Cancer Control Study were assigned to annual or biennial screening or no screening between 1976 and 1992. Those with positive FOBT results underwent colonoscopy with polypectomy if needed. All groups had annual follow-up thereafter through 1998.

Adherence to screening was high in the trial, with 90% of participants in the screening groups completing at least one FOBT, and no difference between men and women, according to Dr. Shaukat.

At each screening, 10% of participants had positive results, and 83% of this subset overall underwent colonoscopy. The complication rate from colonoscopy was low, at less than 0.1%.

In the updated analysis, 71% of trial participants had died as ascertained from the National Death Index.

In intention-to-treat analyses, the risk of colorectal cancer mortality was a significant 32% lower in the group screened annually (relative risk, 0.68) and 22% lower in the group screened biennially (RR, 0.78) as compared with the nonscreened group, according to data reported at the meeting and recently published (N. Engl. J. Med. 2013;369:1106-14).

"We don’t know what happened after 1998," Dr. Shaukat reminded attendees. "At best, the effects that we are seeing might be dilute, and if truly the control group had remained unscreened, we would have seen perhaps larger differences."

The absolute cumulative colorectal cancer mortality rates were 0.02 with annual screening, 0.02 with biennial screening, and 0.03 with no screening. "This separation [in curves] started at about 13 years of follow-up and persisted through 30 years of follow-up," she pointed out.

All-cause mortality was statistically indistinguishable between groups, although the trial was underpowered to assess this outcome.

In subgroup analyses, there was a near-significant interaction of screening with sex (P = .06), whereby the benefit was greater among men (RR, 0.62) than among women (RR, 0.83).

Additionally, among men, there was a significant interaction with age (P = .04), whereby screening was most beneficial among those 60-69 years old at baseline (RR, 0.46). The benefit among women appeared to be restricted to those who started screening at age 60 or later.

"We don’t have information on the incidence of colon cancer, and hence we can’t comment on right- versus left-sided colon cancer mortality," Dr. Shaukat noted.

Dr. Shaukat disclosed no conflicts of interest.