Diana Mahoney

BOSTON – A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study’s treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

"There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant," he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%, he noted.

The vaccine strategy appears to be safe. "The most common associated adverse events were mild, transient injection-site reactions," said Dr. Pockros. Additionally, he stated, "the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms."

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, "mimicked what we saw with a virologic response," he said.

"Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response."

This finding is consistent with the hypothesis that the GI-5005 vaccine corrects a fundamental deficit in cellular immunity in IL28B T/T genotype patients, he said. Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted.

Because the immune response is similar to that observed in HCV-infected patients who are able to clear the virus without treatment, future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed financial relationships with GlobeImmune, Genentech, Vertex, Merck, Gilead, Abbott, Pfizer, Phenomix, Tibotec, Pharmasset, 3RT, Novartis, Johnson & Johnson, Achillon, Regulus, Debio, Zymogenetics, and Human Genome Sciences.

BOSTON – A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study’s treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

"There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant," he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%, he noted.

The vaccine strategy appears to be safe. "The most common associated adverse events were mild, transient injection-site reactions," said Dr. Pockros. Additionally, he stated, "the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms."

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, "mimicked what we saw with a virologic response," he said.

"Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response."

This finding is consistent with the hypothesis that the GI-5005 vaccine corrects a fundamental deficit in cellular immunity in IL28B T/T genotype patients, he said. Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted.

Because the immune response is similar to that observed in HCV-infected patients who are able to clear the virus without treatment, future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed financial relationships with GlobeImmune, Genentech, Vertex, Merck, Gilead, Abbott, Pfizer, Phenomix, Tibotec, Pharmasset, 3RT, Novartis, Johnson & Johnson, Achillon, Regulus, Debio, Zymogenetics, and Human Genome Sciences.

BOSTON – A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study’s treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

"There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant," he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%, he noted.

The vaccine strategy appears to be safe. "The most common associated adverse events were mild, transient injection-site reactions," said Dr. Pockros. Additionally, he stated, "the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms."

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, "mimicked what we saw with a virologic response," he said.

"Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response."

This finding is consistent with the hypothesis that the GI-5005 vaccine corrects a fundamental deficit in cellular immunity in IL28B T/T genotype patients, he said. Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted.

Because the immune response is similar to that observed in HCV-infected patients who are able to clear the virus without treatment, future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed financial relationships with GlobeImmune, Genentech, Vertex, Merck, Gilead, Abbott, Pfizer, Phenomix, Tibotec, Pharmasset, 3RT, Novartis, Johnson & Johnson, Achillon, Regulus, Debio, Zymogenetics, and Human Genome Sciences.

Aortic root aneurysm and ectopia lentis are the cardinal clinical features of Marfan syndrome, and the presence of both of them is sufficient for the “unequivocal diagnosis” of the genetic connective-tissue disorder, according to recently revised diagnostic criteria.

The new criteria update the 1996 Ghent nosology, which comprise a stringent set of major and minor manifestations in multiple organ systems. Although the earlier nosology has proven to be a useful diagnostic guide, “some of the diagnostic criteria have not been sufficiently validated, are not applicable in children, or necessitate expensive and specialized investigations,” lead author Dr. Bart L. Loeys of Ghent University Hospital, Belgium, and colleagues wrote. The revised Ghent nosology addresses these shortcomings, they stated (J. Med. Genet. 2010 47:476–85).

The revised criteria were developed by an international panel of experts based on a critical review of clinical characteristics in large, published patient cohorts. They include five major changes to the earlier guidelines:

▸ More weight is given to aortic root aneurysm/dissection and ectopia lentis. “In the absence of findings that are not expected in [Marfan syndrome], the combination of ectopia lentis and aortic root enlargement/dissection should be sufficient to make the diagnosis,” the authors wrote, noting that all other cardiovascular and ocular manifestations of the condition, as well as findings in the skeleton, dura, skin, and lungs, “contribute to a systemic score that guides diagnosis when aortic disease is present but ectopia lentis is not.”

▸ Molecular genetic testing of the fibrillin-1 (FBN1) gene, which is mutated in Marfan syndrome, and other relevant genes has a more prominent role. Although the updated nosology does not require FBN1 testing, it “allows its appropriate use when available,” they wrote.

▸ Some of the less specific manifestations identified in the previous criteria, such as joint hypermobility, highly arched palate, recurrent or incisional herniae, and dural ectasia have been removed or had their influence minimized.

▸ Additional diagnostic considerations and testing are required for individuals who satisfy the criteria for Marfan syndrome, but also show unexpected findings suggestive of conditions with overlapping symptoms, such as Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, and the vascular form of Ehlers-Danlos syndrome. “It is essential to consider discriminating features because each of these conditions has a unique risk profile and management protocol,” the authors wrote.

▸ Context-specific recommendations for patient counseling and follow-up are outlined for “sporadic” patients (those with no family history), index patients (those with a definitive family history), and patients younger than 20 years old.

A Web-based diagnostic tool for applying the new criteria is available at www.marfan.org

The authors reported having no conflicts of interest with respect to this project. Funding for the development of revised nosology for Marfan syndrome was provided by the National Marfan Foundation, March of Dimes, Merck & Co., and Solvay Pharmaceuticals.

Aortic root aneurysm and ectopia lentis are the cardinal clinical features of Marfan syndrome, and the presence of both of them is sufficient for the “unequivocal diagnosis” of the genetic connective-tissue disorder, according to recently revised diagnostic criteria.

The new criteria update the 1996 Ghent nosology, which comprise a stringent set of major and minor manifestations in multiple organ systems. Although the earlier nosology has proven to be a useful diagnostic guide, “some of the diagnostic criteria have not been sufficiently validated, are not applicable in children, or necessitate expensive and specialized investigations,” lead author Dr. Bart L. Loeys of Ghent University Hospital, Belgium, and colleagues wrote. The revised Ghent nosology addresses these shortcomings, they stated (J. Med. Genet. 2010 47:476–85).

The revised criteria were developed by an international panel of experts based on a critical review of clinical characteristics in large, published patient cohorts. They include five major changes to the earlier guidelines:

▸ More weight is given to aortic root aneurysm/dissection and ectopia lentis. “In the absence of findings that are not expected in [Marfan syndrome], the combination of ectopia lentis and aortic root enlargement/dissection should be sufficient to make the diagnosis,” the authors wrote, noting that all other cardiovascular and ocular manifestations of the condition, as well as findings in the skeleton, dura, skin, and lungs, “contribute to a systemic score that guides diagnosis when aortic disease is present but ectopia lentis is not.”

▸ Molecular genetic testing of the fibrillin-1 (FBN1) gene, which is mutated in Marfan syndrome, and other relevant genes has a more prominent role. Although the updated nosology does not require FBN1 testing, it “allows its appropriate use when available,” they wrote.

▸ Some of the less specific manifestations identified in the previous criteria, such as joint hypermobility, highly arched palate, recurrent or incisional herniae, and dural ectasia have been removed or had their influence minimized.

▸ Additional diagnostic considerations and testing are required for individuals who satisfy the criteria for Marfan syndrome, but also show unexpected findings suggestive of conditions with overlapping symptoms, such as Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, and the vascular form of Ehlers-Danlos syndrome. “It is essential to consider discriminating features because each of these conditions has a unique risk profile and management protocol,” the authors wrote.

▸ Context-specific recommendations for patient counseling and follow-up are outlined for “sporadic” patients (those with no family history), index patients (those with a definitive family history), and patients younger than 20 years old.

A Web-based diagnostic tool for applying the new criteria is available at www.marfan.org

The authors reported having no conflicts of interest with respect to this project. Funding for the development of revised nosology for Marfan syndrome was provided by the National Marfan Foundation, March of Dimes, Merck & Co., and Solvay Pharmaceuticals.

Aortic root aneurysm and ectopia lentis are the cardinal clinical features of Marfan syndrome, and the presence of both of them is sufficient for the “unequivocal diagnosis” of the genetic connective-tissue disorder, according to recently revised diagnostic criteria.

The new criteria update the 1996 Ghent nosology, which comprise a stringent set of major and minor manifestations in multiple organ systems. Although the earlier nosology has proven to be a useful diagnostic guide, “some of the diagnostic criteria have not been sufficiently validated, are not applicable in children, or necessitate expensive and specialized investigations,” lead author Dr. Bart L. Loeys of Ghent University Hospital, Belgium, and colleagues wrote. The revised Ghent nosology addresses these shortcomings, they stated (J. Med. Genet. 2010 47:476–85).

The revised criteria were developed by an international panel of experts based on a critical review of clinical characteristics in large, published patient cohorts. They include five major changes to the earlier guidelines:

▸ More weight is given to aortic root aneurysm/dissection and ectopia lentis. “In the absence of findings that are not expected in [Marfan syndrome], the combination of ectopia lentis and aortic root enlargement/dissection should be sufficient to make the diagnosis,” the authors wrote, noting that all other cardiovascular and ocular manifestations of the condition, as well as findings in the skeleton, dura, skin, and lungs, “contribute to a systemic score that guides diagnosis when aortic disease is present but ectopia lentis is not.”

▸ Molecular genetic testing of the fibrillin-1 (FBN1) gene, which is mutated in Marfan syndrome, and other relevant genes has a more prominent role. Although the updated nosology does not require FBN1 testing, it “allows its appropriate use when available,” they wrote.

▸ Some of the less specific manifestations identified in the previous criteria, such as joint hypermobility, highly arched palate, recurrent or incisional herniae, and dural ectasia have been removed or had their influence minimized.

▸ Additional diagnostic considerations and testing are required for individuals who satisfy the criteria for Marfan syndrome, but also show unexpected findings suggestive of conditions with overlapping symptoms, such as Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome, and the vascular form of Ehlers-Danlos syndrome. “It is essential to consider discriminating features because each of these conditions has a unique risk profile and management protocol,” the authors wrote.

▸ Context-specific recommendations for patient counseling and follow-up are outlined for “sporadic” patients (those with no family history), index patients (those with a definitive family history), and patients younger than 20 years old.

A Web-based diagnostic tool for applying the new criteria is available at www.marfan.org

The authors reported having no conflicts of interest with respect to this project. Funding for the development of revised nosology for Marfan syndrome was provided by the National Marfan Foundation, March of Dimes, Merck & Co., and Solvay Pharmaceuticals.

Major Finding: BDI-II scores decreased by an additional 6.3 points after 3 months and 4.6 points after 6 months in the intervention group, compared with usual care.

Data Source: A quasi-experimental study with 299 participants.

Disclosures: Dr. Watkins reported having no financial conflicts of interest regarding this study.

BOSTON — Integrating cognitive behavioral therapy for depression with residential substance abuse treatment leads to improvements in mood and substance use outcomes in clients with persistent depressive symptoms, a study has shown.

The findings support the delivery of evidence-based mental health care within substance abuse treatment programs, Dr. Katherine Watkins said at the meeting.

Depression often goes hand in hand with substance abuse, yet few individuals in public-sector substance abuse treatment facilities have access to effective depression treatment, according to Dr. Watkins, senior natural scientist at RAND in Santa Monica, Calif.

To determine whether integrating cognitive behavioral therapy (CBT) for depression into the usual-care cognitive model for substance use would improve outcomes in residential substance abuse treatment, she and her colleagues conducted a quasi-experimental study to compare the efficacy of a 16-session, evidence-based CBT intervention plus usual care to that of usual care alone in 299 clients (age range, 18-63 years) with depression being treated in a single public-sector residential alcohol or other drug (AOD) treatment center.

The primary and secondary outcome measures were, respectively, depressive symptoms as measured by the Beck Depression Inventory II (BDI-II) and improved functioning measured by the Short Form 12 (SF-12) health survey at 3 and 6 months after intervention relative to baseline. All patients had baseline BDI-II scores greater than 17 (mean total was 33.5, indicating scores in the clinically severe range), she said.

Of the 299 study participants, 140 received usual care and the group CBT intervention – Building Recovery by Improving Goals, Habits, and Thoughts (BRIGHT) – delivered by a trained substance abuse treatment counselor; and 159 received usual care.

The CBT program included discussions of the connection between mood and substance use and provided strategies for identifying and modifying harmful thoughts, activities, and interactions with people related to both mood and substance use.

To be consistent with CBT, each session had a prescribed agenda of announcements, practice (homework) review, new topics, key messages, assignment of new practice, client feedback, and a description of the next session. New topics were reinforced by embedding interactive activities, such as writing down harmful thoughts the last time they wanted to drink, into each session.

At 3- and 6-month follow-ups, the BDI-II scores decreased by an additional 6.3 and 4.6 points in the BRIGHT group compared with usual care, and the SF-12 scores increased by 6.3 and 4.6 points, respectively, Dr. Watkins reported. “BRIGHT clients reported fewer drinking days and fewer days of problem substance use at 6 months,” she noted.

Group CBT for depression appears to be effective for persistent depression in individuals undergoing treatment for substance use disorders. “The results provide support for a new model of integrated care, in which access to effective depression treatment is increased and outcomes improved by developing the capacity of substance abuse treatment programs to deliver evidence-based mental health care,” she said.

Major Finding: BDI-II scores decreased by an additional 6.3 points after 3 months and 4.6 points after 6 months in the intervention group, compared with usual care.

Data Source: A quasi-experimental study with 299 participants.

Disclosures: Dr. Watkins reported having no financial conflicts of interest regarding this study.

BOSTON — Integrating cognitive behavioral therapy for depression with residential substance abuse treatment leads to improvements in mood and substance use outcomes in clients with persistent depressive symptoms, a study has shown.

The findings support the delivery of evidence-based mental health care within substance abuse treatment programs, Dr. Katherine Watkins said at the meeting.

Depression often goes hand in hand with substance abuse, yet few individuals in public-sector substance abuse treatment facilities have access to effective depression treatment, according to Dr. Watkins, senior natural scientist at RAND in Santa Monica, Calif.

To determine whether integrating cognitive behavioral therapy (CBT) for depression into the usual-care cognitive model for substance use would improve outcomes in residential substance abuse treatment, she and her colleagues conducted a quasi-experimental study to compare the efficacy of a 16-session, evidence-based CBT intervention plus usual care to that of usual care alone in 299 clients (age range, 18-63 years) with depression being treated in a single public-sector residential alcohol or other drug (AOD) treatment center.

The primary and secondary outcome measures were, respectively, depressive symptoms as measured by the Beck Depression Inventory II (BDI-II) and improved functioning measured by the Short Form 12 (SF-12) health survey at 3 and 6 months after intervention relative to baseline. All patients had baseline BDI-II scores greater than 17 (mean total was 33.5, indicating scores in the clinically severe range), she said.

Of the 299 study participants, 140 received usual care and the group CBT intervention – Building Recovery by Improving Goals, Habits, and Thoughts (BRIGHT) – delivered by a trained substance abuse treatment counselor; and 159 received usual care.

The CBT program included discussions of the connection between mood and substance use and provided strategies for identifying and modifying harmful thoughts, activities, and interactions with people related to both mood and substance use.

To be consistent with CBT, each session had a prescribed agenda of announcements, practice (homework) review, new topics, key messages, assignment of new practice, client feedback, and a description of the next session. New topics were reinforced by embedding interactive activities, such as writing down harmful thoughts the last time they wanted to drink, into each session.

At 3- and 6-month follow-ups, the BDI-II scores decreased by an additional 6.3 and 4.6 points in the BRIGHT group compared with usual care, and the SF-12 scores increased by 6.3 and 4.6 points, respectively, Dr. Watkins reported. “BRIGHT clients reported fewer drinking days and fewer days of problem substance use at 6 months,” she noted.

Group CBT for depression appears to be effective for persistent depression in individuals undergoing treatment for substance use disorders. “The results provide support for a new model of integrated care, in which access to effective depression treatment is increased and outcomes improved by developing the capacity of substance abuse treatment programs to deliver evidence-based mental health care,” she said.

Major Finding: BDI-II scores decreased by an additional 6.3 points after 3 months and 4.6 points after 6 months in the intervention group, compared with usual care.

Data Source: A quasi-experimental study with 299 participants.

Disclosures: Dr. Watkins reported having no financial conflicts of interest regarding this study.

BOSTON — Integrating cognitive behavioral therapy for depression with residential substance abuse treatment leads to improvements in mood and substance use outcomes in clients with persistent depressive symptoms, a study has shown.

The findings support the delivery of evidence-based mental health care within substance abuse treatment programs, Dr. Katherine Watkins said at the meeting.

Depression often goes hand in hand with substance abuse, yet few individuals in public-sector substance abuse treatment facilities have access to effective depression treatment, according to Dr. Watkins, senior natural scientist at RAND in Santa Monica, Calif.

To determine whether integrating cognitive behavioral therapy (CBT) for depression into the usual-care cognitive model for substance use would improve outcomes in residential substance abuse treatment, she and her colleagues conducted a quasi-experimental study to compare the efficacy of a 16-session, evidence-based CBT intervention plus usual care to that of usual care alone in 299 clients (age range, 18-63 years) with depression being treated in a single public-sector residential alcohol or other drug (AOD) treatment center.

The primary and secondary outcome measures were, respectively, depressive symptoms as measured by the Beck Depression Inventory II (BDI-II) and improved functioning measured by the Short Form 12 (SF-12) health survey at 3 and 6 months after intervention relative to baseline. All patients had baseline BDI-II scores greater than 17 (mean total was 33.5, indicating scores in the clinically severe range), she said.

Of the 299 study participants, 140 received usual care and the group CBT intervention – Building Recovery by Improving Goals, Habits, and Thoughts (BRIGHT) – delivered by a trained substance abuse treatment counselor; and 159 received usual care.

The CBT program included discussions of the connection between mood and substance use and provided strategies for identifying and modifying harmful thoughts, activities, and interactions with people related to both mood and substance use.

To be consistent with CBT, each session had a prescribed agenda of announcements, practice (homework) review, new topics, key messages, assignment of new practice, client feedback, and a description of the next session. New topics were reinforced by embedding interactive activities, such as writing down harmful thoughts the last time they wanted to drink, into each session.

At 3- and 6-month follow-ups, the BDI-II scores decreased by an additional 6.3 and 4.6 points in the BRIGHT group compared with usual care, and the SF-12 scores increased by 6.3 and 4.6 points, respectively, Dr. Watkins reported. “BRIGHT clients reported fewer drinking days and fewer days of problem substance use at 6 months,” she noted.

Group CBT for depression appears to be effective for persistent depression in individuals undergoing treatment for substance use disorders. “The results provide support for a new model of integrated care, in which access to effective depression treatment is increased and outcomes improved by developing the capacity of substance abuse treatment programs to deliver evidence-based mental health care,” she said.

Major Finding: Hearing loss frequently complicates pneumococcal meningitis and is associated with coexisting otitis on admission and infection with serotype 9V.

Data Source: Two prospective, nationwide observational cohort studies of adults with community-acquired bacterial meningitis in the Netherlands.

Disclosures: Dr. Heckenberg and his colleagues had no financial disclosures.

BOSTON — Otitis on hospital admission and infection with pneumococcal serotype 9V were independently associated with hearing loss in patients who were treated for pneumococcal meningitis.

“Hearing loss is a major cause of morbidity in pneumococcal meningitis, affecting more than 20% of patients with the disease,” study investigator Dr. Sebastiaan G.B. Heckenberg noted. Based on the findings, “patients with coexisting otitis on admission and infection with serotype 9V are at highest risk and should be monitored closely for this outcome,” he said.

Using data from two prospective nationwide cohort studies in the Netherlands, Dr. Heckenberg of the Academic Medical Center in Amsterdam and colleagues identified 531 adults who survived pneumococcal meningitis from 1998-2002 and 2006-2009. All patients underwent neurologic examination at discharge and grading via the Glasgow Outcome Scale (GOS), with an unfavorable outcome defined as a GOS grade of 1-4. Additionally, the majority of patients had audiograms within 1 year after discharge.

Of the 531 patients, 112 experienced “any” hearing loss (defined as audiogram-assessed uni- or bilateral hearing loss of at least 20 decibels within 1 year post discharge, or hearing loss at discharge). A total of 47 experienced severe hearing loss (defined as World Health Organization hearing loss of at least grade 2, or hearing loss as a cause of unfavorable outcome at discharge).

In patients with any hearing loss, otitis on admission was reported in 53%, which was significantly higher than the 32% observed in patients with no hearing loss, Dr. Heckenberg stated. In fact, “on admission, otitis was the only characteristic that was associated with any hearing loss,” he said. “Severity of disease as reflected by low scores on the Glasgow Outcome Scale, systolic blood pressure, and [cerebrospinal fluid] white cell counts were not related to hearing loss in this group.”

With respect to severe hearing loss, otitis on admission was not significantly associated, “but there was a trend among severe hearing loss patients to have lower CSF white cell counts,” Dr. Heckenberg noted. Furthermore, an analysis of hearing loss incidence relative to pneumococcal serotype, which was available for 490 of the 531 patients, showed that serotype 9V was significantly associated with severe hearing loss, he said.

Of interest, Dr. Heckenberg noted, was that severe hearing loss was significantly less common among patients who received dexamethasone. Of the 530 patients for whom the information was available, 10 (4%) of the 240 patients who received dexamathasone experienced significant hearing loss, compared with 37 (13%) of the 290 patients who did not take the glucocorticoid.

This finding suggests that hearing loss associated with pneumococcal meningitis could be a function of inflammation, which is mediated by the steroid, he said. Further research into the preventive effect of glucocorticoid therapy is warranted, he noted.

Major Finding: Hearing loss frequently complicates pneumococcal meningitis and is associated with coexisting otitis on admission and infection with serotype 9V.

Data Source: Two prospective, nationwide observational cohort studies of adults with community-acquired bacterial meningitis in the Netherlands.

Disclosures: Dr. Heckenberg and his colleagues had no financial disclosures.

BOSTON — Otitis on hospital admission and infection with pneumococcal serotype 9V were independently associated with hearing loss in patients who were treated for pneumococcal meningitis.

“Hearing loss is a major cause of morbidity in pneumococcal meningitis, affecting more than 20% of patients with the disease,” study investigator Dr. Sebastiaan G.B. Heckenberg noted. Based on the findings, “patients with coexisting otitis on admission and infection with serotype 9V are at highest risk and should be monitored closely for this outcome,” he said.

Using data from two prospective nationwide cohort studies in the Netherlands, Dr. Heckenberg of the Academic Medical Center in Amsterdam and colleagues identified 531 adults who survived pneumococcal meningitis from 1998-2002 and 2006-2009. All patients underwent neurologic examination at discharge and grading via the Glasgow Outcome Scale (GOS), with an unfavorable outcome defined as a GOS grade of 1-4. Additionally, the majority of patients had audiograms within 1 year after discharge.

Of the 531 patients, 112 experienced “any” hearing loss (defined as audiogram-assessed uni- or bilateral hearing loss of at least 20 decibels within 1 year post discharge, or hearing loss at discharge). A total of 47 experienced severe hearing loss (defined as World Health Organization hearing loss of at least grade 2, or hearing loss as a cause of unfavorable outcome at discharge).

In patients with any hearing loss, otitis on admission was reported in 53%, which was significantly higher than the 32% observed in patients with no hearing loss, Dr. Heckenberg stated. In fact, “on admission, otitis was the only characteristic that was associated with any hearing loss,” he said. “Severity of disease as reflected by low scores on the Glasgow Outcome Scale, systolic blood pressure, and [cerebrospinal fluid] white cell counts were not related to hearing loss in this group.”

With respect to severe hearing loss, otitis on admission was not significantly associated, “but there was a trend among severe hearing loss patients to have lower CSF white cell counts,” Dr. Heckenberg noted. Furthermore, an analysis of hearing loss incidence relative to pneumococcal serotype, which was available for 490 of the 531 patients, showed that serotype 9V was significantly associated with severe hearing loss, he said.

Of interest, Dr. Heckenberg noted, was that severe hearing loss was significantly less common among patients who received dexamethasone. Of the 530 patients for whom the information was available, 10 (4%) of the 240 patients who received dexamathasone experienced significant hearing loss, compared with 37 (13%) of the 290 patients who did not take the glucocorticoid.

This finding suggests that hearing loss associated with pneumococcal meningitis could be a function of inflammation, which is mediated by the steroid, he said. Further research into the preventive effect of glucocorticoid therapy is warranted, he noted.

Major Finding: Hearing loss frequently complicates pneumococcal meningitis and is associated with coexisting otitis on admission and infection with serotype 9V.

Data Source: Two prospective, nationwide observational cohort studies of adults with community-acquired bacterial meningitis in the Netherlands.

Disclosures: Dr. Heckenberg and his colleagues had no financial disclosures.

BOSTON — Otitis on hospital admission and infection with pneumococcal serotype 9V were independently associated with hearing loss in patients who were treated for pneumococcal meningitis.

“Hearing loss is a major cause of morbidity in pneumococcal meningitis, affecting more than 20% of patients with the disease,” study investigator Dr. Sebastiaan G.B. Heckenberg noted. Based on the findings, “patients with coexisting otitis on admission and infection with serotype 9V are at highest risk and should be monitored closely for this outcome,” he said.

Using data from two prospective nationwide cohort studies in the Netherlands, Dr. Heckenberg of the Academic Medical Center in Amsterdam and colleagues identified 531 adults who survived pneumococcal meningitis from 1998-2002 and 2006-2009. All patients underwent neurologic examination at discharge and grading via the Glasgow Outcome Scale (GOS), with an unfavorable outcome defined as a GOS grade of 1-4. Additionally, the majority of patients had audiograms within 1 year after discharge.

Of the 531 patients, 112 experienced “any” hearing loss (defined as audiogram-assessed uni- or bilateral hearing loss of at least 20 decibels within 1 year post discharge, or hearing loss at discharge). A total of 47 experienced severe hearing loss (defined as World Health Organization hearing loss of at least grade 2, or hearing loss as a cause of unfavorable outcome at discharge).

In patients with any hearing loss, otitis on admission was reported in 53%, which was significantly higher than the 32% observed in patients with no hearing loss, Dr. Heckenberg stated. In fact, “on admission, otitis was the only characteristic that was associated with any hearing loss,” he said. “Severity of disease as reflected by low scores on the Glasgow Outcome Scale, systolic blood pressure, and [cerebrospinal fluid] white cell counts were not related to hearing loss in this group.”

With respect to severe hearing loss, otitis on admission was not significantly associated, “but there was a trend among severe hearing loss patients to have lower CSF white cell counts,” Dr. Heckenberg noted. Furthermore, an analysis of hearing loss incidence relative to pneumococcal serotype, which was available for 490 of the 531 patients, showed that serotype 9V was significantly associated with severe hearing loss, he said.

Of interest, Dr. Heckenberg noted, was that severe hearing loss was significantly less common among patients who received dexamethasone. Of the 530 patients for whom the information was available, 10 (4%) of the 240 patients who received dexamathasone experienced significant hearing loss, compared with 37 (13%) of the 290 patients who did not take the glucocorticoid.

This finding suggests that hearing loss associated with pneumococcal meningitis could be a function of inflammation, which is mediated by the steroid, he said. Further research into the preventive effect of glucocorticoid therapy is warranted, he noted.

Major Finding: The HCV protease inhibitors telaprevir and boceprevir improve sustained virologic response rates and shorten treatment duration in patients with chronic hepatitis C virus infection.

Data Source: Four phase III clinical trials evaluating the safety and efficacy of the direct-acting antivirals in treatment-naive and treatment-resistant HCV patients.

Disclosures: Dr. Jacobson and Dr. Sherman disclosed relationships with Vertex Pharmaceuticals, which manufactures telaprevir. Dr. Jacobson also has a relationship with Tibotec, which also is involved with the development of telaprevir. Dr. Poordad and Dr. Bacon also disclosed relationships with Merck, which manufactures boceprevir.

BOSTON — The forthcoming availability of the protease inhibitors telaprevir and boceprevir for the treatment of chronic hepatitis C is likely to vastly improve virologic response rates and cut treatment times, but experts warn that such advancements need to be balanced against the “huge potential” for misuse of the agents and the need to manage side effects and monitor for antiviral resistance.

When used in combination with standard therapy of pegylated interferon plus ribavirin-based therapy, both of these investigational drugs improved sustained virologic response rates and reduced treatment duration, compared with standard therapy alone, in four pivotal, phase III trials reported at the meeting.

Telaprevir Boosts Viral Cure Rates

In the ADVANCE trial, a three-arm, double-blind, placebo-controlled study, investigators compared two telaprevir-based regimens with standard therapy in 1,088 treatment-naive patients with chronic genotype 1 hepatitis C virus (HCV) infection, according to lead investigator Dr. Ira M. Jacobson of New York Weill Cornell Medical Center in New York City.

Patients in treatment arms 1 and 2 received 750 mg of telaprevir plus standard therapy for 8 and 12 weeks, respectively, whereas patients in the control group received standard therapy alone, which consisted of 180 mcg/week of pegylated interferon alfa-2a and 1,000-1,200 mg/day of ribavirin.

Patients who achieved extended, rapid virologic response (RVR) – defined as undetectable HCV RNA viral load at treatment weeks 4 and 12 – were treated with standard therapy for an additional 16 and 12 weeks in the 8- and 12-week telaprevir arms, respectively, for a total of 24 weeks, Dr. Jacobson explained. Patients in whom HCV RNA was detectable at either week 4 or 12 received an additional 40 and 36 weeks of therapy, respectively, for a total of 48 weeks, he said.

Compared with 44% of patients in the control group who achieved sustained virologic responses (SVR) 24 weeks after the last treatment, significantly more patients in both telaprevir arms – 69% of the 8-week group and 75% of the 12-week group – met that end point, Dr. Jacobson reported.

The extended RVR rates in the 8- and 12-week groups were 57% and 58%, respectively, compared with 8% in the control arm, he said.

Significantly improved SVRs were also observed in difficult-to-treat subgroups, according to Dr. Jacobson.

“Among black patients, the [SVR] rates were 58% and 62% in the 8- and 12-week treatment arms, and 25% in the control arm, and in cirrhotic patients the respective rates were 53%, 62%, and 33%,” he reported.

The phase III, open-label ILLUMINATE trial was designed to determine whether extending the telaprevir and standard therapy regimen from 24 to 48 weeks would be beneficial in treatment-naive, genotype 1 HCV patients who achieved extended RVR. In all, 540 patients were initially treated with the 12-week telaprevir regimen described above. Of the 352 patients who achieved RVR, 322 remained on treatment and were randomized to either a 24-week or 48-week treatment arm.

“The [SVR] rates associated with the 24-week and the 48-week arms were statistically similar, at 92% and 87.5%, respectively,” reported Dr. Kenneth E. Sherman of the University of Cincinnati. Analyses of the data based on race and extent of liver damage showed that 88% of black patients who experienced extended RVR achieved SVR in both the 24- and 48-week treatment arms, and 82% and 88% of patients with advanced fibrosis/cirrhosis achieved SVR in the 24-week and 48-week arms, respectively, he said.

The high viral cure rate observed in the study – the overall SVR rate was 72% in an intent-to-treat analysis – “[supports] the role of response-guided therapy with telaprevir-based regimens” in treatment-naive patients,” he said.

Boceprevir Benefits Nonresponders

Response-guided, fixed-duration therapy with boceprevir was safe and effective in a cohort of HCV genotype 1 patients who were enrolled in the RESPOND-2 study and who failed standard therapy, reported lead investigator Dr. Bruce R. Bacon of St. Louis University.

The 403 patients included those in whom prior standard therapy induced no notable decrease in HCV viral load (null responders) or a “not undetectable” decrease in HCV viral load (nonresponders), as well as those in whom prior treatment initially resulted in undetectable HCV RNA, followed by a viral rebound (relapsers), he said.

All the patients underwent a 4-week lead-in phase of standard therapy followed by a random assignment to continue standard therapy alone or in conjunction with 800 mg of boceprevir taken three times daily. The treatment duration for patients in the boceprevir arm with undetectable HCV RNA at study weeks 8 and 12 was 36 weeks, whereas those patients in whom HCV RNA was detectable at study week 8, but undetectable at study week 12, stopped boceprevir at week 36 but continued standard therapy for an additional 12 weeks, for a total treatment duration of 48 weeks, Dr. Bacon said. Patients in the control group were treated for 48 weeks.

The SVR rates at 24 weeks after treatment conclusion were significantly higher in the boceprevir groups, compared with the control group. In the response-guided and fixed-duration boceprevir groups, the SVR rates were 59% and 66%, respectively, compared with 21% in the control patients, he said.

In all study arms, “previous relapsers and previous null responders fared better than prior nonresponders,” Dr. Bacon said, noting that the respective SVR rates for previous relapsers, null responders, and nonresponders were 29%, 7%, and 0% in the control group; 69%, 40%, and 33% in the response-guided therapy group; and 75%, 52%, and 34% in the fixed-duration group.

Boceprevir with a standard therapy lead-in strategy was also evaluated in the SPRINT-2 study involving HCV genotype 1 treatment-naive patients, according to Dr. Fred Poordad of Cedars-Sinai Medical Center in Los Angeles.

The trial included 1,097 patients who underwent a similar 4-week standard therapy lead-in strategy as defined above, followed by the addition of placebo for 44 more weeks or by the addition of boceprevir, either for 24 more weeks for patients with undetectable HCV RNA at week 8 or for 24 more weeks plus 20 additional weeks of standard therapy for patients with detectable HCV RNA at week 8, but not at week 24, Dr. Poordad explained. Patients with detectable HCV RNA at week 24 were discontinued for futility, he said.

“In both the response-guided and fixed-treatment arms, boceprevir increased viral cure rates significantly, by approximately 70%,” he said. Specifically, the SVR rate was 63% in the 28-week response-guided group, 66% in the 48-week fixed-duration group, and 38% in the 48-week control group, he said.

In a cohort analysis of treatment response for the study's 159 black patients, the relative improvement in SVR rates remained significantly improved in the boceprevir arms, although the differences were not as robust, Dr. Poordad said. In this subgroup, the respective SVR rates in the response-guided therapy, fixed-duration therapy, and control groups were 42%, 53%, and 23%, respectively.

The rationale for using a lead-in strategy “is to help physicians identify patient responsiveness to interferon before adding boceprevir,” Dr. Poordad explained. This can provide an early indication of the likelihood of treatment success.

View on the News

The Potential for Misuse Is 'Huge'

In the next year, “we are going to see the approval of two direct-acting antiviral drugs – telaprevir and boceprevir. We anticipate the widespread use of these drugs in the United States and the European Union, as they've been shown to improve sustained virologic response rates by approximately 75% in treatment-naive patients,” Dr. Paul Pockros said at the meeting.

Unfortunately, there is also a “huge potential” for misuse of these drugs, owing to prescribing physicians' poor understanding of the therapeutic populations, inadequate viral-assay testing, poor side-effect management, and lack of monitoring for antiviral resistance, he said.

The designs of the trials on which approval will be based, as well as the resulting treatment regimens, are fairly complex, said Dr. Pockros, “so there will be lots of opportunities to screw things up.” For example, he hypothesized, “I am sure that some patients are going to be put on telaprevir for 44 weeks with a 4-week pegylated interferon/ribavirin lead-in [even though the lead-in strategy was evaluated for boceprevir, not telaprevir], and other patients might be put on boceprevir for 12 weeks with no lead-in.”

For optimal safety and efficacy, physicians must have a good understanding of the treatment regimens, particularly in special populations, and they must actively and frequently monitor for antiviral resistance. Additionally, physicians should anticipate problems with adherence, which is already an issue for some patients on standard therapy, he said.

The objective should be “to keep our eyes on the ball,” said Dr. Pockros. “Our primary goal moving forward with all of the new drugs is going to be eradicating the virus.”

PAUL J. POCKROS, M.D., is head of the division of gastroenterology/hepatology at the Scripps Clinic in La Jolla, Calif. He disclosed relationships with Vertex and Tibotec, which are involved in the development of telaprevir, and Merck, which manufactures boceprevir.

Vitals

Major Finding: The HCV protease inhibitors telaprevir and boceprevir improve sustained virologic response rates and shorten treatment duration in patients with chronic hepatitis C virus infection.

Data Source: Four phase III clinical trials evaluating the safety and efficacy of the direct-acting antivirals in treatment-naive and treatment-resistant HCV patients.

Disclosures: Dr. Jacobson and Dr. Sherman disclosed relationships with Vertex Pharmaceuticals, which manufactures telaprevir. Dr. Jacobson also has a relationship with Tibotec, which also is involved with the development of telaprevir. Dr. Poordad and Dr. Bacon also disclosed relationships with Merck, which manufactures boceprevir.

BOSTON — The forthcoming availability of the protease inhibitors telaprevir and boceprevir for the treatment of chronic hepatitis C is likely to vastly improve virologic response rates and cut treatment times, but experts warn that such advancements need to be balanced against the “huge potential” for misuse of the agents and the need to manage side effects and monitor for antiviral resistance.

When used in combination with standard therapy of pegylated interferon plus ribavirin-based therapy, both of these investigational drugs improved sustained virologic response rates and reduced treatment duration, compared with standard therapy alone, in four pivotal, phase III trials reported at the meeting.

Telaprevir Boosts Viral Cure Rates

In the ADVANCE trial, a three-arm, double-blind, placebo-controlled study, investigators compared two telaprevir-based regimens with standard therapy in 1,088 treatment-naive patients with chronic genotype 1 hepatitis C virus (HCV) infection, according to lead investigator Dr. Ira M. Jacobson of New York Weill Cornell Medical Center in New York City.

Patients in treatment arms 1 and 2 received 750 mg of telaprevir plus standard therapy for 8 and 12 weeks, respectively, whereas patients in the control group received standard therapy alone, which consisted of 180 mcg/week of pegylated interferon alfa-2a and 1,000-1,200 mg/day of ribavirin.

Patients who achieved extended, rapid virologic response (RVR) – defined as undetectable HCV RNA viral load at treatment weeks 4 and 12 – were treated with standard therapy for an additional 16 and 12 weeks in the 8- and 12-week telaprevir arms, respectively, for a total of 24 weeks, Dr. Jacobson explained. Patients in whom HCV RNA was detectable at either week 4 or 12 received an additional 40 and 36 weeks of therapy, respectively, for a total of 48 weeks, he said.

Compared with 44% of patients in the control group who achieved sustained virologic responses (SVR) 24 weeks after the last treatment, significantly more patients in both telaprevir arms – 69% of the 8-week group and 75% of the 12-week group – met that end point, Dr. Jacobson reported.

The extended RVR rates in the 8- and 12-week groups were 57% and 58%, respectively, compared with 8% in the control arm, he said.

Significantly improved SVRs were also observed in difficult-to-treat subgroups, according to Dr. Jacobson.

“Among black patients, the [SVR] rates were 58% and 62% in the 8- and 12-week treatment arms, and 25% in the control arm, and in cirrhotic patients the respective rates were 53%, 62%, and 33%,” he reported.

The phase III, open-label ILLUMINATE trial was designed to determine whether extending the telaprevir and standard therapy regimen from 24 to 48 weeks would be beneficial in treatment-naive, genotype 1 HCV patients who achieved extended RVR. In all, 540 patients were initially treated with the 12-week telaprevir regimen described above. Of the 352 patients who achieved RVR, 322 remained on treatment and were randomized to either a 24-week or 48-week treatment arm.

“The [SVR] rates associated with the 24-week and the 48-week arms were statistically similar, at 92% and 87.5%, respectively,” reported Dr. Kenneth E. Sherman of the University of Cincinnati. Analyses of the data based on race and extent of liver damage showed that 88% of black patients who experienced extended RVR achieved SVR in both the 24- and 48-week treatment arms, and 82% and 88% of patients with advanced fibrosis/cirrhosis achieved SVR in the 24-week and 48-week arms, respectively, he said.

The high viral cure rate observed in the study – the overall SVR rate was 72% in an intent-to-treat analysis – “[supports] the role of response-guided therapy with telaprevir-based regimens” in treatment-naive patients,” he said.

Boceprevir Benefits Nonresponders

Response-guided, fixed-duration therapy with boceprevir was safe and effective in a cohort of HCV genotype 1 patients who were enrolled in the RESPOND-2 study and who failed standard therapy, reported lead investigator Dr. Bruce R. Bacon of St. Louis University.

The 403 patients included those in whom prior standard therapy induced no notable decrease in HCV viral load (null responders) or a “not undetectable” decrease in HCV viral load (nonresponders), as well as those in whom prior treatment initially resulted in undetectable HCV RNA, followed by a viral rebound (relapsers), he said.

All the patients underwent a 4-week lead-in phase of standard therapy followed by a random assignment to continue standard therapy alone or in conjunction with 800 mg of boceprevir taken three times daily. The treatment duration for patients in the boceprevir arm with undetectable HCV RNA at study weeks 8 and 12 was 36 weeks, whereas those patients in whom HCV RNA was detectable at study week 8, but undetectable at study week 12, stopped boceprevir at week 36 but continued standard therapy for an additional 12 weeks, for a total treatment duration of 48 weeks, Dr. Bacon said. Patients in the control group were treated for 48 weeks.

The SVR rates at 24 weeks after treatment conclusion were significantly higher in the boceprevir groups, compared with the control group. In the response-guided and fixed-duration boceprevir groups, the SVR rates were 59% and 66%, respectively, compared with 21% in the control patients, he said.

In all study arms, “previous relapsers and previous null responders fared better than prior nonresponders,” Dr. Bacon said, noting that the respective SVR rates for previous relapsers, null responders, and nonresponders were 29%, 7%, and 0% in the control group; 69%, 40%, and 33% in the response-guided therapy group; and 75%, 52%, and 34% in the fixed-duration group.

Boceprevir with a standard therapy lead-in strategy was also evaluated in the SPRINT-2 study involving HCV genotype 1 treatment-naive patients, according to Dr. Fred Poordad of Cedars-Sinai Medical Center in Los Angeles.

The trial included 1,097 patients who underwent a similar 4-week standard therapy lead-in strategy as defined above, followed by the addition of placebo for 44 more weeks or by the addition of boceprevir, either for 24 more weeks for patients with undetectable HCV RNA at week 8 or for 24 more weeks plus 20 additional weeks of standard therapy for patients with detectable HCV RNA at week 8, but not at week 24, Dr. Poordad explained. Patients with detectable HCV RNA at week 24 were discontinued for futility, he said.

“In both the response-guided and fixed-treatment arms, boceprevir increased viral cure rates significantly, by approximately 70%,” he said. Specifically, the SVR rate was 63% in the 28-week response-guided group, 66% in the 48-week fixed-duration group, and 38% in the 48-week control group, he said.

In a cohort analysis of treatment response for the study's 159 black patients, the relative improvement in SVR rates remained significantly improved in the boceprevir arms, although the differences were not as robust, Dr. Poordad said. In this subgroup, the respective SVR rates in the response-guided therapy, fixed-duration therapy, and control groups were 42%, 53%, and 23%, respectively.

The rationale for using a lead-in strategy “is to help physicians identify patient responsiveness to interferon before adding boceprevir,” Dr. Poordad explained. This can provide an early indication of the likelihood of treatment success.

View on the News

The Potential for Misuse Is 'Huge'

In the next year, “we are going to see the approval of two direct-acting antiviral drugs – telaprevir and boceprevir. We anticipate the widespread use of these drugs in the United States and the European Union, as they've been shown to improve sustained virologic response rates by approximately 75% in treatment-naive patients,” Dr. Paul Pockros said at the meeting.

Unfortunately, there is also a “huge potential” for misuse of these drugs, owing to prescribing physicians' poor understanding of the therapeutic populations, inadequate viral-assay testing, poor side-effect management, and lack of monitoring for antiviral resistance, he said.

The designs of the trials on which approval will be based, as well as the resulting treatment regimens, are fairly complex, said Dr. Pockros, “so there will be lots of opportunities to screw things up.” For example, he hypothesized, “I am sure that some patients are going to be put on telaprevir for 44 weeks with a 4-week pegylated interferon/ribavirin lead-in [even though the lead-in strategy was evaluated for boceprevir, not telaprevir], and other patients might be put on boceprevir for 12 weeks with no lead-in.”

For optimal safety and efficacy, physicians must have a good understanding of the treatment regimens, particularly in special populations, and they must actively and frequently monitor for antiviral resistance. Additionally, physicians should anticipate problems with adherence, which is already an issue for some patients on standard therapy, he said.

The objective should be “to keep our eyes on the ball,” said Dr. Pockros. “Our primary goal moving forward with all of the new drugs is going to be eradicating the virus.”

PAUL J. POCKROS, M.D., is head of the division of gastroenterology/hepatology at the Scripps Clinic in La Jolla, Calif. He disclosed relationships with Vertex and Tibotec, which are involved in the development of telaprevir, and Merck, which manufactures boceprevir.

Vitals

Major Finding: The HCV protease inhibitors telaprevir and boceprevir improve sustained virologic response rates and shorten treatment duration in patients with chronic hepatitis C virus infection.

Data Source: Four phase III clinical trials evaluating the safety and efficacy of the direct-acting antivirals in treatment-naive and treatment-resistant HCV patients.

Disclosures: Dr. Jacobson and Dr. Sherman disclosed relationships with Vertex Pharmaceuticals, which manufactures telaprevir. Dr. Jacobson also has a relationship with Tibotec, which also is involved with the development of telaprevir. Dr. Poordad and Dr. Bacon also disclosed relationships with Merck, which manufactures boceprevir.

BOSTON — The forthcoming availability of the protease inhibitors telaprevir and boceprevir for the treatment of chronic hepatitis C is likely to vastly improve virologic response rates and cut treatment times, but experts warn that such advancements need to be balanced against the “huge potential” for misuse of the agents and the need to manage side effects and monitor for antiviral resistance.

When used in combination with standard therapy of pegylated interferon plus ribavirin-based therapy, both of these investigational drugs improved sustained virologic response rates and reduced treatment duration, compared with standard therapy alone, in four pivotal, phase III trials reported at the meeting.

Telaprevir Boosts Viral Cure Rates

In the ADVANCE trial, a three-arm, double-blind, placebo-controlled study, investigators compared two telaprevir-based regimens with standard therapy in 1,088 treatment-naive patients with chronic genotype 1 hepatitis C virus (HCV) infection, according to lead investigator Dr. Ira M. Jacobson of New York Weill Cornell Medical Center in New York City.

Patients in treatment arms 1 and 2 received 750 mg of telaprevir plus standard therapy for 8 and 12 weeks, respectively, whereas patients in the control group received standard therapy alone, which consisted of 180 mcg/week of pegylated interferon alfa-2a and 1,000-1,200 mg/day of ribavirin.

Patients who achieved extended, rapid virologic response (RVR) – defined as undetectable HCV RNA viral load at treatment weeks 4 and 12 – were treated with standard therapy for an additional 16 and 12 weeks in the 8- and 12-week telaprevir arms, respectively, for a total of 24 weeks, Dr. Jacobson explained. Patients in whom HCV RNA was detectable at either week 4 or 12 received an additional 40 and 36 weeks of therapy, respectively, for a total of 48 weeks, he said.

Compared with 44% of patients in the control group who achieved sustained virologic responses (SVR) 24 weeks after the last treatment, significantly more patients in both telaprevir arms – 69% of the 8-week group and 75% of the 12-week group – met that end point, Dr. Jacobson reported.

The extended RVR rates in the 8- and 12-week groups were 57% and 58%, respectively, compared with 8% in the control arm, he said.

Significantly improved SVRs were also observed in difficult-to-treat subgroups, according to Dr. Jacobson.

“Among black patients, the [SVR] rates were 58% and 62% in the 8- and 12-week treatment arms, and 25% in the control arm, and in cirrhotic patients the respective rates were 53%, 62%, and 33%,” he reported.

The phase III, open-label ILLUMINATE trial was designed to determine whether extending the telaprevir and standard therapy regimen from 24 to 48 weeks would be beneficial in treatment-naive, genotype 1 HCV patients who achieved extended RVR. In all, 540 patients were initially treated with the 12-week telaprevir regimen described above. Of the 352 patients who achieved RVR, 322 remained on treatment and were randomized to either a 24-week or 48-week treatment arm.

“The [SVR] rates associated with the 24-week and the 48-week arms were statistically similar, at 92% and 87.5%, respectively,” reported Dr. Kenneth E. Sherman of the University of Cincinnati. Analyses of the data based on race and extent of liver damage showed that 88% of black patients who experienced extended RVR achieved SVR in both the 24- and 48-week treatment arms, and 82% and 88% of patients with advanced fibrosis/cirrhosis achieved SVR in the 24-week and 48-week arms, respectively, he said.

The high viral cure rate observed in the study – the overall SVR rate was 72% in an intent-to-treat analysis – “[supports] the role of response-guided therapy with telaprevir-based regimens” in treatment-naive patients,” he said.

Boceprevir Benefits Nonresponders

Response-guided, fixed-duration therapy with boceprevir was safe and effective in a cohort of HCV genotype 1 patients who were enrolled in the RESPOND-2 study and who failed standard therapy, reported lead investigator Dr. Bruce R. Bacon of St. Louis University.

The 403 patients included those in whom prior standard therapy induced no notable decrease in HCV viral load (null responders) or a “not undetectable” decrease in HCV viral load (nonresponders), as well as those in whom prior treatment initially resulted in undetectable HCV RNA, followed by a viral rebound (relapsers), he said.

All the patients underwent a 4-week lead-in phase of standard therapy followed by a random assignment to continue standard therapy alone or in conjunction with 800 mg of boceprevir taken three times daily. The treatment duration for patients in the boceprevir arm with undetectable HCV RNA at study weeks 8 and 12 was 36 weeks, whereas those patients in whom HCV RNA was detectable at study week 8, but undetectable at study week 12, stopped boceprevir at week 36 but continued standard therapy for an additional 12 weeks, for a total treatment duration of 48 weeks, Dr. Bacon said. Patients in the control group were treated for 48 weeks.

The SVR rates at 24 weeks after treatment conclusion were significantly higher in the boceprevir groups, compared with the control group. In the response-guided and fixed-duration boceprevir groups, the SVR rates were 59% and 66%, respectively, compared with 21% in the control patients, he said.

In all study arms, “previous relapsers and previous null responders fared better than prior nonresponders,” Dr. Bacon said, noting that the respective SVR rates for previous relapsers, null responders, and nonresponders were 29%, 7%, and 0% in the control group; 69%, 40%, and 33% in the response-guided therapy group; and 75%, 52%, and 34% in the fixed-duration group.

Boceprevir with a standard therapy lead-in strategy was also evaluated in the SPRINT-2 study involving HCV genotype 1 treatment-naive patients, according to Dr. Fred Poordad of Cedars-Sinai Medical Center in Los Angeles.

The trial included 1,097 patients who underwent a similar 4-week standard therapy lead-in strategy as defined above, followed by the addition of placebo for 44 more weeks or by the addition of boceprevir, either for 24 more weeks for patients with undetectable HCV RNA at week 8 or for 24 more weeks plus 20 additional weeks of standard therapy for patients with detectable HCV RNA at week 8, but not at week 24, Dr. Poordad explained. Patients with detectable HCV RNA at week 24 were discontinued for futility, he said.

“In both the response-guided and fixed-treatment arms, boceprevir increased viral cure rates significantly, by approximately 70%,” he said. Specifically, the SVR rate was 63% in the 28-week response-guided group, 66% in the 48-week fixed-duration group, and 38% in the 48-week control group, he said.

In a cohort analysis of treatment response for the study's 159 black patients, the relative improvement in SVR rates remained significantly improved in the boceprevir arms, although the differences were not as robust, Dr. Poordad said. In this subgroup, the respective SVR rates in the response-guided therapy, fixed-duration therapy, and control groups were 42%, 53%, and 23%, respectively.

The rationale for using a lead-in strategy “is to help physicians identify patient responsiveness to interferon before adding boceprevir,” Dr. Poordad explained. This can provide an early indication of the likelihood of treatment success.

View on the News

The Potential for Misuse Is 'Huge'

In the next year, “we are going to see the approval of two direct-acting antiviral drugs – telaprevir and boceprevir. We anticipate the widespread use of these drugs in the United States and the European Union, as they've been shown to improve sustained virologic response rates by approximately 75% in treatment-naive patients,” Dr. Paul Pockros said at the meeting.

Unfortunately, there is also a “huge potential” for misuse of these drugs, owing to prescribing physicians' poor understanding of the therapeutic populations, inadequate viral-assay testing, poor side-effect management, and lack of monitoring for antiviral resistance, he said.

The designs of the trials on which approval will be based, as well as the resulting treatment regimens, are fairly complex, said Dr. Pockros, “so there will be lots of opportunities to screw things up.” For example, he hypothesized, “I am sure that some patients are going to be put on telaprevir for 44 weeks with a 4-week pegylated interferon/ribavirin lead-in [even though the lead-in strategy was evaluated for boceprevir, not telaprevir], and other patients might be put on boceprevir for 12 weeks with no lead-in.”

For optimal safety and efficacy, physicians must have a good understanding of the treatment regimens, particularly in special populations, and they must actively and frequently monitor for antiviral resistance. Additionally, physicians should anticipate problems with adherence, which is already an issue for some patients on standard therapy, he said.

The objective should be “to keep our eyes on the ball,” said Dr. Pockros. “Our primary goal moving forward with all of the new drugs is going to be eradicating the virus.”

PAUL J. POCKROS, M.D., is head of the division of gastroenterology/hepatology at the Scripps Clinic in La Jolla, Calif. He disclosed relationships with Vertex and Tibotec, which are involved in the development of telaprevir, and Merck, which manufactures boceprevir.

Vitals

BOSTON — A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the meeting.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study's treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

“There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant,” he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%.

The vaccine strategy appears to be safe. “The most common associated adverse events were mild, transient injection-site reactions,” said Dr. Pockros. In addition, “the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms.”

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, “mimicked what we saw with a virologic response,” he said.

“Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response.”

Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted. Future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed a financial relationship with GlobeImmune.

The overall benefit in the vaccine vs. control groups was statistically significant.

Source DR. POCKROSwww.nejm.org

BOSTON — A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the meeting.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study's treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

“There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant,” he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%.

The vaccine strategy appears to be safe. “The most common associated adverse events were mild, transient injection-site reactions,” said Dr. Pockros. In addition, “the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms.”

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, “mimicked what we saw with a virologic response,” he said.

“Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response.”

Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted. Future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed a financial relationship with GlobeImmune.

The overall benefit in the vaccine vs. control groups was statistically significant.

Source DR. POCKROSwww.nejm.org

BOSTON — A therapeutic vaccine against the hepatitis C virus was associated with a significantly higher sustained virologic response rate when added to standard-of-care treatment, and the findings justify further development of the vaccine, Dr. Paul Pockros reported at the meeting.

In the proof-of-concept trial, 133 patients infected with hepatitis C virus (HCV) genotype 1 were randomized to either triple therapy comprising the experimental GI-5005 vaccine, which is designed to elicit a T-cell response specific to HCV, along with pegylated interferon alfa-2b plus ribavirin (P/R), or the standard P/R therapy alone.

The primary outcome measure was sustained virologic response (SVR), defined as undetectable HCV RNA at 6 months after treatment, said Dr. Pockros of the Scripps Clinic in La Jolla, Calif.

The 68 patients in the experimental group initially received monotherapy with the vaccine, consisting of five weekly injections followed by two monthly injections for a 12-week lead-in period, before progressing to the standard-of-care P/R treatment and once-monthly injections. The 65 patients in the control group received standard-of-care P/R treatment alone.

In both groups, the treatment duration was 48 weeks for treatment-naive patients and 72 weeks for those who had a poor or partial response to prior P/R treatment, said Dr. Pockros. Patients in whom prior P/R therapy induced no notable decrease in HCV viral load, as well as those in whom prior treatment initially resulted in undetectable HCV RNA followed by a viral rebound, were excluded from the analysis.

Among the study's treatment-naive patients, 58% of those who received the vaccine achieved SVR, compared with 48% of those who received P/R alone. Among the prior poor and partial responders, the respective SVR rates in the vaccine and control groups were 17% and 5%, Dr. Pockros reported.

“There was a slight benefit in the treatment-naive and nonresponders, [but] this was numerical only and was not statistically significant,” he said. However, the overall benefit in the vaccine vs. control groups was statistically significant, with respective SVR rates of 47% and 35%.

The vaccine strategy appears to be safe. “The most common associated adverse events were mild, transient injection-site reactions,” said Dr. Pockros. In addition, “the discontinuation rates due to adverse events were comparable [13%] in both the triple-therapy and standard-of-care arms.”

Of particular interest, Dr. Pockros noted, was the T-cell response in a subgroup of difficult-to-treat patients receiving the vaccine. Previous studies have suggested that patients carrying the T allele of the IL28 gene are at high risk of treatment failure with the standard interferon-based therapy. The T-cell response in vaccine-treated patients, as measured by interferon-gamma enzyme-linked ImmunoSpot assay, “mimicked what we saw with a virologic response,” he said.

“Four of five T/T allele patients had a T-cell response – one did not actually get treated – but none of the patients who received standard of care had a T-cell response.”

Although the findings need to be confirmed in additional studies with larger patient populations, the vaccine will likely be genotype specific, he noted. Future studies will evaluate the efficacy of monotherapy with the vaccine in genotype-specific patients, Dr. Pockros said.

The proof-of-concept study was funded by GlobeImmune, manufacturer of the vaccine. Dr. Pockros disclosed a financial relationship with GlobeImmune.

The overall benefit in the vaccine vs. control groups was statistically significant.

Source DR. POCKROSwww.nejm.org

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, a report shows.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53–90 years, drawn from the study's third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer's disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547–62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes-related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%–50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, a report shows.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53–90 years, drawn from the study's third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer's disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547–62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes-related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%–50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, a report shows.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53–90 years, drawn from the study's third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer's disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547–62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes-related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%–50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

BOSTON – Older adults with mental illness are less likely to undergo chemotherapy after a cancer diagnosis than those without mental illness, a study has shown. The findings are consistent with those from previous studies suggesting disparities in the care of chronic conditions among mentally ill older adults, Dr. Simha E. Ravven reported at the meeting.

“Even though adults with mental illness are often well connected to primary care, our findings suggest that they may not be receiving the same kind of cancer treatment and that they may need more support and counseling to get the same care,” said Dr. Ravven, a fellow at Harvard Medical School, Boston.

To determine whether cancer screening and treatment vary for people with prior mental illness, and if mortality after a cancer diagnosis differs in this population, Dr. Ravven and her colleagues reviewed records for the 19,045 participants of the year 2000 wave of the National Institute on Aging's nationally representative, longitudinal Health and Retirement Study (HRS). The study, conducted by the University of Michigan, Ann Arbor, surveyed adults born in 1947 or earlier to assess mental health, financial status, family support, and retirement planning among aging Americans, she said.

Of the full study cohort, about 14% had a history of mental illness, according to Dr. Ravven. While both men and women with a history of mental illness were as likely to receive clinical cancer screening, including a breast exam, a Pap test, mammography, and a prostate exam within 2 years prior to the survey as part of the general population, individuals with mental illness who had a recent cancer diagnosis were significantly less likely to receive chemotherapy, with an odds ratio of 0.33, she said. No significant differences wee found in receipt of radiation therapy, surgery, or biopsy, she reported.

When assessed by gender, the odds ratio for receiving chemotherapy among women with a history of mental illness was especially low relative to women without mental illness, with an odds ratio of 0.18. No significant difference was found between men with and without mental illness, Dr. Ravven said.

With respect to mortality, men with a history of mental illness and cancer were nearly three times more likely to die from their cancer within 2 years than were men without mental illness, while the opposite was true for women, Dr. Ravven noted. “Women with a history of mental illness who had had a cancer diagnosis had a significantly lower risk of mortality within 2 years than [did] those without,” she said.

While the reasons for the disparities are unclear, it is possible that patients with mental illness avoid chemotherapy because they are not psychologically prepared for the rigorous treatment or their physicians have concerns about treatment adherence, Dr. Ravven hypothesized.

The findings are limited by the study's retrospective design and failure to look at stage of cancer diagnosis or cancer site, Dr. Ravven acknowledged.

It is possible that treatment disparities relate to the fact that chemotherapy might not have been part of the standard treatment protocol for certain stage cancers.

Dr. Ravven and her colleagues plan to further investigate the treatment disparities, she said, noting that future research will include more detailed information, including cancer stage and site, and the nature and severity of the mental illness.

BOSTON – Older adults with mental illness are less likely to undergo chemotherapy after a cancer diagnosis than those without mental illness, a study has shown. The findings are consistent with those from previous studies suggesting disparities in the care of chronic conditions among mentally ill older adults, Dr. Simha E. Ravven reported at the meeting.

“Even though adults with mental illness are often well connected to primary care, our findings suggest that they may not be receiving the same kind of cancer treatment and that they may need more support and counseling to get the same care,” said Dr. Ravven, a fellow at Harvard Medical School, Boston.

To determine whether cancer screening and treatment vary for people with prior mental illness, and if mortality after a cancer diagnosis differs in this population, Dr. Ravven and her colleagues reviewed records for the 19,045 participants of the year 2000 wave of the National Institute on Aging's nationally representative, longitudinal Health and Retirement Study (HRS). The study, conducted by the University of Michigan, Ann Arbor, surveyed adults born in 1947 or earlier to assess mental health, financial status, family support, and retirement planning among aging Americans, she said.

Of the full study cohort, about 14% had a history of mental illness, according to Dr. Ravven. While both men and women with a history of mental illness were as likely to receive clinical cancer screening, including a breast exam, a Pap test, mammography, and a prostate exam within 2 years prior to the survey as part of the general population, individuals with mental illness who had a recent cancer diagnosis were significantly less likely to receive chemotherapy, with an odds ratio of 0.33, she said. No significant differences wee found in receipt of radiation therapy, surgery, or biopsy, she reported.

When assessed by gender, the odds ratio for receiving chemotherapy among women with a history of mental illness was especially low relative to women without mental illness, with an odds ratio of 0.18. No significant difference was found between men with and without mental illness, Dr. Ravven said.

With respect to mortality, men with a history of mental illness and cancer were nearly three times more likely to die from their cancer within 2 years than were men without mental illness, while the opposite was true for women, Dr. Ravven noted. “Women with a history of mental illness who had had a cancer diagnosis had a significantly lower risk of mortality within 2 years than [did] those without,” she said.

While the reasons for the disparities are unclear, it is possible that patients with mental illness avoid chemotherapy because they are not psychologically prepared for the rigorous treatment or their physicians have concerns about treatment adherence, Dr. Ravven hypothesized.

The findings are limited by the study's retrospective design and failure to look at stage of cancer diagnosis or cancer site, Dr. Ravven acknowledged.

It is possible that treatment disparities relate to the fact that chemotherapy might not have been part of the standard treatment protocol for certain stage cancers.

Dr. Ravven and her colleagues plan to further investigate the treatment disparities, she said, noting that future research will include more detailed information, including cancer stage and site, and the nature and severity of the mental illness.

BOSTON – Older adults with mental illness are less likely to undergo chemotherapy after a cancer diagnosis than those without mental illness, a study has shown. The findings are consistent with those from previous studies suggesting disparities in the care of chronic conditions among mentally ill older adults, Dr. Simha E. Ravven reported at the meeting.

“Even though adults with mental illness are often well connected to primary care, our findings suggest that they may not be receiving the same kind of cancer treatment and that they may need more support and counseling to get the same care,” said Dr. Ravven, a fellow at Harvard Medical School, Boston.

To determine whether cancer screening and treatment vary for people with prior mental illness, and if mortality after a cancer diagnosis differs in this population, Dr. Ravven and her colleagues reviewed records for the 19,045 participants of the year 2000 wave of the National Institute on Aging's nationally representative, longitudinal Health and Retirement Study (HRS). The study, conducted by the University of Michigan, Ann Arbor, surveyed adults born in 1947 or earlier to assess mental health, financial status, family support, and retirement planning among aging Americans, she said.

Of the full study cohort, about 14% had a history of mental illness, according to Dr. Ravven. While both men and women with a history of mental illness were as likely to receive clinical cancer screening, including a breast exam, a Pap test, mammography, and a prostate exam within 2 years prior to the survey as part of the general population, individuals with mental illness who had a recent cancer diagnosis were significantly less likely to receive chemotherapy, with an odds ratio of 0.33, she said. No significant differences wee found in receipt of radiation therapy, surgery, or biopsy, she reported.

When assessed by gender, the odds ratio for receiving chemotherapy among women with a history of mental illness was especially low relative to women without mental illness, with an odds ratio of 0.18. No significant difference was found between men with and without mental illness, Dr. Ravven said.

With respect to mortality, men with a history of mental illness and cancer were nearly three times more likely to die from their cancer within 2 years than were men without mental illness, while the opposite was true for women, Dr. Ravven noted. “Women with a history of mental illness who had had a cancer diagnosis had a significantly lower risk of mortality within 2 years than [did] those without,” she said.

While the reasons for the disparities are unclear, it is possible that patients with mental illness avoid chemotherapy because they are not psychologically prepared for the rigorous treatment or their physicians have concerns about treatment adherence, Dr. Ravven hypothesized.

The findings are limited by the study's retrospective design and failure to look at stage of cancer diagnosis or cancer site, Dr. Ravven acknowledged.

It is possible that treatment disparities relate to the fact that chemotherapy might not have been part of the standard treatment protocol for certain stage cancers.

Dr. Ravven and her colleagues plan to further investigate the treatment disparities, she said, noting that future research will include more detailed information, including cancer stage and site, and the nature and severity of the mental illness.

Once perceived as a predominantly benign condition characterized by joint laxity, hypermobility, and associated musculoskeletal symptoms in otherwise healthy children and adults, joint hypermobility syndrome is now understood to be a multifaceted, multisystemic heritable disorder of connective tissue.

Its range of potential clinical consequences "resonate far beyond the confines of the musculoskeletal system," according to Dr. Rodney Grahame, a consultant rheumatologist at University College Hospital in London. "There is hardly a clinical specialty to be found that is not touched in one way or another by joint hypermobility syndrome" (JHS), he said. In addition to "loose" joints, other symptoms can include pain, joint clicking, joint instability, skin changes, a range of autonomic disturbances, and muscle deconditioning because of pain avoidance.

In this column, Dr. Grahame discusses the clinical manifestations of JHS, widespread misperceptions about the disorder, the consequences of missed or delayed diagnoses, and important diagnostic and treatment considerations.

QUESTION: What are the most important clinical and laboratory features of JHS?

Dr. Grahame: JHS was initially defined in 1967 as the occurrence of musculoskeletal symptoms in the presence of generalized joint hypermobility. Patients usually present with noninflammatory joint and/or spinal pain, recurrent soft tissue injury or overuse lesions, and joint dislocations or subluxations. Over the last decade, it has become evident that chronic pain, dysautonomia, and gastrointestinal dysmotility are frequently encountered complications. In addition to joint hypermobility, key diagnostic features include such skin changes as increased stretchiness, paper-thin scars, striae atrophicae, and features of a marfanoid habitus. There are currently no diagnostic laboratory tests for JHS.

QUESTION: Early literature describes JHS as a mostly harmless condition, but more recent data suggest that the syndrome can have serious clinical consequences. How do these different perspectives affect patient management?

Dr. Grahame: Enormously! In the former view, which is still widely held, hypermobility is largely perceived as a trivial disorder that does not merit serious consideration by rheumatologists on the basis that if there are no inflammatory markers, it is of no consequence. Nothing could be further from the truth. Clinicians appear to be frequently unaware of the recent literature concerning systemic complications, so patients’ complaints may be discounted. Patients may even be told that their symptoms are "in the mind" and that they should see a psychiatrist. They are often left to "shop around" in vain, searching for a doctor who understands and believes their symptoms and attempts to alleviate them (Nat. Clin. Pract. Rheumatol. 2008;4:522-4). By contrast, the identification and recognition of features of a heritable disorder of connective tissue (HDCT) are much more likely to attract serious attention. Unfortunately, the HDCTs are not uniformly taught in rheumatology training programs, and accredited rheumatologists may not be familiar with them. By default, the care of patients with HDCTs may pass to clinical geneticists, who have enormously wide knowledge but who are not trained in rheumatology.

QUESTION: How can clinicians distinguish JHS from other HDCTs, such as Ehlers-Danlos syndrome?

Dr. Grahame: The debate as to whether JHS and Ehlers-Danlos syndrome–hypermobility type (HEDS) are one and the same has raged for 40 years. The tide has now definitely turned in favor of the "lumpers" as against the "splitters". Gradually, as incontrovertibly convincing evidence has appeared, it has become obvious that JHS and HEDS are either truly identical, or if not identical, at least indistinguishable from one another (Am. J. Med. Genet. A. 2009;149A:2368-70).

It is clearly incumbent on all clinicians to be aware of the more serious HDCTs such as Marfan syndrome and Ehlers-Danlos syndrome–vascular type (VEDS), which carry the risk of life-threatening complications, such as aortic aneurysm formation in the case of Marfan’s, and arterial, visceral, or uterine rupture in the case of VEDS. Admittedly, however, it is not always easy to differentiate between those HDCTs that carry such high risk from the more benign JHS/HEDS. Both VEDS and Marfan’s have recognizable phenotypic features and their identification has been facilitated in recent years by genetic testing. One must strive to be alert to the possibility of encountering a more serious form and to be armed with a heightened index of clinical suspicion. Eliciting a careful personal and family history is all-important. This entails seeking out detailed information on close family members, and in particular, those who may have died unexpectedly or suddenly early in life. The advent of the echocardiogram has been a major step forward in spotting early aortic root dilatation at a time when surgical intervention can be lifesaving. Examining the eye by slit-lamp is another useful tool in helping to exclude ocular evidence of Marfan’s.

QUESTION: Is a diagnosis of JHS associated with an increased risk for other musculoskeletal disorders?

Dr. Grahame: Most clinicians are aware of the susceptibility and vulnerability to trauma and joint instability that accompanies hypermobility, but few seem to be cognizant of the devastating effects on function and quality of life posed by the frequent occurrence of chronic pain and deconditioning that can occur if the condition is not handled correctly.

QUESTION: What are some of the consequences of delayed diagnosis, and what are some of the benefits of early diagnosis?

Dr. Grahame: Delayed diagnosis leaves patients not knowing what is causing their pain and distress. Being told that hypermobility cannot be responsible for their degree of pain only serves to cause further dismay. Even more serious than the upset to their emotional equilibrium is the progressive loss of mobility that they suffer, resulting ultimately in their becoming potentially chairbound or even bedbound. Because movement is painful, they intuitively adopt a strategy of pain avoidance through movement avoidance. The result is a predictable decline in independence and a descent into disability. The result is that people who are generally young and formerly physically active in various pursuits can be struck down in their prime, in spite of having locomotor systems that are largely intact.

QUESTION: What are some of the most important management considerations?

Dr. Grahame: Hypermobile subjects should be encouraged to achieve maximal fitness at all ages as a means of avoiding many of the musculoskeletal lesions to which they are predisposed by virtue of their fragile tissues. Having strong muscles helps to improve proprioception, stabilize core muscle groups and unstable joints, and improve stamina. Physical therapists have effectively adapted the principles of physiotherapy to the needs of patients with lax and fragile tissues.

Chronic pain in JHS generally does not respond well to analgesic medications, but pain management using cognitive behavioral methods has enabled many patients to return to a reasonable quality of life. Finally, surgery should be undertaken only after careful consideration of the risks of delayed healing, after the anticipated impact on outcome of a connective tissue disorder have been considered, and when conservative alternative nonsurgical treatments are not available.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Grahame is also an honorary consultant in pediatric rheumatology at the Great Ormond Street Hospital for Children and emeritus professor of rheumatology at University College London. He disclosed having no conflicts of interest.

Once perceived as a predominantly benign condition characterized by joint laxity, hypermobility, and associated musculoskeletal symptoms in otherwise healthy children and adults, joint hypermobility syndrome is now understood to be a multifaceted, multisystemic heritable disorder of connective tissue.

Its range of potential clinical consequences "resonate far beyond the confines of the musculoskeletal system," according to Dr. Rodney Grahame, a consultant rheumatologist at University College Hospital in London. "There is hardly a clinical specialty to be found that is not touched in one way or another by joint hypermobility syndrome" (JHS), he said. In addition to "loose" joints, other symptoms can include pain, joint clicking, joint instability, skin changes, a range of autonomic disturbances, and muscle deconditioning because of pain avoidance.

In this column, Dr. Grahame discusses the clinical manifestations of JHS, widespread misperceptions about the disorder, the consequences of missed or delayed diagnoses, and important diagnostic and treatment considerations.

QUESTION: What are the most important clinical and laboratory features of JHS?

Dr. Grahame: JHS was initially defined in 1967 as the occurrence of musculoskeletal symptoms in the presence of generalized joint hypermobility. Patients usually present with noninflammatory joint and/or spinal pain, recurrent soft tissue injury or overuse lesions, and joint dislocations or subluxations. Over the last decade, it has become evident that chronic pain, dysautonomia, and gastrointestinal dysmotility are frequently encountered complications. In addition to joint hypermobility, key diagnostic features include such skin changes as increased stretchiness, paper-thin scars, striae atrophicae, and features of a marfanoid habitus. There are currently no diagnostic laboratory tests for JHS.

QUESTION: Early literature describes JHS as a mostly harmless condition, but more recent data suggest that the syndrome can have serious clinical consequences. How do these different perspectives affect patient management?

Dr. Grahame: Enormously! In the former view, which is still widely held, hypermobility is largely perceived as a trivial disorder that does not merit serious consideration by rheumatologists on the basis that if there are no inflammatory markers, it is of no consequence. Nothing could be further from the truth. Clinicians appear to be frequently unaware of the recent literature concerning systemic complications, so patients’ complaints may be discounted. Patients may even be told that their symptoms are "in the mind" and that they should see a psychiatrist. They are often left to "shop around" in vain, searching for a doctor who understands and believes their symptoms and attempts to alleviate them (Nat. Clin. Pract. Rheumatol. 2008;4:522-4). By contrast, the identification and recognition of features of a heritable disorder of connective tissue (HDCT) are much more likely to attract serious attention. Unfortunately, the HDCTs are not uniformly taught in rheumatology training programs, and accredited rheumatologists may not be familiar with them. By default, the care of patients with HDCTs may pass to clinical geneticists, who have enormously wide knowledge but who are not trained in rheumatology.

QUESTION: How can clinicians distinguish JHS from other HDCTs, such as Ehlers-Danlos syndrome?

Dr. Grahame: The debate as to whether JHS and Ehlers-Danlos syndrome–hypermobility type (HEDS) are one and the same has raged for 40 years. The tide has now definitely turned in favor of the "lumpers" as against the "splitters". Gradually, as incontrovertibly convincing evidence has appeared, it has become obvious that JHS and HEDS are either truly identical, or if not identical, at least indistinguishable from one another (Am. J. Med. Genet. A. 2009;149A:2368-70).

It is clearly incumbent on all clinicians to be aware of the more serious HDCTs such as Marfan syndrome and Ehlers-Danlos syndrome–vascular type (VEDS), which carry the risk of life-threatening complications, such as aortic aneurysm formation in the case of Marfan’s, and arterial, visceral, or uterine rupture in the case of VEDS. Admittedly, however, it is not always easy to differentiate between those HDCTs that carry such high risk from the more benign JHS/HEDS. Both VEDS and Marfan’s have recognizable phenotypic features and their identification has been facilitated in recent years by genetic testing. One must strive to be alert to the possibility of encountering a more serious form and to be armed with a heightened index of clinical suspicion. Eliciting a careful personal and family history is all-important. This entails seeking out detailed information on close family members, and in particular, those who may have died unexpectedly or suddenly early in life. The advent of the echocardiogram has been a major step forward in spotting early aortic root dilatation at a time when surgical intervention can be lifesaving. Examining the eye by slit-lamp is another useful tool in helping to exclude ocular evidence of Marfan’s.

QUESTION: Is a diagnosis of JHS associated with an increased risk for other musculoskeletal disorders?

Dr. Grahame: Most clinicians are aware of the susceptibility and vulnerability to trauma and joint instability that accompanies hypermobility, but few seem to be cognizant of the devastating effects on function and quality of life posed by the frequent occurrence of chronic pain and deconditioning that can occur if the condition is not handled correctly.

QUESTION: What are some of the consequences of delayed diagnosis, and what are some of the benefits of early diagnosis?

Dr. Grahame: Delayed diagnosis leaves patients not knowing what is causing their pain and distress. Being told that hypermobility cannot be responsible for their degree of pain only serves to cause further dismay. Even more serious than the upset to their emotional equilibrium is the progressive loss of mobility that they suffer, resulting ultimately in their becoming potentially chairbound or even bedbound. Because movement is painful, they intuitively adopt a strategy of pain avoidance through movement avoidance. The result is a predictable decline in independence and a descent into disability. The result is that people who are generally young and formerly physically active in various pursuits can be struck down in their prime, in spite of having locomotor systems that are largely intact.

QUESTION: What are some of the most important management considerations?

Dr. Grahame: Hypermobile subjects should be encouraged to achieve maximal fitness at all ages as a means of avoiding many of the musculoskeletal lesions to which they are predisposed by virtue of their fragile tissues. Having strong muscles helps to improve proprioception, stabilize core muscle groups and unstable joints, and improve stamina. Physical therapists have effectively adapted the principles of physiotherapy to the needs of patients with lax and fragile tissues.

Chronic pain in JHS generally does not respond well to analgesic medications, but pain management using cognitive behavioral methods has enabled many patients to return to a reasonable quality of life. Finally, surgery should be undertaken only after careful consideration of the risks of delayed healing, after the anticipated impact on outcome of a connective tissue disorder have been considered, and when conservative alternative nonsurgical treatments are not available.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Grahame is also an honorary consultant in pediatric rheumatology at the Great Ormond Street Hospital for Children and emeritus professor of rheumatology at University College London. He disclosed having no conflicts of interest.

Once perceived as a predominantly benign condition characterized by joint laxity, hypermobility, and associated musculoskeletal symptoms in otherwise healthy children and adults, joint hypermobility syndrome is now understood to be a multifaceted, multisystemic heritable disorder of connective tissue.

Its range of potential clinical consequences "resonate far beyond the confines of the musculoskeletal system," according to Dr. Rodney Grahame, a consultant rheumatologist at University College Hospital in London. "There is hardly a clinical specialty to be found that is not touched in one way or another by joint hypermobility syndrome" (JHS), he said. In addition to "loose" joints, other symptoms can include pain, joint clicking, joint instability, skin changes, a range of autonomic disturbances, and muscle deconditioning because of pain avoidance.

In this column, Dr. Grahame discusses the clinical manifestations of JHS, widespread misperceptions about the disorder, the consequences of missed or delayed diagnoses, and important diagnostic and treatment considerations.

QUESTION: What are the most important clinical and laboratory features of JHS?

Dr. Grahame: JHS was initially defined in 1967 as the occurrence of musculoskeletal symptoms in the presence of generalized joint hypermobility. Patients usually present with noninflammatory joint and/or spinal pain, recurrent soft tissue injury or overuse lesions, and joint dislocations or subluxations. Over the last decade, it has become evident that chronic pain, dysautonomia, and gastrointestinal dysmotility are frequently encountered complications. In addition to joint hypermobility, key diagnostic features include such skin changes as increased stretchiness, paper-thin scars, striae atrophicae, and features of a marfanoid habitus. There are currently no diagnostic laboratory tests for JHS.

QUESTION: Early literature describes JHS as a mostly harmless condition, but more recent data suggest that the syndrome can have serious clinical consequences. How do these different perspectives affect patient management?

Dr. Grahame: Enormously! In the former view, which is still widely held, hypermobility is largely perceived as a trivial disorder that does not merit serious consideration by rheumatologists on the basis that if there are no inflammatory markers, it is of no consequence. Nothing could be further from the truth. Clinicians appear to be frequently unaware of the recent literature concerning systemic complications, so patients’ complaints may be discounted. Patients may even be told that their symptoms are "in the mind" and that they should see a psychiatrist. They are often left to "shop around" in vain, searching for a doctor who understands and believes their symptoms and attempts to alleviate them (Nat. Clin. Pract. Rheumatol. 2008;4:522-4). By contrast, the identification and recognition of features of a heritable disorder of connective tissue (HDCT) are much more likely to attract serious attention. Unfortunately, the HDCTs are not uniformly taught in rheumatology training programs, and accredited rheumatologists may not be familiar with them. By default, the care of patients with HDCTs may pass to clinical geneticists, who have enormously wide knowledge but who are not trained in rheumatology.

QUESTION: How can clinicians distinguish JHS from other HDCTs, such as Ehlers-Danlos syndrome?

Dr. Grahame: The debate as to whether JHS and Ehlers-Danlos syndrome–hypermobility type (HEDS) are one and the same has raged for 40 years. The tide has now definitely turned in favor of the "lumpers" as against the "splitters". Gradually, as incontrovertibly convincing evidence has appeared, it has become obvious that JHS and HEDS are either truly identical, or if not identical, at least indistinguishable from one another (Am. J. Med. Genet. A. 2009;149A:2368-70).

It is clearly incumbent on all clinicians to be aware of the more serious HDCTs such as Marfan syndrome and Ehlers-Danlos syndrome–vascular type (VEDS), which carry the risk of life-threatening complications, such as aortic aneurysm formation in the case of Marfan’s, and arterial, visceral, or uterine rupture in the case of VEDS. Admittedly, however, it is not always easy to differentiate between those HDCTs that carry such high risk from the more benign JHS/HEDS. Both VEDS and Marfan’s have recognizable phenotypic features and their identification has been facilitated in recent years by genetic testing. One must strive to be alert to the possibility of encountering a more serious form and to be armed with a heightened index of clinical suspicion. Eliciting a careful personal and family history is all-important. This entails seeking out detailed information on close family members, and in particular, those who may have died unexpectedly or suddenly early in life. The advent of the echocardiogram has been a major step forward in spotting early aortic root dilatation at a time when surgical intervention can be lifesaving. Examining the eye by slit-lamp is another useful tool in helping to exclude ocular evidence of Marfan’s.

QUESTION: Is a diagnosis of JHS associated with an increased risk for other musculoskeletal disorders?

Dr. Grahame: Most clinicians are aware of the susceptibility and vulnerability to trauma and joint instability that accompanies hypermobility, but few seem to be cognizant of the devastating effects on function and quality of life posed by the frequent occurrence of chronic pain and deconditioning that can occur if the condition is not handled correctly.

QUESTION: What are some of the consequences of delayed diagnosis, and what are some of the benefits of early diagnosis?

Dr. Grahame: Delayed diagnosis leaves patients not knowing what is causing their pain and distress. Being told that hypermobility cannot be responsible for their degree of pain only serves to cause further dismay. Even more serious than the upset to their emotional equilibrium is the progressive loss of mobility that they suffer, resulting ultimately in their becoming potentially chairbound or even bedbound. Because movement is painful, they intuitively adopt a strategy of pain avoidance through movement avoidance. The result is a predictable decline in independence and a descent into disability. The result is that people who are generally young and formerly physically active in various pursuits can be struck down in their prime, in spite of having locomotor systems that are largely intact.

QUESTION: What are some of the most important management considerations?

Dr. Grahame: Hypermobile subjects should be encouraged to achieve maximal fitness at all ages as a means of avoiding many of the musculoskeletal lesions to which they are predisposed by virtue of their fragile tissues. Having strong muscles helps to improve proprioception, stabilize core muscle groups and unstable joints, and improve stamina. Physical therapists have effectively adapted the principles of physiotherapy to the needs of patients with lax and fragile tissues.

Chronic pain in JHS generally does not respond well to analgesic medications, but pain management using cognitive behavioral methods has enabled many patients to return to a reasonable quality of life. Finally, surgery should be undertaken only after careful consideration of the risks of delayed healing, after the anticipated impact on outcome of a connective tissue disorder have been considered, and when conservative alternative nonsurgical treatments are not available.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Grahame is also an honorary consultant in pediatric rheumatology at the Great Ormond Street Hospital for Children and emeritus professor of rheumatology at University College London. He disclosed having no conflicts of interest.

Major Finding: Treatment nonadherence is behind dose escalation in one-third of patients who receive antidepressant therapy.

Data Source: A large-scale analysis of patient nonadherence to chronic antidepressant therapy and subsequent prescribed dose escalation of the same medication using a national patient claims administrative database.

Disclosures: Medco Health Solutions Inc. provided funding for the study. Dr. Muzina became an employee of Medco Neuroscience Resource Center after the study began and received no compensation for his participation.

BOSTON – Nearly one-third of patients on antidepressant pharmacotherapy in a large-scale analysis did not take their original antidepressant dose as prescribed within the 6 months prior to dose escalation, a study has shown.

The findings suggest that the lack of adequate treatment response that drives dosage increases in many patients may be linked to suboptimal medication adherence rather than to dose insufficiency, Dr. David J. Muzina reported at the institute.

To evaluate patient nonadherence to chronic antidepressant therapy and a resulting upward dosage titration of the same medication, Dr. Muzina of Medco Health Solutions Inc. and his colleagues identified 53,530 patients from Medco's administrative patient claims database who were on antidepressant medications at the same dosage level for at least 6 months, followed by a subsequent submission of claims for a higher dose.

Patients with only one claim for antidepressant medicine in a 6-month period were excluded from the analysis, as were those taking multiple antidepressants.

To measure adherence status – determined by the proportion of days the patient possessed a supply of the medication, or the medication possession ratio (MPR) – a minimum of two claims for the same antidepressant drug was required. According to the National Committee for Quality Assurance's antidepressant performance measures, adherence was defined as an MPR of at least 80%.

The study cohort was predominantly female (72%), with a mean age of 51 years. More than two-thirds of the sample (68%) filled their antidepressant prescriptions at retail pharmacies, and 62% received generic medications, Dr. Muzina said. Most of the prescriptions were ordered by nonpsychiatrists, with only 15% ordered by psychiatrists; nearly half of the 49,524 patients for whom Chronic Disease Scores (CDS) were available had scores indicating a high degree of comorbidity.

Nearly 30% of the full cohort were nonadherent, Dr. Muzina reported. Among the nonadherent patients, “one in four was in possession of their prescribed medication during less than 3 months of the 6-month period,” he said.

An analysis of medication adherence by study subgroup – including age, sex, comorbidity, pharmacy channel (mail vs. retail), formulation (brand vs. generic), and prescriber (psychiatrist vs. nonpsychiatrist) – showed significant differences for all but the type of clinician prescriber. Regarding pharmacy channel and formulation, 19.2% of patients who filled prescriptions by mail were nonadherent, significantly lower than the 34.6% of those who used a retail pharmacy. Those receiving generic-only drugs had a small but significantly higher nonadherence rate (30.2%) than the 28.9% rate among patients receiving brand-name drugs.

Older age, male sex, and a higher CDS – perhaps due to increased interaction with clinicians needed by sicker patients – were also associated with significantly improved adherence, he said.

Major Finding: Treatment nonadherence is behind dose escalation in one-third of patients who receive antidepressant therapy.

Data Source: A large-scale analysis of patient nonadherence to chronic antidepressant therapy and subsequent prescribed dose escalation of the same medication using a national patient claims administrative database.

Disclosures: Medco Health Solutions Inc. provided funding for the study. Dr. Muzina became an employee of Medco Neuroscience Resource Center after the study began and received no compensation for his participation.

BOSTON – Nearly one-third of patients on antidepressant pharmacotherapy in a large-scale analysis did not take their original antidepressant dose as prescribed within the 6 months prior to dose escalation, a study has shown.

The findings suggest that the lack of adequate treatment response that drives dosage increases in many patients may be linked to suboptimal medication adherence rather than to dose insufficiency, Dr. David J. Muzina reported at the institute.

To evaluate patient nonadherence to chronic antidepressant therapy and a resulting upward dosage titration of the same medication, Dr. Muzina of Medco Health Solutions Inc. and his colleagues identified 53,530 patients from Medco's administrative patient claims database who were on antidepressant medications at the same dosage level for at least 6 months, followed by a subsequent submission of claims for a higher dose.

Patients with only one claim for antidepressant medicine in a 6-month period were excluded from the analysis, as were those taking multiple antidepressants.

To measure adherence status – determined by the proportion of days the patient possessed a supply of the medication, or the medication possession ratio (MPR) – a minimum of two claims for the same antidepressant drug was required. According to the National Committee for Quality Assurance's antidepressant performance measures, adherence was defined as an MPR of at least 80%.

The study cohort was predominantly female (72%), with a mean age of 51 years. More than two-thirds of the sample (68%) filled their antidepressant prescriptions at retail pharmacies, and 62% received generic medications, Dr. Muzina said. Most of the prescriptions were ordered by nonpsychiatrists, with only 15% ordered by psychiatrists; nearly half of the 49,524 patients for whom Chronic Disease Scores (CDS) were available had scores indicating a high degree of comorbidity.

Nearly 30% of the full cohort were nonadherent, Dr. Muzina reported. Among the nonadherent patients, “one in four was in possession of their prescribed medication during less than 3 months of the 6-month period,” he said.

An analysis of medication adherence by study subgroup – including age, sex, comorbidity, pharmacy channel (mail vs. retail), formulation (brand vs. generic), and prescriber (psychiatrist vs. nonpsychiatrist) – showed significant differences for all but the type of clinician prescriber. Regarding pharmacy channel and formulation, 19.2% of patients who filled prescriptions by mail were nonadherent, significantly lower than the 34.6% of those who used a retail pharmacy. Those receiving generic-only drugs had a small but significantly higher nonadherence rate (30.2%) than the 28.9% rate among patients receiving brand-name drugs.

Older age, male sex, and a higher CDS – perhaps due to increased interaction with clinicians needed by sicker patients – were also associated with significantly improved adherence, he said.

Major Finding: Treatment nonadherence is behind dose escalation in one-third of patients who receive antidepressant therapy.

Data Source: A large-scale analysis of patient nonadherence to chronic antidepressant therapy and subsequent prescribed dose escalation of the same medication using a national patient claims administrative database.

Disclosures: Medco Health Solutions Inc. provided funding for the study. Dr. Muzina became an employee of Medco Neuroscience Resource Center after the study began and received no compensation for his participation.

BOSTON – Nearly one-third of patients on antidepressant pharmacotherapy in a large-scale analysis did not take their original antidepressant dose as prescribed within the 6 months prior to dose escalation, a study has shown.

The findings suggest that the lack of adequate treatment response that drives dosage increases in many patients may be linked to suboptimal medication adherence rather than to dose insufficiency, Dr. David J. Muzina reported at the institute.

To evaluate patient nonadherence to chronic antidepressant therapy and a resulting upward dosage titration of the same medication, Dr. Muzina of Medco Health Solutions Inc. and his colleagues identified 53,530 patients from Medco's administrative patient claims database who were on antidepressant medications at the same dosage level for at least 6 months, followed by a subsequent submission of claims for a higher dose.

Patients with only one claim for antidepressant medicine in a 6-month period were excluded from the analysis, as were those taking multiple antidepressants.

To measure adherence status – determined by the proportion of days the patient possessed a supply of the medication, or the medication possession ratio (MPR) – a minimum of two claims for the same antidepressant drug was required. According to the National Committee for Quality Assurance's antidepressant performance measures, adherence was defined as an MPR of at least 80%.

The study cohort was predominantly female (72%), with a mean age of 51 years. More than two-thirds of the sample (68%) filled their antidepressant prescriptions at retail pharmacies, and 62% received generic medications, Dr. Muzina said. Most of the prescriptions were ordered by nonpsychiatrists, with only 15% ordered by psychiatrists; nearly half of the 49,524 patients for whom Chronic Disease Scores (CDS) were available had scores indicating a high degree of comorbidity.

Nearly 30% of the full cohort were nonadherent, Dr. Muzina reported. Among the nonadherent patients, “one in four was in possession of their prescribed medication during less than 3 months of the 6-month period,” he said.

An analysis of medication adherence by study subgroup – including age, sex, comorbidity, pharmacy channel (mail vs. retail), formulation (brand vs. generic), and prescriber (psychiatrist vs. nonpsychiatrist) – showed significant differences for all but the type of clinician prescriber. Regarding pharmacy channel and formulation, 19.2% of patients who filled prescriptions by mail were nonadherent, significantly lower than the 34.6% of those who used a retail pharmacy. Those receiving generic-only drugs had a small but significantly higher nonadherence rate (30.2%) than the 28.9% rate among patients receiving brand-name drugs.

Older age, male sex, and a higher CDS – perhaps due to increased interaction with clinicians needed by sicker patients – were also associated with significantly improved adherence, he said.