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At this year’s Digestive Disease Week, important announcements were made and clinical advances discussed in every gastroenterologic specialty. Here, Gastroenterology & Hepatology summarizes some of the most important presentations, with expert commentary from opinion leaders in each area.
Dr. William Chey from the University of Michigan Health System, along with associates from the Hospital du St-Sacrement in Québec, Canada and Novartis Pharmaceuticals, noted that no medical therapy has been demonstrated useful in patients with mixed irritable bowel syndrome (IBS-M) symptoms. They examined the efficacy of tegaserod (Zelnorm, Novartis), a promotility agent, which is safe and effective in the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation, in a group of IBS-M patients. IBS-M patients, although clinically distinct, share characteristics with the IBS-C group.
The authors performed a randomized, double-blind, placebo-controlled, multicenter study in women with IBS-C (Rome II criteria) and IBS-M (not IBS-C or IBS-D by Rome II). The primary efficacy variable was patients’ assessment of satisfactory relief over 4 weeks’ treatment with tegaserod 6 mg twice daily or placebo. The proportion of patients reporting satisfactory relief for more than 3 out of 4 treatment weeks (75% rule) and improvement during each of the 4 weeks in individual IBS symptoms were also assessed. Treatments were compared using a generalized linear model with logit link.
A total of 661 women were randomized (IBS-C 337; IBS-M 324). Baseline symptom assessment distinguished between the IBS-C and IBS-M cohorts. Statistically significant differences were found between the two cohorts in bowel movement (BM) frequency, stool consistency and straining. Overall, tegaserod provided statistically significant improvement in satisfactory relief of IBS symptoms over a 4-week treatment period (odds ratio [OR]=1.75; 95% confidence interval [CI]: 1.35–2.25; P<.001) for the IBS-C and IBS-M cohorts. In the two cohorts, the percentage of patients experiencing satisfactory relief of IBS symptoms (75% rule) was significantly higher for tegaserod when compared to placebo (IBS-C: 43.3% vs 28.9%, P=.008 and IBS-M: 52.3% vs 36.3%, P=.010). Tegaserod was significantly superior (P<.05) to placebo at improving weekly BM frequency, stool consistency score using a 7-point scale, and days per week with straining. Adverse event discontinuations were low (IBS-C: tegaserod 1.2% vs placebo 2.4% and IBS-M: tegaserod 2.5% vs placebo 3.6%). The most frequent adverse events with discontinuation of study medication were diarrhea and headache.
WC Recent epidemiologic studies have shown that among IBS classifications (IBS-C, IBS-M, and IBS with predominant diarrhea [IBS-D]), there is very little movement of patients from IBS-C to IBS-D. Most of the movement occurs from the IBS-C or IBS-D groups to the IBS-M group. In other words, over the course of a year, it is relatively unlikely for patients to truly alternate between IBS-D and IBS-C. Instead, they fluctuate in and out of the mixed category. The greatest movement tends to occur between the IBS-C and IBS-M group and this observation provides the rationale for our study. Because the IBS-C and IBS-M groups share a number of characteristics and also, over time, seem to migrate back and forth, it seems to follow that tegaserod may provide benefit to the IBS-M group, where there has been no demonstrated effective therapy until the present. This is one of the first methodologically rigorous trials specifically designed to assess the efficacy of a drug in IBS-M patients. It is also one of the first to show benefit from medical therapy for that group.
One concern that clinicians have raised is that tegaserod is a promotility agent and therefore may not be safe for use in a patient who has occasional loose stools among their symptoms. In this study, tegaserod proved quite safe in treating those patients. It is worth noting that 12% of the patients receiving tegaserod developed diarrhea but in the majority of those cases, diarrhea was mild, transient, and therefore clinically manageable.
Dr. Mark Pimentel and associates of the Cedars-Sinai Medical Center in Los Angeles note data suggesting a relationship between gut bacteria and IBS symptoms such that improvement in IBS is observed after antibiotic treatment. They presented a subanalysis of their own recent report on the beneficial effects of rifaximin (Xifaxan, Salix), a nonabsorbed antibiotic, on global improvement in IBS, examining the component symptoms of IBS and their response to antibiotic therapy.
Rome I criteria-positive IBS patients were enrolled in a double-blind randomized placebo-controlled study. After a 1-week run-in, subjects were asked to complete a symptom questionnaire with diarrhea, constipation, bloating and abdominal pain rated on a VAS score from 0–100 mm, after which a lactulose breath test was conducted. Subjects were then randomized to rifaximin 400 mg or placebo, three times daily for 10 days. One week after completion of treatment and thereafter for the following 9 weeks, subjects repeated responses to their questions. The number of subjects with greater than 50% improvement in each of the symptom categories was determined over the 10-week follow-up time period, with endpoints determined for 1 week after treatment completion and the overall 10 weeks after completing treatment.
A total of 87 subjects were randomized in the study (44 placebo, 43 rifaximin). One week after rifaximin, 48.6% of subjects demonstrated a clinical response with diarrhea (>50% improved) compared to 23.5% for placebo (P<0.05). For bloating, 34.9% of subjects demonstrated relief compared to 18.6% for placebo (P=.07). After 1 week, constipation and abdominal pain were not improved. However, when the proportion of patients with clinical improvement (>50% improvement) was determined for the entire 10-week follow-up period for each symptom, all four symptoms were statistically improved including bloating, diarrhea, abdominal pain, and constipation.
WC Among US gastroenterologists, there is currently much excitement regarding the use of antibiotics to treat small bowel bacterial overgrowth (SBBO) in patients with suspected IBS. It seems quite likely that there is a subset of patients currently diagnosed with IBS who have SBBO; the difficulty in studying them is that there is no gold standard for SBBO diagnosis. Therefore, we cannot accurately determine the prevalence of this condition. In this particular study, a lactulose breath test was administered to test for SBBO but results did not influence entry in the trial.
In any case, the results of this trial indicate that antibiotic therapy improves the cardinal symptoms of IBS in a subset of patients. However, whether this is due to the treatment of bacterial overgrowth, alteration of colonic flora, or some other mechanism, is still not clear. Although this idea requires more study, it potentially offers a paradigm shift in the treatment of this subset of patients. Clinicians have never attempted to alter the flora in the gastrointestinal tract as a means of changing symptoms in patients with IBS but this study and others like it suggest that it is another potentially useful mode of treatment.
John Johanson of Rockford Gastroenterology Associates, Rockford, Ill., along with associates from Sucampo Pharmaceuticals, presented the results from a 12-week dose-ranging study of the novel type-2 chloride channel activator lubiprostone, testing it for the first time exclusively in IBS-C patients, as defined by the Rome II criteria.
Approximately 50 subjects were randomized in a double-blind fashion to one of four treatment groups: placebo (0 µg) or 16, 32, or 48 µg lubiprostone daily (8, 16, or 24 µg bid). Subjects recorded data relating to dosing, abdominal symptoms (bloating and discomfort/pain), bowel movements (frequency and straining and consistency ratings), and rescue medication use. Weekly diary questions queried subjects on their assessment of the treatment effectiveness. Trend tests were used to detect dose-dependent efficacy relationships and a step-down testing procedure was used to make pairwise comparisons between the active lubiprostone and placebo groups in the case of a dose-dependent trend. Safety was assessed by adverse event incidence rates.
Significant dose-dependent trends were observed during at least 2 of the 3 months for abdominal discomfort/pain, abdominal bloating, spontaneous bowel movement frequency, stool consistency, bowel straining, and assessments of constipation severity. Pairwise comparisons revealed many significant differences between the active groups and placebo. During months 1 and 2, improvements in abdominal discomfort/pain and spontaneous bowel movement frequency rates were more than doubled in all lubiprostone groups as compared to placebo. Overall, improvements were typically highest in the 48 µg group. With respect to safety, dose-dependent trends were also observed. AE incidence and drop-out rates typically increased with increasing dose.
WC Lubiprostone is a chloride channel activator that has proven effective in patients with chronic constipation. In the diagnostic criteria for functional or chronic constipation there is no mention of abdominal pain, whereas in IBS-C, abdominal pain is a cardinal feature. However, many clinicians have observed that patients with chronic constipation, if asked enough times and in the correct manner, will all admit to some degree of abdominal pain. This is logical, as constipation inevitably causes abdominal distension and bloating that leads to discomfort.
In order to distinguish between the two conditions, clinicians must question their patients carefully about their symptoms to determine whether their pain is caused by constipation or is an independent feature of the IBS symptom complex. In practice, this distinction can be difficult to make and, given the overlap between the two groups, it follows that a drug that helps for chronic constipation may help patients with IBS-C as well.
In this relatively small dose-ranging study, encouraging results were seen for the treatment of IBD-C with lubiprostone in terms of improving bowel habits. The question that remains, and should be answered by currently on-going phase III studies, is whether this drug will provide significant symptom relief of bloating and abdominal pain. Currently, the data are promising but until we have a global outcome measure that puts an umbrella over the aggregate of IBS symptoms, it will be difficult to know for sure.
Further, it should be noted that the most common side effect from lubiprostone is nausea, which is mostly mild and clinically manageable. However, in treating patients’ abdominal pain it could prove significant and we will need to see what effect it has in further trials and long-term clinical practice.
Dr. Eva van Soest and associates of the Erasmus MC University Medical Center in Rotterdam, The Netherlands, observed that adherence to daily prescriptions of proton pump inhibitors (PPIs) is thought to be high, but it is currently not well known how PPIs are being used under everyday circumstances. The authors conducted a cohort study using a general practice research database containing the complete, longitudinal electronic medical records of 600,000 individuals throughout The Netherlands. For all patients who had started PPI treatment between 1996 and 2003, persistence (treatment duration) and adherence (medication possession ratio) with treatment were calculated. Potential predictors of persistence and adherence were identified.
During the 8-year study period, 17,813 patients started PPI treatment. Persistent use was seen in 25% of patients after 1 year and in 19.5% after 2 years. Overall, 55% of patients had an adherence level greater than or equal to 80%, meaning that they were on treatment at least 80% of the time. Patients using PPIs in combination with aspirin were most adherent (61.5% with adherence level ≥80%). Adherence increased with age and use of comedication. Subgroup analysis showed that patients with Barrett esophagus (BE) were not only more persistent (66% after 1 year), but also more adherent (64% with adherence level ≥80%) compared to the whole group of PPI users. In summary, the authors concluded that almost half of patients use PPIs on a noncontinuous basis (adherence level <80%), indicating intermittent or on-demand use. The consequences of these usage patterns are probably minor in patients treated for symptom control only. However, infrequent use of PPIs may have a more serious impact if prescribed for other purposes, such as treatment of BE or gastroprotection with nonsteroidal anti-inflammatory drugs or aspirin.
JR This study emphasizes that most patients with gastroesophageal reflux disease (GERD), after their symptoms are controlled, self-treat at whatever level will keep them asymptomatic. The idea of “once on a PPI, always on a PPI” for GERD, for the rest of a patient’s life, has never been validated as true evidence-based medicine. This study shows that on-demand treatment is a viable option. This is not necessarily the case for patients with BE, strictures, or severe (Los Angeles Grade C or D) esophagitis, but these patients only account for only 5% of GERD patients overall.
The vast majority of patients have either no esophagitis or only Grades A or B, which does not generally develop into more severe disease. When these patients suppress symptoms with PPI therapy, they generally do very well.
Dr. Nikoleta Javorkova and colleagues of Comenius University and the Martin Teaching Hospital in Martin, Slovakia, and the Johns Hopkins University School of Medicine in Baltimore, Md., tested the hypothesis that acidification of the distal esophagus increases cough reflex sensitivity in patients with GERD and chronic cough. Eight consecutive patients with GERD, complaining of chronic cough (cough persisting for >8 weeks), and 18 gender- and age-matched patients with GERD without cough were recruited. GERD was confirmed by positive fibroscopy and/or pH monitoring. In a randomized, double-blind study, saline and acid (HCl 0.1M) were separately infused into the distal esophagus via nasoesophageal catheter (10 mL/min for 15 min). The infusions were separated by at least 20 minutes. Cough reflex sensitivity was determined immediately after the completion of each infusion using a standard capsaicin inhalation challenge. Cough reflex sensitivity was measured as the lowest concentration of capsaicin evoking 2 coughs.
Infusion of acid but not saline into the distal esophagus induced mild heartburn and/or chest discomfort in 7/26 patients. In patients with GERD and chronic cough, infusion of acid into the distal esophagus increased cough reflex sensitivity (1.95 [0.98–15.6] µM after saline vs 0.98 [0.49–1.95] µM after acid, P<.05). In contrast, infusion of acid into the distal esophagus in patients with GERD without cough had no effect on the cough reflex sensitivity (15.6 [7.81–46.88] µM after saline vs 31.25 [4.88–125] µM after acid, P>0.5). The authors conclude that acidification of the distal esophagus induces cough reflex hyperexcitability in patients with GERD and chronic cough.
JR This study provides additional insight into the pathophysiology of acid-induced cough. It appears to not be related to microaspiration but rather to gastric material coming into the esophagus. There has been some uncertainty on this point, with some researchers contending that the actual cough-associated factor is the volume of material distending the esophagus, rather than its acidic properties. This study suggests that both the volume and acidity of gastric content play a part, as infusion with only saline did not induce cough. What this implies is that if acid content of reflux can be neutralized with PPI therapy, or if reflux can be prevented with surgery, cases of true GERD-related cough can be controlled. In fact, according to these results, acid control with PPI therapy should be as effective as surgery in these patients, though some literature would suggest that this is not the case.
Dr. Gregory Weiner of Chula Vista, Calif., and his associates from Restech Corporation in Poway, Calif., and the San Diego State University observed that despite recognition of multiple manifestations of supraesophageal gastric reflux (SEGR), characterization, identification, and response to therapy have evaded understanding due to lack of a suitable detection device. To address this need, Restech developed the Dx minimally invasive catheter with ionic flow sensor to measure pH in liquid or aerosolized droplets at the site of the posterior oropharynx. The authors tested the device’s sensitivity using a standard, 24-hour triple sensor pH catheter (24pH) for verification. Patients in a gastroenterologic practice with chronic symptoms likely due to SEGR and off reflux medication for 4–7 days underwent 24pH with two esophageal and one pharyngeal sensor (Sandhill PHI10-V) positioned with a lower esophageal sphincter (LES) indicator at 5 cm above the LES, an indicator 5 cm below the upper esophageal sphincter (UES), and one 1 cm above the UES. The 1.5 mm nasopharyngeal catheter was placed at the oropharynx behind the uvula, above the patients’ discomfort position. Tracings from all four synchronized pH inputs and patient diary were analyzed graphically on a single screen. SEGR was defined as rapid pH drops at the Dx sensor, greater than 3 standard deviations from a 60 second baseline, sequential to drops in pH to less than 4 as measured by 24h pH sensors, then classified as acid pH or weakly acid pH.
A total of 15 patients, at an average age of 57.5 years, with symptoms ranging from cough to tooth enamel loss, sleep apnea, and asthma, were tested. Four had normal 24pH. In 10 patients, 48 Dx-detected SEGR events occurred, with gradual return to baseline and synchronous to esophageal pH drops. All 5 Dx-negative patients had normal 24pH in the esophagus. The authors concluded that SEGR exists in the oropharynx and is detectable with the Dx device; there is a gradient of increasing pH from the esophagus to the oropharynx, the latter rarely less than 4; redefinition of significant pH events above the UES as percentage or more than 3 times the standard deviation in pH drops merits consideration; and clinical management may be influenced by Dx results.
JR These authors have developed a very small device, which can be attached directly above the uvula, causing no patient discomfort. They believe it provides sensitivity superior to that of established detectors of reflux into the hypopharyngeal area. As Dr. Michael Vaezi of Vanderbilt University has stated, we are desperately searching for ways to identify these patients, aside from therapeutic trial. This device has the potential to allow for this and its utility needs to be further explored beyond this anecdotal, gross assessment. The other important finding of this study is that once acidic content enters the hypopharyngeal area, pH is often no longer below 4 but in the range of 5.
Dr. Pai-Wain Lo and colleagues from Northwestern University in Chicago note that Bravo monitoring increases the sensitivity of pH testing by allowing for 48- rather than 24-hour recordings. Their study aimed to determine the feasibility of 4-day pH recordings using the Bravo pH system to encompass 2-day periods both before and during PPI therapy. A total of 16 patients underwent 4-day pH recordings (2 days off; 2 days on) using 2 separate receivers calibrated to a single Bravo capsule. Indications for pH testing were refractory heartburn, chest pain, and chronic cough. Patients were off PPI therapy for days 1 and 2. Rabeprazole (Aciphex, Eisai Medical) 20 mg twice daily was administered on days 3 and 4. Of the original cohort, 13 patients completed the 4-day study and were included in the analysis. Off therapy, 5 patients (38%) had esophageal acid exposure values exceeding 5.3%. On therapy, all patients showed significant and progressive acid reduction. By day 4, esophageal acid exposure value was 0% in 8 patients and less than 1% in 5 patients. The symptom index was significantly higher off (median 50%) than on (median 0%) PPI therapy (P<.001). Two patients with capsule detachment on day 3 and 1 on day 2 were excluded. Of the excluded patients, 2 had normal off-PPI acid exposure and the lack of day 4 data did not change the overall test interpretation. The authors concluded that prolonged recordings using the Bravo pH system are feasible and allow for combined testing both off and on therapeutic trial of PPI. The initial 2 days off PPI allow for increased sensitivity and symptom association for the diagnosis of GERD compared with on PPI testing. Such combined studies may allow for acquisition of information useful in the evaluation of refractory and atypical reflux symptoms.
JR When patients on PPI therapy are not experiencing symptom relief, there are two questions we ask as clinicians. First, do these patients really have GERD? Second, if they do have the disease, is their medication controlling their acid reflux? The problem at this point has always been how to assess these patients. In order to test for the disease state, they need to be off medication. However, in order to test for control of acid, they need to be on medication. The Bravo technology allows clinicians to get serial 2-hour studies from a capsule that stays attached for at least 4 days, and in some cases for as long as 7–10 days. This allows us to assess patients on the first day off medication in order to get a baseline value for their acid exposure. Afterward they can be started on PPI therapy, in this case rabeprazole, to examine acid control. In this way both questions can be answered at once.
These authors studied the patients for 2 days off medication and then for an additional 2 days on medication. Some patients require 3 or 4 days of therapy to achieve acid control so this design may not accurately test acid control in everyone. However, the idea presents an excellent use for this type of technology, the advantage of which is its accommodation of the patient. Previously used methods, which required nasogastric catheterization, would not allow for readings over more than a 24-hour period because of patient discomfort.
Dr. Revital Kariv and coworkers from the Cleveland Clinic sought to validate the Seattle protocol of 4-quadrant jumbo biopsies plus biopsies of any mucosal abnormalities for any finding of high-grade dysplasia (HGD) in BE. This single-center study examined 32 consecutive BE patients with a biopsy diagnosis of HGD who underwent esophagectomy between 1999 and 2005. None had mass lesions suggestive of obvious malignancy at the time of preoperative endoscopy. All biopsies were confirmed by expert gastroenterology pathologists prior to surgery. Patients were divided into two groups. Group 1 had preoperative surveillance biopsies done according to the Seattle protocol as described above; Group 2 had 4 quadrant biopsies every 2 cm. Postoperative pathology findings confirmed by expert gastroenterologic pathologists were compared to preoperative findings in both groups. There were 21 patients in Group 1 and 11 patients in Group 2. Postoperatively, unsuspected intramucosal cancer was found in 7/21 (33.3%) patients in Group 1 versus 3/11 (27.3%) of patients in Group 2 (P=.99). No patients in either group had a postoperative diagnosis of submucosal cancer or lymph node metastases. The authors concluded that intensive preoperative surveillance biopsies using the Seattle protocol do not reliably predict the presence of intramucosal carcinoma at the time of esophagectomy any better than a less intensive surveillance biopsy protocol. This calls into question the concept that the Seattle protocol consistently detects early cancer arising in BE patients with HGD.
JR If BE patients present with nodules or ulcers, endoscopists have an indication of where to biopsy for cancerous tissue. However, in patients with flat BE, there are no landmarks, so we go in and sample randomly. These authors have shown that in patients with flat BE without any nodules who still have high-grade dysplasia, biopsies can be taken with small and large forceps, both randomly and utilizing the Seattle protocol, but this does not ensure that the esophagus has been examined thoroughly enough to feel confident of no underlying esophageal cancer. Therefore, negative biopsy results from the Seattle protocol do not mean these patients are out of risk.
In this light, there are two choices regarding the manner in which to proceed. These patients can be sent to surgery, realizing that 60% will not have a cancer but that 40% of them will, and surgery optimizes our chances of resecting it early. Or, these patients can be followed with repeat biopsy. In my opinion, if we elect to follow these patients, we should do what Dr. Stephen Sontag of the Loyola University School of Medicine suggests, and put them in some type of “hunt-and-seek” program, in which they receive endoscopy with intensive biopsy every 3 months.
Utilizing any one protocol, whether taking random biopsies or the standard protocol from Seattle, still provides only a small sampling from the esophagus. Dr. Sontag’s method, in which patients are sampled 4 times over a year, is a much more effective way to find the needle in the haystack. With flat BE, if the affected area is short (1–2 cm), I recommend taking 8–12 biopsies. However, some patients’ BE extends for 5–10 cm. Given the limited amount of time an endoscopist can spend with one patient in one session, that is too large an area to examine thoroughly, even with protocols that call for 20 or 30 biopsies. However, Dr. Sontag’s method of endoscopy every 3 months allows for approximately 160 biopsies over the course of the year, which greatly increases the chance of finding an underlying cancer.
Dr. Kathryn Peterson and associates of the University of Utah note that exercise-triggered asthma (ETA) develops when vigorous physical activity triggers symptoms of cough, wheezing, dyspnea, and/or chest tightness during or directly after exercise and that it can occur both in people with chronic asthma and in otherwise healthy individuals. In patients prone to symptoms of supraesophageal reflux, exercise may trigger GER, resulting in shortness of breath and cough. They sought to determine the prevalence of abnormal pH in patients with ETA and whether acid suppression improves respiratory symptoms during exercise in ETA patients.
The authors performed a randomized, double-blind trial of rabeprazole versus placebo in the treatment of patients (both asthmatic and nonasthmatic) with ETA. Patients reported heartburn less than twice weekly. Upon enrollment, subjects underwent 24-hour pH testing while performing a 30-minute treadmill program, exercising at a predetermined level, 60–65% of their VO2max. They were subsequently randomized to rabeprazole 20 mg Qam and placebo Qpm, rabeprazole 20 mg bid, or placebo bid for 12 weeks. At the end of 12 weeks, exercise testing was repeated. Subjects reported whether their treadmill symptoms improved or did not improve at the end of the study. A total of 30 patients completed the study in its entirety (20 asthmatics, 10 nonasthmatics). Of the 30 subjects, 22 (73%) had abnormal pH studies. For all subjects, rabeprazole improved symptoms more often than placebo (P=.04). In the pH-positive group, rabeprazole resulted in even greater improvement (P=.02). The authors conclude that acid reflux is common in ETA patients. Many patients with exercise-related respiratory symptoms are underdiagnosed (or misdiagnosed) as chronic asthmatics. In addition, exercise-related symptoms improve with the use of acid suppression. Such patients may benefit from an empiric trial of high-dose acid suppression.
JR This study suggests, but is not definitive in uncovering, a causal relation between reflux and exercise-induced asthma. My concern is that a second pH study was not performed at the end of the randomization period. The patients who received rabeprazole did better than the patients on placebo and the patients who were initially positive for reflux had the greater improvement, which is good evidence. However, it assumes that they improved because of better acid reflux control, which is something of an insinuation, not an actual finding from monitoring of the physiology.
I think the next step is to repeat the study with the patients again randomized to placebo or drug, and see how well the acid is controlled, not only at baseline but during the exercise period. Pulmonary function testing immediately before and after the exercise might also be instructive. In order to feel fully confident in these findings, it needs to be demonstrated that patients who had acid reflux during their exercise before they were on medication had less or no acid reflux after they were on the drug and also saw an improvement in both duration of exercise and peak expiratory flow rate. The authors are currently planning a follow-up study to examine additional pulmonary endpoints and provide more definitive pH monitoring.
Dr. Gary Lichtenstein from the University of Pennsylvania, along with colleagues from the University of Chicago; Robarts Clinical Trials, London, ON, Canada; the Mayo Clinic, Rochester, Minn.; Atlanta Gastroenterology Associates; Ovation Research Group, Highland Park, Ill.; and Centocor, Inc., Horsham, Penn., reported analysis from the TREAT Registry, studying the long-term safety of infliximab (IFX; Remicade, Centocor) and other therapies in the treatment of Crohn’s disease (CD). As of August, 2005, 6,273 patients were enrolled, of whom 3,272 received IFX (8,314 patient-years [PY]) (88% ≥2 infusions) and 3,001 received other therapies only (6,596 PY) with a mean follow-up of 2.7 years. More IFX-treated patients had moderate-to-severe (31.5% vs 10.7%, P<.0001) or severe-fulminant (2.6% vs 0.6%, P<.0001) CD, more had been hospitalized (27.4% vs 19.1%, P<.0001) in the prior year, and more were taking prednisone (27.2% vs 15.9%, P<.0001) or immunomodulators (49.4% vs 31.9%, P<.0001). Infusion reactions occurred in 4.0% of 28,281 infusions; severe reactions in 0.1%. Mortality was identical for both IFX- and non–IFX-treated patients (0.47 per 100 PY vs 0.47; RR=1.0, 95% CI=0.64–1.56). In Cox proportional hazard analysis, only the use of prednisone (HR=2.24, CI=1.37–3.66, P=.001) and narcotics (HR=2.63, CI= 1.60–4.32, P<.001) were associated with increased risk of mortality.
The incidence of malignancies in the two groups was similar (0.58 per 100 PY in IFX pts vs 0.53 in non-IFX pts; RR=1.1, 95% CI=0.71–1.63), as was the incidence of lymphoma (0.06 per 100 PY in IFX pts vs 0.05 in non-IFX pts; RR=1.3, 95% CI=0.36–5.03). The incidence of serious infections was 1.29 per 100 PY within 3 months of an IFX infusion and 0.68 not within 3 months of an IFX infusion (RR=1.9, 95% CI=1.34–2.70, P<.001). However, Cox analysis showed IFX was not an independent predictor of serious infection (HR=1.40, 95% CI=0.95–2.07). The only medications independently associated with serious infection were prednisone (HR=2.01, CI=1.40–2.90, P<.0001) and narcotics (HR=2.72, 95% CI=1.87–3.96, P<.0001). One IFX-treated patient with known latent tuberculosis, who did not receive adequate prophylaxis, developed active tuberculosis.
SK The overall experience with the TREAT registry is somewhat reassuring, in terms of the idea that, compared to other standard therapies for moderate-to-severe CD, clinicians are not putting patients at increased risk for mortality or infection with the prescription of IFX. The data presented here reinforce the findings from the 2005 DDW, when 4,000 patients were enrolled in the registry. There continues to be a signal for risk of infection, particularly associated with narcotic use and also for steroid therapy, that shows IFX to be a comparatively safe option for these patients. This year, with 6,000 patients and another 1.5 years of observation, it still seems that IFX does not increase or cause mortality, or contribute to infection at a rate as significant as steroids and narcotics.
Of concern, however, are the 6 cases of hepatosplenic T-cell lymphoma reported worldwide in IFX-treated patients. This is a signal that should be noted, particularly as it only seems to occur in CD patients, as opposed to those with rheumatoid arthritis (RA). Whether this is a function of CD IFX patients’ cotherapy with immunomodulators or an epidemiologic phenomenon related to the characteristic age groups of CD versus RA patient populations needs to be examined.
Drs. William Sandborn and Stephan Targan of the Mayo Clinic, Rochester, Minn., and Cedars-Sinai Medical Center, Los Angeles, respectively, performed a safety evaluation in all patients who had recently been treated with natalizumab (Tysabri, Biogen Idec) in clinical trials to screen for progressive multifocal leukoencephalopathy (PML).
Natalizumab is a humanized IgG4 monoclonal antibody against α4 integrins, which was approved by the US Food and Drug Administration in November 2004 for the treatment of multiple sclerosis (MS). Phase III trials for treatment of CD had completed enrollment and a phase II trial in RA was ongoing. Clinical trials and marketing were voluntarily suspended in February 2005 based on the reports of 2 patients developing PML while receiving combination therapy with natalizumab and interferon beta-1a in an MS clinical trial. Subsequently, a previously diagnosed malignant astrocytoma in a natalizumab-treated patient with previous exposure to azathioprine was reclassified as PML.
Drs. Sandborn and Targan developed a safety evaluation protocol including informed consent and urgent additional follow-up visit(s) to include a physical exam, referral to a neurologist, brain MRI, polymerase chain reaction (PCR) analysis of cerebral spinal fluid (CSF), and serum for JC virus. MRI scans of the brain were performed and interpreted at each center. MRI images were also sent to a core laboratory facility for central interpretation by a neuroradiologist with expertise in white matter disease. An independent adjudication committee (IAC) consisting of experts in JC virology, neurological and clinical manifestations of PML, and MRI imaging of neuroinflammation was created to adjudicate all suspected cases of PML and make a final determination of whether the patient had PML. In addition to patients from clinical trials, four post-marketing MedWatch reports of suspected PML were also referred to the IAC.
Enrollment in the safety evaluation included 87% (1,275), 91% (2,248), and 92% (296) of all eligible CD, MS, and RA patients, respectively. Neurological exams and MRIs were completed in over 97% of CD, MS, and RA patients. CSF was analyzed for JC virus in 6% of CD, 16% of MS, and 4% of RA patients, and plasma in 88% of CD, 56% of MS, and 95% of RA patients. No additional cases were judged by the IAC to have PML. The 4 postmarketing cases referred to the IAC were also judged not to have PML.
SK After only 6 weeks on the market with an indication for MS and amid clinical trials for CD, natalizumab was pulled after 2 MS patients and 1 with CD developed PML and died. The manufacturer appropriately shut down the trial and took the drug off the market, in order to reassess safety. Nearly every patient who may have been potentially exposed to the drug was tracked down and examined through MRI imaging and a full neurological exam, and was offered spinal taps.
They found no new cases of PML and noted that the 1 CD patient who was affected had been receiving concomitant immunomodulator therapy. Their conclusion is that natalizumab is best used as monotherapy and that the absolute risk of development of PML in patients exposed to natalizumab is 1 in 1275. Currently, plans are being made for a modified version of the CD trial with natalizumab, which will have a screening mechanism for neurologic events in place.
As physicians, we are taught first to do no harm. Initially, therapy with natalizumab will be utilized only at major inflammatory bowel disease centers, which have the resources and the research background to follow these patients closely. It will most likely be some time before a comfort level is reached allowing for widespread use among community gastroenterologists, despite the excellent efficacy profile of this drug.
Dr. Daniel Hommes of the Academic Medical Center in Amsterdam, with colleagues from H Hart Ziekenhuis, Roeselare, Belgium; the University Hospital Gasthuisberg, Leuven, Belgium; Ziekenhuis Oost-Limburg, Genk, Belgium; Groeninge Ziekenhuis, Kortrijk, Belgium; Medisch Centrum Alkmaar, Alkmaar, Netherlands; University Hospital Gent, Gent, Belgium; University of Western Ontario, and Robarts Research Institute, both in London, Ontario, Canada; and the Imelda GI Clinical Research Center, Bonheiden, Belgium, examined aggressive induction therapy with IFX and azathioprine (AZA) as an alternative to glucocorticosteroids (GCS) in patients with moderate-severe CD, to compare remission rates, toxicity, and other complications. Current management of moderate-severe CD consists of GCS therapy, which leads to a 26% 1-year remission rate, steroid dependency, and significant toxicity.
A total of 133 CD patients with CD Activity Index (CDAI) scores greater than 220, diagnosed more than 4 years previously, and never treated with GCS/immunomodulators/IFX were randomized to either top-down (TD) treatment with 3 infusions of IFX (weeks 0, 2 and 6) and AZA 2–2.5 mg/kg daily or step-up (SU) therapy with topical (budesonide 9 mg daily) or systemic (prednisone 40 mg daily) GCS. In the TD group, relapse was treated with repeat IFX infusions and GCS only with failed response to IFX. In the SU group, AZA was added in case of repeated need for GCS or dependency and IFX was only given after failure of immunosuppression. Patients were examined at week 0, 2, 6, 10, and 14 and every 3 months thereafter until month 24. The primary endpoint was remission (CDAI <150 without GCS and no resection) at months 6 and 12. Secondary endpoints included overall treatment success (remission at week 14 and beyond, no resection, no GCS or IFX after week 14), mean CDAI scores, toxicity, and prolonged remission up to month 24.
Mean CDAI at baseline was 331 in the TD group versus 306 in the SU group. Of the total cohort,19 patients dropped out before month 12. Induction therapy was successful in 81% and 73% of TD and in 60% and 67% of SU patients at weeks 10 and 14, respectively. Remission without GCS and without resection was attained in 60% (TD) versus 41% (SU) (P=.03) at 6 months and in 61% (TD) versus 50% (SU) at 12 months (P=.19). At 6 months, 31% of patients in the SU group were still receiving GCS (median dose 26 mg daily) compared with 0% in the TD group; at 12 months, 17% of SU patients remained on GCS (median dose 23 mg) compared with 0% for TD (P<.001). At 6 and 12 months, 84% and 93% of patients were using immunomodulators in the TD group, versus 41% and 65 % in the SU group, respectively (both P<.001).
Overall treatment success was seen in 29% of TD and 5% of SU patients (P<.001). During the first 12 months, 13% of patients in the SU group needed IFX infusions to induce remission and 41% of patients in the TD group required at least one further IFX infusion. Serious adverse events were observed in 49% of TD and 41% of SU patients (P value not significant).
SK This trial was developed, and the patients enrolled several years ago, prior to the recommendation of maintenance therapy with IFX. Therefore, the patients who were treated with TD therapy received an induction dose of IFX and AZA concomitantly, which means they received doses of infliximab at 0, 2, and 6 weeks but no every-8-week maintenance therapy. If the trial were redone with maintenance, we would most likely see a decrease in the relapse rate and sustained remission would go up. However, it could also cause a rise in serious adverse events.
That stated, the manner of dosing utilized in the TD arm of the trial may reduce efficacy if patients require subsequent dosing with IFX, after they have had time to develop antibodies to it. The data showing a reduced need for steroids in the TD group are impressive but if these patients are relapsing, are they really being helped in the long run? This data coupled with the negative safety data regarding steroids from the TREAT registry, would seem to say “yes.” However, further study with standard maintenance dosing of IFX will be needed to answer the question definitively.
Dr. Stephan Targan of the Cedars-Sinai Medical Center, Los Angeles, along with associates from Robarts Clinical Trials, London, Ontario, Canada; the University of Alberta, Edmonton, AB, Canada; the Center for Inflammatory Bowel Disease, Cleveland; the University of Calgary Medical Clinics, University of Calgary, Calgary, Alberta, Canada; the Mount Sinai School of Medicine, New York; Asklepios Westklinikum, Hamburg, Germany; the University Hospital Gasthuisberg, Leuven, Belgium; Semmelweis University, Budapest, Hungary; Hepato-Gastroenterology HK, Budapest, Hungary; Atlanta Gastroenterology Associates, Atlanta; and the Mayo Clinic, Rochester, Minn., announced the primary results of ENCORE (Efficacy of Natalizumab in Crohn’s Disease Response and Remission), a phase III, international, randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of natalizumab induction therapy in CD patients with moderately to severely active disease and objective evidence of active inflammation (elevated C-reactive protein [CRP] levels).
Patients (n=509) with CDAI scores from 220 to 450 and CRP levels greater than the upper limit of normal (2.87 mg/L) were randomized 1:1 and received natalizumab (300 mg; n=259) or placebo (n=250) infusions at weeks 0, 4, and 8. Efficacy and safety were assessed at weeks 4, 8, and 12. The primary endpoint examined the ability of natalizumab to induce a clinical response (≥70 point decrease in baseline CDAI score) by week 8 that was sustained through week 12. Additional efficacy endpoints included the proportion of patients achieving clinical remission (CDAI <150) by week 8 and through week 12, and the proportion of patients in response or remission at any assessment.
A significantly higher proportion of patients in the natalizumab group were in response at both weeks 8 and 12 compared to patients in the placebo group (48% vs 32%, P<.001). Response at week 4 (following the first infusion) was 51% for natalizumab versus 37% for placebo (P=.001), and remained significantly higher in the natalizumab group at all subsequent assessments (P<.001 for all comparisons with placebo). Remission at both weeks 8 and 12 was achieved by a higher proportion of patients in the natalizumab group compared with placebo (26% vs 16%, P=.002). Patients receiving natalizumab also had superior remission rates at all assessments (P≤.009 for all comparisons with placebo). The incidence and types of adverse events were similar between groups.
SK As described above, this study had just finished enrollment when the first cases of PML associated with natalizumab were reported. Because of the timing, the investigators were able to close the trial instead of simply shutting it down, then follow up with intensive neurologic examination of all patients, on treatment and on placebo, as well as locating and examining those lost to follow-up. Regardless, they were able to report these full, final results.
These results show excellent efficacy for natalizumab, with significant benefit demonstrated for every targeted endpoint. Even in patients with CRP levels in the low-to-normal range, there was a response. As CRP levels increased, the placebo response decreased and there was a larger absolute benefit with natalizumab therapy.
Dr. Richard Rothstein of the Dartmouth-Hitchcock Medical Center and Dr. Jeffrey Ponsky of the University Hospitals of Cleveland chaired a video symposium sponsored by the American Society for Gastrointestinal Endoscopy (ASGE) on a novel surgical technique, natural orifice transluminal endoscopic surgery (also known as natural orifice transvisceral endoscopic surgical approach [NOTES]), which is currently being investigated in pig models.
JS In the early stages of laparoscopic technology, the only application in gastroenterologic practice was in guided biopsy or examination. The physician operating the laparoscope looked through an optical system with no video monitor, only an optical head. The procedure would be done in the same room as endoscopy but in a semisterile environment. The patient’s abdomen would be scrubbed down, draped, and all involved physicians and nurses would be gowned and masked. Procedures consisted of inflating air into the abdomen, inserting the scope, and essentially looking around because there were no operating ports on the first laparoscopes. With the patient under conscious sedation, a second physician might perform a needle biopsy through the abdominal wall, with oral instruction from the laparoscope operator.
With the advent of surgical techniques such as cholecystectomy, laparoscopy became a technique used by surgeons rather than gastroenterologists, as gastroenterologists are not generally accredited to perform any kind of open surgery. In the event of a complication from a laparoscopic procedure, surgery may be necessary. The new NOTES technology is an extension of laparoscopic surgery that may evolve similarly into a combined gastroenterologic/surgical application.
In NOTES, there is no puncture of the abdominal wall. The endoscope is inserted either into the stomach by way of the mouth and esophagus or into the sigmoid colon through the rectum. A deliberate perforation of approximately 3 cm in length is made to the stomach or the sigmoid colon wall and a flexible instrument is inserted into the abdominal cavity to perform diagnostic and surgical procedures. There is no scarring because the only incision is internal. The ASGE video symposium examined the potential application of NOTES in clinical practice to address some of the pathology within the abdominal cavity and possibly perform some therapeutic procedures.
The challenge with NOTES, as with the early stages of laparoscopy before it, is in sealing the incision, both to allow for consistent inflation of the abdominal cavity and to thoroughly close and heal the incision after the procedure. In laparoscopy, ports have been developed with valves, so that the surgeon can go in and out of the abdominal cavity with a scope or a probe and the air does not leak out. Researchers working with NOTES are trying to develop similar ports with valves that can be placed in the wall of the stomach or the sigmoid colon, so that instruments can be taken in and out of the peritoneal cavity without losing inflation. Successful procedures in the pig model have utilized continuous pumping of air, which cannot be done in a live human, as it would severely distend the abdomen and potentially cause internal damage.
In order to seal the incision after a procedure, NOTES researchers have developed clips, a series of which can hold the incision in place until it heals and then erode and pass out of the body as part of a stool. They also presented a device that holds four clips so that the entire 3-cm incision could be sealed without removing the scope and reloading. Another idea being considered is the endoscopic administration of stay sutures to mark the folds of the incision and allow for proper rejoining after a procedure.
Similar clip technology is being investigated in the treatment and control of bleeding that may occur during colonoscopy and polypectomy. If the colon is perforated during the procedure or removal of a polyp, the perforation or bleeding can potentially be sealed and healed with a clip or clips and no surgery will be necessary. This may also have application in perforated diverticula.
Dr. Ponsky, a surgeon and past president of both the ASGE and the Society of American Gastrointestinal Endoscopic Surgeons (SAGES), also gave an overview lecture on the applications and limitations of new technology in endoscopic surgical techniques, as part of the Society for Surgery of the Alimentary Tract (SSAT) program.
JS Dr. Ponsky summarized the therapeutic uses of endoscopy, from the initial application of polypectomy, through the development of sphincterotomy and stenting techniques, to the advances that have led to our current investigations in treating and healing perforations. His main point with regard to NOTES was that as gastroenterologists, we are progressing to the point where many new procedures will be possible without referral to a surgeon. However, he did caution against attempting to remove the gallbladder because of the many complications that can arise, even in open or laparoscopic surgery.
Dr. Bart Veldt of the Erasmus Medical Center in Rotterdam, the Netherlands and associates from the University of Toronto, the MediZinische Hochschule, Hannover, the University of Berne, and Saarland University Hospital, Homburg examined the relationship of sustained virologic response (SVR) to hepatitis C therapy as an outcome predictor in patients with advanced fibrosis. In a retrospective international multicenter cohort study, they examined the course of treatment in 541 patients with advanced fibrosis/cirrhosis (Ishak 4–6), with a mean follow-up of 3.3 years. Of the full cohort, 358 patients received interferon with or without ribavirin (Copegus, Roche) and 276 had followed a treatment-regimen including pegylated interferon. Seventy-one percent were nonresponders (NR) and 29% achieved SVR. In multiple regression analysis, genotype 1 and previous nonresponse were associated with a smaller probability of achieving an SVR, whereas higher pre-treatment albumin levels and treatment with pegylated interferon were associated with a higher probability of achieving SVR. The 5-year occurrence of hepatic failure and hepatocellular carcinoma (HCC) was 0% and 5.6% (95% CI 0.0–12.1) among sustained responders versus 12.2% (95% CI 8.1–16.3) and 8.2% (95% CI 4.4–11.9) among NR (P<.01 for liver failure and P=.04 for HCC). The five-year occurrence of liver-related death was 2.4% (95% CI 0.0–7.1) among sustained responders and 10.1% (95% CI 6.0–14.3) among NR (P<.01). Time dependent Cox regression analysis showed that nonresponse, old age, high pretreatment bilirubin, low albumin levels, and low platelet counts are independently associated with the development of clinical events during follow-up.
Dr. Masatoshi Akamatsu and associates from the University of Tokyo observed that interferon therapy improves life-expectancy among chronic hepatitis C patients and HCC patients after tumor ablation. They conducted a retrospective study to evaluate the prognosis of HCC in patients who had achieved SVR to previous interferon therapy. Overall and recurrence-free survival rates were compared among 18 HCC patients who received interferon therapy and achieved SVR before HCC development (SVR group) and 468 HCC patients with Child-Pugh class A liver function who had not received interferon (controls). The overall survival rates were 77.2%, 45.9%, and 23.3% in the controls and 94.1%, 85.6%, and 85.6% in the SVR group at 3, 6, and 9 years, respectively. Cox proportional hazard regression revealed that the risk of death was significantly reduced in the SVR group (risk ratio [RR]: 0.225, 95% CI: 0.056–0.910, P=.0363). Recurrence-free survival, analyzed exclusively among those who received curative ablation or surgery, did not differ significantly.
NZ Endpoints for disease treatment, including chronic HCV, must regularly be examined to ensure effectiveness in decreasing morbidity and mortality. In hepatitis C therapy, the validity of the currently accepted endpoint of viral eradication or SVR as an appropriate clinical end-point has recently been considered in terms of preventing complications of cirrhosis and lowering rates of liver-related death. These two studies sought to address this question by examining patients with significant fibrosis or cirrhosis, and determining whether or not SVR could be correlated to better outcomes in terms of complications and subsequent liver-related adverse events.
Dr. Veldt’s group attempted to confirm earlier, preliminary Japanese literature suggesting that if SVR is achieved, even in patients with significant fibrosis and cirrhosis, the rate of complications including liver failure, liver cancer, or liver-related death would be lower. They found that this was the case and that SVR could be independently associated with decreased incidence of complications. Although these findings are exciting and reaffirm the need to treat HCV patients with advanced fibrosis whenever appropriate, it is important to note that some patients with advanced fibrosis may still be at increased risk for the development of HCC, despite achieving SVR, and may need to continue medical follow-up at regular intervals for surveillance.
Dr. Akamutsu’s group looked at the same question from another angle, positing the idea that achievement of SVR before the development of subsequent HCC would favorably affect the outcome of HCC treatment. They compared two cohorts of HCV/HCC patients. The first had achieved viral eradication of HCV before the development of cancer. The second developed cancer and had never received any HCV therapy. Again, all patients in both groups were cirrhotic. Using Cox proportional regression analysis, the group demonstrated that the overall tumor-free survival was much better in the prior-SVR group and that improved survival seemed to be directly related to achieving prior SVR, rather than other cofactors including the type of HCC therapy (curative ablation versus surgery). The main shortcoming of this study, in addition to its retrospective nature, is the small number of patients in the “prior-SVR” group. However, these findings are intriguing.
These studies together reinforce the idea that achievement of SVR is not only beneficial in eradicating a state of chronic viral infection, but that it decreases the rate of subsequent complications from fibrosis and cirrhosis. Other potential endpoints of HCV therapy, including chronic viral suppression or histologic improvement in the absence of viral eradication are yet to be validated or endorsed.
Dr. Charles D. Howell of the University of Maryland Medical School and colleagues from the University of Pittsburgh, the University of California, San Francisco, the University of Miami, Rush University, and Indiana University noted that African Americans infected with hepatitis C virus (HCV) genotype 1 have significantly lower rates of HCV clearance than white Americans following treatment with peginterferon alfa and ribavirin. They compared peginterferon alfa pharmacokinetics and pharmacodynamics (ie, serum 2,5-OAS kinetics) in relation to virologic responses during the first 28 days of peginterferon alfa-2a (Pegasys, Roche) and ribavirin treatment in African American and white American HCV genotype 1 patients. Treatment-naive, HCV genotype 1 patients (196 African American and 205 white) were treated with peginterferon alfa-2a (180 µg weekly) and ribavirin (1,000–1,200 mg daily) for up to 48 weeks. Ninety-six patients who received peginterferon alfa-2a without dose alteration during the first 4 weeks of treatment and who had peginterferon alfa-2a and 2,5-OAS serum levels measured before treatment and on treatment-days 1, 2, 3, 7, 14 and 28 were selected for this study. Peginterferon alfa-2a and serum 2,5-OAS (pharmacodynamic marker) levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA) and by RIA (Roche Molecular Diagnostics, Alameda, CA). The maximum peginterferon alfa-2a concentration (Cmax) and area under the serum concentration-time curve (AUC) values from day 0 to 7 were determined using non-compartment PK analysis. Serum HCV RNA levels were measured using the Amplicor HCV Monitor Test, version 2.0 assay.
At baseline, African American and white American patients were similar in regard to age, gender distribution, body weight, body mass index, alcohol or tobacco use, liver histology, creatinine clearance, baseline HCV RNA levels, and HCV 1 subtype distribution, but African Americans had a lower mean serum alanine aminotransferase level (P=.003). There were no differences between African Americans and white Americans in either Cmax or AUC from day 0-7 after first peginterferon dose, but African Americans were more likely to have a Tmax by day 3 (P=.03) and on average had greater peginterferon levels on day 28 (18.0 ± 8 vs. 15.5 ± 7 ng/mL, P=.03) and higher 2,5-OAS levels on days 2, 3, 14, and 28 (P<.05). However, African Americans had a significantly smaller decline in serum HCV RNA from pretreatment to day 28 (P=.02, days 14 and 28). There was a negative correlation between serum peginterferon alfa-2a (P<.05) and HCV RNA levels on days 7, 14, and 28 in white Americans but not in African Americans. Likewise, there was a negative correlation between serum 2,5-OAS levels on days 2–14, and HCV RNA levels on days 2–28 in white Americans (P<.05) but not in African Americans.
Dr. Jeff Douglass and coworkers from the University of New Mexico Hospital in Albuquerque and the Albuquerque Veterans Medical Center observed that ethnicity has been shown to be an important factor in chronic HCV therapy and that previous studies have suggested Hispanic patients have increased treatment discontinuation rates and a nonsignificant trend to lower treatment response when compared to non-Hispanic whites. They conducted a retrospective study to determine whether or not Hispanic patients, when compared to those of non-Hispanic white ethnicity, with chronic HCV infection, have a lower rate of SVR to combination pegylated interferon and ribavirin therapy and also examined the HCV genotype distribution, pretreatment viral load, and treatment discontinuation rates in Hispanic compared to non-Hispanic white patients.
The authors reviewed the cohort of all treatment-naive Hispanic and non-Hispanic white patients with chronic HCV infection at the University of New Mexico Hospital (n=181) and the Albuquerque Veterans Administration Hospital (n=83) who had received treatment, including follow-up 6 months posttherapy with pegylated interferon and ribavirin between October 2001 and November 2005. An intention to treat statistical analysis included t-test, Fisher’s exact test, and logistic regression.
Hispanics (n=116) when compared to non-Hispanic whites (n=148) were similar in age (mean 48.4 +/- 8.8 vs 48.6 +/-7.5, respectively), female gender (42% vs 32%, P=.12), body mass index (27.5 vs 28), and in HCV genotype distribution 1 or 4 (65% vs 58%), and 2 or 3 (35% vs. 42%). There was no difference in pretreatment HCV viral load. Pretreatment labs were similar including platelet count, hematocrit, white blood count, and iron percent saturation. Overall SVR across genotypes was similar (36.5% vs 47.3%, P=.10). SVR in genotype 1 or 4 patients was 33% versus 30%, P=ns. Hispanic genotype 2 or 3 patients had a lower SVR (42.5% vs 71%, P=.007). Overall treatment discontinuation rates were similar (33% vs 24%, P=.10). In multivariate analysis, treatment discontinuation was the largest predictor of treatment failure (P<.001). After excluding patients with treatment discontinuation, Hispanic ethnicity continued to be an independent predictor of lower SVR in genotype 2 or 3 patients (59% vs 86%, P=.01).
NZ To date, most large clinical trials in hepatitis C have excluded minority populations, either by design or due to low enrollment. It has been repeatedly demonstrated that ethnicity is an important factor in the natural history and treatment outcome of human diseases, including chronic HCV infection. African Americans with HCV have lower response rates to interferon-based therapy compared to white Americans.
Dr. Howell and coworkers attempt to uncover potential mechanisms for this difference in response to HCV therapy between the two ethnic groups by examining the pharmacokinetics and pharmacodynamics of pegylated interferon in African Americans compared to white Americans. Patients in both groups were similar in terms of genotype distribution, body mass index, and pretreatment viral load. The authors examined pegylated interferon serum levels and 2,5-OAS levels in the serum and compared them to rates of viral response. They found that although African Americans had similar or even greater peginterferon serum levels during the first 4 weeks of therapy and they had somewhat greater 2,5-OAS levels, their virologic response was fairly poor, suggesting that differences in treatment outcome between those two ethnic groups could not be explained by differences is pharmacokinetics and pharmacodynamics. These data suggest that simple alterations in therapeutic regimens such as the use of a higher dose interferon or a longer duration of therapy may not be sufficient to overcome resistance in African Americans. Other mechanisms including specific immune responses to interferon in African Americans or high rates of insulin resistance should be examined in future studies.
Similar to our understanding of response rates in African Americans, emerging data have suggested that Hispanic Americans have lower response to standard HCV therapy compared to non-Hispanic white Americans. The low response in Hispanics has been attributed in some studies to higher rates of therapy discontinuation rather than a lack of efficacy although this has not been proven.
Douglass and colleagues examined two cohorts, Hispanics and non-Hispanic whites, who were otherwise similar in their pretreatment parameters. They found that Hispanics and whites with genotype 1 HCV infection have similar response to therapy but that Hispanics with HCV genotype 2 or genotype 3 infection have particularly low responses compared to their non-Hispanic counterparts. This lower response continued to be present even when discontinuation rates were factored out. Results of this study may explain, at least in part, why treatment results in industry-sponsored randomized controlled trials, which exceed 70–90% in genotype 2 and 3 patients, are often not reproducible in practice. The proportion of minority patients, including Hispanics, varies from one practice to another, which may lead to differences in SVR rates.
Dr. David Nelson of the University of Florida, Gainesville, along with colleagues from Human Genome Sciences, Inc, Georgetown University, the Mayo Clinics in Scottsdale, Rochester, and Jacksonville, Johns Hopkins University, Baylor University Medical Center, Duke University, and Bar Ilan University in Ramat Gan, Israel, reported results from an ongoing phase II dose-ranging study of the novel compound albuferon (Human Genome Sciences) in treatment-resistant chronic HCV patients. Albuferon is a recombinant protein consisting of interferon alfa genetically fused to human albumin. The authors are evaluating the safety and efficacy patients who failed to achieve early virologic response or to clear HCV RNA on therapy with previous interferon alfa–based regimens.
Subjects were randomized into three albuferon-treatment cohorts (900 µg every 2 weeks, 1,200 µg every 2 weeks, or 1,200 µg every 4 weeks, all doses administered subcutaneously) in combination with ribavirin 1,000–1,200 mg daily. After evaluating safety data, two higher-dose cohorts of albuferon, 1,500 µg every 2 weeks and 1,800 µg every 2 weeks, were enrolled. Treatment duration is set at 48 weeks with 24 weeks follow-up. The primary efficacy endpoint is SVR. The initial 3 cohorts have completed 48 weeks treatment, and 12-week data for the highest dose cohort are currently available.
At week 12, the overall antiviral response in the 1,800 µg cohort was the highest, despite having a greater proportion of prior peginterferon plus ribavirin nonresponders. The slope of HCV RNA decline from weeks 4 to 12 was significantly more rapid (P<.01) for the 1,800 µg cohort compared to the 900–1,500 µg cohorts in genotype 1, prior peginterferon plus ribavirin nonresponders. The week 24 antiviral response was comparable across the 900–1,500 µg cohorts. Most patients who were RNA negative at week 24 remained negative at week 48. Antiviral response at weeks 12 and 24 was predictive of week 48 end-of-treatment response for the 900–1,200 µg cohorts. Overall, albuferon plus ribavirin was well tolerated and the safety profile in the 1,500 µg and 1,800 µg cohorts was comparable to the 900–1,200 µg cohorts in type, incidence, and severity of adverse events.
NZ There are several ways to alter the structure of a medication in order to make it long-acting. Pegylation of the active molecule is one. Another is liposomal formulation. Still another is the creation an albumin-bound formulation. This method allows for the drug to be dosed less frequently. Albuferon has a longer half life than pegylated interferon that allows for dosing once every 2 weeks rather than once weekly. If this medication proves to be safe and at least as effective as its pegylated counterparts, it will have a clear advantage to patients in terms of dosing.
These data comprise the follow-up from an ongoing phase II, dose-ranging study. The authors reported that 1,800 µg every 2 weeks of albuferon combined with ribavirin is as safe as lower doses and it seems to be associated with the most robust antiviral response, at least during the first 12 weeks of treatment in comparison to 1,500, 1,200, and 900 µg doses. The findings will likely guide the design of larger, phase III clinical trials of albuferon in patients with chronic HCV.