FDA Announcement Aug 3, 2017: FDA approves Mavyret for Hepatitis C
The U.S. Food and Drug Administration today approved Mavyret (glecaprevir and pibrentasvir) to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis. Mavyret is also approved for adult patients with HCV genotype 1 infection who have been previously treated with a regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both.
Mavyret is the first treatment of eight weeks duration approved for all HCV genotypes 1-6 in adult patients without cirrhosis who have not been previously treated. Standard treatment length was previously 12 weeks or more.
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From NY Times: Overtreatment is Common, Doctors Say
Researchers surveyed 2,106 physicians in various specialties regarding their beliefs about unnecessary medical care. On average, the doctors believed that 20.6 percent of all medical care was unnecessary, including 22 percent of prescriptions, 24.9 percent of tests and 11.1 percent of procedures. The study is in PLOS One.
Reasons for overtreatment that were cited:
- Fear of malpractice “that fear is probably exaggerated, the authors say”
- Patient demand
- Financial incentive
My take: It takes more time explaining why a test/medicine/procedure is a waste of time than to order it; even then, many patients/families are unhappy if the physician does not order the test/medicine/procedure that they think is necessary. Changing this dynamic is not easy.
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A recent study (JC Robinson et al. NEJM 2017; 377: 658-65) examined the topic of “reference pricing” and how this could be used to lower costs of medication usage.
“Under reference pricing, the insurer or employer establishes a maximum contribution it will make toward the price of a drug or procedure, and the patient pays the remainder.”
In this study, the authors examined 1302 drugs and more than 1.1 million prescriptions (2010-2014). Specifically, the authors compared RETA Trust, a national association of 55 Catholic organizations, which implemented reference pricing and compared costs with a labor union that maintained a drug formulary with copayments similar to RETA Trust but did not implement reference pricing. Key findings:
- “Implementation of reference pricing was associated with a higher percentage of prescriptions that were filled for the lowest-priced reference drug within its therapeutic class” (increase in 7%) along with a lower average price paid per prescription (-13.9%) than the comparison group.
- Reference pricing was associated with increase in copayment by patients (5.2%)
- Reference pricing was associated with reduced spending for employers by $1.34 million and increase in copays for employees by $0.12 million than in the comparison group.
Reference pricing has been associated with decreases of 10-12% in medication costs in European nations, as well.
The authors conclude: “Reference pricing may be one instrument for influencing drug choices by patients…pharmaceutical manufacturers who wish to charge premium prices may need to supply evidence of commensurately premium performance.”
My take: Although in concept reference pricing makes sense, I do worry that patients may be pushed towards less effective medications as not all medications in the same class are equally-effective.
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This graph shows the percentages of prescriptions for the lowest-priced drugs before and after implementation of reference pricing for RETA Trust. Union Trust is the comparison control.
A recent study (V Takyar et al. Hepatology 2017; 66: 825-33) examined a total of 3160 subjects enrolled in 149 clinical trials from 2011-2015. These patients were derived from the NIH Clinical Center, ≥18 years, had ALT and BMI measurements available. Presumed NAFLD (nonalcoholic fatty liver disease) was classified if patient had elevated ALT (≥20 for women and 31≥ for men) along with BMI >25 kg/m-squared.
- 27.9% (n=881) of these healthy volunteers had presumed NAFLD. These patients also had higher triglycerides, low-density lipoprotein, cholesterol and HbA1c (P<0.001 for all)
- The authors note that the presence of these presumed NAFLD as controls “likely” affected the study validity in 10 studies and “probably” affected another 41 studies.
My take: This study shows that patients with presumed NAFLD are often enrolled in research studies as healthy controls. Furthermore, this can affect study outcomes.
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A recent study (LR Jolving et al. Inflamm Bowel Dis 2017; 23: 1440-46) used a nationwide (Denmark) register-based cohort to examine the health outcomes of children whose mothers have inflammatory bowel disease (IBD). This cohort of 9238 children were compared with nearly 1.4 million children born to women without IBD. Median follow-up time was 9.7 years of the children whose mothers had IBD.
- Hazard ratio for developing IBD in the offspring was 4.63 if maternal ulcerative colitis
- Hazard ratio for developing IBD in the offspring was 7.70 if maternal Crohn’s disease
- “Our data otherwise do not provide evidence for an increased risk of any of the other examined diseases in the offspring.” This included diabetes mellitus, thyroid diseases, rheumatoid arthritis, epilepsy, chronic lung disease, mood disorders, schizophrenia, epilepsy, and anxiety disorders.
Raw numbers for developing IBD:
My take: This study documents the expected finding of an increased risk of IBD among the offspring of women with IBD. No other chronic diseases were increased in this study.
Briefly noted: SM Yoon et al. Inflamm Bowel Dis 2017; 23: 1382-93. This retrospective registry study included the following:
- 314 subjects with Crohn’s disease (CD) who were primary nonresponders, and 179 with CD who were secondary nonresponders
- 145 subjects with ulcerative colitis (UC) who were primary nonresponders and 74 with UC who were secondary nonresponders
Key findings: “Colonic involvement (OR 8.0) and anti-TNF monotherapy (OR 4.9) were associated with primary nonresponse to anti-TNF agents in CD.” Higher ANCA levels in UC (HR 1.6) were associated with time to loss of response to anti-TNF agents.
A recent study (JM Chalbhoub et al. Inflamm Bowel Dis 2017; 23: 1316-27) performed a systematic review and meta-analysis to examine the effectiveness of Adalimumab (ADA) combination therapy compared with monotherapy. With infliximab (IFX), the SONIC study, showed that combination therapy with an immunomodulator (IMM) (azathioprine) improved response; combination therapy resulted in reduced immunogenicity, lower rates of infusion reactions, and higher IFX levels.
With the advent of widespread use of therapeutic drug monitoring, some have questioned the need for combination therapy with IFX. The need for combination therapy for ADA is also a matter of debate. ADA has less immunogenicity than IFX and it is unclear if combination therapy will improve outcomes. There have been conflicting studies regarding combination therapy with ADA, prompting the current meta-analysis.
The authors identified 24 articles for inclusion from an initial pool of 1194. Key findings:
- No significant difference between combination therapy and monotherapy was noted for induction of remission (OR 0.86) or response (OR 1.01). The induction of remission is based on data from 3096 patients (1400 on combination treatment).
- No difference was noted for maintenance of remission (OR 0.97) or response (OR 0.91). The maintenance of remission is based on data from 1885 patients (859 on combination treatment).
- Patients receiving combination therapy had lower odds of developing antidrug antibodies (OR 0.24)
- Subgroup analysis in anti-TNF experienced patients showed improved successful induction of remission (OR 1.26) but also more frequent opportunistic infections (OR 2.44)
Overall, the authors conclude that “combination of ADA and immunomodulators does not seem superior to ADA monotherapy for induction and maintenance of remission and response to Crohn’s disease.” They do comment on the recent DIAMOND study which was a randomized open-label top-down strategy trial in anti-TNF-naive and IMM-naïve patients. While no overall advantage of combination therapy was evident, better endoscopic response (84% vs. 64% with monotherapy) was seen at 26 weeks (but not at 52 weeks).
This study has several limitations. Overall, there were a small number of randomized trials and the trials had significant heterogeneity.
My take (borrowed from authors): “It is unclear whether the addition of IMM impacts the efficacy of a less immunogenic anti-TNF biologic such as ADA in CD.” Though, in the subgroup of anti-TNF exposed patients, “combination therapy was associated with higher odds of induction of remission.”
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A recent study (CV Almario et al. Clin Gastroenterol Hepatol 2017; 15: 1308-10) was titled: “Old Farts -Fact or Fiction? Results from a Population-Based Survey of 16,000 Americans Examining the Association Between Age and Flatus.” I was surprised that this was not in an April Fools edition, though I had to read the article because of the intriguing title. The authors premise was to determine if the elderly pass more flatus.
- Based on self-reporting using a mobile app (MyGiHealth), the authors found that individuals ≥65 years passed flatus less often than the younger age groups. Among those reporting flatulence every 1-2 hours, only 22.6% of those ≥65 years had this frequency; this compared to at least 33% in all other age groups.
- Most commonly, individuals in all age groups reported passing flatus about every 3-4 hours (36-41%); the next most common frequency was about every 1-2 hours (23-38%) across all age groups. The other frequent category was passing flatus once or twice a day which was reported between 24-29% across all age groups.
The authors indicate that limitations of their study include “social desirability bias” and “information bias.” In addition, while the entire cohort was >16,000, there were only 296 who were ≥65 years of age.
While I’m not an expert in this field, other limitations could include worsened ability to detect/record flatus with age and/or worsened memory about frequency of passing flatus.
My take: This study shows that almost any study could find a home in some medical journals. In my view, self-reported frequency of passing flatus may not be accurate (the dog did it!).
Pitt Street Bridge, Charleston, SC