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Archive for May, 2014

Primary Care Corner with Geoffrey Modest MD: Celiac Disease in Kids with Irritable Bowel Syndrome

28 May, 14 | by EBM

article in jama pediatrics looked at kids with functional GI disease and assessed the incidence of concomitant celiac disease  (see doi:10.1001/jamapediatrics.2013.4984). background is that approx 1% of US population has celiac disease (often asymptomatic). adults with IBS have approx 4-fold increased prevalence of celiac disease. the present study is a 6-year prospective cohort study in Italy, where prior large epidemiologic studies have found celiac disease prevalence to be in the 0.5-1% range. 992 kids (43% male, median age 6.8y) referred by their primary care MD for recurrent abdominal pain, 782 of whom had diagnosis of IBS, functional dyspepsia, functional abdominal pain, or abdominal migraine by Rome III criteria. these kids were then assessed for celiac disease, with total IgA, IgA tissue transglutaminase antibody, and endomysial antibodies, then duodenal bx if positive.  results for these 992 children:

–270 had IBS, of whom 12 tested positive for celiac disease = 4.4%
–201 had functional dyspepsia, of whom 2 tested positive for celiac disease = 1%
–311 had functional abdominal pain, of whom 1 tested positive for celiac disease = 0.3%
–210 were excluded from this study because they had some “organic disorder”, mostly GERD, gastritis, lactose intolerance
–of note, there was no difference in wt, ht, iron levels, ferritin, albumin, hemoglobin, or ALT in those diagnosed with celiac disease vs those without the diagnosis

so, recurrent abdominal pain is common (10-15% of school-aged children). one could argue, as the editorialists do, that those who meet criteria for IBS are at high enough risk (4% range) that they should be tested for celiac disease (at the 1% prevalence rate and given the sens and specificity of the serum tests, there would be a 68% false positive rate for celiac disease, suggesting that universal testing is not useful. at the 4.4% prevalence rate, 32% would be false positive). in fact NICE (natl institute for health and clinical excellence in the UK) does recommend celiac testing on all patients meeting criteria for IBS. there are some advantages to an earlier diagnosis (avoiding osteopenia, short stature, delayed puberty, infertility, intestinal lymphoma) in later life, so it seems reasonable to me to test kids and adults with IBS.

fyi, full set of Rome III diagnostic criteria for functional GI disorders — see here.


Primary Care Corner with Geoffrey Modest MD: Dolutegravir for HIV — Flamingo Study

27 May, 14 | by EBM

article came out in lancet on a very effective and simple HIV regimen using the new integrase-inhibitor dolutegravir (see in the FLAMINGO study 484 patients naive to antiretroviral therapy were put on an investigator chosen background therapy of either tenofivir-emtricitabine (67% of the patients) or abacavir-lamivudine (33%), then randomized to either dolutegravir 50mg daily or the protease inhibitor darunavir 800mg plus ritonivir 100mg. primary endpoint was HIV viral load <50 copies/ml at 48 weeks. patients recruited from 64 research centers in eastern and western europe, US, puerto rico. results, after 48 weeks:

–baseline: 71% white, 25% of african origin; 85% men,  CD4 was 395, 25% with viral load > 100K
–90% on dolutegravir and 83% on darunavir/ritonivir achieved <50 copies/ml (statistically significant)
–in those with baseline viral load >100K, significant difference in those on dolutegravir (94% vs 71%, esp significant in those on tenof/emtricit as background therapy, given higher “n” for this group)
No patient developed drug resistance
–both well-tolerated: 3% in dolutegravir and 9% in darunavir/riton discontinued meds for nonvirologic reasons. mostly diarrhea, nausea, headache, nasopharyngitis, and most were grade 1-2
–higher treatment satisfaction scores with dolutegravir

so, several advantages of dolutegravir regimen:

–better efficacy at 48 weeks, statistically significant. part of this is that integrase-inhibitors (such as dolutegravir) reduce viral load much more rapidly than protease inhibitors (such as darunavir), with the former achieving viral suppression often in less than 8 weeks (in this study, 80% had viral suppression at 4 weeks, 85% by 8 weeks; vs 10% and 25% in the PI group). so possible that darunavir would be just as good if look further out than 48 weeks. esp in those with very high viral loads which take longer to decrease on meds
–the dolutegravir regimen is just 2 pills once a day (and combo may be coming out as a 1 pill regimen). the darunavir regimen was 4 pills once a day
–dolutegravir is really easy to take: few drug-drug interactions, can take with/without meals, better lipid profile
–one sort-of adverse reaction is increase in creatinine, which is related to decreased creatine secretion and NOT to decreasing the true GFR (ie, the calculated GFR looks worse than the true GFR, as also found with cimetidine and trimethoprim), and in this study no one had a concerning (grade 3-4) increase in serum creatinine.
–study not include patients co-infected with hep b or c, and few patients with advanced HIV disease (they consciously excluded pts with moderate to severe hepatic impariment or anticipated need for hep c treatment)

so, sounds like a really fantastic regimen (supported by some other posts I’ve made). some concern about the generalizability of the results to sicker or co-infected patients (hep b or c), nonwhite, women. and, no doubt, the price tag will be high — this may become much more of an issue when the older drugs, such as efavirenz, become available generically. a head-to-head trial of dolutegravir/abacavir/lamivudine was significantly superior to tenof-emtricit-efavirenz (atripla), though in my experience the vast majority of patients on atripla do really well and tolerate the regimen adequately.   but the tolerability, efficacy, lack of resistance, lack of food restriction and drug-drug interactions of dolutegravir is really impressive.


Primary Care Corner with Geoffrey Modest MD: Kidney Stone Predictive Model

21 May, 14 | by EBM

a recent study developed a clinical prediction rule for uncomplicated ureteral stones (see doi: 10.1136/bmj.g2191).  there were 2 components to the study. first was a retrospective observational study to develop the screening tool, a random selection of 1040 adults (derivation cohort) who underwent non-contrast CT for suspected uncomplicated kidney stone from 2005 to 2010. their data was used to derive the top five factors associated with stones analysis and ascribe points reflecting their importance (see STONE score below). the second study was the validation study, 491 patients where the ER physicians felt that the patient presentation was consistent with ureteral stone.

–for the observational component: the five key factors were — male sex, short duration of pain, non-black race, presence of nausea or vomiting, and microsopic hematuria.
–in the derivation and the validation cohorts (respectively)
–STONE score of 0-5: 8.3% and 9.2% had stones (this reflected 19.8% and 15.5% of patients)
–STONE score of 6-9: 51.6% and 51.3% had stones (this reflected 49.6% and 46.8% of patients)
–STONE score of 10-13: 89.6% and 88.6% had stones (this reflected 30.6% and 37.7% of patients)
— of note, in this high probability group, acutely important alternative findings were present in 0.3% and 1.6% (mostly diverticulitis, appendicitis, cholecystitis and a spattering of other diagnoses)

STONE score:

male sex =2

duration of pain: >24 hours =0, 6-24 hours =1, <6 hrs =3

race: nonblack=3

nausea alone=1, vomiting  alone=2

erythrocytes in urine: present =3

max total = 13

so, interesting study in that it could decrease the use of CT scans and the attendant ionizing radiation (average of 11.2 mSv), especially in the 1/3 of patients who are high risk. CT scans are the diagnostic procedure of choice in the US, though ultrasounds are preferred in Europe. the authors comment that “despite a 10-fold increase in the utilization of CT scanning for diagnosis of kidney stones from 1996-2007, the proportion of patients with a diagnosis of kidney stone, findings of significant alternative diagnoses, or hospital admission has not changed”. one potential plus for CT in those in the high probability STONE score is to find the 20% or so with large stones who likely need an intervention. they offer the possibility of a substantially reduced dose CT scan (which could miss some important alternative findings, though present in <2% of their groups), or ultrasound (which sometimes cannot see the stone well). or possibly limiting the reduced dose CT to younger patients who are even less likely to have an important alternative finding.

but a few caveats: this is one study done in 2 centers at Yale, so needs to be repeated. 85% of patients were white (more common for stones in whites, but interestingly also more common in men and 46% of the patients were women). so not sure about generalizability to other regions, ethnicities. however, i am always concerned about the amount of ionizing radiation we subject patients to. the thought of low-dose CT is appealing, though ultrasound makes a lot of sense to me for initial imaging


Primary Care Corner with Geoffrey Modest MD: Pneumococcal Vaccine Efficacy

20 May, 14 | by EBM

general population study in Spain to assess benefits of 23-valent pneumococcal vaccine (see DOI: 10.1093/cid/ciu002).  PPV-23 was recommended for all people over 60 yo. 27,204 people in the cohort were followed prospectively from 2008-2011, of whom 8981 received the vaccine. mean age 72. primary outcome: hospitalization for pneumococcal community-acquired pneumonia (CAP), and all-cause CAP. pneumoccocal etiology determined if pos blood culture, pos sputum culture with no other likely bacterial pathogen, or positive urinary antigen test. results:

–incidence rate (per 1000 person-years) were 0.21 for bacteremic pneumococcal CAP, 1.45 for nonbacteremic pneumococcal CAP, and 7.51 for all-cause CAP.  None of these were significantly different between vaccinated and unvaccinated.
–BUT, in those vaccinated  within the past 5 years (n=2390)  there was a reduced risk of bacteremic pneumococcal CAP (HR=0.38, .09-1.68), nonbacteremic pneumococcal CAP (HR=0.52, .29-.92), overall pneumococcal CAP (HR=0.49, .29-.84), and all-cause CAP (HR=0.75, .58-.98). [the latter 3 were statistically significant]

 note: this is not a randomized controlled trial, only an observational study comparing these outcomes in those who elected to take the vaccine vs those who did not, and there were differences between those vaccinated and not (though, not surprisingly, those choosing vaccination were sicker: older, more likely to have chronic pulmonary, heart, liver, or kidney disease and more htn, hyperlipidemia, obesity, smoking, cancer, alcoholism, immunocompromise). but there also may be unknown biases in this type of trial.

pneumococcal vaccine (PPV-23) is somewhat mixed in the studies of effectiveness, with more suggestion that it helps with invasive pneumococcal disease (recent cochrane review suggested vaccine efficacy of 74% for invasive disease). there was initial concern of severe/anaphyllactic reactions if revaccinated soon after a first dose, though subsequent trials indicated that this really did not happen if there was a several-year hiatus. other previous studies have found significant decreases in antibody levels after 3-5 years (and, i must admit, based on those studies, low cost, and apparent lack of toxicity, i have been revaccinating people every 5-6 years all along and have not seen any toxicity in patients receiving 3-4 shots). but it should be stated that this is not the CDC recommendation  — for normal risk: one vaccination at age 65. for high risk (age 19-65) revaccinate one time after 5 years, then again at age 65 if at least 5 years after last vaccination,



Primary Care Corner with Geoffrey Modest MD: Diabetes-related Complications Decreasing

15 May, 14 | by EBM

NEJM with recent article on the trend in diabetes-related complications from 1990 to 2010 (seeDOI: 10.1056/NEJMoa1310799), comparing age-standardized incidence of lower-extremity amputation, end-stage renal disease (ESRD), acute MI, stroke, and death from hyperglycemic crisis (either DKA or hyperosmolar hyperglycemic state). results:

–acute MI: -67.8% (95.6 fewer cases per 10,000 persons per year)
–death from hyperglycemic crisis: -64.4% (2.7 fewer cases per 10,000 persons per year)
–stroke: -52.7% (58.9 fewer cases per 10,000 persons per year)
–amputations: -51.4% (30 fewer cases per 10,000 persons per year)
–ESRD: -28.3% (7.9 fewer cases per 10,000 persons per year)

–these rate reductions were first noted in 1995 and were consistent thereafter.
–the greatest decline in absolute and relative terms was in people >75 yo (except from ESRD): ie, the difference between rates of disease in older people vs younger narrowed considerably
–of note, the decline was dramatically more pronounced in diabetics vs nondiabetics: in diabetics, acute MI had 2x the decline, stroke 10x, amputation 4x, ESRD decreased 28.3% as noted above, but increased 65% in nondiabetics

so, what does all this mean??  good news overall (for a change), but should be tempered by the fact that a larger % of the population has diabetes [eg, only the rates for hyperglycemic crisis (-42%) and MI (-32.3%) decreased when the increase in diabetes incidence factored in, rates of amputation and stroke did not change, and ESRD increased by 90.9%)]. clearly a lot of things changed during this time period: there was better blood pressure control, improved lipid levels and more aggressive use of highly effective statins, decreased smoking, decreased A1c levels (which, i believe, also parallels increased and more aggressive use of metformin, the drug with the best data for lowering macrovascular complications), improved hospital care (and better ability to handle the hyperglycemic crises), dietary changes (fewer trans fats), improved management of renal disease and peripheral vascular disease. also, maybe earlier detection of diabetes and more aggressive risk factor management at an earlier stage?

so, what this really means is that despite the dramatic increases in diabetes incidence (MMWR came out with data comparing 1995-7 vs 2005-7, finding a doubling!! of the age-adjusted rate of diabetes in the US, from 4.8 to 9.1 cases/1000 people in only one decade), we are basically compensating for diabetic medical complications by advances in many medical and social aspects of care (decreased smoking, better medications, higher percentages of people controlling risk factors), with a combination of significant improvements in heart disease, breaking even in amputation and stroke, and losing ground in ESRD.


Primary Care Corner with Geoffrey Modest MD: Spironolactone in Diastolic Heart Failure

14 May, 14 | by EBM

the current nejm study follows one i sent out last year from jama (see doi:10.1001/jama.2013.905) of the Aldo-DHF, a european study looking at whether spironolactone improved diastolic function and exercise tolerance in 422 ambulatory patients with diastolic heart failure, finding an improvement in left ventricular diastolic function but no difference in maximal exercise capacity, patient symptoms or quality of life.

in the current TOPCAT nejm study (see doi: 10.1056/NEJMoa1313731), 3445 pts with symptomatic diastolic heart failure (EF>45%) given low dose spironolactone (15-45mg/d) vs placebo, assessing primary outcome of cardiovasc death, aborted cardiac arrest, or hosp for heart failure. followed 3.3 years. results:

–baseline characteristics: ave age 69, half female, 90% white, LVEF 56%, 96% NYHA functional class 2 or 3, serum K=4.3, 82% on diuretic, 84% ACE-I/ARB, 78% b-blocker, and either had hospitalization for heart failure in past year (72%) or elevated BNP in previous 60 days.
–primary outcome in 320 spironolactone patients (18.6%) vs 351 placebo (20.4%), with HR=0.89 (0.77-1.04, nonsignificant). of note, in assessing prespecified subgroups, spironolactone significantly reduced the primary outcome in those patients stratified by BNP levels vs those stratified by prior hospitalizations.
–of the components of the primary outcome, hospitalization for heart failure significantly improved, with 206 pts on spironolactone (12%) vs 245 on placebo (14.2%): HR 0.83 (0.69-0.99).
–for deaths from cardiovasc causes: spironolactone assoc with 160, placebo 172 (HR 0.90, 0.73-1.12, nonsignif). insignif # of aborted cardiac arrest.
–adverse events: overall no diff between groups, but spironolactone assoc with increased hyperkalemia (18.7% vs 9.1%) though less hypokalemia (16.2% vs 22.9%) as well as doubling of creatinine (10.2% vs 7.0%). no diff in serious adverse events with frequent monitoring (eg, no creat>3 or dialysis)
–from their figure 1, the efficacy of spironolactone was largely evident from 12–48 months after start of trial

so, as the background issue, unlike systolic heart failure, the pharmacologic therapy for diastolic is much less effective. mineralocorticoid-receptor antagonists (eg spironolactone) have been found to decrease overall mortality and hospitalizations in those with systolic dysfunction, as have ACE-I/ARBs and b-blockers. diastolic heart failure, though the general approach to treatment is the same, does not have these important benefits, though there is symptomatic improvement and the CHARM-preserved trial did find a lower hospital admission rate in those on candasartan.  b-blocker efficacy is less clear. to me, this study at least shows statistical benefit in some results of spironolactone use, so i think it is reasonable to first use the basic meds (esp diuretics, ACE/ARB), consider adding b-blockers (esp if afib/fast rate or persistent hypertension, but also may get some improvement of cardiac hemodynamics), but then use spironolactone (carefully monitoring K) if persistent symptoms or high BNP.


Primary Care Corner with Geoffrey Modest MD: Geriatrics issues, choosing wisely

13 May, 14 | by EBM

The Am Geriatrics Soc released a second set of “five things physicians and patients should question” (see here). the items:

1. don’t prescribe cholinesterase inhibitors for dementia without periodic assessment of cognitive benefits and adverse GI effects. benefits overall are modest, impact on quality of life unclear. so give 12 weeks and stop if no significant improvement. continue with nondrug management (pt/caregiver education, diet, exercise, direct nonpharm behavioral approach depending on the specific issues).

2. not do routine screening for breast, colon, prostate cancer without considering life expectancy and risks (testing, overdiagnosis, overtreatment). esp if life expectancy less than 10 years. basically for these tests (per their numbers) need to screen 1000 patients to prevent 1 death in 10 years for each of these three tests)

3. avoid prescription appetite stimulants or high-calorie supplements for treating anorexia/cachexia in older adults. best to optimize social supports, provide feeding assistance, and clarify patient goals and expectations. supplements do increase weight, but no evidence of change in quality of life. megestrol assoc with thrombotic events, fluid retention, death and no clear improvement in quality of life. mirtazapine leads to wt gain in setting of depression, little evidence of utility in absence of depression [though i have had limited positive experience, with very low-dose: 7.5mg/d]. cyproheptadine (and megestrol) to be avoided per Beers criteria. [that being said, the only one i have used several times is low dose cyproheptadine (4mg once a day) and anecdotally –> no adverse effects, but increased appetite/weight and improved quality of life of my patients — they have been clearly happier.]

4. don’t prescribe new medicine without conducting drug regimen review. lots of polypharmacy in older adults, lots of drug-drug interactions, and increased risk of problems in elderly (cognitive impairment, falls, functional decline)

5. avoid physical restraints to manage behavioral symptoms of hospitalized elderly with delirium.

The 2013 list (see here):

1. not use percutaneous feeding tubes in pts with advanced dementia. offer oral assisted feeding. no clear diff in outcomes, and tube-feedings assoc with agitation, more use of restraints, more bedsores.

2. not use antipsychotics as first chose to treat behavioral/psych symptoms of dementia. increased risk of stroke, death. use if nonpharm measures fail and pts pose threat to themselves/others.

3. avoid meds to achieve A1c<7.5% in most adults > 65yo. harms outweigh risks. they suggest: 7-7.5% goal in healthy older adults with longer life expectancy, 7.5-8% if moderate comorbidity and life expectancy <10years, 8-9% if multiple comorbidities and shorter life expectancy [seems reasonable to me, though not based on actual data, just mathematical modeling. as per previous posts, important to treat the patient and not the number: some patients cannot be safely brought to A1c of 9 without significant risk of hypoglycemia]

4.don’t use benzos or other sedative/hypnotics as first choice for insomnia, agitation or delirium. more adverse events, eg falls.

5. don’t use antibiotics for asymptomatic bactiuria in older adults. screening not generally appropriate unless about to get urologic procedure where mucosal bleeding anticipated.



Primary Care Corner with Geoffrey Modest MD: AHA lipid guidelines, again

9 May, 14 | by EBM

as per several prior blogs, there are (to me) significant problems with the new AHA guidelines for assessment/treatment of lipid abnormalities. one of my concerns is the very large number of people (esp men) over the age of 60 who meet criteria for statin therapy by these guidelines. i gave the following examples:

–60 yo white male, no known atherosclerotic disease, systolic blood pressure of 130 on meds, total cholesterol 130, HDL 70 (so LDL around 70) would qualify for moderate intensity statins
–60 yo african-american with same risk factors qualifies for high intensity
–all men age 70 would qualify for high intensity statins, including a white male nonsmoker with syst blood pressure of 130 and the same pristine lipids
–a 70 yo woman with similar risk profile qualifies for moderate intensity statins.

an assessment was just published of the difference between the old and new guidelines, looking at baseline data from the NHANES database of 3773 people aged 40-75 (see DOI: 10.1056/NEJMoa1315665). results:

–by the old guidelines (ATP-III), 42% would be eligible for statins. for the new ones, 56.6%
–this extrapolates to the 40-75 yo US population as 43.2 M adults (37.5% of the population aged 40-75) by the old guidelines qualify for statins. 56M (48.6% of the population) qualify by the new guidelines
for adults 60-75: 30.4% of men and 21.2% of women are eligible by old guidelines; 87.4% of men and 53.6% of women by the new ones
 –applying the Framingham Risk Calculator to the NHANES dataset, over 10 years we would expect 11.4M cases of cardiovasc disease (CVD) among 103.5M adults aged 40-75 without known prior CVD. by the new guidelines, 16.8% of these 11.4M adults not eligible for statins by ATPIII would now be eligible per the new AHA recs (1.9M people). if, as per the primary prevention studies, there would be 25% relative risk reduction by using statins, 475K future cardiovasc events would be avoided, 90% of which would be among older adults within this age range. (of course, this is a rough estimate, based on different sources of info, using primary prevention studies which had patients at much higher risk than in my above examples and scaling up from NHANES to the full population).

so, bottom line: the new guidelines would dramatically overtreat older people without significant atherosclerotic risk factors. on the one hand, statins are well-tolerated and perhaps it is better to overtreat in order to avoid undertreating a minority of people (increased sensitivity, decreased specificity). on the other hand, treatment is expensive, leads to medicalization/blood tests/office visits and is associated with some potentially serious adverse events (rhabdo/acute renal failure, diabetes, ???dementia, etc) as well as more common annoying effects (myalgias), which also increase health care utilization.  as i have mentioned in the past, i am pretty aggressive in treating lipids in primary prevention, first by aggressive lifestyle modification if appropriate, then by statins. i have always felt that the ATPIII did not go far enough in the risk assessment [i always included periph art dz, stroke, chronic inflammatory conditions such as HIV/lupus…, A1c (which despite a recent negative study, there have been 2 dramatically positive ones over the past decade) in my gestalt risk assessment, meaning that someone with lipid abnormalities which placed them at a framingham score in the 5+% range and nonresponsive to lifestyle changes would get statins]. that being said, it is hard for me to justify using a statin on a 60-70yo man with no risk factors and an LDL of 70 and HDL of 70!!!!  and my guess is that this person has a much lower relative risk reduction by statins than the high-risk patients in the primary prevention studies.


Primary Care Corner with Geoffrey Modest MD: Hep C, a few things

7 May, 14 | by EBM

1. new WHO guidelines on screening, care, treatment of hep c (see here).

not much new, but reviews epidemiology, reinforces importance of testing and goes through some of the newer regimens (though these seem to change on a daily basis — see next 3 reviews below). they do add a nice global health perspective, including treatment in resource-poor countries. a few points:

 –estimated 185M people worldwide with hep c (!!), 350,000 die each year. largest # people infected (>50M each) are in east asia and south asia
–(although i never thought i’d be able to say it) hep c differs from other chronic hepatitis infections because it can be cured, over 90% of the time!!!
–they suggest screening all people with high HCV prevalence or hx of possible exposure (note USPSTF suggests one-time screening of everyone born between 1945-65, since HCV prevalence in this age group is relatively high
–screen for alcohol use and advise reduction
–screen for liver fibrosis and cirrhosis. they give 2 pathways: for resource-limited settings, screen with APRI ((AST/ALT)/platelet ratio). or FIB4 (age x AST/plt). their Table 6.4 has the cutpoints for signficant cirrhosis and fibrosis (low quality evidence, conditional recommendation). some tests require special and expensive equipment (eg ultrasound-based transient elastography). still, liver bx does best.
–everyone (adults/kids) should be assessed for antiviral treatment.
–treatment with telaprevir or boceprevir, in combo with peg-interferon/ribivirin in genotype 1 over interferon/ribiv
–treat with sofosbuvir in combo with ribivirin +/- interferon depending on genotype,
–treat with simeprevir in combo with peg-interferon/ribivirin with genotype 1b or in those with genotype 1a but without Q80K polymorphism  (these last 2 recommendations do not take resources into account, since pricing info internationally not available)
–hard to recommend one of the new therapies over another, since studies so far are from drug registration trials and no comparative outcome trials.  and many of the prices for these new meds are not fixed yet.
–in terms of prioritizing this very expensive treatment: those with less advanced fibrosis respond to treatment best, BUT if treatment availability is limited, priority should be given to those with advanced fibrosis and cirrhosis [METAVIR stages F3 (numerous septa without cirrhosis) and F4 (cirrhosis)], since highest risk of developing cirrhosis and hepatocellular ca (ie, they respond somewhat less well but achieve the greatest benefit)
–their table 8.3 has drug-drug interactions between HIV and hep C meds. chapter 9 is for specific populations, with long section on HIV/hep c co-infection

2. shorter course treatment of genotype 1 infection in people without cirrhosis (see DOI: 10.1056/NEJMoa1402355). 647 treatment naive pts randomized to ledipasivir and sofosbuvir for 8 weeks, that combo plus ribivirin for 8 weeks, or the 3 drugs for 12 weeks. looked at sustained viral response (SVR) 12 weeks after completion of therapy. results:

–ledipasivir and sofosbuvir for 8 weeks: 94%
–ledipasivir and sofosbuvir with ribivirin for 8 weeks: 93%
–ledipasivir and sofosbuvir with ribivirin for 1 weeks: 95%
–more adverse effects (not shockingly) with ribivirin. no one in the first group stopped therapy because of adverse effects

3. treatment naive patients without cirrhosis, with genotype 1 and another interferon-free regimen, using ABT-450/ritonivir plus ombitasvir (ABT-267), plus dasabuvir (ABT-333) with ribivirin for 12 weeks (see DOI: 10.1056/NEJMoa1315722). 632 patients given the above regimen (a grand total of 3 pills/d!!) vs placebo. results:

–SVR of 96.2%. genotype 1a with 95.3% and genotype 1b with 98%
–rate of discontinuation 0.6% in each group. major adverse effects nausea, pruritus, insomnia, diarrhea, asthenia

4. same as the previous study, but in genotype 1 patients without cirrhosis who failed prior peginterferon/ribivirin treatment (see DOI: 10.1056/NEJMoa1401561). 394 pts randomized to above for 12 weeks, or placebo

–SVR 96.3% (which they compared to historical control of pts with genotype 1, no cirrhosis, failed peg-interferon/ribiv, and given telaprevir and peginterferon/ribivirin, who had 65% SVR)
–SVR was 100% in pts with partial response to prior peginterferon/ribivirin, and 95.2% in those with no response to that treatment

 so, as an observer over time (as in, decades) and with lots of patients with hepatitis c, these results are really, really shocking.  genotype 1 response before was in the 20+% range. seeing mid 90% with a couple of pills and almost no significant side-effects is awesome, in the strict sense of the word. the cost, availability, and actually showing this therapy works in larger populations (different ethnicities, co-infections, degrees of hepatic impairment) is still to come, however these are the advances we have been waiting for….


Primary Care Corner with Geoffrey Modest MD: Neuraminidase Inhibs for Flu– Lack of Significant Efficacy

6 May, 14 | by EBM

BMJ came out with 2 articles from the Cochrane group on neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) (see here for oseltamivir and here for zanamivir). these papers are updated systematic reviews, and for oseltamivir (per the editorialist) “is the culmination of a four and a half year battle for access to the raw data from industry funded trials of oseltamivir, a drug on which the world has spent billions of dollars”, and reflects very different results than that presented to regulators, policy makers, the public etc by the drug makers. brief summaries:

oseltamivir: 83 RCTs on adults and kids. results:

–treatment studies:

–time to first alleviation of symptoms: decreased 16.7 hours (from 7 days to 6.3 days). no effect on kids with asthma, but healthy kids decreased symptoms by 29 hours
–no diff in admissions to hospital for adult. sparse data on kids.
–no diff in pneumonia, bronchitis, otitis media, sinusitis or any serious complication
–but increased nausea (number needed to harm NNTH 28) and vomiting (NNTH 22) with oseltamivir in adults and and vomiting in kids (NNTH 19). also inc QTc (NNTH 25)
–prophylaxis trials, oseltamivir dec symptomatic flu in pts by 55% and households by 13.6%, but no effect on asymptomatic flu and no evidence of dec transmission. in prophylaxis trials, inc risk of psych adverse events (NNTH 94), with dose response curve. increased headaches (NNTH 32), renal events — esp dec creat clearance (NNTH 150) and nausea (NNTH 25)
–authors note: “in a primary or secondary prophylaxis indication the postulated central effect of oseltamivir is confined to suppressing symptoms, because infection, according to Roche (the manufaturer) is not prevented”.

zanamirir:  54 RCTs in kids and adults.

–treatment studies:

–zanamivir reduced time to first alleviation of sx by 0.60 days (from 6.6 to 6.0 days, 14.4 hours) in adults. not significant in kids.
–no diff in pneumonia (investigator-reported or by CXR) in adults. also nonsignificant effect in kids
–no diff in otitis media or sinusitis in adults and kids, small effect in bronchitis only in adults (1.8%)

–prophylaxis studies:
–no diff in asymptomatic flu cases in individuals or households. only 2 small studies found effect in symptomatic flu in adults by 14.8%.
–no signif adverse events

so, what does this all mean?  of note the WHO has oseltamivir on their list of “essential drugs”. but neither of these drugs have significant effects on preventing or treating major complications of flu. the CDC also fully embraced these drugs (without having full transparent access to data) as did the am acad of pediatrics, making claims that starting these drugs early prevent serious complications. in these studies, it is unclear if using zanamivir, for example, actually reduces symptoms more than taking symptom relief meds.  the data from these studies are pretty compelling (and quite striking, since these drugs have been around for 15 years!): the benefits of these drugs are pretty minimal, the cost is high, the incidence of adverse effects (with oseltamivir) is high, and the imperative to use them comes from the lack of transparency and withholding info by big pharma.


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