{"id":377,"date":"2023-03-13T13:32:17","date_gmt":"2023-03-13T17:32:17","guid":{"rendered":"https:\/\/www.bumc.bu.edu\/cmu\/?page_id=377"},"modified":"2024-02-25T15:16:34","modified_gmt":"2024-02-25T20:16:34","slug":"cmu-blogs","status":"publish","type":"page","link":"https:\/\/www.bumc.bu.edu\/cmu\/cmu-blogs\/","title":{"rendered":"CMU Blogs"},"content":{"rendered":"
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NT-PROBNP PREDICTS FUTURE HEART FAILURE AND MORALITY IN ASYMPTOMATIC<\/h1>\n<\/header>\n
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March 12, 2023<\/strong><\/div>\n<\/div>\n

A recent article tracked changes over time of N-terminal B-type natriuretic peptide (NT-proBNP) in those without known heart failure (ie primary prevention) finding that changes in\u00a0NT-proBNP were<\/span>\u00a0associated with both incident heart failure and death (see\u00a0<\/span>chf bnp predicts HH development JAMAcardiol2023<\/b>\u00a0in dropbox or\u00a0\u00a0doi:10.1001\/jamacardio.2022.5309<\/span>)\u00a0<\/span><\/p>\n

Details<\/b><\/span>:<\/span><\/p>\n

\u2014 9776 individuals in the Atherosclerosis Risk in Community (ARIC) study from 4 US communities (in North Carolina, Mississippi, Minnesota, and Maryland)<\/span><\/p>\n

\u2014 data were collected from patient at visits 2 and 4, approximately 6 years apart, both with measurements of NT-proBNP<\/span><\/p>\n

\u2014 patients with prevalent heart failure were excluded<\/span><\/p>\n

\u2014 mean age 63, 57% women, 79% white\/21% Black<\/span><\/p>\n

\u2014 hypertension 46%\/on hypertension medications 34%\/mean blood pressure 128\/70, LDL 123, triglyceride 62, on cholesterol-lowering medications 14%, diabetes 15%, BMI 29, eGFR 86, current smoking 14%, prevalent coronary heart disease 7%<\/span><\/p>\n

\u2014 primary outcome: incident heart failure (HF) hospitalizations and all-cause death, with NT-proBNP grouped as either <125 pg\/ml vs >125 pg\/ml, as well the relationship with the percent change in\u00a0NT-proBNP<\/span><\/span><\/p>\n

\u2014 also assessed was the association between changes in cardiovascular risk factors with changes in NT-proBNP<\/span><\/p>\n

\u2014 the fully-adjusted model included systolic and diastolic blood pressures, being on hypertensive medication use, diabetes, fasting glucose, LDL, triglyceride, being on cholesterol-lowering medication, cigarette smoking, eGFR, BMI, and prevalent heart disease.<\/span><\/p>\n

Results<\/b><\/span>:<\/span><\/p>\n

\u2014<\/span>as compared to those with NT-proBNP <125pg\/ml at both visits (reference), all with adjusted hazard ratios:<\/span><\/p>\n

\u2014 NT-proBNP <125pg\/ml at visit 2 and\u00a0<\/span>>125 pg\/ml at visit 4<\/span><\/p>\n

\u2014 incident HF: HR 1.86 (1.60-2.16)<\/span><\/p>\n

\u2014 mortality risk: HR 1.32 (1.19-1.47)<\/span><\/p>\n

\u2014 NT-proBNP >125pg\/ml at visit 2 and\u00a0<\/span><125 pg\/ml at visit 4<\/span><\/p>\n

\u2014 incident HF: HR 1.01 (0.71-1.43)<\/span><\/p>\n

\u2014 mortality risk: HR 0.79 (0.61-1.01)<\/span><\/p>\n

\u2014 NT-proBNP >125pg\/ml at visit 2 and\u00a0<\/span>>125 pg\/ml at visit 4<\/span><\/p>\n

\u2014 incident HF: HR\u00a0<\/span>2.40 (2.00-2.88)<\/span><\/b><\/p>\n

\u2014 mortality risk: HR 1.68 (1.47-1.91)<\/span><\/b><\/p>\n

\u2014 ie, as compared to those who remained with a low NT-proBNP, those whose\u00a0NT-proBNP<\/span>\u00a0increased on visit 4 had a significant rise in HF, which was even more significant in those who started with a higher NT-proBNP and remained high. But those who started high and then had a lower level of NT-proBNP had no worse outcomes than those who began low and remained low<\/span><\/p>\n

\u2014 there was no interaction between NT-proBNP\u2019s relationship between HF incidents vs death (i.e. these were independent phenomena)<\/span><\/p>\n

\u2014 Stratification by percent change in NT-proBNP:<\/span><\/p>\n

\u2014 visit 2 NT-proBNP <125pg\/ml, as compared to no change by visit 4 (reference), all with adjusted HRs:<\/span><\/p>\n

\u2014 >25% decrease:<\/span><\/p>\n

\u2014 incident HF: HR 1.15 (0.86-1.53)<\/span><\/p>\n

\u2014 mortality: HR 1.14 (0.94-1.38)<\/span><\/p>\n

\u2014 >25% increase:<\/span><\/p>\n

\u2014 incident HF: HR 1.93 (1.39-2.67)<\/span><\/p>\n

\u2014 mortality: HR 1.56 (1.26-1.94)<\/span><\/p>\n

\u2014 visit 2 NT-proBNP >125pg\/ml, as compared to no change by visit 4:<\/span><\/p>\n

\u2014 >25% decrease:<\/span><\/p>\n

\u2014 incident HF: HR 0.86 (0.57-1.29)<\/span><\/p>\n

\u2014 mortality: HR 0.59 (0.44-0.79)<\/span><\/p>\n

\u2014 > 25% increase:<\/span><\/p>\n

\u2014 incident HF: HR 6.56 (2.27-18.99)<\/span><\/b><\/p>\n

\u2014 mortality: HR 5.47 (2.58-11.60)<\/b><\/span><\/p>\n

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\u2014 Changes in cardiovascular risk factors:<\/span><\/p>\n

\u2014 levels of NT-proBNP were positively associated with age, systolic blood pressure, being on hypertension medication use, smoking, and prevalent heart disease<\/span><\/p>\n

\u2014 but there was an inverse association of\u00a0NT-proBNP levels\u00a0<\/span>in men, diastolic blood pressure, triglyceride level, cholesterol medication use, eGFR, BMI, and\u00a0those of Black race<\/span><\/span><\/p>\n

\u2014 absolute change in NT-proBNP did correlate positively with systolic blood pressure change, particularly in those with an increase in NT-proBNP by at least 132 pg\/mL<\/span><\/p>\n

Commentary<\/b><\/span>:<\/span><\/p>\n

\u2014 NT-proBNP has been documented to be an effective biomarker for both the diagnosis and prognosis of heart failure. In those without known cardiovascular disease, it is associated with subsequent HF, cardiovascular disease, stroke, and all-cause mortality. The current AHA\/ACC guidelines on heart failure include NT-proBNP as part of their HF classification, with those having levels greater than 125 pg\/mL being considered to be in stage B or pre-HF category (stage B includes either high BNP determinations as well as persistently elevated cardiac troponin levels:\u00a0<\/span>2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines | Circulation (ahajournals.org)<\/span><\/a><\/p>\n

\u2014 this all brings up the question of the differences\u00a0<\/span>between the NT-proBNP and BNP markers<\/span><\/p>\n

\u2014 whereas BNP is the biologically active hormone and is degraded, NT-proBNP is its nonfunctional precursor,\u00a0<\/span>is cleared passively, and has a much longer half-life<\/span><\/p>\n

\u2014 levels of both NT-proBNP and BNP do have a significant genetic component, explaining about 40% of their variation<\/span><\/p>\n

\u2014 BNP levels tend to increase with age and be higher in women; NT-proBNP levels tend to be higher in those with left ventricular dysfunction; and the measured levels tend to be more standardized for NT-proBNP than for BNP. Levels of both hormones tend to be lower in obese individuals<\/span><\/p>\n

\u2014 both levels are higher in patients with renal failure, though much more significantly so with NT-proBNP (so these\u00a0NT-proBNP\u00a0<\/span>levels are not so helpful in diagnosing and managing heart failure, but a low level<\/span>of BNP would reasonably effectively rule out left ventricular dysfunction. NT-proBNP is renally excreted, which might explain its higher levels in patients with renal failure (see\u00a0<\/span>https:\/\/pubmed.ncbi.nlm.nih.gov\/24372567\/<\/span><\/a>\u00a0and\u00a0<\/span>https:\/\/bmcnephrol.biomedcentral.com\/articles\/10.1186\/1471-2369-14-117<\/a><\/span>)<\/span><\/p>\n

\u2014 one study (<\/span>J Am Coll Cardiol. 2006;47(1):91<\/span>)<\/span>\u00a0found \u201c<\/span>NT-proBNP values of >450 pg\/ml for patients ages <50 years and >900 pg\/ml for patients\u00a0<\/span>\u2265<\/span>50 years had a sensitivity of 85% and a specificity of 88% for diagnosing acute CHF among subjects with GFR\u00a0\u2265<\/span>60 ml\/min\/1.73 m2<\/sup>. Using a cut point of 1,200 pg\/ml for subjects with GFR< 60 ml\/min\/1.73 m<\/span>2<\/sup>, we found sensitivity and specificity to be 89% and 72%, respectively\u201d : [ie pretty large variations in\u00a0<\/span>NT-proBNP in\u00a0<\/span>different types of patients, and much larger numbers than the small 125 pg\/mL cutpoint in this study, or the 25% changes]<\/span><\/p>\n

\u2014 of note, the Framingham Study found that higher BNP levels predated higher blood pressure (as was found in the ARIC trial with\u00a0<\/span>NT-proBNP): see\u00a0<\/span>https:\/\/www.ahajournals.org\/doi\/10.1161\/01.hyp.0000061116.20490.8d#:~:text=Increased%20brain%20natriuretic%20peptide%20(BNP,BP%20increase%20and%2For%20hypertension<\/span><\/a><\/span>\u00a0)<\/span><\/p>\n

\u2014\u00a0<\/span>NT-proBNP levels are more accurate in those on sacubitril-valsartan than BNP levels, since the latter rises with neprilysin inhibition as found in the combo sacubitril-valsartan:\u00a0\u00a0<\/span>https:\/\/pubmed.ncbi.nlm.nih.gov\/30846338\/<\/a><\/span><\/p>\n

\u2014 and, unfortunately, there was a poor<\/span>correlation between BNP and NT-proBNP in a study of 3,029 patients, both inpatient and outpatient:\u00a0<\/span>https:\/\/www.aacc.org\/science-and-research\/scientific-shorts\/2019\/bnp-or-nt-probnp<\/span><\/a><\/span>\u00a0. so makes sense to stick with one of BNP\/NT-proBNP to follow for changes<\/span><\/p>\n

\u2014 this ARIC study had several important findings:<\/span><\/p>\n

\u2014 there was a graded response of both increased risk of heart failure and mortality (though these were found to be independently associated) as patients were stratified from low levels of NT-proBNP in both the initial and subsequent visits, and increasing lots to those with higher levels at both visits<\/span><\/p>\n

\u2014 those with higher NT-proBNP initially (visit 2), but had at least a 25% decrease 6 years later by visit 4, actually had a lower risk of death than those who had low levels at both visits (ie a decrease in\u00a0NT-proBNP from high to low seemed to be unexpectedly better than just remaining low)<\/span><\/span><\/p>\n

\u2014\u00a0<\/b>and, this relationship was found with as little as a\u00a0NT-proBNP\u00a0<\/span>being 9 pg\/mL higher at visit 2 than visit 4<\/span><\/p>\n

\u2014 some other studies have found a relationship between increased NT-proBNP and cardiovascular disease, including the MESA study, but these other studies have included people both with and without baseline heart failure<\/span><\/p>\n

\u2014 and, this ARIC study had younger patients than the other studies, had longer follow-up than others, and involved patients without baseline heart failure (ie, likely a real \u201cprimary prevention\u201d study)<\/span><\/p>\n

Limitations:<\/span><\/p>\n

\u2014 this was an observational study, and as a result one cannot draw causal conclusions (i.e. one cannot clearly conclude that it is specifically the NT-proBNP levels that are causing incident heart failure and mortality, since there could be known or unknown confounders that mediate this relationship hence the need for RCTs); for example several cardiovascular risk factors were increased or decreased with NT-proBNP levels which could potentially mediate\u00a0NT-proBNP\u2019s\u00a0<\/span>association with these clinical outcomes)<\/span><\/p>\n

\u2014 in particular, as an observational study, we cannot draw clear conclusions that in a cohort of asymptomatic patients without known history of heart failure such as those included in ARIC, that interventions to lower NT-proBNP is beneficial<\/span><\/p>\n

\u2014 this study also had only two measurements of NT-proBNP 6 years apart. We do not have information on any intermediate levels to get a more informed understanding of the clinical effect of fluctuations in NT-proBNP or when to consider repeated measuring\u00a0NT-proBNP (eg, the unexpected finding that going from a higher to a lower\u00a0NT-proBNP might be explained by unmeasured changes in the 6 year period between ARIC visits)<\/span><\/span><\/span><\/p>\n

\u2014 there was no echocardiographic confirmation of the heart failure, or what classification of heart failure was present, though these patients were all admitted to the hospital and presumably this information was known<\/span><\/p>\n

\u2014 they limited the outcomes to clinical heart failure leading to admission to the hospital, limiting our understanding of those with lesser degrees of heart failure who were treated as outpatients<\/span><\/p>\n

\u2014 there was also no granular information about the causes of the heart failure in those admitted to the hospital: was it related to atrial fibrillation, valvular heart disease (both of which can impact NT-proBNP levels), thyroid disease, tachycardia, etc. So, not sure we can generalize the aggregate outcome (hospital admission for HF) to all subtypes or causes of HF<\/span><\/p>\n

So, a few comments:<\/span><\/p>\n

\u2014 it seems to may make sense to check NT-proBNP levels as a predictor of higher risk of heart failure and mortality (though we do not have information on them appropriate interval for repeated tests, and it seems that a single high value that subsequently normalizes at 6 years is actually beneficial vs the level always being low\u2026)<\/span><\/p>\n

\u2014 given the strong push for prescribing SGLT-2 inhibitors as a means to decrease heart failure, perhaps it makes sense to check NT-proBNP levels and selectively consider prescribing SGLT-2\u2019s, maybe especially in those with high levels (eg >125 pg\/mL) who have a subsequent one also high (especially since SGLT-2\u2019s are not such benign drugs: see\u00a0<\/span>https:\/\/gmodestmedblogs.blogspot.com\/2019\/05\/sglt-2-inhibitors-and-fourniers-gangrene.html<\/span><\/a>and\u00a0<\/span>https:\/\/gmodestmedblogs.blogspot.com\/2018\/11\/sglt-2-inhibitors-twice-risk-of.html<\/span><\/a>\u00a0, as well as being assoicated with severe urinary tract infections (and urosepsis), mycotic infections, DKA at even low blood sugar levels, etc<\/span><\/p>\n

\u2014 it remains likely but unproven that interventions to lower NT-proBNP levels would be clinically helpful in asymptomatic patients with higher levels.<\/span><\/p>\n

\u2014 it does seem that the conclusions of this current ARIC study should lead to more aggressive general cardiovascular risk factor reductions (lipids, hypertension, diabetes, smoking, overweight, etc) in those with high NT-proBNP levels, since this seems to be a predictor of cardiovascular disease<\/span><\/p>\n

\u2014 given the clinical differences between NT-proBNP and BNP, it would be useful to have a study assessing the relationship between changes in BNP levels and incident heart failure and mortality (notably, per the AHA\/ACC guidelines, they do not differentiate between these two entities in terms of defining pre-HF)<\/span><\/p>\n

\u2014 and it is important that the laboratories we use have access to each of these tests\u00a0<\/span><\/p>\n<\/div>\n

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LOWER INCOME, HIGHER MORBIDITY AND MORTALITY<\/h1>\n<\/header>\n
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January 9, 2023<\/strong><\/p>\n<\/div>\n

A new article confirmed the relationship between low family income and high morbidity\/mortality in children and adolescents, using a more robust database and study design than prior studies (see income kids and inc morbidity JAMA2022 in dropbox, or doi:10.1001\/jama.2022.22778) Details: \u2014 795,000 individuals from age 5 to 17 who were enrolled in Medicaid from 2011-2012 with family income 200% of the federal poverty threshold, were followed through December 2021 \u2014 mean age 10.6 years (44% aged 5 to 9, 56% aged 10 to 17), 50% female, 35% white\/34% Hispanic\/25% non-Hispanic Black \u2014 5 states with the largest sample: California 14%\/Texas 10%\/Illinois 6%\/New York 6%\/Ohio 5% \u2014 income level below median income for these Medicaid recipients: 387,000 people; higher than median income in 408,000 \u2014 income-to-poverty ratio: those below median income 46%, above median income 134% \u2014 this measure is a ratio of the total family income, adjusted for family size, divided by the dollar amount assessed by the federal poverty threshold 200% \u2014 the 200% for the federal poverty threshold for a family of 3 corresponded to $36,212 in 2011 and $43,622 in 2021 \u2014 this study linked national Medicaid claims data in 2011-2012, the American Community Survey (2008-2013, a cross-sectional nationally representative household survey of 1% of the US population, with 3 to 3.5 million addresses selected annually and with a response rates 90-97%), the US Census Bureau version of the Social Security Administration death records (to measure the association between income and prevalence of medical conditions) \u2014 Main outcomes: prevalence of infection, mental health disorder (aggregation of ADHD, conduct disorders, and hyperkinetic syndromes; anxiety disorders; autism spectrum disorder; bipolar disorders; depressive disorders; personality disorders; PTSD; and schizophrenia\/psychoses), injury, asthma, anemia, substance use disorders; including alcohol, tobacco, or drug use disorders), and death within the 10 years of observation, based on ICD-9 codes in children and adolescents enrolled in Medicaid or in the Children\u2019s Health Insurance Program (CHIP) \u2014 clinical outcomes overall: infection in 33%, mental health disorder 13%, injury 6%, asthma 5%, anemia 2%, substance use disorder 1% \u2014 overall mortality, 0.6% with mean age at death: 20yo \u2014 a few states (Florida and Idaho) did not have full databases Results: \u2014 prevalence for each condition\/mortality assessed was lower in children and adolescents in families with above median income (p0.001), except for substance use disorder \u2014 mortality had the largest difference: 15% lower among children and adolescents in families having income above versus below the median \u2014 anemia and asthma were both 13% lower in higher income, mental health disorders 10% lower, injuries 8% lower, and infection 6% lower in families above the median \u2014 prevalence of conditions and mortality differed between those 5-9yo versus 10-17yo: \u2014 those aged 10 to 17 versus 5 to 9: \u2014 infection: 1.2 percentage points lower \u2014 asthma: 1.2 percentage points lower \u2014 mental health disorders: 6.6 percentage points more likely, 69% times higher \u2014 of note, for both age groups ADHD was the dominant mental health disorder, though anxiety disorders, depressive disorders, bipolar disorders, PTSD, and schizophrenia\/psychosis were prevalent in both age groups) \u2014 injury: 3.9 percentage points more likely, 105% times higher \u2014 substance use disorder: 1.5 percentage points more likely, 573% times higher \u2014 10-year mortality: 0.8 percentage points higher (more than 3-fold) \u2014 children aged 5-9 living in a family with 100% more income relative to the federal poverty threshold: \u2014 infection: 2.3 percentage points lower, 7% lower \u2014 those 10-17yo: 12% lower \u2014 mental health disorders 1.9 percentage points lower, 19% lower \u2014 those 10-17yo: 15% lower \u2014 injury: 0.7 percentage points lower, 18% lower \u2014 those 10-17yo: 12% lower \u2014 asthma: 0.3 percentage points lower, 5% lower \u2014 those 10-17yo: 12% lower \u2014 anemia: 0.2 percentage points lower, 9% lower \u2014 substance use disorder: 0.6 percentage points lower, 22% lower \u2014 those 10-17yo: 21% lower \u2014 mortality within 10 years: no significant difference \u2014 those 10-17yo: 21% lower \u2014 the graph below depicts the relationship between outcomes measured and family income relative to the federal poverty threshold: Graph: prevalence of income-to-poverty ratio, adjusted for sex, race and ethnicity, state of residence, year that age was measured, and year that income was observed. Note the much higher slopes of the curves for infection and mental health disorders for both groups, and 10-year mortality for those 10-17yo Commentary: \u2014 prior studies finding a relationship between income and clinical outcomes were much more primitive and contaminated: socioeconomic status was not well measured, health status was typically self-reported, and studies were often small or limited to a single area. This current study was much more rigorous and expansive, leading to more reliable results \u2014 the many thousands of studies of stress (and stress would generally be higher in those with lower income) have found an association with dramatic increases in clinical disease: for example, see http:\/\/gmodestmedblogs.blogspot.com\/2022\/01\/stress-induced-cardiovascular-disease.html for studies on cardiovascular disease \u2014 stress is associated with an array of adverse effects on physical and mental health: for a review, see stress and health JHealth and Social Behavior2010 in dropbox or DOI: 10.1177\/0022146510383499 \u2014 stress is also associated with sleep disorders, which themselves are associated with significant adverse cardiometabolic and cognitive problems: see https:\/\/link.springer.com\/article\/10.1007\/s11920-013-0418-8 \u2014 one real advantage of this study is they assessed people who had insurance (Medicaid) and who were consistently enrolled for a long period of time (eliminating the bias of people coming in and out of Medicaid and at times having poorer insurance coverage over the 10 years) \u2014 this study tracked those enrolled in Medicaid for 10 years. A few relevant points: \u2014 we cannot extend the results of this study to those without health insurance: those living in poverty without Medicaid have much less access to health care and likely worse clinical outcomes \u2014 there are some data suggesting that getting on Medicaid (and likely with the current Medicaid expansion) leads to more access to medical care; one study found that there was an association with improved outcomes in pregnant women and infants (see medicaid expansion health outcomes HealthAffairs2022 in dropbox, or doi: 10.1377\/hlthaff.2021.01150 HEALTH AFFAIRS 41, NO. 1 (2022): 60\u201368) \u2014 we need more data on adults, a group pretty consistently found to have a stronger inverse association between income and adverse clinical outcomes. And this database would need to be evaluated over many years, since measurable population differences may take years to be seen (especially in terms of routine preventative care interventions) \u2014 that being said, Medicaid expansion and improved health outcomes is still likely a very small benefit as compared to the effects of poverty itself \u2014 and, the narrow assessment of Medicaid participants does not allow for comparison to those of higher income. But, per the graphs above, the curves\/slopes of change with income in those with Medicaid but higher incomes was quite profound, especially for infection, mental health disorders and mortality: all of this suggests that the improvements in clinical outcomes would likely continue with increasing income (though would likely plateau at some point) \u2014 the finding of more adverse effect in the older children reinforces the likelihood that the effects of stress are cumulative: the more stress over more time is increasingly detrimental. This cumulative effect of stress might also be part of the explanation why adults have a stronger relationship between stress and adverse clinical outcomes than kids Limitations: \u2014 there were some notable differences in the demographics of average family income in families having income above the median: they were 8.2 percentage points less likely to be non-Hispanic Black, 7.2 percentage points more likely to be non-Hispanic white (p0.001), and 0.3 percentage points more likely to be Hispanic (p=0.02) \u2014 the study was a retrospective one assessing associations between income and clinical events, and therefore does not have the rigor of a randomized controlled trial in proving causality (ie, there are likely unanticipated confounders that could alter the results, eg diet, exercise, etc) \u2014 there is a potential for reverse causation here: were some of those on Medicaid because they had health problems interfering with their ability to work? To the extent this is true, it would bias the results \u2014 this was a non-random sample of Medicaid recipients, with some states over-represented and some not represented (Florida and Idaho were not included because of insufficient databases) \u2014 there was no information about children 5yo (the authors felt this group was likely uncercounted by the Census Bureau) \u2014 diseases were only recorded if the individual \u201csought formal health care and received a diagnosis and for which Medicaid claims were generated\u201d, possibly missing some clinical outcomes and relying on billing systems to work well \u2014 the assessment of income relied on the initial baseline information, and this possibly changed over the 10-year period. And the income was self-reported and potentially inaccurate \u2014 and, the other limitations noted above by including only Medicaid patients So, a few comments \u2014 not so surprising that the old and less reliable studies on income and health outcomes were validated in this higher quality study
\n\u2014 the role of stress in disease, both physical and mental, as is really clear in the myriad of articles published, is profound. And low income is a pretty great stressor for most people \u2014 the prior articles on stress, however, are a bit mixed. It seems that a person\u2019s perception of stress and their level of social support tends to moderate their physiologic reaction, both in terms of quantifying levels of the stress hormones (eg cortisol and catecholamines) as well as measured blood pressure. For example, a study done in 2 states several decades ago found that people living in poorer areas who felt that their areas were bad (as measured by a Social Insecurity Scale asking about perceptions of crime in the neighborhood, crowded housing, poor housing stock, fears of going outside, etc) had higher blood pressure than those feeling that their areas were okay. \u2014 and other older studies have found that people with higher levels of personal supports had lower levels of biomarkers of stress \u2014 this article also points to the likely importance of cumulative stress being a driver in adverse outcomes. Animal studies have found that acute stressors lead to transient increases in blood pressure, but chronic continued acute stress led to sustained hypertension. There have been several suggestive human studies: eg a study where workers who were moved to a more stressful job in a workplace reorganization had more cardiac symptoms and increased left ventricular mass vs those moved to a less stressful work situation (and sympathetic stimulation\/catecholamines are associated with increased left ventricular mass: https:\/\/academic.oup.com\/eurheartj\/article-abstract\/10\/11\/1036\/411112?redirectedFrom=fulltext ) \u2014 though there are real benefits to having health insurance, it is pretty clear (though not well studied) that the main issue here is poverty\/income inequality \u2014 so, obviously, poverty needs to be addressed as a basic public health issue\u2026. (as well as a basic social one) geoff \u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2013 If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@bidmc.harvard.edu to get access to all of the blogs (2 options): 1. go to https:\/\/bucommunitymed.wpengine.com\/ , a website from the Community Medicine section at Boston Medical Center. This site does have a very searchable and accessible list of my blogs and is the easiest to view blogs and displays more at a time. 2. go to http:\/\/gmodestmedblogs.blogspot.com\/ to see the blogs in reverse chronological order \u2014 click on 3 parallel lines top left, if you want to see blogs by category, then click on \u201clabels\u201d and choose a category\u200b \u2014 or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them if you would like to see the article, please email me. please feel free to circulate this to others. also, if you send me their emails, i can add them to the list.<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n

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HYPERTENSION: HCTZ VS CHLORTHALIDONE<\/h1>\n<\/header>\n
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January 5, 2023<\/strong><\/div>\n<\/div>\n

A recent large pragmatic trial from the VA found that there was no difference between chlorthalidone vs hydrochlorothiazide (HCTZ) in terms of actual clinical outcomes (see<\/span>\u00a0<\/span>htn chlorthal vs hctz no diff nejm2022\u00a0<\/b>in dropbox, or\u00a0 DOI: 10.1056\/NEJMoa2212270)<\/span><\/p>\n

Details:<\/b><\/p>\n

\u2014 a multicenter study (72 VA systems involving 537 locations) with 4128 primary care providers and 13,092 patients at least 65yo, from June 2016-November 2021<\/p>\n

\u00a0\u00a0\u00a0 \u2014 open-label study (ie patients and clinicians knew what they were taking) of people on HCTZ 25-50mg who were then randomized to continuing the HCTZ vs switching to chlorthalidone (at \u00bd the HCTZ dose)<\/p>\n

\u00a0\u00a0\u00a0 \u2014 this was a pragmatic study, recruiting primary care providers and patients in a point-of-care study, with recruitment and results based on an ongoing review of the electronic medical record (ie, an easy study and potentially replicable type of study for\u00a0many other interventions)<\/span><\/p>\n

\u2014 mean age 72, 97% male, 77% white\/15% Black, 93% non-Latinx<\/p>\n

\u2014 BMI 32, diabetes 44%, heart failure 8%, stroke 8%, prior MI and stroke 11%<\/p>\n

\u2014 eGFR <60 in 23%, current smoker 23%<\/p>\n

\u2014 baseline HCTZ dose was 25mg in 94% (ie very few on 50mg), systolic BP 139mmHg<\/p>\n

\u2014 number of BP meds prescribed: mean of 2.6<\/p>\n

\u2014 primary outcome: composite of nonfatal MI, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death; safety was also assessed (including electrolyte abnormalities, hospitalizations, and acute kidney injury)<\/p>\n

\u2014 secondary outcomes: individual components of the primary outcome, within pre-specified subgroups<\/p>\n

\u2014 mean follow-up: 2.4 years<\/p>\n

Results:<\/b><\/p>\n

\u2014 primary composite outcome:<\/p>\n

\u2014 chlorthalidone: 702 events (10.4%), annual rate of 4.5%<\/p>\n

\u2014 HCTZ: 6875 events (10.0%), annual rate of 4.3%<\/p>\n

\u2014 HR 1.04 (0.94-1.16), p=0.45, nonsignificant difference<\/p>\n

\u2014 secondary outcomes (individual components, etc):<\/p>\n

\u2014 MI:<\/p>\n

\u2014 chlorthalidone: 142 events (2.1%)<\/p>\n

\u2014 HCTZ: 140 events (2.1%)<\/p>\n

\u2014 Stroke:<\/p>\n

\u2014 chlorthalidone: 83 events (1.2%)<\/p>\n

\u2014 HCTZ: 83 events (1.2%)<\/p>\n

\u2014 heart failure hospitalization:<\/p>\n

\u2014 chlorthalidone: 242 events (3.6%)<\/p>\n

\u2014 HCTZ: 232 events (3.4%)<\/p>\n

\u2013unstable angina with urgent coronary revascularization:<\/p>\n

\u2014 chlorthalidone: 20 events (0.3%)<\/p>\n

\u2014 HCTZ: 13 events (0.2%)<\/p>\n

\u2014 deaths from any cause:<\/p>\n

\u2014 chlorthalidone: 446 events (6.6%)<\/p>\n

\u2014 HCTZ: 448 events (6.6%)<\/p>\n

\u2014 expected adverse reactions:<\/p>\n

\u2014 new allergic or adverse reactions:<\/p>\n

\u2014 chlorthalidone: 109 events (1.6%)<\/p>\n

\u2014 HCTZ: 21 events (0.3%)<\/p>\n

\u2014 HR 5.23 (3.28-8.35)<\/p>\n

\u2014 hypokalemia:<\/p>\n

\u2014 chlorthalidone: 335 events (5.0%)<\/p>\n

\u2014 HCTZ: 243 events (3.6%)<\/p>\n

\u2014 HR 1.39 (1.18-1.64)<\/p>\n

\u2014 those with history of MI or stroke:<\/p>\n

\u2014 chlorthalidone: 105 events in 733 patients (14.3%)<\/p>\n

\u2014 HCTZ: 140 events in 722 patients (19.4%)<\/p>\n

\u2013HR 0.73 (0.57-0.94), statistically favoring chlorthalidone<\/p>\n

\u2014 those without history of MI or stroke:<\/p>\n

\u00a0\u00a0\u00a0 \u2014 chlorthalidone: \u00a0597 events in 6023 patients (9.9%)<\/p>\n

\u00a0\u00a0\u00a0 \u2014 HCTZ: 535 events in 6045 patients (8.9%)<\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2013HR 1.12 (1.00-1.26), statistically favoring HCTZ<\/p>\n

\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u2014 so, chlorthalidone was associated with 27% decrease in events in those with history of MI or stroke, but 12% increase in those without (this was a pre-specified subgroup analysis)<\/p>\n

\u2014 adherence to study meds:<\/p>\n

\u2014 chlorthalidone: 1039 patients (15.4%) switched back to HCTZ<\/p>\n

\u2014 HCTZ: 260 patients (3.8%) switched to chlorthalidone<\/p>\n

\u2014 overall mean medications possession ratio (sum of days that a patient was supplied with filled prescription of assigned drug): 79.5% in those on chlorthalidone and 79.1% on HCTZ<\/p>\n

\u2014 mean daily dose of meds taken:<\/p>\n

\u2014 chlorthalidone: \u00a012.3 mg<\/p>\n

\u00a0\u00a0\u00a0 \u2014 HCTZ: 23 mg<\/p>\n

\u00a0Commentary:<\/b><\/p>\n

\u2014 HCTZ remains by far the most popular initial antihypertensive in the US, despite it being NOT recommended in more recent guidelines (see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2017\/11\/new-aha-hypertension-guidelines.html<\/a>\u00a0)<\/p>\n

\u2014 though early studies found that chlorthalidone was significantly better than HCTZ, this has not been found in some other studies<\/p>\n

\u00a0\u00a0\u00a0 \u2014 and chlorthalidone is about twice as strong as HCTZ and is associated with more hyperkalemia (as found in this study)<\/p>\n

\u00a0\u00a0\u00a0 \u2014 Medicare D expenditures have found that in 2020 there were 11.5 million prescriptions for HCTZ vs 1.5 million for chlorthalidone (again, despite US recommendations to preferentially use chlorthalidone)<\/p>\n

\u2013There is a pretty strong argument that chlorthalidone is superior to HCTZ:<\/p>\n

\u00a0\u00a0\u00a0 \u2014 many studies have confirmed that 24-hour ambulatory BP monitoring (ABPM) is the gold standard for predicting clinical cardiovascular outcomes, leading the USPSTF to recommend ABPM as the best means documenting hypertension, see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2015\/01\/uspstf-recs-on-ambulatory-blood.html<\/a>\u00a0and\u00a0https:\/\/www.uspreventiveservicestaskforce.org\/uspstf\/document\/final-evidence-summary\/hypertension-in-adults-screening<\/a><\/p>\n

\u00a0\u00a0\u00a0 \u2014 it is clear that HCTZ does NOT provide even close to 24-hour coverage, though in-clinic blood pressures seem to be okay (and therefore may mislead us into thinking that HCTZ works well): see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2016\/04\/chlorthalidone-is-better-than-hctz-for.html<\/a>: these studies have found that the ABPM for HCTZ was\u00a0\u00bd\u00a0the blood pressure lowering of other BP meds tested, including chlorthalidone.\u00a0<\/span>there are data suggesting that HCTZ 50mg may have a prolonged effect, but we are now mostly using 12.5mg, or up to 25mg<\/p>\n

\u00a0\u00a0\u00a0 \u2014 combination pills including HCTZ may work better than HCTZ by itself:<\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 the combination of lisinopril and HCTZ does seem to maintain 24-hour effectiveness (https:\/\/pubmed.ncbi.nlm.nih.gov\/8117053\/<\/span><\/a>), although this does not seem to be as true with the combination of losartan and\u00a0HCTZ (https:\/\/pubmed.ncbi.nlm.nih.gov\/16372579\/<\/span><\/a>)<\/p>\n

\u00a0\u00a0\u00a0 \u2014 which all means to me: if one decides to use a diuretic as first-line antihypertensive therapy, chlorthalidone is likely the best choice (assuming renal function permits). There is a much higher incidence of hypokalemia (so potassium should be followed). And it is a small pill, so not so easy to decrease to less than the 25mg dose (though, when I wrote a prior blog on chlorthalidone, a physician reader responded that he cut the 25mg tablet in quarters, no mean feat, and did very well with that)<\/p>\n

\u00a0\u00a0\u00a0 \u2014 my bias as per prior blogs is still to use amlodipine as my first line BP med for almost everyone (except those with significant proteinuria), since it has great 24-hour effectiveness, has the least blood pressure variability (and BP variability is a marker for adverse cardiovascular outcomes), is often very effective at low dose (eg 2.5mg\/d), has less renal toxicity than ACE\/ARBs, and several studies have found that ACEs or ARBs are associated with more strokes than amlodipine (eg see\u00a0https:\/\/www.ahajournals.org\/doi\/10.1161\/hypertensionaha.107.089763<\/a>\u00a0). this stroke issue is likely related to the wearing off of ACE\/ARB blood pressure control in the early AM when the cortisol surge happens and strokes are more common<\/p>\n

Another issue is that chlorthalidone may have additional pleiotropic effects over thiazides. For example, chlorthalidone may decrease platelet aggregation and vascular permeability and promote angiogenesis, significantly different from the thiazide bendroflumethiazide (and, presumably, other thiazides) in this study:\u00a0https:\/\/pubmed.ncbi.nlm.nih.gov\/20625077\/<\/a>.\u00a0But there are some conflicting reports on this (see\u00a0https:\/\/pubmed.ncbi.nlm.nih.gov\/36067089\/<\/a>\u00a0)<\/p>\n

Limitations:<\/p>\n

\u2014 as a VA study, this was predominantly older white males (all >65yo, 97% male, 77% white), limiting generalization to others<\/p>\n

\u2014 patients were on multiple BP meds (mean of 2.6 meds, only 13% were on HCTZ alone), making the direct comparison of HCTZ and chlorthalidone a bit murky (and, per above, HCTZ may provide more 24-hour coverage when combined with other meds: the results of this study should not be translated into clinical effectiveness in those on one of these diuretics as a single agent)<\/p>\n

\u2014 there was a real selection bias: these participants were already on HCTZ and presumably tolerating it well. The switch for \u00bd of them to chlorthalidone is therefore not an unbiased comparison: there is likely a nocebo effect of starting a new med. And this might have led to a higher number of participants switching back to HCTZ (which occurred in 15% vs 4% the other way); those switched from HCTZ to chlorthalidone were more likely to suspect the new med vs just continuing the HCTZ that they had tolerated for perhaps many years (hence the likely nocebo effect with more reported adverse reactions).<\/p>\n

\u00a0 \u00a0 \u2014 also, the much more substantial numbers of people changing from chlorthalidone back to HCTZ would likely understate the potential chlorthalidone benefit<\/p>\n

\u2014 there was also \u201ccontamination\u201d of the results: likely many participants were on long-term HCTZ prior to the study and may have suffered significant cardiovascular disease before beginning the study, perhaps related to less cardiovascular protection (with 11% having known MI or stroke, and likely the vast majority of the others having significant but less symptomatic cardiovascular disease). So, how much of the results above were from the long-term legacy of being on the less-than-optimal HCTZ but only on chlorthalidone for 2.4 years??\u00a0 ie, was the horse already out of the barn, the die was cast, or some other aphorism\u2026<\/p>\n

So, a few comments:<\/p>\n

\u2013This study had the advantage of being pragmatic (real-world), easily done if the electronic medical record is extensive and will allow such a study to be embedded in the record system, and involving a large network of providers and patients who can easily be recruited.<\/p>\n

\u2014 based on the above comments, I do not think that HCTZ in the 12.5 or 25 mg dosages provide the important 24-hour protection and should not be used as a single agent<\/p>\n

\u2014 if a diuretic is chosen as a single agent, I think that the data so far (and the national and international recommendations support) the use of chlorthalidone. I would start with 12.5 mg (or even 6.125 in those dexterous enough to split the pill into quarters), pending the unlikely event that pills <25 mg become available<\/p>\n

\u2014 I still would continue with the 2011 NICE guidelines from the UK (referenced in the above-mentioned prior blogs) suggesting that for most people, amlodipine is the best first med. (they do strongly support chlorthalidone as the diuretic of choice if a diuretic is selected as a first agent, and they basically trash HCTZ)<\/p>\n

\u2014 and the limitations, I think it is hard to make the case based on this study that HCTZ is as clinically effective as chlorthalidone as a single agent\u2026.<\/p>\n

geoff<\/p>\n

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\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2013<\/span><\/p>\n

If you would like to be on the regular email list for upcoming blogs, please contact me at\u00a0<\/span>g<\/a><\/span>modest@bidmc.harvard.edu<\/span><\/p>\n

\u00a0<\/span>\u00a0<\/span><\/p>\n

to get access to all of the blogs (2 options):<\/span><\/u><\/u><\/span><\/p>\n

1. go to\u00a0<\/span>https:\/\/bucommunitymed.wpengine.com\/<\/a>\u00a0, a website from the Community Medicine section at Boston Medical Center.\u00a0 This site does have a very searchable and accessible list of my blogs and is the easiest to view blogs and displays more at a time.<\/span>
<\/span><\/p>\n

2.<\/span><\/span>\u00a0go to\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/<\/a><\/span>\u00a0to see the blogs in reverse chronological order<\/span><\/p>\n

\u00a0 \u2014 click on 3 parallel lines top left, if you want to see blogs by category, then click on \u201clabels\u201d and choose a category\u200b<\/span><\/u><\/u><\/span><\/p>\n

\u00a0 \u2014 or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them<\/span><\/u><\/u><\/span><\/p>\n

\u00a0<\/span>\u00a0<\/span><\/p>\n

For access to the\u00a0dropbox, go to link:\u00a0<\/span>https:\/\/www.dropbox.com\/sh\/0bmvtita8mzms11\/XDTwHySFFg<\/a><\/span><\/u><\/u><\/span><\/p>\n

Then go to \u201cclinic\u201d, then to \u201cclinical stuff\u201d for articles<\/span><\/p>\n

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list<\/span><\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n

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H PYLORI: ANTIMICROBIAL RESISTANCE IN RHODE ISLAND<\/h1>\n<\/header>\n
\n
January 5, 2023<\/strong>
\n<\/span>\u00a0<\/span><\/a><\/p>\n
<\/div>\n<\/div>\n

A study fro<\/span>m Rhode Island documented antibiotic resistance to H Pylori (thanks to Boris Skurkovich for bringing this to my attention): see\u00a0<\/span>h pylori resistance rhode island Gastro2021<\/b><\/span>\u00a0in dropbox or\u00a0<\/span>doi:10.1053\/j.gastro.2021.02.014.\u00a0<\/span><\/p>\n

\u00a0<\/span><\/p>\n

Details<\/b>:<\/p>\n

\u2014 189 patients from 2 hospitals in Rhode Island (total 1000 beds), who had positive gastric biopsies for H Pylori and assessed its eradication after treatment<\/p>\n

\u00a0\u00a0\u00a0\u00a0 \u2014 eradication determined by urea breath test in 51%, stool antigen in 40%, and biopsy in 10%<\/p>\n

\u2014 mean age 45, 68% male, 29% white\/25% Black\/ 44% Latinx<\/p>\n

\u2014 treatment duration 14 days (the standard now) in 91%<\/p>\n

\u2014 antimicrobial resistance was determined through the PyloriAR assay, which evaluates DNA mutations in the H Pylori genome associated with fluoroquinolones, metronidazole, clarithromycin, ampicillin, tetracycline and rifabutin, using \u201cnext-generation sequencing\u201d<\/p>\n

\u2014 H Pylori presence was determined by quantitative real-time PCR testing<\/p>\n

Results<\/b>:<\/p>\n

\u2014 eradication rates by treatment:<\/p>\n

\u00a0\u00a0\u00a0 \u2014 bismuth-based quadruple therapy: given to 54% of the patients; 88% had eradication<\/p>\n

\u00a0\u00a0\u00a0 \u2014 triple therapy: 46% of patients; 61% had eradication<\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 quad therapy had statistically significant benefit over triple: OR 4.8 (2.3-10.1), p<0.001<\/p>\n

\u2014 overall, 66% of H Pylori strains were resistant to at least one antibiotic<\/p>\n

\u2014 84 patients receiving clarithromycin-containing therapy had clarithromycin-resistant H Pylori: eradication failures were quite high at 56%, vs eradication success at 14%, p<0.001<\/p>\n

\u2014 123 patients received metronidazole-containing therapy but had metronidazole-resistant H Pylori: no real difference in eradication failures: failures in 37% and successes in 33%, p=0.72<\/p>\n

\u00a0\u00a0\u00a0 \u2014 and, those regimens in patients who had metronidazole-resistant H Pylori but had at least one other antimicrobial that the bug was sensitive to:\u00a094% eradiation<\/b>\u00a0after a 14 day treatment (ie, despite metronidazole resistance)<\/p>\n

<\/p>\n

Commentary<\/b><\/p>\n

\u2014 this study complements another broader scale one noted in a recent prior blog\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2022\/11\/h-pylori-resistance-patterns-in-us.html<\/a><\/p>\n

\u2014 these studies are really important, given the high prevalence of H Pylori infections (>50% of the global population infected), widespread use of several of the antibiotics that are also used in combination for H Pylori (and leading to H Pylori resistance), importance of successful H Pylori treatment to decrease the myriad of H Pylori symptoms, and importance of treating even asymptomatic H Pylori infections in decreasing subsequent gastric cancer and major GI bleeds in those on NSAIDs (see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2022\/11\/h-pylori-resistance-patterns-in-us.html<\/a>\u00a0for more detailed information)<\/p>\n

\u00a0\u00a0\u00a0 \u2014 not only do we not have much information about H Pylori antimicrobial resistance patterns in the US, but we have even more limited data on H Pylori variants. For example, the CagA H Pylori variant has a higher risk of gastric cancer (see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2018\/01\/h-pylori-ppi-use-and-gastric-cancer.html<\/a>\u00a0), and the VacA variant with colorectal cancer. I suspect that these variants (and perhaps others) may be at least part of the explanation of the large variability of gastric cancer incidence around the world. But too little data or testing to know\u2026<\/p>\n

\u2014 the antimicrobial resistance assay they used was successful in 95% of the cases and has a really rapid turnover, results being available in 72 hours (see\u00a0http:\/\/resistancecontrol.info\/wp-content\/uploads\/2019\/05\/Rupp%C3%A9.pdf<\/a>\u00a0for more info on this). This technique would be particularly helpful for hard-to-grow bugs (like H Pylori) that would then be subjected to an array of antibiotics to determine the extent of growth retardation by those antibiotics: all of which can take lots of time and limit scaling up the assay to lots of samples (ie not so useful clinically)<\/p>\n

\u2014 I personally have been using one of the following 2 treatment regimens:<\/p>\n

\u00a0\u00a0\u00a0 \u2014 sequential therapy still involving clarithromycin: it seems that clarithromycin resistance is related to\u00a0<\/span>the development of reflux channels in the cell membrane (that basically kick the clarithromycin out of the cell), and that amoxicillin pretreatment changes the structure of the organism\u2019s cell membrane and prevents this efflux. So, amoxicillin effectively reverses clarithromycin resistance. A \u00a0study assessed patients with H Pylori and documented clarithromycin resistance and found the vast majority were cured with\u00a0<\/span>a<\/span>\u00a0sequential regimen,<\/span>\u00a0<\/span>though those without amoxicillin pretreatment failed miserably<\/span>\u00a0(ie 89% vs 29% success rates:\u00a0hpylori rx sequential annals 2007<\/b>\u00a0in dropbox, or<\/span>\u00a0see\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/2013\/11\/h-pylori-therapy-sequential-vs-standard.html<\/span><\/a>.) the sequential regimen in basically twice-daily amoxicillin 1 gram, and a PPI for one week, then\u00a0<\/span>twice-daily\u00a0<\/span>clarithromycin 500mg, metronidazole 500mg, and PPI for the next week.\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 a potent newer approach involves\u00a0amoxicillin, omeprazole, and rifabutin, as a means to avoid clarithromycin resistance\u00a0 (and also avoids using metronidazole, with the issue of resistance but also intolerance<\/span>, both of which are high with both meds<\/span>):\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/2022\/06\/h-pylori-rifabutin-based-therapy.html<\/span><\/a>\u00a0<\/span>. the basic drawback of this therapy is drug-drug interactions with rifabutin<\/span><\/span><\/p>\n

\u2013the issue of metronidazole resistance is interesting: in the above study, if patients had at least one other antibiotic to which the H Pylori was sensitive, they had exceptionally high cure rates. This suggests that metronidazole may not really provide any clinical effectiveness if the other antibiotics work. This finding of little metronidazole benefit has been found in other studies using other methods of assessing metronidazole resistance: see\u00a0https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6905086\/<\/a>\u00a0and\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2022\/11\/h-pylori-resistance-patterns-in-us.html<\/a>\u00a0.<\/p>\n

Limitations:<\/p>\n

\u2014 we do not have much granular data on these individuals. Were they exposed to clarithromycin, for example, prior to having their H Pylori detected\/treated? How long before? What was the intensity of the exposure if they had one? Were there underlying comorbidities that might have affected their clinical courses and response to treatment?<\/span><\/p>\n

\u2014 as with all locally-specific studies (ie Rhode Island in this case), there are questions about generalizability of the results elsewhere, and these results may change over time even in one locality. Hence, the need to perform enhanced and regular checking<\/p>\n

\u2014 how accurate is next-generation sequencing in determining clinical response to treatment? Are the targets of this genetic sequencing of antibiotic resistance genes complete enough? Does this approach deal with other mechanisms of antibiotic resistance, such as mediated through plasmids? This lab technique is quite impressive, but would be great to have confirmation from larger studies that the test does truly predict clinical outcomes.<\/p>\n

So, I bring up this article for a few reasons:<\/p>\n

\u2014 a selfish one: it is very likely that antibiotic resistance patterns are similar in Providence, RI to my base in Boston, MA. So the results are likely generalizable to my area<\/p>\n

\u2014 the technique used next-generation sequencing (seems pretty great and would allow for location-specific resistance patterns pretty rapidly, and could then detect changes over time)<\/p>\n

\u00a0\u00a0\u00a0 \u2014 the technique would also be an important public health tool to track antibiotic resistance to perhaps several different microbes as well as H Pylori<\/p>\n

\u2014 this is another study suggesting that metronidazole may not play a significant role in clinical outcomes. Metronidazole, however, still plays a significant role in conferring adverse effects!!! Maybe the sequential treatment above would work just fine without the second week of metronidazole?? worth studying\u2026.<\/p>\n

\u2014 overall, i think this study supports the above 2 treatment regimens in those areas with increased clarithromycin resistance (eg, prevalence >15% or so): the sequential and rifabutin-based ones<\/p>\n

geoff<\/p>\n

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\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2014\u2013<\/span><\/p>\n

If you would like to be on the regular email list for upcoming blogs, please contact me at\u00a0<\/span>g<\/a><\/span>modest@bidmc.harvard.edu<\/a><\/span><\/p>\n

to get access to all of the blogs (2 options):<\/span><\/p>\n

1. go to\u00a0https:\/\/bucommunitymed.wpengine.com\/<\/a>\u00a0, a website from the Community Medicine section at Boston Medical Center.\u00a0 This site does have a very searchable and accessible list of my blogs and is the easiest to view blogs and displays more at a time.
<\/span><\/p>\n

2.<\/span>\u00a0go to\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/<\/a><\/span>\u00a0to see the blogs in reverse chronological order<\/span><\/p>\n

\u00a0 \u2014 click on 3 parallel lines top left, if you want to see blogs by category, then click on \u201clabels\u201d and choose a category<\/span><\/p>\n

\u00a0 \u2014 or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them<\/span><\/p>\n

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list<\/span><\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n

\n

HIV TREATMENT RECOMMENDATIONS 2022<\/h1>\n<\/header>\n
\n
\n
December 13, 2022<\/strong><\/div>\n
<\/div>\n<\/div>\n

The International Antiviral Society-USA Panel issued their 2022 recommendations on antiretroviral drugs for treatment and prevention of HIV infections in adults (<\/span>see\u00a0hiv antiretrov recs 2022<\/span><\/b>\u00a0in dropbox, or\u00a0doi:10.1001\/jama.2022.22246).\u00a0<\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/p>\n

Details of recommendations<\/span><\/b>, along with commentary embedded in brackets\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/p>\n

Initiation of antiretroviral therapy (ART)\u00a0<\/span><\/span><\/p>\n

\u2014 Treat early and aggressively, preferably within seven days of diagnosis, but including the option of same-day initiation of ART on the day of diagnosis or the first clinic visit (though this assumes that there is no evidence of an opportunistic infection, which might delay starting the ART (see their Box 1 for more details on this)\u00a0<\/span><\/span><\/p>\n

\u2014 Early therapy initiation is beneficial for a few reasons:\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 starting therapy early leads to a higher likelihood that patients will get into therapy. [This is similar to starting statins in hospitalized patients who have an MI: starting meds right away leads to much improved long-term medication taking]\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 \u201ctreatment as prevention\u201d: the new medications are so powerful and lead to much more rapid declines in viral load than older meds; early treatment therefore is even more powerful in preventing the spread of HIV to others\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 even in \u201celite controllers\u201d who may have very low or undetectable HIV viral loads without therapy, they do have elevated levels of inflammation that are\u00a0 reduced when ART is initiated. So treating elite controllers should be helpful, based on theoretical benefits of reducing inflammation [chronic inflammation is associated with an array of bad outcomes, including everything from cardiovascular disease to diabetes to depression\u2026\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 the risk of cardiovascular disease remains high even in those on well-treated HIV, likely related to\u00a0 the generalized inflammatory response, though diminished in those with virologic control [ie, even well-treated HIV should be incorporated into our cardiac risk model as an atherogenic risk factor]\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 the risk of cancer is also increased, even in those on ART (see\u00a0<\/span>https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2794862<\/a><\/span>\u00a0<\/span>), reinforcing the importance of routine cancer screening.\u00a0 Overall, the HIV-associated cancers (eg kaposi, non-Hodgkin lymphoma) are decreasing but some\u00a0 non-HIV defining cancers have increased. For example, cervical cancer in women is higher in those with HPV (see\u00a0<\/span><\/span>https:\/\/www.researchgate.net\/profile\/Manuela-Ceccarelli-2\/publication\/334279700_Cervical_cancer_in_women_living_with_HIV_a_review_of_the_literature\/links\/5e7e23d8a6fdcc139c0c36b6\/Cervical-cancer-in-women-living-with-HIV-a-review-of-the-literature.pdf<\/a><\/span>\u00a0),\u00a0<\/span>which likely informs the need for increased cervical cancer screening (eg, every 3 years, with no cutoff at age 65)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/span><\/p>\n

Initial ART regimens in those with HIV\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 preferred regimens are those containing InSTIs, integrase strand transfer inhibitors: dolutegravir and bictegravir\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 bictegravir plus TAF (tenofovir alafenamide) plus FTC (emtricitabine)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 dolutegravir plus TXF (this connotes either TAF or TDF) plus XTC (this connotes FTC or 3TC)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 dolutegravir plus 3TC<\/span>\u00a0(dual therapy), but only if the HIV viral load is <500K and hepatitis B co-infection has been ruled out. Also, the studies\u00a0done on this combo\u00a0did not include patients with severe HIV infections and CD4 counts <200, so unclear if this dual therapy is adequate\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 also, initiation of this regimen should not be a rapid one, since genotype, HIV viral load, and HBV serology may not be available. See below for further commentary on this dual therapy\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014\u00a0 those who do not have measurable hepatitis B virus and are not immune to hepatitis B should be vaccinated and have immunity assessed\u00a0 post-vaccination, just to make sure that they are getting adequate hepatitis B coverage and\u00a0<\/span>the\u00a0decreased\u00a0likelihood of hepatitis B resistance, as happens with\u00a0a\u00a0single agent of XTC\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 long-acting cabotegravir-rilpivirine (the parenteral\u00a0<\/span>option)\u00a0is\u00a0not recommended for initial ART\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 abacavir is no longer recommended as initial therapy (it is associated with cardiovascular disease, and has no advantage over the dolutegravir\/3TC combo)\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 in those with PrEP\u00a0 failure:\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 if on cabotegravir for pre-exposure HIV prophylaxis:\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 important to get InSTI genotype before starting an InSTI-based regimen, given that cabotegravir may be present in the blood after stopping it for up to 2.5 years in males and 4 years in females\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 if resistant or genotype\u00a0<\/span>are\u00a0not available, prescribe a boosted darunavir regimen with TXF\/XTC\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 in those with a TXF-based PrEP, perform resistance testing but do not delay starting ART with a three drug InSTI-based regimen as above. If resistance is found (in the worst case: with both K65R and M184V mutations), these InSTI-based regimen<\/span>s seem to\u00a0be active\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 in pregnant women:\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 begin ART immediately<\/span>\u00a0but\u00a0avoid any regimen with cobicistat;\u00a0 dolutegravir with TAF\/FTC is the preferred regimen, having lower rates of adverse events and improved infant outcomes (the preliminary data from the Tsepamo study suggesting increased neural tube defects\u00a0was overturned in updated results)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 if patients are already stable on regimens with bictegravir, doravirine, cabotegravir, and dolutegravir\/3TC, women may choose to stay on these meds but should be followed more frequently with HIV viral load monitoring (though these regimens should not be initiated during pregnancies)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/span><\/p>\n

Switching ART regimens\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 any switch should lead to more frequent clinical and laboratory follow-up until the regimen is demonstrated to be well-tolerated and effective, preferably the initial test<\/span>\u00a0being\u00a0one month after changing therapy, whether patient has viral suppression are not\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 in those with viral suppression, switching from a three drug strategy to dolutegravir\/3TC\/TAF is works well even in those who had historic M184V mutations (found in those with\u00a0<\/span>XTC\u00a0resistance mutations)\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 for those who are switching because of virologic failure, viral load testing should be repeated monthly until suppression is undetectable, and then every six months thereafter\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 the most common reason for virologic failure is poor med adherence. Should get genotypes when there is virologic failure\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/span><\/p>\n

Laboratory testing\/monitoring\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 HIV RNA viral load: every 3 months until suppressed, then every 6 months\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 CD4: every 6 months until >250 for 1 year, then can stop if viral load continues to be suppressed\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 cryptococcal antigen: if CD4 <100\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 assess treatment adherence within 6 weeks of starting ART\u00a0 [I usually have a nurse or HIV counselor reach out to patients in the first week to see if they have any adverse effects or issues with med adherence]\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/span><\/p>\n

Preexposure prophylaxis\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 condoms remain the cornerstone of STI prevention, and clearly should be emphasized\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 PrEP should be discussed with all sexually active adolescents and adults, and anyone who injects nonprescription drugs (e.g. opioids, methamphetamine) or anyone with a substance use disorder; also in populations with high HIV incidence rates\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 there several options for PrEP, summarized in their table 4, including the following<\/span>, though\u00a0the most important factor is what is most acceptable to the patient:\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 for cisgender males, can use TDF\/FTC (available as a generic), initiated as a double dose on the first day followed by daily single tablets, and they should not be discontinued until at least two days after the last sexual activity\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 for non-cisgender males, seven days of daily dosing is likely to be required to reach maximum\u00a0<\/span>protection\u00a0and is recommended for at least seven days after last risky activity; this daily regimen is also suggested for people are pregnant or breast-feeding\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 on-demand oral dosing is also recommended for cisgender men of any sexual orientation, but there is insufficient data to support its use in people having receptive vaginal sex or injection drug use.\u00a0<\/span>For on-demand testing, there should be a double dose 2 to 24 hours before plan sexual activity and a single dose at 24 and 48 hours subsequently\u00a0(see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2020\/01\/on-demand-prep-works-if-fewer-meds-and.html<\/a>\u00a0)<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0<\/span>\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u2014 if there is additional sexual activity within seven days of the initial planned activity, daily single dosing should be continued until two doses after the last planned activity\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u2014 this regimen should be used with caution in transgender women receiving gender-affirming hormone therapy, especially with the first dose, or reinitiating TDF\/FTC after a prolonged hiatus because rectal tissue concentrations may be somewhat lower early after starting the 2-1-1 regimens\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 daily TAF\/FTC is preferred over TDF\/FTC in people with creatinine clearance between 30 and 60, or when there is osteopenia or osteoporosis\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u2014 TAF\/FTC should be limited to cisgender\u00a0 men of any sexual orientation and anyone whose risks do not include receptive vaginal sex, or those whose risk is exclusively posed by injection drug use\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 injectable regimen: long-acting injectable cabotegravir is recommended for the prevention of sexual transmission of HIV, but there is insufficient data on those with injection drug exposures (though it is still recommended for those who also have a sexual exposure)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 there is no need for an oral lead-in of cabotegravir, as with HIV therapy noted below, other than those with severe atopic histories\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 onset of protection is likely about seven days after the first injection; barrier protection is therefore recommended for the first week of the first injection cycle\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 there is concern for InSTI resistance, given that there is potentially a prolonged pharmacologic \u201ctail\u201d after stopping the injections, with progressively decreasing blood levels\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 if there any questions, there is a very accessible PrEP Warmline at 855-HIV-PRe<\/span>P\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/span><\/p>\n

Postexposure prophylaxis\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 a three-drug ART regimen for 28 days is recommended, beginning as rapidly as possible but within 72 hours of a percutaneous, mucous membrane, or sexual exposure to known or suspected HIV-positive blood, genital secretions, or visibly bloody secretions\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 medication should be given even before getting HIV testing on the source person if necessary for rapid initiation\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 if there is concern for drug-resistant HIV, or in the setting of pregnancy or breast-feeding, they advise expert consultation\u00a0<\/span><\/span><\/span><\/p>\n

\u2014 recommended regimen is either dolutegravir or bictegravir\u00a0 with TXF\/XTC\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/span><\/p>\n

There are also sections in these recommendations on substance use in persons at risk for and with HIV, Covid and HIV, and monkeypox and HIV. Please consult the full paper for these issues\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/span><\/p>\n

Further commentary:\u00a0<\/span><\/b><\/span><\/span><\/p>\n

\u2014 I personally have\u00a0<\/span>switched to\u00a0the dolutegravir plus 3TC regimen\u00a0in almost all patients\u00a0(there is a combination pill for this called Dovato, a once a day regimen), after using an initial treatment of bictegravir\/TAF\/ FTC (Biktarvy, a combination pill for this, also a once a day regimen) that yields viral suppression (which happens essentially all the time), for the following reasons:\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 HIV has become a chronic disease, and many patients are likely to live with HIV, often for many decades\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 TAF is associated with several potential adverse effects, especially with long-term therapy:\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 chronic kidney disease: I personally have seen two cases of people developing major increases in their creatinine after starting a TAF-containing medication, which has resolved relatively quickly after switching to one not including TAF. And, it is clear that TDF is associated with significant renal toxicity (in particular Fanconi syndrome: see\u00a0<\/span><\/span>http:\/\/gmodestmedblogs.blogspot.com\/2015\/06\/tenofovir-nephrotoxicity.html<\/a><\/span>\u00a0<\/span>but also increased creatinine levels), and long-term TAF may well have long-term renal complications\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 TDF is associated with decreased bone mineral density, and though TAF has less bone toxicity, over the long term there may be clinically significant bone demineralization\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014\u00a0 Tenofovir is associated with significant weight gain, in particular in the first year after starting the medication. This increased weight gain is more profound in those with TAF vs TDF\u00a0<\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 there was a Swiss cohort study finding that switching from TDF to TAF led to increased weight gain of about 1 kg (see\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/2021\/03\/hiv-taf-inc-weight-metabolic-changes.html<\/a><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0<\/span><\/span>\u2014\u00a0a meta-analysis of 8 RCTs in treatment-na\u00efve HIV patients found a 4 kg increases with INSTIs, 2 to 3 kg increases with NNRTIs, and varying high amounts of weight gain with TAF (4.25 kg),\u00a0 abacavir (3.08 kg), TDF (2.07 kg), and ZDV ( 0.39 kg). Interestingly, TAF in this study had the highest weight gain of all, though only marginally higher than the InSTI (see\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/2020\/10\/hiv-treatmentprevention-guidelines-2020.html<\/a><\/span>\u00a0)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0 \u2014 and, baseline, why give tenofovir long-term when dolutegravir\/3TC works as well for the vast majority of people (see the GEMINI-1 and -2 trials: Lancet. 2019; 393 (10167), or\u00a0<\/span><\/span>https:\/\/www.thelancet.com\/article\/S0140-6736(18)32462-0\/fulltext<\/a>\u00a0), and\u00a0<\/span><\/span>this dual therapy\u00a0does not include an unnecessary and a potentially toxic medication????\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/p>\n

\u2014 As I have mentioned in prior blogs, I am very concerned about using ritonavir<\/span>\u2013\u00a0or cobicistat\u2013based\u00a0\u00a0<\/span>regimens, given the potential drug interactions with steroids, even from injected intra-articular steroids or those administered by nasal or pulmonary sprays (see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2019\/05\/hiv-meds-local-steroids-and-cushings.html<\/a>\u00a0)<\/span><\/p>\n

\u00a0<\/span><\/p>\n

\u2014 another concern is renal dosing of medications. This is quite problematic given:<\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0<\/span><\/span>\u2014 the remarkable inaccuracy of estimated GFR readings versus measured GFR (see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2022\/07\/egfr-not-such-great-estimate-of-renal.html<\/a>\u00a0)<\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0<\/span><\/span>\u2014 the general lack of data in the studies of people with significantly abnormal GFRs (ie they were excluded from the studies), leading for example to specific eGFR limits for lamivudine (3TC) , for example. Paul Sax in his blogs cited an article suggesting that real-world experience in those with very low eGFRs suggests they did fine on higher lamivudine dosing (see\u00a0https:\/\/academic.oup.com\/ofid\/article\/5\/10\/ofy225\/5094657?login=false#122156569<\/a>, though this was a small study)<\/span><\/p>\n

\u00a0<\/span><\/p>\n

\u2014\u00a0 I am also somewhat concerned about using the injectable cabotegravir\/rilpivirine combination, since the recommendation in general is to give a 1-month trial of oral meds to ensure tolerability. But oral rilpivirine should not be given with a proton-pump inhibitor (rilpivirine needs stomach acid) and there is a potential\u00a0<\/span>problem\u00a0with an H2-blocker.\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 and, the concern is that both the PPIs and H2Bs are available over-the-counter and used often for GI symptoms\u00a0 (and rilpivirine itself is<\/span>\u00a0occasionally\u00a0associated\u00a0with nausea, vomiting, and abdominal pain)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0 \u2014 also, there is a 1-2% risk of treatment failure\u00a0<\/span>with this injection, leading to the potential\u00a0emergence of\u00a0\u00a0InSTI resistance, and this seems to be higher in those getting injections every 8 vs 4 weeks\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2013and, those with treatment failure should avoid NNRTI- and InSTI-based regimens given the potential for resistance to either component of the injection (eg they should get a boosted darunavir regimen with TXF\/XTC)\u00a0<\/span><\/span><\/span><\/p>\n

\u00a0<\/span><\/p>\n

So, a useful resource for those of us treating HIV or helping patients prevent getting HIV. It is still mind-boggling to me how far we have come with HIV, to the point that it has evolved to a much more easily treatable condition than diabetes. But, we and the population in general must not let our guard<\/span>s\u00a0down: HIV infections remain a problem, with 34,800 new cases in 2019, which means that we all must still keep testing for HIV, even in the elderly (we found 2 cases in 75yo people at our health center\u2026), and promoting PrEP to those at high risk\u00a0<\/span><\/span><\/span><\/p>\n

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geoff<\/span><\/p>\n

If you would like to be on the regular email list for upcoming blogs, please contact me at\u00a0gmodest@uphams.org<\/a><\/span><\/p>\n

to get access to all of the blogs (2 options):<\/span><\/p>\n

1. go to\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/<\/a><\/span>\u00a0to see them in reverse chronological order<\/span><\/p>\n

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on \u201clabels\u201d and choose a category\u200b<\/span><\/p>\n

3. or you can just click on the magnifying glass on top right, then\u00a0 type in a name in the search box and get all the blogs with that name in them<\/span><\/p>\n

or: go to\u00a0https:\/\/bucommunitymed.wpengine.com\/<\/a>\u00a0, a website from the Community Medicine section at Boston Medical Center.\u00a0 This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.<\/span><\/p>\n

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list<\/span><\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n

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COVID: BIVALENT MRNA VACCINE WORKS ON NEW SUBVARIANTS<\/h1>\n<\/header>\n
\n
December 1, 2022<\/strong>
\n<\/span>\u00a0<\/span><\/div>\n

There is always some concern about the effectiveness of Covid\u00a0\u00a0<\/span>vaccines as new variants emerge. Of course, to get good clinical data on vaccine effectiveness requires waiting\u00a0<\/span>months<\/span>\u00a0<\/span>after that new variant has emerged<\/span>\/<\/span>\u00a0proliferated<\/span>\u00a0<\/span>sufficiently\/actual clinical effects can be assessed<\/span>, and that data may not arrive before the next variant comes along. So, the best testing we can\u00a0<\/span>do quickly<\/span>\u00a0is assessing neutralizing antibodies.\u00a0\u00a0<\/span>In this light, an impressive study was published showing that the newest variants (including BA.4, BA.5 and BA.2.75) were well covered by the new bivalent mRNA vaccine (the one they tested was mRNA-1273.214), see\u00a0covid BA2.75 neutral by bivalent vax NEJM2022<\/b>\u00a0in dropbox, or DOI: 10.1056\/NEJMc2212772)<\/span><\/p>\n

\n

\u00a0<\/span><\/p>\n

Details<\/span><\/b>:<\/span><\/p>\n

\u2014 this study was based on assessing the geometric mean titers (GMTs) of neutralizing antibodies at a 50% inhibitory dilution, at day 29 after the administration of the bivalent mRNA-1273.214\u00a0vaccine<\/span>; these adult participants had\u00a0previously received both the primary mRNA-1273 vaccines and a first booster dose at least three months earlier;\u00a0<\/span>they also\u00a0had no evidence of a SARS-CoV-2 infection within the three month period prior to study enrollment<\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0<\/span><\/span>\u2014 the neutralization assay used was based on lentivirus-based pseudo-viruses that were transduced to overexpress the angiotensin-converting enzyme-2 (the<\/span>\u00a0cellular\u00a0receptor that binds SARS-CoV-2)<\/span><\/p>\n

\u2014 428 participants were recruited.<\/span><\/p>\n

\u00a0<\/span><\/p>\n

Results<\/span><\/b>:<\/span><\/p>\n

\u2014 All 428 people given the mRNA-1273.214 vaccine had a potent neutralizing antibody response to the BA.2.75 subvariant<\/span><\/p>\n

\u00a0\u00a0\u00a0<\/span><\/span>\u2014 this was true whether or not they had a previous SARS-CoV-2 infection<\/span><\/p>\n

\u00a0<\/span><\/p>\n

<\/span><\/p>\n

\u00a0<\/span><\/p>\n

this figure tells it all:<\/span><\/p>\n

\u00a0 \u00a0 \u2014 they tested the effects of the vaccine against the original virus (ancestral one), the omicron BA.1, the omicron BA.4 and 5, and the newest omicron BA.2.75, finding:<\/span><\/p>\n

\u00a0 \u00a0 \u00a0 \u00a0 \u2014 in the group overall: 4.1<\/span>\u2013\u00a0to 5.7- fold increase in GMT,\u00a0<\/span>highest for\u00a0the new BA.2.75 subvariant (this is a log chart, so the bars\u00a0<\/span>may not seem to\u00a0reflect such a huge increase)<\/span><\/p>\n

\u00a0 \u00a0 \u00a0 \u00a0 \u2014 in those without previous infection: a 4.7<\/span>\u2013\u00a0to 6.6-fold increase<\/span><\/p>\n

\u00a0 \u00a0 \u00a0 \u00a0 \u2014 in those with a prior infection: a 2.6<\/span>\u2013\u00a0to 4.8-fold increase<\/span><\/p>\n

\u00a0<\/span><\/p>\n

Commentary<\/span><\/b>:<\/span><\/p>\n

\u2014 the new bivalent mRNA vaccines contain the spike sequences\u00a0<\/span>specifically\u00a0from both the ancestral SARS-Cov-2 virus as well as the Omicron B.1.1.529\u00a0<\/span>subvariant<\/span><\/p>\n

\u2014 this new vaccine elicit<\/span>ed\u00a0a strong neutralizing antibody responses against the\u00a0<\/span>Omicron BA.1, as well as the more recent BA.4 and BA.5 subvariants<\/span>\u00a0and the new\u00a0BA.2.75 one.<\/span><\/p>\n

\u2014 the BA.2.75 subvariant has had increasing prevalence<\/span>\u00a0in\u00a0at least 36 countries<\/span><\/p>\n

\u00a0 \u00a0 \u2014 this variant was first recognized in June 2022 in India,\u00a0<\/span>but has\u00a0now<\/span>\u00a0been\u00a0found in many cou<\/span>ntries including Australia, Canada, Germany, New Zealand,<\/span>\u00a0and\u00a0the US. In India<\/span>,\u00a0it is outcompeting<\/span>\u00a0the\u00a0other omicron subvariants<\/span>\u00a0(ie, spreading rapidly and taking over), and is likely to do so globally (see\u00a0https:\/\/www.seattletimes.com\/nation-world\/nation\/omicron-subvariants-ba-4-6-and-ba-2-75-are-here-how-concerned-should-u-s-be\/<\/a><\/span><\/p>\n

\u00a0 \u00a0 \u2014\u00a0<\/span>the B.2.75 subvariant\u00a0has \u201ca high number of mutations in genome sequences, mainly in the spike proteins of the virus\u201d, per\u00a0https:\/\/www.dovepress.com\/could-the-new-ba275-sub-variant-cause-the-emergence-of-a-global-epidem-peer-reviewed-fulltext-article-IDR<\/a>\u00a0.<\/span><\/p>\n

\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u2014 and since the vaccines target the spike protein, the real concern is that major mutations\u00a0<\/span>in that protein\u00a0might lead to vaccine failure\u00a0<\/span><\/p>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u2014\u00a0<\/span>but,\u00a0this study offers significant hope that the new bivalent mRNA vaccines will be effective against\u00a0<\/span>B.2.75, since the neutralizing antibody response was as great as in all the other variants assessed<\/p>\n

Limitations:<\/span><\/p>\n

\u2014 this is a laboratory study using quite artificial conditions: pseudoviruses that were manipulated to have lots of ACE-2,\u00a0<\/span>with no\u00a0real clinical outcome data (which takes many months to get and more time to analyze)<\/span><\/p>\n

\u00a0 \u00a0 \u2014 that being said, neutralizing antibodies\u00a0<\/span>overall\u00a0have been quite predictive of actual immune protection from symptomatic covid infections (see\u00a0https:\/\/www.nature.com\/articles\/s41591-021-01377-8<\/a>\u00a0)\u00a0<\/span><\/p>\n

\u00a0<\/span><\/p>\n<\/div>\n

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geoff<\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/p>\n

If you would like to be on the regular email list for upcoming blogs, please contact me at\u00a0gmodest@uphams.org<\/a><\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/p>\n

For access to the\u00a0dropbox, go to link:\u00a0<\/span>https:\/\/www.dropbox.com\/sh\/0bmvtita8mzms11\/XDTwHySFFg<\/a><\/span><\/span><\/p>\n

Then go to \u201cclinic\u201d, then to \u201cclinical stuff\u201d for articles, or go to\u00a0https:\/\/www.dropbox.com\/sh\/nyle22q1fn6lkpk\/AAB9B2hBj5Kw4gtrJAkI-UF8a?dl=0<\/a>\u00a0for\u00a0the\u00a0powerpoint\u00a0presentations<\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/p>\n

to get access to all of the blogs (2 options):<\/span><\/span><\/p>\n

1. go to\u00a0<\/span>http:\/\/gmodestmedblogs.blogspot.com\/<\/a><\/span>\u00a0to see them in reverse chronological order<\/span><\/span><\/p>\n

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on \u201clabels\u201d and choose a category\u200b<\/span><\/span><\/p>\n

3. or you can just click on the magnifying glass on top right, then\u00a0 type in a name in the search box and get all the blogs with that name in them<\/span><\/span><\/p>\n

\u00a0<\/span><\/span><\/p>\n

or: go to\u00a0https:\/\/bucommunitymed.wpengine.com\/<\/a>\u00a0, a website from the Community Medicine section at Boston Medical Center.\u00a0 This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.<\/span><\/span><\/p>\n

<\/span>please feel free to circulate this to others. also, if you send me their emails, i can add them to the list<\/span><\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

NT-PROBNP PREDICTS FUTURE HEART FAILURE AND MORALITY IN ASYMPTOMATIC March 12, 2023 A recent article tracked changes over time of N-terminal B-type natriuretic peptide (NT-proBNP) in those without known heart failure (ie primary prevention) finding that changes in\u00a0NT-proBNP were\u00a0associated with both incident heart failure and death (see\u00a0chf bnp predicts HH development JAMAcardiol2023\u00a0in dropbox or\u00a0\u00a0doi:10.1001\/jamacardio.2022.5309)\u00a0 Details: […]<\/p>\n","protected":false},"author":21743,"featured_media":0,"parent":0,"menu_order":11,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/pages\/377"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/users\/21743"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/comments?post=377"}],"version-history":[{"count":13,"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/pages\/377\/revisions"}],"predecessor-version":[{"id":447,"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/pages\/377\/revisions\/447"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/cmu\/wp-json\/wp\/v2\/media?parent=377"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}