CMU Blogs

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 NT-proBNP were associated with both incident heart failure and death (see chf bnp predicts HH development JAMAcardiol2023 in dropbox or doi:10.1001/jamacardio.2022.5309)

Details:

— 9776 individuals in the Atherosclerosis Risk in Community (ARIC) study from 4 US communities (in North Carolina, Mississippi, Minnesota, and Maryland)

— data were collected from patient at visits 2 and 4, approximately 6 years apart, both with measurements of NT-proBNP

— patients with prevalent heart failure were excluded

— mean age 63, 57% women, 79% white/21% Black

— 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%

— 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 NT-proBNP

— also assessed was the association between changes in cardiovascular risk factors with changes in NT-proBNP

— 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.

Results:

—as compared to those with NT-proBNP <125pg/ml at both visits (reference), all with adjusted hazard ratios:

— NT-proBNP <125pg/ml at visit 2 and >125 pg/ml at visit 4

— incident HF: HR 1.86 (1.60-2.16)

— mortality risk: HR 1.32 (1.19-1.47)

— NT-proBNP >125pg/ml at visit 2 and <125 pg/ml at visit 4

— incident HF: HR 1.01 (0.71-1.43)

— mortality risk: HR 0.79 (0.61-1.01)

— NT-proBNP >125pg/ml at visit 2 and >125 pg/ml at visit 4

— incident HF: HR 2.40 (2.00-2.88)

— mortality risk: HR 1.68 (1.47-1.91)

— ie, as compared to those who remained with a low NT-proBNP, those whose NT-proBNP increased 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

— there was no interaction between NT-proBNP’s relationship between HF incidents vs death (i.e. these were independent phenomena)

— Stratification by percent change in NT-proBNP:

— visit 2 NT-proBNP <125pg/ml, as compared to no change by visit 4 (reference), all with adjusted HRs:

— >25% decrease:

— incident HF: HR 1.15 (0.86-1.53)

— mortality: HR 1.14 (0.94-1.38)

— >25% increase:

— incident HF: HR 1.93 (1.39-2.67)

— mortality: HR 1.56 (1.26-1.94)

— visit 2 NT-proBNP >125pg/ml, as compared to no change by visit 4:

— >25% decrease:

— incident HF: HR 0.86 (0.57-1.29)

— mortality: HR 0.59 (0.44-0.79)

— > 25% increase:

— incident HF: HR 6.56 (2.27-18.99)

— mortality: HR 5.47 (2.58-11.60)

— Changes in cardiovascular risk factors:

— levels of NT-proBNP were positively associated with age, systolic blood pressure, being on hypertension medication use, smoking, and prevalent heart disease

— but there was an inverse association of NT-proBNP levels in men, diastolic blood pressure, triglyceride level, cholesterol medication use, eGFR, BMI, and those of Black race

— 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

Commentary:

— 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: 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)

— this all brings up the question of the differences between the NT-proBNP and BNP markers

— whereas BNP is the biologically active hormone and is degraded, NT-proBNP is its nonfunctional precursor, is cleared passively, and has a much longer half-life

— levels of both NT-proBNP and BNP do have a significant genetic component, explaining about 40% of their variation

— 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

— both levels are higher in patients with renal failure, though much more significantly so with NT-proBNP (so these NT-proBNP levels are not so helpful in diagnosing and managing heart failure, but a low levelof 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 https://pubmed.ncbi.nlm.nih.gov/24372567/ and https://bmcnephrol.biomedcentral.com/articles/10.1186/1471-2369-14-117)

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

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

— 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: https://pubmed.ncbi.nlm.nih.gov/30846338/

— and, unfortunately, there was a poorcorrelation between BNP and NT-proBNP in a study of 3,029 patients, both inpatient and outpatient: https://www.aacc.org/science-and-research/scientific-shorts/2019/bnp-or-nt-probnp . so makes sense to stick with one of BNP/NT-proBNP to follow for changes

— this ARIC study had several important findings:

— 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

— 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 NT-proBNP from high to low seemed to be unexpectedly better than just remaining low)

— and, this relationship was found with as little as a NT-proBNP being 9 pg/mL higher at visit 2 than visit 4

— 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

— 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 “primary prevention” study)

Limitations:

— 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 NT-proBNP’s association with these clinical outcomes)

— 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

— 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 NT-proBNP (eg, the unexpected finding that going from a higher to a lower NT-proBNP might be explained by unmeasured changes in the 6 year period between ARIC visits)

— 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

— 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

— 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

So, a few comments:

— 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…)

— 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’s, maybe especially in those with high levels (eg >125 pg/mL) who have a subsequent one also high (especially since SGLT-2’s are not such benign drugs: see https://gmodestmedblogs.blogspot.com/2019/05/sglt-2-inhibitors-and-fourniers-gangrene.htmland https://gmodestmedblogs.blogspot.com/2018/11/sglt-2-inhibitors-twice-risk-of.html , as well as being assoicated with severe urinary tract infections (and urosepsis), mycotic infections, DKA at even low blood sugar levels, etc

— it remains likely but unproven that interventions to lower NT-proBNP levels would be clinically helpful in asymptomatic patients with higher levels.

— 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

— 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)

— and it is important that the laboratories we use have access to each of these tests

LOWER INCOME, HIGHER MORBIDITY AND MORTALITY

January 9, 2023

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: — 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 — 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 — 5 states with the largest sample: California 14%/Texas 10%/Illinois 6%/New York 6%/Ohio 5% — income level below median income for these Medicaid recipients: 387,000 people; higher than median income in 408,000 — income-to-poverty ratio: those below median income 46%, above median income 134% — 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% — the 200% for the federal poverty threshold for a family of 3 corresponded to $36,212 in 2011 and $43,622 in 2021 — 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) — 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’s Health Insurance Program (CHIP) — clinical outcomes overall: infection in 33%, mental health disorder 13%, injury 6%, asthma 5%, anemia 2%, substance use disorder 1% — overall mortality, 0.6% with mean age at death: 20yo — a few states (Florida and Idaho) did not have full databases Results: — 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 — mortality had the largest difference: 15% lower among children and adolescents in families having income above versus below the median — 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 — prevalence of conditions and mortality differed between those 5-9yo versus 10-17yo: — those aged 10 to 17 versus 5 to 9: — infection: 1.2 percentage points lower — asthma: 1.2 percentage points lower — mental health disorders: 6.6 percentage points more likely, 69% times higher — 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) — injury: 3.9 percentage points more likely, 105% times higher — substance use disorder: 1.5 percentage points more likely, 573% times higher — 10-year mortality: 0.8 percentage points higher (more than 3-fold) — children aged 5-9 living in a family with 100% more income relative to the federal poverty threshold: — infection: 2.3 percentage points lower, 7% lower — those 10-17yo: 12% lower — mental health disorders 1.9 percentage points lower, 19% lower — those 10-17yo: 15% lower — injury: 0.7 percentage points lower, 18% lower — those 10-17yo: 12% lower — asthma: 0.3 percentage points lower, 5% lower — those 10-17yo: 12% lower — anemia: 0.2 percentage points lower, 9% lower — substance use disorder: 0.6 percentage points lower, 22% lower — those 10-17yo: 21% lower — mortality within 10 years: no significant difference — those 10-17yo: 21% lower — 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: — 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 — 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 — 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 — 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 — 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) — this study tracked those enrolled in Medicaid for 10 years. A few relevant points: — 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 — 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): 60–68) — 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) — that being said, Medicaid expansion and improved health outcomes is still likely a very small benefit as compared to the effects of poverty itself — 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) — 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: — 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) — 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) — 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 — 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) — there was no information about children 5yo (the authors felt this group was likely uncercounted by the Census Bureau) — diseases were only recorded if the individual “sought formal health care and received a diagnosis and for which Medicaid claims were generated”, possibly missing some clinical outcomes and relying on billing systems to work well — 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 — and, the other limitations noted above by including only Medicaid patients So, a few comments — not so surprising that the old and less reliable studies on income and health outcomes were validated in this higher quality study
— 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 — the prior articles on stress, however, are a bit mixed. It seems that a person’s 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. — and other older studies have found that people with higher levels of personal supports had lower levels of biomarkers of stress — 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 ) — 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 — so, obviously, poverty needs to be addressed as a basic public health issue…. (as well as a basic social one) geoff ———————————– 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 — click on 3 parallel lines top left, if you want to see blogs by category, then click on “labels” and choose a category — 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.

HYPERTENSION: HCTZ VS CHLORTHALIDONE

January 5, 2023

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 htn chlorthal vs hctz no diff nejm2022 in dropbox, or DOI: 10.1056/NEJMoa2212270)

Details:

— 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

— 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 ½ the HCTZ dose)

— 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 many other interventions)

— mean age 72, 97% male, 77% white/15% Black, 93% non-Latinx

— BMI 32, diabetes 44%, heart failure 8%, stroke 8%, prior MI and stroke 11%

— eGFR <60 in 23%, current smoker 23%

— baseline HCTZ dose was 25mg in 94% (ie very few on 50mg), systolic BP 139mmHg

— number of BP meds prescribed: mean of 2.6

— 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)

— secondary outcomes: individual components of the primary outcome, within pre-specified subgroups

— mean follow-up: 2.4 years

Results:

— primary composite outcome:

— chlorthalidone: 702 events (10.4%), annual rate of 4.5%

— HCTZ: 6875 events (10.0%), annual rate of 4.3%

— HR 1.04 (0.94-1.16), p=0.45, nonsignificant difference

— secondary outcomes (individual components, etc):

— MI:

— chlorthalidone: 142 events (2.1%)

— HCTZ: 140 events (2.1%)

— Stroke:

— chlorthalidone: 83 events (1.2%)

— HCTZ: 83 events (1.2%)

— heart failure hospitalization:

— chlorthalidone: 242 events (3.6%)

— HCTZ: 232 events (3.4%)

–unstable angina with urgent coronary revascularization:

— chlorthalidone: 20 events (0.3%)

— HCTZ: 13 events (0.2%)

— deaths from any cause:

— chlorthalidone: 446 events (6.6%)

— HCTZ: 448 events (6.6%)

— expected adverse reactions:

— new allergic or adverse reactions:

— chlorthalidone: 109 events (1.6%)

— HCTZ: 21 events (0.3%)

— HR 5.23 (3.28-8.35)

— hypokalemia:

— chlorthalidone: 335 events (5.0%)

— HCTZ: 243 events (3.6%)

— HR 1.39 (1.18-1.64)

— those with history of MI or stroke:

— chlorthalidone: 105 events in 733 patients (14.3%)

— HCTZ: 140 events in 722 patients (19.4%)

–HR 0.73 (0.57-0.94), statistically favoring chlorthalidone

— those without history of MI or stroke:

— chlorthalidone: 597 events in 6023 patients (9.9%)

— HCTZ: 535 events in 6045 patients (8.9%)

–HR 1.12 (1.00-1.26), statistically favoring HCTZ

— 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)

— adherence to study meds:

— chlorthalidone: 1039 patients (15.4%) switched back to HCTZ

— HCTZ: 260 patients (3.8%) switched to chlorthalidone

— 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

— mean daily dose of meds taken:

— chlorthalidone: 12.3 mg

— HCTZ: 23 mg

Commentary:

— HCTZ remains by far the most popular initial antihypertensive in the US, despite it being NOT recommended in more recent guidelines (see http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html )

— though early studies found that chlorthalidone was significantly better than HCTZ, this has not been found in some other studies

— and chlorthalidone is about twice as strong as HCTZ and is associated with more hyperkalemia (as found in this study)

— 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)

–There is a pretty strong argument that chlorthalidone is superior to HCTZ:

— 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 http://gmodestmedblogs.blogspot.com/2015/01/uspstf-recs-on-ambulatory-blood.html and https://www.uspreventiveservicestaskforce.org/uspstf/document/final-evidence-summary/hypertension-in-adults-screening

— 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 http://gmodestmedblogs.blogspot.com/2016/04/chlorthalidone-is-better-than-hctz-for.html: these studies have found that the ABPM for HCTZ was ½ the blood pressure lowering of other BP meds tested, including chlorthalidone. there are data suggesting that HCTZ 50mg may have a prolonged effect, but we are now mostly using 12.5mg, or up to 25mg

— combination pills including HCTZ may work better than HCTZ by itself:

— the combination of lisinopril and HCTZ does seem to maintain 24-hour effectiveness (https://pubmed.ncbi.nlm.nih.gov/8117053/), although this does not seem to be as true with the combination of losartan and HCTZ (https://pubmed.ncbi.nlm.nih.gov/16372579/)

— 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)

— 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 https://www.ahajournals.org/doi/10.1161/hypertensionaha.107.089763 ). 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

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: https://pubmed.ncbi.nlm.nih.gov/20625077/. But there are some conflicting reports on this (see https://pubmed.ncbi.nlm.nih.gov/36067089/ )

Limitations:

— as a VA study, this was predominantly older white males (all >65yo, 97% male, 77% white), limiting generalization to others

— 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)

— there was a real selection bias: these participants were already on HCTZ and presumably tolerating it well. The switch for ½ 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).

— also, the much more substantial numbers of people changing from chlorthalidone back to HCTZ would likely understate the potential chlorthalidone benefit

— there was also “contamination” 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?? ie, was the horse already out of the barn, the die was cast, or some other aphorism…

So, a few comments:

–This 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.

— 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

— 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

— 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)

— 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….

geoff

———————————–

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

— click on 3 parallel lines top left, if you want to see blogs by category, then click on “labels” and choose a category

— 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

For access to the dropbox, go to link: https://www.dropbox.com/sh/0bmvtita8mzms11/XDTwHySFFg

Then go to “clinic”, then to “clinical stuff” for articles

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list

H PYLORI: ANTIMICROBIAL RESISTANCE IN RHODE ISLAND

January 5, 2023

A study from Rhode Island documented antibiotic resistance to H Pylori (thanks to Boris Skurkovich for bringing this to my attention): see h pylori resistance rhode island Gastro2021 in dropbox or doi:10.1053/j.gastro.2021.02.014.

Details:

— 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

— eradication determined by urea breath test in 51%, stool antigen in 40%, and biopsy in 10%

— mean age 45, 68% male, 29% white/25% Black/ 44% Latinx

— treatment duration 14 days (the standard now) in 91%

— 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 “next-generation sequencing”

— H Pylori presence was determined by quantitative real-time PCR testing

Results:

— eradication rates by treatment:

— bismuth-based quadruple therapy: given to 54% of the patients; 88% had eradication

— triple therapy: 46% of patients; 61% had eradication

— quad therapy had statistically significant benefit over triple: OR 4.8 (2.3-10.1), p<0.001

— overall, 66% of H Pylori strains were resistant to at least one antibiotic

— 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

— 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

— and, those regimens in patients who had metronidazole-resistant H Pylori but had at least one other antimicrobial that the bug was sensitive to: 94% eradiation after a 14 day treatment (ie, despite metronidazole resistance)

Commentary

— this study complements another broader scale one noted in a recent prior blog http://gmodestmedblogs.blogspot.com/2022/11/h-pylori-resistance-patterns-in-us.html

— 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 http://gmodestmedblogs.blogspot.com/2022/11/h-pylori-resistance-patterns-in-us.html for more detailed information)

— 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 http://gmodestmedblogs.blogspot.com/2018/01/h-pylori-ppi-use-and-gastric-cancer.html ), 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…

— 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 http://resistancecontrol.info/wp-content/uploads/2019/05/Rupp%C3%A9.pdf for 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)

— I personally have been using one of the following 2 treatment regimens:

— sequential therapy still involving clarithromycin: it seems that clarithromycin resistance is related to 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’s cell membrane and prevents this efflux. So, amoxicillin effectively reverses clarithromycin resistance. A study assessed patients with H Pylori and documented clarithromycin resistance and found the vast majority were cured with a sequential regimen, though those without amoxicillin pretreatment failed miserably (ie 89% vs 29% success rates: hpylori rx sequential annals 2007 in dropbox, or see http://gmodestmedblogs.blogspot.com/2013/11/h-pylori-therapy-sequential-vs-standard.html.) the sequential regimen in basically twice-daily amoxicillin 1 gram, and a PPI for one week, then twice-daily clarithromycin 500mg, metronidazole 500mg, and PPI for the next week.

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

–the 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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905086/ and http://gmodestmedblogs.blogspot.com/2022/11/h-pylori-resistance-patterns-in-us.html .

Limitations:

— 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?

— 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

— 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.

So, I bring up this article for a few reasons:

— 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

— 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)

— the technique would also be an important public health tool to track antibiotic resistance to perhaps several different microbes as well as H Pylori

— 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….

— 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

geoff

———————————–

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):

2. go to http://gmodestmedblogs.blogspot.com/ to see the blogs in reverse chronological order

— click on 3 parallel lines top left, if you want to see blogs by category, then click on “labels” and choose a category

— 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

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list

HIV TREATMENT RECOMMENDATIONS 2022

December 13, 2022

The International Antiviral Society-USA Panel issued their 2022 recommendations on antiretroviral drugs for treatment and prevention of HIV infections in adults (see hiv antiretrov recs 2022 in dropbox, or doi:10.1001/jama.2022.22246).

Details of recommendations, along with commentary embedded in brackets

Initiation of antiretroviral therapy (ART)

— 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)

— Early therapy initiation is beneficial for a few reasons:

— 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]

— “treatment as prevention”: 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

— even in “elite controllers” who may have very low or undetectable HIV viral loads without therapy, they do have elevated levels of inflammation that are 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…

— the risk of cardiovascular disease remains high even in those on well-treated HIV, likely related to 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]

— the risk of cancer is also increased, even in those on ART (see https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794862 ), reinforcing the importance of routine cancer screening. Overall, the HIV-associated cancers (eg kaposi, non-Hodgkin lymphoma) are decreasing but some non-HIV defining cancers have increased. For example, cervical cancer in women is higher in those with HPV (see 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 ), which likely informs the need for increased cervical cancer screening (eg, every 3 years, with no cutoff at age 65)

Initial ART regimens in those with HIV

— preferred regimens are those containing InSTIs, integrase strand transfer inhibitors: dolutegravir and bictegravir

— bictegravir plus TAF (tenofovir alafenamide) plus FTC (emtricitabine)

— dolutegravir plus TXF (this connotes either TAF or TDF) plus XTC (this connotes FTC or 3TC)

— dolutegravir plus 3TC (dual therapy), but only if the HIV viral load is <500K and hepatitis B co-infection has been ruled out. Also, the studies done on this combo did not include patients with severe HIV infections and CD4 counts <200, so unclear if this dual therapy is adequate

— 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

— those who do not have measurable hepatitis B virus and are not immune to hepatitis B should be vaccinated and have immunity assessed post-vaccination, just to make sure that they are getting adequate hepatitis B coverage and the decreased likelihood of hepatitis B resistance, as happens with a single agent of XTC

— long-acting cabotegravir-rilpivirine (the parenteral option) is not recommended for initial ART

— abacavir is no longer recommended as initial therapy (it is associated with cardiovascular disease, and has no advantage over the dolutegravir/3TC combo)

— in those with PrEP failure:

— if on cabotegravir for pre-exposure HIV prophylaxis:

— 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

— if resistant or genotype are not available, prescribe a boosted darunavir regimen with TXF/XTC

— 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 regimens seem to be active

— in pregnant women:

— begin ART immediately but avoid any regimen with cobicistat; 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 was overturned in updated results)

— 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)

Switching ART regimens

— 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 being one month after changing therapy, whether patient has viral suppression are not

— 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 XTC resistance mutations)

— 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

— the most common reason for virologic failure is poor med adherence. Should get genotypes when there is virologic failure

Laboratory testing/monitoring

— HIV RNA viral load: every 3 months until suppressed, then every 6 months

— CD4: every 6 months until >250 for 1 year, then can stop if viral load continues to be suppressed

— cryptococcal antigen: if CD4 <100

— assess treatment adherence within 6 weeks of starting ART [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]

Preexposure prophylaxis

— condoms remain the cornerstone of STI prevention, and clearly should be emphasized

— 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

— there several options for PrEP, summarized in their table 4, including the following, though the most important factor is what is most acceptable to the patient:

— 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

— for non-cisgender males, seven days of daily dosing is likely to be required to reach maximum protection and is recommended for at least seven days after last risky activity; this daily regimen is also suggested for people are pregnant or breast-feeding

— 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. 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 (see http://gmodestmedblogs.blogspot.com/2020/01/on-demand-prep-works-if-fewer-meds-and.html )

— 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

— 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

— daily TAF/FTC is preferred over TDF/FTC in people with creatinine clearance between 30 and 60, or when there is osteopenia or osteoporosis

— TAF/FTC should be limited to cisgender 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

— 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)

— there is no need for an oral lead-in of cabotegravir, as with HIV therapy noted below, other than those with severe atopic histories

— 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

— there is concern for InSTI resistance, given that there is potentially a prolonged pharmacologic “tail” after stopping the injections, with progressively decreasing blood levels

— if there any questions, there is a very accessible PrEP Warmline at 855-HIV-PReP

Postexposure prophylaxis

— 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

— medication should be given even before getting HIV testing on the source person if necessary for rapid initiation

— if there is concern for drug-resistant HIV, or in the setting of pregnancy or breast-feeding, they advise expert consultation

— recommended regimen is either dolutegravir or bictegravir with TXF/XTC

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

Further commentary:

— I personally have switched to the dolutegravir plus 3TC regimen in almost all patients (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:

— HIV has become a chronic disease, and many patients are likely to live with HIV, often for many decades

— TAF is associated with several potential adverse effects, especially with long-term therapy:

— 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 http://gmodestmedblogs.blogspot.com/2015/06/tenofovir-nephrotoxicity.html but also increased creatinine levels), and long-term TAF may well have long-term renal complications

— 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

— 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

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

— a meta-analysis of 8 RCTs in treatment-naïve 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), 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 http://gmodestmedblogs.blogspot.com/2020/10/hiv-treatmentprevention-guidelines-2020.html )

— 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 https://www.thelancet.com/article/S0140-6736(18)32462-0/fulltext ), and this dual therapy does not include an unnecessary and a potentially toxic medication????

— As I have mentioned in prior blogs, I am very concerned about using ritonavir– or cobicistat–based regimens, given the potential drug interactions with steroids, even from injected intra-articular steroids or those administered by nasal or pulmonary sprays (see http://gmodestmedblogs.blogspot.com/2019/05/hiv-meds-local-steroids-and-cushings.html )

— another concern is renal dosing of medications. This is quite problematic given:

— the remarkable inaccuracy of estimated GFR readings versus measured GFR (see http://gmodestmedblogs.blogspot.com/2022/07/egfr-not-such-great-estimate-of-renal.html )

— 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 https://academic.oup.com/ofid/article/5/10/ofy225/5094657?login=false#122156569, though this was a small study)

— 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 problem with an H2-blocker.

— and, the concern is that both the PPIs and H2Bs are available over-the-counter and used often for GI symptoms (and rilpivirine itself is occasionally associated with nausea, vomiting, and abdominal pain)

— also, there is a 1-2% risk of treatment failure with this injection, leading to the potential emergence of InSTI resistance, and this seems to be higher in those getting injections every 8 vs 4 weeks

–and, 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)

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 guards down: 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…), and promoting PrEP to those at high risk

geoff

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org

to get access to all of the blogs (2 options):

1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on “labels” and choose a category

3. 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

or: 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 (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.

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list

COVID: BIVALENT MRNA VACCINE WORKS ON NEW SUBVARIANTS

December 1, 2022

There is always some concern about the effectiveness of Covid vaccines as new variants emerge. Of course, to get good clinical data on vaccine effectiveness requires waiting months after that new variant has emerged/ proliferated sufficiently/actual clinical effects can be assessed, and that data may not arrive before the next variant comes along. So, the best testing we can do quickly is assessing neutralizing antibodies. 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 covid BA2.75 neutral by bivalent vax NEJM2022 in dropbox, or DOI: 10.1056/NEJMc2212772)

Details:

— 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 vaccine; these adult participants had previously received both the primary mRNA-1273 vaccines and a first booster dose at least three months earlier; they also had no evidence of a SARS-CoV-2 infection within the three month period prior to study enrollment

— the neutralization assay used was based on lentivirus-based pseudo-viruses that were transduced to overexpress the angiotensin-converting enzyme-2 (the cellular receptor that binds SARS-CoV-2)

— 428 participants were recruited.

Results:

— All 428 people given the mRNA-1273.214 vaccine had a potent neutralizing antibody response to the BA.2.75 subvariant

— this was true whether or not they had a previous SARS-CoV-2 infection

this figure tells it all:

— 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:

— in the group overall: 4.1– to 5.7- fold increase in GMT, highest for the new BA.2.75 subvariant (this is a log chart, so the bars may not seem to reflect such a huge increase)

— in those without previous infection: a 4.7– to 6.6-fold increase

— in those with a prior infection: a 2.6– to 4.8-fold increase

Commentary:

— the new bivalent mRNA vaccines contain the spike sequences specifically from both the ancestral SARS-Cov-2 virus as well as the Omicron B.1.1.529 subvariant

— this new vaccine elicited a strong neutralizing antibody responses against the Omicron BA.1, as well as the more recent BA.4 and BA.5 subvariants and the new BA.2.75 one.

— the BA.2.75 subvariant has had increasing prevalence in at least 36 countries

— this variant was first recognized in June 2022 in India, but has now been found in many countries including Australia, Canada, Germany, New Zealand, and the US. In India, it is outcompeting the other omicron subvariants (ie, spreading rapidly and taking over), and is likely to do so globally (see https://www.seattletimes.com/nation-world/nation/omicron-subvariants-ba-4-6-and-ba-2-75-are-here-how-concerned-should-u-s-be/

— the B.2.75 subvariant has “a high number of mutations in genome sequences, mainly in the spike proteins of the virus”, per https://www.dovepress.com/could-the-new-ba275-sub-variant-cause-the-emergence-of-a-global-epidem-peer-reviewed-fulltext-article-IDR .

— and since the vaccines target the spike protein, the real concern is that major mutations in that protein might lead to vaccine failure

— but, this study offers significant hope that the new bivalent mRNA vaccines will be effective against B.2.75, since the neutralizing antibody response was as great as in all the other variants assessed

Limitations:

— this is a laboratory study using quite artificial conditions: pseudoviruses that were manipulated to have lots of ACE-2, with no real clinical outcome data (which takes many months to get and more time to analyze)

— that being said, neutralizing antibodies overall have been quite predictive of actual immune protection from symptomatic covid infections (see https://www.nature.com/articles/s41591-021-01377-8 )

geoff

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org

For access to the dropbox, go to link: https://www.dropbox.com/sh/0bmvtita8mzms11/XDTwHySFFg

Then go to “clinic”, then to “clinical stuff” for articles, or go to https://www.dropbox.com/sh/nyle22q1fn6lkpk/AAB9B2hBj5Kw4gtrJAkI-UF8a?dl=0 for the powerpoint presentations

to get access to all of the blogs (2 options):

1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on “labels” and choose a category

3. 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

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list