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Research Briefs May 2016

Insulin Resistance and Coronary Stenosis in HIV

Targeting insulin resistance (IR) may be an important strategy to reduce cardiovascular events in human immunodeficiency virus (HIV)-infected patients, say researchers from Johns Hopkins and Northwestern University.

To find out whether IR was greater in HIV-infected men and, consequently, whether coronary artery disease would be amplified in those patients, the researchers analyzed data collected over 10 years from 448 men with HIV and 306 uninfected men in the Multicenter AIDS Cohort Study. They measured fasting serum insulin and glucose and computed the homeostatic model assessment of IR. At the end of the study, they assessed atherosclerotic disease with computed tomographic angiography (CTA).

IR was higher in HIV-infected men, both when averaged over the course of the study and when measured with CTA. The prevalence of coronary stenosis was similar between both groups. Men with mean IR values in the highest tertile had nearly three times the odds of coronary stenosis (50% or higher than men in the lowest tertile).

HIV-infected men (of whom about 11% also had hepatitis C infection) were more insulin resistant than those without HIV. IR was associated in all the study participants with common cardiovascular disease (CVD) risk factors, such as hypertension, but also with hepatitis C infection. The association between IR and coronary artery stenosis remained after adjustment for multiple CVD risk factors, as well as HIV-related variables. That may mean, the researchers say, that the association is independent of the severity of immune suppression or HIV control.

Coronary artery stenosis was associated with IR in both groups, particularly as observed when IR values were assessed over the 10 years, rather than just at the time of the angiography. The researchers say this suggests that long-standing IR is an important contributor to CVD in HIV-infected patients.

Source: American Journal of Cardiology, March 2016

The High Cost of Being Overweight

The better off you are socioeconomically, the more likely you are to live longer and in better health. The taller and thinner you are, the better off you are socioeconomically. Studies have shown that height, weight, and socioeconomic status are often linked—but why? To find out, researchers from Royal Devon and Exeter Hospital, University of Exeter, Boston Children’s Hospital, and Harvard University conducted a study using data from 119,669 participants in the United Kingdom Biobank.

They used Mendelian randomization, or gene-based analysis, to test for a causal relationship between socioeconomic status and genetically influenced phenotypes, such as body mass index (BMI) and height. “Genetic evidence has the advantage of being largely free from the problems that afflict observational studies,” the researchers say. “Analyses using inherited DNA variation are much more robust to confounding, bias, and reverse causality.”

They assessed differences and correlations in BMI, height, age, education, job class, and income. They also used the Townsend deprivation index, a composite measure of deprivation based on unemployment, not owning a car or a home, and household overcrowding.

Taller stature was strongly correlated with participants spending longer in full-time education, and with having obtained a degree. It was also strongly associated with job class: one standard deviation (SD) (6.3 cm) greater height was associated with increased odds of working in a “more professional role.” Being taller was also correlated with higher household income (a correlation about 50% stronger in men): An extra 6.3 cm was worth about £2,940 ($4,134) more per year. Genetic analysis determined that one SD greater height was associated with an increase of approximately £1,130 ($1,589). Taller stature was also associated with less deprivation.

Higher BMI was associated with lower odds of having obtained a degree, greater odds of less-skilled employment, and lower household income. However, that income effect was “very strongly driven” by the association in women, the researchers found. In men, a one SD higher BMI meant £201 ($283) less per year, but for women a one SD higher BMI equated to £1,890 ($2,658) less per year. Genetic analysis found that effect was equivalent to £2,940 ($4,134) less for women. Similarly, a one SD higher BMI was associated with more deprivation, and the association was twice as strong in women. The researchers say one of the reasons women were more affected could be discrimination in the workplace; discrimination may occur at lower weight levels for women than for men.

Two of the strongest measures in women were income and deprivation, which the researchers say are not just specific to the individual, but also indicative of the partner’s income. However, genetically determined higher BMI was associated with lower income both in nonworking women with partners and working women without a partner, suggesting that the associations were not just driven by a partner’s income. And, although higher BMI leads to poorer health, which could affect productivity, the researchers found evidence of genetic associations between higher BMI and socioeconomic status in women who reported no adverse health outcomes, as well as those reporting health problems.

Source: BMJ, March 2016

Some Progress in Shutting Down Superbugs

There’s some good news in the battle against “superbugs” in acute care hospitals: For instance, central-line–associated bloodstream infections were down 50% and surgical site infections declined 17% between 2008 and 2014. In addition, some progress toward reducing catheter-associated urinary tract infections was seen between 2009 and 2014. Hospital-onset infections caused by Clostridium difficile, the most common bacteria responsible for hospital-acquired infections (HAIs), dropped by 8% between 2011 and 2014.

However, that’s not good enough, says the Centers for Disease Control and Prevention (CDC): “Antibiotic-resistant HAIs are a threat to all patients.” According to the CDC’s Vital Signs report, six bacteria are among the “most deadly”: carbapenem-resistant Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, ESBL-producing Enterobacteriaceae (extended-spectrum beta-lactamases), vancomycin-resistant Enterococcus, multidrug-resistant Pseudomonas aeruginosa, and multidrug-resistant Acinetobacter. Those bacteria cause one in seven catheter- and surgery-related HAIs in acute care hospitals, and one in four infections in long-term acute care hospitals.

“Doctors and health care facilities have the power to protect patients—no one should get sick while trying to get well,” said CDC Director Tom Frieden, MD, MPH. The CDC’s report calls on health care professionals to continue prevention efforts. “For clinicians, prevention means isolating patients when necessary,” said Clifford McDonald, MD, Associate Director for Science at CDC’s Division of Healthcare Quality Promotion. The Vital Signs report advises being aware of antibiotic resistance patterns in facilities, following recommendations for preventing infections, and prescribing antibiotics correctly (including reassessing and stopping appropriately). It also urges health care facility CEOs and administrators to establish a stewardship program and enroll their hospitals to submit data to the CDC’s Antimicrobial Use and Resistance Module to target improvements (www.cdc.gov/nhsn/acute-care-hospital/aur/index.html).

Along with the annual progress report, the CDC has released the Antibiotic Resistance Patient Safety Atlas (www.cdc.gov/hai/surveillance/ar-patient-safety-atlas.html), a new Web app with interactive data on HAIs. National, regional, and state maps show the percentage of resistance over time using data reported to the National Healthcare Safety Network by more than 4,000 health care facilities.

Source: Centers for Disease Control and Prevention, March 2016

With HCV Triple Therapy Comes Infection

Triple therapy with first-generation protease inhibitors may be a milestone in treatment for chronic hepatitis C virus (HCV) infection, but it comes with substantially increased rates of infection, especially in patients with advanced liver disease.

Researchers from Medical University of Graz, Austria, citing reports that link boceprevir (BOC) and telaprevir (TPV) to impaired neutrophil elastase activity in vitro, conducted a study to find out whether protease inhibitors were at the root of the infections.

Their study compared 152 patients with chronic HCV who were treated with peginterferon and ribavirin (P/R) with or without BOC and TPV with 33 healthy volunteers. In both retrospective and prospective cohorts, clinically relevant infections were significantly more common during protease inhibitor therapy: six retrospective patients (13%) developed infections while on P/R versus 19 (31%) on protease inhibitors. Similarly, 18% of the prospective patients on TPV and 33% of the BOC group developed clinically relevant infections, whereas none of the P/R patients did. Moreover, infections in the P/R patients led less often to hospitalization or treatment discontinuation.

Neutrophil phagocytosis dropped to 40% of baseline when protease inhibitors were added to P/R but recovered six months after treatment ended.

The researchers advise selecting patients for triple therapy carefully, especially focusing on other risk factors for infection, and then monitoring them closely during treatment.

Source: PLOS One, March 2016

Melanoma Treatment Elevates Serum Creatinine

Vemurafenib (Zelboraf, Hoffmann La Roche), used to treat advanced melanoma, has been shown to increase serum creatinine, but neither the prevalence nor the mechanism for the increase is known, say researchers from Assistance-Publique-Hôpitaux de Paris. Their study, though, suggests two mechanisms are at work.

In their retrospective study of 70 patients, they found 97% had an immediate—but stable—increase in creatinine after vemurafenib was started. At the first visit, one month after starting the drug, 68 patients had a significant increase in serum creatinine levels, with a median variation of 22.8%. However, in 44 of 52 patients who discontinued the drug (mostly because the melanoma had progressed), creatinine levels returned to baseline.

Serum cystatin C also rose, although less than serum creatinine, which the researchers say shows the creatinine increase was partly due to a renal function impairment. Moreover, renal explorations showed that vemurafenib led to inhibition of creatinine tubular secretion.

That dual mechanism of both inhibition of creatinine tubular secretion and slight renal function impairment, the researchers conclude, makes interpreting creatinine variations difficult. They offer a decision tree to help clinicians manage creatinine elevations due to the drug. They also suggest testing for serum creatinine and cystatin C before beginning the treatment and during monthly follow-ups.

But their data are actually reassuring, the researchers add: Apart from rare cases of serious adverse events, such as severe acute renal failure, an increase in serum creatinine below 50% and/or moderate signs of tubular dysfunction need not lead to stopping the treatment if it’s otherwise effective.

Source: PLOS One, March 2016