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Research Briefs October 2018

Obesity Extends Viral Shedding of Flu

Obesity not only makes flu more severe, it also lengthens the period of viral shedding for influenza A, according to a study by University of Michigan researchers, funded in part by the National Institute of Allergy and Infectious Diseases.

Over three flu seasons, the researchers monitored 1,783 people from 320 households in Managua, Nicaragua. During that time, 87 people became ill with influenza A and 58 with influenza B.

More than 40% of the adults were obese, as defined by body mass. Obese adults with two or more symptoms of influenza A (n = 62) shed the virus 42% longer than non-obese adults, or 5.2 days compared to 3.7 days. Obese adults with one or no symptoms of influenza A (n = 25) shed the virus 104% longer than non-obese adults—3.2 days compared to 1.6 days.

Obesity was not a risk factor for increased viral shedding duration in children ages 5–17 or for adults with influenza B.

The researchers suggest that that chronic inflammation caused by obesity may be responsible for the increased viral shedding. Reducing obesity rates could be an important target to limit the spread of viral infectious diseases, they suggest. Their findings may have particular significance in the United States, where in 2014, 35% of adults were obese, compared to 17.4% in Nicaragua.

Source: NIH, August 2018

Opioid Prescribing May Need a Behavioral ‘Nudge’

When clinicians find out one of their patients died from an overdose of a controlled substance, they’re more likely to reduce the number and dose of opioid drugs they prescribe, according to a study funded in part by the National Institute on Aging.

Between July 1, 2015 and June 30, 2016, San Diego County in California reported 222 deaths for which Schedule II, III or IV drugs were the primary or contributing cause. Of these, 170 deaths were listed in the Controlled Substance Utilization Review and Evaluation System (CURES) database.

In the study of 861 prescribing clinicians, 388 received a notification letter from the Chief Deputy Medical Examiner of San Diego County; 438 did not receive a letter. The letter identified the deceased patient by name, address and age. It also outlined the annual number and types of prescription drug deaths seen by the medical examiner, discussed how to access the state’s prescription drug monitoring program, and reviewed safe prescribing strategies.

Physicians who received the letter wrote 9.7% fewer opioid prescriptions in the three months following the intervention.

“Behavioral ‘nudges’ like these letters could be a tool to help curb the opioid epidemic,” said NIA Director Richard J. Hodes, MD. “This finding could be very useful in the effort to reduce inappropriate prescribing of opioids without severely restricting availability of legally prescribed opioids for patients who should be getting them.”

Source: NIH, August 2018

How is the Colorectal Cancer Control Program Doing?

The CDC developed the Colorectal Cancer Control Program (CRCCP) to provide direct colorectal cancer (CRC) screening services to low-income, uninsured, or underinsured populations known to have low CRC screening rates. However, early evaluators found the program was insufficient to detect an impact at the state level. In response to those findings, the CDC redesigned CRCCP and funded a new five-year grant period beginning in 2015. How did the program fare this time? CDC researchers say it “shows promise.”

The CRCCP funds 23 states, six universities, and one tribal organization to partner with health care systems, implementing evidence-based interventions (EBIs). In this study, the researchers analyzed data reported by 387 of 413 clinics of varying sizes, representing 3,438 providers, and serving a screening-eligible population of 722,925 patients.

The researchers say their evaluation suggests the CRCCP is working as intended: Program reach was measurable and “substantial,” clinics enhanced EBIs in place or implemented new ones, and the overall average screening rate rose.

At baseline, the screening rate was low (43%), and lowest in rural clinics—although evidence indicates that death rates for CRC are highest among people living in rural areas. In the first year, the overall screening rate increased by 4.4 percentage points, to 47.4%. Still, that number is much lower than the commonly cited 67.3% from the 2016 Behavioral Risk Factor Surveillance System, the researchers note. They add, though, that the results confirm that grantees are working with clinics serving the intended populations and indicate the significant gap in CRC screening rates between those reached by the CRCCP and the U.S. population overall.

Many clinics had at least one EBI or supporting activity (SA) already in place. Grantees used CRCCP resources to implement new EBIs or to enhance existing EBIs in 95% of the clinics, most often patient reminder activities and provider assessment and feedback. The majority of the clinics used CRCCP resources for SAs, such as small media and provider education. Only 12% of clinics used resources for supporting community health workers. However, nearly half of the clinics conducted planning activities for future implementation of community health workers and patient navigators.

Nearly 80% of the clinics reported having a CRC screening champion; 73% had a CRC screening policy; and 50% had either 3 or 4 EBIs in place at the end of the first year—all factors that the researchers suggest may support greater screening rate increases.

Source: CDC, August 2018

Number of Pregnant Women With Opioid Use Disorder Is on the Rise

The number of women with opioid use disorder (OUD) at the time of labor and delivery more than quadrupled between 1999 and 2014, according to a first-ever multi-state analysis of trends by the CDC.

Researchers found that the national prevalence rate of OUD rose from 1.5 per 1,000 delivery hospitalizations in 1999 to 6.5 in 2014. On average, the national prevalence rate grew by 0.39 cases per 1,000 each year.

The increases were significant and seen in all of the 28 states with at least three years of data available for analysis. The average increases were lowest in California and Hawaii, and highest in Maine, New Mexico, Vermont, and West Virginia.

OUD during pregnancy has been associated with a range of negative health outcomes, including maternal death, preterm birth, stillbirth, and neonatal abstinence syndrome (NAS).

The CDC’s recommended strategies include:

  • implementing universal substance use screening at the first prenatal visit
  • ensuring pregnant women with OUD have access to medication-assisted therapy and related addiction services
  • ensuring that mothers with OUD receive adequate patient-centered postpartum care, including mental health and substance use treatment, relapse-prevention programs, and family planning services

The CDC is also supporting state-based perinatal quality cooperatives, networks of teams working to better identify women with OUD during pregnancy and to standardize care for mothers and NAS-affected infants.

Source: CDC, August 2018

Disappointing Results For Cetuximab in HPV-Positive Oropharyngeal Cancer

Cetuximab plus radiation therapy had worse outcomes than the current standard of radiation and cisplatin for patients with human papillomavirus (HPV)-positive oropharyngeal cancer, according to data analysis from a recent study. In fact, the researchers, who reported preliminary findings from the phase 3 study, funded by the National Cancer Institute, were “surprised by the loss of tumor control with cetuximab.”

Cetuximab with radiation is an accepted standard of care, especially for patients who cannot tolerate cisplatin, and it is approved for patients with head and neck cancer, including oropharyngeal cancer. Researchers and NCI are looking for more ways to “de-escalate” therapies for cancers that have a good prognosis, such as HPV-positive cancer of the oropharynx. The goal of this trial was to find an alternative to cisplatin that would as effectively control the cancer but with fewer side effects.

The researchers enrolled 849 patients to randomly receive either cetuximab or cisplatin with radiation. The third, final interim analysis, after a median follow-up of 4.5 years, found that overall survival in the cetuximab arm was significantly inferior to the cisplatin arm. Moreover, serious adverse events were similar in both groups, although toxic side effects were more common in the cisplatin arm.

The study is the first randomized clinical trial specifically designed for patients with HPV-positive oropharyngeal cancer, and, researchers say, “it establishes cisplatin with radiation as the standard of care.”

Source: NIH, August 2018

Long-Awaited New Edition of the ‘Go-to’ Book on Diabetes

A “one-stop source” for crucial scientific information on diabetes and its complications, last published in 1995, is out now in its third edition.

It was written to serve as the “go-to book for anything you ever wanted to know about diabetes,” says Catherine Cowie, PhD, editor and senior advisor for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetes Epidemiology Program. “It’s a resource for everyone, because diabetes affects just about everyone.”

Written by recognized experts who “represent every facet of diabetes,” the book covers relevant research, data and trends, complications and related conditions, and prevention and medical care. It’s “rich in data,” the editor says, including cross-sectional national data, as well as smaller geographic community and longitudinal studies. This edition includes both published and unpublished data that were specifically analyzed for it.

Clinical trial data are summarized to show the strongest evidence available for the effectiveness of interventions, but the book also emphasizes “points of hope” found through research: For example, people at high risk can prevent or delay type 2 diabetes by losing a modest amount of weight, and rates of some complications, such as lower extremity amputations, are on the decline.

Cowie says Diabetes in America is designed to be useful to a variety of readers. Patients can use it to better understand their condition or risk factors; practitioners can use it to assess patients’ risk of diabetes and associated complications; health policy makers who need “sound quantitative knowledge” can use it to guide decision making; scientists can use it to help identify areas of needed research.

To download the book, visit: https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/diabetes-in-america-3rd-edition..

Source: NIH, August 2018

Virus Clusters Explain Disease Severity and Rapid Spread

Until just a few years ago, scientists believed that viruses acted alone. Then, in 2015, researchers showed that polioviruses could travel in groups—or “packets”—that is, membrane-bound (or “cloaked”) vesicles containing multiple virus particles. The researchers used the Trojan horse analogy to describe the phenomenon, but they couldn’t say whether it applied to both animals and humans, or how effective the “horses” were in infecting host cells.

To find out, they focused on rotaviruses and noroviruses, which are mainly spread through stool-contaminated food or liquids. And they found that, indeed, the viruses were shed as packet-enclosed clusters in the stool. Moreover, the virus clusters were significantly more infectious than the free, unbound viruses in the fecal samples that were tested.

The researchers say the high level of infectiousness is likely due to the vesicles delivering many viruses at once to the target tissue. The vesicles also protect their “viral cargo” from being destroyed by prolonged exposure to enzymes and may even make it invisible to the antibodies in the stool or gut.

The virus packets are not only extremely potent, but also aggressive. More studies are needed, along with more antiviral agents, the researchers say, but in the meantime, soap and water can help keep their numbers down.

Source: NIH, August 2018

Could an Antibiotic Be the Next Great Leukemia Drug?

An antibiotic drug used, among other things, to treat acne, may turn out to have potential well beyond that. Researchers from the University of Antioquia, Colombia, suggest that minocycline could be a promising anti-leukemic drug.

Minocycline is a well-established tetracycline derivative, used clinically since 1971, with a safe track record. But it also has non-antibiotic properties, exerting both antioxidant and anti-apoptotic effects. There is even “compelling” preclinical evidence, the researchers say, that minocycline induces apoptosis in an acute myeloid leukemia cell line and a chronic myeloid leukemia cell line. Could the same be true of acute lymphoblastic leukemia (ALL) cells? To test their hypothesis, the researchers examined minocycline’s mechanism of action in the Jurkat cell line, an “immortalized” ALL tumor line established in the 1970s from the peripheral blood of a 14-year-old boy.

The researchers found that minocycline did in fact induce apoptosis in Jurkat cells through an H2O2-mediated signaling pathway. Indeed, they add, H2O2 triggers a whole cascade of effects, including up-regulation of pro-apoptotic proteins. They suggest that minocycline might even be capable of generating H2O2, which could explain the cytotoxic effects not only of minocycline, but of other tetracycline analogues. “Interestingly,” the researchers say, minocycline did all that without inducing oxidative stress or apoptosis markers in human peripheral blood lymphocyte cells.

The significance of their study is twofold, the researchers say: First, that minocycline is a safe and specific apoptosis-inducing drug against Jurkat cells in vitro; second, that it’s pharmacologically well characterized and widely available.

They note that no information is available on whether minocycline might efficiently kill ALL cells in vivo. However, they also note that minocycline has been found to be safe and well tolerated in doses up to 10 mg/kg in stroke patients—a dose that could be a sufficient concentration to reduce the viability of leukemia cell lines.

Source: Toxicology In Vitro, April 2018

Etravirine Lowers Risk of Hospitalization for HIV Patients

When all three original classes of antiretroviral drugs no longer suppress viral load in a patient with HIV, the next step may be a new drug like etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor (NNRTI). And, according to a French study, that could be a good way of keeping patients out of the hospital.

Using data from the French Hospital Database on HIV (FHDH), researchers analyzed hospitalization rates among heavily treated HIV-1–infected patients on failing regimens between 2005 (etravirine became available in France in 2006) and 2011. They compared two groups of patients: those who had received ETR plus a ritonavir-boosted protease inhibitor (PI) and those who had not. The primary endpoint of the study was hospitalization, divided by AIDS-defining cause and non–AIDS-defining cause.

Of 3,884 patients who had been exposed to at least two nucleoside reverse transcriptase inhibitors (NRTIs), two protease inhibitors (PIs), and one NNRTI, 838 received ETR + PI.

During 13,986 person-years of follow-up, there were 2,484 hospitalizations among 956 patients: 617 were from an AIDS-defining cause in 301 patients, and 1,867 from a non–AIDS-defining cause in 828 patients.

ETR + PI was associated with a 20% reduction in the hospitalization rate, mainly due to the reduction in AIDS hospitalizations. The researchers suggest that the clinical benefit of ETR could be explained by a high rate of virologic suppression (62% at month 6) and excellent tolerability. The FHDH did not include adherence data, but adherence is unlikely to explain the better outcome, the researchers say, given that ETR is a twice-daily drug, which may lead to slightly lower adherence than a once-daily regimen.

Theirs is the first study, to their knowledge, the researchers say, to focus on the risk of hospitalizations in current clinical practice and to show a positive effect.

Source: BMC Infectious Diseases, 2018

HIV, HBV, and HCV Increase Risks After Joint Replacement

As patients with HIV, hepatitis B, and hepatitis C live longer, more active lives with the help of antiviral treatments, they’re now more often having joint replacement surgeries. But HIV, HBV, and HCV can increase the risk of postoperative complications, say researchers from Duke University.

They studied 16,338 patients in four cohorts: those with HIV, HBV, HCV, and HIV plus HBV or HCV. They evaluated the patients at 30 days, 90 days, and two years after total joint arthroplasty (TJA), comparing their progress with that of a control group.

Patients with HBV and HCV were at risk of both acute and long-term medical and surgical complications. At 90 days and two years, they had an increased risk of pneumonia, sepsis, joint infection, and the need for revision surgery. They also had a greater risk of complications than HIV patients, especially for infection, within the first 90 days post-surgery.

Notably, after TJA, patients with HCV had an increased risk of acute kidney injury, sepsis, and transfusion at 30 and 90 days. After hip replacement, patients with HBV had a higher risk of acute kidney injury, pneumonia, and transfusion at 30 and 90 days.

Patients with HIV were at greater risk for deep vein thrombosis and transfusion, rather than infection, following total hip arthroplasty. The lower incidence of infection is likely to be related to effective highly active anti-retroviral therapy (HAART), the researchers say. HIV patients were also more likely to have mechanical complications such as loosening, periprosthetic fracture and revision at 90 days, but not at two years. Patients with HIV who underwent total knee arthroplasty had a higher risk of death at 30 days, and medical complications at 90 days. At two years, they had a higher risk of periprosthetic joint infection, irrigation and debridement, and revision. The researchers say the higher incidence of mechanical complications can be explained by the younger, more active, and healthy HIV patients in the cohort—the majority were younger than 65. They also emphasize that the only risk of infection following TJA in their study was two years after total knee arthroplasty (TKA).

The researchers suggest that their findings could help prompt future guidelines supporting routine screening prior to elective TJA.

Source: Journal of Arthroplasty, 2018

A Safe Treatment Switch for Patients With Hormone-Sensitive Prostate Cancer

Degarelix was developed as a novel gonadotropin-releasing hormone (GnRH) antagonist, with the aim of counteracting the testosterone surge often experienced with GnRH agonists. Degarelix blocks the GnRH receptors in the pituitary gland, rapidly reducing testosterone production, but the effects only last for a month. So it’s common practice to switch from degarelix to a GnRH agonist once the testosterone levels are down and stable. Safe and effective for the short term, but what about the long term?

Researchers from Osaka City University and Bell Land General Hospital, Osaka, evaluated five-year survival and time to castration-resistant prostate cancer (CRPC) in 108 patients with prostate cancer treated with degarelix. In the study, 57 patients were switched from degarelix to a GnRH agonist; 51 continued on degarelix.

Overall five-year survival was high (89%) but statistically superior in the changed group (97% vs. 74%). The five-year cancer-specific survival was also longer in the changed group (100% vs. 85%). Average time to CRPC was comparable in both groups (43 months in the changed group, 35 months in the continued group). The CRPC conversion did not reach the median at the time of data analysis. The median percentage decrease in prostate-specific antigen (PSA) level for all patients treated with degarelix was 99.7%. The lowered levels were maintained even after switching to GnRH agonists.

The researchers say theirs is the first report of long-term data on degarelix, and the first study to report that changing the treatment from a GnRH antagonist to a GnRH agonist did not affect the oncological outcomes in patients with hormone-sensitive prostate cancer.

Source: Basic and Clinical Andrology, 2018