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Research Briefs April 2019

A New Way to Measure How HIV Drugs Are Working

One of the tricky aspects of HIV drug therapy is determining just how well the drugs have worked. The HIV DNA (provirus) in resting cells is usually too defective to replicate itself the way intact proviruses can. But most current tests can’t tell the difference between the two. Now, however, researchers from Johns Hopkins University have developed an accurate and scalable assay to easily count the cells in the HIV reservoir.

A stable, latent reservoir for HIV-1 in resting CD4+ T-cells is “the principle barrier to a cure,” the researchers say. Quantitative outgrowth assays and assays for cells that produce viral RNA after T-cell activation may underestimate the reservoir size because one round of activation does not induce all proviruses. Many studies, the researchers say, rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of those assays is unclear, as the vast majority of proviruses are defective.

In their study, supported by the National Institute of Allergy and Infectious Diseases, the researchers analyzed DNA sequences from more than 400 HIV proviruses from 28 people with HIV. They mapped two types of flaws: deletions and lethal mutations. They then developed strategically placed “genetic probes” that could distinguish between deleted or highly mutated proviruses and intact ones. Finally, they developed a nanotechnology-based method to analyze one provirus at a time to determine how many in a sample are intact.

The researchers say their findings show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. Their hope is that their method will speed HIV research by allowing scientists to easily quantify the number of proviruses in an individual that must be eliminated to achieve a cure.

Source: Nature., January 30, 2019

Survey Suggests Many People Take Vitamins Unnecessarily

Four of five American adults are taking vitamins or supplements— although only 24% have a confirmed nutritional deficiency, according to a Harris poll.

The survey was conducted on behalf of the American Osteopathic Association. Of 2,001 respondents, 1,749 said they took vitamins or supplements. When asked how they decided what to take, half said they followed physician recommendations. The next top sources were their own research (39%) and recommendations from friends or family (22%). Another 13% chose based on what items interested them in stores and 13% followed recommendations from a trainer, exercise professional, or nutritionist. (Experts from the nutrition field took exception to some of the data, saying the numbers of people taking supplements was higher than that seen in other surveys.)

Six percent of the respondents said they based their choices on endorsements by celebrities or social media influencers.

Most people are wasting their money, said Mike Varshavski, DO, an osteopathic family physician speaking about the survey. People with a documented nutritional deficiency can often correct the problem through their natural diet, he noted, and suggests that the money spent on supplements could be better used to add high-nutrition foods to their diets. He also cautions that some supplements may render common medications such as warfarin, insulin, and alprazolam less effective.

“Obviously, there is a great need for real education on this topic, even among health care professionals,” Varshavski says. When patients insist on buying supplements, he encourages them to choose vitamins that carry a seal of approval or certification by a trusted independent organization so they can at least be assured of getting the correct ingredients in the correct amounts.

He also says consumers should be advised to avoid trends, such as vaping supplements, until the research is conclusive, and to be skeptical of gummy vitamins, which are “basically sugar tablets.”

Source: The DO., January 30, 2019

Intensive Blood Pressure Control Reduces Mild Cognitive Impairment

Intensive blood pressure control has not yet been shown to significantly reduce the risk of dementia, but it does have a measurable impact on mild cognitive impairment—a well-established precursor of dementia, according to results from the landmark Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition in Decreased Hypertension (SPRINT MIND).

SPRINT, which investigated the effects of intensive control on cardiovascular and renal disease in more than 9,000 patients, found that a systolic blood pressure target of < 120 mm Hg, compared to the standard target of < 140 mm Hg, reduced both cardiovascular events and overall mortality. SPRINT was intended to last five years but was stopped after three because of treatment success.

SPRINT MIND investigators were interested in whether intensive control would reduce the risks of dementia and cognitive impairment. Although the main trial ended early, assessment continued for the planned five years.

Participants in SPRINT MIND were classified as having no cognitive impairment, MCI, or probable dementia. The primary results of the analysis showed no statistically significant difference between standard and intensive treatment in the proportion of participants diagnosed with dementia. Surprisingly, the researchers say, fewer patients than expected had dementia.

The NIH says the study adds further support and “nuanced evidence” to the link between vascular health and the brain. The shorter study time and unexpectedly fewer cases of dementia may have made it difficult to determine the role of intensive blood pressure control on dementia. However, Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the National Institute of Aging Division of Neuroscience says, “The fact that there was still an MCI result when the study was cut short makes these results encouraging.”

Source: National Institutes of Health., January 28, 2019

Middle-aged Women: Underrecognized Risk For Drug Overdose Deaths

The numbers are stunning: a 1,643% increase in rates of deaths involving synthetic opioids; a 915% increase for heroin, and an 830% increase for benzodiazepines.

Even more stunning: those are only the increases in overdose death rates for women aged 30 to 64 years.

According to Centers for Disease Control and Prevention (CDC) data, between 1999 and 2010 the largest percentage change in the rates of overall drug overdose deaths was among women between the ages of 45 and 64 years. But that research did not take into account trends in specific drugs or consider changes in age group distributions, say researchers from the CDC’s National Center for Injury Prevention and Control.

They examined overdose death rates among women aged 30 to 64 years during 1999 and 2017. The unadjusted death rate jumped 260%, from 4,314 deaths to 18,110. Among women aged 55 to 59 years, the number of deaths involving antidepressants increased by approximately 300%; among women aged 60 to 64 years, the increase was almost 400%. The crude rate of deaths involving prescription opioids skyrocketed by more than 1,000%.

The drug epidemic is evolving, the researchers note. In 1999, overdose death rates were highest among women 40 to 44 years old. In 2017, they were highest among women aged 50 to 54 years. And as demographics shift, prevention programs need to shift as well. As women age, individual experiences can change the type of substance used or misused; and concerning pain experiences that may result in an opioid prescription.

The researchers observed that “substantial work” has focused on informing women of childbearing age about the risks and benefits of certain drugs. The current analysis demonstrates the remaining need to consider middle-aged women who are at risk.

Targeted efforts are needed. The researchers suggest interventions: Medicaid and other health insurance programs can review records of controlled substance prescribing, and states and local communities can expand their drug-use disorder treatments and links to care, particularly by adding “genderresponsive” substance-use disorder treatment centers.

A “multifaceted approach involving the full spectrum of care services is likely necessary,” the researchers say. Health care practitioners who treat women for pain, depression, or anxiety can discuss treatment options that consider the unique biopsychosocial needs of women.

Practitioners can also consider implementing the CDC’s Guideline for Prescribing Opioids for Chronic Pain, which states that “Opioids are not first-line or routine therapy for chronic pain.” The guideline also says that before starting and periodically during opioid therapy, clinicians should discuss with patients the “known risks and realistic benefits of opioid therapy.”

In other words, listen to the women and prescribe carefully.

Source: Morbidity and Mortality Weekly Report., January 11, 2019

African American Smokers May Have Higher Risk of PAD

Even though peripheral artery disease (PAD) is almost three times more prevalent among African Americans compared with whites, it’s understudied, say researchers from the University of Mississippi. They claim that earlier studies didn’t include significant numbers of African Americans, limiting the ability to single out the effects of smoking in African Americans as distinct from, for example, diabetes, hypertension, and obesity.

This National Institutes of Health (NIH)-funded study, however, provides some new information about what raises the risks of PAD in blacks. The researchers studied participants in the Jackson Heart Study, the largest single-site cohort study investigating cardiovascular disease in African Americans.

They divided 5,258 participants into three groups: smokers, past smokers, and never-smokers. After taking other risk factors into account, they found that people who smoked more than one pack a day had a significantly higher risk than did those who smoked fewer than 19 cigarettes a day. A longer history of smoking also raised the risk of PAD.

Their findings point to the benefits of stopping smoking, the researchers say: Although never- smokers had the lowest risk, past smokers also had lower odds.

However, the researchers caution that despite strong associations between smoking and PAD, their findings do not establish a causal link.

Source: National Institutes of Health., January 23, 2019

PTSD and Emotional Eating

Nearly 80% of veterans are overweight or obese. According to researchers from Walter Reed Army Medical Center and Yale University, obesity is more common among veterans with post-traumatic stress disorder (PTSD) compared to other veterans in the Veterans Health Administration (47% vs. 41%). Moreover, they say, veterans with PTSD lose less weight during treatment than do those without comorbid mental health conditions. PTSD has also been associated with night eating, food addiction, binge eating, and eating as a coping strategy. In a national survey, veterans who self-reported a diagnosis of PTSD were more likely to endorse eating because of emotions or stress.

The researchers conducted a study of 120 veterans who had been referred to the MOVE! Weight management program at VA Connecticut Healthcare System. Although the study replicates and extends findings from other studies, they believe theirs is the first to examine emotional eating among veterans seeking treatment for obesity.

The veterans were given the Yale Emotional Overeating Questionnaire (YEOQ), which assesses how often the respondent has eaten an unusually large amount of food in response to anxiety, sadness, loneliness, tiredness, anger, happiness, boredom, guilt, and physical pain. The researchers also used the Primary Care PTSD Screen to test for PTSD.

A positive PTSD screen was associated with significantly higher scores on the YEOQ overall, as well as higher scores on each individual item. Higher scores on the PTSD screen were also associated with more frequent emotional eating for all emotions.

The researchers note that findings about the predictive validity of emotional eating questionnaires have been mixed. Although emotions may influence eating patterns, they say, there could be other mechanisms at work, such as a general concern about, or a lack of control over, eating.

However, they suggest that veterans with PTSD may need specific attention to be given to alternative coping strategies when they are facing difficult emotions as part of weight-loss treatment.

Source: Eating Behaviors., December 2018

Science Has Spoken: Undetectable Equals Untransmittable

The consensus is in: U = U.

That is, scientific experts are finally willing to say that the concept of “Undetectable is Untransmittable” for HIV treatment is now “firmly established.” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), wrote in the Journal of the American Medical Association (JAMA) that an “overwhelming” body of clinical evidence provides a firm basis for accepting the concept as scientifically sound.

In the JAMA commentary, Fauci and colleagues review the results from clinical trials validating U = U. One landmark study, for instance, showed that no linked HIV transmissions occurred among HIV serodifferent heterosexual couples when the partner living with HIV had a durably suppressed viral load. Subsequent studies confirmed the findings and extended them to male–male couples.

The key, the experts all agree, is to be absolutely adherent to antiretroviral therapy (ART). Viral suppression measured at six months after starting therapy is required for U = U. Stopping ART represents a “significant challenge” to the successful implementation of U = U. According to the clinical trials, when ART is stopped, viral rebound usually occurs within two to three weeks. In two studies, stopping ART caused viral rebound to levels that would have been associated with an increased risk of HIV transmission.

The NIH experts say this consensus has a variety of implications. It provides an incentive to people living with HIV to start and adhere to treatment, removes the sense of fear and guilt they may have about harming others, and reduces the risk of legal penalties arising from putting virus-free partners at risk. And because “prevention as control” is a critical tool, the U = U concept can support worldwide efforts to control—or even eliminate—the pandemic.

Source: National Institutes of Health., January 10, 2019

Proximity to Muscle Cells May Lead to Prostate Cancer Spread

Prostate cancer cells may be more likely to spread if they’re near muscle cells, according to an early study by NIH researchers led by Berna Uygur, PhD, of the National Institute of Child Health and Human Development, with colleagues from the National Eye Institute and the Maine Medical Center Research Institute.

Interactions with non-malignant cells within the tumor microenvironment play an important role in cancer progression, but those interactions are poorly understood, the researchers say. Thus, they designed their study to test the relation between human prostate cancer cells and human muscle cells and discovered a “novel and specific pathway” in which muscle cells promote cell fusion and cancer progression.

They found that co-culturing prostate cancer cells with skeletal or smooth muscle cells expands the subpopulations of cancer cells with features that are “characteristic of cancer stem-like cells,” including anchorage-independent growth, elevated CD133 expression, and drug resistance.

In the laboratory tests, the human muscle cells were “stand-ins” for the smooth muscle surrounding the prostate gland and the striated muscle of the urethral sphincter. The muscle cells secreted interleukins 4 and 13, which stimulated the prostate cancer cells to produce two other proteins, syncytin 1 and annexin A5, causing the cancer cells to fuse. Further testing revealed that the fused cells developed characteristics of more malignant cells.

Because expression of syncytin 1 and annexin A5 positively correlated with cancer development, the researchers suggest that these proteins might be used as biomarkers to evaluate cancer progression and potential therapeutic targets.

Source: Molecular Cancer Research., December 26, 2018

Loan Repayment Plan for Substance Use Clinicians

The opioid emergency, says George Sigounas, MS, PhD, administrator at the Health Resources and Services Administration (HRSA), claims more than 130 lives every day. By strengthening the health workforce, HRSA aims to ensure that there are enough clinicians to cope with the growing epidemic.

That’s why, in December 2018, HRSA launched a program that Sigounas says is “critical to HHS’ response to the opioid crisis.” The new National Health Service Corps (NHSC) Substance Use Disorder (SUD) Workforce Loan Repayment Program (LRP) will provide eligible health care clinicians with student loan repayment assistance in exchange for service in underserved communities.

A clinician may be awarded up to $75,000 for three years of full-time service at an NHSC-approved substance use disorder site or $37,500 for part-time service. Eligible providers use evidence-based treatment models to treat substance use disorders and must be trained and licensed to provide SUD treatment at NHSC-approved facilities. Qualification criteria are available at https://nhsc.hrsa.gov/loan-repayment/nhscsud-workforce-loan-repayment-program.html..

Clinicians can also apply to the NHSC Loan Repayment Program for primary care, dental, and behavioral health professionals. If accepted, they may receive up to $50,000 for two years of full-time service, or $25,000 for part-time service.

Military reservists are also eligible to participate in either the NHSC LRP or the NHSC Students to Service Loan Repayment Program. (Military training or service will not satisfy the NHSC service commitment.) More information is available at https://nhsc.hrsa.gov/loan-repayment/military-reservists.html..

Clinicians can apply for only one program.

Source: Health Resources & Service Administration., February 25, 2019

Testing the Effectiveness of CBT Phone Sessions for Chronic Pain After TBI

Chronic pain—pain that lasts beyond the point of healing and for at least three months—is extremely common among veterans, with estimated rates as high as 81.5%. It is particularly prevalent among veterans who have traumatic brain injury (TBI) and is often accompanied by comorbid conditions. Almost 90% of veterans with a history of TBI have a psychiatric diagnosis, some 75% have insomnia, and 70% have a pain diagnosis, say researchers from the University of Washington.

Cognitive behavioral therapy (CBT) has been shown to help reduce pain, and pain-related disability and distress, but no randomized controlled trials have examined the efficacy of CBT for pain after TBI in veterans, say the researchers.

Therefore, they have designed a randomized, controlled trial that compares phone-based CBT with phone-delivered pain education for veterans who have TBI and chronic pain. The single-center two-group trial will enroll up to 160 veterans with TBI to examine the relative efficacy of the interventions on average pain intensity, pain interference, sleep, depression, and life satisfaction.

Participants will be drawn from the VA Puget Sound Health Care System, and can be enrolled via clinician referral, medical record review, and self-referral. The outcome variables will be collected pre-, mid-, and post-treatment, and six months following randomization.

Both the interventions will consist of eight hour-long phone sessions over a period of approximately 8 to 12 weeks. The interventions will also use a participant treatment workbook, with session-specific content to be discussed during the telephone sessions and audio recordings to augment the material covered. Clinicians will make brief “booster” calls at two, six, and 10 weeks after the final treatment session.

The trial is innovative, the researchers say, as it is tailored to veterans, through relatable examples, and to those with TBI, by reducing content and providing multiple ways of engaging with information, as well as using known strategies for helping with recall. If effective, the intervention could be disseminated throughout the VHA system, potentially to other personnel who have difficulty accessing specialty pain care.

The trial is registered at ClinicalTrials.gov., protocol NCT01768650.

Source: MDedge., February 13, 2019

After 12 Years, HIV Reportedly Cured In a Second Patient

For the second time since the global epidemic began, a patient appears to have been cured of infection with human immunodeficiency virus (HIV), the virus that causes AIDS. Publicly, scientists are describing the case of the anonymous “London patient,” as he is known, as a long-term remission. Most experts are calling it a cure, with the caveat that it is hard to know how to define the word when there are only two known successful cases.

The news comes nearly 12 years to the day after the announcement about the first patient (known as “the Berlin patient”) known to be cured, a feat that researchers have long tried, and failed, to duplicate. Both milestones resulted from bone-marrow transplants given to infected patients. But the transplants were intended to treat cancer in the patients, not HIV.

Bone-marrow transplantation is unlikely to be a realistic treatment option in the near future. Powerful drugs are now available to control HIV infection, while the transplants are risky, with harsh side effects that can last for years. However, equipping the body with immune cells similarly modified to resist HIV might well succeed as a practical treatment, experts said.

The investigators’ report will be published in the journal Nature and they will present some of the details of their findings at the Conference on Retroviruses and Opportunistic Infections in Seattle.

Source: The New York Times, March 4, 2019