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Study reveals how HIV infection may contribute to metabolic conditions

Baker Institute scientists showed that the HIV protein, Nef, released from infected cells in specialized vesicles, is taken up by uninfected ‘bystander’ cells, impairing cholesterol metabolism in these cells. This impairment triggers inflammation, contributing to the development of diseases including dementia, heart disease and diabetes.

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A single viral factor released from HIV-infected cells may wreak havoc on the body and lead to the development of chronic and potentially deadly diseases like heart disease, diabetes and dementia, according to a new study by scientists at the Baker Heart and Diabetes Institute in Melbourne.

By explaining the mechanisms, it paves the way for targeted treatment that could help provide a longer and healthier life for the 36 million people globally living with HIV/AIDS.

The treatment of HIV/AIDS is so advanced that today life expectancy of people living with HIV is very similar to that of uninfected persons. However, people with HIV may experience co-morbidities like heart disease, diabetes, dementia or related complications. Studies show that not only are people living with HIV at increased risk of these chronic diseases, they are occurring at an earlier age and progress faster.

These co-morbidities persist even after successful application of antiretroviral therapy, when no virus is found in the blood. Scientists have been intrigued as to what is going on in the small number of infected cells, believing that HIV-infected cells instead of the virus release a toxic substance that kills cells around them.

Most co-morbidities of HIV infection share a common element in their pathogenesis, impairment of cholesterol metabolism but exactly how and what was happening remained a mystery. But in this new study published in PLOS Pathogens, Baker Institute scientists have been able to pinpoint the mechanisms involved.

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Baker Institute scientists showed that the HIV protein, Nef, released from infected cells in specialized vesicles, is taken up by uninfected ‘bystander’ cells, impairing cholesterol metabolism in these cells.

This impairment triggers inflammation, contributing to the development of diseases including dementia, heart disease and diabetes.

Head of Lipoproteins and Atherosclerosis at the Baker Institute, Professor Dmitri Sviridov says the study demonstrates how a single viral molecule released from infected cells into circulation may contribute to a range of pathogenic responses.

“The good news is that there are many drugs on the market and in development to tackle impaired cholesterol metabolism which could be repurposed for this specific population to effectively treat these diseases,” says Professor Sviridov.

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Repeated semen exposure may help prevent HIV infection in women, says study

But semen-treated animals that remained uninfected after exposure to low viral amount became infected when subsequently challenged with high doses of virus, confirming that they were still susceptible to infection and that repeated semen exposure provides only partial protection and does not block HIV infection.

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Semen exposure CAN promote host resistance but DOES NOT protect against infection.

This is according to scientists at The Wistar Institute and the University of Puerto Rico, who found that frequent and sustained semen exposure can change the characteristics of the circulating and vaginal tissue immune cells that are targets for infection, reducing the susceptibility to a future infection. This goes contrary to the long-held view that semen can only act as a way to transmit HIV-1 from men to women.

This finding, published in the journal Nature Communications, also provides a potential explanation as to why a small number of female sex workers worldwide continue to test negative for infection despite continuous high-risk sexual activity.

Research previously reported by the laboratory of Luis J. Montaner, D.V.M., D.Phil., the Herbert Kean, M.D., Family Professor and director of the HIV-1 Immunopathogenesis Laboratory at Wistar’s Vaccine & Immunotherapy Center, together with investigators at the University of Puerto Rico, showed in a 2015 paper how continued semen exposure in female sex workers resulted in changes in the cervicovaginal tissue that predicted an increased resistance to HIV infection. The current study directly addressed if semen could be a factor in resistance.

“While HIV infection has been with us for more than 30 years, this is the first study that describes how semen exposure over time could result in local tissue changes that limit HIV infection in humans,” said Montaner, lead author of the new study. “Apart from defining a new factor that may regulate HIV transmission, this unexpected finding could directly impact the design of future HIV vaccine studies that commonly recruit female sex workers. Currently, condomless sex is assumed to only promote the likelihood of infection. Our observation, however, raises the hypothesis that frequent semen exposure may potentially reduce HIV transmission.”

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According to Edmundo N. Kraiselburd, Ph.D., professor at the University of Puerto Rico (UPR), “this research clearly shows the valuable information the macaque model can provide when used to study what may determine HIV infections in humans.”

Kraiselburd co-directed this research project and supervised the use of non-human primates (NHP) from the Caribbean Primate Research Center. NHPs are a principal pre-clinical research model used to test prophylactic anti-HIV interventions. 

In the study, animals were exposed to semen twice a week over 20 weeks with or without inactivated particles of the simian immunodeficiency virus (SIV is an HIV-like virus that infects primates and causes a disease similar to AIDS). After this conditioning period, the animals received low-dose intravaginal SIV challenges. 

Semen-exposed animals showed a 42% decrease in the risk of infection. Scientists analyzed specific markers of immune activation in the cervicovaginal microenvironment and in the bloodstream. On circulating CD4+ cells, semen conditioning was associated with lower expression of the CCR5 receptor, which acts as a binding site for HIV to enter its host cells, supporting the observation of a lower susceptibility to SIV vaginal challenge. Furthermore, semen-conditioned animals had higher levels of the CCL5 cytokine, a natural HIV-suppressive factor, in the cervicovaginal compartment in response to SIV challenge. 

Repeated semen exposure also resulted in elevated cervicovaginal tissue levels of antiviral factors such as MX1, which also positively correlated with levels of IFN-epsilon. IFN-epsilon, which can be induced by semen and protects human cells from bacterial and viral pathogens, has direct anti-HIV properties and was described to be induced in tissues from sex workers in association with sex without condoms.  

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Nonetheless, semen-treated animals that remained uninfected after exposure to low viral amount became infected when subsequently given with high doses of virus. This confirms that they were still susceptible to infection, stressing that repeated semen exposure provides only partial protection and does not block HIV infection.

“Importantly, we show that semen exposure can promote host resistance but does not protect against infection,” said Montaner. “Therefore, our data do not change the fact that prevention methods, such as condom use and PrEP (pre-exposure prophylaxis) remain our best strategies to prevent infection.” 

Co-authors of the study included: first author Shaheed Abdulhaqq, Jocelin Joseph, Livio Azzoni, Xiangfan Yin, Megan Wise, David Weiner, and Qin Liu from Wistar; Melween Martinez, Idia V. Rodriguez, Stephanie M. Nichols, Carlos Sariol, and Edmundo N. Kraiselburd from University of Puerto Rico; Guobin Kang and Qingsheng Li from University of Nebraska; David Beaumont and Georgia D. Tomaras from Duke University; Andrea Foulkes from Mount Holyoke College, South Hadley, MA; Jan Münch and Frank Kirchhoff from Ulm University, Germany; Christos Coutifaris from University of Pennsylvania; and Preston A. Marx from Tulane University.

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HIV spreads through direct cell-to-cell contact

Despite over 30 years of research, many key aspects of how HIV, the causative agent of the acquired immune deficiency syndrome (AIDS) spreads are still not understood. One of these unresolved questions concerns the interactions between the virus with the environment in the human body.

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Microscopic recording and computer model of the interaction between infected cells (green) and non-infected cells (red) in collagen structures (grey). Credit: Oliver Fackler/Frederik Graw

The spread of pathogens like the human immunodeficiency virus (HIV) is often studied in a test tube, i.e. in two-dimensional cell cultures, even though it hardly reflects the much more complex conditions in the human body. Using cell culture systems, quantitative image analysis, and computer simulations, an interdisciplinary team of scientists from Heidelberg University has now explored how HIV spreads in three-dimensional tissue-like environments. The researchers’ results show that the tissue structure forces the virus to spread through direct cell-to-cell contact.

Despite over 30 years of research, many key aspects of how HIV, the causative agent of the acquired immune deficiency syndrome (AIDS) spreads are still not understood. One of these unresolved questions concerns the interactions between the virus with the environment in the human body.

Traditionally it has been assumed that infected cells release viral particles which then diffuse and eventually infect other cells. But it is also possible that viral particles are directly transferred from one infected cell to the next through close contact. Until now it was unknown which of these modes of transmission prevailed in tissue.

“Studies on HIV replication in the lab are mostly conducted in simple cell culture experiments in plastic dishes that do not reflect the complex architecture and heterogeneity of tissue”, explains study director Prof./Dr. Oliver Fackler of the Center for Integrative Infectious Disease Research (CIID) at Heidelberg University Hospital.

In their approach, the Heidelberg researchers took into account that the so-called CD4 T helper cells, the preferred cell type infected by HIV, are highly motile in their physiological environment. They used a novel cell culture system, in which a three-dimensional scaffold was generated with the help of collagen. This allowed for maintaining the cells’ mobility and monitoring primary CD4 T cells infected with HIV-1 in a tissue-like environment over the course of several weeks. Using this approach, the researchers measured a number of factors that characterize cell motility, virus replication, and the gradual loss of CD4 T helper cells.

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“This yielded a very complex set of data that was impossible to interpret without the help from scientists of other disciplines,” explains Dr. Andrea Imle, who worked on the project during her PhD at the CIID.

In analyzing the data, the scientists who conducted the experiments collaborated with colleagues from the fields of image processing, theoretical biophysics and mathematical modeling. Together they were able to characterize the complex behavior of cells and viruses and simulate it on the computer. This made it possible to make important predictions on the key processes that determine HIV-1 spread in these 3D cultures, which were confirmed by subsequent experimentation. “Our interdisciplinary study is a good example of how iterative cycles of experimentation and simulation can help to quantitatively analyze a complex biological process,” states Prof./Dr. Ulrich Schwarz of the Institute for Theoretical Physics at Heidelberg University.

The data analysis revealed that the 3D environment of the cell culture system suppresses infection with a cell-free virus while simultaneously promoting direct virus transmission from cell to cell. “Our models allowed us to integrate short single-cell microscopy films with long-term cell population measurements and thereby to estimate the minimal time span required for cell-to-cell contacts to transmit infection,” explains Dr. Frederik Graw of the BioQuant Centre of Heidelberg University. The researchers hope that these findings will eventually lead to new therapeutic approaches in the treatment of HIV.

The research was conducted within the Collaborative Research Centre, “Integrative Analysis of Pathogen Replication and Spread”, (CRC 1129) funded by the German Research Foundation and supported by the Center for Modelling and Simulation in the Biosciences (BIOMS) of Heidelberg University. The results were published in Nature Communications.

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Holes in the immune system left unrepaired despite HIV drug therapy

A study showed that ART leaves unrepaired holes in the immune system’s wall of defence. This suggests that some of these long-lasting defects may contribute to the lack of viral control once the antiretroviral therapy is interrupted.

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If they don’t receive antiretroviral therapy (ART), most HIV patients see a progressive weakening of their immune system. But a very small percentage of patients–0.3%–spontaneously control the virus themselves, without ART. Could an explanation lay partly in the sets of genes expressed by scarce white blood cells that recognize HIV? Yes, according to a study published in Nature Immunology and conducted by researchers at the University of Montreal Hospital Research Centre (CRCHUM).

Critical for the coordination of immune responses, CD4 T cells are important white blood cells (lymphocytes) that help control chronic infections like HIV. But on average only about one cell in 1,000 in the CD4 T cell population can recognize the virus.

“With my research team and my collaborators, we comprehensively determined the entire set of genes expressed by these rare cells from the blood of people chronically infected with HIV in whom the virus was abundant prior to ART,” said Daniel Kaufmann, a CRCHUM researcher and an infectious disease specialist. “We then compared it to the cells of HIV controllers, infected people who control the virus in the absence of therapy. This type of powerful approach, also called genome-wide transcriptional profiling, measures the activity of thousands of genes at once, thus creating a global picture of cellular function.”

Using sophisticated cell analysis techniques, lead author Antigoni Morou, a postdoctoral fellow in Kaufmann’s lab, identified major functional differences between the two groups of patients in the study. The HIV controllers had much more robust immune responses, known as Th17 and Th22, which are important for the defense of the gastrointestinal tract, for example. But chronically infected patients with high levels of viral replication showed dysregulated CD4 T cells targeting HIV, and some of their cell subsets showed signs of abnormal functioning.

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Continuing their investigation, the CRCHUM scientists wondered whether ART leads to an immune response akin to the one found in HIV controllers. “We followed up chronically infected patients after control of the virus by ART and checked if the treatment can ‘repair their immune system’ and allow them to have CD4 T cells with features similar to those of the HIV controllers,” said Kaufmann, a professor at Université de Montréal.

The result was double-edged: some gene modules were sensitive to ART, while others turned out to be expressed very differently than in HIV controllers.

“We showed that ART leaves unrepaired holes in the immune system’s wall of defence,” said Kaufmann. “Our results suggest that some of these long-lasting defects may contribute to the lack of viral control once the antiretroviral therapy is interrupted. We now know which holes linger in the immune system. Do we have to fill them in, and if so, how? This is another science question.”

Paving the way to new therapies that could complement ART, Kaufmann’s team identified important features of an effective HIV specific immune response compared to a dysfunctional one and showed how the response can be affected by ART.

The next step will be to study the underlying programming of these CD4 T cells (epigenetics) in the hope of developing new targeted strategies to reverse immune dysfunction and complement ART. Kaufmann’s lab is now using the same approach to evaluate candidates for an HIV vaccine.

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In 2017, nearly 37 million people were living with HIV. Every day, 5,000 new infections are reported to health authorities around the world.

“Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease” by Antigoni Morou et al. was published July 15, 2019 in Nature Immunology. The research was funded by the US National Institutes of Health; the Canadian Institutes of Health Research; the AIDS and Infectious Diseases Network of the Fonds de Recherche du Québec-Santé; and a Canada Foundation for Innovation Program Leader grant.

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For children born with HIV, adhering to medication gets harder with age

Researchers found that from preadolescence to young adulthood, the prevalence of non-adherence increased from 31% to 50%. In addition, the prevalence of detectable viral load among the same age groups increased from 16% to 40%.

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Paolo (not his real name), now nine years old, doesn’t know he has HIV.

Ang alam niya lang, kailangan niya uminom ng gamot gabi-gabi (He just knows he has to drink his meds every night),” his aunt, Virginia, said. “‘Di niya alam para saan ‘yun; basta gamot lang na kailangan niya (He doesn’t even know what they’re for; just that they’re meds that he needs).”

Paolo calls Virginia “mama”, but his biological mother – Virginia’s younger sister Vicky* – already passed away over eight years ago. And when his biological mother died, Vicky’s child Paolo was given to Virginia, the ate (elder sister).

And now that Paolo is growing up, this – the taking of medicines – continues to be an issue that Virginia said is one of those that “we continue to face.”

Apparently, though, this issue is not exactly surprising.

A new study in the US found that children born with HIV were “less likely to adhere to their medications as they aged from preadolescence to adolescence and into young adulthood.” The study – led by researchers at Harvard T.H. Chan School of Public Health – found that additionally, the prevalence of detectable viral load – an indication that the virus is not being managed by medications and a factor that’s often associated with non-adherence – also increased with age.

The study is one of the first to examine why different age groups stop adhering to treatment (non-adherence). While the factors related to non-adherence varied by age group, youth who were concerned about side effects of the drugs were less likely to be adherent at most ages.

READ:  For children born with HIV, adhering to medication gets harder with age

“As they approach adulthood, many youth face challenges, such as entering new relationships, managing disclosure of their HIV status, and changing to an adult HIV care provider. Ensuring successful HIV medication adherence before and throughout adolescence is critical,” said lead author Deborah Kacanek, research scientist in Harvard Chan School’s Department of Biostatistics. “We found that the factors that either supported adherence and a suppressed (undetectable) viral load, or made it harder for youth to adhere to treatment, varied depending on their age.”

The study was published in AIDS.

This study is worth highlighting in the Philippines because HIV continues to also affect younger Filipinos.

In April 2019, there were 38 newly diagnosed adolescents 10-19 years old at the time of diagnosis. Further, two cases were 17 years old and 36 cases were 18-19 years old. Almost all (95%) were infected through sexual contact (six male-female sex, 19 male-male sex, and 11 had sex with both males and females), one was infected through sharing of needles and one had no data on mode of transmission. In addition, there were three diagnosed cases less than 10 years old and all were infected through vertical (formerly mother-to-child) transmission.

Globally, 1.8 million adolescents live with HIV; and adhering to regimens of antiretroviral therapy (ART) is key to managing the disease and reducing the risk of transmission. And yet “sticking to a daily regimen of medicine, however, is especially challenging for adolescents and young adults, who are navigating a range of physical, cognitive, social and emotional changes.

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“Adherence can be more complicated for youth growing up with perinatal HIV, whose lifelong experiences with HIV, stigma, and multiple antiretroviral medications may pose challenges to achieving viral suppression that are different from youth who acquire HIV later in life.”

To better understand these challenges and why young people may not adhere to their medications, the researchers followed 381 youth with perinatally acquired HIV for an average of 3.3 years. The youth were participants in the Pediatric HIV/AIDS Cohort Study, which follows children and youth born with HIV or born exposed at birth to HIV to determine the impact of lifelong HIV and the long-term safety of antiretroviral regimens.

The preadolescents, adolescents and young adults in the study ranged from age 8 to 22 and were recruited from 15 different clinical sites in the US, including Puerto Rico. As part of the study, the researchers examined results from blood tests that measured viral loads, and they examined nearly 1,200 adherence evaluations in which study participants or their caregivers self-reported any missed doses of medication in the prior seven days.

The researchers found that from preadolescence to young adulthood, the prevalence of non-adherence increased from 31% to 50%. In addition, the prevalence of detectable viral load among the same age groups increased from 16% to 40%.

For each age group, different factors were associated with nonadherence. For example, during middle adolescence (15-17 years old), alcohol use, having an unmarried caregiver, indirect exposure to violence, stigma, and stressful life events were all associated with nonadherence.

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“It is important to talk with youth about how to take medications properly, but our study highlights the need for those who care for these youths to focus also on age-related factors that may influence adherence,” Kacanek said. “Services to help support adherence need to address both the age-related risks and build on the sources of strength and resilience among youth at different stages of development.”

Other Harvard Chan School researchers who contributed to the study include Claire Berman, Yanling Huo, and Katherine Tassiopoulos.

Back in the Philippines, Virginia said that “mabuti ngang may gamot na (si Paolo)… pero marami pa ring isyu na di nasasagot, di nagagawan ng paraan (it’s good Paolo’s already taking antiretroviral medicine… but there are still numerous unanswered/unresolved issues).”

And with dealing with children living with HIV, this still continues to be the case…

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Antiretroviral agent such as rilpivirine could improve pre-exposure prophylaxis

In an ex vivo model of HIV PrEP using tissue samples in the laboratory, the drug was associated with significant inhibition of HIV replication in rectal tissue, which persisted for up to four months after the last dose of rilpivirine. The drug was not, however, associated with viral suppression in cervicovaginal tissue.

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A long-acting antiretroviral agent such as rilpivirine could further improve pre-exposure prophylaxis (PrEP), already shown to be safe and effective at preventing AIDS in high risk populations, as it could overcome problems with poor medication adherence.

This is according to a new study examining the safety, acceptability, and effectiveness of multiple doses of injected rilpivirine, published in AIDS Research and Human Retroviruses, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers.

The article entitled “A Multiple Dose Phase 1 Assessment of Rilpivirine Long Acting in a Model of Preexposure Prophylaxis Against HIV” was coauthored by Ian McGowan, Orion Biotechnology (Ottawa, Canada) and an international team of researchers from University of Pittsburgh (PA), Magee Women Research Institute (Pittsburgh, PA), Alpha StatConsult (Damascus, MD), University of Liverpool (U.K.), University of Pittsburgh Graduate School of Public Health, Janssen Research and Development (Beerse, Belgium), The Translational Science Corp. (Los Angeles, CA), and University of Miami, Miller School of Medicine (Miami, FL).

In this phase 1 study, women and men received three intramuscular doses of rilpivirine eight weeks apart. The injections were shown to be safe and well tolerated, with injection site pain being the most common adverse effect. In an ex vivo model of HIV PrEP using tissue samples in the laboratory, the drug was associated with significant inhibition of HIV replication in rectal tissue, which persisted for up to four months after the last dose of rilpivirine. The drug was not, however, associated with viral suppression in cervicovaginal tissue.

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Thomas Hope, PhD, Editor-in-Chief of AIDS Research and Human Retroviruses and Professor of Cell and Molecular Biology at Northwestern University, Feinberg School of Medicine, Chicago, IL states: “There is currently a significant effort to develop long-acting formulations of drugs that prevent HIV replication and can be utilized to prevent HIV acquisition (PrEP). PrEP works if properly taken. Long-acting formulations can eliminate problems when high risk individuals forget to take their pills every day. The development of successful long-acting PrEP formulations will decrease new HIV infections by providing improved protection from HIV acquisition by eliminating problems for individuals who don’t like pills or can’t remember to take their pill every day.”

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PLHIV who have compassionate care providers start, remain in treatment longer

Rutgers researchers find patients who perceive their primary care providers as lacking empathy and not willing to include them in decision making are at risk for abandoning treatment or not seeking treatment at all.

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Photo used for illustration purpose only. Photo by Vittore Buzzi from Unsplash.com.

Adults with HIV are more likely to continue life-saving treatments if their primary health care providers show respect, unconditional empathy without judgement and demonstrate an ability to partner with patients in decision making to address their goals, a Rutgers study finds.

The systematic review appears in the Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports.

The findings showed that the complexity of the illness, treatment regimen and overall healthcare system frequently overwhelms the patient and fear of stigma often prevents them from beginning or continuing treatment. The researchers found that patients need help in understanding their illness and care needs using understandable language to translate complex information, letting patients know what to expect and reinforcing that HIV is now a treatable, yet complex, chronic illness.

“Today, HIV is considered a chronic, treatable condition. However, this study found that many patients continue to view it as a death sentence,” said lead author Andrea Norberg, executive director of the François-Xavier Bagnoud Center at Rutgers School of Nursing, which provides care for people with HIV, infectious diseases and immunologic disorders. “We know that people who are knowledgeable about HIV, who are engaged in care and taking antiretroviral therapy medications remain relatively healthy. Our challenge is to reach those people diagnosed with HIV and who are not retained or engaged in ongoing care. In the United States, this is approximately 49 percent of the 1.1 million people diagnosed.”

The researchers included 41 studies published between 1997 to 2017. The sample populations included adults with HIV and their healthcare providers. All adults with HIV were between the ages of 18 and 65, represented diverse races and ethnicities, sexual orientations and gender identities. Healthcare providers included physicians, nurse practitioners, physician assistants, pharmacists, social workers and others. The included studies had 1,597 participants.

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They found that many patients experience stigma and a lack of compassion that is often grounded in primary care providers’ ignorance about HIV and transmission risks. The resulting poor communication between providers and patients results in many patients’ failure to seek or remain in care and adhere to antiretroviral therapy medications.

Patients reported feeling “grilled” by providers who often assumed they were not taking medications. Norberg suggested providers would be more successful in getting information from patients by allowing them to be honest, inquiring about their health goals and telling them how other patients have managed treatment.

Conversely, the researchers found that patients were more inclined to adhere to HIV treatment when their primary care providers showed empathy, true listening, trust, consideration of the whole person and involvement in decision making. However, many patients reported that healthcare providers viewed care only as “prescribing antiretroviral therapy medicine.”

“Providers should use common language, not medical jargon, to educate patients about HIV, medications and how they can live a healthy life,” Norberg said. “They should thoroughly teach them about the disease, the medications and side effects, and the meaning of the tests.”

The researchers noted that providers who help patients navigate the health system, offer one-stop location of services and provide connections to psychological support, health insurance, medicine, transportation and other services, can help their patients stay engaged in care.

Primary healthcare providers can enroll in professional education to improve their knowledge about HIV, use of motivational interviewing skills and seek opportunities for experiential learning, observation and hands-on practice working directly with patients with HIV, Norberg said.

READ:  When hero leads to zero

Other Rutgers authors included John Nelson, Cheryl Holly, Sarah T. Jewell and Susan Salmond.

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