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A new way to study HIV’s impact on the brain

Using a newly developed laboratory model of three types of brain cells, Penn and CHOP scientists reveal how HIV infection–as well as the drugs that treat it–can take a toll on the central nervous system.

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Though many negative repercussions of human immunodeficiency virus infection can be mitigated with the use of antiretroviral therapy (ART), one area where medical advances haven’t made as much progress is in the reduction of cognitive impacts. Half of HIV patients have HIV-associated neurocognitive disorders (HAND), which can manifest in a variety of ways, from forgetfulness and confusion to behavior changes and motor deficiencies.

To better understand the mechanisms underlying HAND, researchers from Penn’s School of Dental Medicine and Perelman School of Medicine and from the Children’s Hospital of Philadelphia (CHOP) brought together their complementary expertise to create a laboratory model system using three of the types of brain cells thought to be involved. Led by doctoral student Sean Ryan, who was co-mentored by Kelly Jordan-Sciutto of Penn Dental Medicine and Stewart Anderson of CHOP and Penn Medicine, the model recapitulates important features of how HIV infection and ART affect the brain.

“Frankly the models we generally use in the HIV field have a lot of weaknesses,” says Jordan-Sciutto, co-corresponding author on the paper, which appears in the journal Stem Cell Reports. “The power of this system is it allows us to look at the interaction between different cell types of human origin in a way that is more relevant to patients than other models.”

In addition to studying HIV, members of the team plan to use the same model to shed light on the neurological mechanisms that underlie other conditions, such as schizophrenia, Alzheimer’s, and even normal aging.

“We’re collaborating with a variety of colleagues to use this system to study Alzheimer’s disease as well as schizophrenia,” says Anderson, co-corresponding author on the paper. “We have the components in a dish that we know are interacting in these diseases, and this gives us a new mix-and-match way to understand how certain cells are contributing to neuronal damage.”

Indeed, the impetus to create the model grew not out of HIV research but work that Ryan was pursuing in Anderson’s lab on schizophrenia.

“We had been looking at the role of microglia, the resident immune cells of the central nervous system,” says Ryan, first author on the work. “We wanted to see if we could see the mechanistic changes that occur with microglia in schizophrenia.”

To do so, Ryan and Anderson were interested in using human-induced pluripotent stem cells–adult cells that are reprogrammed to resemble embryonic stem cells–which can be coaxed into differentiating into a variety of different cell types.

But schizophrenia is a complicated disease with a variety of contributing genetic and environmental factors and a broad spectrum of presentations. Rather than looking at something complex, they sought to apply their new system to a disease that likewise causes neurological damage but does so in a more dramatic way and in which microglia are also implicated: HIV/AIDS infection.

They reached out to Jordan-Sciutto, who has deep experience investigating the mechanisms of HAND and was eager for the opportunity to develop a model superior to those currently available. Together, the scientists identified the three cell types they were most interested in studying: neurons, astrocytes, and microglia.

Neurons aren’t directly infected by HIV but are known to be damaged during infection. Meanwhile astrocytes are believed to interact with neurons, causing damage by sending pro-inflammatory factors into the spaces between cells, called synapses. And microglia, which are responsible for maintaining a healthy environment in the absence of disease, are seen to expand and contribute to inflammation during HIV infection.

After nailing the technical challenge of creating this tractable model in which each cell type is generated independently and then mixed together, the team used it to probe how HIV infection and ART impact the cells, both alone and in combination.

“A lot of people are taking PreEP [pre-exposure prophylaxis] if they’re in a situation where their risk of contracting HIV is heightened,” says Ryan. “Just as we want to understand the cognitive impacts of HIV, we also want to see whether these drugs alone are impacting the brain health of otherwise healthy people.”

The researchers looked at RNA expression in their cultures to get a sense of what proteins and signaling pathways were becoming activated in each scenario. During infection, they saw inflammatory pathways that had previously been implicated in HIV in earlier research. When they introduced the antiretroviral drug EFZ, which is not in common use in the United States but remains a frontline therapy in many other areas of the world, with an infection, the activity of most of these pathways was reduced.

“But this scenario involved its own unique response,” says Ryan. Certain pathways associated with inflammation and damage remained despite the introduction of EFZ.

“EFZ treatment of the tri-cultures that included HIV-infected microglia reduces inflammation by around 70%,” Ryan says. Interestingly, EFZ by itself also triggered inflammation, though to a lesser extent than infection.

“It seems a combination of infection and ART is creating its own unique response that is different from the sum of its parts,” Ryan says. “Knowing what pathways are still active due to ART could help us appropriately target additional therapies so patients don’t develop HAND.”

Many features of infection seen in the three-cell culture mirror what is known from HIV infection and ART treatment in people, giving the researchers confidence in the reliability of their model.

“Just looking at the microglia,” says Anderson, “we see in our system that they are taking on both of their normal roles in keeping key signaling systems balanced during their normal state and activating and causing damage when they’re fighting infection. We’re able to model normality and abnormality in a way we haven’t been able to before.”

For Jordan-Sciutto, the new system “is really going to change the way my lab operates going into the future.” She’s hopeful many other HIV scientists will take it up to further their studies as she also explores more aspects of HIV’s impact on the brain, such as how it navigates through the blood-brain barrier that normally protects the central nervous system from inflammation and infection.

The study authors give credit to the collaborative environment at Penn for this cross-disciplinary project. “Tentacles of this project extend from CHOP to the dental school to the vet school to the medical school,” says Anderson. “Penn is a very special place where people seem to be more likely to share their technologies around and let other people work with and develop them. This project is a great example of that.”

Kelly L. Jordan-Sciutto is vice chair and professor in the Department of Basic and Translational Sciences in Penn’s School of Dental Medicine, associate dean of graduate education, and director of biomedical graduate studies at the Perelman School of Medicine.

POZ

FDA approves first long-acting HIV treatment

The FDA in the US approved CABENUVA as the first once-monthly, long-acting injectable (LAI) for the treatment of HIV-1 infection in adults. CABENUVA consists of rilpivirine (Janssen) and cabotegravir (ViiV Healthcare Ltd.), for treating HIV-1 infection in adults.

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The FDA in the US approved CABENUVA as the first once-monthly, long-acting injectable (LAI) for the treatment of HIV-1 infection in adults. CABENUVA consists of rilpivirine (Janssen) and cabotegravir (ViiV Healthcare Ltd.), for treating HIV-1 infection in adults.

Before proceeding with the news (and dampening the good news), here’s an FYI: As quoted by NBC News, ViiV Healthcare Ltd. stated that the shot combo would cost $5,940 for an initial, higher dose and $3,960 per month afterward.

According to the FDA, the safety and efficacy of CABENUVA were established through two randomized, open-label, controlled clinical trials in 1,182 HIV-infected adults who were virologically suppressed (HIV-1 RNA less than 50 copies/milliliter) before initiation of treatment with CABENUVA. The patients in both trials continued to show virologic suppression at the conclusion of each study, and no clinically relevant change from baseline in CD4+ cell counts was observed (https://www.fda.gov/news-events/press-announcements/fda-approves-first-extended-release-injectable-drug-regimen-adults-living-hiv).

In first trial, the ATLAS study, CABENUVA was said to have met the primary endpoint for noninferiority (or the proportion of participants with plasma HIV-1 RNA ≥50 copies per milliliter [c/mL] at Week 48), with a comparable number of patients receiving either CABENUVA or their daily current antiretroviral regimen (CAR) having an HIV-1 RNA level ≥50 c/mL. Two percent of patients receiving the long-acting injectable and 1% of patients receiving CAR had an HIV-1 RNA level ≥50 c/mL at Week 48 (Treatment difference 0.7%; 95% CI: -1.2%, 2.5%).

In second trial, the FLAIR study, a comparable number of patients receiving either CABENUVA or daily oral dolutegravir/abacavir/lamivudine therapy had an HIV-1 RNA count ≥50 c/mL, meeting noninferiority criteria. Two percent of patients in both treatment arms had an HIV-1 RNA count ≥50 c/mL at Week 48 (Treatment difference -0.4%; 95% CI: -2.8%, 2.1%).

Rilpivirine and cabotegravir are able to act as a complete regimen for people with HIV, allowing it to replace the antiretroviral regimen for those who are virologically suppressed with HIV-1 RNA at less than 50 copies per milliliter [c/mL], have no history of treatment failure, and are not known or suspected to have any resistance to either cabotegravir or rilpivirine.

To administer the therapy, a provider would conduct a once-monthly administration that would consist of two individual intramuscular injections in the buttocks.

Added the FDA: The most common adverse reactions with CABENUVA were injection site reactions, fever (pyrexia), fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness and rash. Cabenuva should not be used if there is a known previous hypersensitivity reaction to cabotegravir or rilpivirine, or in patients who are not virally suppressed (HIV-1 RNA greater than 50 copies/milliliter).

In a press release, Paul Stoffels, MD, vice chairman of the executive committee and chief scientific officer at Johnson & Johnson said: “With the approval of CABENUVA, we’re proud to bring a new treatment option to people living with HIV that removes the burden of taking a daily pill… While much more remains to be done to make HIV history, today’s milestone reminds us how far medical innovation has come since the first reported cases of the virus almost 40 years ago.”

Now, and realistically, with newer HIV medicines like rilpivirine and cabotegravir not even widely offered in countries like the Philippines yet, the even newer injectables may sound promising but remain stuff of dreams…

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Op-Ed

I may be HIV+ but that still doesn’t mean I’ll sleep with you

This is something every PLHIV needs to learn. That we are still “worth it”. Forget these notions of you being a “damaged good” or a “dirty person” or banalities given us along those lines. Because my HIV status is just one facet of my outrageous (and fabulous) personality; it does not define me.

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“I’m HIV-positive.”

That was the short sentence I remember telling this guy I used to date.

Okay – to backtrack – I met a guy while I was in Northern Mindanao. We dated for a while, and – at least I thought – things between us went smoothly for a while. I’d say he wasn’t bad-looking even if he looked somewhat common. He had one of those “if you stay long enough, I can teach myself to maybe even like you” face.

And then one night, we became more intimate than the usual. So I had to stop what we were doing (before we progressed further). And then – after prepping him up by first discussing with him his views about HIV and people living with HIV – I told him I had something important to tell him (if we were to advance what we had).

Thus that short sentence.

His face immediately changed; from what I saw was longing to… shocked. He couldn’t even say a word. And when he was finally able to utter a word, it was just to tell me that “I forgot I had to be elsewhere.”

The alibi was lame. But what made it more insulting was that I wasn’t even that into him to begin with; he was just a possible lay (if it came to that).

But that moment taught me two important things.

On one hand, how the sexuality of so many PLHIVs are tempered by their status.

I have frequently heard of medical practitioners who tell PLHIVs to “already stop having sex now that you’re HIV-positive; dadami pa kayo (you’d abet in increasing the number of PLHIVs)” – all too obviously unaware of safer sexual practices and U=U, among others. Worse, this sentiment is shared by a lot of PLHIVs themselves, who see their status as a “punishment”, and the only “cure” is to stop having sex altogether. Oh, please!

On the other hand, recognizing that being sexual doesn’t disappear (and doesn’t need to vanish) with being HIV-positive, there seems to be this supposition of PLHIVs being “desperate”.

That guy I dated, for instance, had every right NOT to have sex with me (it’s called power over one’s body); but that he had to lie just to get away from me was – to admit the truth – not only discourteous but even insulting. I suppose particularly because… I wasn’t even that into him.

Here’s the thing: Me living with HIV means just that – that I have HIV. But it doesn’t mean that I’ve lost my (yes!) sexual appetite and (for that matter) taste/preferences/standards on who to do it with.

And I believe this is something every PLHIV needs to learn. That we are still “worth it”. Forget these notions of you being a “damaged good” or a “dirty person” or banalities given us along those lines. Because my HIV status is just one facet of my outrageous (and fabulous) personality; it does not define me. And if (some) guys can’t see that, well…

Because remember dearie, just because I am HIV-positive still doesn’t mean I’ll sleep with you.

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POZ

CDC in the US releases recommendations for Covid-19 vaccine for PLHIVs

According to the CDC, “adults of any age with certain underlying medical conditions are at increased risk for severe illness from the virus that causes Covid-19.” It added that “mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine.”

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With the Department of Health (DOH) still not releasing guidelines re vaccinations in the Philippines including of Filipinos living with HIV, eyes are turning – instead – to international bodies that already released recommendations for the same. One such body, the Center for Disease Control and Prevention (CDC) – released in end-2020 its “Vaccination Considerations for Persons with Underlying Medical Conditions”.

According to the CDC, “adults of any age with certain underlying medical conditions are at increased risk for severe illness from the virus that causes Covid-19.” It added that “mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine.”

The CDC noted that PLHIVs were actually included in clinical trials, but “safety data specific to this group are not yet available at this time.” It saw fit to stress this point: “Information about the safety of mRNA COVID-19 vaccines for people who have weakened immune systems in this group is not yet available.”

Nonetheless – and this is worth stressing – because “PLHIVs and those with weakened immune systems due to other illnesses or medication might be at increased risk for severe Covid-19… they may receive a Covid-19 vaccine.”

Aside from v=being aware of the potential for reduced immune responses to the vaccine, those with weakened immune systems (including PLHIVs) should continue following all current guidance to protect themselves against Covid-19.

  • Wearing a mask
  • Staying at least six feet away from others
  • Avoiding crowds
  • Washing hands with soap and water for 20 seconds or using hand sanitizer with at least 60% alcohol
  • Following (CDC) travel guidance
  • Following quarantine guidance after exposure to Covid-19
  • Following any applicable workplace guidance
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POZ

Risk of developing cervical cancer is six times higher in women with HIV

Cervical carcinomas are usually caused by infections with Human papillomavirus (HPV), which are sexually transmitted just as HIV is. Based on the results of a new study, it can be assumed that an infection with HIV represents a risk factor for an infection with HPV.

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The risk of developing cervical cancer is six times higher in women who are infected with HIV.

This is according to a study from the TUM School of Medicine’s Center for Global Health and the chair of Epidemiology at the TUM Department of Sport and Health Sciences – “Estimates of the Global Burden of Cervical Cancer Associated with HIV” – that was published in the The Lancet Global Health.

According to WHO statistics, cervical cancer is the fourth most common type of cancer for women. In 2018 an estimated 570,000 women worldwide were diagnosed with cervical carcinoma, with approximately 311,000 of these women dying.

On the other hand cervical cancer, usually caused by Human Papillomavirus (HPV), is also one of the most successfully preventable and treatable types of cancer, as long as it is detected at an early stage and treated effectively.

Cervical cancer is at the same time the most frequently detected cancer for women who live with HIV, since their immune systems are weakened by the HIV infection.

Systematic review and meta-analysis of 24 studies

The lead authors Dr. Dominik Stelzle (Center for Global Health and Chair of Epidemiology) and Dr. Luana Tanaka (Chair of Epidemiology) conducted a systematic review as well as a meta-analysis of a total of 24 studies from the years 1981 to 2016, in which 236,127 women with HIV from four continents (Africa, North America, Asia and Europe) participated.

These studies covered a total of 2,138 cervical carcinoma cases. The results were linked with data from UNAIDS on worldwide HIV infection and with data on cervical carcinoma from the International Agency for Research on Cancer (IARC), the WHO’s Cancer Research Center, and then evaluated.

“Until now there have only been estimates from countries with high net income levels,” says Dr. Stelzle. “That’s why we looked at the figures on global incidence of cervical carcinoma in connection with an HIV infection and included estimates for countries with low net incomes. In most parts of the world the numbers are under five percent. In some countries however we’re talking about well over 40 percent of cases.”

Risk is six times higher for women with HIV

The objective of the study was to calculate the share of women living with HIV among the number of women with cervical cancer. The authors found that 5.8 percent of all new cervical cancer cases worldwide in the year 2018 were diagnosed for women with an HIV infection. This is equivalent to 33,000 cases a year, 85 percent of which occurred in Sub-Saharan Africa.

Furthermore, based on their results the team was able to show that women with HIV have a sixfold higher risk of developing cervical cancer than women without HIV infection.

“The association between cervical carcinoma and HIV is plausible,” says Prof. Andrea S. Winkler, co-director of the Center for Global Health. “Cervical carcinomas are usually caused by infections with Human papillomavirus (HPV), which are sexually transmitted just as HIV is. Based on our results it can be assumed that an infection with HIV represents a risk factor for an infection with HPV.”

Based on the results, the TUM authors determined that women with an HIV infection have a significantly higher risk of developing cervical cancer. They also pointed out that this means that HPV vaccinations and early-stage cervical carcinoma screenings are of particular importance.

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POZ

How the vaginal microbiome may affect HIV prevention

With no effective vaccine for HIV, alternative strategies such as pre-exposure prophylactic (PrEP) drugs are necessary to prevent transmission. PrEP drugs are highly effective in preventing the acquisition of HIV infection in men, but they are much less effective at preventing HIV infection in women.

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Photo by Timothy Meinberg from Unsplash.com

Healthy Lactobacillus bacteria in the vagina are critical for women’s health, but the accumulation of additional bacterial genera can imbalance the vaginal ecosystem. Such an imbalance may result in bacterial metabolism of drugs designed to prevent HIV infection, thereby decreasing their effectiveness and enhancing risks to women.

This is according to a study published in the open-access journal PLOS Pathogens by Dr. Nichole Klatt of the University of Minnesota Medical School, and colleagues.

With no effective vaccine for HIV, alternative strategies such as pre-exposure prophylactic (PrEP) drugs are necessary to prevent transmission. PrEP drugs are highly effective in preventing the acquisition of HIV infection in men, but they are much less effective at preventing HIV infection in women.

Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. To better design and conduct clinical studies assessing HIV prevention in women, it is essential to understand how microbes in the female reproductive tract affect therapeutic drug levels.

In the new study, Klatt and her colleagues investigated how vaginal bacteria alter PrEP drug levels and impact HIV infection rates using cervicovaginal lavage samples from women with and without bacterial vaginosis (BV) – a highly common syndrome in women that is caused by bacteria that can induce itching, discharge and discomfort, and has been associated with increased sexually transmitted infections and negative reproductive tract outcomes in women.

However, current treatments for BV frequently fail and recurrence is common. The researchers found that bacteria associated with BV – but not healthy Lactobacillus bacteria – can metabolize PrEP drugs and may potentially reduce PrEP efficacy due to reduced levels of available preventative drug. According to the authors, better measurements and interventions for bacterial vaginosis will be critical for improving the efficacy of HIV prevention efforts in women.

Dr. Klatt highlights, “women’s health, and factors that contribute to health and disease prevention in women are grossly under studied. This study demonstrates the critical need to develop better treatments for bacterial vaginosis, and in general, to promote more studies of women’s health.”

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POZ

Dep’t of Health dispenses newer HIV drug in the Phl

The Department of Health (DOH) is introducing LTD (lamivudine, tenofovir, dolutegravir) in the country.

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Took them long enough…

Xander (not his real name) has been HIV-positive since December 2012; and from the very first time he took his antiretroviral (ARV) medicines, “it has always been LTE (for lamivudine, tenofovir, efavirenz),” he said.

There have been adverse side effects – e.g. “At night, my dreams are so vivid I am unable to distinguish what’s real or what’s not,” Xander said, adding with sadness that “the doctor just told me to ‘Drink more water!’ as if that’d solve my problem.”

Those like Xander may now have their ARVs changed, with the Department of Health (DOH) introducing LTD (for lamivudine, tenofovir, dolutegravir) in the country.

This December, the Global Fund for treatment of people living with HIV (PLHIV) donated 197,260 bottles of LTD. The stock is being managed by the DOH’s Disease Prevention and Control Bureau – National HIV, AIDS and STI Prevention and Control Program.

The first tranche of 98,630 bottles were already allocated to various Centers for Health Development, while the last tranche (98,630 bottles) are expected to arrive in the country before the end of the year.

In an advisory signed by Undersecretary of Health Dr. Myrna Cabotaje, the DOH stated that based on the National Plan for LTD Introduction, the new ARV will be introduced from now until December 2021. These sub-populations of PLHIVs can benefit from LTD:

  • ART-naive adults, adolescents and children (30 kg and above), excluding TB patients on rifampicin-based regimen
  • PLHIVs on LTE with severe adverse events (dizziness, insomnia, abnormal dreams, anxiety, depression, mental confusion, convulsions, hepatoxicity, severe skin and hypersensitivity reactions and gynecomastia)
  • Patients with treatment failure to zidovudine (AZT) and abacavir (ABC)-based regimens

Xander knows he has to broach his concerns to the doctor in his treatment hub again to ascertain if he can shift from LTE to LTD. And “the DOH really took its time,” he mused, adding that hopefully, “this is just one of the steps wherein Filipino PLHIVs actually already start being able to access life-saving HIV meds already widely available in more developed countries.”

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