What Matters in Global Health - 156

Lenacapavir Injections Show 100% Efficacy in Major Trial, Offering New Hope for At-Risk Women from HIV

It’s rare for scientists to get a standing ovation for presenting their data. But after South African researcher Linda-Gail Bekker finished her talk about an HIV prevention trial at the AIDS 2024 conference in Munich last week, the audience stood up and clapped for almost 1 minute.

Bekker told the audience that among more than 2,000 African women who had received a twice-yearly injection of the antiviral drug lenacapavir as pre-exposure prophylaxis (PrEP), not one contracted HIV. Some view the result as a game-changer.

The drug’s manufacturer, Gilead Sciences , had presented the main outcomes of the PURPOSE 1 trial in a?June press release. Still, some researchers had reserved judgment until seeing more details, such as side effects and the study’s methodology. The?full results, described by Bekker and published?in?The New England Journal of Medicine?last week, “were better than anyone had hoped,” says Vincent Kioi , an IAVI vaccine researcher based in Nairobi. He adds that they are sure to complicate the long quest for an HIV vaccine.

Scientists still want to know whether the results of a?second efficacy trial?in the United States and six other countries on men who have sex with men are similarly promising. (Data are expected late this year or in early 2025.) Also unclear is how fast the drug can be approved by regulators and produced, how much it will cost—especially in low- and middle-income countries—and how fast the virus will develop resistance.

Still, the findings provide hope at a crucial moment. New HIV infections have come down from more than 2 million globally in 2010 to 1.3 million last year. But a report released last week by the Joint United Nations Programme on HIV/AIDS (UNAIDS) shows progress has stalled, and the world seems likely to miss its target of just 370,000 infections by 2025.

Existing PrEP strategies have proved safe and effective but have had limited impact. Regimens consisting of one pill a day haven’t reduced the risk much for young women in countries with a high HIV burden because factors such as stigma and a lack of privacy or autonomy keep many women from taking the pills as prescribed. Another long-acting injectable drug, cabotegravir, developed by the pharma company ViiV Healthcare and given every two months, was licensed in 2021 and recommended by the World Health Organization for at-risk groups in 2022; a trial in cisgender women?showed it lowered the risk of HIV infection?by 88% compared with oral PrEP. But its rollout has been slow partly because of ongoing price negotiations.

In PURPOSE 1, 2,134 adolescent girls and young women in South Africa and Uganda received injections of lenacapavir every six months. The trial ended when half the participants had been enrolled for one year, and the drug was shown to be 100% protective. The more than 3,000 participants in the trial’s two other arms received either a daily pill of emtricitabine/tenofovir, licensed in many countries as PrEP, or a newer version of the pill that has fewer side effects. Among them, there were 55 new HIV infections, not significantly less than the background rate of infection in women eligible for the trial. From measuring blood drug levels in 10% of participants, researchers learned that the majority took three or fewer pills per week instead of one every day. Those taking the fewest pills were most likely to acquire HIV.

Whether injectables will be easier to take in the long term is still a question. Lenacapavir is injected into the tissue under the skin, usually in the abdomen. If not done carefully, this can create painful nodules and inflammation. A few trial participants developed ulcers after a nurse injected the drug too deep, Bekker says. "And that is in the context of a well-conducted clinical trial”, notes Jeanne Marrazzo , director of the U.S. National Institute of Allergy and Infectious Diseases. As the use of the drug is scaled up, it will be crucial to train healthcare workers in how to give the shots correctly, she says.

Activists are already pushing to make lenacapavir available at an affordable price worldwide. Gilead has said it will license generics companies to produce the drug for low-income countries. “But they lock out the middle-income countries because they think they can get a higher price there,” says UNAIDS Executive Director Winnie Byanyima .

Lenacapavir is a novel type of drug that attaches to the capsid enveloping the viral genome and interrupts the viral life cycle. So far, scientists have seen no signs of HIV developing resistance against the drug, but that’s likely a matter of time, says Salim Abdool Karim, an epidemiologist who runs the Centre for the AIDS Programme of Research in South Africa. He worries that when people stop taking lenacapavir, the drug will linger in the body for weeks at concentrations low enough to allow the virus to survive and adapt. “If you get infected in that long tail, that could create resistant viruses,” Karim says.

Another critical period is when the regimen begins, as experience with cabotegravir has shown. Although anyone starting on that drug must have tested negative for HIV, some acquire the virus around their first injection and escape detection, leading to a slow-developing infection that can be hard to detect, with test results flip-flopping between positive and negative. “That can make management of these cases really difficult,” says Susan Eshleman, a clinical pathologist at Johns Hopkins University. Researchers worry that resistant strains could develop stealthily while the patient’s viral load is too low for standard resistance testing.

These missed infections seem rare; researchers in PURPOSE 1 retrospectively identified four participants who had an acute HIV infection when they received lenacapavir. Once on PrEP, such patients may be unlikely to transmit the virus—but managing them will become important as their numbers increase.

HIV vaccine researchers, meanwhile, are pondering what the breakthrough means for their field. For one thing, it may now require more compelling data that a vaccine candidate will likely provide very good protection to stage an efficacy trial, Kioi says. And researchers will have to think about how to ethically design such trials when an available option gives 100% protection. “Any study that we do with a potential vaccine will need to take into account the use of such products,” says Beatriz Grinsztejn , an HIV researcher at Brazil’s Oswaldo Cruz Foundation. “And, of course, it makes studies much more difficult.”

Breakthrough Nasal Spray Shows Promise in Reversing Alzheimer's and Dementia by Clearing Harmful Tau Proteins?

Researchers at the University of Texas Medical Branch recently discovered a significant advancement in the fight against neurodegenerative diseases such as Alzheimer’s disease and dementia. The study, published in?Science Translational Medicine,?introduces an innovative nasal spray treatment that has shown promising results in clearing harmful tau protein build-up and improving cognitive functions in aged mice models with neurodegenerative diseases.??

“This nasal spray approach opens new avenues for non-invasive delivery of tau therapeutic antibodies directly to the brain, and it holds promise for many neurodegenerative diseases,” said Dr Rakez Kayed , lead author and professor at the Department of Neurology at UTMB.??

Tau is?a microtubule-associated protein found in human brains that helps stabilise microtubules, part of the framework that gives the cell its shape and helps it stay organised in neurons. In healthy brains, tau proteins help keep things in order. However, in neurodegenerative diseases, they can become abnormally twisted and form tangles that disrupt neuronal function and lead to cognitive decline. Current tau immunotherapies have struggled with efficacy due to their limited ability to penetrate intracellular compartments where these tau buildups reside.?

Kayed and his team developed a specific type of antibody, TTCM2, which selectively recognises and targets toxic tau buildup. The antibody was packaged in particles to enhance its delivery via the nasal route to the brain. This method bypasses the blood-brain barrier, a significant hurdle in neurodegenerative disease treatment, ensuring rapid and effective therapy delivery.?

?“Our research highlights the potential of nasal tau immunotherapy to effectively target intracellular tau aggregates– a primary driver of neurodegeneration and cognitive decline in diseases like Alzheimer’s and other tauopathies,” added Kayed. “This method not only improves the delivery of therapeutic antibodies but also enhances their efficacy in clearing tau aggregates and improving cognitive functions”.??

An essential aspect of this approach is that it involves TRIM21, an intracellular receptor for antibodies, and E3 ligase, known for mediating the clearance of antibody-bound pathogens like viruses. In the study, TRIM21 facilitated the clearance of antibody-bound intracellular tau aggregates, thereby enhancing the therapeutic effect and cognitive improvements in the mouse model.?

?“This advancement could significantly impact the treatment strategies for Alzheimer’s and related tauopathies, offering new hope for millions of patients suffering from these debilitating conditions,” said Sagar Gaikwad, first author of the study and postdoctoral fellow at UTMB.?

This study highlights the potential impact of future treatments for neurodegenerative diseases. Researchers at UTMB plan to advance this research by conducting further preclinical trials and exploring the potential of TTCM2-ms in human clinical trials. The goal is to translate these promising results into a viable treatment option for patients suffering from Alzheimer’s disease and other tau-related disorders.?

Half of Cancer Types Increasing Among Younger Americans, Major Study Reveals?

Seventeen of 34 types of cancer have become more common in younger generations in the United States, the broadest study of its kind to date has found. The analysis, published this week in?The Lancet Public Health, examined data from 23.7 million people born between 1920 and 1990 and diagnosed with cancer between 2000 and 2019.

It found, for example, that people born in 1990 were 2.6 to 3.6 times more likely to develop cancers of the small intestine, kidney, and pancreas than those born in 1955 and 2.6 times more likely to develop endometrial cancer than someone born in 1930. The authors say the findings suggest people are increasingly exposed to carcinogens during early life or young adulthood. However, younger birth cohorts were at the same or lower risk of death from most types of cancer than older ones.

The study's authors suggest that the rising cancer rates among younger generations may be attributed to increased exposure to carcinogens during early life or young adulthood. Environmental pollutants, lifestyle habits, and obesity are believed to play a significant role. Notably, 10 of the 17 cancers with increasing incidence rates are related to obesity, including colon and rectal, kidney, gallbladder, uterine corpus, pancreas, estrogen receptor-positive breast, ovary, myeloma, and liver cancers. Andrea Cercek , a gastrointestinal medical oncologist, emphasised that the rise in cancer incidence among young adults could be due to early exposure to environmental factors or lifestyle changes. However, pinpointing specific causes remains challenging, as the evidence remains inconclusive.

While the incidence rates of these cancers have increased, the study found that younger generations are at the same or lower risk of death from most types of cancer compared to older generations. This suggests improvements in cancer treatments and early detection methods. However, mortality rates have increased for some cancers, including endometrial, liver, gallbladder, testicular, and colorectal cancers among younger individuals.

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