HIV Drugs May Reduce Alzheimer’s Risk

Summary: Common HIV medications may reduce the incidence of Alzheimer’s disease (AD). Using anonymized prescription data from more than 225,000 people, the study found that HIV-positive patients taking reverse transcriptase (RT) inhibitors had a significantly lower rate of AD than the general population.

This finding builds on previous findings that genes linked to Alzheimer’s disease could be recombined by enzymes similar to those targeted by HIV treatments. The findings could pave the way for new therapeutic strategies using existing drugs to combat the growing AD crisis.

Highlights:

1. The study analyzed prescription data from 225,000 people, revealing that HIV-positive patients over the age of 60 taking RT inhibitors had fewer Alzheimer’s diagnoses than their non-HIV-positive counterparts.
2. RT inhibitors, originally developed for HIV, may inhibit similar enzymes in the brain, suggesting a potential mechanism for their effect on Alzheimer’s disease.
3. The research was supported by notable foundations and the NIH, highlighting its credibility and the considerable interest in translating these findings into new treatments for AD.

Source: Sanford Burnham Prebys

Alzheimer’s disease (AD) currently affects nearly seven million people in the United States. This number is expected to reach nearly 13 million by 2050. The lack of effective therapies represents a major unmet medical need. Sanford Burnham Prebys scientists have now identified concrete and promising links between common anti-HIV medications and reduced incidence of AD.

The study, led by Jerold Chun, MD, Ph.D., was published in Drugs.

Chun’s new research builds on his lab’s landmark publication in Nature in 2018, which described how somatic gene recombination in neurons can produce thousands of new genetic variants in the Alzheimer’s brain. Importantly, the study also revealed for the first time how the APP gene, linked to Alzheimer’s disease, is recombined using the same type of enzyme found in HIV.

The enzyme, called reverse transcriptase (RT), copies RNA molecules and transforms them into complementary DNA duplicates that can then be inserted back into the DNA, producing permanent sequence changes in the DNA blueprint of the cell.

HIV and many other viruses rely on RT to hijack a host’s cells to establish chronic infection, so drugs that block the activity of the RT enzyme have become a common part of Therapeutic cocktails designed to keep HIV at bay.

The brain appears to have its own RTs that are different from those of viruses, and the research team wondered whether inhibiting brain RTs with anti-HIV drugs actually helped AD patients.

To assess the link between real-world exposure to RT inhibitors and AD in humans, the team analyzed de-identified medical records with prescription requests from more than 225,000 control and HIV-positive patients, and found that the Exposure to RT inhibitors was associated with a statistically significant reduced incidence. and prevalence of AD.

“So we looked at HIV-positive people taking RT inhibitors and other combination antiretroviral therapies as they got older, and we asked the question: How many of them got Alzheimer’s disease? Chun said.

“And the answer is that there were far fewer than one would expect compared to the general population. »

Of the more than 225,000 people with claims data in the study, just under 80,000 were HIV-positive people aged over 60. More than 46,000 had taken RT inhibitors during an observation period of almost three years, from 2016 to 2019. The data was obtained through a collaboration with the information technology company on the health and clinical research IQVIA, led by Tiffany Chow, MD

Among living HIV-positive people, there were 2.46 diagnoses of Alzheimer’s disease per 1,000 people among HIV-positive people taking these inhibitors, compared to 6.15 for the general population.

This control group was represented by more than 150,000 HIV-negative patients over the age of 60 who received medical insurance claims related to cold treatment.

“It is impossible to conduct a prospective clinical trial with such a large number of patients,” adds Chun. “This approach is a way to examine how a drug may work in a large population of patients. »

Chun points out that the drugs patients took in this retrospective study were designed to counter HIV’s RT activity and likely had only a limited effect on many possible forms of the enzyme active in the brain.

“What we’re seeing now is very rudimentary,” Chun says. “The obvious next step for our laboratory is to identify which versions of RT are at work in the AD brain so that more targeted treatments can be discovered, while prospective clinical trials of RT inhibitors currently available on of people with early AD should be prosecuted.”

Jerold Chun, MD Ph.D., is a professor at the Sanford Burnham Prebys Genetic Disorders and Aging Research Center.

Other authors of the study include Tiffany W. Chow, Mark Raupp, Matthew W. Reynolds, Siying Li and Gwendolyn E. Kaeser.

Funding: The work was supported by the National Institute on Aging – NIH (R01AG071465, R01AG065541, and R56AG073965), the Shaffer Family Foundation, and the Bruce Ford & Anne Smith Bundy Foundation.

About this research news on Alzheimer’s disease and neuropharmacology

Author: Greg Calhoun
Source: Sanford Burnham Prebys
Contact: Greg Calhoun – Sanford Burnham Prebys
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Exposure to nucleoside reverse transcriptase inhibitors is associated with lower risk of Alzheimer’s disease: a retrospective cohort proof-of-concept study” by Jerold Chun et al. Drugs

Abstract

Exposure to nucleoside reverse transcriptase inhibitors is associated with lower risk of Alzheimer’s disease: a retrospective cohort proof-of-concept study

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RT) that produce it have been implicated in the etiology of Alzheimer’s disease (AD), suggesting that RT inhibitors are novel prophylactics or therapeutics .

This retrospective proof-of-concept study assessed the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical data .

Eligible participants were aged ≥60 years, without a pre-existing diagnosis of AD, and had attended medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923 ) were HIV positive.

Cohort 1 had prescription requests for at least one NRTI during the exposure period; This is not the case for cohort 2. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy.

The cumulative incidence of new AD cases during the subsequent 2.75-year observation period was lowest in NRTI-exposed patients and highest in controls.

Age- and sex-adjusted hazard ratios showed a significant decrease in AD risk in cohort 1 compared to cohort 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p <0.05).

The subgroup identified a decreased risk of AD in patients exposed to NRTIs but without exposure to protease inhibitors (PIs).

Prospective clinical trials and development of next-generation agents targeting brain RTs are warranted.