HIV: Antiretroviral therapy can only partially reverse

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HIV is associated with accelerated aging and antiretroviral therapy can only partially reverse

HIV: Antiretroviral therapy can only partially reverse. According to a recent study published in The Lancet HIV Journal, untreated HIV infection is associated with accelerated epigenetic age, which is more pronounced in people with severe immunodeficiency.

The study also showed that two years after starting antiretroviral therapy, epigenetic aging can be partially reversed. However, no significant difference in epigenetic age was found between the two antiretroviral therapies taken by the study participants.

Background introduction

Antiretroviral therapy has turned HIV into a chronic disease, and the life expectancy of HIV-infected people is close to that of the general population. However, the rate of age-related comorbidities, including metabolic disorders, cardiovascular, skeletal, nervous system, kidney and liver diseases, as well as cancer and weakness, is higher in HIV-infected persons.

This observation leads to the hypothesis that HIV-infected people may age prematurely or more significantly than others. In other words, their biological age (how their body functions) may be greater than their age (how many years have they lived). It is also believed that this phenomenon may be related to residual immune system deterioration and inflammation. Although antiretroviral therapy is very successful, inflammation still exists in HIV-infected patients.

Epigenetics is considered to be the key to understanding biological aging. The term refers to the metabolic process that regulates gene function and the study of it. DNA methylation is one of these processes: a set of methyl molecules attach to a gene to promote its expression or generate instructions for genetic material when needed, without changing its DNA structure.

However, changes in DNA methylation can occur under the influence of external factors, such as persistent HIV inflammation, and therefore accelerate epigenetic aging and the risk of age-related diseases. This is why DNA methylation has become an important marker for calculating epigenetic aging.

A mathematical algorithm called the epigenetic clock or DNA methylation clock has been developed to estimate the epigenetic age. Based on DNA methylation and other biomarkers, their interest is that the acceleration of epigenetic age can predict the occurrence of age-related comorbidities and deaths in the general population.

Studies:

Dr. Andrés Esteban-Cantos of the La Paz Hospital in Madrid and colleagues from other European research centers discussed the potential benefits of antiretroviral therapy for epigenetic ageing. To this end, the research team used frozen blood samples from 168 participants in the NEAT001/ANRS143 clinical trial, with 84 people in each group in the trial. For comparison, it also used blood samples from a control group of 44 HIV-negative individuals whose age and gender distribution were similar to those of the 168 trial participants. However, in this small control sample, the only variables that matched were age and gender. Therefore, the comparison between HIV-positive and HIV-negative participants cannot account for potential confounding factors, such as socioeconomic status, lifestyle, and the prevalence of cytomegalovirus co-infection, which have been shown to be related to epigenetic ageing .

NEAT001/ANRS143 is a European clinical trial conducted in 2010-2013 among people living with HIV who have never taken antiretroviral drugs. It shows that in 96 weeks, the economical antiretroviral regimen of nucleoside drugs (enhanced darunavir+letgevir) and traditional regimen (enhanced darunavir+fumarate) Norfovir dipivoxil + emtricitabine) are equally effective.

The researchers used four different clocks to calculate the acceleration of epigenetic age. Horvath’s clock, Hannum’s clock, PhenoAge and GrimAge. Each of these tools takes into account a large number of biomarkers, but the method of calculating epigenetic age is different. The latter two predict morbidity and mortality more reliably than the first two, and GrimAge is generally considered to be the most reliable of these four tools.

Rsults:

At the beginning of the NEAT trial, at baseline, the characteristics of the participants in the two treatment groups were similar. They are relatively young (median 38 years old), mostly male (88%) and white (82%), with a median CD4 count of 346.

In addition, at the 96th week of the trial, there was no difference in the immunological and virological responses of the treatment groups. It was observed that the CD4 count and CD4/CD8 ratio increased from baseline.

At any point in time, no difference in age acceleration was observed between the two treatment groups. At baseline and at week 96, a strong correlation was found between the age of HIV-infected individuals and the four epigenetic clocks, as did the control group.

By comparing with the HIV negative control group, the researchers found that before starting antiretroviral treatment, according to all four clocks, trial participants showed a higher epigenetic age acceleration: Horvath averaged 2.5 years, 95% CI It is 1.89 to 3.22; Hannum is 1.4 years, 0.74 to 1.99; GrimAge is 2.8 years, 1.97 to 3.68; and PhenoAge is 7.3 years, 6.40 to 8.13.

This acceleration decreased significantly after 96 weeks of antiretroviral therapy. Compared with the above baseline data, the average difference is as follows.

Horvath is -1.1 years, and the 95% CI is -1.51 to 0.66 years.
Hannum is -1.6 years, and the 95% CI is -2.08 to -1.21.
GrimAge is -0.6 years, and the 95% CI is -1.14 to -0.05.
PhenoAge is -3.6 years, and the 95% CI is -4.27 to -2.88.

In other words, before starting antiretroviral therapy, the epigenetic age of HIV-infected individuals was “2.8 years older” than the control group, as measured by GrimAge. Two years of treatment reduced them by 0.6 years, so their age was 2.2 years. The results of each epigenetic clock are slightly different.

This result is important because it shows the positive effect of antiretroviral therapy on epigenetic ageing. However, compared with the control group, despite receiving two years of antiretroviral therapy, participants with HIV still showed a significant epigenetic age acceleration with PhenoAge and GrimAge.

Since this suggests that HIV has a negative impact on epigenetic ageing, the researchers assessed whether later HIV infection is associated with higher epigenetic age acceleration.

In 28 participants with a CD4 count of less than 200 at baseline, higher levels of epigenetic age-accelerating markers were found, and the results were slightly different depending on the estimator. Among the 51 participants with a baseline viral load of greater than 100,000 copies, the epigenetic age acceleration index also improved, again depending on the clock used.

Interestingly, a statistical model showed that after two years of antiretroviral therapy, participants with a baseline CD4 count of less than 200 had a more pronounced decline in epigenetic ageing than participants with a CD4 count of more than 200. However, no similar differences were observed based on baseline viral load.

Many previous studies have shown that the root cause of the relationship between HIV and epigenetic age acceleration remains unclear. Since this study was done with frozen blood samples, the researchers estimated the subpopulations of the main white blood cells (the proportion of each type of white blood cells) to examine their relationship with the acceleration of epigenetic age.

They found that there were significant differences in the white blood cell composition among HIV participants who were not treated at baseline, participants who received 96 weeks of HIV treatment, and control participants. After adjusting the white blood cell composition, the epigenetic difference between Horvath clock and GrimAge is no longer found. Further research should investigate this further.

When discussing their results, Esteban-Cantos and colleagues highlighted their main findings.

Participants infected with HIV had accelerated epigenetic aging, which was more pronounced in those with a CD4 count below 200 or a viral load of more than 100,000 copies at baseline.

After only two years of antiretroviral therapy, a partial reversal of epigenetic aging was observed, and there was no difference between the NEAT trial treatment groups.

This reversal was more pronounced in participants with more severe baseline CD4 immunodeficiency.

Of course, many questions remain unanswered. For example, compared with the antiretroviral drugs used in the NEAT001/ANRS143 trial, is the epigenetic aging reversal of the latest antiretroviral drugs more obvious? How long does it take to observe?

Esteban-Cantos and colleagues concluded: “Further research is needed to evaluate the long-term effects of antiretroviral therapy on the dynamics of epigenetic aging and to reveal the clinical significance of epigenetic biomarkers in HIV-infected individuals. If They have been shown to be clinically relevant, and epigenetic biomarkers of aging can be used to identify which HIV-infected people are at higher risk of age-related complications and may therefore benefit from more aggressive preventive interventions than today.

(source:internet, reference only)

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