Montreal study finds integrase inhibitors linked to better T-cell ratios

• The ratio of CD4 to CD8 cells gives an overall picture of the health of the immune system
• Montreal researchers studied nearly 4,000 people with HIV who used different HIV treatments
• People on a regimen containing an integrase inhibitor had better CD4/CD8 ratios

If left untreated, chronic HIV infection slowly degrades the immune system in multiple ways. However, once HIV treatment (ART) is initiated and taken as directed, levels of HIV in the blood fall. Usually within three to six months after ART initiation, HIV levels in the blood will fall to very low levels (commonly called “undetectable”).

Having an undetectable HIV viral load has at least the following benefits:

• The immune system can begin to repair itself.
• Studies have found that people who maintain an undetectable viral load with continued treatment do not pass on the virus to their sexual partners.

The benefits of ART are so profound that researchers project that many ART users will have near-normal life expectancy.

However, ART cannot resolve every health-related matter, and subtle immunological issues persist despite good adherence. Some studies have found that in older HIV-negative people, the common herpes virus CMV appears to prematurely age the immune system. Infection with CMV is associated with a reduced CD4/CD8 ratio in this population. So, it is possible that CMV coinfection in people with HIV may have similar or other effects on their immune system.

Another issue is the gut. The lining of the gut serves as a barrier, keeping out proteins produced by harmful bacteria and fungi that are in the digestive tract. Some research suggests that the barrier function of the gut is weakened in people with HIV. This weakness persists despite good adherence to ART and may allow proteins from some bacteria and fungi to enter the blood. These proteins can in turn partially weaken the immune system.

Scientists in Canada and other countries are studying ways to reduce the impact of co-infections such as CMV and to strengthen the barrier function of the gut.

A study about ART and T-cell ratios

An overall measure of the immune system’s health is the level of a group of T-cells called CD4+ cells. In addition to suppressing HIV, one of the goals of ART is to help raise the number of CD4+ cells in the blood over the medium- and long-term. Higher CD4+ cell levels (or CD4+ counts) significantly reduce the risk of AIDS-related infections.

Another measure to gauge the health of the immune system is the ratio of two types of T-cells—CD4+ and CD8+ cells—which is written as CD4/CD8.

In healthy HIV-negative people, a normal CD4/CD8 ratio is 1 or greater. As HIV attacks the immune system, cell ratios fall below 1 in most people prior to initiating ART.

In Montreal

Researchers in Montreal have been studying the impact of ART on changes to CD4/CD8 ratios over time. They have found that some ART users are eventually able to achieve a ratio of 1 or greater. The chances of doing so were heightened among people who took a combination of anti-HIV drugs that contained an integrase inhibitor compared to other classes of HIV treatments.

As the present study was observational in design, its findings are suggestive, not definitive. However, the study enrolled people from HIV clinics in Montreal, so the findings are reflective of people that doctors in HIV clinics treat and what they may expect. Other studies have also found that integrase inhibitor–based regimens are more likely to be associated with improved T-cell ratios.

Study details

Researchers analysed health-related information from 3,907 people enrolled with the Quebec HIV Cohort. The researchers focused on data collected between 2006 and 2017.

Researchers divided participants into three groups based on the medicine that anchored their HIV treatment:

• a non-nuke (NNRTI – non-nucleoside reverse transcriptase inhibitor)-based regimen; this class includes drugs such as efavirenz (in Atripla and sold in generic formulations), rilpivirine (Edurant and in Odefsy) and doravirine (in Delstrigo and Pifeltro)
• a protease inhibitor–based regimen; this class includes drugs such as darunavir (sold as Prezista and in generic formulations) and atazanavir (sold as Reyataz and in generic formulations)
• an integrase inhibitor–based regimen; this class includes bictegravir (in Biktarvy), dolutegravir (Tivicay and in Dovato and Triumeq) and raltegravir (Isentress and sold in generic formulations)

The breakdown was as follows:

• non-nuke group – 972 people
• protease inhibitor group – 1,996 people
• integrase inhibitor group – 939 people

Upon entering the study, the average profile of participants was as follows:

• age – 42 years
• CD4+ count – 300 cells/mm³
• CD4/CD8 ratio – 0.4
• 25% had an undetectable viral load (less than 50 copies/mL); most people were either not on ART or had only recently initiated ART
• length of time since HIV diagnosis – six years
• length of time in the study – five years

Results

Over the course of the study, the proportion of people in each treatment group whose CD4/CD8 ratio reached 1 or higher was as follows:

• non-nukes – 14%
• protease inhibitors – 10%
• integrase inhibitors – 20%

Statistical analysis confirmed that people on an integrase inhibitor–based regimen were more likely to normalize their CD4/CD8 ratio.

When researchers restricted their analysis to 1,041 people who were receiving their first regimen, the trends were similar. That is, people who were taking integrase inhibitors were more likely to achieve a CD4/CD8 ratio of 1 or higher.

Bear in mind

A strength of this study is the relatively long period of observation—five years. Also, it included people typically seen in clinics that provide HIV care and treatment.

The study is observational in design, and such studies can sometimes inadvertently lead scientists to draw biased conclusions. However, the researchers took steps to minimize this possibility. There may be factors not considered that could have affected researchers’ conclusions. For instance, the researchers did not assess adherence to treatment. Also, the reasons some people were prescribed certain regimens were not clear.

Nevertheless, the findings from the Montreal study are broadly similar to findings from several other studies, also observational in design. A trial that could provide a more definitive outcome—such as a large, long and randomized clinical trial—would be expensive and time consuming. Furthermore, in an era of limited research funding, a large, randomized trial primarily designed to assess changes in CD4/CD8 cell ratios and link these changes to the type of ART used may not be prioritized.

A consideration for studies such as the one from Montreal is that treatment guidelines change. Specifically, they privilege different classes of drugs over time as data from clinical trials accumulate. For instance, in the early ART era, protease inhibitors were largely recommended. Only in subsequent years were non-nukes recommended. In the past decade, integrase inhibitors became available, and that is now the class that is judged as most effective and well tolerated, and therefore prioritized by leading treatment guidelines. In the future, perhaps a new class of drugs will be found to be more effective or better tolerated and will displace integrase inhibitors.

Although the Montreal study has found a promising outcome with the use of integrase inhibitors, people should not rush to switch their regimens based on this or another single study. Doctors carefully weigh many issues when choosing a regimen and switching regimens carries risks of potential side effects. Therefore, equally careful deliberation will be needed when changing a regimen, particularly if a person’s current regimen is well tolerated, safe and effectively suppresses HIV.

Cell ratios and cancer risk

A large North American study with more than 83,000 people with HIV who were taking ART found that people who had a CD4/CD8 ratio of 0.8 or greater were significantly less likely to develop cancer compared to people who had a ratio of 0.3. Specifically, this study found that people with low CD4/CD8 ratios had a 24% increased risk of cancer than people with higher ratios. Other studies have also found low T-cell ratios to be associated with an increased risk of cancer and other complications. This does not mean that most people with a low CD4/CD8 ratio will get cancer or other complications, just that their risk is likely greater.

By Sean R. Hosein

Resources

Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV – Department of Health and Human Services

North American study finds low CD4/CD8 ratio can help predict cancer risk in people with HIV – CATIE News

Attention on inflammation also turns to fungi – TreatmentUpdate 232

Looking to letermovir to reduce inflammation and other issues in people with HIV – CATIE News

Canadian researchers point to CMV as a problem for the immune system – CATIE News

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