Less than 100% adherence to HIV therapy, even with viral suppression, can lead to more inflammation and immune activation

Research involving men taking antiretroviral therapy, all with an undetectable viral load, has shown that imperfect adherence to therapy is associated with higher levels of key markers of inflammation and immune activation. The study is published in the online edition of Clinical Infectious Diseases. The authors believe their findings could explain the residual inflammation observed in people taking HIV therapy who have a suppressed viral load.

“To our knowledge, this is the first report in which suboptimal cART [combination antiretroviral therapy] adherence has been associated with heightened levels of inflammation and immune activation despite suppressed HIV viremia using standard clinical assays,” comment the investigators. “cART adherence variations could have significant biological consequences despite apparent HIV suppression, since persistent inflammation and immune activation are associated with increased morbidity and mortality among HIV-infected persons.” Low level HIV replication due to imperfect adherence could, the investigators suggest, be an explanation.

Improvements in treatment and care mean that many people with HIV now have a normal or near-normal life expectancy. Starting antiretroviral therapy and attainment of an undetectable viral load (below 50 copies/ml in most test assays, with some modern tests having a threshold of 20 copies/ml) is associated with reductions in markers of systemic inflammation and immune activation.

Glossary

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

biomarker

Genes, proteins or chemicals that can act as signals for certain diseases.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

residual inflammation

HIV-associated inflammation that persists at very low, undetectable levels, in the HIV reservoir and might reactivate HIV replication. 

longitudinal study

A study in which information is collected on people over several weeks, months or years. People may be followed forward in time (a prospective study), or information may be collected on past events (a retrospective study).

However, viral suppression does not reduce levels of inflammation and immune activation to those observed in the HIV-negative population. Persistent inflammation and immune activation may have serious clinical consequences and have been linked to the development of serious non-AIDS-related illnesses including cardiovascular, renal and liver disease, cognitive decline, frailty and malignancies. The reasons for the low-level inflammation and immune activation observed in people who have a suppressed viral load are not yet fully understood, but it is plausible that imperfect adherence and ongoing low-level viral replication may have a role.

Investigators from the ongoing Multicenter AIDS Cohort Study (MACS) therefore undertook a prospective, longitudinal study to assess whether adherence to HIV therapy below 100%, even when it attained viral suppression (below 50 copies/ml), was associated with residual inflammation and immune activation.

The study population comprised 912 men who received care between 1998 and 2009. The men provided information about adherence to their HIV therapy in the four days just before their six-monthly follow-up visits and were asked whether it was typical of the previous six months. Participants in the study were also tested for 24 biomarkers of inflammation and immune activation. Biomarker levels were compared between participants with 100% adherence and those with less than perfect adherence. Two sets of analysis were performed, comparing four-day adherence (100%; 85 to 99%; below 85%) and six-month adherence (100% vs below 100%).

Participants contributed a total of 2816 study visits (median 3 per person). Their median age was 48 years and median CD4 count was 584 cells/mm3.

Perfect and imperfect six-month adherence was reported at 87% and 13% of study visits, respectively. Analysis of four-day adherence showed that 100% adherence was reported at 88% of visits, 85 to 99% adherence at 4% of visits and below 85% adherence at 8% of visits.

In the six-month adherence analysis, imperfect adherence (compared to 100% adherence) was associated with higher concentrations of 21 out of the 24 biomarkers, with significantly higher levels of c-reactive protein (CRP)(21%, p = 0.006), IFN-gamma (15%, p = 0.008), IL-2 (14%, p = 0.022), IL-6 (12%, p = 0.014), TNF-alpha (11%, p < 0.001), IL-10 (11%, p =0.023). After adjustment for multiple confounders, imperfect adherence remained significantly associated with higher concentrations of TNF-alpha.

In the four-day adherence model, adherence between 85 and 99% was not associated with higher concentrations of any biomarkers compared to 100% adherence, with the exception of TNF-alpha (10% increase, p = 0.019). However, adherence below 85% was associated with significantly higher levels of six biomarkers, compared to perfect adherence: CRP (22%, p =0.01), IL-2 (20%, p = 0.011), IFN-gamma (17%, p = 0.012), IL-6 (16%, p = 0.01), IL-10 (13%, p = 0.035) and TNF-alpha (10%, p = 0.001). As with the six-month analysis, TNF-alpha remained significant in models taking into account multiple confounders.

Models adjusting for statin use did not significantly affect the study’s principal findings.

“We demonstrated that suboptimal cART adherence is associated with enhanced inflammation and immune activation despite apparent HIV virologic suppression,” conclude the investigators. “Our findings set the framework to better understand the biological consequences of cART adherence variations and has identified adherence as a target for future investigations aimed at further reducing residual chronic inflammation and immune activation in HIV-infected individuals.”

References

Castillo-Mancilla JR et al. Suboptimal cART adherence is associated with higher levels of inflammation despite HIV suppression. Clin Infect Dis, online edition, 2016.