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Less than 100% adherence to HIV therapy, even with viral suppression, can lead to more inflammation and immune activation
Michael Carter, 2016-10-12 07:40:00
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.
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.
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
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.
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%).
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.
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.
for statin use did not significantly affect the study’s principal findings.
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