Complete adherence to antiretroviral
therapy is needed to ensure suppression of cell-associated HIV, investigators
from the Netherlands report in the online edition of the Journal of Infectious Diseases.
A total of 40 people taking long-term HIV
therapy were included in the study, all of whom maintained an undetectable viral
load. However, modest non-adherence to treatment was associated with increases
in cell-associated virus.
“Patients who do not fail on ART, but are
even modestly nonadherent, may still have ongoing low-level residual HIV
replication,” comment the authors. “ART only blocks infections of new cells,
and not HIV-1 RNA transcription in infected cells.”
They believe their findings could have
important clinical implications, and that “full adherence to modern ART” is
required to achieve suppression of cell-associated virus.
Adherence – taking all doses of anti-HIV drugs exactly as prescribed – is central to the success of HIV
therapy. Poor adherence can lead to inadequate viral suppression in plasma, the
emergence of drug resistance and treatment failure.
The level of adherence needed to achieve
and maintain viral suppression with early antiretroviral regimens was 95%.
However, more potent drugs with long half-lives have since been developed,
meaning that an undetectable plasma viral load can be achieved with much lower
levels of adherence, possibly as low as 70%.
However, it is unclear if HIV replication
is completely suppressed when adherence is less than perfect. Research has
focused on changes in plasma viral load. It has not previously addressed the
association between adherence and HIV replication in cells.
“We investigated whether residual
replication could be promoted by modest nonadherence to ART,” explain the
investigators. “We studied the influence of slightly decreased adherence to
therapy on the changes in levels of cell-associated viral markers”: unspliced
RNA (usRNA) and DNA.
The study population comprised participants
enrolled in a long-term study investigating an adherence-support intervention.
Adherence was monitored electronically using MEMS (Micro-Electro-Mechanical Systems) technology.
All the participants had regular viral load
tests. The virological success of therapy was also assessed by monitoring
cell-associated HIV in peripheral blood mononuclear cells (PBMC). These markers
were monitored on three occasions at intervals of three to four months.
At the start of the study, the participants had
been on successful HIV therapy with undetectable viral load (except for occasional 'blips', transient increases in viral load of below 1000 copies/ml) for a
median of 46 months. Their median CD4 cell count was 620 cells/mm3.
HIV usRNA was detectable in 76% of samples
and HIV DNA in 96%.
These samples were paired with viral load
measurements obtained at the same time. Viral load was undetectable in 91% of instances;
the other samples were all below 400 copies/ml.
Adherence was monitored one week before
measurement of HIV RNA and DNA in PBMC. Most of the participants (58%) had perfect
adherence at all three time points; 20% had less-than-perfect adherence when
this was first assessed, but achieved 100% adherence at a later time point; and
22% of patients had “poor adherence” – less than 100% without improvement over
the course of the study. Participants with less than 100% adherence took a median
of 82% of their doses.
None of the participants experienced a rebound
in their viral load.
However, the investigators found a clear
association between level of adherence and changes in usRNA.
Median usRNA fell in people with 100%
adherence, remained unchanged in those with improving adherence and
increased in people with poor adherence (comparison optimal vs poor
adherence, p = 0.006).
“Poor adherence was associated with a
significant longitudinal increase in levels of usRNA, whereas no significant
longitudinal trends in usRNA were observed for patients with optimal or improving
adherence,” write the investigators. “This indicates that HIV-1 usRNA in PBMC
is a viral molecular marker with a significantly better sensitivity to modest
changes in adherence than viral RNA in plasma, measured by an assay with a
detection limit of 50 copies/ml.”
They believe their results “suggest that
constantly optimal adherence to ART may be required life-long”.
The findings could have real clinical
significance. Antiretroviral therapy has been associated with significant
improvements in prognosis for people with HIV. However, even with such treatment,
the life expectancy of HIV-positive people is generally still poorer than that of
HIV-negative individuals. The investigators speculate that this could be due to
damage caused by residual HIV replication when adherence is less than perfect.
“It is plausible that constant low-level virus replication would exert
continuous pressure on the immune system and cause additional morbidity as a
result of persistent immune activation, inflammation, and immunosenescence.”
The findings of the study could therefore have
implications for advice given to people about adherence. “Forgiveness of ART,
defined as an ability to maintain complete viral suppression despite imperfect
adherence, may require re-evaluation in view of our results,” conclude the