HIV therapy with the addition of an extra drug that crosses the blood-brain
barrier does not reduce residual levels of viral replication in cerebrospinal
fluids or the blood, an international team of investigators report in the online
edition of the Journal of Acquired Immune
The researcher also
found that patients continued to have evidence of immune activation and
inflammation in the brain.
intensification with a potent CNS [central nervous system]-penetrating
antiretroviral drug does not reduce residual CSF [cerebrospinal fluid] HIV RNA
levels or intrathecal immune activation”, write the investigators.
antiretroviral therapy has dramatically reduced rates of illness and death in
patients with HIV. Recent advancements in antiretroviral treatment mean that an
undetectable viral load is a realistic goal for the vast majority of patients.
When combination treatment first
became available in 1996 there were initially hopes that long-term suppression
of HIV in the blood would eventually lead to eradication of the virus. However,
it soon became apparent that HIV levels in blood were being repopulated from
latent CD4 cells that were infected with the virus.
ultrasensitive viral load tests have shown that the majority of patients taking
treatment continue to have very low levels of HIV in their blood.
Residual viral load (2
to 20 copies/ml) has also been observed in the cerebrospinal fluid of
individuals with undetectable blood viral loads. In addition, many patients
taking HIV therapy, even if taking drugs capable of crossing the blood-brain
barrier have evidence of intrathecal immune activation and inflammation.
Because of these
findings, investigators wished to see if adding an extra antiretroviral drug to
regimens that were already suppressing viral load would reduce residual HIV levels in the
cerebrospinal fluid and immune activation and inflammation in the brain.
Their study involved
ten patients. These individuals had had an undetectable blood viral load (below
50 copies/ml) for a median of 6.5 years. Their median CD4 cell count was 465
cells/mm3, eight were men and their average age was 52.
The study lasted eight
weeks. Lumbar punctures were performed on entry to the study, at baseline,
after four weeks of treatment, and again at the end. Viral load was measured in cerebrospinal fluid and markers of
intrathecal immune activation and inflammation were also monitored.
intensified by the addition of either maraviroc (Celsentri) or lopinavir/ritonavir (Kaletra), both of which have good penetration into the central
nervous system, or with T-20 (enfuvirtide, Fuzeon),
which does not.
During the first four
weeks of the study, the patients received a brain-penetrating drug, after which
they switched to T-20.
At baseline, median
blood viral load was 5 copies/ml, and median viral load in cerebrospinal fluids
was 2 copies/ml. Immune activation or inflammation in the brain was evident in
the majority of patients.
therapy did not further reduce residual viral load levels in cerebrospinal
fluids which remained unchanged through the eight weeks of the study. Seven
patients had detectable viral load in this compartment at least once. Viral
load in blood was also unaffected, as were markers of intrathecal inflammation
and immune activation.
maraviroc and Kaletra were well
within their therapeutic ranges, and maraviroc was detectable in the
cerebrospinal fluids of seven patients.
“We show that
treatment intensification has no effect on either residual CSF HIV RNA levels
or intrathecal immune activation over the course of 4 weeks with an
antiretroviral drug that penetrates in the CNS”, comment the authors. “We could
not detect any significant changes in the level of residual plasma viremia
during the total treatment intensification period of 8 weeks.”
The investigators do
not believe that their findings have any immediate implications for HIV care.
Rather, they are of interest regarding “HIV persistence and reservoirs…these
findings argue against the hypothesis that ongoing cycles of viral replication
are the main source of residual CSF viremia and intrathecal immune