The first observation was that the addition of maraviroc further suppressed
viral replication beyond that achievable by the four-drug regimen. SIVmac251
is more difficult to control virologically than HIV is in humans (because monkey immune cells produce about 20 times more viral particles) and the
tenofovir/FTC/raltegravir regimen only suppressed viral load in one monkey out
of the original four and, with added darunavir/r, in three out of four. All monkeys
achieved undetectability on maraviroc. Adding in maraviroc increased viral load
suppression from about 1.5 logs (a fifty-fold reduction in viral load) to about
3 logs (an 800-fold reduction).
In one case (a monkey in which treatment persistently failed to suppress HIV), the animal was
found to have a higher viral load in its cerebrospinal fluid (CSF) than
in its blood. It finally reached undetectability (in both blood and CSF) when
the ritonavir-boosting dose was doubled: ritonavir facilitates drug transport
over the blood-brain barrier. This finding provides interesting support for the hypothesis
that a number of cases of treatment failure are caused by unsuppressed HIV in
the central nervous system.
Secondly and unexpectedly, it was found that adding in
maraviroc produced a continued decline in viral DNA – a measure of the number of
infected cells rather than free virus. Normally, even on fully suppressive ART,
there is a residual viral load that stays fairly constant. The investigators found that,
under the five-drug regimen, there was a slow but continued decline in viral DNA
over 200 days of five-drug therapy, indicating that the proportion of
circulating lymphocytes that were HIV-infected declined from 20 per million to
four per million.
Thirdly, measurements in three monkeys of the subsets of T-cells that
comprise the chronically infected reservoir of cells – the central-memory and
effector-memory cells – found that, in two out of three cases, the proportion of
these cells relative to the total T-cell population declined over a period of
four months, whereas naive T-cells, a subset not thought to be part of the reservoir,
Fourthly, in four monkeys that were taken off therapy, it was found
that the viral load ‘set point’ – the average viral load maintained off therapy
– was lower than it was before therapy, in three out of four cases by about one
log (ten times lower). The only experiments in humans that have managed to
produce a permanently lower set point were in people treated in very early infection.
Finally, the two monkeys subjected to treatment interruptions not only
maintained much lower viral loads when taken off therapy, but intermittently
had undetectable HIV. The monkey in the original study that included auranofin,
which was given three treatment interruptions, initially had a viral load of
two million copies/ml but, after the second treatment interruption, maintained
one of about 800 copies/ml, varying between undetectable and a couple of peaks
of about 10,000 copies/ml.
The second, which had escalating ART, then three months on five drugs and
auranofin, then two treatment interruptions, had a pre-treatment viral load of
about 80,000 copies/ml and a post-treatment viral load that averaged about 250
copies/ml, varying between undetectability and about 4000 copies/ml. Neither
showed any signs of breakthrough to higher viral loads within a time period of
about 200 days.
Andrea Savarino, one of the investigators, told aidsmap that the team is now optimising the treatment protocol in macaques. When asked if
there would, in his opinion, be benefit in adding maraviroc to ART regimens in humans right now, he said: "Yes, and human studies point in the same direction."