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VRC01 antibody can delay but not prevent viral rebound after interruption of early treatment
Liz Highleyman, 2017-08-02 11:20:00
A broadly neutralising antibody modestly delayed
the resurgence of viral replication following interruption of antiviral therapy
(ART) started during very early infection, but all study participants
ultimately experienced viral rebound, according to results presented last week at the 9th International AIDS Society Conference on HIV Science (IAS
2017) in Paris.
"These findings give us
hope that combination therapies, especially those employing the newest and
strongest monoclonal antibodies, may have some efficacy," said presenter Trevor Crowell of the US Military HIV
Researchers have explored a wide range of
approaches for curing HIV, or more accurately, bringing about periods of long-term
remission while off antiretroviral drugs. Most of these avenues have been disappointing
so far, but researchers hold out some hope for broadly neutralising monoclonal
antibodies, or bNAbs, that can disable multiple strains of HIV.
Crowell presented findings from a study
testing one such antibody, known as VRC01, in people who started ART soon after
VRC01 targets the CD4 binding site on the HIV
envelope, preventing the virus from latching on to susceptible T cells. This binding site is
conserved, or consistent across HIV strains, enabling VRC01 to neutralise
diverse viral isolates in laboratory studies.
Findings from a previous small non-randomized study
(ACTG A5340) presented last year showed that VRC01 modestly delayed HIV rebound in people who had
maintained viral suppression
for more than 6 months on an ART regimen containing an HIV protease inhibitor
or integrase inhibitor before interrupting therapy.
The present RV397
study, conducted in Thailand, looked at adults who had initiated ART during
acute HIV infection. Starting treatment very early
limits the size of the latent HIV reservoir and reduces viral diversity, giving
a better chance of achieving remission.
The study enrolled
participants from the Thai Red Cross RV254 study cohort. They had started ART soon
after infection (Fiebig stages I to III) and had well-controlled virus (HIV RNA
<50 copies/ml) for at least two years. Although initially intended to include
24 people, enrolment was halted at 19 due to problems with importing the VCR01
participants were all men, with a median age of approximately 30 years and a
median treatment duration of about 3 years. As is typical of early infection,
CD4 counts were still high (median 769 and 562 cells/mm3 in the in
the VRC01 and placebo groups, respectively).
were randomly assigned in a three-to-one ratio to receive VRC01 at a dose of 40
mcg/kg, or a placebo, every 3 weeks. At the time of their first IV infusion
they stopped ART. Infusions continued for 24 weeks, and at that point people
who still maintained viral control could continue observation without any
treatment for up to 24 more weeks.
therapy in healthy, asymptomatic people with HIV who are doing well on ART is
controversial, as studies such as SMART have shown the detrimental effects of treatment
interruption. In this study participants were monitored every 3 to 7 days, and ART
was resumed if they had a confirmed viral load above 1000 copies/ml, their CD4 count
fell below 350 cells/mm3 or they showed signs of clinical disease
was generally safe and well tolerated. One person had a severe skin rash after
the first infusion and never underwent ART interruption. There were no other
serious adverse events. Infusion-related side effects included fatigue,
headaches, nausea and injection site pain, but these were similar in the VRC01
and placebo groups. No one developed acute retroviral syndrome or new drug
Viral load rose rapidly after treatment
interruption in the placebo arm, with all but one of these participants having
HIV RNA over 1000 copies/ml after 1 to 3 weeks. There was a "modest"
delay in viral rebound in the VRC01 group, with a majority reaching this
threshold by 3 to 5 weeks. The median time to rebound was 26 days in the VRC01
group, compared with 14 days in the placebo group.
Two VRC01 recipients experienced viral rebound
a bit later, around week 7 and week 9. One man maintained undetectable viral load
through 42 weeks. He had initiated ART during Fiebig stage III and been virally
suppressed for about 3 years on a regimen of tenofovir, lamivudine, and
efavirenz. However, Crowell reported that he had his first detectable HIV RNA
measurement just days before the presentation.
Other than the last man, who was still below
the 1000 copies/ml threshold at the time of presentation and had not yet
restarted treatment, all participants achieved viral re-suppression after
Crowell said that viral rebound was associated
with a small but significant rise in total HIV DNA in the placebo group, but
not in the VRC01 group. The number of infected cells in both the VRC01 and
placebo groups remained low compared to the levels usually seen in people who
start ART during chronic infection.
The results from this study, which confirm
those of ACTG A5340, show that VRC01 alone is unable to maintain viral
suppression off ART, but it does show some activity and may play a role as part
of a combination strategy for achieving remission.
"Although the delayed time to viral load rebound with VRC01 seen
here is likely not clinically significant, it taught us two important
lessons," Jintanat Ananworanich said in a MHRP
press release. "It provides the basis for future studies in
early treated people with combination bNAbs of higher potency, and we can now
investigate the samples from this study to identify factors that might have
contributed to the delay in rebound."
VRC01 is also being
evaluated as an HIV prevention approach in the on-going AMP (Antibody-Mediated