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IAS 2017: VRC01 Antibody Can Delay But Not

Prevent HIV Rebound


A broadly neutralizing 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 at the 9th International AIDS Society Conference on HIV Science (IAS
2017) last month in Paris.

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 experts hold out some hope for broadly neutralizing monoclonal antibodies, or bNAbs, that can disable
multiple strains of HIV.

Trevor Crowell of the US Military HIV Research Program presented findings from a study testing one such
antibody, known as VRC01, in people who started ART soon after HIV infection.

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 neutralize 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 2 years.
Although initially intended to include 24 people, enrolment was halted at 19 due to problems importing the VCR01
product.

The 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/mm 3 in the in
the VRC01 and placebo groups, respectively).

Participants were randomly assigned in a 3:1 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.

Stopping 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/mm 3, or they showed signs of clinical disease progression.

VRC01 treatment 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 resistance mutations.
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 resuppression after resuming ART.

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.

"These findings give us hope that combination therapies, especially those employing the newest and strongest
monoclonal antibodies, may have some efficacy," Crowell said.

"Although the delayed time to viral load rebound with VRC01 seen here is likely not clinically significant, it taught
us 2 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-goingAMP (Antibody-Mediated
Prevention) trial.

8/9/17

Source
TA Crowell et al. HIV-specific broadly-neutralizing monoclonal antibody, VRC01, minimally impacts time to viral
rebound following treatment interruption in virologically-suppressed, HIV-infected participants who initiated
antiretroviral therapy during acute HIV infection. 9th International AIDS Society Conference on HIV
Science.Paris, July 23-26, 2017. Abstract TUAB0106LB.