HIV Cure Research: Separating the Hope from the Hype
Sound science takes time. As Richard Jefferys of Treatment Action Group explained in a recent webinar, “
HIV Cure Research—Getting Past the Media Hype,” a number of
clinical trials are underway
in the quest for an HIV cure, but none of the interventions currently
under study are expected to cure people of HIV. Rather, those studies
provide essential information to get cure science to “the next round” of
development, said Jefferys.
Jefferys and webinar co-host David Evans, director of research
advocacy at Project Inform and community advisory board member with the
Delaney AIDS Research Enterprise, unpacked the concept of “cure,”
outlined the types of cure currently under study, and highlighted key
questions at the heart of cure research today.
Defining “Cure”
According to Evans, in cure research, “one of the biggest areas of
concern is how we define a cure in the first place, and what that says
about people’s hopes and desires.” So what exactly constitutes a cure,
and what does “cured” look like in the real world, beyond clinical trial
settings?
While acknowledging that definitions of “cure” continue to be
refined, Jefferys described the most widely agreed-upon potential types:
- A sterilizing cure would involve total elimination
of all replication-competent HIV (that is, HIV that is capable of making
more copies of itself) from the body.
- With a functional cure, the virus may not have been
completely eliminated but no HIV replication is detectable and
individuals experience no disease progression in the absence of
antiretroviral treatment.
- Remission, the latest definition to enter the HIV
cure dialog, refers to control of HIV viral load at low levels (such as
below 50 copies/mL) in the absence of treatment.
Timothy Brown,
who had both HIV and leukemia and underwent intensive radiation and
chemotherapy and received transplanted stem cells from an HIV-resistant
donor, appears to represent a sterilizing cure, Jefferys said. The most
ultrasensitive tests have detected no replication-competent HIV in his
tissues in the eight years since his radical treatment. (
Timothy Brown tells his own amazing story here.)
However, the treatment Brown received was in itself life-threatening,
and is not seen as a scalable approach to curing HIV. In addition, a
sterilizing cure is the most difficult to prove, involving extensive
tissue sampling and testing with the most sensitive assays to look for
viral RNA, HIV’s own genetic material: “It’s a huge challenge to figure
out how to measure such tiny amounts of HIV RNA,” Jefferys noted.
“We may never get to a place where we totally eradicate the virus in
most people,” added David Evans, “but instead place them in a kind of
remission, whereby HIV is fully controlled, but not causing much harm
without the need for antiretroviral drugs.”
Current Approaches to Curing HIV
Evans detailed the current major avenues of HIV cure research, and progress to date.
“Shock and Kill”
One of the biggest obstacles to curing HIV is posed by viral
reservoirs, cells harboring “latent” or non-replicating HIV. Because
these latently infected cells do not display pieces of HIV on their
surfaces, Evans explained, the immune system cannot not recognize and
destroy them.
A handful of anti-cancer drugs belonging to a class known as histone
deacetylase inhibitors (HDAC inhibitors for short) alter viral genes,
allowing the body to recognize infected cells. HDAC inhibitors are being
tested for their ability to force latent HIV out of hiding, then kill
infected cells—a strategy known as “shock and kill.”
When researchers tested the HDAC inhibitor vorinostat (also known as
SAHA) with once-daily dosing over several days, they saw a rise in viral
RNA—“what we want to see,” as Evans put it, when testing a drug to
shock the virus into the open. However, the increase was only temporary,
and HIV
DNA—the genetic material produced when HIV
replicates—did not decline, indicating that no “kill” had occurred. Two
clinical trials are currently underway to address the safety and
efficacy of vorinostat for draining HIV reservoirs.
Another HDAC inhibitor, panobinostat, launched
a media frenzy
when researchers reported evidence that the drug induced HIV
replication in an early-stage clinical trial; however, results on viral
DNA are not yet available from the research team in Denmark, Evans
stated. A trial of the HDAC inhibitor romidepsin is also underway, with
results anticipated in late 2015.
Stem Cell Transplantation
The “Boston patients” made headlines in 2012, when researchers
reported on two men who underwent stem cells transplant procedures
similar to Timothy Brown’s, but with a few key differences: The two men
had “gentler” chemotherapy and no full-body radiation, so they retained
host immune system cells; they received donor cells that were
susceptible to HIV infection, unlike the HIV-resistant cells Brown
received; the Boston men were themselves heterozygous for the
HIV-blocking mutation, meaning they each had a single copy of the
protective gene; and both continued to take antiretroviral drugs
throughout and following their procedures.
Up to four and a half years after the transplants,
the research team could detect no HIV
using highly sensitive tests, and the two individuals and the research
team agreed to an analytical treatment interruption to see whether the
virus would return. “Initially, things looked really good,” noted Evans
in the webinar. But within weeks to months of stopping antiretroviral
therapy,
the virus returned.
Both men saw huge spikes in their formerly undetectable viral load,
Evans explained, and both experienced retroviral syndrome—the immune
system’s reaction to unchecked viral replication, typically seen in
people recently infected with HIV.
“I think what this is telling us is how difficult it is to actually
kill the virus,” said Evans. Both men were able to get the virus under
control again with antiretroviral therapy (ART).
Extremely Early Treatment
As
reported previously,
the “Mississippi baby” was diagnosed with HIV using RNA and DNA tests,
which detect HIV’s genetic material rather than antibodies to the virus
(which can be carried over from the mother). She was started on
triple-drug antiretroviral treatment just 30 hours after birth, and
within a month, her viral load was undetectable. She continued on
treatment until around 18 months of age, when she was lost to care for
several weeks. When the child was brought back for medical visits at
roughly two years old, she had been off treatment for five months—yet
she had an undetectable viral load.
In March 2014, when the child was approximately three years old and had been off ART for 23 months,
Persaud reported
at the 21st Conference on Retroviruses and Opportunistic Infections
that “there has been no detectable rebound in plasma virus using
standard clinical assays with detection limits of less than 20
copies/mL,” and suggested that the child is “in remission.”
Persaud also reported on a
second infant,
born in California, who was started on ART just four hours after
delivery. HIV infection was confirmed by the same HIV RNA and DNA tests
administered to the Mississippi baby. Nine months old at when Persaud
reported the case, the Long Beach child had had no detectable viral RNA
or DNA since day 11 and day 6 after birth, respectively. However, the
child remains on ART. “These tests that we’re doing are really being
done under antiretroviral treatment cover, quite unlike the Mississippi
child,” Persaud said in a press conference. “Having said that, at nine
months of age, there’s less than 2 copies of HIV DNA [per mL in blood
cells] and we have not detected a replication-competent reservoir,” she
added.
In the May 8 webinar, Evans also noted that five Canadian children
born with HIV and treated within 24 hours after birth are being followed
by cure researchers. All had undetectable viral load to as old as eight
years of age; however, all remain on antiretroviral therapy. One child
whose treatment was interrupted saw the virus return.
If most of these children are still on treatment, asked one webinar
participant, why are we even talking about them? “They’re being
discussed because they don’t have any detectable virus, no matter how
hard we look,” explained Evans. An as Persaud put it in March, “There’s a
signal here that giving very early antiretroviral drug treatment in
neonates really restricts HIV spread [in the body], to the point that it
becomes difficult to detect infection.”
Also as previously reported, the
VISCONTI Cohort
in France includes adults who began ART within days to weeks after
infection with HIV, remained on treatment for several years with
undetectable viral load, and have now been off ART for as long as ten
years with no major viral rebound.
As Evans emphasized, these individuals are genetically distinct from
“elite controllers”—a small population of people whose immune systems
are able to keep HIV in check without treatment. The cohort originally
included 14 individuals, but Evans noted that roughly 20 are being
followed today.
Key Questions
Cure trials to date have provided essential data that point the way
for future research. However, as Richard Jefferys explained, many
significant questions remain that have important implications for the
way we pursue cure science.
For example, we know draining viral reservoirs is key—but by how
much? “How much do you have to reduce the HIV reservoir to really have
an effect, and not have it return off antiretroviral treatment?” asked
Jefferys. Long-term monitoring of trial volunteers will be essential as
more studies tackle viral reservoirs.
Other major questions highlighted in the webinar included:
- Can combinations of interventions be used to reverse HIV latency and eliminate infected cells?
- Are there immune responses that can be induced or revived that would lead to HIV control?
- Can gene therapies generate enough HIV-resistant cells to cure infection?
- Can early treatment lead to a cure in more children? In adults? And how early is early enough?
- How and when can we confidently deem a person “cured”?
To explore these and other questions, Jefferys added, the Forum for
Collaborative HIV Research will host a public meeting on June 17 in
Washington, DC. The meeting will be webcast to allow for greater
participation;
click here for details and to register.
The webinar concluded with a thought-provoking Q&A session, in
which one participant questioned the wisdom of funneling limited
resources into cure research rather than expanding access to HIV
treatment. “As good as antiretroviral therapy is, and as close as we are
getting people to a place where they would live out a natural, normal
life span, we still do see long-term toxicities and health concerns
because of that low level of virus that is able to persist,” stated
Evans. A scalable cure or way to get people into HIV remission in the
absence of ART, he said, would be “a net win for all.”
