The news broke in April 2013. Danish researchers were
mere months from finding a cure for HIV. As other media outlets eagerly
picked up the Telegraph’s electrifying report, word coursed
lightning-swift online and through social media, stoking hopes that talk
of ending the HIV epidemic,
increasingly common of late, might soon become reality.
There was one snag: The U.K. paper’s astonishing headline, "
Scientists on Brink of HIV Cure,"
wasn’t true. Researchers at the Aarhus University Hospital in Aarhus, Denmark, were, and
still are,
researching an HIV cure—that much was a fact. The Danish facility is
one in a collection that is investigating cancer drugs known as histone
deacetylase (HDAC) inhibitors as a means to flush the virus from the
so-called latent reservoir where it hunkers down, craftily evading
antiretroviral (ARV) treatment. But the Aarhus University research is
only in an early phase of the multi-year process of human trials. And
there is no guarantee that the investigators are more than scratching
the surface of the daunting task of finding a broadly applicable cure
for such a complex viral infection as HIV.
The Telegraph, which eventually revised the
online article
while the hospital released its own correction (the paper does not
appear to have run one), is hardly alone in claiming, or at least
implying, that an HIV cure is imminent. Nor is HIV the only health
concern to inspire such erroneous hyperbole. Ever since President
Richard Nixon announced the “war on cancer” in 1971, news outlets have
repeatedly raised hopes of major victory on that front.
A typically tantalizing HIV-related headline comes from the website
Medical Daily, which in March enthused that a functional cure—wherein
the virus is not totally eliminated from the body but is under control
without ARVs— was a
“step closer to reality.”
However, Michael Farzan, PhD, a prominent HIV cure researcher and a
professor at Scripps Research Institute in Florida, says, “It’s hard to
say how far along we are, from start to finish” in the quest for an HIV
cure. “Who knows; we could have moved one inch in a 100-mile race.”
Zhi Hong, PhD, head of infectious disease research at GSK
(GlaxoSmithKline), which is one of several pharmaceutical companies
investing in cure research, puts the matter more definitively: “There’s
no illusion that [a cure] is not going to take decades to come to
fruition.”
Overzealous members of the media are hardly the only ones contributing
to public misperceptions of cure research. Perhaps unintentionally—his
words ran contrary to all other
public messaging from his global health-focused foundation—Microsoft co-founder Bill Gates
told attendees
of the World Economic Forum in January that both an HIV vaccine and the
means to save people living with the virus from the need to take daily
ARVs would arrive by 2030.
Richard Jeffreys, an HIV vaccine and cure expert at Treatment Action Group, scrutinized Gates’s words in a
post on TAG’s website, reasoning that “hope does not equate to inevitability.”
“Gates’s buoyancy,” Jeffreys wrote, “does have some scientific
basis—there have been encouraging signs of progress on both the vaccine
and cure fronts in recent years—but the challenges that lie ahead must
not be underestimated.”
Then there’s the exuberant fundraising messaging coming from amfAR, The
Foundation for AIDS Research, which sends frequent emails signed by CEO
Kevin Frost in which he characterizes the nonprofit’s “Countdown to a
Cure” initiative as devoted to “unlocking HIV’s final mysteries” or
clearing the “final hurdles” blocking an HIV cure.
A high-concept
fundraising video
published on the foundation’s website in April says that the fight
against HIV has made it to “the final mile of an epic journey,” and that
“a cure for all is so close. The end is finally in sight. All we need
to do is grab the torch and take it over the finish line.” Only at the
very end of the 1,000-word
promotional text
does amfAR pivot from its repeatedly underlined claim that the
foundation’s goal is to find “a broadly applicable cure for HIV by 2020”
to finally clarifying that it actually aims to help establish the
“scientific underpinnings of a cure” by then. The initial amfAR
news release announcing the cure initiative in February 2014 never made such a clarification.
Meanwhile, Anthony Fauci, MD, director of the National Institute of
Allergy and Infectious Diseases (NIAID), a division of the National
Institutes of Health (NIH), says that success on the cure front is a
matter of “if” rather than “when.”
“That doesn’t mean that there’s any giving up on trying,” he says. “But you’ve got to realize where you are in the process.”
Bucking the trend of overly effusive reports on cure progress, CNN ran a
headline
on its website in July quoting the French virologist Françoise
Barré-Sinoussi, PhD, co-discoverer of HIV, who argued that “to develop a
cure is almost impossible.”
Headlines are by their nature reductive, certainly because of space
constraints, but perhaps more so because journalists’ efforts to lure
readers often subvert nuance or specificity in the text. In this case,
CNN left many with the dispiriting impression—just as inaccurate as the
notion that a cure is around the corner—that Barré-Sinoussi thought all
hope was lost. But as the interview clarifies, the Nobel laureate’s
claim was
more pragmatic than pessimistic,
and hinged on her description of the extreme difficulty of eliminating
every last HIV-infected cell from the body. (When referring to success
in such a feat, many scientists use more specific terminology, calling
it a sterilizing cure.) She argued that what she called remission, in
which the virus is brought to very low levels and kept there without
daily meds, is a more viable goal, one that others call a functional
cure.
******
Of course there is one person who has been cured of HIV:
Timothy Ray Brown. The 49-year-old American is also known as the
Berlin Patient,
after the city in which he was treated for leukemia and given two bone
marrow transplants, in 2007 and 2008, from a donor whose immune cells
were naturally resistant to HIV thanks to an inherited genetic mutation
about 1 percent of Caucasians possess. (Leukemia is cancer of the bone
marrow, which manufactures immune cells. A bone marrow transplant gives
an individual someone else’s immune system after theirs has been
intentionally destroyed, typically by chemotherapy.)
Until Brown’s case was first reported, and then
widely heralded,
in 2008, a cure for HIV was the research ambition that dared not speak
its name. The absence of replicating virus in Brown’s body established
what scientists call a proof of principle—in this case, that a cure is
possible—and it jolted the cure field to life. More scientists got on
the bandwagon, and research grants flowed.
The challenge before them is formidable. The principal foe is the viral
reservoir, an amorphous entity made up of cells infected with the virus
in an unreplicating form, and which may also include infected cells out
of reach of standard treatment, such as in the brain. Standard HIV
treatment doesn’t eliminate the reservoir because ARVs only work when a
cell is replicating, and because not all the meds can cross the
so-called
blood-brain barrier.
Unfortunately, Brown’s cure is not widely applicable. Such cancer
treatments, which are highly expensive, have a steep fatality rate;
post-Brown,
similar efforts
to cure HIV and cancer simultaneously in six others have failed, or the
individuals have died before researchers could establish if the HIV
cure pursuit was successful. Attempts to prepare the body for a bone
marrow transplant with less potentially lethal means have also failed to
vanquish HIV.
A critical obstacle facing cure efforts is that scientists haven’t
developed tools refined enough to determine with absolute certainty that
there are no latently infected cells hiding out in someone’s body that
might years later come to life, start producing new copies of HIV and
ultimately repopulate the reservoir. A major element of the
search-and-discovery work that largely characterizes the cure field
today is the attempt to
map the reservoir,
and to develop tests that can accurately measure its presence. Nascent
versions of such tests are helping scientists determine the success of
current attempts to at least reduce the size of the reservoir.
The disappointing case of the famed Mississippi Baby illustrates not
only the pitfalls of this inability to properly detect and measure the
reservoir, but also the scientific community’s lack of standards for
describing an HIV cure, or anything in that general ballpark.
At the 2013 Conference on Retroviruses and Opportunistic Infections
(CROI) in Atlanta, Deborah Persaud, MD, a pediatric infectious disease
researcher at Johns Hopkins Children’s Center, set off a
media frenzy when
she announced that a then-18-month-old child in Mississippi had been functionally cured of HIV.
In some ways, the qualifier “functional” acknowledges the impossibility
of declaring success in achieving a sterilizing cure. Again, a
functional cure is generally defined—there is no official definition—as a
case in which someone is not infectious, and although he or she still
harbors HIV, the virus is under control without the need for ARVs.
After the Mississippi Baby was infected at birth by her mother, doctors
quickly started her on an atypically aggressive cocktail of ARVs. Her
mother eventually interrupted the treatment, and by the time Persaud
first presented the case to fellow scientists, the girl had spent 10
months off ARVs without a viral rebound. Highly sensitive tests could,
however, still detect traces of the virus in her body. Persaud says she
used the word “functional” at the time because she felt not enough time
had passed to confirm that the child was, simply, cured.
This period
came to a close after 27 months, when the child’s viral load rebounded and she was put back on ARVs in 2014.
“The field has to really stop and think about terminology and
expectations,” reflects Persaud, who is among the leaders of a trial
seeking to replicate the Mississippi case in newborns infected at birth
around the world.
There is hope that other children will fare better than the Mississippi
Baby (whose case, along with other failed cure attempts, has taught
scientists a great deal and helped shape and propel future research).
July’s
International AIDS Society Conference in Vancouver, British Columbia,
heard news
that an 18-year-old French woman has 12 years of remission under her
belt after being born with HIV, initially receiving prophylactic
treatment, and then spending six years on ARV combination therapy before
quitting treatment. Researchers can still find some HIV DNA in her
body, but she has no detectable viral replication in her plasma.
Another dozen French individuals, known as the Visconti cohort, have
been in a state of remission for a median decade after stopping the ARV
treatment all of them started within six months of contracting HIV.
Scientists believe that, in each of them, such prompt treatment
prevented the viral reservoir from significantly entrenching itself.
Asier Sáez-Cirión, PhD, of the Institut Pasteur in Paris, first
presented data on the Visconti cohort at CROI 2011; but, in his words,
the news went “almost unnoticed” at the time. In recent years it has
garnered more interest, but nothing compared with the Mississippi Baby.
The vast disparity in attention directed at Sáez-Cirión’s and Persaud’s
respective announcements may be attributable to semantics. Sáez-Cirión
has from the start eschewed the glamour and excitement of the word
“cure,” with or without a qualifier, and has steadfastly insisted on
characterizing these French individuals as being in a state of
remission.
The word “remission,” Sáez-Cirión reasons, evokes a concept people are
familiar with from cancer: The disease is gone, but there’s always a
chance it could return. “When you use the term ‘functional cure,’” he
adds, “sometimes the ‘functional’ part is dropped and the ‘cure’ part
remains. It creates some confusion.”
Indeed,
many of the
headlines concerning the Mississippi Baby
stated
only that she was cured, thus stripping the message of any nuance.
Touting its contributions to the case (another possible reason the case
received so much media attention), amfAR stated in a
press release that “confirmation of the cure was made possible” in part by an amfAR grant supporting Persaud’s research.
******
In marked contrast to the foundation’s fundraising pitches, amfAR’s
director of research, Rowena Johnston, PhD, strikes a measured tone when
describing the current state of HIV cure research, saying, “Thoughts
around the key challenges are starting to coalesce. Not that
[researchers] have necessarily found answers or all of the answers. But
that people are really starting to agree what the challenges are.”
One major element that is increasingly coalescing is money. According to a
July report
from the global HIV advocacy group AVAC, worldwide public and
philanthropic investment in cure research leaped by 82 percent between
2012 and 2014, from $88 million to $160 million. The lion’s share comes
from the United States, mostly in the form of NIH grants, with $114
million given in 2014 and an estimated $127 million slated for 2015.
AmfAR intends to rapidly scale up its annual cure funding from $4.4
million in 2014 to give researchers a total of $100 million over a
six-year period starting in 2015. The Gates Foundation granted about $9
million to cure research in 2014.
Such figures are still paltry compared with recent HIV vaccine research
investment; the NIH spends over half a billion dollars annually on that
front. According to Fauci, the disparity between cure and vaccine
funding is not a reflection of the agency’s lack of enthusiasm for the
cure cause. Rather, vaccines get more money because the field is more
advanced; vaccines are primarily in the development, rather than
discovery, phase.
“The investment goes up once you have specific leads to pursue, and the
relatively greater NIH investment in HIV vaccine research at this point
in time reflects that,” Fauci says.
AVAC’s overall cure research figures don’t account for
industry spending. GSK
recently pledged
$20 million over five years for a joint effort with the University of
North Carolina (UNC), Chapel Hill. Additionally, Merck, Gilead Sciences,
Janssen, and the biotech companies Sangamo BioSciences and Calimmune
are all in the search.
The field is increasingly collaborative. In 2011, the NIH established
the Martin Delaney Collaboratories, which has encouraged cooperation
between academia and the private sector. There also is collaboration
between amfAR grantees.
When it comes to research that goes beyond background study and
progresses into actual curative therapies, the biggest focus is on a
method known as shock and kill, or kick and kill. In the first part of
this strategy—the shock or kick phase—an agent, or combination of
agents, spurs the machinery of latently infected cells back into action.
The subsequent challenge—the kill part—is to find ways to clear the
body of those newly active cells.
Unfortunately, ARVs don’t kill HIV-infected cells. Nor does the immune
system, in part because these particular cells have so few HIV antigens
on their surfaces. (Antigens flag a cell as infected and help summon an
immune response.) Confounding the issue, a person’s immune response to
HIV may have lessened after years of taking ARVs, and the virus in
latently infected cells may have mutated to resist the immune system’s
primary line of attack.
The lab of Robert Siliciano, MD, PhD, at Johns Hopkins University, leads
the shock-and-kill field, which includes efforts from more than two
dozen groups around the world, such as the UNC-GSK team and the Danish
lab that spawned those erroneous headlines. Researchers are testing at
least six latency-reversing agents in humans, including the HDAC
inhibitors
vorinostat, panobinostat and
romidepsin.
Scientists on the kill front are exploring
various means
of boosting the immune response in order to give rise to immune cells
or antibodies that can more effectively attack the reawakened infected
cells.
According to David Margolis, MD, who heads up the UNC effort, shock and
kill is still in “in its infancy,” but it has enjoyed some recent
advances. “The biggest limitation to forward progress right now,”
Margolis says, “is that we haven’t yet really developed safe and
effective ways to substantially deplete the reservoir that we can
measure.” In other words, with research into the kill part of the
strategy only just beginning, any results are particularly insufficient.
“I think that after hopefully not too long, maybe a year or two, we
will have forward motion in that regard.”
Fauci, however, is “not at all sure” that the overall shock and kill approach will prove successful.
Delving further into the realm of science-fiction-come-true is
research into curative
genetic therapies.
Researchers are trying to recreate Tim Brown’s case (or at least
partially so), but without the danger and impracticality of a
traditional bone marrow transplant.
Brown’s donor had a genetic mutation that prevented development of
what’s called the CCR5 coreceptor, which is located on the surface of
the CD4 immune cells that HIV targets. Without CCR5, most copies of HIV
can’t latch onto the immune cell, much less infect it. So scientists at
Sangamo and the Fred Hutchinson Cancer Research Center, among others,
are experimenting with drawing out an HIV-positive individual’s immune
cells, or immune cell-producing stem cells, and editing their genetic
code to ultimately prevent the development of the CCR5 coreceptor.
Sangamo has had some
promising results
from the company’s genetic treatment, with one 32-year-old man off ARVs
for over a year and a half following an infusion of edited,
HIV-resistant immune stem cells. He isn’t cured—the virus is still
actively replicating—but his viral load is only about 500 and his CD4
level has remained stable.
This is an example of the partial success that researchers may build
upon as they reach for the pie in the sky. Each of these individual
steps may offer new and exciting health benefits to people living with
HIV. Ultimately, multiple approaches may be required to beat back the
virus further than ARV treatment is already able to do.
“There are many routes of attack” in the cure quest, says the Nobel
prize–winning virologist David Baltimore, PhD, a professor at the
California Institute of Technology and the founder of Calimmune, “and
from my point of view, the word cure is perhaps misleading. What we want
to do is make this a less and less debilitating disease. And what that
means is limiting the effects of the virus and also moving toward forms
of therapy that are less debilitating to the patient.”
Another incremental advance that cure research may achieve is to reduce
the kind of low-level viral replication that occurs even in the presence
of successful ARV treatment. Scientists suspect this activity from the
virus may spur the immune system into a state of chronic inflammation,
which is believed to contribute to the increased risk of age-related
disorders among people living with the virus. Another shorter-term
ambition is for treatments that would allow for periods of extended
viral remission, giving HIV-positive people a safe way to take time off
from the toxicities of ARVs.
Vastly shrinking but not totally eliminating the reservoir may allow for
such extended remission. Case in point, the members of the Visconti
cohort don’t have zero reservoir; it’s just very small in each of them.
(Scientists do have the tools to determine this.) A
recent study
found that if someone stops taking ARVs, on average, a week will pass
before at least one latently infected cell successfully reactivates and
is able to kick start a viral rebound. Considering the vast number of
cells in the typical reservoir, the implication is that any given cell
only rarely jumps into significant action. Based on these observations,
the paper’s authors estimated that a 50-to-70-fold reduction in the size
of the reservoir could extend the time between stopping ARVs and a
viral rebound to an average of one year. Siliciano has made his
own projection that some people with HIV may experience lifelong remission with as little as a 1,000-to-10,000-fold reservoir reduction.
“We might get interventions that work a good part of the time in good
sections of the people,” says amfAR’s Johnston. “And so it will be this
interactive process over time until you get to an intervention that
cures most people most of the time. Maybe that’s as good as we can hope
for.”
Assuming such advances do come, there is the pressing question of
access. The new $100,000 hepatitis C cures are threatening state
Medicaid and prison health budgets nationwide, and insurers have been
restricting who can receive treatment.
The process required to draw out, edit and reinfuse an HIV-positive
person’s immune cells is quite expensive, and the cost can’t necessarily
be brought down simply by pharmaceutical companies allowing generic
production, as with ARVs used in poorer nations. (Although compared with
lifelong ARV treatment, the cost for such a cure might be a bargain,
especially if a one-time curative therapy is all that’s required.) With
the ultimate goal of expanding such a potential opportunity to
populations beyond the wealthy Western world, researchers hope that a
similarly successful outcome wouldn’t require such a complicated
process, and instead would come from a generalized vaccine-like shot, or
maybe a series of shots.
“At the end of the day, if you have what you’re calling a cure or a
sustained virologic remission, it’s got to have the three S’s: safe,
simple and scalable,” says NIAID’s Fauci. “Otherwise you’re going to
cure a handful of people that are going to make the front page of The
New York Times, and then you can’t do much else for the 36 million other
people who are infected.”
HIV Cure Research, In Short
HIV cure research is in what’s known as the discovery phase. The field
is largely characterized by efforts to better understand just what
scientists are up against in their quest to cure the virus.
Major avenues include:
- Characterizing the viral reservoir. What kind of cells are in the reservoir and where in the body are they located?
- Developing tests to measure the reservoir. This is vital to be
able to measure the success of attempts to reduce the size of the
reservoir.
- Determining how the reservoir manages to persist.
Current therapeutic pursuits include:
- “Shock and kill” or “kick and kill,” in which an agent or
combination of agents, such as cancer drugs called HDAC inhibitors, are
used to flush the virus out of latently infected cells. Then another
method is used to prompt the body to better eliminate those cells.
- Genetic therapies. Researchers are trying to recreate the Berlin
Patient’s cure by editing immune cells or immune-cell-producing stem
cells to ultimately populate the body with HIV-resistant immune cells.
Common terms:
- Sterilizing cure: totally ridding the body of HIV.
- Functional cure: There is still some virus in the body, but it’s under control without the need for daily meds.
- Remission: Some researchers prefer to use this term instead of
“functional cure,” because it is familiar to people from the world of
cancer and implies that the virus may rebound, as was the case with the
Mississippi Baby.
International investment in cure research:
2012: $88 million
2013: $105 million
2014: $160 million
These figures do not reflect for-profit investment. Many biotech and
pharmaceutical companies are pursuing cure strategies. For example, GSK
recently pledged $20 million over five years to the University of North
Carolina, Chapel Hill.
