Since the
first cases of what would become known as AIDS were reported in June
1981, nearly 700,000 Americans have died due to complications from the
disease. Though they might not physically remain with us, their spirits
continue to inspire our stories and progress us towards an HIV-free
generation.
In the last couple of decades, science has discovered HIV
began much earlier than the 1980s, too. Researchers have delivered
medications able to suppress the virus to undetectable levels
(ultimately saving millions of lives), and has edged closer to finding a
cure. But, even as technology becomes more sophisticated, researchers
have also discovered that curing — or even stopping — the virus is far
more complicated than they had anticipated. HIV can now be suppressed to
such low levels that it becomes impossible to transmit to others. With
the right combination of antiretroviral drugs, HIV-positive people can
keep the virus at bay — allowing them to live long and healthy lives
without the fear of death looming over them. But it wasn’t always this
way…
The First Anti-HIV Drug
It took the U.S. Food and Drug Administration seven years to
approve the first anti-HIV drug, and tens of thousands died in the
interim. To combat the rising death rates, public health officials were
pressured to give something — anything — to treat those living with HIV.
They found it in azidothymidine, also known as AZT, a drug originally
developed to fight cancer by inserting itself into the DNA of a cancer
cell to stop it from replicating.
When the AIDS crisis was at its height, the pharmaceutical
company Burroughs Wellcome found a version of AZT that appeared to block
HIV activity in animal cells. A clinical trial of 300 people diagnosed
with AIDS compared AZT to a sugar pill. After four months, many of the
participants on the sugar pill had died, but AZT helped stabilize those
with HIV, and on March 19, 1987, the FDA approved it as the first AIDS
medication.
Dr. Anthony Fauci, who has been the director of the National
Institute of Allergy and Infectious Diseases since 1984, has played a
leading role in the fight against HIV since day one. “For the years…
‘85, ‘86, it was frustrating, but AZT changed things,” he recalls.
“There was a degree of optimism when we showed that AZT prolonged the
lives of individuals. That optimism was quickly dampened by the fact
that, in many of the patients who were treated with AZT — that’s the
only drug we had — after a finite period of time, the virus developed
resistance against it.”
There are several classes of HIV drugs today, and AZT is
still included in many antiretroviral regimens at very low doses. But at
the levels it was first prescribed, AZT ate away at a person’s immune
system like rat poison. Still, for nearly a decade it was the best
option available, as virtually every other additional medication
developed to treat HIV proved disappointing.
1996, The Great Suppression
Protease inhibitors were the second class of antiretroviral
drugs developed — with saquinavir and ritonavir approved by the FDA in
1996. Within a couple years, the Centers for Disease Control and
Prevention reported that annual AIDS-related deaths plummeted from
50,000 to 18,000 in the United States.
These miracle drugs were proven to prevent viral
replication, and when combined with AZT (and later other drugs), were
less prone to the development of drug resistance. Fauci remembers the
development of highly active antiretroviral therapy as “about as
transforming a moment as when we first discovered the virus back in
1983.”
HIV Reservoirs, The Great Barrier
As our ability to suppress viral replication with
antiretroviral treatment increased — especially now that people on
treatment are achieving undetectable viral loads — it has enabled those
living with HIV to have long and healthy lives, as well as prevent
transmission. Still, people around the world dream of a cure, or the
complete eradication of HIV from a person’s body.
By far, the greatest barrier to reaching that goal is the
existence of viral reservoirs where HIV lies dormant, ready to come
roaring back and begin replicating again when someone goes off ART or
develops drug resistance.
Of course, scientists have tried to outsmart these
reservoirs by conceiving new strategies — particularly one called “kick
and kill,” in which latency reversing agents “wake” the inactive virus,
and antiretroviral medications kill it on the spot. But Fauci worries it
isn’t enough. “Decreasing the size of the reservoir doesn’t really get
you much,” he explains, because “when you stop therapy… they almost
invariably bounce back.”
Is a Cure Even Possible?
In the last decade, reports of people being “cured” of HIV
or experiencing years-long viral suppression without medications have
captivated the imaginations of both researchers and those living with
the virus. The most important of these cases involves Timothy Ray Brown —
dubbed the “Berlin Patient” — who was cured after being treated for
leukemia with a bone-marrow-supplied stem cell transplant in 2011.
It was later discovered that his donor happened to be part
of the one percent of European descendants who appear immune to HIV
(likely as a result of their ancestors having survived the Bubonic
Plague).
Unfortunately, later efforts to replicate Brown’s results
via stem cell transplants have failed. And, as Dr. Warner Greene,
director of Gladstone Institute of Virology and Immunology points out,
“doing stem cell transplants puts patients at considerable risk.”
Although Timothy Brown remains HIV-negative, David Margolis,
the head of Collaboratory of AIDS Researchers for Eradication, has
argued, “there are close to 80 million people that have been infected
around the globe over the last century. So, one in 80 million [cured] is
not great odds.”
Those odds were raised slightly with the announcement at
this year’s International AIDS Society conference that a 9-year-old
HIV-positive girl has remained undetectable for eight years, after only
receiving 40 weeks of antiretroviral treatment. More good news from
South Africa came last year when Science Translation Medicine reported on a group of HIV-positive children with high viral loads who have no symptoms.
Greene believes he has found one way someone could be
asymptomatic despite high viral loads. It involves keeping the immune
system’s CD4 T cells from killing themselves, which they do in a vain
attempt to stop the spread of the virus. These cell deaths trigger the
immune system to send even more CD4 T cells, which end up repeating the
deadly cycle. But, if you could stop the T cells from committing suicide
— even if you didn’t attack the virus itself — Greene believes you
could eliminate most of the symptoms of HIV.
Greene has found that the cellular death spiral can be
broken by inhibiting an enzyme known as Caspase-1. One highly potent
Caspase-1 inhibitor already exists but was sold to a company that
appears to have no interest in developing it for HIV treatments. Greene
says, because of this, “we have had to revert to creating our own
[drug]… at considerable cost, which has slowed [research].”
Other researchers have turned to the promise in gene
editing, but Fauci fears that idea may end up being more science fiction
than science fact. “From a concept standpoint, gene editing is
interesting and can work, but it may not work unless you do other
interventions that are going to be dangerous for the patient,” Fauci
says. “Just editing a gene without necessarily ablating the rest of the T
cells in the body, may not work. It may protect those cells that were
edited, but it’s not going to protect those other cells.” Still, he
admits, “I like the idea about pursuing research on gene editing.”
But if curing millions of HIV-positive people isn’t possible, what is?
Medication-free Remission
“We’ve not given up entirely on the notion of eradication,”
Greene argues, “but I think where the successes and the gains are being
made is around the area of being able to reduce and control the virus.”
Fauci goes one step further, suggesting we need to give up
on the old notion of an HIV “cure,” and embrace what he calls “ART-free
remission.”
“In other words, getting people to the point where you can
give them either sustained time off ART or intermittently be able to get
them off ART for months, maybe even years at a time,” Fauci says. Even
getting a few months of a medication vacation — without the long-term
impacts that currently come from treatment interruption — would be a
great advantage. But suppressing HIV for years without additional
treatment is the ultimate goal. “That’s where a lot of work is going
on.”
Whether you call it antiretroviral-free remission or a
functional cure, a number of recent findings suggest we could be on the
cusp of much longer-acting treatments.
As Fauci’s team at Emory University reported last year in Science, a drug used to treat gut inflammation (Entyvio) produced long-lasting viral remission in monkeys.
“When the animals were released from antiretroviral therapy,
they didn’t rebound,” Greene explains. “Actually, they rebounded and
then they reestablished a control. Amazing. The Alpha 4 Beta 7 antibody…
seems to be somehow arming an immune defense against the virus that
keeps it controlled,” even after ART stopped. Human trials with the
antibody have already begun.
Earlier this year at the Conference on Retroviruses and
Opportunistic Infections, Fauci said the antibody therapy may “teach the
immune system to recognize HIV in a way it doesn’t recognize it if it
just sees HIV alone. Our job now is to find out just what the nature of
that immune response is.” Understanding that could be a game changer —
because the difficultly in training the immune system to respond to HIV
has hindered both treatment and vaccine efforts.
All Eyes on a Vaccine
For decades, researchers have been seeking another holy
grail: an HIV vaccine. But like those searching for a cure, they quickly
discovered creating one wouldn’t be easy. Usually vaccines involve
introducing small amounts of a virus to our immune system, which
develops antibodies to it. But when our immune system encounters even a
small amount of HIV, it kicks into the suicidal-death spiral that Greene
uncovered.
Still, a vaccine is seen as essential to ending the global
HIV epidemic, and several perspective vaccines are currently in clinical
trials. They aren’t all aimed at keeping HIV-negative people negative
either. Some are evaluating the possibility of utilizing a vaccine to
achieve a functional cure.
In a study published in Nature last year, Dr.
Hanneke Schuitemaker from Janssen Vaccines reported that when her team
combined an investigational vaccine (which was a combo of two other
vaccines) with an immune booster and used it to treat HIV-positive
monkeys, they not only reached undetectable viral loads, but also saw
reduced viral reservoirs and achieved long-term viral remission.
To do that, Schuitemaker explains, “You need to further
educate the immune system through vaccination and if you then wake up
the latent virus… [it] can be taken out by the immune system.” In
collaboration with Dr. Dan Barouch of Beth Israel Deaconess Medical
Center, Schuitemaker’s team found that one-third of their test subjects
remained virally suppressed for years after the discontinuation of treatment.
The treatment is now being studied on newly HIV-positive
people in Phase I/II clinical trials, but Schuitemaker acknowledges
they’ll probably end up needing to add additional drugs to the treatment
regimen to increase its effectiveness. That fits with what Greene
imagines: “some type of cocktail approach, just like we use with
therapy, is probably going to wind up being important for the ultimate
functional cure or eradication of the virus and of the latent reservoir
as well.”
Schuitemaker and Greene also share ethical concerns,
pointing out that any potential cure, even one that is just a temporary
remission, must be worth the risk of removing people from antiretroviral
treatments known to be working.
“We have to have a safe and effective therapy… for subjects
that are doing well on antiretroviral therapy,” Greene says. “We can’t
put them at high risk to achieve a cure.”
This article first appeared in Time Ideas, here.
