In 1984, a Canadian gay man named Gaëtan Dugas died of complications from AIDS. Dugas is thought to be the first patient identified as HIV-positive, thus securing a nickname that was one for the history books: Patient Zero.
In 2008, a gay man living in Berlin named Timothy Ray Brown was given the second of two experimental stem cell treatments, from a donor his doctors chose due to a genetic immunity to HIV. The treatment not only cured Brown’s leukemia, it also cleared his body of the virus. Brown remains the one example of a proven cure.
Because of Brown’s leukemia and particular genetic profile, his case is unique; subsequent efforts to replicate the procedure’s success have fallen short. Still, the differing fates of these two men mark the extraordinary progress HIV researchers have made in bringing to heel a disease that has gone from a surefire death sentence to a manageable condition with a normal lifespan.
Now, two more patients — with the first names Luis and Clark, no less — may find themselves at least footnotes in the narrative of HIV’s trajectory from pandemic to cure, should the latter be achieved. The cases of Clark Hawley, 54, and Luis Canales, 31, have provided at least a temporary answer to a big question: Can very early treatment after exposure to HIV lead to complete eradication of the virus — an actual cure?
No, not yet.
But almost. In Hawley’s case, nearly immediate treatment did usher in a striking period of long-term remission, also called a “functional cure,” in which zero trace of HIV was detected in his blood or tissue samples, without the benefit of drugs.
Both Hawley and Canales spoke at this year’s amfAR HIV Cure Summit, at UCSF in San Francisco on Nov. 28, just before World AIDS Day. There, top researchers and community activists reviewed the latest progress toward both a cure and HIV latency, or remission, where the virus lies dormant without having to be corralled by antiretroviral drugs.
Hawley and Canales regaled the crowd with tales of providing copious amounts of blood and spinal fluid, as well as samples from two of HIV’s primary hiding places, the gut and lymph nodes. In one session, Hawley said, he donated 30 vials of blood.
The men were recruited as part of an ongoing observational UCSF study. Both were given an initial dose of the antiretroviral combination Truvada, also known as pre-exposure prophylaxis, or PrEP, within two weeks after their suspected exposure to the virus. The treatment came so soon after infection that their immune systems had yet to generate an antibody response. In Hawley’s case, only a more sensitive genetic test called PCR, which measures an individual’s viral load, showed signs of HIV. After the initial treatment, both men were switched to a daily four-drug antiviral regimen, which drove the virus below detectable levels.
What happened next is a mystery.
As reported Nov. 7 in PloS Medicine, a UCSF team led by Drs. Timothy Henrich and Steven Deeks said it failed to detect any trace of HIV in Hawley’s blood or tissue for the two years he remained on medication. Typically individuals on successful HIV therapy are classified as “undetectable” when drugs drive viral activity below observable levels in the blood. But it’s known that a small amount of residual virus called the HIV reservoir may be found in tissue using sensitive PCR tests. These came up negative.
Hawley then went off the drugs, a step that was part of the study design. About seven months later, the virus rebounded, quickly multiplying into an active infection. He immediately resumed antiretroviral treatment, which again rendered the virus undetectable.
But what puzzled scientists was that his body still showed no sign of an antibody response. That suggested his immune system had never had sufficient time to generate a defense because the drugs had worked so quickly that they halted the initial infection. Yet, they knew he still had HIV from the results of a viral load test. More genetic tests confirmed the resuscitated virus was the same strain he was initially exposed to.
Deeks said Hawley probably has a small latent reservoir of HIV somewhere in his body, which hasn’t grown due to Truvada’s suppression of the virus’s initial spread. His status is now in a kind of limbo, somewhere between having HIV and not.
“The whole excitement around Clark is that we were able to initiate therapy so early that we were hoping to prevent the establishing of latency,” says Deeks. “But it did not happen. We got close; we may have been off by a day or two. We did not achieve a real cure.”
Even if Hawley had been permanently freed of HIV, the problem with any protocol based on such early treatment is that doctors rarely detect a patient’s infection in the first days after exposure. Rather, the case is significant due to the milestone of pushing a patient into long-term remission free of medication, and because it might offer new clues on how to induce a permanent state of HIV dormancy.
Dramatically Reducing HIV Reservoirs
Canales’ case is also tantalizing. He was given a PrEP dose of Truvada 12 days after exposure, and for two years showed no sign of HIV in blood or tissue samples on both viral load and PCR tests. Because of Hawley’s relapse experience after stopping therapy, doctors kept him on the treatment. The only way they could detect signs of the virus in Canales was by transferring some of his cells into mice bred with a copycat human immune system. They were able to intermittently spy a virus particle here or there upon removing the cells from the mice. As with Hawley, early treatment had dramatically limited the amount of virus that would later coalesce into a dormant pool in his body.
“I think we have proven to ourselves that early treatment will never be curative,” Deeks said, referring to complete eradication of the virus within someone’s body. When pressed whether he really meant “never,” he amended his answer: “No, not yet.”
“But we can definitely shift the balance in favor of the patient,” he went on, “because the reservoir is reduced a hundred- to a million-fold.”
Deeks and his team are now investigating a series of HIV vaccines aimed at providing an immune booster to control the pieces of virus that remain in a patient’s body, the final step in sending HIV patients into remission — no medication required. Beyond that, if such tools could wipe out the last pockets of HIV, medical science would have finally achieved its ultimate goal in the fight against AIDS — an actual cure.
By Anne-christine d’Adesky