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.
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.
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.”