A stir in Kuala Lumpur

I attend a lot of scientific meetings. At the end of most, I ask participants what they thought were the highlights. But at this year’s 7th International AIDS Society conference on HIV Pathogenesis, Treatment and Prevention, held in Kuala Lumpur, Malaysia, from June 30th to July 3rd, I didn’t need to ask. The thing that had everybody excited was the announcement that researchers might have replicated the HIV cure achieved in Timothy Brown—the so-called Berlin patient. 

Last year, we reported that two HIV infected patients, who, like Brown, received bone marrow transplants from HIV negative donors, no longer had signs of an HIV DNA reservoir—at least while they were kept on antitretroviral therapy (ART). This suggested that the virus might not come back if treatment is interrupted. 

At the Malaysia meeting, Timothy Henrich, an infectious disease doctor at Brigham and Women’s Hospital in Boston, reported that since stopping ART 8 weeks ago in one patient and 15 weeks ago in the other, he had not yet detected any HIV RNA in either patients’ blood. He and his colleague Daniel Kuritzkes cautioned, however, that it will take years of follow up to be reasonably sure that the virus isn’t coming back. What’s more, the treatment remains far too risky to be used routinely. 

Still, the mere possibility that the Berlin cure might have been replicated caused quite a stir among the researchers gathered at Kuala Lumpur.   

Another heavily discussed topic at the meeting—the first IAS meeting in Asia and the first in any Muslim country—was the WHO’s recommendation that ART be initiated earlier—when the CD4+ T cell count of HIV infected patients reaches 500—up from the previous threshold of 350. While the new guidelines were widely welcomed, they pose a challenge to donors and health systems alike: They raise the number of eligible patients worldwide from 17 to 26 million, said Tsitsi-Mutasa Apollo of the Ministry of Health & Child Welfare in Harare, Zimbabwe. 

Some, however, felt the WHO hadn’t gone far enough. Bill Bahlman, a long time treatment advocate and a producer at Gay USA TV in New York, said that given that the US guidelines already recommend treating all infected people immediately irrespective of CD4 count, the WHO should have done the same. “I welcome the new treatment guidelines from WHO,” he said, “[but] I think they are unfortunately too conservative. I think the sooner we treat people with HIV, the less new infections we are going to have worldwide.” 

But Gottfried Hirnschall, who directs the HIV department at the WHO and co-chaired the guidelines process, said there is currently not enough high quality evidence from randomized trials to recommend treatment at higher cell counts than 500. One such trial, called START, is currently underway: It examines whether net health benefits are different if patients start ART above 500 CD4+ T cells or defer treatment until CD4+ counts have dropped to levels below 350 (see Is it Ever Too Early?, IAVI Report, Sep.-Oct. 2012). The WHO also weighed factors such as availability of the drugs and concerns about side effects, Hirnschall added: “There is no regimen yet that is completely free of any side effects and toxicity.”

Still, Hirnschall believes the WHO will eventually move towards recommending treatment for all, provided there is enough evidence. “My personal view,” he said, “is this is the direction in which we will be going, in which we should be going.”

Meanwhile, evidence for the benefits of early treatment initiation keeps accumulating. This theme pervaded the main IAS meeting, but became especially clear at a two-day symposium on HIV cure between June 29 and 30th. 

Laurent Hocqueloux, an infectious disease doctor in Orléans, France, reported that when followed up after several years of treatment, people who started therapy at a T cell counts over 500 had lower levels of integrated HIV DNA in blood cells, and higher T cell counts, than those who started later. 

While Hocqueloux’ patients started treatment during chronic infection, starting it during the acute phase of infection could have even greater benefits. Antoine Chéret from the Font-Pré hospital in Toulon reported early results from a 90-patient trial called OPTIPRIM, in which patients who started treatment within three months after infection had a roughly 20-fold (about 1.3 log) reduction of the HIV DNA reservoir in blood cells after one year of ART. So far, he said, this is the largest reservoir reduction observed after early treatment initiation. 

This means that early treatment initiation could bring patients closer to an eradication of viral reservoirs, the most important goal of strategies for curing HIV infection. Such strategies involve inducing HIV replication in latently infected, resting CD4+ T cells. The expectation is that the cells would then either die as a result of renewed viral replication or become vulnerable to antiretroviral drugs or immune responses. 

One family of drugs researchers use to lure the virus out of hiding are  HDAC inhibitors, such as SAHA, which is currently being evaluated in human trials and has been shown to increase HIV RNA levels inside CD4+ T cells. However, SAHA doesn’t seem to consistently induce free virus in the blood. This suggests that it might not be potent enough to sufficiently activate HIV expression. 

At the meeting, Martin Tolstrup of Aarhus University in Denmark reported evidence suggesting that a more potent HDAC inhibitor named Panabinostat can increase the levels of free HIV RNA in the blood of people on HAART who have an undetectable viral load. “We believe that we see an increase in the amount of free virus being produced,” Tolstrup said. “I think it’s profoundly important,” said Steven Deeks of UCSF, who co-chaired the cure symposium. This, he said, is the first time anyone has shown induction of latently infected cells to make virus in vivo in humans. 

Such virus production alone might suffice to kill reactivated cells that harbor the reservoir. Still, researchers are working on ways to actively detect and eliminate reactivated cells. Richard Koup of the NIAID’s Vaccine Research Center reported, however, that this could be a challenge. He isolated a population of CD4+ T cells from individuals not on ART that were rich in cells actively transcribing HIV , and found it to be very difficult to detect Envelope expression on the surface of these cells. That means, he said, that any approach that uses Env-specific antibodies to detect and eliminate such cells is unlikely to succeed. 

The meeting also featured updates on so-called post treatment controllers, who started treatment during early infection and subsequently controlled the virus after  stopping treatment. So far, such cases are only anecdotal, such as the 14 patients of the VISCONTI cohort in France, or the so-called Mississippi baby, which started ART about 31 hours after birth. 

Still, the excitement was palpable at a session on post treatment controllers. Asier Sáez-Cirión from the Institut Pasteur in Paris, one of the researchers involved in the VISCONTI study, told the standing-room-only crowd that he is now looking for additional cases to build an international cohort of post treatment controllers. He asked that anyone aware of such cases share them with his team. Additional examples will make it possible, he said, to better understand the mechanism of post treatment control and to find markers that can predict which patients are likely to show such control. 

Others are now also planning to look into the Visconti effect. “We have a cohort of over 100 people, who we can start to investigate. Maybe we have got some VISCONTI-like patients,” said John Frater from the University of Oxford. 

The updates on the benefits of early therapy prompted one audience member at the cure symposium to ask Hocqueloux whether the START trial should be stopped. “My personal opinion,” he responded, “is to treat every patient [who] is not an elite controller. That’s what I do as a clinician every day.” 

The question, of course, is when the WHO will take that view.