The 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention took place in Vancouver July 19-22, 2015 preceded by a private symposium devoted to HIV Cure/Remission research. Spoiler alert: There were no presentations of the transformative or groundbreaking kind accelerating the search for ways to cure or control HIV and thereby remove lifelong dependence on expensive and often inaccessible antiretroviral therapy (ART) for the 36.9 million people worldwide now estimated to harbor the virus in their bodies.
ART does not cure HIV mostly because small amounts of virus hide away in blood or tissue “reservoirs” where drugs are not effective. Take away the drugs and the virus rebounds mightily. HIV cure/remission research seeks to overcome this damnably difficult barrier to a life without ART.
There were some interesting, important advances at the conference, hints too of harmful results and safety concerns and also some realities about the business of research and collaboration affecting how this international effort lumbers along. Here’s my unapologetically individual perspective on selected HIV cure news at the conference.
First, it’s encouraging to see that HIV cure research made up a hefty percentage of all the scientific sessions, capturing a major share of the time, attention, abstract submittal and presentation space at the conference as a whole. Major news for implementation science – such as the results of the START trial confirming the wisdom of early treatment, or success with PrEP and treatment to prevent infection – drew crowds. But for new innovative, discovery science to support experimental interventions, the It Girl of Vancouver was HIV cure research. That’s good.
The number of actual discoveries that caught my attention were few – important yet modest.
People Make Good Test Cases
Most news outlets reported the story we are eager to hear: An 18 year old French teenager appears to have controlled the virus for over 12 years after discontinuing ART. She was found to be perinatally infected at birth, received ART for six years and experienced more than one episode when significant amounts of virus could be detected in blood samples early on and even in two very small short duration amounts during the 12 year period off ART. Although HIV can still be found lurking in her system using sophisticated measurements, the teenager may be an example of using ART for infants with HIV very early in life to support later therapy free control of infection. Less widely reported is that a second child followed by the researchers successfully remained off ART for three years before needing to restart therapy when HIV returned. No data were presented on this second case.
There is no explanation yet why the French teenager is able to achieve this outcome or how it can be duplicated for others. Parallels to the Mississippi child experience (successfully off ART for over two years before viral rebound and restarting ART) should be made with care as well as noting differences between the two. We don’t know if the French case may be an example of natural viral control.
Another interesting study suggested women may be controlling the HIV reservoir because of their estrogen levels. The study also asked whether estrogen blocking may be a way to perturb the reservoir. This preliminary effort at evaluating biological population differences also suggests that transgender women using controlled higher amounts of hormone therapy may be an important population to engage to explore this question further.
Population differences in cure research – including biological, social and lived experienced realities around the world – were the subject of an IAS sponsored global stakeholders workshop. Panelists discussed what it takes to work with people with HIV as they really are in settings of stigma, diversity, health system development, coinfection, and immunological variety in order to mount powerful responses for HIV remission and control.
Planned clinical trials in humans will test whether antibodies to HIV can be used to treat infection. Until now, these new potent antibodies have been studied to produce experimental preventive vaccines. But symposium talks by John Mascola from NIH and Deborah Persaud from Johns Hopkins University described studies where antibodies may be used also with other interventions – a therapeutic vaccine or traditional therapy – to treat adults or infants with HIV.
Monkeys Are People Too
HIV cure or remission research is difficult to conduct in people. It entails risks and burdens of procedure that we cannot always ask volunteers to endure so early in experimental learning. The many variables scientists want to understand before testing in humans cannot be manipulated or controlled ethically or safely in most instances today. That is why animal models are so important to have available.
At this year’s conference and symposium, researchers showed that they could use rhesus macaque monkeys to mimic how people remain undetectable on ART and test drugs to flush HIV out of hiding from its hidden reservoir. Another group showed it could perform gene therapy procedures in pig-tailed macaques that might provide protection from infection with newly grown immune cells. In this second case, results were not shown yet to see if the monkeys are resistant to HIV. Leading primate expert Jeff Lifson cautioned that these demonstrations are encouraging but not yet where we need them to be for fully robust studies of cure research that can be easily applied to humans.
Very Cool Science in My Opinion
Fascinating other presentations were also made at the conference.
One study showed that some people who can remain virally suppressed on ART but not recover strong CD4 counts (immunological nonresponders - INR) may have different immune and gene profiles and different reservoir problems than those who can recover CD4 levels more powerfully. INR may represent 10-20% of people with HIV and they generally experience poorer health outcomes. A poster at the symposium suggests – along with the main study – that it is worth looking at cholesterol control to respond to these INR differences in reservoir. Don’t try this at home; it’s just a good line of thinking so far.
Andrés Finzi from Montréal described a way to open or expose parts of the surface of cells infected with HIV using “cd4 mimetics” so that they can be subject to important immune responses that kill the virus. Susana Valente described a way to put the reservoir to sleep and keep the virus always under wraps instead of waking it up from hidden slumber. If that can be done, then our current ART could be taken for a shorter –less than lifelong – period of time.
Bad News is Not Good. Safety First
Eager scientists at conferences understandably want to show progress and good results. But risks of research and safety must always be paramount. Two posters at the symposium pointed to safety concerns – not extremely alarming at this stage – but cautions that must be addressed.
John Bui and his colleagues showed that when some laboratory attempts are made to activate the reservoir and bring HIV out of hiding, some cells may expand and be allowed to produce even more virus. The impact of this research compared to other activation studies actually done in humans is still unclear. Adam Capoferri reported a case where a patient with HIV receiving a bone marrow transplant – like two other Boston patients - presented with a serious event similar to meningitis and with HIV rebound because of virus remaining in his system from before the transplant.
These hints of safety concerns are the kind that must also be answered before we leap to provide new and unusual therapies to people in the hope of cure. Expectations for success must be tempered by a long slow process of confirming that approaches work in large groups of people and over their lifetime.
Getting Down to Business
During the last few years, academic cure researchers and the IAS have announced the importance of partnering with the pharmaceutical private sector if there is to be an efficient work plan towards HIV cure. The private sector – like any other - is made of all types, big, small and in between. Companies need to make a business case to invest in research because they have to respond to their owners, shareholders or investors.
Just before the conference and at the meetings, BMS announced it would no longer support new research in virology for its company. That means no more money for HIV cure research from them. The fate of its pipeline maturation inhibitor drug – another ART class drug - which was also discussed at the conference is uncertain. This announcement does not affect the availability of the approved drugs it already sells like atazanavir and efavirenz. Other big companies are looking for ways to stay in the game of cure research by encouraging approaches that fit their corporate plans.
Smaller companies need even more support to invest in HIV cure research. The international effort struggles to recruit and retain these companies in ongoing work that takes a long time to complete. Although some companies like Sangamo for gene therapy are able to continue for now, the future of these entrepreneurial efforts is not simple to predict.
This short summary review is not the place to lay out and critique the pros and cons of these partnerships for the benefit of public health and the goal for cures that are affordable, scalable and accessible to all. Recent history shows examples of successful partnerships – like the recent development of malaria vaccines – where widespread health improvements may result from this research. But in a very crowded, complex and competitive field like HIV cure research, broad freedom to share and examples of genuine substantial collaboration taking all patients as the central focus are concepts yet to be proven – in my opinion of course. ;-)