The AIDS-Free Generation
The Berlin Patient. The VISCONTI cohort. A baby in Mississippi. None of these represent the wide-reaching HIV cure that we've spent decades looking for, but they do get us a little bit closer to one.
We now have a cure for HIV. But it's not the magic bullet we had hoped for.
In the 30 years since HIV was discovered, governments and philanthropists, hoping to find a cure, have poured billions of dollars into research on the virus and its impact on the body. In the process, scientists and activists knocked this former death sentence down to a chronic disease. The year before the approval of combination antiretroviral therapy (ART), HIV killed more people between 25 and 44 than any other disease; two years later, deaths almost halved. Today, whether in New York or Nigeria, people on ART live with nearly-normal immune systems and only traces of the virus in their body. Given the efficacy of these medicines, do we even need the magic bullet?
If we could treat everyone who had HIV, then maybe not. But only eight million of the nearly 15 million sufficiently immune compromised to necessitate medication were on antiretrovirals in 2012, according to UNAIDS, the Joint United Nations Programme on HIV/AIDS. Medication only works if taken every day and geographic isolation and social disadvantage complicate consistent delivery of drugs to many of these people. In total, about 34 million people around the world have HIV and, each year, that numbers grows: in 2012, 1.7 million people with HIV died and 2.5 million were newly infected. Even the United States’ domestic HIV policy fails to protect its citizens’ health; here at home, 50,000 people are newly infected—which adds 30,000 net HIV cases—each year (PDF).
Worldwide, only about 50 percent of those infected with HIV know their status. Far fewer know with certainty when they contracted HIV and get tested soon enough to start ART during primary infection.
Before we can achieve the AIDS-free generation that Hillary Clinton and others have called for, the number of cases needs to begin to fall. But unless the pool of money available for treatment stops shrinking, this will not be achievable without a mechanism to cure HIV in millions of people.
Unlike bacteria such as syphilis or a flu virus, our immune system cannot eradicate HIV from our bodies even with the help of medicine. After infecting a white blood cell, HIV embeds its DNA in the cell’s genome. In many cases it does not replicate and kill the cell but remains dormant. As long as that cell survives, it can produce HIV. Many white blood cells have short life spans, but memory cells that confer immunity against past diseases live for years and make up a reservoir of HIV-viral DNA. While ART prevents HIV from replicating and infecting new cells, it cannot cleanse existing cells of this dormant HIV DNA and, once therapy stops, the HIV begins to replicate again. Ideally, a cure for HIV would wipe clean all traces of infection, but a functional cure that suppressed HIV replication without medication would still transform the dynamic of the pandemic. Yet even a functional cure, despite the efforts of thousands of researchers and billions of dollars, remained elusive for 25 years.
Scientists first proved that HIV could be cured six years ago in a middle-aged German resident named Timothy Brown. Now known as the Berlin Patient, Brown had HIV for more than 10 years before developing leukemia that required a bone marrow transplant. Brown’s new marrow came from an “elite controller,” a person with a protein deficiency occurring in only one percent of people that prevents HIV from infecting their white blood cells. HIV could not infect the new cells and, even after stopping his ART regimen, Brown’s body continued to control the virus. Even though HIV DNA remains in his blood cells and could start to grow again, Brown remains HIV free. But bone marrow transplants are expensive, and require complex donor-recipient matches and pose such risk that this means of cure cannot safely scale to help even a fraction of those currently living with HIV.
In March, media erupted at the news that a team of doctors from across the country cured a newborn baby of HIV. Unlike the Berlin Patient, though, the source came not from an invasive procedure but normal antiretroviral drugs. While most HIV+ women in the United States receive drugs that drastically reduce the chance of mother-to-child transmission of HIV, this baby’s mother had not learned her status until she was in labor. Rather than wait weeks before starting ART in the baby, doctors initiated full treatment within 30 hours of birth and within a month the virus could no longer be detected. After 18 months, the mother stopped coming for treatment and took the baby off ART but the virus did not rebound. Although viral DNA persists in the patient, a year later it has not lead to any viral growth and the baby appears to be functionally cured.
Despite the media hullabaloo, this baby was not the first person to experience a functional cure from antiretrovirals. A paper published in PLOS Pathogens two weeks after the baby’s public recognition detailed a trial in France that had functionally cured 14 people. Named the VISCONTI study, it placed newly-infected people on ART. In the weeks immediately after HIV enters the body, a person becomes sick as the virus rapidly replicates for a period before entering into a time of chronic, slow growth and the establishment of viral reservoirs. Patients started on therapy during this primary infection have long been known to see better outcomes than those started later. Shockingly, 15 percent of these patients continued to control HIV for an average of seven years after suspending treatment. None of these patients possessed the genes associated with the immunity conferred by the Berlin Patient’s marrow donor. Additionally, the pattern of inflammation and illness during primary infection in these patients resembled that of normal patients rather than those with innate immunity. Early treatment with ART disrupted the establishment of the virus in their immune system and endowed HIV resistance even after withdrawal of treatment.
Like the Berlin Patient, neither the early infant therapy nor the VISCONTI trial results provide a cure that will drive down the number of new infections or eradicate existing infections in any significant way. And with the Mississippi baby, questions remain about the validity of the case because the data has not been peer reviewed. It is not clear yet whether ART induced the functional cure in the patient or if it could have come from natural resistance to HIV or some other confounding factor.
While more than 300,000 babies are born with HIV every year, few of these births occur in places where parents have access to prevention of mother-to-child therapy (PMTCT). In the United States, with near universal PMTCT coverage, the number of children infected from birth or before 13 years of age dropped from 250 in 2008 to 190 in 2011 (PDF). Where women have access to PMTCT, they are unlikely to need a functional cure induced, and those places unable to deliver PMTCT will likely not be able to deliver ART soon after birth. Expanded PMTCT would drastically drive down early infection rates.
The induced functional cure in adults from VISCONTI holds little more practical value in directly reducing the scourge of HIV. Worldwide, only about 50 percent of those infected with HIV know their status. Far fewer know with certainty when they contracted HIV and get tested soon enough to start ART during primary infection. But the VISCONTI results still offer hope to those who contract HIV through rape or some other definite event. More important than its clinical application will be its impact on policy. Like a 2011 study on transmission within couples that showed early treatment with ART prevented the transfer of HIV, VISCONTI adds evidence to calls for immediate treatment for all HIV+ people rather than just those with AIDS.
Even if the serendipitous conditions necessary for these two cures precludes them from broad application, they nevertheless provide further hope for a functional cure. In the past month, two research groups—one at Duke University and another at The Scripps Research Institute—demonstrated significant progress toward a potential vaccine. HIV evolves too quickly for a traditional vaccine that primes the immune system to neutralize the virus. Instead, these works-in-progress stimulate an evolutionary process in the immune system that enables the production of broadly neutralizing antibodies to disarm most or all HIV. While both remain years away from human application, they regardless offer mechanisms that may be able to block HIV despite its rapid pace of evolution. Additionally, a review published last month in The Lancet highlighted progress toward a complete cure that sterilizes the body of viral reservoirs.
Despite the abundance of promising work in the pipeline, a cure that can change the dynamic of the HIV pandemic still may take years—or decades—to come to fruition. Until a method of eradicating the virus proves effective, affordable, and safe, our control of it will continue to rely on the ability of public health programs to recognize and prevent new cases and treat the infected with fewer and fewer dollars, further and further away.