World AIDS Day

Belated World AIDS Day post: Although HIV/AIDS remains a scourge of humanity—particularly in it’s likely place of origin, Africa—we have made tremendous progress in reducing both infections and rates of death. Being HIV positive is no longer the death sentence it once was—ironically the large number of people living with the disease is in part a testament to the success of treatments and of policies to make them widely affordable and accessible (aided in large part by the much-maligned WHO).

As usual, German data-crunching company Statista lays it all out beautifully in their Instagram (which I highly recommend following).

Even though #worldaidsday has been used to promote awareness of the disease and mourn those who have died from it since 1988, the global epidemic is far from over.

According to data by @unaidsglobal, more than ten million people with HIV/AIDS don’t currently have access to antiretroviral treatment and the number of new infections with #HIV has remained the same compared to 2019 at roughly 1.5 million. When taking a closer look at the numbers, there are enormous regional differences in terms of battling the epidemic. Eastern and southern Africa, for example, combine for 55 percent of all known HIV/AIDS cases, while reducing new infections by 43 percent between 2010 and 2020. Western and central Africa also saw a decline of 37 percent when comparing 2010 and 2020, although it falls short of the benchmark of 75 percent set by the United Nations General Assembly.

While the number of new infections has dropped from 2.9 million in 2000 to 1.5 million last year, the number of people living with HIV increased from 25.5 million to approximately 37.7 million over the past two decades. According to UNAIDS, the increase is not only caused by new infections, but also a testament to the progress that has been made in treating HIV with antiretroviral therapy, which has vastly improved the outlook of those infected with HIV.

The even more astute data-lovers at Our World in Data vividly convey both the scale of the problem and just how much we have progressed, even in the most hard-hit places:

While in law school, I and some colleagues had the incredible opportunity to meet the hard working and earnest people at UNAIDS headquarters in Geneva. This unique entity is the first and only one of its kind in the world, combining the personnel and resources of nearly a dozen U.N. agencies to offer a comprehensive response to this pandemic. UNAID is also the only initiative to include civil society organizations in its governing structure.

Since it was launched in 1994, UNAIDS has helped millions of people worldwide get antiretroviral treatment for HIV/AIDS, provided millions more with preventative methods. Thanks to their efforts, and those of their partners across the world, the rate of infection and death by HIV/AIDS has stagnated or even declined in many areas, while the rate of treatment has increased.

As with so many other things, the COVID-19 pandemic has weakened the fight against HIV/AIDS, disrupting preventative measures and sapping away at an already-taxed healthcare system. With reports of individuals who seem to have naturally cured themselves of the virus, I have hope that we can regain momentum and maybe even develop an outright cure. Fortunately, the progress of the past several years proves we do not have to wait until then to make a difference to tens of millions of lives.

The Berlin Patient and a Possible Cure for HIV/AIDS

A few years ago, at the Charité Medical Universityin Berlin, Germany, a 42-year-old American named Timothy Ray Brown was given an experimental transplant of bone marrow to treat his leukemia, which had failed to respond to first-line chemotherapy. Incidentally, he had also been infected with HIV for more than a decade, for which was taking treatment. The difficult procedure was remarkably successful, but what happened afterward was even more extraordinary, as the Wall Street Journal reports:

The transplant specialists ordered the patient to stop taking his AIDS drugs when they transfused the donor cells, because they feared the powerful drugs might undermine the cells’ ability to survive in their new host. They planned to resume the drugs once HIV re-emerged in the blood.

But it never did. Nearly two years later, standard tests haven’t detected virus in his blood or in the brain and rectal tissues where it often hides.

The man who cured HIV. Will his work lead to a more applicable version?

Almost two years after the transplant, the patient was still recovering from the therapy; but despite reportedly ceasing the taking of antiretroviral medications, HIV remained absent. As of December 2010, three years after the transplant, Brown was still free of any detectable HIV in his blood – he was even indentified in a report posted in the hematological journal, Blood, as effectively “cured”.

Of course, the immediate question on everyone’s mind is: how? HIV is notorious for its incurability, perhaps the most horrific aspect of it. Anti-retrovirals can extend health and longevity by stopping it from replicating and impeding its effects. But they must be taken everyday, are very expensive – especially in the poorer countries that are most ravaged by the disease – and are by no means a sustainable option. Normally when a patient stops taking these treatments, the virus rushes through the body within a few days, or at most a few weeks – any longer than that is unprecedented, especially a full three years.

As it turns out, the blood doctor responsible for the transplant had the search for a cure in mind.

The breakthrough appears to be that Dr. [Gero] Hütter, a soft-spoken hematologist who isn’t an AIDS specialist, deliberately replaced the patient’s bone marrow cells with those from a donor who has a naturally occurring genetic mutation that renders his cells immune to almost all strains of HIV, the virus that causes AIDS.

The mutation in question is an unusual but natural variant of the CCR5 cell-surface receptor, a part of the cell scientists liken to a “door.” This variation had already been known to scientists to make some cells from people born with it resistant to infection with some strains of HIV. But to our knowledge, it had never before been transferrable through a transplant. To understand the significance of this receptor, observe the image and excerpt below:

Back in 1996, when “cocktails” of antiretroviral drugs were proved effective, some researchers proposed that all cells harboring HIV might eventually die off, leading to eradication of HIV from the body — in short, a cure. Those hopes foundered on the discovery that HIV, which integrates itself into a patient’s own DNA, hides in so-called “sanctuary cells,” where it lies dormant yet remains capable of reigniting an infection.

But that same year, researchers discovered that some gay men astonishingly remained uninfected despite engaging in very risky sex with as many as hundreds of partners. These men had inherited a mutation from both their parents that made them virtually immune to HIV.

The mutation prevents a molecule called CCR5 from appearing on the surface of cells. CCR5 acts as a kind of door for the virus. Since most HIV strains must bind to CCR5 to enter cells, the mutation bars the virus from entering. A new AIDS drug, Selzentry, made by Pfizer Inc., doesn’t attack HIV itself but works by blocking CCR5.

About 1% of Europeans, and even more in northern Europe, inherit the CCR5 mutation from both parents. People of African, Asian and South American descent almost never carry it.

Coincidently, most of the countries with the highest rate of infection are in Africa andAsia, where such a mutation is practically nonexistent. But that wouldn’t matter much since very few Europeans, in whom this fascinating trait emerges, seem to have it either. But finding a way to transfer or produce this genetic variation could go a long way to discovering both a preventative measure and a real cure. The prescient German doctor behind this transplant seemed to have that in mind.

Dr. Hütter, 39, remembered this research [with CCR5] when his American leukemia patient failed first-line chemotherapy in 2006. He was treating the patient at Berlin’s Charité Medical University, the same institution where German physician Robert Koch performed some of his groundbreaking research on infectious diseases in the 19th century. Dr. Hütter scoured research on CCR5 and consulted with his superiors.

Finally, he recommended standard second-line treatment: a bone marrow transplant — but from a donor who had inherited the CCR5 mutation from both parents. Bone marrow is where immune-system cells are generated, so transplanting mutant bone-marrow cells would render the patient immune to HIV into perpetuity, at least in theory.

There were a total of 80 compatible blood donors living in Germany. Luckily, on the 61st sample he tested, Dr. Hütter’s colleague Daniel Nowak found one with the mutation from both parents.

To prepare for the transplant, Dr. Hütter first administered a standard regimen of powerful drugs and radiation to kill the patient’s own bone marrow cells and many immune-system cells. This procedure, lethal to many cells that harbor HIV, may have helped the treatment succeed.

Basically, the entire transplant was a complicated – though still ethical – test to replicate HIV immunity. And miraculously, it worked almost immediately. Apparently, a doctor in California had a very eerily similar, though more accidental, experience in 1998. In that instance, a leukemia patient who also had HIV also received a transplant of bone marrow cells, and subsequently had no trace of the disease. Unfortunately, that patient died of the cancer a month and a-half later, and its unknown if the donor cells also had the CCR5 receptor mutation.

The "Berlin Patient:" the first known case of an HIV cure.

Its hard to believe that so little attention has been given to this incredible find, even after all these years. Indeed, though its been covered by numerous major media outlets, few people seem aware of it, and most sources on the subject date from 2008 or 2009.

Of course, a lack of interest could be understandable: HIV has long been established in the popular imagination as an incurable super-illness, and in light of that, many people would probably be initially skeptical of any cure for it. Furthermore, there have been plenty of false-positives before, given the complexity of the HIV virus and its workings.

But even normally incredulous scientists so far seem convinced.

The case was presented to scientists earlier [in 2008] at the Conference on Retroviruses and Opportunistic Infections. In September [of that year], the nonprofit Foundation for AIDS Research, or amFAR, convened a small scientific meeting on the case. Most researchers there believed some HIV still lurks in the patient but that it can’t ignite a raging infection, most likely because its target cells are invulnerable mutants. The scientists agreed that the patient is “functionally cured.”

So far, to my knowledge, no one was raised suspicions or doubts as to the legitimacy of this cure. By early 2011, as reported in New York Magazine, the medical community has come to accept Hütter’s results (New York Magazine has a beautiful and detailed narrative of this cure as well). Of course, as with any potentially ground-breaking discovery, there are numerous caveats to keep in mind, and many more studies will have to be done to confirm the longer-term validity of this cure and whether or not it’s even tenable on a mass scale.

If enough time passes, the extraordinarily protean HIV might evolve to overcome the mutant cells’ invulnerability. Blocking CCR5 might have side effects: A study suggests that people with the mutation are more likely to die from West Nile virus. Most worrisome: The transplant treatment itself, given only to late-stage cancer patients, kills up to 30% of patients. While scientists are drawing up research protocols to try this approach on other leukemia and lymphoma patients, they know it will never be widely used to treat AIDS because of the mortality risk.

…One big hurdle: doctors can’t yet genetically modify all target cells. In theory, HIV would kill off the susceptible ones and, a victim of its own grim success, be left only with the genetically engineered cells that it can’t infect. But so far that’s just theory

Furthermore, as discussed candidly in New Scientist, very few people are compatible donors with the cells that harbor this mutation, making such transplants extremely rare to replicate even a few times, much less on the massive scale required. The same article also noted that HIV sometimes invades white blood cells through an alternative route, the receptor CXCR4.

Of course, this hasn’t stopped researchers and doctors from exploring the implications further and trying to develop alternatives based on what we now know. The most commonly cited venue is gene therapy, which would re-engineer a patient’s own cells to develop the HIV-resistant receptor mutation (or something similar to it). Already, some scientists have formed private companies or undertaken research to better develop this strategy.

We reported on one earlier this year that uses molecular “scissors” called zinc-finger proteins, specifically designed to ruin the CCR5 protein in patients. The approach, developed by a company called Sangamo in San Diego, worked in mice.

Other teams, such as the one led by Nobel-prizewinner David Baltimore at the California Institute of Technology in Pasadena, are developing a similar approach, using molecules called small interfering RNAs (siRNAs) to sabotage production of CCR5 by white blood cells.

Unfortunately, gene therapy carries its own risks and complications. Still in its infancy, there have been some cases where it has failed miserably, often at the cost of a patient’s life. Even some of its successful instances have come at a high price, by costing too much money or causing other serious illnesses to develop in the patient.

Gene therapy is also quite daunting on a technical level. The process currently involves removing cells, modifying them outside the body, and then transfusing them back in – a procedure that is prohibitively expensive and operationally delicate. Even after that threshold is crossed, any therapeutic genes that are developed can so far only be returned using re-engineered viruses as carriers, also known as viral vectors – obviously, they must be made perfectly safe, which is no easy task given the nature of a virus.

Based on my research, most scientists agree that we’re still a long way from improving these methods cheaply and effectively enough to implement on the massive scale required, though we’ve made much advancement over the last few years (including curing a fatal brain disease using, of all things, an HIV vector).

A few of scientists, including Dr. Baltimore, are working on ways of developing carrier viruses of their own that will administer a cure as simply as a flu vaccine does. At the City of Hope Cancer Center inDuarte,California, researchers are even using HIV itself, genetically engineered to be safe, to deliver to a patient’s white blood cells three genes: one that deactivates CCR5, the remainder to disable HIV. The procedure has already been performed on a few patients, though I’ve yet to find any updates on it.

For me, the greatest obstacle of all, which wasn’t mentioned in the sources I consulted, is one of compassion: even if we developed a working, mass-producible cure, administering it to the millions of mostly impoverished people who are infected is a whole different challenge altogether. After all, we’ve long had cures for such virulent diseases as tuberculosis, malaria, and others, yet millions of people continue to die of these diseases every year.

So aside, from technological and medical challenges, there are social, political, economic, and ethical factors that must be addressed for the cure to have any meaning – and these things are arguably more complex and difficult to solve.

One thing that is clear is that we’re a lot closer to a cure than ever before, and if history is any indicator, we’ll continue with exponential developments for years to come (so long as ample research funding is continued that is). It would be amazing to think that, within my lifetime, it’s probable that this horrible affliction will join dozens of other diseases in being extinguished into the annals of history.