An Endgame for an Epidemic

IN 1981, YOUNG MEN with remarkably low white blood cell counts began showing up in emergency rooms in Los Angeles, San Francisco, New York and other cities. The collapse of their immune systems led to devastating infections, and doctors could do little more than try to make these patients comfortable. Most of them died. Soon the condition was linked to other populations, and the research community began referring to the four Hs—homosexuals, heroin users, Haitian immigrants and hemophiliacs.

This new scourge soon gained a name—acquired immunodeficiency syndrome, or AIDS—and in 1983, researchers isolated its cause: HIV, the human immunodeficiency virus. The devastation of the disease would continue to expand exponentially, and those who had it were stigmatized by a terrified public. In response, a coalition of activists, policymakers and researchers launched the first World AIDS Day on Dec. 1, 1988. Their stated goal was to extend tolerance to those living with the disease, and to support initiatives that would stop the plague for good.

Three decades later, even after enormous progress, that quest remains incomplete. In many ways the epidemic seems under control, in large part because of medications that can turn HIV infection into a chronic condition. But not everyone has access to those drugs, and the number of new cases continues to grow. In 2016, there were 1.8 million new HIV infections globally and 1 million people died of AIDS. In the United States, nearly 40,000 people were diagnosed with HIVinfection in 2015, and a quarter of those cases had progressed to AIDS. “Black gay men in southern states have a one-in-two chance of developing HIV, a rate comparable to that of South Africa, which has the highest incidence of HIV in the world,” says Rochelle Walensky, chief of infectious diseases at Massachusetts General Hospital and former chair of the Office of AIDS Research Advisory Council at the National Institutes of Health.

The Joint United Nations Programme on HIV/AIDS (UNAIDS) is counting on big strides in both prevention and treatment, and it has an ambitious goal for the near future: to end the AIDS epidemic by 2030. To achieve that, UNAIDS has established interim “90-90-90” treatment targets for 2020: 90% of people living with HIV will know they are infected by then, 90% who have been diagnosed will be on treatment and 90% of treated people will have had their HIV virus suppressed to a point of not being transmissible. At least 18 countries have stated that they have or soon will have achieved those milestones, most of them in Europe but some in Asia and sub-Saharan Africa.

Yet whether the rest of the world is able to get there, too—and whether the virus can be contained more completely—depends on advances still to be made. It will require research gains in how to control the disease in those who have it, and to prevent the uninfected from catching it along with a reinvigorated search for a cure, after decades of dead ends. And above all, the effort will require wise policy choices and continued funding at a time when many people seem to think this is a problem that has already been solved.

HIV WORKS BY ATTACKING a class of white blood cells—CD4-positive (CD4+)—that helps the immune system fight infection. After infiltrating the DNA of CD4+ cells, HIV replicates, infecting and killing those cells and rendering the body’s immune system increasingly ineffective. Then, as HIV spreads, the virus mutates, constantly changing its genetic sequences and creating new variants that flummox the immune system’s ability to recognize it as a pathogen.

Without treatment, the immune systems of people infected with HIV become weaker and weaker. AIDS is the final stage of HIV infection, when infections such as tuberculosis, pneumocystis pneumonia, Kaposi’s sarcoma and other cancers take hold, or when the count of CD4+ cells falls below 200 per cubic milliliter of blood. The life expectancy of someone with AIDS at the beginning of the epidemic was about three years. Then, in the mid-1990s, came the first effective treatment: combination antiretroviral therapy, or ART.

Today’s combination antiretroviral therapy packages three or more drugs in as little as one pill, which can suppress the activity of HIV to undetectable and intransmissible levels. “We now have extremely effective treatment for people who have access to it and are motivated to take a pill every day for life,” says Steven Deeks, HIV researcher and professor of medicine at the University of California, San Francisco. “They can have a normal lifespan.”

Still, committing to a lifetime of treatment, which in the United States currently has a price tag of about $380,000, is no small thing. “Continuing to take those pills through decades of midlife crises, losing health insurance, going off the wagon with substance abuse, getting burnt out by the whole thing—most people cannot sustain that indefinitely,” Deeks says. Long-term ART can also cause bone and kidney problems, and people who have lived with HIV for many years tend to have accelerated aging and develop other diseases at a higher rate than the rest of the population. “The cumulative toxicity of the drugs we used prior to 2005 has taken a toll,” says Paul Sax, clinical director of the HIV Program and Division of Infectious Diseases at Brigham and Women’s Hospital in Boston. So while treatments exist that can keep HIV under control, there is plenty of room for improvement, with other approaches that could reduce the need for daily adherence while limiting the toll on the body.

WHEN PEOPLE WITH HIV strictly adhere to the ART regimen, the possibility of transmitting the virus becomes vanishingly small, even when those infected with the virus don’t use condoms or otherwise fail to follow HIV-prevention strategies. Yet not everyone with HIV is on ART, and in 2012, a new defense became available for those at risk of catching the disease. That pill, Truvada, contains two antiretroviral drugs and provides pre-exposure prophylaxis (PrEP). Men who take two doses of Truvada before a sexual encounter with an infected male partner and for two days after lower their chances of getting HIV. PrEP also protects women, but they need to take the pill for at least a week before and a week after sex, because the drug works more slowly to block HIV in the vagina and the cervix than it does in the rectum. The Centers for Disease Control and Prevention recommend that anyone at high risk for HIV take PrEP every day.

Not nearly enough people in this group do take it, however. In 2016, there were 77,120 PrEP users in the United States—a small fraction of the 1.2 million people at high risk of getting HIV, according to the CDC—and most of those who avail themselves of the treatment are middle-aged white gay men, among the at-risk populations least likely to contract HIV. “African-Americans, Hispanics and women tend to be left behind, and very few injecting drug users have ever heard of a pill to prevent HIV,” says Dawn Smith, epidemiologist and medical officer in the CDC’s Division of HIV/AIDS Prevention.

In any case, for women, a different approach to prevention—a vaginal ring that releases dapivirine, an antiretroviral drug, for a month at a time—may offer better protection. Tested in two advanced human trials in South Africa, Malawi, Uganda and Zimbabwe, the ring reduced the rate of HIV infection by 56% among women who used it consistently. “That compares with the first trials of oral PrEP, which reduced HIV infection by 44%,” says Jared Baeten, vice chair of Global Health at the University of Washington’s Schools of Public Health and Medicine in Seattle and an investigator on the pivotal PrEP and vaginal ring trials. The vaginal ring is currently under review for use in several African countries that have a high prevalence of HIV, while a vaginal ring that releases an antiretroviral for three months and one that includes a contraceptive are also being tested.

EVEN BETTER THAN PREVENTION, of course, would be a cure, and in 1997, at the breakthrough moment when the Food and Drug Administration approved the first combination antiretroviral treatment for HIV/AIDS, it appeared that a cure might also be within reach. But then a research team led by Robert Siliciano established that HIV infection created reservoirs of latent virus in the body.

Within a few days of infection, the virus hides itself, becoming latent in a particular type of CD4+ cell known as a memory T cell. Reservoirs of memory T cells with the DNA of HIV may reside throughout the body, particularly in lymph nodes, the spleen and the gastrointestinal tract, persisting indefinitely. Although ART can block HIV from replicating, it can’t eliminate the latently infected memory cells, and if someone stops taking ART, production of HIV begins again, leading to a raging infection in as few as two weeks.

“Once we showed that HIV-infected cells would be present for life, it crushed much of the enthusiasm for a cure,” says Siliciano, professor of medicine at Johns Hopkins Medicine in Baltimore. “For nearly a decade after that, the word cure became taboo because it falsely raised patients’ hopes.”

In 2009, however, American Timothy Ray Brown was pronounced cured of HIV. After taking ART for more than a decade, Brown was diagnosed with leukemia, and to treat the cancer, Brown received bone marrow transplants in 2007 and 2008 from a donor with a rare genetic mutation called CCR5 that provides immunity to HIV. Because Brown had stopped taking ART as part of his cancer treatment, his reservoirs of sleepingvirus should have been activated. Yet he had no detectable HIV in his blood, and physicians concluded that all of the virus, even in the reservoirs, had been eliminated.

Steven Deeks, who treated and studied Brown, says researchers aren’t fully sure why Brown’s bone marrow transplant cured him, but he suspects that a complication of the treatment might have killed all of Brown’s cells harboring HIV. Still, the therapy almost killed him, too. “He was in and out of the hospital for years,” Deeks says. “Brown has said that being cured was much worse than being treated for HIV.”

Building on lessons from Brown’s case, a team of investigators supported by the advocacy organization amfAR recently performed stem cell transplants, some from donors with the CCR5 mutation, to about 30 HIV-infected patients with cancer. “Even if they aren’t cured, we believe we will learn a lot from these patients, such as whether there are some types of cells that more persistently harbor HIV,” says Rowena Johnston, vice president and director of research for amfAR.

Another, perhaps more promising approach to a cure—known as “shock and kill”—uses a drug to activate the CD4+ T cells containing sleeping HIV so that the immune system can detect them and make them vulnerable to additional treatment. Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston, created a stir in the research community with preliminary results of monkey studies he presented at an HIV/AIDS conference this year. Rhesus monkeys infected with an HIV-like virus in Barouch’s experiment started ART and then received an immune-boosting drug to stimulate and awaken the T cells with latent virus, followed by a potent HIV antibody that recruited other immune system cells to kill the infected T cells. After stopping ART, the virus did not rebound in five of the 11 monkeys that received the combination therapy, and in the other six monkeys, the virus was at levels 100 times lower than in untreated monkeys with HIV.

As potentially transforming as such a treatment might be, it’s probably too early to risk trying it in people. “There’s no way to know for sure whether the reservoirs of latent virus have been completely eliminated, so the idea of doing treatment-interruption studies in people is controversial,” says Robert Siliciano. For now, Barouch is testing the antibody given to the monkeys in preliminary human trials.

Deeks, meanwhile, says he believes HIV could be cured through a kind of permanent remission rather than by eliminating reservoirs of the virus. His approach is to use a vaccine and other agents to revive an exhausted immune system to fight the virus, in part by reversing some of the chronic inflammation that HIV causes. Then another drug stimulates natural killer cells, a separate part of the immune system, to control the virus and force it into remission, allowing people to stop ART. “This is exactly the type of immunotherapy that is having a revolutionary effect in oncology, using drug research that was being done in the 1990s with HIV,” Deeks says. There are now about a dozen clinical trials of HIV immunotherapy that are planned or underway.

A VACCINE AGAINST HIV would be another effective means of reducing and potentially eliminating infection with the virus. Its pursuit has inspired some of the most ambitious research efforts in the field, including the founding of the Ragon Institute of MGH, MIT and Harvard, which brings together specialists across disciplines and funds promising research across the globe. But vaccine development has been hampered by the enormous variability of HIV. A truly effective vaccine would prevent infection and the establishment of latent reservoirs. “These are huge hurdles,” Barouch says. “But we are cautiously optimistic that these challenges can be solved.”

Indeed, previous large-scale human trials of traditional vaccines against HIV have failed. Only one, using a novel “prime-boost” regimen, had any success, and it reduced the risk of infection by a modest 31% compared with a vaccine placebo among study participants in Thailand.

Today, however, there is renewed hope for a vaccine, with two large trials currently underway in Africa, one of which is testing a more robust version of the vaccine tried in Thailand. The other experimental vaccine was developed by Barouch, one of the founding members of the Ragon Institute, and theoretical biologist Bette Korber at Los Alamos National Laboratory. Funded by the NIH, the Ragon Institute and others, it has a unique “mosaic” design that combines pieces of different HIV strains from around the world. “The theory is that a mosaic vaccine will elicit immune responses against all the diversity that HIV exhibits so only one vaccine will be needed globally,” says Bruce Walker, director of the Ragon Institute.

Both new candidates are prime-boost vaccines, which use two injections to increase the body’s immune response. One injection delivers HIV genes in a harmless carrier and the second contains a protein found on the HIV surface, which doesn’t mutate along with the rest of the virus. “Although vaccine-induced antibodies against the surface protein aren’t very potent, they should be able to bind to the virus to either block infection or kill infected cells,” says John Mascola, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases.

The mosaic vaccine, now being tested in 2,600 women in sub-Saharan Africa, provided 67% protection in monkeys that received the vaccination and then were infected with a simian HIV virus. “This vaccine has the best results seen in animal models, and we’ll know in two-plus years whether it works in humans,” says Walker. Should the vaccine prove to be at least 60% effective in humans, “it would have a dramatic effect on the epidemic,” Mascola says.

THE EFFECTIVENESS OF THESE research advances will ultimately depend on a coordinated global public health infrastructure, one that can quickly implement vaccines, treatments or cures. In 2003, President George W. Bush established the President’s Emergency Plan for AIDS Relief (PEPFAR) to provide HIV testing and treatment to developing countries. Since then, the United States has invested more than $70 billion to fight HIV and AIDS, the largest commitment by any country to address a single disease. Most of that assistance goes to the countries in which HIV infections are not yet under control, and the investments have led to significant improvements, slashing AIDS deaths by half and decreasing new HIV infections by an average of 23% annually. PEPFAR, funded entirely by U.S. contributions, underwrites the cost of ART for more than 15 million people in developing countries, and U.S. HIV funding has averted an estimated 5 million AIDS deaths in sub-Saharan Africa alone.

Yet continued progress could be impeded by a decline in financial support. “HIV and AIDS funding began slowing around 2011, when the global financial crisis caused many countries to re-evaluate their priorities,” says Gregorio Millett, vice president and director of public policy at amfAR and a former CDC researcher and senior policy advisor on HIV in the Obama administration. PEPFAR’s funding has stayed constant since 2010 after dodging a large proposed cut by the Trump administration this year. Yet it will take even more money to meet goals for reducing HIV infection worldwide. “The only way to get viral suppression for more people with HIV is to put them on treatment, and that requires more investment,” Walensky says.

She would like to see that happen, so that UNAIDS goals can be met and HIV and AIDS could finally be conquered. But she’s also aware of how far the world has already come. “HIV has inspired tremendous global solidarity among governments, scientists and community activists,” Walensky says. She also notes that the benefits of that effort have grown beyond the disease itself. The cure of hepatitis C directly followed from what researchers learned in treating HIV, and work on HIV vaccines has sparked development of better vaccines for other diseases. “The progress we’ve made in 20 years is unprecedented,” Walensky says, “but we cannot stop now.”