The present-day HIV treatment toolbox is well stocked. More than 30 antiretroviral therapies (ARTs) available in an ever-growing array of drug classes means people living with HIV (PLWH) can manage the virus with just one pill once a day. Treatments are not only safe and effective, but tolerable and convenient, with minimal side effects or dietary requirements. Nevertheless, there are many PLWH whose virus is resistant to most if not all available treatments and who need access to new drugs in existing classes, or drugs in completely novel classes, in order to continue living a healthy life with HIV.
What’s more, conditions in many parts of the world, particularly in sub-Saharan Africa, often make HIV treatment difficult for particular groups of PLWH, especially women. For these PLWH, it is important to develop treatments that are not only safe, effective, tolerable, and convenient in the traditional sense, but that also put control in the hands of the women with HIV who often are subject to difficult life circumstances, including intimate partner violence and other social and cultural barriers to accessing the HIV care they need. Long-acting treatments and novel delivery systems such as implants and injectables—many of which would mean moving from daily pills to therapies taken once a week, once a month, or even just once every six months—are particularly urgent for PLWH in challenging circumstances.
Current research into long-acting HIV treatments falls into three high-level categories: long-acting drugs, broadly neutralizing antibodies, and therapeutic vaccines. We will be watching the research and providing deeper dives into these emerging treatment strategies in the coming weeks and months. In the meantime, read on for an overview of each.
Farewell to Daily Pills?
Current research is focused on developing new, longer-acting oral medications (pills) to treat HIV—you’d take them once a week, as opposed to daily—as well as other ways of getting these drugs into the body, including injections, patches, and implants. To advance this goal, the National Institute of Allergy and Infectious Diseases (NIAID, the federal agency headed by Anthony Fauci, M.D.) has started a project to get the experts talking to each other and working together to transform ideas into reality. This project, called LEAP (Long-Acting/Extended Release Antiretroviral Resource Program), includes scientists and clinicians from academia, industry, and government, as well as participants from community-based organizations that advocate for the needs of PLWH.
In January, the U.S. Food and Drug Administration (FDA) granted approval to Cabenuva, an injectable combination of long-acting cabotegravir (CAB LA), an integrase strand transfer inhibitor (INSTI), and long-acting rilpivirine (RPV LA), a non-nucleoside reverse transcriptase inhibitor (NNRTI). Another study currently in the works, and with results expected in 2022, will evaluate the effectiveness of combination monthly injections of CAB LA and infusions every two months of another kind of treatment called a broadly neutralizing antibody, or bNAb (more about bNAbs below). Infusion means administering the treatment intravenously, also known as an IV drip. The study will determine whether this combination therapy can keep HIV suppressed (undetectable viral load) in people who were previously undetectable on conventional HIV drugs.
Coaxing Your Body’s Built-in Defenses
With a number of promising candidates currently making their way through clinical trials, it’s become increasingly evident to researchers that highly potent bNAbs hold much promise for treating HIV. While feasibility and use in the real world are still murky, here’s what we do know: bNAbs have few side effects and can be designed to last for a long time in the body, which offers the possibility of dosing just once a month or even less often.
So, what are bNAbs? First, antibodies are a natural part of your immune system. Your body produces these proteins in response to an infectious agent, such as a virus. The antibody binds with the virus—like a space capsule docking with the space station.
The antibodies currently under development are called “broadly neutralizing” because they are active against a wide range of HIV strains. After binding with the virus, bNAbs can fight the virus in three ways:
- By binding directly to the virus, thus preventing it from entering human cells that are targeted by HIV, such as CD4 cells;
- By binding to an HIV-infected cell and then recruiting other components of the immune system that destroy the virus;
- By binding to a key fragment of HIV, forming a unit that stimulates the immune system to fight the infection in a manner similar to how vaccines work.
Clinical studies have shown that giving bNAbs to PLWH via infusion or injection can partially suppress the virus. But studies have also shown that treating PLWH with just one bNAb leads to the emergence of viral resistance, similar to the way HIV can develop resistance to conventional antiretroviral (ARV) drugs. This observation has led to more recent studies using combination therapy—either combining multiple bNAbs, or combining bNAbs and long-acting drugs—to achieve and maintain viral suppression. Studies in monkeys infected with a simian (monkey) version of HIV (simian immunodeficiency virus, or SIV) have already shown that combinations of bNAbs provide powerful viral suppression for an extended time. With additional studies underway to investigate combination therapy with bNAbs for treating HIV in PLWH, we can expect to see trial data in 2022.
In another promising development, scientists are developing “designer” bNAbs, making structural changes to naturally occurring bNAbs to optimize them for HIV treatment and prevention. These changes increase the breadth of the antibodies, that is, the number of HIV strains against which the antibody is effective. Such changes also increase the amount of time the antibody lasts in the body, the power with which the antibody attaches to the virus, and how efficiently the antibody triggers an individual’s immune response to attack both the virus and HIV-infected cells.
A Jab for HIV
While we generally think of vaccines as preventing infections, like the flu or COVID-19, therapeutic vaccines are another emerging area of research. These vaccines are designed to treat an already established viral infection, as well as certain cancers. A therapeutic vaccine for HIV, once administered to a PLWH whose virus is suppressed (undetectable), would trigger the immune system to control any future emergence of HIV. This would end the need to continue conventional ART. With therapeutic vaccines still in very early stages of development, we do not yet know whether such vaccines would be administered in just one dose or more than one dose, or whether boosters might be required periodically.
While we know that the immune system can control HIV in some PLWH (so-called elite controllers or long-term non-progressors), attempts to stimulate this level of viral control using therapeutic HIV vaccines have not yet been successful. Research in this area is therefore currently focused on the basic science of therapeutic HIV vaccines, including increasing our understanding of the correlates of immunity to HIV—that is, the aspects of the immune response that lead to long-term, sustainable suppression of HIV—as well as scientific advances that would allow for the development of more potent vaccines that would stimulate a more robust immune response.