HIV Drugs in Clinical Trials to Treat COVID-19—What You Need to Know

The first drug to treat HIV infection was AZT, approved by the U.S. Food and Drug Administration (FDA) in 1987, six years after the start of the AIDS epidemic. Truly effective triple-combination therapy, colloquially known as the cocktail, was not approved until 1996.

Now, just months into the still-unfolding coronavirus pandemic, scientists and clinical researchers are turning to HIV drugs as they hunt for treatments that may be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Such “repurposing” of drugs originally developed and approved to treat HIV has clear advantages. For one, the safety profile of these drugs is generally well known. In addition, since medical providers may legally prescribe drugs “off label” (that is, to treat a condition other than those for which the drug is approved by the FDA), any such drugs proven effective in clinical trials can be used in clinical settings even before they receive FDA approval for treating COVID-19.

The HIV drugs that are being studied to treat COVID-19 are mostly in a class of drugs called protease inhibitors. Protease inhibitors block (inhibit) a viral enzyme called protease. Enzymes are substances that regulate the life processes of cells, including viruses, which are one-celled organisms. Protease is like a cellular jigsaw. After an existing virus infects a human cell, it starts making copies of itself. Each copy starts out as one big piece, called a polyprotein. The viral protease cuts the polyprotein into smaller pieces (functional proteins), so the virus can assemble them into a whole new copy of itself, like the pieces of a jigsaw puzzle (a process called viral replication). If you can jam up the protease jigsaw, you can stop the virus from replicating—and that is exactly what protease inhibitors do.

Ten protease inhibitors have been approved by the FDA for treating HIV—including (in alphabetical order by generic name) amprenavir (Agenerase), atazanavir (Reyataz), darunavir (Prezcobix, co-formulated with cobicistat), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir (Kaletra, co-formulated with ritonavir), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase or Fortovase), and tipranavir (Aptivus).

All 10 FDA-approved HIV protease inhibitors have been screened for possible effect against COVID-19, using computers to simulate the interactions between the drugs and the virus, a process called “molecular modeling.” These computer-based studies use a method called “docking” to predict how the drug is going to fit into a particular spot on the virus, sort of like a video game where you dock a spacecraft with a space station; or like shooting virtual pool—the target on the virus is, in fact, a molecular pocket in the viral protease where the drug needs to fit in order to inhibit the virus.

All the HIV protease inhibitors have scored well in COVID-19 docking studies—meaning that, in these computer simulations at least, they fit in the pocket well enough stop the virus from replicating.

Evidence from a docking study in Iran suggests that the six most promising HIV protease inhibitors are likely to be effective against COVID-19 in the following order:

1. tipranavir
2. indinavir
3. atazanavir
4. darunavir
5. ritonavir
6. amprenavir

In addition to the HIV protease inhibitors, the list of HIV drugs identified by screening studies includes abacavir (Ziagen), efavirenz (Sustiva, Stocrin), dolutegravir (Tivicay), elvitegravir (Vitekta), raltegravir (Isentress), and bictegravir (a component of Biktarvy). Results from these molecular modeling studies do not guarantee that these drugs will be active against COVID-19 either in test tube studies or in humans; but they help researchers choose candidates for laboratory and clinical studies.

To date, the HIV treatment that has been most studied in COVID-19 clinical trials is the combination of the HIV protease inhibitors lopinavir and ritonavir, marketed as Kaletra. Kaletra took the lead in the search for COVID-19 treatments because researchers years ago identified it as a promising treatment for severe acute respiratory syndrome, or SARS, and Middle East respiratory syndrome (MERS), two other deadly infections caused by coronaviruses.

A trial by Bin Cao, M.D., and colleagues published in the New England Journal of Medicine has received the most mainstream media attention. That study compared treatment with Kaletra plus standard care to treatment with standard care alone, and included 199 patients. Standard care included measures like oxygen, ventilators, antibiotics, blood pressure medication, kidney dialysis, and life support. The study found that adding Kaletra to standard care provided no additional benefit. Other, smaller trials of Kaletra have also shown no benefit.

Kaletra may be down as a treatment for COVID-19, but it’s not out. In a study published in May, Kaletra was combined with two other drugs—an antiviral called ribavirin, approved to treat hepatitis C, and an anti-inflammatory drug called interferon beta-1b, approved to treat multiple sclerosis. One group of patients in this study received the triple combination, while others received Kaletra alone. The study found that the patients on the triple-combination faired significantly better than the patients receiving only Kaletra. Their symptoms cleared up completely in four days, and their COVID-19 tests turned negative in seven days.

This was an open-label trial, meaning that both doctors and patients knew who was getting which treatment, and there was no placebo group. Moreover, these patients were not critically ill, so the researchers could not draw any conclusions about how the combination would work in sicker patients. Evidence from the trial suggests that inclusion of interferon beta-1b was key to the success of the regimen, so the authors recommend proceeding to a placebo-controlled trial that includes interferon beta-1b as the “backbone” of a combination drug regimen.

Other HIV protease inhibitors have also entered clinical trials for treating COVID-19. Four studies are currently underway treating COVID-19 with the HIV protease inhibitor darunavir, co-formulated with the pharmacologic boosting agent cobicistat. In addition, there are two studies underway of an investigational HIV protease inhibitor—that is, a drug not yet approved by the FDA, even for treating HIV. The studies will assess a protease inhibitor called ASC09.

The company developing ASC09 is Ascletis Pharmaceuticals, a Chinese company. Ascletis licensed the drug from the U.S. drug company Janssen, a subsidiary of Johnson & Johnson, in 2013. At that time, Janssen stopped developing the drug, which was then in phase 2 clinical trials, for marketing in the U.S. But Janssen still retains its rights and stands to profit from the drug if it is successfully developed by Ascletis for HIV, COVID-19, or both.

There is another investigational HIV drug soon to enter a clinical trial for COVID-19, this one in an entirely new class of drugs. Leronlimab is a monoclonal antibody. Leronlimab binds to a protein on the surface of human CD4 cells called CCR5—a receptor that HIV hijacks to enter human CD4 cells—thereby preventing HIV from entering the CD4 cell.

The drug is manufactured by Oregon-based CytoDyn, Inc., and leronlimab is the only drug in their pipeline at this time. In addition to a phase 2 trial for COVID-19, leronlimab is in phase 3 trials for HIV, and in various phases of trials for a number of cancers and some autoimmune conditions, including Crohn’s disease and multiple sclerosis.

Finally, a clinical trial is currently underway to test Truvada (emtricitabine/tenofovir disoproxil fumarate)—the same drug currently approved for HIV treatment and HIV pre-exposure prophylaxis (PrEP)—for preventing COVID-19 among hospital health care workers in Spain. The randomized, double-blind clinical trial will enroll 4,000 patients. The trial is expected to be completed by July 31, 2020.

The list of clinical trials evaluating FDA-approved HIV drugs for treating COVID-19 is bound to grow over the coming weeks, months, and years. Thanks to research and development efforts undertaken some 25 years ago by scientists, doctors, allied health care professionals, academic institutions, pharmaceutical companies, government agencies, community-based organizations, and grassroots AIDS activists, a clear path now exists to make treatments for COVID-19 available much sooner than the 15 years it took to develop lifesaving treatments for AIDS. The whole world stands to benefit.