An HIV Injectable Regimen Comes of Age

Without the Pill Box?
The First Long-Acting Injectable Regimen for Individuals Living with HIV Comes of Age
by Mel Baker

A funny thing happened on the way to the 2019 Conference on Retroviruses and Opportunistic Infections in Seattle. Dr. Brian Woodfall, Global Head, Development, Infectious Diseases, Janssen, and his colleagues were expecting to make a big splash. They were releasing positive results from a clinical trial that could radically change the way many HIV patients take their medicine, but the international media was captivated by another story.

“HIV is reported cured in Second Patient” and similar headlines were the first news out of the conference, when researchers announced that a man being treated for bone cancer showed no signs of infection, after getting a bone marrow stem cell transplant from a donor who is among the less than one percent of people who are immune to HIV (See Hank Trout’s report).

All the breathless coverage was a surprise to Dr. Woodfall. “I saw it on the news before I even came here and I had no idea, I hadn’t heard of it [a second patient] before. My only exposure to it was on the national news and I thought wow! But the context of it was—in my opinion—really off, in that this is fantastic, we found a second patient, but you have to have cancer, get a stem cell transplant and be immuno-suppressed.”

For HIV patients the headline grabbing story was the very definition of the adage, “The cure is worse than the disease.” It would require radiation and chemotherapy to destroy the infected immune system and come with around twenty-five percent chance of dying of complications in the first year.

At best the London Patient’s story shows that grafting genetic immunity from the virus into a person’s genes can in essence cure HIV, but research into a viable therapy that doesn’t involve destroying and replacing the bone marrow is still years away.

A Dozen Pills to One Pill to Once a Month Injection
When the so-called HIV drug cocktail appeared in the mid-90s patients took a dozen or more pills spread throughout the day. Many of those came with nearly immediate side-effects including headaches, nausea and diarrhea. Today most patients take one pill a day, with relatively few short term side effects. Now comes the possibility of a once a month or even once every two months injection by a healthcare provider.

The FLAIR trial (First Long-Acting Injectable Regimen) of 263 people using the two-drug combination of cabotegravir, an integrase inhibitor (INIs), from ViiV Healthcare, and Janssen’s rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), has demonstrated that a once a month intramuscular injection is as effective at controlling HIV as a standard three-drug combination.

A patient questionnaire found that nearly a year into the trial, eighty-six percent of the patients preferred the once-a-month injection over taking a pill every day. The study found that eighty-three percent of patients reported mild to moderate discomfort from the injection at some point during the trial, but only about one-percent dropped out because of discomfort related to the injections.

VIIV Healthcare (which conducted the trial0 also announced at the conference the success of its three yearlong ATLAS trial (Antiretroviral Therapy as Long-Acting Suppression), which shows that the two-drug injectable is as effective as a three-drug oral regimen in controlling HIV. The announcement adds to the weight of evidence showing that the drug used in the injectable trial has proven effective in suppressing HIV over the long-term.

Creating a Drug Depot in the Body
There are three types of injections; intravenous (directly into the bloodstream), subcutaneous (under the skin)—the kind diabetics give themselves—and intramuscular (into muscle tissue, usually the buttocks).

Dr. Woodfall says the injectable regimen involves an intramuscular injection that creates a drug reservoir in the tissue. “Nano particles of the drug combo create very, very small particles that are like beads that form a depot in the muscle and in the lymph nodes, which then are released over time to give you a nice long presence of the drug (at levels) necessary to suppress HIV replication.” Imagine a pile of marbles with the top layer melting away into the surrounding tissue, exposing the next layer, until all of the drug has been absorbed.

Anytime a person goes on new drugs, there is a chance their personal reaction and side-effects will be too severe to continue, which would be a problem if you had a month of meds slowly dissolving in your body.

Dr. Woodfall says that on the injectable regimen plan, patients will take the pill form of the injectable for four weeks to determine if there are any side-effects, before getting their first injection. “Most of the adverse events that people might have, usually happen within those first weeks; particularly rash or hypersensitivity.”

The challenge with intramuscular injections is that they aren’t something a person can easily do themselves, requiring a medical professional to help. Keeping to a once every four week doctor’s visit could prove challenging. Dr. Woodfall says people would keep a few pills on hand to help them maintain therapy. “So say somebody’s traveling, and they won’t be able to get their injection, we will have instructions on how to use oral bridges. So you could use pills for an oral dosing for a certain period of time until you can get your next injection.” He says the pill as back-up method was effective during the trial. “The important thing is none of those patients that did use the strategy of oral bridging had viralogic failure.”

From Clinic to Lab
Dr. Woodfall didn’t begin his career in drug development. He treated patients in one of Canada’s first HIV clinics. “When I finished medical school in Saskatchewan—which is a very rural province—I moved to Vancouver to do my internship. I had planned to go into anaesthesiology, but I did my internship at St. Paul Hospital in Vancouver, which was the epicenter of the AIDS epidemic in the eighties, the equivalent of San Francisco General in San Francisco or St Vincent’s in New York. As part of my training there I was involved in hospital care of a tremendous number of HIV patients. It was the cutting edge of science, medicine, and social activism. The feeling that we were working on an incredible fight and struggle, so I gave up my residency, and became an HIV clinician and helped build out our clinic and a lot of the services and the treatment guidelines that were all new in the late eighties early nineties.”

Dr. Woodfall and his colleagues at St. Paul’s would surely have liked something like a monthly injectable once the so-called protease cocktail became available in the mid-nineties. In fact his current employer Janssen has been using a once a month or longer injectable for schizophrenia for well over a decade. So called depot formulations have long been used in contraceptives, anabolic steroids and corticosteroid injections for inflammation.

The challenge in creating HIV injectable therapies relates back to those early HIV cocktails, which required a dozen or more pills a day. Dr. Woodfall says those individual drugs were simply less powerful milligram for milligram than the latest generations of HIV meds, such as the combination used in FLAIR.

“The technology depends upon having a molecule that is very potent against the target at a relatively low dose, so that the amount of drugs needed for a long period of time, can be adequately accommodated in an injection. The two drug combo that we use has a daily oral dose of 25 milligrams, which is very potent. So that looking at it once a month that’s 25 milligrams times 30 days, which gets you into a few hundred milligrams. If your daily dose of a drug is say 600 mg, 30 days of that is going to be a much bigger drug load, and really isn’t amenable to the limitations you have from a volume perspective for an injectable.”

Two Months or More?
In April, Jansen and ViiV Healthcare submitted the monthly injection for approval by the Food and Drug Administration. Dr. Woodfall and his colleagues are hopeful the treatment will be available to patients sometime in 2020.

The researchers are also conducting a trial of a once every two month injection of rilpivirine and cabotegravir. Results from the FLAIR 2M trail should be released later this year. In an A&U interview (“Under One Roof, ViiV Healthcare Strives for New HIV Treatments,” November 2018) Dr. Max Lataillade, Vice President and head of clinical development at ViiV Healthcare suggested that the companies are also exploring a once every three month injection.

Longer lengths of time between injections could be a real game changer for HIV treatment in the developing world where easy access to care is limited or for those in any region who cannot maintain a daily pill schedule.

The challenge of the FLAIR 2M trial and future trials will depend on how well patients can tolerate increasingly large drug depots in their muscle tissue, potential long-term side effects and how cautious the FDA and other regulators are when they weigh the evidence and approve or disapprove HIV injectable treatments for the marketplace.

The FLAIR trial results for the injectable regimen and other drugs he has helped develop are deeply satisfying to Dr. Woodfall who moved from treating HIV patients to being on several teams that have worked to create new, less toxic and more effective HIV drugs.

“From a professional perspective, what a tremendous experience to have been at the first identification of an epidemic, then the identification that it’s a virus and being able to eventually develop medicines that have a huge impact in people’s lives. To see all of that in one professional lifetime is fantastic. One couldn’t ask for more.”

He is well aware that advances have only come from of a constellation of compassionate and committed people. “How fantastic when people do come together, from diverse areas, whether they are advocates or politicians, social workers or doctors, the power of that communal work is beyond impressive. The richness of different opinions and different experiences makes me think how we’re all better for that.”

Mel Baker is a broadcast journalist and former LGBT and anti-nuclear weapons activist. He is married to artist Leslie Aguilar and lives in San Francisco, California.