If we think of HIV as carrying a kind of a malware that takes over human T cells and turns them into a machine to create more copies of itself, then the goal has always been to try and cripple some part of the machine before it consumes the living immune system.
We can think of the early medicines such as AZT as doing little more than throwing sand in the gears, slowing the machine until it adapts and moves on.
In our analogy, other classes of HIV medicines might disable the gear shaft or the drive pistons, but it wasn’t until the viral machine was attacked on many fronts at once that the treatments we use today were able to halt the virus and allow the ravaged landscape of the immune system to recover.
But the war against HIV is never completely won.
Dr. Max Lataillade and the multi-discipline team at ViiV Healthcare’s Branford, Connecticut research facility have an ambitious agenda: They are working to find less toxic (HAART) drugs to fight HIV, to reduce the number of drugs used to treat most HIV patients and to make it easier to take medicine to fight the virus and prevent infection (PrEP). They are also introducing a new drug class that will help patients who are no longer responding to the current medicines.
Dr. Lataillade is the Vice President and head of clinical development at ViiV Healthcare and has been studying the HIV machine for most of his career. He did his original master’s degree work in public health policy at George Washington University studying HIV and tuberculosis in the developing world, focusing on hard-hit Haiti. That work inspired him to go onto medical school to become an infectious disease specialist. “I developed a fascination for understanding HIV and how it infects a patient, but also understanding the life-cycle of the virus so we could develop new medications to treat HIV.”
He’s since become an Associate Professor at Yale University’s School of Medicine and highly experienced HIV drug development specialist in the commercial sector.
Ever since Dr. Lataillade began studying the virus, the gold standard of treatment has been a three-drug regimen attacking two or three parts of the life-cycle of the virus.
But that approach comes at a cost. Beyond the numerous side effects and long-term damage to the body, Dr. Lataillade says the meds can also interfere with non-HIV medicines. “A lot of the patients that have been taking HIV drugs for a long time—such as the boosted protease inhibitors—have a lot of drug interactions with their blood pressure and lipid medicines and with hepatitis C treatments as well as rifampin, which is used to treat tuberculosis.”
Dr. Latailliade and his colleagues at ViiV believe that a good place to reduce toxicity and the cost of HIV treatment is to question the three-drug regimen “gold standard” to fight the virus.
Two Is Better
“The thinking for us at ViiV is that if you can use two drugs vs. three drugs, you can use less drug vs. more drug with the same efficacy. The more drugs you use the more your liver and your mitochondria have to clear out of the system.”
As part of ViiV’s GEMINI trials, Dr. Latailiade says the integrase inhibitor (IINST) dolutegravir is a good choice to make a two-drug combo work. “We have a drug that is very potent in dolutegravir [as] we can use less drug vs. more drug to treat patients.”
Dolutegravir was approved last year for use with the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine, marketed as Juluca.
Following a successful Phase III study, ViiV filed last month for FDA approval of a drug formulation combining dolutegravir with a much older, but low toxicity (NRTI) lamivudine also known as 3TC.
Dr. Lataillade says a head-to-head comparison study of their two drug combination of 3TC and dolutegravir vs. a three-drug regimen that added nucleotide analog reverse-transcriptase inhibitor (NtRTI) tenofovir was promising.
The ViiV lab has been making rapid progress on several fronts because it operates as an all-in-one research and development shop funded by GlaxoSmithKline, Pfizer and Shionogi. All three companies transferred their HIV research and drug patents to ViiV Healthcare in 2009.
Most pharmaceutical companies have the people making new discoveries for potential treatments separate from the early development groups. Dr. Lataillade says they have all of those people under one roof in their Connecticut lab. “We have our chemists, biologists, synthetic chemists all working in the same building; we can talk the same language. We can take a drug from this early discovery stage and start to run with it into the development stage. It increases what we like to call the ‘speed to patient’ strategy.”
ViiV is also placing a big bet on replacing daily pill regimes, with “Antiretroviral Therapy as Long-Acting Suppression” (ATLAS), a once-a-month intramuscular injection given by a health provider.
Dr. Lataillade noted,“I think this sort of long-acting formulation improving convenience is something we are going to see more of.”
The company has two Phase III ATLAS trials that have been underway for several years. One combines two drugs; the integrase inhibitor (INSTI) cabotegravir and the (NNRTI) rilpivirine. That combination is being tested on people who are already infected. Another injectable trial using just cabotegravir is being tested as a PrEP drug to prevent infection.
Both approaches could be a game changer for many patients.
For those with the virus, it would reduce the threat of viral resistance if they miss daily doses of their medicine.
For those on PrEP, getting an injectable once a month would be far easier than remembering to take a pill every day, when the prospect of becoming HIV-positive is only a seemingly remote possibility, instead of the reality of illness faced by those already infected. Dr. Lataillade says while the current injectable trials focus on once a month injections, it is theoretically possible to extend that time frame. “We will try to push the envelope even more to make it once every two months or potentially every three months.”
Helping Those Running Out of Time
Refining current drugs and delivering them in novel ways isn’t the only thing on ViiV’s agenda. Dr. Lataillade is especially bullish on their new drug fostemsavir, an attachment inhibitor that would prevent HIV from connecting with the gp120 protein on the surface of the virus which acts as the gateway for HIV to gain access to the T cell and hijack it.
“Once fostemsavir binds with the gp120 protein it keeps it in a conformational state, that does not allow it to bind to the CD4 cells.”
Unlike other drugs that attack parts of the life-cycle of the virus once it is in a T cell, this drug would act as glue in the lock of still healthy T cells preventing HIV from getting a foothold in the body.
It could be an ideal drug for PrEP therapy, standing in for a fully effective HIV vaccine that continues to remain elusive.
As a treatment, it could potentially be far less toxic than other drugs, because it works directly on the virus, not the immune cell host. Protease inhibitors, for instance, can affect other healthy protease related functions in the body, leading to side effects.
Attachment inhibitors like fostemsavir could also be a godsend to patients whose virus has become resistant to other therapies, providing another drug to bring the rampaging viral machine under control. Fostemsavir is in a Phase III clinical trial.
ViiV is also working on another drug that would make any viral particles produced by a hijacked T cell incapable of infecting other cells. The maturation inhibitor has begun early human trials.
Returning to our analogy of HIV as zombie machine, we are reminded that the current treatments haven’t removed the deadly virus from the body; it can be brought to a standstill, but only as long as it remains under constant attack. The ongoing war between drug and virus takes its toll on the land upon which the battle is fought: the human body.
Anything ViiV and other HIV labs around the world can do to find treatments that reduce the collateral damage from the weapons used to fight HIV, can only be to the good of those who are infected, those who will become infected and hopefully the many who will be protected from HIV.
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.