London - Two decades ago, Gus Cairns was certain Aids would kill him. He had buried his partner and seen countless friends succumb to the disease.
Cairns was constantly tired, he lost 35 pounds because he couldn’t keep food down, and he suffered from chronic stomach bugs. In 1993, he retired from his work as a therapist to start preparing for the inevitable.
But death didn’t come.
“We were at the peak of people dying of Aids, and then the drugs came along - and we all started living,” says Cairns, appearing fit and vigorous as he sips tea at a café near London’s King’s Cross railway station. “It’s astounding.”
At age 60, Cairns has become the new face of HIV. Antiretroviral therapy has turned what was once a death sentence into a chronic disease, which means more patients are living into their 60s and even 70s. Some 36 percent of HIV-positive adults in developed countries are now 50 or over, up from 13 percent in 2000, according to UNAIDS. By 2020, more than 70 percent of HIV-positive people in the US will be over 50, according to the Aids Community Research Initiative of America.
That’s an unalloyed success, but HIV medications are typically toxic not only for the virus, but also for the people who take them. That poses a new challenge for drugmakers: Making medications that subdue the illness without wreaking havoc on ageing bodies, and minimising the risk of harmful drug interactions for people who might have to take their HIV medications alongside pills for blood pressure, cholesterol or diabetes.
Combination therapies
Since 1996, HIV has been treated with so-called combination therapies, where three or more drugs attack the virus so it has a harder time developing resistance. For nearly a decade, Truvada from Gilead Sciences has been the preferred basis of therapy, but it’s known for harsh side effects such as kidney damage and loss of bone density - concerns that are typically even worse for older patients.
GlaxoSmithKline - the company that created the first HIV drug, AZT - is now working on two-drug combinations. In 2013, Glaxo introduced a new treatment that scientists say is less toxic than older formulas and which makes it hard for the virus to evolve resistance. Though the drug, called Tivicay, is usually used in combination with other medications - often including Truvada - researchers say it could become the foundation of simpler two-drug regimens.
The drive to simplify treatment could dramatically rearrange the competitive landscape. As word of Tivicay spread, Glaxo in 2014 made small gains in market share, reversing more than a decade of losses. UBS says that if Glaxo’s dual regimens prove effective, the company could capture half the market by 2023, up from 17 percent today.
Existing treatments “have long-term toxicity problems”, says Dominique Limet, Chief Executive Officer of ViiV, a joint venture of Glaxo, Japan’s Shionogi & Company and Pfizer that makes HIV treatments. Two-drug regimens, rather than today’s three-drug cocktails, “would mean less product in the body, better profile, and potentially less cost”.
Gilead this year received Food and Drug Administration approval for an upgraded version of Truvada that replaces the ingredient connected to kidney and bone problems with a formulation that causes fewer side effects. The company says it has introduced two new combination therapies based on the compound and is developing more. The upgrade will help Gilead offset lost revenue when a key patent for the original Truvada expires next year, opening the door to low-cost generic versions.
The growing numbers of HIV patients over 50 could benefit from simpler treatment options. As infected people reach retirement age, their medical regimens become more complex because of viral resistance combined with health problems related to aging.
“It gets complicated as you get older,” says Caspar Thomson, executive director of NAM/Aidsmap, a 30-year-old information portal on HIV.
Virus factories
Tivicay belongs to a new group of drugs called integrase inhibitors that can prevent HIV from replicating in the body. Left unchecked, HIV turns immune cells into virus factories, using the enzyme integrase to insert its DNA into healthy cells - but Tivicay and similar compounds block that process.
Shionogi was a pioneer of these treatments, and the Japanese drugmaker’s work soon drew Glaxo’s attention. The companies set up a partnership in 2001, giving Glaxo access to groundbreaking research at a time when its new-drug pipeline was weak. Shionogi benefited by tapping into Glaxo’s global sales network and its worldwide research operation - important because Japan didn’t have enough HIV patients for human trials of the drugs.
The companies say they evaluated over 4 000 compounds, but rejected the vast majority long before they made it to human trial. And even the handful tested on humans ran into a host of problems. An early version showed promise in test tubes, but failed in human trials because it got broken down too quickly in the body. Another stalled after it was shown to cause liver problems in monkeys.
Then in November 2007, the research team hit upon a compound that worked in the lab and in healthy subjects. A few months later, they tried it on HIV-infected patients, and after 10 days of treatment their viral loads had plunged. That was the compound that became Tivicay.
Buried treasure
“Most people probably think that drug discovery is like finding buried treasure,” says Tamio Fujiwara, global project leader for integrase inhibitors at Shionogi. “But in reality it’s the result of consistent, diligent, daily work.”
Glaxo presented data from the first human trial of Tivicay in 2009 at the International Aids Society conference in Cape Town. The drug, they said, decreased the virus to undetectable levels in 70 percent of patients and was less likely to induce viral resistance than rival therapies. Tivicay won FDA approval in 2013 and Glaxo’s ViiV unit has acquired global rights to the drug and similar formulas in the pipeline at the Shionogi joint venture.
Two-drug combinations would represent almost unimaginable progress for Cairns, who recalls the early days of antiretroviral therapy, when treatment often consisted of 20 to 30 pills a day. In 1989, four years after he was diagnosed, Cairns enrolled in a trial of Glaxo’s AZT. But after six weeks, the side effects - fatigue, nausea and a strange taste in his mouth, metallic and salty at the same time, like chewing bouillon cubes - made him swear off treatment. Since he wasn’t yet sick from Aids, he decided to “just sort of try to survive by living well”.
He was also taking care of his partner, who had tested positive and passed away in the first week of 1990, at the age of 28. During those years, Cairns says, so many friends had the disease that he stopped going to funerals.
Fellow soldiers
“It was like a war, and half your fellow soldiers are dying,” he says. “Most of the time, you’re too busy getting on with the business of survival to be scared.”
By the mid-1990s, his weight had dropped to 133 pounds, he felt too sick to work, and he had difficulty even getting out of bed. In 1995, Cairns decided it was time to try new treatments that had become available - though some of these turned out to be even worse than AZT, such as one he tried that seemed to strip all the fat from patients’ faces and limbs.
“People would actually be better but look worse,” Cairns recalls. “It was terribly stigmatising.”
Then in 1996, he was offered one of the first triple antiretroviral therapies - so-called cocktails that could suppress the virus. The first one went straight through his body without getting absorbed. Next, he tried a Merck product that was effective but too complicated as it needed to be taken three times a day, two hours away from food, and he frequently missed his midday dose once he started work again.
His doctor finally hit on an effective therapy in 1998, adding a booster that made the Merck offering last longer in the body, reducing the frequency of doses. His chronic stomach pain stopped within weeks and he began gaining weight. On his 42nd birthday, Cairns’s doctor told him the virus was completely suppressed.
Five pills daily
The treatment really began to take effect “a month before my dad died”, Cairns says, his blue eyes clouding over. “He saw the evidence of my recovery, which I’m so pleased about.”
Today Cairns takes five pills a day in a regimen based on Truvada, and the virus has been virtually undetectable in his blood for 18 years. He continues his work as a therapist, edits a newsletter for an HIV group, and in his spare time, tends his garden and has returned to a great passion of his 20s: singing.
He says he’s heard about Tivicay and is intrigued - it’s got limited side effects, he’d need to take fewer pills, and the virus is slower to develop resistance - but for now, he’s going to stick with his current therapy since it’s working.
Tivicay “has the sort of profile you want for an HIV drug”, Cairns says. “But at the moment I’m fine with what I’ve got.”
* With assistance from Takako Taniguchi, Yusuke Miyazawa and Caroline Chen
BLOOMBERG