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Virtually everyone who has been on HIV therapy for long is either taking – or has taken – one or more drugs manufactured by pharmaceutical giant GlaxoSmithKline. The company’s portfolio of HIV drugs is the most extensive in the industry, and their sales of HIV medications in the United States are more than twice that of their nearest competitor.

We had the opportunity to talk with Mark Shaefer, PharmD, acting Vice-President for Clinical Research at GSK’s Infectious Disease Medicines Development Center; and Deborah Thomas, PhD, a Director in GSK’s Infectious Disease Medicines Development Center. We asked them about the full array of drugs in GSK’s arsenal, starting with the grand-daddy of them all: Retrovir (zidovudine, AZT), the first drug found to be effective against HIV – and still one of the most popular.

RETROVIR (zidovudine, AZT)

Most people still refer to Retrovir by its investigative name, AZT. Retrovir was approved by the FDA on March 19, 1987.

“Marty St. Clair was working in the lab and performed the first tests on AZT,” Dr. Shaefer says. “You have to remember that, at the time, there was absolutely nothing that worked against the virus. Marty ran a sample, and the effect was so dramatic she thought there must have been a mistake. She didn’t tell anybody until she ran it a second time. That’s when she knew we had something.”

In the early days, AZT got a bad reputation because it didn’t work for long by itself. (Nothing does – successful HIV therapy requires a combination of at least three drugs.) Also, it was originally given in much higher doses than today.

“In the early days of AZT we didn’t know as much about how the drug works inside the cells,” Dr. Shaefer says. “We were giving the drug every four hours, and the total daily dose was 1,200 mgs. As we learned more we cut the dose in half, to 600 mgs-a-day. And we reduced the frequency of dosing to twice-a-day.”

Today, AZT is still a mainstay of multiple-drug therapy. It is a key ingredient in both Combivir and Trizivir. It has just come off patent, and it is likely that other pharmaceutical companies will offer a generic version soon.

“Advisors told us years ago that when new HIV drugs came out, AZT would be defunct,” Dr. Shaefer said. “But it hasn’t worked out that way. It has kept its usefulness through the entire patent life of the drug.”

EPIVIR (lamivudine, 3TC)

Perhaps the most valuable drug in the GSK arsenal – and certainly the best-selling HIV drug of all time - is Epivir, which was approved by the FDA on November 17, 1995.

“Ninety-eight percent of people with HIV have used Epivir at some point in their therapy,” Dr. Shaefer notes. “It is one of very few HIV drugs that can say on its label that it prevents the progression of the disease, because its trials were done before viral load markers came into play. It is one of the most potent of all the HIV drugs, and one of the best tolerated.”

Epivir can be taken either one-a-day or twice-a-day. It is one of the ingredients in all three of GSK’s popular combination drugs: Combivir, Trizivir and Epzicom.

COMBIVIR (lamivudine, zidovudine)

Once GSK had both AZT and Epivir in their line-up, it seems like an obvious decision to combine the two into one pill. But the idea wasn’t obvious to everyone.

“At an advisory board meeting we asked, ‘What would you think if we put these together in one pill?’” Dr. Shaefer remembers. “One person said it was a stupid idea.”

GSK went ahead anyway, and the new combination pill – the first to combine two HIV medicines into one – was approved by the FDA in September of 1997. It was tremendously popular from the beginning because it was effective and because it reduced the number of pills people with HIV had to take. The combination of Combivir and Sustiva has been, and continues to be, highly popular. (Sustiva’s development trials were done with Combivir.)

Combivir has to be taken twice-a-day, and now it is getting competitive pressure from Truvada, a two-drug combo from Gilead Sciences which only needs to be taken once-a-day; and from Epzicom, GSK’s own once-a-day two-drug combination.

“Because of ease-of-use, 55% of new HIV patients are starting on once-a-day regimens,” Dr. Shaefer says. “But Combivir is still used because it has been so well studied. And many patients who take other medications twice-a-day find it just as convenient to take their HIV meds twice-a-day also.”

ZIAGEN (abacavir)

Ziagen, approved by the FDA in 1998, was the next drug added to the GSK arsenal. It’s a popular and effective drug that works extremely well for roughly 19 out of 20 people who take it.

But for the other roughly one out of twenty, it can produce what is called a “hypersensitivity reaction.” This reaction may include fever, rash, fatigue, nausea, vomiting, diarrhea, and abdominal pain. You should quit taking Ziagen as soon as a hypersensitivity reaction is suspected, and never try it again – it is potentially fatal.

“Ziagen is a great drug,” comments Dr. Shaefer. “It’s very potent and well-tolerated – but for some people it has a potentially life-threatening reaction. The company has bent over backwards to make sure doctors, nurses and patients are all educated about the risk of hypersensitivity reaction. The number of reactions – about 5% - 8% in clinical trials – has remained constant or dropped over time. We’re doing research to see if we can find a genetic marker. One day we may be able to do a relatively simple test for genetic predisposition to hypersensitivity reaction.”

Ziagen is one of the ingredients of both Trizivir and Epzicom.

TRIZIVIR (zidovudine/lamivudine/abacavir)

In 2000, the FDA approved GSK’s second combination drug, Trizivir, which combines three nucleoside reverse transcriptase inhibitors into one. Trizivir is made up of Retrovir (zidovudine), Epivir (lamivudine) and Ziagen (abacavir).

In terms of reducing the “pill burden” associated with HIV, Trizivir was a Godsend. Instead of taking handfuls of pills every day, people on Trizivir take only one pill in the morning and one pill at night, without regard to meals. Also, Trizivir has very few interactions with other drugs – it can be taken with birth control pills, for example.

There were other advantages to Trizivir. “Unfortunately, patient prescriptions don’t always run out at the same time,” Dr. Shaefer notes. “When people were taking three different pills, sometimes one would run out before the others and they’d wind up taking only two-thirds of their regimen for a while. With Trizivir, one pill is the whole regimen, so that problem was solved. Additionally, one pill means one co-pay, which in some cases means substantial cost-savings.”

Trizivir ran into a set-back as the result of the publication of results from a trial called ACTG 5095 that suggested that the combination of three drugs of the same class in Trizivir was not as potent as a regimen including Sustiva (efavirenz) and might not be potent enough to control the virus. “The ACTG 5095 data sent shock waves through the HIV community that were in many ways really inappropriate,” Dr. Shaefer notes. “Trizivir may not be as potent as some other drug combinations, but there are patients who have been on Trizivir for years and are still doing fine. Trizivir is still widely used with Sustiva, with a protease inhibitor, or with a boosted protease inhibitor. It can be used with Viread (tenofovir) to make a quadruple-nuke regimen that appears to work well. It is also being used with later-stage patients who have run out of options to put together a five- or six-drug regimen with a limited pill count.”

LEXIVA (fosamprenavir)

Lexiva, approved by the FDA on October 20, 2003 is a “pro-drug” of an earlier protease inhibitor called Agenerase (amprenavir). Essentially, Lexiva turns into Agenerase in your body. The big advantage is in the dosing. The standard dose of Agenerase was eight huge pills twice-a-day. With Lexiva, the dose is only two smaller pills twice-a-day.

“Lexiva is part of GSK’s commitment to meeting the human needs of its customers,” Dr. Shaefer notes. “Agenerase was a good molecule, but the formulation just wasn’t making it. We developed Lexiva as a way to make the dosage much simpler and easier.”

Dr. Thomas adds, “Even with a dosage of 16 pills a day, some people thrived on Agenerase, and we had a hard time convincing them Lexiva’s just as good - and much easier to take.”

Agenerase has been taken off the market, except for children’s dosages. Interestingly – and this is a positive note indeed! – progress has been slow on trials to establish pediatric doses of Lexiva because so few children are born with HIV in the United States that it is hard to enroll pediatric trials.

EPZICOM (lamivudine/abacavir)

The latest entry in GSK’s HIV drug line-up is Epzicom, approved by the FDA in August, 2004. The name stands for “Epivir and Ziagen in Combination.” Epzicom is GSK’s entry into the one tablet, once-a-day sweepstakes. When taken in combination with Sustiva (efavirenz), you can take a complete, effective three-drug regimen with just two pills, typically taken at night before bed. It’s one of the simplest dosing regimens currently available.

“Because of the convenience, a lot of newly diagnosed people with HIV are starting on either Epzicom and Sustiva or Epzicom and Lexiva or another protease inhibitor,” Dr. Shaefer notes.

WHAT'S NEXT?

GSK is actively researching new drugs to add to the growing number of weapons available to combat HIV. They had two promising candidates that had to be dropped from development recently due to adverse events. But one very promising candidate in late-stage development is still going strong: brecanavir.

“Brecanavir is a next-generation protease inhibitor,” says Dr. Thomas. “We recently presented data from an early safety study in a mixed group of naïve and experienced patients through 24 weeks. Eight-one per cent of patients in the trial had less than 400 copies of HIV, and 77% had less than 50 copies. Of the six patients in the study with multiple drug resistance, all were less than 400 and five were less than 50."

“We’re currently doing a Phase IIb dose-ranging study on brecanavir,” Dr. Thomas said. “We plan to start a Phase III study in the fourth quarter of this year. You’ll be hearing a lot more about brecanavir over time.”

The world of HIV has changed dramatically – for the better - in the last ten years. And GlaxoSmithKline deserves its share of the credit for the improvement.

“I came into HIV about ten years ago from transplantation,” Dr. Shaefer says. “At the time I thought, well, this isn’t much different. I’m still working with people who are really sick, they’re on a lot of drugs, and their immune systems are suppressed.”

“But with better and better therapy available, that has changed completely,” Dr. Shaefer adds. “Now it is incredibly unusual for us to have a death in one of our trials. And when it happens, it is usually not related to HIV.”

“But there are still too many people getting infected,” Dr. Shaefer says. “Developing a vaccine has been frustrating, but we still believe that in the distant future, an AIDS vaccine is a possibility. And we continue to work toward that. We’d be glad to go out of business if we could stop the infections.”

Copyright 2018, Positive Health Publications, Inc.

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