Robin Isaacs Pt2: New drugs and HIV explained
By Jay Bennie
18th May 2008 - 09:02 pm
Ex-Auckland doctor Robin Isaacs, now a US-based senior figure in the drug and vaccines research unit of global drug giant Merck Sharpe and Dhome, has been visiting New Zealand. In part one of his interview with GayNZ.com he remembered the early, terrifying, days of the epidemic in New Zealand and overseas, and his career change from front line doctor to researcher.
Whilst in New Zealand he has been combining work with family visits. "Merck was very nice to bring me out here, because it means I get to see my family and see New Zealand. And we have this new HIV drug, Raltegravir, which is approved in the United States and in Australia and hopefully in New Zealand sometime in the future. It represents a total new class of HIV therapy for patients who have multi-resistant virus, who have no - or extraordinarily limited - treatment options. It is going to be a very important drug for HIV positive people, as they move from their first to second line regimens."
Isaacs is on a roll and certainly not shy about trumpeting Raltegravir's virtues. "It's on the same seismic scale as protease inhibitors and AZT. It really is," he enthuses. "It's just phenomenal. I have to acknowledge with the caveat that we're talking early game here... we’ve got data on over a thousand people... but with that caveat in mind, people are getting to undetectable incredibly quickly."
Raltegravir is arriving at an opportune time, just as New Zealand starts to see a rise in the number of people infected with strains of HIV which have become resistant to previous life-saving medications. "I think there is this window that’s suddenly opened up, in the last 12 to 18 months on a worldwide basis. [Raltegravir] is the first integrase inhibitor so it’s not cross-resistant with any of the other classes of drugs. You have CCR5 inhibitors. You have a new generation protease inhibitor, a new generation Non-nucleoside Reverse Transcriptase Inhibitor that are partially effective against virus resistant to other drugs in those classes. Suddenly you have three or four drugs that you can mix and match to produce very potent regimens, which provide an opportunity for people who were looking down the barrel of a shotgun again, because they had no treatment options."
Raltegravir takes an entirely new approach to stopping the flood of replicating HIV in the host's body. "In order for HIV to replicate, [its] genetic material has to become stably incorporated in the host's genetic material. That's why HIV is a chronic disease. When you stop giving drugs for viral suppression, the virus starts replicating again. It's doing that because it's become stable and part of the DNA of the person it's infected."
That process of getting the viral DNA as part of the human DNA is called integration. "The virus produces an enzyme called integrase," explains Isaacs, "with the specific job for the virus to take the virus's genetic material and inset it into the host's genetic material. So integrase inhibitors, of which Raltegravir is the first in it’s class, stop that process happening."
For almost a quarter of a century HIV has screwed up the lives of hundreds of thousands of gay men in developed western nations including New Zealand. Many, many have died. In poorer countries it is straight people who have become its targets. Why is HIV so difficult to find a vaccine or a cure for?
The reason the vaccines are so [difficult] to develop, says Isaacs, is that HIV is not very good at reproducing itself. "It keeps on making mistakes all the time. And sometimes those mistakes are a failure for the virus, and the virus doesn’t replicate, but in other cases it isn't a failure and keeps on replicating the 'mistake.' The upshot is that the way HIV looks to the human immune system changes all the time."
Vaccines cause antibodies to be generated in our bodies which stop the virus or the bacteria doing what they are supposed to do. After exposure to the vaccine, usually a weakened or dead form of the virus, our immune systems remember what the virus looks like and how to produce the specific antibodies more or less indefinitely. "The thing that makes [successful vaccines] work is that the antibodies are very specific, and what they are targeted against doesn’t change," clarifies Isaacs. Also, viruses that don't kill us teach our immune system what to look out for next time.
One of the more promisingly reported vaccine trials, by Merck Sharpe and Dhome, came to nothing last year. "The failure of the Merck vaccine last year, was devastating for the people who were hoping for the vaccine, but for the people who worked on it, it was also truly a devastating experience. People had dedicated their professional lives to it for over a decade or more."
But with influenza outbreaks stemming from a different 'flu strain each year, a tweaked vaccine is created each year and distributed to at-risk people around the world. The process is an offshoot the great international efforts against infectious diseases of early last century. How come twenty five years into the HIV epidemic we don’t seem to see that level of success, or cooperation, or determination happening with HIV?
"Well I think there is a lot of cooperation and determination on a worldwide basis," says Isaacs, "but the 'flu example is a good example on one hand, but it's a bad example on another... for influenza, you're looking at cycles that take about a year. In HIV, that's happening every four hours, in each individual person. So it's just a tremendous amount of diversity every day, day in and day out, as the virus is replicating."
Our immune systems can't cope with such rapid, relentless changes. "HIV just totally overwhelms the immune system because every time it looks at the virus, it looks different. For the flu, the amount of 'antigenic drift' that you get is very slow and not predictable, but you can sort of predict on a year to year basis where it's going to go, based on where it’s been." Despite decades of HIV research, scientists still can’t do that, so the antibody approaches have not worked. "What people have been trying to do is find a part of the virus which is so critical that it never mutates. Stable, but critical. And we haven’t managed to do that yet."
Not yet, but maybe some day? "I can't tell you when it's going to happen, but it’s going to take a long time.”
So in the meantime, with nothing medical to protect against HIV infection and no way to kill it once it’s in the body, it’s drugs, drugs and more drugs to try to stop the virus multiplying at will before it overwhelms the patient's immune system. Taking HIV drugs has been likened to having chemotherapy every day of your life, trying to stall the HIV without actually killing the patient.
"I think that what you're describing is accurate, and I think that in the first generation of these drugs the aim was to get drugs which would be effective because we had nothing else," reflects Isaacs. "And I believe that as time has gone on, an attempt has been made to try and develop products which represent improvements on the previous products, which have less toxicity, or are more convenient to take."
Until the dosages were finally sorted out, early AZT treatments created serious side effects many patients couldn"t bear, such as nausea, headaches, even anemia and bone marrow suppression. Then Crixivan arrived. It was one of the breakthrough series of drugs called protease inhibitors. "I have to tell you, it was a great product. It saved many many lives. But it wasn't very convenient to take, and it had the problem of kidney stones with it. So they moved forward and they get better tolerated drugs which were more convenient to take, so now you have once-daily protease inhibitors which still aren’t as well-tolerated as you would like, but are much better than the first lot that we had."
Protease inhibitors are taken as part of a 'drug cocktail', a rather camp sounding term for handfuls of pills which still cause unpleasant side-effects. "Part of the problem with the protease inhibitor class is that in order to get really good daily regimens that work, you need to boost them with Ritonavir, but Ritonavir brings its own baggage along with it." That 'baggage' includes nausea, vomiting, farting, and diarrhea. Some people also experience tingling or numbness around the mouth, or find that foods taste strange. "There is a desire as we move forward to bring forward compounds which are better tolerated."
For many HIV patients, despite the best drug cocktails, even when taken on time with the right foods and with relentless precision, the virus can eventually become immune to the effects of currently used drugs. Like his ex-colleagues in the NZ medical fraternity, Isaacs is enthusiastic about Merck’s Raltegravir. "The best thing about Raltegravir is that it seems to be fairly well tolerated. And, based on what we hear from patients receiving it through their investigators, seems to have less of the toxicity issues than other agents have had. But we won’t really know for sure what that’s like until it’s been available for several years."
Raltegravir is already available to people with HIV in New Zealand, but only on a limited basis called 'compassionate access.' People whose HIV is resistant to all the currently prescribed drugs can apply through their physicians to be one of a limited number of people for whom Merck is supplying Raltegravir free of charge while Medsafe and Pharmac decide if and when to make it more freely available.
Today is AIDS Candlelight Memorial Day, when people gather around the country to remember the hundreds lost to HIV and renew their commitment to fighting the spread of the disease. Places and times for these events are listed through the link below.
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