Today, 22 drugs and four drug combinations are approved by the FDA for use against AIDS; another 33 are currently under investigation
In the early days of the AIDS epidemic, the only medical treatments available for people with the disease were those intended to stave off the deadly opportunistic infections primarily Pneumocystis carinii pneumonia and Kaposi’s sarcoma that were killing patients at a staggering rate.
Then in 1987, AZT was approved for use as a drug that directly attacked HIV, the virus that causes AIDS. But AZT proved to be highly toxic, its side effects often as debilitation as the virus itself.
Treatments took a giant leap forward in 1996 with the introduction of protease inhibitors and the idea of drug “cocktails” combinations of medications that worked more effectively in concert with others.
Today, there are 22 separate drugs and four drug combinations approved by the U.S. Food and Drug Administration for use against AIDS. Another 33 are under investigation.
The investigational drugs are divided into six classes, depending on the point in the virus’ life cycle at which the drug attacks and attempts to interfere with its replication. The classes are entry and fusion inhibitors, Integrase inhibitors, microbicides, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors and protease inhibitors.
Among the already-approved medications, one class stands out.
“The best of the classes of drugs are obviously the protease inhibitors,” said Martin Delaney, founding director of Project Inform, an AIDS treatment information and advocacy organization started in 1985.
Protease inhibitors prevent replication of HIV by disabling the virus’ protease, an enzyme that breaks down long polypeptides into smaller protein units used by the virus in replication.
When they were first introduced, protease inhibitors signaled a tremendous step forward in the treatment of AIDS, Delaney said.
They had their drawbacks: the first generation of the new drugs often had a detrimental effects on patients’ kidneys, and the class of drugs in general appears to affect the way the body processed fats that could lead to heart problems and diabetes, Delaney said.
“Collectively, they also cause a lot of pressure on the liver,” Delaney said. “But you have to put these things in context. When you first see any list of side effects for any drug, it sounds horrible. But you have to think about the fact that no drug comes without any side effects. And plenty of people who take protease inhibitors suffer no side effects, and others suffer only mild side effects.”
As with any kind of medication used over long periods of time, protease inhibitors lose effectiveness as the AIDS virus eventually becomes resistant, Delaney said. But a new entry in the class TMC114, also known as Prezista or Darunavir was just recently approved for use, and it appears to be “a big step forward” in protease inhibitors, Delaney said.
“It seems to be a real advance because it appears to work against all the resistant viruses,” he said.
“Beyond that, though, you don’t see a lot happening in the protease inhibitor field,” Delaney continued. “That’s partly because there are so many of them already. You reach the point where the drug companies start asking themselves, “‘How many is enough?’ That’s where we are now, I think, and the drug companies probably feel like it is better to start finding new drugs in new classes.”
Including Duranovir, there are 10 protease inhibitors approved for use. Only one protease inhibitor GW640385 is listed by the Department of Health and Human Services as being under investigation at this time.
There are only two new drugs under investigation in a new class of medications called integrase inhibitors. But these drugs GS 9137 and MK-0518 “are clearly the most promising thing on the horizon” when it comes to treating AIDS, Delaney said.
Integrase inhibitors working by preventing the HIV integrase protein from inserting the virus’ genetic information into an infected cell’s DNA.
“It has taken a long time to come up with a drug that can do that,” Delaney said. “It looks like a real big step beyond anything we have had so far.”
Trials of MK-0518, which is being developed by Merck, are just now going into Phase 3, the final stage before a drug can be made available for use, Delaney said. The early data is based on small numbers of study participants, but seems to be extremely promising, he said.
He added, “This may take us places where other drugs have never gone. What is really sort of interesting is the speed with which the integrase inhibitors are able to supress the virus. And the information so far indicates it might even be supressing the virus in what are called “‘HIV reservoirs,’ placed where the virus hides from other drugs.
“The early indications are that the Merck drug may be getting into those hidden reservoirs of the virus and producing better results than we have ever seen before. And it seems to be doing very well in people who have failed other therapies,” Delaney said.
He said that it is premature to say what side effects the integrase inhibitors will have long-term. But so far, side effects seem to be minimal, he said.
Delaney said the MK-0518 is expected to be made available by the end of August to people failing existing treatment regimens. GS 9137, being developed by Gilead, is “a little further behind” in the investigational process, he said.
Delaney said another promising development is not a new drug, but instead new ways of administering existing drug combinations.
One example is the common three-drug cocktail of Sustiva, Viread and FTC, which researchers believe they have simplified into a single pill to be taken once a day.
“That is a huge advance in terms of ease of use,” Delaney said. “It has huge implications, especially in developing countries where the ease of use is extremely important. Simplifying the therapy helps keep people on the therapy, which means that it works better and it prevents resistance in the virus.
“But it would require two competing pharmaceutical companies to come together and combine their drugs into one pill, and this is the first time we have ever seen that happen. Getting two drug companies to work together this way is like herding cats.”
Sustiva, made by BMS, is a non-nucleoside reverse transcriptase inhibitor. FTC (also known as Emtriva or emtricitibine) and Viread (also known as tenofovir) are nucleoside analogue reverse transcriptase inhibitors made by Gilead.
Non-nucleoside reverse transcriptase inhibitors bind to and disable HIV’s reverse transcriptase enzyme, a protein that the virus needs to make more copies of itself.
The nucleoside analogues are faulty versions of the building blocks necessary for HIV reproduction, and when the virus’ reverse transcriptase enzyme uses an nucleoside analogue instead of a normal nucleoside, reproduction of HIV’s genetic material is stopped.
At present, three non-nucleoside reverse transcriptase inhibitors are approved for use, and three more are being studied. Eight separate nucleoside analogues and four combinations thereof are approved for use, and seven more are being studied.
Delaney, however, does not believe either of these classes of drugs hold any real promise for the future of AIDS treatments.
“There is a real need for a non-nucleoside that overcomes the resistance HIV has built up to the previous drugs,” he said. “Right now, if you become resistant to one of them, you are resistant to all of them. A number of companies are trying to come up with something that can overcome that resistance.”
Delaney continued, “But do we really need seven more nucleoside analogues? This is the oldest class of drugs, and they don’t have a very good reputation in terms of side effects. I think a lot of those studies are just half-hearted attempts by drug companies to raise stock prices.”
There is one drug in the class of medications known as entry or fusion inhibtors that has already been approved for use, and nine others being studied. Entry inhibitors are designed to disrupt HIV’s ability to enter a host cell through its surface, and this class of drugs includes receptor inhibitors such as CD4, CCR5 and CXCR4.
The fusion inhibitors are a kind of sub-class of entry inhibitors, and they stop HIV’s outer envelope from fusing with the membrane of a host cell and thereby prevent the host cell from becoming infected.
From Delaney’s point of view, though, the entry and fusion inhibitors look to be a dead end in terms of effectiveness.
“These drugs were sort of the “‘big thing’ for the last few years. They were the great hope there for awhile. But there are a lot of difficulties around this whole class of drugs,” he said.
In order for an entry inhibitor to be effective, Delaney explained, “you have to be sure the virus a specific patient has is using the type of connection a specific drug blocks.”
“There are multiple ways that HIV can connect to T cells. For instance, CCR5 works fine if that person’s body and virus is using the CCR5 connection. But if not, then the drug might not work at all, and in fact, it might make things worse,” Delaney said. “A patient has to first take a special, very expensive test to see if an entry inhibitor is the right drug in the first place. And that is a real complication because it is a lot of money and it could even make things worse,” he continued. “This class of drugs was really talked up big time in the last few years. But the bloom is really off the rose by now.
Delaney said that there is only one fusion inhibitor being used so far Fuzeon. “It works fairly well, but it is outrageously expensive. And it has to be taken as a twice-a-day injection. So it hasn’t been very popular.”
The last class of drugs under study at present are microbicides, which, Delaney said, are not actually a category of antivirals but instead are topical compounds applied externally to stop HIV from being transmitted.
Microbisides are most commonly developed for use by women, who can use the medication “to protect themselves from infection without their partner knowing it,” because women often contract AIDS from sexual partners who do not disclose their HIV-positive status or who force themselves on the women, Delaney said.
“The development of the microbisides is one of the most important things done in AIDS research specifically for that reason. Something like this should have had a much higher priority much earlier in the epidemic. It is so sad to know that the needs of women have been ignored for so long. But it is finally coming along,” Delaney said.
Delaney said he believes that with the advent of new drugs, particularly the integrase inhibitors, the field of AIDS treatment is “heading into an era when we will see the basic paradigm of treatment change again, like we did in 1996 when protease inhibitors were introduced.”
“I also think we are going to see a lot more situations where they combine multiple drugs into one pill, plus I think we will see a reduction of the number of drugs in the regimens,” he said. “Finding new drugs and simplifying the therapy is the key to success.”
This article appeared in the Dallas Voice print edition, July 7, 2006