"There is a scary trend in federal funding for AIDS," Delaney said, emphasizing what he feels is a critical issue. "One of the ways it will manifest itself this year is in the dwindling federal support of the ADAP (AIDS Drug Assistance) program. Future progress and care are jeopardized by a changing political climate."
The ADAP program provides access to medications that prolong and enhance the quality of their lives for people with no other resources. In Georgia alone, at the end of 2001, there were nearly 700 people on a waiting list for ADAP assistance. "Write your Congress people," he urged. "Tell them that you're angry with the lack of funding and that you won't put up with it anymore."
Speaking to a group of 50 people on March 28, Delaney didn't wait long to deliver updates on what's coming down the pipeline for AIDS treatments. He covered such topics as new therapies and new approaches, side effects and coping strategies, scheduled treatment interruption updates and vaccine news.
"In the next year or two, you'll see a few important changes and additions," Delaney said. "There are improved classes of existing drugs coming out of the pipeline and new targets that treat HIV differently which are entry inhibitors and integrase inhibitors."
Bristol Myers will soon be releasing a new protease inhibitor (PI) called Atazanavir. Its main advantage so far is that it has little or no effect on cholesterol or triglyceride levels. This will be helpful to those who experience lipodystrophy, a redistribution of body fat, while taking PIs. Atazanavir offers a once-daily dosing and may work despite some forms of prior resistance (but not all).
Beginning this spring, Atazanavir will be available through an expanded access program. This program will be the largest since 3TC (lamivudine, Epivir with nearly 16,000 participants). To participate you should have a viral load over 5000, CD4+ count less than 300, plus a "need to make a viable regimen." The FDA may require a baseline EKG. You can sign up for the program by having your doctor call 1-877-726-7327.
Fusion inhibitors are a new class of drugs coming out of the pipe behind Atazanavir. When HIV gets near a healthy cell it fires what looks like a harpoon into the cell to pull itself closer so it can lock on to receptors that will allow the virus into the cell.
"Fusion inhibitors are the first step of blocking and blocking entry to the cell and they work by preventing the 'harpoon' from connecting to the cell," Delaney explained. "Entry inhibitors work at in the next stage of entry to block the receptor connection."
T-20 is the first fusion inhibitor. This drug will be most important to people who have become highly resistant to other drugs. The largest drawback will be the large price tag for the drug, expected to be the highest yet for any antiviral (as much as $10,000/yr). Also, T-20 has to be taken twice daily via an injection similar to what people do for diabetes.
There is currently a small, expanded access program with T-20 that is expected to grow larger by July. The drug is expected to be approved by the FDA later this year. Trailing the heels of T-20 is T-1249, a more potent fusion inhibitor due in about one to two years.
If the virus is successful at fusing with the cell, the next class of drug aims to prevent entry via the receptor site. Schering "C" is an entry inhibitor that has shown good proof of concept that it can be effective and lower viral loads. Schering "C" prevents docking to the CCR-5 receptor site. Given as monotherapy to 12 people for ten days, participants in the study showed an average viral load decrease of .5 log, some as high as 1.5. Also being developed is Schering "D," a more potent entry inhibitor. "Assuming continued good results, look for Schering 'C' is to become available in expanded access," Delaney said.
Bristol Myers has also announced it has developed an entry inhibitor that blocks connection to the gp120 receptor site that is about three years down the road from being near market. Still at the earliest stages of development, it has been shown to have a high potency. Because the fusion and entry inhibitors do not enter a cell, they are less toxic and users shouldn't experience the harsh side effects of other drugs.
"There is a lot of toxicity with the older drugs that we were not aware of," said Delaney, laying ground to introduce tenofovir (Viread), a nucleotide analogue approved last December. It has proven 85-90 percent effective at lowering viral loads for people who are resistant to older nucleoside drugs (i.e. AZT, ddI, d4T, etc.). "So far this appears to be the least toxic drug yet seen for HIV."
TMC 125 is the newest non-nucleoside reverse transcriptase inhibitor (NNRTI) and has shown to have little toxicity. TMC 125 retains substantial antiviral activity despite resistance to other drugs of this type, such as efavirenz (Sustiva) and nevirapine (Viramune). In patients who have not been exposed to HAART (highly active anti-retroviral therapy), it causes a very fast and steep decline in viral load.
In just seven days, TMC 125 lowered participants' viral load down to 7 copies/ml or undetectable. First produced by Tibotec-Virco, Johnson and Johnson recently bought the company and Delaney expects delays in getting TMC 125 to market. The purchase of the company is likely to add an additional two years to the drug's development time, which had been optimistically calculated to be two years or less.
Lipodystrophy continues to be a problem for many people on HAART. In recent smaller studies it has been found that:
Remaining a controversial subject, structured treatment interruptions (STI) have been shown to improve immune response in only 15-20 percent of chronically infected people. There is continued evidence of improved suppression in a portion of people treated during primary infection. One French salvage study looked at whether treatment interruptions could restore activity to drugs that had become useless due to resistance. The study showed a major benefit (using treatment interruptions followed by five to eight drugs in a "gigaHAART" combination) There has been some evidence of 3TC and NNRTIs growing resistant during an STI (though also a common occurrence while not on an STI).
"Whatever you read in the newspapers about vaccines is bull***t," said Delaney. "It's just that simple. There are so many little companies out there promoting their vaccine and the reason is simple: It raises the price of their stock and attracts investors."
A very large Phase III study of the "prime-boost" strategy using "canary pox" vaccine plus VaxGen was scrapped. In the Phase II study which proceeded it, less than 30 percent of volunteers showed evidence of improved HIV immunity at even a single test period. There is also little enthusiasm for the "booster" vaccine proposed for the large study because it produces only weak and narrow antibody response. Wide consensus holds that a vaccine by Merck has shown the most potent responses yet seen in animal studies. It's still not likely to be a protective vaccine, but may reduce disease severity. However, the outcome of the Merck vaccine is still years away.
The very high potency of newer drugs has renewed interest by some researchers that they may be able to eradicate HIV from the body, though they are being much quieter about their hopes than a few years ago. Recently, a small study of three people used a multi-step approach to eradication; HAART, followed by two additional drugs to reach viral reservoirs, followed by a chemical injection used to stimulate latently infected cells, and finally a two-week course of interleukin-2 to stimulate latent pro-virus, after which all therapy was stopped. All three people had profound decrease of the virus below detectable on both standard and advanced laboratory assays. One remained virus-free for several months while the other two had renewed viral expression after a few weeks. The researcher concluded eradication was not possible with current drugs.
"I applaud research like this," said Delaney. "As activists and people who care about the disease, we should not settle for lifetime therapy. I just wanted to let you know, there are still people out there working on a cure."