PI Perspective #40

January 2006     View PDF     En español

Lessons in Hope

Today, anyone who follows HIV treatment with a casual interest may get the impression that things are progressing wonderfully. A recent publication of the Pharmaceutical Manufacturers’ Association asserts that 82 new medicines are in development for treating various aspects of HIV infection. Of these, 36 are antivirals, the kind of drugs that has made the most profound advances against HIV and AIDS. Surely, this sounds like good news, especially for those who have developed resistance to the current therapies.

We’ve been hearing for years of the likely wonders of a new class of drugs called entry inhibitors as well as hoping for better drugs in the existing classes. For people with HIV, this was expected to be a cheerful holiday season indeed. It wasn’t. Instead, the last half of 2005 offered one of the most discouraging lessons in drug development in a long time. News came of the complete failure of one entry inhibitor candidate and the partial failure of two another, as well as discouraging results in some of the studies of new NRTIs.

Though one new protease inhibitor came to market promising to help people with highly resistant virus, it offered limited utility, significant toxicity and exorbitant cost. Shortly after 2006 began, the largest-ever study that tested whether people needed to be on constant therapy was abruptly halted. All in all, this was one heck of a discouraging period.

In the interests of keeping hope alive, it’s important to remember that the media’s coverage of HIV issues tends to exaggerate the truth, whether good or bad. That is once again the case. Though some setbacks have occurred, several striking successes have gotten little or no fanfare. It’s appropriate then that we start the New Year by looking not only at the failures, but also at some of what’s working … and working well.

Woes upon Woes
For the last two years, researchers and industry reps couldn’t say enough good things about entry inhibitors. This new class of drug blocks HIV from attaching to receptors on T cells. If the virus can’t attach to cells and insert its genetic material, there is no infection of the cell … at least in theory. Several companies have had entry inhibitors in studies for up to two years already. The high hopes associated with entry inhibitors stemmed from two ideas. First, any new way of treating HIV is welcome, especially for people who are running out of treatment options. Second, the fact that these new drugs worked outside of the cell was hoped to mean that they would have fewer side effects. Many hinted that these drugs would open a whole new era in HIV treatment. Actual study results, however, have proved sobering.

First, GlaxoSmithKlein (GSK), one of the giants of HIV medicine, announced that it was ending studies of its entry inhibitor, aplaviroc, in people who had used it as first-time therapy. This was due to the appearance of liver disease in a few volunteers. Soon, they stopped all study of the drug when similar problems appeared in people with more advanced disease.

Another company, Schering Plough, was one of the first to develop an entry inhibitor. It began with two different compounds and eventually settled on developing one of them, vicriviroc. To everyone’s surprise, in the fall they suddenly announced that they were ending its development as first line therapy because of its weak activity compared to a Sustiva. Studies using it as an add-on to proven therapy combinations will continue, but it’s already evident that the drug isn’t going to have the kind of powerful effect once hoped for.

The other hope among this type of entry inhibitors is the Pfizer drug, maraviroc. It too has run into some problems. In a study looking at two different doses of maraviroc (once a day and twice a day) versus Sustiva, the once-a-day arm was stopped due to poor results. Right now it looks like the drug fails to produce the large and rapid decline in viral load seen with Sustiva and protease inhibitors. Years of data clearly show that the durability of treatment depends mostly upon how quickly and thoroughly it reduces viral load (in addition to patient adherence, of course). On this score, the Pfizer drug has so far scored no better than average.

Whatever the fate of oral entry inhibitors, the bloom is off the rose. However, hope remains that they will still be useful in the HIV tool kit. For more in-depth information, see the article Entry Inhibitors: A Race to the Finish Line.

The bad news isn’t limited to entry inhibitors though. A once promising NRTI, Reverset, also lost ground when the FDA was less than satisfied with study results and ordered its manufacturer, InCyte, to conduct another study. The company was already running thin on cash reserves and hasn’t yet found a large pharmaceutical company willing to partner with it. At the least, the drug will be delayed in the pipeline; at worst, it won’t survive the approval process.

Last and not least, hope took a bit of a beating this year even in the approval of a new protease inhibitor, Aptivus (tipranavir), that was expected to offer renewed anti-HIV activity for people with resistance to most other protease inhibitors. The drug had a long and difficult history as it moved through the FDA approval process. Still, people were surprised at how modest the supporting data were when it went before an FDA review. In the end it was approved, but only with the apparent reluctance of the FDA and its committee.

The drug could indeed work against protease-resistant virus, but it only showed significant and lasting results when paired with a second drug, Fuzeon (enfuvirtide, T20), being used for the first time. Fuzeon is the most expensive antiviral available, and unfortunately, Aptivus carried the highest price ever asked for a protease inhibitor. Consequently, the combination is only available with special prior approval in many state ADAPs. To further complicate the situation, using Aptivus also requires using Norvir (ritonavir) as a booster. While it is common for protease inhibitors to require the Norvir booster, Aptivus requires a double dose of it, which increases the side effects of Norvir as well as the cost. Abbott Labs, manufacturer of Norvir, is willing to provide Norvir free for anyone who needs it as a booster for Aptivus, but getting the free drug requires filing additional paperwork and getting the Norvir from a separate program. Aptivus may indeed work against resistant virus, but making it work well is far from easy.

Hopefully Hype-less Hope
Despite the discouraging events of the last year, there is still plenty of hope. The last year has still been one of the most productive in the history of the epidemic. The good news just didn’t get the attention it deserved.

At the top of the list of hopeful developments was Merck’s announcement that their long-awaited integrase inhibitor had successfully passed Phase II studies and is now recruiting people for Phase III studies that should lead to FDA approval. Though the integrase step in HIV reproduction has been known as a potential target for drugs since the earliest days of HIV research, creating a drug that would safely block the “integration” step of viral reproduction has been daunting.

Integration is a step in the reproduction of HIV in which HIV inserts its newly formed viral DNA into the DNA of the cell it infects. Once HIV’s DNA is inserted, it integrates into the cell’s genetic machinery and uses it to make new copies of the virus. The enzyme, integrase, makes this integration of viral DNA into the cell possible. An integrase inhibitor is thus a drug that blocks this action.

Since the process takes place entirely inside a cell, it has been difficult to find compounds that could do the job without interfering with other essential cell activity. Several companies have searched for years for a useful compound. Most gave up over time and focused on other targets. A few, particularly Merck in the US, pursued the goal year after year. The first compound of this type the company tested in humans proved that inhibiting integrase would indeed reduce viral load, but animal studies warned of a possible serious toxicity.

Merck dropped that compound and proceeded to develop a second one. A phase II study showed evidence of strong anti-HIV activity, likely on the level of the best protease inhibitors. For a full report on the Phase II study of the Merck integrase inhibitor reported at the Conference on Retroviruses and Opportunistic Infections, see Project Inform's reports from the conference. Although tested in only a relatively small number of people so far, the drug has shown few side effects. Phase III studies are beginning in March 2006 and some form of expanded access to the drug is likely in the last quarter of 2006.

Resistance to any previously used drugs should not affect an integrase inhibitor since it targets a completely different step in viral reproduction. Is the hope once assigned to the entry inhibitors on its way to becoming a reality with integrase inhibitors? Integrase inhibitors are simple oral drugs that will be taken once or twice a day. Based on what’s known to date, the Merck drug can be combined with almost any other HIV therapy. More research is needed before we will know how this new drug will be used.

At least two other companies have also conducted human studies of an integrase inhibitor. GSK bought the rights to one from the Japanese firm Shinogi. Unfortunately, this compound failed to show the high levels of antiviral activity achieved by the Merck drug, so studies have halted. GSK remains committed to developing an integrase inhibitor and is current screening additional compounds. A third firm, Gilead Sciences, maker of Viread, Emtriva and Truvada, has an integrase inhibitor in early phase II trials, perhaps a year behind Merck in the development process. The success of these two companies will undoubtedly spur competitive research at other firms.

Aside from the growing excitement over integrase inhibitors, two other types of compounds are in development that target the control of HIV in a different way. One is a maturation inhibitor. This refers to a step in viral reproduction that occurs just before new copies of virus burst out from the infected cell. An early study, from the company Panacos, showed evidence of significant viral suppression from a single dose. Further studies will determine the ultimate hope of this target.

A second approach is using a monoclonal antibody that targets HIV. A monoclonal antibody is a cloned copy of one or more of the antibodies made by the immune system in its effort to control HIV. This has been tried before, and many such artificial antibodies are possible. Earlier efforts failed because of the high cost of making the antibodies combined with the high cost of delivering them to the body. These antibodies are given intravenously, a procedure normally typically done in a medical facility. One such antibody, made by Tanox, has shown evidence of viral suppression at levels similar to those of entry inhibitors. Tanox claims it will be able to make it cheaply enough for practical use, though the cost of the periodic IV infusions is still an obstacle.

Not all hope requires new classes of drugs. Many companies prefer to work with proven viral targets, such as protease and reverse transcriptase. Sometimes, a better version of an existing drug may be as significant as one aimed at a new target. Darunavir (TMC 114), a new protease inhibitor from Tibotec, shows evidence of great strength against viruses resistant to other protease inhibitors. The FDA was so impressed with their phase II data that they encouraged the company to submit an application for approval before they had even begun their phase III study. This is unprecedented in HIV and reflects the agency’s apparent belief that the drug will offer a major advance for people who are resistant to all other protease inhibitors. The drug is now available in an expanded access program and will likely be approved in the second quarter of 2006.

Another area of hope comes from making therapy much easier to use. Gone are the days of taking handfuls of pills three times daily. A number of drugs are now available as two-drug combinations in a single pill. But an even greater advance has been achieved by the collaboration of two companies, Bristol-Myers Squibb and Gilead Sciences. They worked together to create a single pill that combines three highly potent drugs—Sustiva, Viread and Emtriva. Such efforts were inspired by generic drug makers who have been creating similar combinations for use in developing nations. The result is that an entire day’s regimen is now reduced to taking a few pills, greatly simplifying adherence. The goal of such simplification is to help make it possible for people to use a regimen for a decade or longer without developing resistance due to adherence challenges.

Another avenue of genuine hope is research that challenges the once sacred rule requiring a combination of three drugs. Studies of Abbott Labs’ highly potent protease inhibitor, Kaletra, have revisited the question of whether everyone needs to use at least three drugs all the time. An initial study comparing a typical three-drug combination to using Kaletra as a single drug produced surprisingly favorable results, with rapid and long-lasting viral suppression for both the combination and for Kaletra alone. This approach may initially be limited to use in people with low level viral activity beginning therapy for the first time. But over time, other experiments will test whether it is possible even in advanced disease to reduce the number of drugs used after several months of strong viral suppression. This concept was tested once in the early days of protease inhibitors and found unsuccessful, but today’s drugs are more potent and may produce better results.

Beyond Maintenance Therapy
As emphasized in PI Perspective #39, we believe the ultimate goal of HIV research should not be limited to creating drugs good enough to be used for a lifetime. Rather, the goal must be an outright cure of the disease—the achievement of a state of wellness either despite or without HIV that can be sustained without constantly using drugs. This is perhaps the most controversial area of HIV research, as many scientists and activists question whether this is achievable. Many believe it is impossible. However, we remember that back in the early days of treatment research, many scientists believed that it would never be possible to treat the disease at all. Happily, others disagreed and took up the challenge.

Today the question is whether to believe in the outright cure of HIV. The answer to that question must be a resounding yes! Moreover, the pursuit of a cure must be a rallying cry of people with HIV and their advocates worldwide. A lifetime made possible by the constant use of expensive and sometimes toxic drugs may be far better than the death sentence once expected of HIV, but it is far from ideal. Medical science is making enormous strides with each passing year. We must make sure that one of them is the ultimate and complete cure of HIV disease.

Hope for this outcome is alive and well, burning like a series of small fires in the dark. In late 2005, Dr. David Margolis and his team conducted the next round of their experiments using valproate (valproic acid) in an effort to clear the body’s reservoirs of HIV. Though they haven’t yet succeeded, they clearly showed evidence of dramatic reduction of the reservoir. Many follow-up experiments are possible and in development. We salute this team and its leader for their courage and vision.

In another area, a small firm named Koronis is pursuing an unusual theory that turns most treatment research on its head. Almost all other research seeks to slow the rate at which HIV produces mutations because they are the mechanism that produces resistance to anti-HIV drugs. Instead, the theory under study at Koronis seeks to speed up the mutation rate of HIV. Lab studies suggest that just a small increase in the rate of mutations leads over time to a dysfunctional virus—an HIV that can no longer reproduce itself. It’s a long way from doing this in a lab setting to making it happen to every copy of HIV in humans, but that doesn’t make it impossible. We are watching and encouraging this work as it faces a series of difficult hurdles.

Lastly, our hopes were encouraged regarding a cure this past year when the American Foundation for AIDS Research (amfAR) held its first think tank meeting of researchers addressing the subject of emptying the reservoirs of HIV. In other words, it was a meeting about “the cure.” Following the meeting, grant proposals are being sought for this kind of research. The Linda Grinberg FAIR Foundation, which funds leading edge research via grants channeled through Project Inform, has noted an interest in furthering amfAR’s work in this area through additional funding for new research proposals. Combined with Project Inform’s research advocacy efforts, this growing movement focusing on curative research cannot help but influence the National Institutes of Health to address this area.

Hope is still alive, despite setbacks, and a cure is possible. A cure will someday happen—because people who believe in it will make it possible.

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Results of a "Cure" Study