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The Coming Crisis

By Paul Dalton

October 2008

The last few years have witnessed remarkable progress in treating people with advanced and drug-resistant strains of HIV. Four powerful drugs became available that either overcame drug resistance (Prezista [darunavir, TMC-114], Intelence [etravirine, TMC-125]) or were from entirely new classes [Selzentry (maraviroc), Isentress (raltegravir)].

This marked an important and unique moment in HIV drug development. Never before had so many new and effective drugs emerged in such proximity. People with extensive experience taking HIV drugs have been able to put together powerful regimens with two or more fully active agents -- often for the first time.

The tremendous promise of these new drugs represented an exciting moment, but emphasis needed to be placed on using them carefully and correctly, while also noting that this moment was unlikely to recur. The message was clear: "Seize this opportunity, use the new drugs carefully, and don't waste this once-in-a-lifetime chance."

As good as some of these newer drugs have looked in studies, there are emerging signs of trouble. Dr. Steven Deeks, a prominent HIV physician and researcher says, "Although the current generation of drugs are generally doing great, many patients are not responding in a durable manner. We are now following about 25 individuals who have failed all six drug classes. The key now is to design regimens to maintain immunologic and clinical stability while we wait for more drugs. I am concerned, however, as it will likely be a few years before we have another shot at getting the virus under control. We desperately need a second generation integrase inhibitor that works against viruses resistant to raltegravir."1

Dr. Deeks' experience is far from typical. He follows many of the most treatment experienced people in the San Francisco Bay Area, many of whom have been on therapy since 1987. Although not typical, his experiences have been reported elsewhere, if in smaller numbers.

Nonetheless, this suggests a burgeoning problem of people beginning to run out of treatment options, as has happened a couple of times during the epidemic. Some are concerned that the most vulnerable people living with HIV will be left with few or no viable treatment options, possibly for many years.

One of the unintended effects of the recent successes in drug development is that fewer people are available for studies of experimental drugs aimed at treatment experienced folks. We saw this coming and have been counseling drug companies and the Food and Drug Administration (FDA) that the era of "TORO-like" studies was coming to a close. These studies give volunteers optimized background therapy (the best combination of HIV drugs chosen with resistance test results) with either the experimental drug or a placebo. The design allows regulators, scientists and activists to clearly see the benefit of the new drug. Some call these studies "TORO-like" after those that led to the approval of Fuzeon [enfuvirtide, T20]).2

This contrasts with how studies of first line treatment are done.3 When studying HIV drugs as first line, the basic model is head-to-head noninferiority studies,4 which are designed to tease out the relative contribution of entire regimens rather than the individual drugs.

The FDA has allowed non-inferiority studies for drugs being studied as first line, but has insisted on placebo controlled superiority studies for treatment experienced studies. Treatment experienced patients have been exposed to prior HIV treatment regimens. The current process made a good deal of sense when there were many people signing up for these studies, but the situation is now quite different.

While there are not enough people signing up for these kinds of studies, there is still a sizeable need for studying new HIV drugs. This, combined with the thin drug pipeline and the current difficulty recruiting for studies, may add up to real trouble down the line.

In meetings with every drug company working in HIV, Project Inform has warned of this impending problem and recommended adopting new ways of studying their drugs. The reaction has been mixed. While some companies have been quite open to new ideas, it is fair to say that most would prefer to stick with models that, until now, have proven successful.

We have struggled to argue -- to the companies and the FDA -- that new ways of studying and developing drugs are both necessary and possible. It would take some creative thinking on the part of the companies and their scientists, along with open mindedness and flexibility on the part of the FDA.

Gilead Sciences is one of the first to grapple with this. When it came time to do large, pivotal studies of their experimental integrase inhibitor, elvitegravir, there were not enough participants in the US to initiate a typical study of treatment experienced patients. Project Inform had warned Gilead and others of this eventuality and argued for studies that would more closely resemble the head-to-head, non-inferiority studies used for studying first-line drugs.

At first, Gilead thought they could follow the old, tried and true development plan. They explored performing a TORO-like study for elvitegravir, fully believing that it gave them the best chance at moving their drug ahead.

Over time Gilead came to see that a new plan was needed to move forward. They submitted a plan to the FDA that closely resembled the type of study for which many had been advocating.

The FDA eventually allowed Gilead to move forward with this study design for elvitegravir. There was great concern that they wouldn't, as it took longer than usual for the FDA to make a decision on Gilead's phase III trial proposal.

This is a great victory for people living with HIV. Both the company and the FDA came around to see that new thinking was required to respond to a new environment. With this new situation, there is a great need for new treatments to be developed and for the FDA and companies to think and act creatively to ensure this happens.

The Current State of HIV Drug Development

The Industry

As a whole, the pharmaceutical industry has done a tremendous job developing HIV drugs. However, many signs are showing a fading commitment to HIV. Fewer new companies are getting into HIV, and some well established ones are either cutting back or eliminating their drug development plans. The marketplace for HIV drugs is both crowded and competitive. The scientific hurdles for developing new HIV drugs have also grown more difficult, making it a less attractive market for companies.

While there are real challenges facing the industry at this time, it is a mistake to think either that HIV is largely a solved problem, or that there isn't room for new drugs. While it is true that drugs have improved and most people are able to get good, durable responses from their drug combinations, there is plenty of room for improvement. HIV is largely a data driven market, and good drugs will always find their way into wide use.


The Food and Drug Administration (FDA)

The FDA is responsible for ensuring that drugs are safe and effective before they become available outside clinical studies, as well as when they are on the market. Recent media stories that focused on drug safety, particularly on Vioxx and Heparin, have created a somewhat fearful climate inside the FDA where new ideas are met skeptically. Their recent decision to green light elvitegravir's development shows that at least its antiviral division is open to creative drug development plans.

The FDA must strive to find a balance between protecting the safety of health care consumers while not unduly discouraging drug development. While it isn't always easy, the FDA has been largely successful when it comes to HIV.


The Current Drug Pipeline

All in all, the pipeline is both thin and unimpressive. There are a few "me too" drugs (slight changes in existing drugs) which are helpful but not game-changing. A few novel compounds may prove promising down the line, but they are struggling right now, due to either study results, or in one case, the company is being bought by a company that does not want to work in HIV.

As for those drugs in human studies, the closest to approval is rilpivarine (TMC-278), a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) for first-line treatment being studied against Sustiva.5 Sustiva has gone largely unchallenged as a first line NNRTI, but its neuro-psychological side effects make it difficult for many people to take. A new, potent first-line NNRTI that is free of such side effects could be a great advance for people with HIV. Also of note, rilpivarine is an ideal candidate for co-formulation, which would allow it to combine with another drug in a single dosage form. Thus, not only could it be competitive against Sustiva, but Atripla might be seeing some real competition too.

Vicriviroc, Schering's CCR5 drug, continues to flounder but is still viable.6 Bevirimat, a maturation inhibitor from Panacos, has been hamstrung by formulation problems, which we understand have been overcome. Other promising drugs are Pharmasset's racivir, and Avexa's apricitabine.

The lack of excitement with the current pipeline offers a real opportunity for both new and established companies to make a real move in to HIV. There is a demonstrated need for improved versions of existing drugs and, more importantly, new types of drugs. The greatest needs right now are second generation Integrase Inhibitors, CCR5 antagonists, unboosted protease inhibitors and novel targets.


The Bottom Line

The past two years have been a boon to people with extensive treatment experience. Four successful new drugs, including two new classes, have meant most people can put together powerful, effective and tolerable regimens, even if they've never been able to get to undetectable before. However, this period is now over, and we're experiencing a major downturn in the number of promising drugs in the pipeline.

This reinforces the importance of using the current crop of new drugs correctly. Your best chance at getting to and staying undetectable is to start a regimen with at least two and hopefully three fully active drugs. If you are able to do this and get your HIV level to undetectable, good adherence is the best way of keeping it there.

This also points to the need for treatment activists to continue to work with the companies, scientists and regulators to ensure that new drugs are developed.

Lastly, this situation points toward the need for a cure. It is only going to become more difficult to keep the companies, their researchers and the general public interested in HIV drugs. There is a growing sense that HIV is not that much of a problem anymore, at least not in wealthy countries.

The only real solution is a cure. Many promising approaches are under study, as well as resurgence in community activism aimed at cure research. A conscientious program mounted by academia, industry, government and community is necessary to reach this goal.

Paul Dalton is Director of Treatment Information and Advocacy at Project Inform.

References

  1. Integrase inhibitors, such as raltegravir are a class of antiretroviral drug that block the action of integrase, an enzyme that integrates genetic material from the virus into its target cell.
  2. Fuzeon is in a class of antiretroviral drugs, fusion inhibitors, which are used in combination therapy for the treatment of HIV. Fusion inhibitors interfere with the binding, fusion and entry of HIV to a human cell. By blocking this step in HIV's replication cycle, fusion inhibitors work to slow the progression from HIV infection to AIDS.
  3. A first-line treatment is a medical therapy recommended for the initial treatment of a disease, such as HIV.
  4. Non-inferiority means that one drug or regimen is equivalent or nearly equivalent to another.
  5. NNRTIs inhibit the activity of reverse transcriptase, a viral DNA polymerase enzyme that HIV needs to reproduce.
  6. CCR5 is a protein expressed on the surface of cells, including T-cells, that is most commonly targeted by the virus.

Want to read more articles in the October 2008 issue of GMHC Treatment Issues? Click here.




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