For several years now, HIV drug development has seemed to be a series of incremental advances, with a noticeable lack of new approaches or major advancements. A quick review of the most recently approved anti-HIV drugs tells a story of "me-too" drugs -- Emtriva (emtricitabine, FTC), Lexiva (fosamprenavir) -- and niche drugs, like Aptivus (tipranavir) and Fuzeon (enfuvirtide, T20). While these are real and important advances for people with limited treatment options (sometimes referred to as treatment experienced or "salvage" patients) and for people seeking easier and more convenient treatment options, there has been little of anything truly new or different.
Currently there are four classes of anti-HIV drugs: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and entry inhibitors. While pharmaceutical companies continue to work on developing new drugs in these classes, this article focuses on drugs with new ways of working -- or novel mechanisms of action.
Perhaps the most compelling story out of this year's CROI was integrase inhibitors. Three companies -- Merck, GlaxoSmithKline (GSK) and Gilead -- presented data on their integrase inhibitors. Merck's drug (MK-0518) is the furthest along and is now in the last stage of studies -- Phase III. GSK and Gilead's drugs are now entering Phase II testing and are at least two to three years away from approval. The data on MK-0518 were surprisingly good and generated quite a bit of excitement among conference attendees.
The results of research on another new type of anti-HIV drug, called CCR5 inhibitors, had decidedly mixed results as reported at CROI. Part of the larger class of drugs called entry inhibitors (EI) that includes Fuzeon, this type of drug attempts to stop HIV from entering immune system cells, by blocking the virus from attaching to receptors on the cell's surface called CCR5. Data on two CCR5 inhibitors were presented at CROI.
Pfizer's drug, called maraviroc (UK-427857) is the furthest along in development. Little new was reported about it at CROI. Two small studies were discussed: one looking at how long the drug stayed attached to the CCR5 receptor and another one looking at how HIV develops resistance to maraviroc.
Shortly before the conference, the discontinuation of one study of maraviroc was announced. In this study, maraviroc was taken once a day in people who had never taken anti-HIV drugs. When the researchers looked at the first 200 people enrolled, they found that those taking maraviroc once a day together with Combivir (Retrovir [AZT, zidovudine] + Epivir [3TC, lamivudine]) didn't do as well as people taking Sustiva (efavirenz) + Combivir. Ongoing research is looking at maraviroc twice a day in people new to anti-HIV drugs and both once a day and twice a day in people who have taken anti-HIV drugs before.
Schering-Plough presented data on their CCR5 inhibitor vicriviroc (Schering-D). The main study of vicriviroc discussed at CROI was on the closure of a study comparing vicriviroc + Combivir to Sustiva + Combivir in people taking anti-HIV drugs for the first time. The study was stopped early because of unacceptably high viral breakthrough in the group on the vicriviroc combination. Vicriviroc is still being studied in people with heavy experience taking anti-HIV drugs.
While the development of the CCR5 inhibitors has hit some speed bumps in the past year, development of three other kinds of entry inhibitors continues. Trimeris and Roche Pharmaceuticals -- makers of the fusion inhibitor Fuzeon -- presented early data on two new fusion inhibitors, called TR-290999 and TR-291144. The most notable feature of these two drugs is that they are being developed for possible once a week -- with some quiet suggestion of even less frequent dosage. Both of these fusion inhibitors have been studied in laboratories (called in vitro studies) against HIV and shown to be effective. Neither has been studied in humans yet.
Another new approach to try and keep HIV from entering cells is really not new at all. The Houston-based company Tanox is developing an immune therapy, called a monoclonal antibody targeting CD4, called TNX-355. This therapy is given through an intravenous infusion given either once a week or once every other week. It blocks the very fist step in HIV's entry process, where the virus attaches to the CD4 molecule. Early data suggest this therapy may be useful for people who have dwindling anti-HIV drug options. Another company, Progenics, has monoclonal CD4 antibodies called PRO-542 and PRO-140, which seek to block the CCR5 receptor -- much like the CCR5 antagonists discussed above.
Another new entry inhibitor is AMD-070, Anormed's CXCR4 inhibitor. While most HIV uses CCR5 as its way into cells, in some cases the virus uses another co-receptor, called CXCR4 (or X4). This most often happens in advanced HIV disease. This drug is still in the earliest phase of development and not much is known about it yet.
In addition to the integrase inhibitors and the various entry inhibitors, several other novel targets or strategies are being developed. While each is very early in the development process, they represent new and innovative ways of stopping HIV and merit some attention.
Two such approaches try to interfere with the reverse transcription process in new ways. The first is called a covert nucleoside and is an especially different approach. While one of the goals of all anti-HIV drugs is to prevent or delay the development of resistance, this approach actually seeks to accelerate the evolution of resistant virus. Ultimately, this process seeks to force HIV to mutate into a crippled state where it can't infect cells and can't reproduce -- something scientists call terminal mutagenesis. One such experimental drug, being developed by Koronis, uses this approach. While this idea is quite fascinating and theoretically sound, it raises some interesting issues for both the company and the Food and Drug Administration (FDA) -- particularly how to evaluate its effectiveness. The traditional measure of anti-HIV activity is a reduction in viral load. For a covert nucleoside, such a measure won't make sense -- at least not at first. The company will have to get the FDA to evaluate this drug in a whole new way if they are to succeed.
In order to explain the next new approach, it is helpful to describe the process of reverse transcription. HIV stores its genetic code in the form of RNA. In order to replicate inside an immune cell, HIV must use its RNA to make a DNA copy of itself. This process is called reverse transcription. The DNA copy is made with the help of an enzyme called reverse transcriptase (RT). The RT enzyme works by reading the instructions written into the RNA, and assembling the DNA using the cell's own building blocks -- called nucleotides.
There are currently two classes, or types, of drugs that interfere with reverse transcription. The first, NRTIs, are analogs, or "look-a-likes" of the nucleotides. The RT enzyme is tricked into using these non-functional building blocks, and the resulting DNA chain is non-functional. The other type of RT inhibitors is called NNRTIs. They work by physically attaching to RT, which harms its ability to build the HIV DNA chain.
A new class of drugs, called nucleotide competitor reverse transcriptase inhibitors (NcRTIs), can be seen as a mix of the two older approaches. They resemble the NRTIs chemically, appearing to the RT enzyme as the real DNA building block. But unlike the NRTIs, these drugs won't be incorporated into the DNA chain. Instead they will stick to the RT enzyme in the area that the building blocks are put together and physically block the process. This differs slightly from the NNRTIs, which stick to the enzyme in a different place. Tibotec has one such drug, called simply "Compound X," which is being studied in laboratories now.
Another new approach works at the latest stage of the HIV replication cycle. These drugs are called maturation inhibitors. Maturation is when HIV accumulates its inner protein coat called its capsid. Several maturation inhibitors are in laboratory studies and one, called PA-457 being developed by Panacos, is in small human studies.
Project Inform recognizes that the advances in HIV medicine in the past 20 years are truly remarkable, but are still not enough. Our ultimate goal remains the same today as it always has been ... a true cure. While we will never be fully satisfied with incremental improvements of existing types of drugs, we nonetheless welcome all advances in the treatment of HIV -- whether being simplification (fewer pills, fewer doses), increased potency, decreased side effects and toxicity, or novel targets.
Since the introduction of the NNRTIs in 1998, the only truly new approach to treating HIV has been Fuzeon (enfuvirtide, T20), which has seen limited use in part because of cost and injection site reactions. As we look at the pipeline today, we see many new and hopeful approaches -- attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, monoclonal antibodies, integrase inhibitors, covert nucleosides, nucleotide competitors and maturation inhibitors. While it remains to be seen how effective any of these new drugs are, it is undeniable that the anti-HIV drug pipeline has more diversity than ever before. Novel targets are important for two reasons. First they offer hope to people who aren't fully benefiting from the older kinds of drugs, due to resistance or tolerability. Second, they offer the hope of better, or at least more anti-HIV drugs to all people with HIV.