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New HIV drug classes on the horizon
http://www.nature.com/nrd/journal/v6/n4/full/nrd2294.html

Abstract

Novel modes of action of emerging therapies could enhance strategies to combat drug-resistant HIV.

Two new classes of HIV drugs are poised to hit the market in 2007, signalling what many say is a watershed in HIV treatment, second only to the introduction of cocktail therapy more than a decade ago.

The new drugs — Pfizer's maraviroc and Merck's raltegravir — could be particularly beneficial for those who have become resistant to existing drugs.

"It's an exciting time," says Steven Deeks, an AIDS expert at the University of California, San Francisco. "Because of the way the drugs have emerged before, one at a time, we've never had the opportunity to use three [new] drugs to which the virus is susceptible at one time. That could change this year."

More than 20 antiretroviral drugs are currently available, which fall into three classes — reverse-transcriptase inhibitors, protease inhibitors and fusion inhibitors — each of which relies on a different mechanism to fight the virus.

The approval of maraviroc and raltegravir would add two new classes, researchers said in February at the Conference on Retroviruses and Opportunistic Infections in Los Angeles.

Pfizer's maraviroc belongs to a much anticipated class of drugs called entry inhibitors. It prevents HIV from entering and infecting immune cells by blocking CCR5, a cell-surface receptor that is exploited by HIV to bind to cells before viral entry. Merck's raltegravir inhibits HIV integrase, an enzyme that integrates the viral DNA into the DNA of the host cell.

In the mid-1990s, scientists discovered that HIV is best controlled with combinations of two or three drugs from one or more classes. However, some infected individuals develop resistance after taking the drugs for years and become unresponsive to all the drugs in a particular class.

Between 5–20% of people in Europe, the United States and Canada are infected with HIV strains that are resistant to at least one class of drugs, according to the World Health Organization. Because maraviroc and raltegravir combat HIV through new mechanisms, they are a promising alternative for those who have exhausted the available options.

Maraviroc and raltegravir are both expected to be available by the end of this year. An estimated 20 other drugs are in different stages of development (Table 1), with most belonging to entirely new classes of drugs.

Table 1 | Selected anti-HIV drugs in development
Full table
Figures and tables index
Download Power Point slide (436 KB)


Several companies have tried to develop CCR5 inhibitors, but with limited success. In 2005, GlaxoSmithKline discontinued its CCR5 blocker aplaviroc after people taking the drug suffered liver problems, and Schering–Plough's development of vicriviroc, once on track with maraviroc, has slowed owing to concerns about the risk of cancer in those taking the drug.

"Maraviroc seems to be the best in class, in terms of safety profile and activity," says John Mellors, Chief of Infectious Diseases at the University of Pittsburgh, USA (who has no financial ties to Pfizer).

In two large Phase III studies of individuals resistant to the three available drug classes, the virus was undetectable in more than 40% of those who took maraviroc once daily in combination with an antiretroviral cocktail, compared with about 24% of those given the cocktail only.

Maraviroc is fast-tracked for approval in the United States, Europe and Canada and is expected to receive approval in the United States this summer, according to Karen Robins, a Pfizer spokesperson.

However, not everyone will benefit from the drug. In most cases, HIV infects cells after binding to the CCR5 receptor in the early stages of disease, but as the disease progresses, the virus can switch to another receptor, CXCR4. California-based Monogram Bioscience has developed a test to determine whether a particular viral strain is likely to use the CCR5 receptor or the CXCR4 receptor.

Much of the buzz since the conference has been about integrase inhibitors, the other new class. Similar to existing drugs, these also target HIV after it has invaded immune cells. But because all integrase inhibitors are similar, researchers fear that resistance to any one drug in the class will render the rest ineffective.

Merck's raltegravir is the furthest along in the class. In two Phase III studies of individuals resistant to existing drugs, the virus was undetectable in about 60% of those who received raltegravir twice daily in combination with a drug cocktail, compared with about 35% who received the cocktail alone.

Efforts are already underway at Merck and other companies to develop better integrase inhibitors, in case resistance develops to the first generation of the drugs, says Robin Isaacs, Executive Director of Clinical Research at Merck. Like maraviroc, raltegravir will be used in combination with other drugs and the two might even be used together, Isaacs says. Merck plans to file for approval in Europe and the United States in the second quarter of this year.

Merck and Pfizer are already testing raltegravir and maraviroc as first-line drugs, but it's too early to know whether any of the drugs in the pipeline will replace first-line treatment, or what the long-term effects of CCR5 and integrase inhibitors might be.

Gilead's elvitegravir, another integrase inhibitor, is about 18 months behind raltegravir in development and looks promising in Phase II trials. "It's potent, superior to protease inhibitors and very well tolerated," says Norbert Bischofberger, Gilead's Executive Vice President for Research and Development. Unlike raltegravir, elvitegravir is taken once daily and, if approved, it could be combined with other drugs that are also taken once a day.

Because maraviroc and raltegravir combat HIV through new mechanisms, they are a promising alternative for those who have exhausted the available options.
Among other new classes of drugs are bevirimat, developed by Massachusetts-based Panacos Pharmaceuticals, which blocks a late step in the life cycle of HIV, resulting in non-infectious virus particles, and KP-1212, made by Koronis Pharmaceuticals in Redmond, Washington, which rapidly inserts mutations along the viral genome to make it non-functional.

There are also some promising reverse-transcriptase inhibitors in development. Johnson & Johnson's subsidiary Tibotec has developed etravirine (TMC125), a non-nucleoside reverse-transcriptase inhibitor intended to treat viruses that have become resistant to other drugs in the class. Tibotec plans to file for approval later this year. Another compound in that class, Tibotec's rilpivirine (TMC278), has also shown encouraging results in a Phase II study.

The more options in every class, the better, notes Deeks, "because we will continue to see individuals who develop resistance to available drugs."

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