Treatment Issues: Newsletter of Current Issues in HIV/AIDS - Volume 20, Numbers 8, 9, 10, 11, & 12, August / December 2006
Bob Huff

Progress toward solving the AIDS crisis seems to move at a torturously slow pace, and it is a bright day when new developments in HIV therapies appear. In 1996, the impact of triple combination antiretrovirals seemed miraculous, and the dramatic decline in U.S. AIDS death statistics that soon became evident continues to this day. AIDS was not eradicated and HIV-related deaths did not cease, but the daily devastation was brought under control wherever the drugs were available. Unfortunately, the miracle is denied to most people living with AIDS in the world because their governments are not yet willing or able to provide the drugs. Although the number receiving antiretroviral treatment continues to rise, at nearly 8,000 per day, the global AIDS death rate remains out of control.

Eleven years ago, despite having identified and developed three classes of drugs that could contain HIV in a body, scientists understood little about how the virus infected cells and ultimately caused immune havoc; in 2007 the latter question is still open. But in 1996 a flurry of research papers appeared that described how HIV enters its T cell targets. The research findings unleashed a wave of new ideas about therapy and launched a race to develop an entirely new way of stopping the virus.

It is now understood that HIV infects new target cells through a multistep process. Researchers had long known that immune cells bearing the CD4 receptor were the primary target for HIV infection. CD4 T cells play a coordinating role in the body's immune system, and when they became dysregulated or eliminated by HIV, immunity to certain common infections is lost, with acquired immune deficiency syndrome (AIDS) the result. But the new research showed that after the virus attaches to the CD4 receptor, it must still make contact with a different receptor before HIV can enter the cell, hijack its machinery, and begin making new copies of itself. One type of necessary secondary receptor is called CCR5, and virus that uses CCR5 to enter a cell has certain qualities that distinguish it from HIV using other secondary receptors, like CXCR4. One observation that caught the attention of drug developers was that some people are born without functional CCR5 receptors, yet had normal immune systems. Furthermore, people lacking CCR5 rarely seemed to become infected with HIV, despite abundant risk factors. And those who did become infected (presumably though CXCR4 or another minor receptor) seemed to have a very slow course of disease progression. All in all, it appeared that if one could block CCR5 with a drug, then one could possibly halt HIV infection of new T cells and thwart the virus—all without disrupting the normal functioning of immunity.

Soon researchers at drug companies around the world were searching through their vast libraries of chemical compounds looking for a molecule that prevented HIV from binding to CCR5. Typically in the drug development process, once a candidate molecule is found that has some activity, it is taken into the pharmaceutical chemists' lab and tweaked and tested until a version is developed that maximizes activity and minimizes the potential for toxicity. This optimized compound is then subjected to further tests for safety in cell samples, then animals, and finally, when the FDA has been assured that the risk is well understood, in humans. By 2002 the race to develop a CCR5 blocking compound had been taken up in earnest by three major drug companies: Schering-Plough, Pfizer, and GlaxoSmithKline.

Schering was the first company to put a CCR5 blocker into humans, but that compound, dubbed SCH C, produced cardiac abnormalities in a few of the first people to take it, so it was scrapped and Schering started over with SCH D, an unrelated compound with improved potency and no obvious toxicities. Unfortunately, starting over cost Schering its head start in the race, and in 2004, Pfizer became the first to announce successful results from a proof-of-concept study in HIV-infected people (the nature of the race led Schering to cut corners on its catch-up SCH D program, a decision that contributed to the drug's ultimate downfall). A range of doses of the Pfizer drug was tested as monotherapy for 10 days in patients who were currently off treatment. The drug knocked down HIV levels as effectively as other antiretrovirals had in similar tests, and any side effects were quite tolerable. The results of this small study gave Pfizer a green light to launch an ambitious and unprecedented program to develop this new class of drugs in record time. Barring any last-minute setbacks, the drug, maraviroc, will likely be approved for sale in the United States by June of 2007.

Despite the solid theoretical foundation for preventing HIV infection by blocking CCR5, the inherent risks in developing a first-in-class drug were amplified by its novel target and by catastrophes that befell maraviroc's competition. Unlike every other of the 20 or so approved HIV drugs, the CCR5 blockers do not attack the virus directly, but rather stick to a human cellular protein, altering its shape to prevent HIV from binding. Despite the well-documented experience of people born without CCR5 who turned out fine, there was—and is—much speculation that CCR5 may play an unrecognized but important role in the immune system that shouldn't be tampered with. In 2006 fears were heightened when a small cluster of five cancers appeared in very advanced HIV patients taking the Schering CCR5 blocker. Statisticians ultimately decided that there was no causal link between the cancers and the drug, but the episode triggered a careful examination of all patients receiving any CCR5 blocker and renewed a call for long-term follow-up of all participants in clinical trials involving the class. So far, no link between CCR5 blockers and cancer has been demonstrated, and data from phase III studies of maraviroc presented at the 14th Retrovirus Conference in Los Angeles showed no difference in the rate of cancers in patients who received maraviroc and those who did not.

Studies in mice lacking CCR5 have triggered worries that maraviroc or one of the other CCR5 blockers might cause compromised immunity to certain infections such as West Nile virus (WNV). Because the mouse immune system depends on CCR5 in a way that the human system doesn't, most of these concerns seem misplaced, although a 2006 epidemiological study reported that individuals born without CCR5 receptors were more likely to be infected with West Nile virus than their small number would suggest. This finding set off a lively discussion about the need to protect people on maraviroc from the mosquito-borne disease, although no increase in WNV has been seen in trial participants so far.

In late 1995, a few months before the nervousness over cancers and mosquitoes surfaced, GlaxoSmithKline announced that it was canceling development of its CCR5 blocker, aplaviroc, due to severe liver toxicity that appeared in a number of patients receiving the drug in clinical trials. Shortly after that bad news, Pfizer announced that one patient receiving maraviroc in a trial had experienced serious liver damage and required a transplant. Subsequently it was shown that this was an isolated case and was likely due to errors made by the hospital that treated her, although for a time it seemed as if the entire class was in danger. A thorough examination of patient records for all maraviroc and vicriviroc trial participants strongly suggested that the liver problems were specific to aplaviroc and were not a problem with the class. (Schering's vicriviroc ultimately fell out of the running because the top dose studied in its rushed, early study proved unable to suppress virus as well as the competition. Schering says it will try again with a higher dose, although little activity has been evident to date.)

Now that the drug has survived worries about cardiac abnormalities, liver disease, and cancers (the jury is still out on West Nile virus), the safety profile of maraviroc in its large clinical trials seems to be reassuring. Data from the Motivate I and II trials in treatment-experienced patients presented at the 14th Retrovirus Conference in Los Angeles indicated no difference in deaths or discontinuations due to adverse events between once-daily and twice-daily doses of maraviroc and placebo. Only cough, upper respiratory tract infections, and dizziness were reported more frequently in maraviroc recipients (~10%) than placebo recipients (~5%) in the North American Motivate I study. There was also a small cluster of esophageal candidiasis in seven patients on the once-daily maraviroc arm compared to one in the twice-daily group and none in the placebo arm.

Most of the highly treatment-experienced patients in the Motivate I study had CD4 cell counts below 200 and fewer than two active HIV drugs available to them. Despite having "difficult-to-treat" HIV with multiple resistance mutations, nearly twice as many patients receiving twice-daily maraviroc (60.4%) achieved viral suppression below 400 copies at 24 weeks than did placebo recipients (31.4%). When the more stringent test of achieving less than 50 copies was used, twice-daily maraviroc still conferred twice the benefit of placebo, although the proportion of successes slipped from 60% to about 48%. The once-daily dose of maraviroc lagged the twice-daily dose by about 6%. These results, along with a slightly better safety profile, has led Pfizer to seek marketing approval for 150mg maraviroc twice daily in treatment-experienced patients when given along with a ritonavir-boosted protease inhibitor. (Although maraviroc does not raise or lower the blood levels of other drugs, its levels are increased when given with ritonavir. In treatment-naïve patients not receiving ritonavir, the maraviroc study doses are 300mg once or twice daily.)

Most observers at the Los Angeles Retrovirus Conference agreed that maraviroc had performed remarkably well in this advanced group of patients (though not as well as the upstart newcomer raltegravir, a novel integrase inhibitor from Merck that reduced HIV RNA below 400 copies in 80% of its highly treatment-experienced study group). One often-heard reason for skepticism about using a CCR5 blocker in patients with advanced disease is that not all HIV variants depend on CCR5 for cellular entry and that the other variants tend to become increasingly common the longer one has been infected. Typically, nearly 100% of the HIV circulating in a recently infected individual uses CCR5. However by the time CD4 counts have dropped below 100, perhaps only half of this advanced population has HIV that uses CCR5 exclusively; the rest carry a virus that is also able to use the CXCR4 cellular receptor to gain entry, and maraviroc won't stop that virus. Of course, participants enrolled in the maraviroc studies were first tested to see whether their virus used CCR5 or something else. Only those with exclusively CCR5 virus were admitted to the trial, which meant that fewer than half of those who applied to join the study made the cut.

One of the early (and lingering) fears about using CCR5 blockers concerned not what the drug might do to the body but what the drug might do to the virus. There were worries that if HIV became unable to use CCR5 to gain entry, it might mutate or be forced to use a less favorable entry pathway involving CXCR4. Fears were heightened because the emergence of CXCR4-using virus has been associated with advanced and rapidly progressing HIV disease. If blocking CCR5 caused a switch to CXCR4, would patients be at risk of experiencing a catastrophic collapse of their immune systems? Fortunately, beginning with the earliest use of CCR5 blockers in people, there has been no evidence to support those fears.

As it turns out, the CCR5 screening assay cannot reliably identify people with small amounts of CXCR4-using virus, and some were inadvertently admitted to the maraviroc trials. It is now well accepted that a founding strain of HIV develops a myriad of minor mutations that can persist and coexist in the body over time. When unsuppressed HIV is allowed to replicate, random mutations are produced on a daily basis, and although most mutations result in nonviable virus, a few can persist at very low levels, perhaps in protected compartments in the body. Therefore, if the dominant CCR5-using HIV is suppressed with maraviroc, a preexisting minor variant that uses CXCR4 might be free to flourish.

The good news is that when CXCR4 HIV broke free in people receiving maraviroc, it had no dramatic effect on their immune systems. Pfizer actually performed a small pilot study of maraviroc in patients who tested positive for CXCR4-using HIV at baseline. In a preliminary report, no dramatic loss of immune function was observed for any participant. Paradoxically, many of these individuals may have actually experienced an increase in CD4 counts, despite having no apparent reduction in HIV RNA. There has long been a "chicken or egg" controversy about the meaning of CXCR4-using HIV in advanced disease: Does CXCR4 usage cause the increased pace of immune damage? Or is it a protective response to other changes in the body's HIV ecology? Therapeutic potential aside, drugs such as maraviroc might offer a scalpel-like tool to help basic scientists understand how HIV interacts with different components of the immune system.

For now, the CCR5 screening assay will be recommended before starting maraviroc therapy. But drawbacks to the assay—its high cost and three- to seven-week waiting period—mean that pressure is growing to either find a simpler assay or perhaps find evidence that justifies dispensing with the assay altogether. If there is no downside to exposing someone with a mixed viral population to a CCR5 blocker—and if there is a possibility of immunological benefit, then physician investigators—particularly those who practice in health systems where funds for expensive assays are tight—will likely want to explore the parameters for using this new class of drugs.

Because of the higher prevalence of CCR5-using HIV in more recently infected patients, there is eager anticipation to hear the results of maraviroc studies in treatment-naïve patients expected later in 2007. However other key questions about the drug, such as its long-term impact on immune markers, will not be answered for several years. Certainly, if maraviroc is ever to have an impact on treating HIV in the developing world (and much more must be done to determine the susceptibility of the world's many subtypes of HIV to the class before that can be known), a way around the burdensome need for CCR5 screening must be found.

A great deal of work has been accomplished to bring this drug to market in the 11 years since CCR5 was revealed as a target. Yet, in many ways, the real drug development work will begin the day maraviroc appears on pharmacy shelves in the United States. What best to combine it with? Which populations get the most benefit? What is the five-year side effect profile? How common is resistance? Is there benefit despite resistance? If you can suppress CCR5-using HIV, then does viral load matter anymore? Is CCR5 screening necessary? Is maraviroc safe for people all over the world? Is maraviroc effective against HIV subtypes more common in Africa or Asia?

It is too soon to predict how this drug will be ultimately used. There could be surprises in store. With maraviroc being the last drug standing after an amazing race and the sole survivor of its class, the real story—its impact on HIV disease—is just beginning to be written.

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