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

July 1996
Rapidly increasing understanding of the way in which HIV gains access to new cells may lead to new strategies for stopping the virus. (The) new receptor is designated chemokine receptor 5, or CC-CKR-5. HIV was able to infect cells bearing both the CD4 and CC-CKR-5 receptors, but not just CD4. That infectability was practically eliminated in the joint presence of (chemokine) RANTES. The simplest explanation seems to be that by binding to CC-CKR-5, the chemokine blocks HIV from joining with cell membranes and entering the cells. It should be possible to develop benign drugs that bind to either part of CC-CKR-5 or, more likely, to the part of HIV's gp120 envelope protein that attaches itself to this receptor.

March 1998
Important discoveries over the last two years have demonstrated that HIV also uses chemokine receptor sites on the host cell's surface, such as CCR5 and CXCR4, in conjunction with CD4, to gain entry to the cell. Several posters at the 5th Retrovirus Conference looked at possible chemokine receptor site inhibitors. This research is still at a preclinical stage, and many of the approaches being studied have not yet been developed into drug form. With more pharmaceutical companies jumping on the chemokine bandwagon, more progress is expected.

March 2002
A new drug to block HIV at a new point in its lifecycle will be a welcome development. But approving a new drug from a new chemical class will also bring great uncertainties. It's not enough to simply be active against HIV, the new drug will also have to leave host functions alone and meet all of the other criteria for a medicine that is tolerable, easy to take, safe, and affordable.

Entry inhibito... take a different approach to blocking viral attachment. Instead of sticking to the virus, they bind to receptors on a cell's surface that HIV uses to gain entry. Schering's SCH-C is in human trials and moving through a series of doses to find the best balance between activity and toxicity. SCH-C stops HIV from using the CCR5 receptor to infect new cells. A more virulent strain of HIV employs the CXCR4 receptor, and is not inhibited by SCH-C. One fear is that using the drug could favor the evolution of CXCR4-using mutants and actually accelerate disease progression. So far there is no evidence from test tube or animal studies that this occurs, but experience in human trials is the test that matters. Work is proceeding carefully because of abnormalities in a cardiac rhythmic parameter called QTc observed after volunteers received a single 600mg dose.

September 2002
Schering Plough held a meeting to update community members about the progress of the company's novel CCR5 inhibitor, SCH-C, which is moving through the first phases of clinical development. The pace of testing has slowed because of cautions put in place by the FDA after transient electrical abnormalities were detected in the heart rhythms of three patients receiving SCH-C at high doses. The abnormality, a prolongation of the QTc interval, indicates an event when the heart is signaled to beat before the muscle is fully prepared to contract. This condition can possibly result in the heart losing its ability to move blood, with sudden death the outcome. Because of this potentially catastrophic consequence, the FDA has asked for close monitoring of patients receiving SCH-C until the significance of this observation is clarified.

May 2003
Schering has pulled a switch in their CCR5 entry inhibitor development program. SCH-C, which had been slowed by a concern with QT heart rhythm prolongation problems, has been shuffled back to let SCH-D take the fast track. Schering had downplayed the heart issue in meetings with community members, but much skepticism remained. SCH-D is a different molecule with much better activity in laboratory studies and, so far, no safety issues. Phase I trials are in progress.

May 2003
The virus one starts out with may not be the virus that causes trouble down the line. Early in the epidemic scientists recognized that HIV has two faces: one attacks a limited set of immune cells slowly and steadily, wearing down defenses over time. This form of the virus gives AIDS its reputation as a slow but relentless killer. But another form of the virus, one that eventually develops in about half of those with HIV, shifts the disease into high gear as it begins taking out T cells aggressively, causing rapid immune cell loss that can quickly plunge a person into a dangerous state of AIDS.

The differences between the two forms of HIV have been traced to a few simple mutations on one of the virus' outer envelope proteins responsible for latching on to new target cells. Most of the mutations occur in a region called the V3 loop of the gp120 protein. When HIV first attaches to a potential target cell, the gp120 protein hooks up with the cell's CD4 molecule, which is the main cellular receptor for infection. But attachment is not enough; the gp120 also needs to plug into a co-receptor molecule on the cell that helps pull the virus into contact with the cell's surface so the two can merge. In the slow form of the virus, the V3 loop of gp120 is able to connect with a cellular co-receptor called R5 (CCR5). This R5 co-receptor is found on mature T cells that have already been primed to fight infection as well as on immune system sentinels, the macrophages. The R5-using HIV may cause a slower-paced infection because it has only a limited set of target cells to infect and because it seems to replicate at only a moderate rate.

But if the V3 loop changes its chemical properties slightly, the virus starts to be able to use a different co-receptor called X4 (CXCR4). The X4 co-receptor is found primarily on immature T cells that are still being formed in the immune system's incubator, the thymus, and on newly activated T cells that have recently met their antigen.

The reason for the shift is not clear. Some believe that the virus is trying to escape antibody attack directed at its R5-using site; others think that the virus simply starts to look for different co-receptors once the supply of mature R5-bearing T cells becomes too scarce. Once the shift begins, however, the use of X4 becomes more and more common until in a few people the body's predominant strain of HIV is using X4 exclusively. Clinically, this is bad news, for although antiretrovirals are able to suppress X4 HIV as well as its R5-using ancestor, T cell destruction now proceeds at an alarming pace. If the R5-using virus is like a sniper picking off selected target cells, the X4 virus is a weapon of mass destruction in the thymic maternity ward.

June 2004
There are several CCR5 blockers/entry inhibitors in development, including Schering's SCH-D, Pfizer's UK 237, Glaxo's GW873140, and Progenics' PRO140. These drugs are keenly anticipated by people who have developed resistance to all drugs in the conventional classes and the FDA has seemed to signal that they favor larger, Phase III clinical trials in people with multi-drug resistant virus. But there may be a hitch. People with few remaining treatment options tend to be people with more advanced HIV disease. And the longer people have had HIV, the more likely they are to have evolved virus that is capable of using CXCR4, a development associated with accelerated disease progression. These people won't be helped by a CCR5 blocker and they may be put in danger if the drugs force a shift to X4-using virus that speeds up immune deterioration. The possibility of this risk would seem to favor first investigating the CCR5 blockers in a more recently infected population, where the X4 virus will be less common. To do this safely, though, a sensitive and reliable screening test to detect low levels of X4-using virus must be developed. All of this may call for a rethinking of how to test these new drugs.

September 2004
There is a critical open question about using the new CCR5 blocking drugs: will they cause HIV to start using CXCR4? And will that be worse than letting the R5-using virus chug along at its own, slower, but no less dangerous pace? So far there's no solid evidence that blocking R5 will lead to HIV mutations that prefer using X4. But there is increasing evidence that some people may have small amounts of X4 virus in their bodies that could be given a green light to take over if their R5-using cousins are shut down. Again, it's not clear if these were acquired at the time of infection or if HIV can mutate step-by-step from exclusively using R5, to using both R5/X4, to using only X4. While there is now an experimental phenotype assay that can detect R5, X4 and dual R5/X4-using virus in a person's blood, it may not be sensitive enough in all cases to identify X4-using variants that are hiding in tissues or are only present in very small numbers. Now, as several pharmaceutical companies are getting ready to start large phase III trials for their R5 blocking drugs, discussion of the X4 problem is heating up.

Ideally, it seems, one would want to use an X4-blocker in tandem with an R5-blocker to prevent the possibility of an X4-using HIV variant escaping and causing accelerated immune damage. But, in the first few upcoming trials, at least, the R5 blockers may have to work without a safety net as researchers rely on the imperfect assay to screen out those at risk for switching to an X4-using virus. If all goes according to schedule and no unforeseen problems with toxicity arise (and there is no guarantee that they won't), the first oral entry inhibitors could possibly appear in expanded access studies by late 2006 and be approved for sale in 2007.

November 2005
Until recently, three companies were developing competing versions of CCR5 antagonists, although in the weeks before this conference one competitor had been swallowed by the whale of toxicity and another had been lured astray by the glittering temptation of once-a-day dosing. All studies of aplaviroc, GSK's CCR5 candidate, were terminated after several cases of severe liver toxicity began to appear among study subjects. Fortunately, the liver problems abated when the drug was removed but this unforeseen safety problem proved fatal to the drug's future and it was dropped. A few weeks later, Schering announced that it was canceling clinical trials of its CCR5 blocker in treatment-naive patients due to low potency and an inability to compete with efavirenz in reducing viral load. Schering's drug, called vicriviroc, benefits from boosting with ritonavir, and trials of the drug in treatment-experienced patients who are taking it in combination with boosted protease inhibitors will continue. It appears likely that blood levels of unboosted vicriviroc, especially when dosed once per day, were not reliable in all patients. This study seems to have been a gamble on Schering's part, since it did not test the once-a-day dose in the initial trial that proved that vicriviroc worked. It's possible that the temptation of achieving the holy grail of one-pill-a-day led to a leap of faith that vicriviroc's long half-life in the blood could carry it through. Alas, whether precipitated by greed or by pride, expectations for vicriviroc have been diminished.

Later in the conference fears about the viability of this entire class of compounds were heightened when word came that there had been a case of serious liver toxicity in a patient taking Pfizer's maraviroc. After the aplaviroc experience, some wondered if this was a problem with all CCR5 blockers. But as details filtered out, it appeared likely that other liver-toxic drugs were responsible for this incident and no other cases involving maraviroc have been reported. Still, this one case, coming on the heels of the other disasters, has put everything to do with vicriviroc and maraviroc under closer scrutiny.

July 2006
Another new drug due in 2007 that also blocks HIV infection in a unique way is Pfizer's maraviroc, a CCR5 antagonist that prevents the virus from entering target CD4 immune cells. Although data is limited, in preliminary studies, the drug was effective and no safety or tolerability issues have emerged so far. One limitation is that maraviroc is only effective at blocking HIV that uses the CCR5 coreceptor. HIV variants using a different coreceptor are not inhibited by the drug and these variants may be present in 10%-60% of people with HIV, mainly depending on the duration of their infection. This means that maraviroc may not be reliable for use in broad populations without expensive diagnostic monitoring.

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