Entry Inhibitors: A Race to the Finish Line
As reported in PI Perspective #38, entry inhibitors are a promising new class of anti-HIV drugs. One of them, enfuvirtide, is already approved and two others (maraviroc and vicriviroc) are currently being studied. A third drug was close behind but its development was stopped in October 2005 due to serious side effects. Several others are in early stages of development.
People are hopeful about entry inhibitors for a couple of reasons. Most importantly, they suppress HIV in a completely different way than other classes of anti-HIV drugs, meaning they should be effective in people with resistance to the older drugs. Because entry inhibitors work without interfering with what's going on inside cells there's also hope that they will not have some of the troubling side effects of other drugs, like body composition changes (lipodystrophy).
Recently, some of the excitement about these new drugs has been tempered by new concerns about unexpected side effects and somewhat disappointing effectiveness. Early articles hailed them as the leading edge of a new era in HIV therapy, yet the most recent experiences may suggest a more modest future for them. As the two most advanced drugs are studied, researchers should better understand their strengths and weaknesses and how best to use them.
New Entry Inhibitors in Study
Several companies are rushing to bring entry inhibitors to market. Each believes it has come up with the best way to block HIV from entering cells. Currently, there are two frontrunners -- drugs that are able to be taken by mouth in pill form. Each is being developed by a large company with substantial resources and expertise in drug development. The drugs are:
GlaxoSmithKline's entry inhibitor was recently withdrawn from development due to indications of liver toxicity.
Other entry inhibitors not covered in this article, but show some promise in early studies, include:
Co-Receptor Blocking Drugs
Maraviroc and vicriviroc interfere with HIV's attempts to enter a CD4+ cell by binding to a cell receptor called R5 (CCR5). If HIV cannot bind to R5, it generally cannot fuse to the cell and enter it. HIV can use several receptors on CD4+ cells, but X4 (CXCR4) is the only other one that it uses with any frequency. It is unclear whether HIV will eventually "learn" to use the other receptors after being blocked at R5. Because HIV must first bind to the CD4+ receptor on the cell, R5 and X4 are called co-receptors. These receptors have other functions for the cell -- not all of which are understood -- but HIV takes advantage of them in order to infect the cell.
All cells in a person's body produce R5. Some people make a damaged or non-functional form of it. Researchers began developing drugs to block R5 after it was found that people whose CD4+ cells do not make functional R5 rarely become infected with HIV.
For reasons that are not fully understood, HIV has a hard time establishing a foothold in a person whose cells have no functional R5. Also, some people have CD4+ cells that carry fewer functional R5 than normal. These people can still be infected with HIV, but they seem to carry greater protection against infection than people with normal amounts of functional R5. When they do get infected, the course of their disease is generally slower.
These facts alone are reason enough to explore therapies that block HIV from using R5. However, another reason was learning that people without functional R5 appear to suffer no negative health effects. This is significant and hopeful, as studies have found that there may be severe consequences to blocking other co-receptors from HIV.
Drugs That Block R5 -- Are There Risks?
The immune system is complex and controlling it with drugs is tricky. Researchers simply don't know whether giving someone a drug to block R5 will provide the same protection from HIV as that seen in people who are genetically unable or less able of making functional R5. Also, using drugs to block R5 may be harmful in ways that are not apparent in people who naturally do not make functional R5.
One of the most serious, though theoretical, risks has to do with how changes in receptor use by HIV may hasten disease progression. At least half of all people with HIV eventually have measurable changes in the type of HIV found in their blood. Instead of using R5, HIV begins to use another receptor called X5. This change seems to correlate with a rapid decline of CD4+ cell counts and the onset of opportunistic infections. Other research suggests that nearly everyone with HIV, at some time during their disease, may experience this shift -- but about half may revert back to R5 virus.
HIV primarily uses R5 along with the CD4+ receptor to enter cells. However, it can evolve to use X4. Some strains appear to use both (dual tropic virus). In test tubes, HIV that uses X4 has been found to cause CD4+ cells to clump together (syncitia inducing) and die in a way that R5 virus does not. This, along with the fact that X4 virus usually has been found in people when they begin to have rapid disease progression, has led many to label it as more aggressive and dangerous than R5 virus. However, others point to the fact that half of people who die from HIV disease mostly have R5 virus. This may be because the amount of X4 virus in blood can vary.
So, when researchers looked for X4 virus in these people, it may be that it simply wasn't measurable at that time, but was in fact present. Or, it may be that people with R5 virus are also in danger, whether or not they ever change over to X4 virus. Thus, the story may be too complex to simply label R5 virus as moderately bad and X4 virus as really bad. But given that some researchers may overstate the negative effects of X4 virus, there are some entirely new risks posed by the studies of R5-blocking drugs.
The greatest potential risk by blocking R5 on CD4+ cells is that it may give HIV that uses X4 a chance to take over and become the dominant strain. If X4 virus turns out to be more lethal than R5 virus, using these new entry inhibitors could actually harm people rather than helping them. This is most likely to happen in those who already have some measurable degree of X4 virus, are heavily treatment experienced, and have CD4+ cell counts below 200 (or lowest-ever counts, nadirs, below 200). This risk is theoretical and no one can say for sure that it will occur, but it still is a concern.
Evidence of R5 to X4 Shift?
Because using drugs to block R5 might increase disease progression, the earliest studies did not allow people with any trace of X4 virus to participate. Several people who originally showed no X4 virus on the screening tests had X4 virus emerge after taking a short course of the new drugs. When this occurred, other tests were done on the blood that was originally collected. In most cases, these other tests found that X4 virus had been present all along but had been missed. In at least two cases, however, the presence of X4 virus before using the study drug could not be confirmed by using the standard screening tests.
Researchers followed these two people very closely in the months after the studies ended and sent samples of their virus for further evaluation. The results appeared to show that X4 virus had likely been present before they took the study drug, but that there was too little present for the standard tests to pick up. In one of the two, X4 virus disappeared within a few weeks after stopping the drug. In the other person, X4 virus has remained detectable more than a year after stopping the drug. So far, neither case has shown evidence that the shift in virus has caused harm.
Spotlight on the Drugs in Study
So far there's a striking similarity between the R5 inhibitors in terms of their effects on viral load and the degree to which they remain stuck to R5 receptors for hours (or days) after a person stops taking the drug. One main difference so far is the degree to which the older anti-HIV drugs may increase or decrease the blood levels of each of the new drugs. Though further data are needed, scientists have developed virus in the lab that is resistant to each of the new drugs. Safety problems have already stopped one R5 drug, and potency problems are being seen in another.
Large studies of maraviroc started in December 2004 while large studies of vicriviroc started in the summer of 2005. Development of a third R5 drug, aplaviroc, has stopped due to several cases of liver-related side effects. AIDS Community Research Initiative of America (ACRIA) maintains one of the best resources for finding studies that may be recruiting near you. It can be found online at www.acria.org/clinical_trials/index.html. Another resource by the National Institutes of Health (NIH) is available online at www.aidsinfo.nih.gov/clinical_trials/ or by phone at 1-800-448-0440.
The first safety studies of maraviroc took place in healthy HIV-negative people. Various doses were tried, including single doses as high as 900mg per day and multiple doses of 300mg twice a day, for 28 days. The most frequent side effects were headache and upset stomach. A more serious side effect in those who took more than 600mg per day was a feeling of dizziness or faintness from quickly sitting up or standing (postural hypotension).
Animal studies showed that maraviroc could cause irregular heartbeats. So far, this has not been found in human studies. Studies also found that while maraviroc blood levels were reduced by almost half with food, there was very little difference in viral suppression between people taking it with or without food.
Interactions are expected between maraviroc and other drugs. Ritonavir, even at low doses, and saquinavir greatly increase blood levels of maraviroc -- by up to four times. On the other hand, drugs like efavirenz and rifampin can greatly lower its blood levels. Pfizer provides information on adjusting the dose of maraviroc when taking it with these drugs. Drug interaction studies are ongoing.
Studies examining the effect of maraviroc on viral load in people with HIV were reported in 2004. It was found that doses of 100mg to 300mg taken twice a day for ten days (without other anti-HIV drugs) resulted in viral load decreases of up to 1.6 logs.
Several studies (phase II/III) started in December 2004. One study of 1,071 people who had never taken anti-HIV therapy is comparing one of two doses (300mg once or twice daily) of maraviroc + 3TC + AZT to efavirenz + 3TC + AZT. All will be screened for X4 virus and anyone who has it will not participate.
A US study is recruiting people who are heavily treatment experienced. They plan to enroll 500 volunteers to determine whether one of two doses (150mg once or twice daily) of maraviroc added to an optimized regimen of approved drugs (based on resistance testing and treatment history) will suppress a person's HIV better than by using the optimized regimen alone.
Eligible volunteers must have known resistance to at least one drug in each of the three older classes of anti-HIV drugs. They will be screened for X4 virus. If it is found, these people will not be eligible but may be allowed to enroll in another study limited to those with X4 virus. Other studies are looking at maraviroc in people with X4-only virus and R5/X4 (dual tropic) virus.
Vicriviroc (Schering D)
Schering-Plough has presented data on a 14-day dose finding study of 48 people living with HIV. Volunteers had CD4+ cell counts above 200 and were off all anti-HIV drugs for at least eight weeks before starting the study. People were randomized to take one of three doses (10mg, 25mg or 50mg) of vicriviroc once a day or a placebo. All who took vicriviroc had a major reduction in viral load by day 14, at which point they were scheduled to stop taking the drug.
Viral Load Results From Phase I Dose-Finding Study
Of note, the decreased viral load was sustained for at least 48 hours after they stopped the drug, and it did not return to its original (baseline) level until two weeks after the drugs were stopped.
A larger ongoing study is comparing three different once-daily doses of vicriviroc given together with a ritonavir boost. To enter the study people must be failing on a ritonavir-boosted protease inhibitor regimen and have viral loads above 5,000. A total of 120 people will receive one of three doses (5mg, 10mg or 15mg) of vicriviroc or a placebo, added to their failing regimen for the first two weeks. The ritonavir dose will be the same as the one used in the failing regimen. Then, people will switch to a new optimized regimen (with input from drug resistance tests) and continue taking the original dose of vicriviroc or a placebo, together with the new regimen and a ritonavir boost, for 46 weeks. The study results will not likely be available until Spring 2006.
An ongoing phase II trial of vicriviroc was recently stopped because of treatment failure. It compared vicriviroc plus AZT/3TC to efavirenz plus AZT/3TC in people who had never taken anti-HIV drugs. An independent group (called a Data and Safety Monitoring Board) evaluating results from the trial recommended that it be stopped when too many people taking vicriviroc were having increases in viral load. This was a somewhat surprising outcome as most people had expected a regimen using vicriviroc to work about as well as a standard three-drug combination. It did not. Studies of the drug in treatment-experienced patients, so far, will go ahead as planned. However, there's no reason to expect the drug to work better in experienced patients than those just starting treatment, so any further studies will be watched very carefully.
The similarity in the design of this study and the ongoing trial of maraviroc raises some concern. After all, the two drugs have shown similar strength in earlier trials and the two studies use the same additional drugs (AZT+3TC). It is important to note that similar problems haven't been reported for maraviroc, though the study is far from complete.
A large study of vicriviroc in treatment-experienced patients is scheduled to begin in 2005. Those interested in learning more about it can call Project Inform's InfoLine or call or visit the ACRIA or NIH websites as noted earlier. Vicriviroc has not been used long enough to know what side effects it may have. However, some drug interactions are expected given the way that it is broken down by the body and because it must be used with ritonavir. Schering-Plough will provide recommendations for study doctors and volunteers about adjusting the dose of vicriviroc or the other drugs. Other drug interactions studies are ongoing.
GlaxoSmithKline's (GSK) R5 drug, aplaviroc, ran into problems and its development has been stopped. The first problems were seen in studies of people who had never taken anti-HIV drugs (naïves), when two volunteers developed serious liver problems. In both cases the problems got better when they stopped taking aplaviroc. This led GSK to halt all studies of aplaviroc in naïve people while researchers try to determine the cause and severity of the problems. Initially the company said it would proceed cautiously with studies of aplaviroc in people who have taken other anti-HIV drugs. However, the same problem was later seen in the study of people who had taken anti-HIV drugs before. This wasn't surprising as here has never been a side effect of an anti-HIV drug that only affected people beginning therapy for the first time while not affecting people who have use treatment before. In general, people who have used treatment for longer periods tend to have more, not fewer, drug side effects.
Putting R5 Blockers Into Place
After a year when only one new anti-HIV drug (tipranavir) came to market, it is gratifying and hopeful to have several drugs of an entirely new class making it into larger studies. Because these drugs work so differently than the older drugs and so little is known about how treatment-experienced people will respond to them, it is wise to proceed cautiously.
For instance, people who wish to volunteer for any of these studies should fully understand the potential risks and benefits. As Project Inform has stated since its inception, it is vital to make informed treatment decisions. This is particularly true when a person considers volunteering for a study. The newest experimental drug is not always the best choice for one's treatment, especially when there are so many proven therapies already available.
It may also be that wide-scale access to these drugs may be slow to arrive or may be limited, compared to most drugs that have been approved in the past several years. This is because of safety concerns and the other studies that may be needed. Fortunately, as promising as these drugs are, they are by no means the only or even the best drugs currently being studied in HIV. At least two other anti-HIV drugs have shown viral load results superior to all three R5 blockers discussed above. Most are covered in more detail HERE. With so many new anti-HIV drugs in development, there are an equal number of reasons to be hopeful that they will result in the next major advance in treating HIV.
GlaxoSmithKline Terminates Patient Enrollment for Phase 3 Studies of Investigational HIV Entry Inhibitor Aplaviroc (GW873140)
This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.