Peering Into the Pipeline: New Drug Candidates
As I further my medical training, I find that the management of HIV remains intricate, requiring both an increasing understanding of the disease and a growing tool set. So many resources come into play when deciding on a treatment regimen, including information on when to start, what to start with, side effects, and how and when to use resistance test results (which continue to mesmerize me with their bright green and red boxes). These tools, combined with an arsenal of over 20 HIV medications, have helped us to optimize treatment regimens. Yet even with these, resistance continues to limit treatment options. The need for a greater arsenal of HIV medications remains strong -- luckily for us, it looks as if we have several promising candidates on the horizon.
Many HIV drugs approved to date have taken a good idea and given us more of the same. First came the reverse transcriptase inhibitors (also referred to the "nukes" and "non-nukes"), which block HIV's ability to convert its RNA to DNA. Then came the protease inhibitors, which expanded our treatment options because they worked at a different step in the HIV lifecycle. Many more protease inhibitors followed, but all worked in more or less in the same way. A fusion inhibitor followed in 2003. But all in all, the over 20 drugs approved to date work on just three steps in the life cycle of HIV.
For many treatment-experienced patients, resistance can still limit treatment options. We need new HIV meds that will work differently, targeting a different part of the HIV life cycle and working on virus that is resistant to multiple drugs, in addition to being safe and tolerable.
The 14th Conference on Retroviruses and Opportunistic Infections (CROI), held in Los Angeles from February 25-28, 2007, included over 1,000 posters, presentations, and abstracts. Of these, some of the most promising dealt with an alphabet soup of new drugs: MK-0518, GS-9137, TMC-278, and UK-427857. With the exception of TMC-278, these drugs work at new steps in HIV's life cycle, and may be important options for people with HIV that is resistant to existing medications.
The first two drugs, MK-0518 and GS-9137, are the first of a new class of HIV drugs that target the integrase enzyme, effectively blocking HIV from weaving its DNA into the host cell's DNA. UK-427857 (maraviroc) also works differently from approved HIV drugs, as it targets one of the coreceptors on the CD4 cells, blocking HIV from entering the cell. By interfering with new steps in the lifecycle of HIV, these drugs may work when approved HIV drugs do not. The fourth drug discussed at the conference, TMC-278, works like drugs already available (Sustiva and Viramune), but may have fewer side effects and may be as effective as Sustiva, one of the more potent HIV drugs.
This article will review current data on these four drug candidates, and look at where they are headed.
MK-0518MK-0518, newly christened Isentress (raltegravir), was shown to be potent in people with resistance to many HIV medications. In two worldwide large Phase III studies, BENCHMRK 1 and 2, a total of 700 people who had taken HIV drugs for about 10 years were randomly assigned to receive 400 mg of MK-0518 or placebo twice a day, together with an individualized combination of HIV medications. People in both studies had viral loads over 30,000 and CD4 counts below 200. The studies will follow them for three years, but the initial four- and six-month study results were reported at CROI.
After four months, the studies reported that more than twice as many of those taking MK-0518 had viral loads below 50 as those taking placebo: 61% compared to 33% -- compelling results in this highly resistant group. CD4 counts also rose, more than twice as much in people taking MK-0518.
People taking both Fuzeon and Prezista for the first time saw the greatest benefit from MK-0518. Of those, an impressive 98% had viral loads below 400 at four months, compared to 87% those taking placebo. When people took only one of the two (either Fuzeon or Prezista), 90% had viral loads below 400 copies, compared to 63% on placebo. As has been shown in many other studies, the best results occur when a new HIV drug is combined with other active drugs.
More good news: After six months, 61% of people taking MK-0518 who were resistant to all the approved HIV drugs were able to get their viral loads below 400 at four months, compared to only 5% without MK-0518. These results are significant, as few of the other drugs presented at CROI did as well in people with multidrug resistant virus.
With regard to side effects, people taking MK-0518 seemed to report similar side effects to those taking placebo. The most common side effects reported were diarrhea, headaches, or nausea. About 12% in both groups reported a serious side effect. On the whole, four months of MK-0518 use was concluded by the researchers to be generally well tolerated.
In a nutshell, MK-0518 appears to lower viral load significantly and increase CD4 counts in people who have had a long history of HIV treatment, and may work well even in people with HIV that is resistant to all other HIV medications. As expected, it works best when combined with other active drugs (like Fuzeon and Prezista), and generally seems to be well tolerated. All in all, MK-0518 looks like an exciting future drug option that may receive FDA approval before the end of the year. For people who need the drug sooner, it is available now through an early access program. Doctors can call 877- 327-6751 for information on how to enroll patients.
GS-9137In a smaller trial, Gilead's 0105 study looked at various doses of another integrase inhibitor, GS-9137 (elvitegravir). In this study, 278 people who had an average viral load of 36,000 and about 10 protease mutations in their virus took either 20 mg, 50 mg, or 125 mg of GS-9137 twice daily with a small dose of Norvir or a protease inhibitor that included Norvir. Everyone also took at least two other nucleoside analogs (NRTIs) with or without Fuzeon. 26% of those in the study used Fuzeon for the first time while in the study. After just two months, however, many taking the 20 mg dose had much smaller drops in viral load than those taking the larger doses, so the trial eliminated the 20 mg dose and switched those taking it to the 125 mg dose. (Their data were not included in the report; only those initially taking the 50 mg and 125 mg doses were followed.)
After four months, 38% of those on the 50 mg dose and 40% of those on the 125 mg dose had viral loads below 50, compared to 30% of those on placebo. These results, not as impressive as those for MK-0518, were perhaps due to the restrictions on the other HIV drugs allowed in the trial. No non-nukes were allowed, for example, so it's likely that a number of people with resistant virus were on virtual monotherapy. As has been the case with many drugs, GS-9137 works best when taken with at least one active HIV drug. People taking the 125 mg dose who had at least one other active drug saw a viral load drop of 2.1 logs. Those with no other active drugs saw only a 0.7 log drop. So having just one other active HIV med can make a huge difference when taking GS-9137.
Those taking GS-9137 also saw their CD4 counts rise. After four months, people taking the 50 mg and 125 mg doses had their CD4 counts increase by 52 and 61 respectively, compared to 28 cells in those taking approved drugs only. Side effects were similar in both groups. Between 1% and 3% of the groups stopped taking GS-9137 due to side effects. There also were similar rates of moderate to severe grade 3 and 4 side effects and abnormal lab results.
Gilead Sciences will be moving forward with a 150 mg dose of GS-9137 into larger phase III clinical trials, and hopes to see similar results to the 125 mg dose.
MaravirocHIV uses one of two coreceptors, R5 or X4, to get into a CD4 cell. Early in infection, HIV seems to prefer R5, but later may switch to the X4 receptor. Maraviroc works by blocking the R5 receptor. (This is different from Fuzeon, which prevents HIV from fusing with the CD4 cell's wall after a coreceptor is engaged.) Maraviroc therefore offers the exciting possibility of using a different target to block HIV from entering cells.
In the MOTIVATE 1 and 2 studies, 1,076 people living with HIV in Europe, Australia, and North America took 300 mg of maraviroc once or twice a day, or took a placebo. Both groups also took at least three other individually optimized HIV drugs. (People taking Rescriptor or a protease inhibitor other than Aptivus took 150 mg once or twice a day.) People in both studies had previously taken HIV drugs and had viral loads above 50,000 and CD4 counts below 200. People are to be followed for one year, and the initial six-month results were reported.
After six months, nearly twice as many people taking maraviroc had viral loads below 50 compared to those taking placebo with approved drugs: 41-48% of those taking maraviroc had viral loads below 50, compared to only 21-25% of those taking placebo. CD4 counts increased by 102-112 in those taking maraviroc, compared to an increase of 52-64 in those on placebo.
Between 84% and 89% of all patients experienced at least one mild side effect, and up to 91% reported experiencing any side effect. There was no significant difference between those taking maraviroc and those taking the placebo in the number of side effects experienced. In MOTIVATE 1, four people in each of the maraviroc-dosed groups died, as compared to none of those in the placebo group. In MOTIVATE-2, one person in the placebo group, two in the once-daily, and one in the twice-daily groups died. According to the investigators, the deaths were not related to the medications used.
It's interesting to note that in both studies, people who began with viral loads over 100,000 did just as well as those below 100,000. This is good news for people who can't get their viral loads below 100,000 on their current regimen. For those who have resistance to many HIV drugs, the twice-daily dose seemed to work better at reducing viral load than the once-daily dose. 29% of those with high-level resistance reached viral loads below 400 when taking the drug twice daily, compared to 18% in the once-daily group and 3% in the placebo group. Thus maraviroc seems to work best when taken with at least one antiretroviral to which one's HIV is not resistant. An official dose has not been decided upon, but these results will have to be weighed against the simplicity and convenience of the also effective once-a-day dosing.
A concern with maraviroc is whether using a drug active against the R5 receptor will prompt more HIV to switch to using the X4 receptor. In this study, 31 patients in the once-daily group and 32 patients in the twice-daily group had their virus switch to the X4 receptor, so they may be less responsive to future R5 receptor inhibitors. The Monogram Trofile Assay should help patients and doctors identify which type of receptor someone's HIV uses, and will be useful when deciding to start or continue maraviroc.
TMC-278TMC-278, also known as rilpivirine, is a newly designed non-nuke in the same class as Sustiva and Viramune. In the Tibotec study presented at CROI, 90 people who had never taken HIV drugs before took either 25 mg, 75 mg, or 150 mg of TMC-278, or the standard dose of Sustiva. Everyone also took Truvada or Combivir. On average, people had viral loads about 70,000 and an average CD4 count of about 200. About a third of the people in the study were women.
After a year, it looks like TMC-278 may be as effective as Sustiva. Here's what we saw: 81%, 80% and 77% of those on the 25 mg, 75 mg, and 125 mg doses of TMC-278 respectively saw their viral loads drop to below 50. This is comparable to the 81% of those taking Sustiva. People saw CD4 count increases of 125-145. Larger clinical trials are needed to see how well TMC-278 works in various populations, but these initial results look promising.
TMC-278 may have fewer side effects than Sustiva, as far as these study results go. While similar numbers of people experienced nausea (18% and 20%), fewer people experienced central nervous system effects (dizziness, abnormal dreams, vertigo) and rash. Overall, 33% of people on TMC-278 experienced CNS effects compared to 53% of those on Sustiva, while 8% of those on TMC-278 experienced rash compared to 19% of those on Sustiva. In addition, TMC-278 may be easier on the lipids, or blood fats, than Sustiva. In this study people taking TMC-278 had their total cholesterol rise 5 mg, compared to 31 mg in the Sustiva group. The "bad" LDL cholesterol also did not increase in those taking TMC-278, compared to a 16 mg rise among those on Sustiva.
Further studies will need to be done on TMC-278 before we can have a full sense of how TMC-278 will work in larger populations, such as those who have previously taken antiretrovirals, etc. Tibotec is looking into larger clinical trials of the 75 mg dose among people who have never taken HIV meds before.
ConclusionFrom the looks of things, we have some exciting new possibilities on the drug horizon. Maraviroc and MK-0518 are furthest along in development, and are both slated to be considered for approval by the FDA in the upcoming months. If approved, they may be available as soon as this summer or fall. GS-9137 is further behind in development, but is heading for the larger trials it needs to show its stuff. TMC-278 is also moving into larger trials, and may also help expand our arsenal of HIV drugs, with the benefit of fewer side effects. In total, what sounds like alphabet soup may provide just the right flavors we need to meet the challenges we face in HIV treatment.
Donna M. Kaminski formerly was ACRIA's Associate Director of Treatment Education, and is currently a second-year medical student.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.