The news from the frontier of HIV/AIDS treatment gets better all the time. Here, we gaze into the crystal ball to look at new developments that may enhance our care
Since HIV was discovered in 1983, those who carry it (and those who love and provide care to them) have looked to the future, eagerly awaiting new treatment developments to extend and improve the quality of life for people with HIV. For those who chose anti-retroviral treatment, especially those who took early monotherapy and duotherapy options that facilitated the development of resistant virus, survival was sometimes about hanging on until a newer, more powerful class of drugs was released and hoping they would result in viral suppression and increased T cells with few side effects if our current combo was no longer effective.
Things have changed dramatically since the early days of AZT (Retrovir) monotherapy. Treating HIV has become an increasingly complex and highly personal decision. The number of classes of different drugs available, not to mention the variety of drugs in each class, is impressive. We now know more about side effects, drug interactions, drug resistance and how best to use available treatments than ever before. The good news? The arsenal for fighting HIV is getting bigger and better all the time.
When I was first diagnosed a decade ago, my doctor handed me a prescription for AZT and said, “Try this. It may buy you some time.” I took it, swallowed it and put up with the side effects. I didn’t know that nucleoside analog monotherapy—while still the standard of care—wasn’t the cutting-edge way to go at the time. Shortly after, I found a new doctor and the nuke Epivir was approved; a little while later, Crixivan, a protease inhibitor (PI), got its FDA stamp of approval. Within months of starting AZT monotherapy, I found myself on a combo HAART regimen, powering down six Crixivan capsules, two AZT capsules and two Epivir tablets a day. I had “hit hard and hit early” by default. I felt pretty smug for many years: My viral load went totally missing; my T cells stabilized above 400; and the general consensus among my doctors was that I’d chosen a pretty good regimen. I was “lucky” to have contracted the disease at a time when combo therapy was available. For many years, I felt I’d made the right choice.
But as time has passed, I’ve begun to feel less secure that I picked the right paths. Not necessarily because what I did was wrong. I did the best with the information, advice and resources I had at the time. But recent advances in the science of HIV/AIDS mean that there’s a possibility I could be getting even better care. While I feel fine and my labs are good, I wonder if some of what I don’t know about my body (and what I may soon be able to discover using the latest science) might mean I could be on a more ideal treatment plan.
There’s a lot of new stuff brewing that could soon affect choices I might make in my regimen. For example, technology may eventually allow my doctor to analyze my genetic makeup and to determine which drugs and which doses will be safe and effective for me. I could, someday, look forward to one pill, once a day. There is new thinking that might enable me to drop some of the meds in my current combo and keep my viral load down and my T-cell count up. There are new drugs in existing classes (in case resistance testing indicates that something I’m on isn’t working), and there are whole new classes of drugs in development, aimed at outsmarting HIV in brand-new ways. It’s an amazing thing to have lived through a time when there was not a great deal of hope on the medical front for people with HIV to a day when treatment has become advanced enough to help us be proactive in our care and, potentially, enable us to strategize for days to come.
I have upgraded my regimen three times in ten years: once to replace AZT with Zerit (the word on the street was that it was less toxic than AZT), once to replace Zerit with Ziagen (though no one knew for sure, Zerit had likely caused the lipoatrophy in my arms, legs and buttocks) and once to swap the six-pill a day Crixivan for the once-a-day, two-pill dose of PI Reyataz (boosted by a once-a-day, one-pill dose of Norvir). It was scary when I switched, but each time I did, my life—and my body—seemed to benefit, at least in the short term. Whenever I made a change, I thought about how that shift would impact my choices in days to come. What an empowering thing to know that just when you can’t seem to take one more day of a side effect or an aspect of treatment, something new is being developed to make treatment easier to swallow.
There are times when I wonder whether I should have started treatment so soon—or at all. Maybe I could have gone off meds when my T cells bounced back. I poured drugs proven to be hard on the body in high doses down my throat when there didn’t seem to be a thing wrong with me except for the detectable presence of HIV in my bloodstream. When I was first diagnosed—and shortly after, when protease inhibitors were approved—everyone was so gung ho about the promise of new meds (and I was so afraid of getting sick, as I’d been told I would if I didn’t pop pills) that it never occurred to me to question whether I was making the right decision. Sure, for over a decade I haven’t been sick, which is great. But I can’t help but wonder what’s happening to my insides and whether, over the next decade or several, I’ll see the effects of their presence in my body.
Being aware and planning for the future can enhance your quality of care and life in the long term. Looking to the future of HIV treatment, the mantra “Knowledge = Power” is as relevant as it ever was. It can be mentally taxing to keep on top of the complex and technical world of treatment—not to mention that it’s a real chore to slog through the technical jargon. I, myself, have had to read and reread some of the material. But being aware and periodically reevaluating your options can help improve how you feel and maybe even improve your longevity. In the end, no one cares more about our survival than we do. Which is why we need to be advocates for our best care, educating ourselves and those who treat us with the most current information. In that spirit, we offer you an update on the most exciting treatment developments from the brave new world of HIV/AIDS care.
Oh, one last thing: the vaccine. Though it has been looked at primarily as a preventive measure as opposed to a treatment option, there have been small trials investigating a therapeutic use for an HIV vaccine, that if developed, could positively train the cells in your immune system to control HIV, maybe without other meds. While it’s still a dream at this time, just the notion that it’s being studied gives me hope. And we all know what a healthy dose of hope can do, especially on top of powerful treatment. Until they find the cure.
Pharmacogenetics/Pharmacogenomics Making meds fit your genes
A front-page headline in the December 8, 2003 edition of The Independent, one of the United Kingdom’s leading daily newspapers, was shocking. It read: glaxo chief: our drugs do not work on most patients. Relying on statements made by Allen Roses, MD, worldwide vice-president of genetics at GlaxoSmithKline, the article explained that “most drugs work in fewer than one in two patients, mainly because the recipients carry genes that interfere with the medicine.” Though his comments weren’t specific to HIV meds, they hinted at the future of HIV treatment: profiling HIV positive people based on their genetic makeup to identify those who would benefit from standard doses of therapy and those who might need lower or higher doses of their meds to limit side effects and maximize their effectiveness.
Welcome to the science of pharmacogenetics and pharmacogenomics. Simply put, pharmacogenetics is the study of genetic variances that cause some people to respond differently to drugs than others. Pharmacogenomics is an even broader study that examines the effects of the entire human genome—the genes that define us as a species—on drug activity in the body. The distinction between the two is arbitrary, and the terms are frequently interchangeable. But don’t confuse either of these new approaches with the resistance testing that’s been around for years. Resistance testing indicates only which drugs are better for treating a given strain of the virus, not the individual.
About 99.9% of the human genome is the same in every human being. We are all brothers and sisters under the skin. But that other 0.1% can make a significant difference, especially when it comes to HIV. There are mutations—known as “polymorphisms” in sciencespeak—that can affect genes responsible for drug metabolism (the way drugs are broken down and removed from the body) as well as the transportation of drugs in and out of cells. These mutations can cause drug levels in the body and inside cells to become higher or lower than needed, increasing the risk of side effects or even treatment failure.
Scientists are also looking at genetic mutations that can affect the immune system itself. For example, human leukocyte antigen (HLA) is a substance located on the surface of white blood cells that plays an important role in the body’s immune response. Some people have a gene that produces an HLA variant called HLA B*5701. Researchers found that many long-term nonprogressors—people who have been HIV positive for many years but still have low viral loads and high T cell counts without taking meds—have this genetic variant. HLA B*5701 has also been documented in many people who experience a Ziagen (abacavir) hypersensitivity reaction—a potentially serious allergic reaction affecting 8% of positive people taking the drug.
A recent study conducted at the Claude Nicole Center in Brighton, England, proved the value of looking for this genetic variant: All those who had HLA B*5701 were kept off Ziagen, and all those who didn’t have it were allowed to start the drug. The result? Not a single case of hypersensitivity was seen among patients who underwent testing.
A further example of the power of pharmacogenetics is how it helped researchers understand that specific genetic mutations may also be the culprits in increases in lipids (the fat in your blood) and in lipodystrophy (abnormal body-fat changes) resulting from certain HIV drugs.
Right now, none of these genetic tests are widely available in the United States or used much outside the research setting. Eventually, though, with continued research to determine the usefulness of these tests, people with HIV and their doctors will be able to customize their treatment based on genetic information, including which drugs to avoid and which drug doses to adjust. But this will take time and money.
One Pill, Once a Day Increasing convenience makes adherence easier
Combination HIV drug treatment has been the standard of care for ten years. The basic recipe for combination treatment is still much the same as it has been: a protease inhibitor or a non-nuke plus two nukes. What’s changed considerably—and definitely for the better—are the serving sizes of these powerful ingredients.
No one wants to take ten to 15 pills a day, three times a day, with all sorts of dietary restrictions. New formulations of certain treatments allow us to take fewer pills fewer times a day. Most current drug combos can be taken twice a day, and there are a handful of drugs (some available and some looming on the horizon) that we can take once a day. The future of pill popping is all about simplifying therapy. Soon, we may be able to take one pill, one time a day. And, hopefully, there will come a day when we take no pills!
The advantages to simpler regimens are obvious. Whereas I used to have to hide out to take my morning and late-afternoon doses, now I swallow all that I need just before going to bed, in the privacy of my own home. A drug regimen that’s easy to down generally results in better adherence. But remember: Missing one dose of a once-daily combo leaves your virus unattended for a longer period of time than missing one dose of a combo taken three times daily, so if you’re on once-a-day treatment, try never to skip your pills. Worried that taking fewer pills will mean less effective therapy? Recent studies indicate that some (not all) once-daily drugs can be combined with one another to form regimens that are at least as effective and safe as those with more frequent dosing schedules. Some once-daily drugs have been studied only with twice-daily compounds, so be sure to ask your doctor about complete once-daily regimens with proven track records.
While the notion of having to swallow only a single pill that contains all of your meds every 24 hours is not yet a reality, fixed-dose combinations (FDCs)—pills that contain single doses of more than one HIV drug—are. Currently, there are several FDCs on the market (including Trizivir, Combivir, Epzicom, Kaletra and Truvada). But each of those involves drugs produced by one manufacturer. What’s more, they still need to be combined with other drugs—often drugs produced by other pharmaceutical companies—to make a complete regimen. What has been needed is the collaboration of the drug companies to produce FDCs that will allow for once-daily, single-pill combinations.
In December 2004, Gilead and Bristol-Myers Squibb announced an effort to develop an FDC containing Truvada and Sustiva. After a few false starts in the development process, a suitable FDC was developed that, according to Gilead, produced blood concentrations of all three drugs that were comparable to those of the three drugs taken individually. The FDC is currently being reviewed by the FDA, and a decision is expected sometime in 2006. If approved, it will be the first complete one-pill, once-daily HIV drug regimen. Boehringer Ingelheim, maker of the non-nuke Viramune, and GlaxoSmithKline, maker of the nuke combo Combivir, have also announced plans to team up and develop an FDC of these two popular compounds.
Hopefully, the pursuit of FDCs will not end with these two efforts. FDCs involving protease inhibitors, including those that need to be combined with Abbott’s Norvir, are also in demand. Someday, we may even see FDCs that can be individually tailored to meet a patient’s specific needs.
Induction-Maintenance Approaches Lightening your load
This approach is based on the idea of starting on a standard combo therapy containing several HIV-busting drugs (induction therapy), then dropping certain drugs once the virus is under control (maintenance therapy). The goal of this approach is simple: to make long-term treatment simple and easier to take (and potentially less costly, too), with a reduced risk of long-term side effects.
“But wait,” you’re saying, “haven’t I heard all this before?” It’s true that this idea has been kicking around for a long time. Sadly, earlier studies were not successful. For example, in the federally funded ACTG 343 study reported in 1998, 316 volunteers with undetectable viral loads who were taking a combo of Crixivan, Retrovir and Epivir for at least 24 weeks were allotted to either continue their triple-drug regimen or to drop the Crixivan, remaining only on Retrovir and Epivir. During this maintenance phase of treatment, viral load rebounded in 23% of those taking Retrovir/Epivir, compared with only 4% of those who remained on the triple-drug combo.
One possible reason for the sobering results of ACTG 343—along with several other studies reported in the late 1990s—is that three-drug combos might have been too weak for induction therapy. In turn, researchers have returned to the scene of their former defeats with more potent induction- and maintenance-therapy regimens, including the commonly used Norvir-boosted protease inhibitor combos.
Last summer, Jose Arribas, MD, of Hospital La Paz in Madrid reported data from a study involving 24 HIV positive patients taking Kaletra plus two nukes. After having viral loads of below 50 copies/mL for at least four weeks, half were permitted to drop their nukes, remaining only on twice-daily Kaletra. After a year of this maintenance-therapy approach, 81% of those on Kaletra monotherapy had viral loads below 50 copies/mL, compared with 95% of those who remained on their Kaletra/nuke regimen. Only three patients in the Kaletra monotherapy group saw their viral loads increase to above 500 copies/mL. Resistance to Kaletra did not appear to be the reason for the viral load increase in these three patients, and when nukes were once again added to their treatment, their viral loads once again dropped to undetectable levels.
There’s also new data from ACTG 5201, a study that enrolled 36 HIV positive folks who had viral loads below 50 copies/mL while taking Norvir-boosted Reyataz plus two nukes. The nukes were then stopped, leaving only Reyataz/Norvir as their maintenance therapy. Within six months, three patients experienced virologic failure. The study volunteers will be followed for at least a year and, with luck, similarly encouraging data will be reported as the trial continues.
New Drugs Uncovering a fresh arsenal to fight HIV
For those of us with persistent resistance issues, researchers continue to develop and evaluate new compounds designed to stop HIV in its tracks. With hope, viral suppression will be not only a luxury for those on their first regimens—it will be a feasible goal for those with many years of treatment experience under their belts. In 2006 and 2007, look for the approval of a number of new medications, including: TMC-114 (darunavir), an experimental protease inhibitor being developed by Tibotec, a division of Johnson & Johnson. The drug is expected to be licensed for sale in the United States sometime in 2006. Darunavir (a once-a-day drug that needs to be combined with a low dose of Norvir) has a different structure than other PIs. It may be active against strains of HIV that are resistant to the other protease inhibitors that are currently available. This could be particularly good news for people with HIV whose PI options are exhausted.
TMC-125 (etravirine) and TMC-278 (rilpivirine) are two non-nukes (NNRTIs) being developed by the same company developing darunavir. Preliminary evidence suggests that these drugs have a high barrier to resistance and may be effective against strains of virus that are resistant to other non-nukes.
New Drug Classes Teaching an old virus new tricks?
Along with everyone else in the field of HIV, we’ve been watching with great interest the development of three entirely new classes of drugs, namely, CCR5 antagonists, integrase inhibitors and maturation inhibitors. While they’re not yet approved, they’re getting closer.
Regarding CCR5 antagonists, Pfizer’s maraviroc is leading the pack of these new agents that block the CCR5 receptor on the surface of T cells. Once that’s blocked, HIV is unable to bind to and enter the cells in order to do its dirty work. Of the two other drugs in this class, Glaxo’s aplaviroc has been dropped due to liver toxicities, and Schering’s vicriviroc is being studied only in treatment-experienced patients.
These drugs offer us new hope, especially those of us at the end of our treatment rope, as they target a stage in the HIV life cycle that to date has not been exploited by HIV meds currently on the market. Phase II and III studies of maraviroc and vicriviroc are ongoing.
The development of CCR5 antagonists comes with some special considerations. All of the approved HIV drugs—and most others currently in development—target the virus itself in various stages of its life cycle. CCR5 antagonists don’t target the virus; they target a component of immune cells in the body. This means there’s potentially some good news and some bad. The bad news? These drugs may block a normal process of the immune system. However, with so little known about the normal function of CCR5, it’s not clear what the short- or long-term effects of CCR5 blockage will be. The good news? Targeting cells that do not mutate nearly as quickly as HIV may mean that resistance develops much more slowly to these new compounds. Only extensive testing, currently under way, will answer these and other important questions about CCR5 antagonists.
Integrase inhibitors work at a stage in the HIV life cycle when the virus’ genetic information is being integrated into the host cell’s DNA (the material inside the center of your cells that carries your genetic information). If the virus’ genetic material is allowed to be incorporated into the cell’s genetic material, T cells become an HIV factory, producing lots more nasty virus in a very short period of time. The enzyme integrase is the tool that HIV uses to accomplish integration, and inhibiting it using this new class of drugs—in combination with drugs targeting other stages in the HIV life cycle—may help stop HIV dead in its tracks.
Two contenders, Gilead’s GS-9137 and Merck’s MK-0518, made a favorable debut at the 13th Conference on Retroviruses and Opportunistic Infections in February in Denver. They’re the first of many integrase inhibitors developed over the years to make it to Phase II studies. Good things are expected in trial results to come.
Maturation inhibitors have nothing to do with making you more childish! They get their name from the process of virus maturation that occurs in the last stages of the HIV life cycle, after the virus has been released from the HIV infected cell. They work later in the viral life cycle than any other class. During viral maturation, viral proteins are processed that are necessary for the virus to infect other cells. As the name suggests, this new class of drugs blocks this process.
Currently there is only one maturation inhibitor being studied—PA-457, from Panacos Pharmaceuticals. Because of its unique mechanics, researchers hope it will be effective for HIV positive people who are new to HIV treatment and also for those who have failed other HIV treatments in the past.