Once-a-Day HIV Treatment: Ready for Prime Time?
HIV Treatment Series: Part One of Four
Everywhere you look these days there are sound bites for the treatment of HIV: "... Simplify your HIV regimen" and "Now, one tablet, once daily for simpler HIV combination therapy." Some pharmaceutical companies have been deploying ads, implementing educational programs and other concentrated marketing efforts to promote QD therapy (QD, meaning once daily). The once-a-day push is attracting the attention of people with HIV who are weary of popping fists full of pills two or three times a day, and some companies have also responded to these concerns with treatment options that reduce pill burden. Researchers, who are either employees or agents of pharmaceutical companies, are reformulating existing drugs and designing new drugs.
At the recent International AIDS conference in Barcelona, a lot of buzz was generated about the pros and cons of QD dosing. Doctors are already prescribing the QD drugs to their patients. Clearly, there is a need for simplified HIV regimens, be that fewer pills or once-a-day dosing. And for some people this is important, however it should not be the only factor when considering meds. Few QD drugs have been studied in randomized clinical trials in combinations -- the way HIV drugs must be taken to be effective at slowing virus replication. Without these trials the following questions can't really be addressed. What is the long-term effectiveness of QD drugs against HIV? Do they minimize resistance? Are they tolerable in HIV positive individuals?
Is once-a-day really ready for prime time? Are the QD regimens currently available proven to be better or equal to BID (twice a day) or TID (three times a day) in randomized clinical trials? Will once-a-day be an option for everyone with HIV? Is QD another pharmaceutical ploy to sell drugs? Will the QD drugs cost more? There are a lot of unanswered questions. It is clear that people not sacrifice efficacy for dosing simplicity.
Standard of Care
The Health and Human Services (HHS) guidelines strongly recommend a combination of antiviral medications from two drug classes as the standard for HIV treatment. This may involve taking a combination of several drugs, two or three times a day. HIV treatment combinations require sometimes as much as 30 pills a day. Swallowing that many pills can create many problems for appropriate adherence. Progress has been made to reduce the numbers of pills, and there are now regimens that don't require as many pills. However, not all QD drugs are reformulated to reduce pill burden. The reality is that even though a drug may be approved for QD, it may mean swallowing the same number of pills at once rather than splitting up the amount in two or three doses. Therefore, pill burden remains an issue, even with QD dosing.
HAART (highly active antiretroviral therapy) has been shown to reduce sickness and death, making HIV a chronic condition for many people. As a result, the emphasis of treating HIV has been shifted to improving quality of life. Since HAART has to be taken indefinitely -- not necessarily a rosy prospect for individuals living with HIV -- this means better efficacy with less side effects, fewer pills and less dosing. This is not an easy task as the virus can mutate easily to resist the drugs. HIV meds have to be taken 95% of the time in order to be the most effective. And yet some drugs are adhered to 95% of the time and still resistance to them develops. On the one hand, you need a regimen that will continue to work long-term. On the other hand, you need a regimen that you can continue taking long-term.
The longer one has to "adhere" the more chances forgetfulness will occur. We are, after all, only human. So, the idea of simplified regimens, fewer pills, lower dosing and less toxicity can ultimately help to achieve the goals of HIV therapy and the needs of HIV-positive individuals: keeping people healthy by keeping the amount of HIV in the body below detectable and CD4 T-cells as high as possible. Therefore in terms of having a regimen that works and is tolerable, is QD all that better than BID?
How Drugs Are Broken Down in the Body
According to research on adherence, the biggest improvement in adherence is noted when there is no middle of the day dose. There is only a slight difference in adherence between once a day and twice a day. Food and Drug Administration (FDA) regulations require approved drugs to maintain blood levels in the body long enough to keep working. But that's assuming you don't miss a dose. What happens if you miss a QD dose? Will resistance set in faster if you miss a QD dose compared to a BID dose? Some drugs, like Sustiva, remain active in the body for much longer than 24 hours. If people remember to take their dose shortly after they miss it -- at least not 24 hours later -- the blood levels will remain at a safe level. As long as drug levels remain high enough to control virus replication, drug resistance is less likely to happen.
One important piece of information to remember is that what is "high enough" varies, from person to person and from drug to drug. HIV does not operate the same from one person to the next. For example, in some people, the virus is more difficult to treat in resistant form. In this form, drug levels may need to be consistently higher to keep the virus from developing additional mutations. With all of the buzz on increasing rates of resistant HIV, this is an important consideration for everyone, not just HIV-positive individuals who have been on therapy for awhile.
Another factor to consider is the drugs themselves. Some drugs are known for maintaining higher levels in the body, whereas others have lower levels. How long after a missed dose before drug levels are dangerously low depends on, in part, two things. First, how high the drug levels were in the first place. And secondly, how long it takes the drug levels to drop.
In order to evaluate how once or twice dosing works one needs to understand how drugs are "metabolized" in the body. Drugs are swallowed, then broken down by saliva, stomach acid and liver or kidney enzymes so that the active chemical can get into the blood stream to do its work. Over time the amount of chemical is used up, then excreted. Then, more drug needs to be taken to keep up the level of the drug in the blood. In HIV it is critical to keep drug levels constant and well above the amount needed to control the virus. If the rate of HIV production can't be slowed down enough then the virus can change and go on multiplying, spreading a mutant virus. This is HIV's strategy for survival -- clever yet dangerous, even more reason to adhere to drugs and more corroboration for QD therapies.
There is speculation by some physicians that the effectiveness of a once-a-day dose schedule may depend on how each person metabolizes the drug individually, and that different cellular levels absorbed in a QD regimen may be quite different than in a twice a day regimen, therefore raising concerns regarding toxicity. In a new move to monitor this phenomenon, therapeutic drug monitoring assays are being developed to look at how each individual processes different drugs, but the science is clearly lagging behind the realities of treatment.
The bottom line is that many QD meds are not as forgiving as certain BID meds, when a dose is missed. Therefore, taking a dose at or near the appropriate time is still the optimal choice and efforts should always be made to teach physicians and patients to adhere to a regular dosing schedule.
QD HIV Drugs
There are currently five drugs available in once-a-day formulations today: Sustiva (efavirenz), Videx EC (didanosine enteric coated), Viread (tenofovir), boosted Agenerase (amprenavir), and Epivir (3TC). (See Newsbriefs in this issue.) New QD agents such as Reyataz (atazanavir), Emtriva (emtricitabine), and T-1249, a fusion inhibitor, may be available soon. New formulations of existing antivirals such as Viramune (nevirapine), Ziagen (abacavir) and Zerit XR (extended release stavudine) are in development. And Kaletra (lopinavir/ritonavir) is being studied as a QD option. One can see the interest and results of simplified drug development in our market-driven society.
Will drug companies pursue a price increase for the new QD therapies? Their contention is that in order to develop the drugs they need to pay for the research. According to past history, new drugs, especially new classes, have always resulted in an increase in price. Any price increases in new therapies will place ADAPs (AIDS Drug Assistance Programs), already teetering on the verge of collapse, in jeopardy. Pricing is a complex issue. When a drug is reformulated to reduce pill burden or dosing in half, it does not mean that manufacturing costs associated with the drug are also cut in half. It will be up to the community to hold the companies accountable as far as pricing is concerned.
What HAART Regimens Are Effective in QD?
Up to this point only individual drugs have been discussed for once-daily dosing, however, remember that HIV meds must be used in combination. Drug companies are promoting QD drugs individually, but they have not necessarily been studied together. Several different companies may produce the drugs within any one given combination, but the question remains: Is QD a viable option available to those who need therapy?
The QD regimen with the most data demonstrating effectiveness is Videx, Epivir and Sustiva. An open label prospective study (people knew what they were taking and were followed from the time they were put on treatment) looked at the feasibility of using this QD regimen. Though the study was not compared with other drugs, everyone ended with a lower viral load and higher CD4 T-cells at the end of 48 weeks, showing the combination was effective. Another study looking at a new drug, Emtriva, in combination with Videx and Sustiva in treatment naive patients (patients initiating therapy for the first time) has been reported. This combination has demonstrated an ability to suppress viral load for up to two years, showing another potential effective QD regimen. However, Emtriva has not yet been approved.
Doctors are prescribing combinations besides Videx EC, Epivir and Sustiva. Viramune is being looked at in combination with Videx and Epivir. Crixivan is being studied in combination with the same QD background. The studies are not complete. And therein lies the problem of combining drugs that have not been studied together in controlled clinical settings. Unknown cross reactions have been reported, as was found with Viread and Videx EC after the drugs were being combined in community practice. People using the new Videx EC capsule must not take it with any food, and Epivir and Sustiva should be taken with food, so the regimen is not a QD regimen as is thought.
From a Consumer's Perspective
How does switching to a QD regimen affect people in the real world? Paul Dalton, a PWA (person with AIDS) from San Francisco, switched to a once-daily regimen of Epivir, Viread and Viramune. Previously, he was on the same drugs, but used Viramune twice a day until studies showed that it was effective once daily. So, he made a relatively safe change based on what we know about these drugs. The outcome has been good in terms of viral control. However, he did have a 50% reduction in CD4 T-cells, but feels that the "disconnect" between his success in switching and his CD4 count was more related to stress in his life than to the therapy having failed (does this constitute a failure?). Paul said he has been 100% adherent with the new QD regimen and believes it can be beneficial for others if they stick to the simpler strategy. "QD can make sense if people can construct a viable regimen based on their history." Still, the disconnect in Paul's case (viral load decline, T-cell decline) should be carefully monitored by a physician. Adherence is not the lone factor in determining whether or not a regimen is effective.
Jeff Gustavson, also from San Francisco, had trouble with his regimen, which was Viread (QD) in combination with twice daily drugs. He mistakenly took the Viread twice daily with his other drugs, doubling the dosage, which is one of Cafaro's concerns. This anecdote highlights the fact that QD dosing is individual and must be geared for each person. It remains a treatment model in transition until all the bugs can be worked out.
A Matter of Choice ... How to Decide?
Many factors, including lifestyle, emotional readiness and ability to adhere, come into play when you decide to initiate HIV therapy. However, other factors that are just as important are drug efficacy, tolerability and minimizing resistance. Someone who has never taken HIV treatment may have more treatment options than the more treatment experienced individuals. Individuals who have taken antivirals in the past may have fewer therapeutic options. However, as previously stated, HIV therapy must be individualized. A treatment naive patient may have acquired a resistant strain of HIV, and therefore have more drug resistance than a treatment experienced patient. So the question becomes, are pharmaceuticals doing what is really in the best interest of the patient? Should they develop more resistance minimizing meds, as well as those that are more tolerable and convenient? Or are they merely responding to market opportunities when promoting drugs as QD?
A hospital cohort study presented in Barcelona looked at 1,313 patients and their consecutive regimens. The rate of treatment change was high in the study due to adverse events. So, after five consecutive regimens, most patients had been exposed to almost every available antiretroviral drug. Therefore, in this heavily treated group, QD would likely be impossible.
For people who have previously used anti-HIV drugs, it is critical that resistance tests be performed and medical histories looked at before switching or constructing any regimen. The tests can help determine which drugs are still viable options for each individual. Individuality must be considered in deciding upon any regimen.
Howard Grossman, a physician from New York City, has been prescribing once-daily regimens for years. According to Grossman's cohort data presented in Barcelona, his patients are benefiting from once-daily dosing. Whereas many physicians would not offer QD to patients who can't adhere due to the risk of resistance, Grossman offers patients with the worst adherence problems once-a-day regimens and looks at toxicity issues and effectiveness. His cohort was a retrospective analysis looking at 40 people from his clinic who either started on a QD regimen or switched from one QD regimen to another, or from BID to QD. At the completion of the study, viral load values were stable at less that 4,000 in all groups, not undetectable by any clinical standard. However, he states that those who began on a QD regimen did the best. But again research demonstrates that individuals have the best results on their initial regimen.
Virginia Cafaro, a long-term HIV doctor in San Francisco, presents an opposing point of view, "A lot of my patients are on BID and think it's fine, they have the rhythm and figure 'if it ain't broke, don't fix it.' They have been stable for years." Some motivated people are satisfied if they are doing well with their regimen. However, people who are having adherence problems, or who are dealing with pill fatigue, who can afford to switch may want to consider QD. But they should talk over their options with a doctor. According to Cafaro, a major concern is that people with HIV simply want to switch, whether QD is geared for them or not. Cafaro muses, "I think it's [QD] a lot of hype and marketing from drug companies all saying their drugs are, or will be able to go QD. Is QD really all meds at one time? We have to worry about drug interactions [such as] with tenofovir and ddI-EC. Patients hear 'once-a-day' and may drop half of their present regimen or pile them all up into one dose."
Grossman believes that many progressive doctors are reluctant to switch their patients to QD. He states, "there are so many treatment options and they want to wait until more proof is in. No one wants to do harm [to the patient]." However, it begs the question, how are less experienced doctors who have fewer HIV-positive patients going to react to the new QD paradigm? In the land of HIV treatment and care, treatment trends always take time to take hold.
Experienced doctors such as Cafaro and Grossman, who understand the complexities, drug interactions and other restrictions of HIV treatments, are more in tune to their patient's needs, but care needs to be taken with those prescribing without a specialist's knowledge.
We are upon an era of a major treatment shift in HIV disease, where efficacy, tolerability, avoiding resistance and dosing convenience are all key factors. Adherence to mega-dosing of the older drugs has been a systematic and complex problem for people with HIV and their providers. However, progress has been made in this area. Treating a virus that is capable of a multitude of changes still has to be sorted out, so we must not put the cart before the horse in pushing ahead with simpler regimens that might fail for multiple reasons.