Antiretroviral therapy has undergone a renaissance of sorts, seeing an outpouring of newer and, more importantly, truly unique agents during the last two years. This has had a major impact on treatment, and has advanced our goals for patients who are HIV-positive, almost without regard to their treatment history. The purpose of this article is not really to describe these newer agents individually while affixing a rubber stamp, but instead to provide some different perspectives on where we can improve as we embark into the future. A recent experience I had while seeing a new patient had a saddening effect on me. I had the displeasure of observing his previously prescribed cocktail, which showed me that inferior treatments are still being offered despite all the progress in HIV therapy. Overall, however, I was so glad to be able to assume his care and eventually remedy his situation. This example is the vehicle for my message.
Atripla, the one pill, once-daily drug cocktail is a reality for a small subset of HIV-positive individuals. But nevertheless, one can't overemphasize its milestone in development. Patients who are starting treatment for the first time (antiviral naïve), and those that have never been exposed to any of Atripla's components are candidates for this landmark in HIV therapy.
Patients experienced or resistant to one or more of Atripla's components must rely on other treatment, often many more pills and often administered twice daily. These patients are the majority in care and cannot take advantage of a drug like Atripla. Thus, there is an unmet need for more co-formulations using newly developing agents that could be utilized for a wider-based audience. Therefore, as an early preview of what should be coming, the new non-nuke, TMC 278 (rilpivirine), currently in phase III development at Northstar in Chicago, as well as a new nucleotide developed for resistant virus which should be going into phase I, can be pictured as candidates for other co-formulations and more simplified regimens. These, in contrast to Atripla, may become useful for patients with antiviral resistance, but it will take several years before this becomes a reality.
A smorgasbord of new antivirals has become part of our armamentarium within record time. These include a new protease inhibitor, Prezista (darunavir), and the first in the integrase inhibitor class, Isentress (raltegravir). These agents are approved for patients that harbor resistance to conventional treatment and have helped allow us to achieve undetectable virus for highly treatment-experienced patients. In addition, early and ongoing studies have shown excellent safety and effect for use in patients starting their first treatment regimen. Thus you can bet that we'll see these drugs being used also in this naïve patient population.
While Atripla's formulation of being one pill, once daily is tough to beat, patients who may have the propensity for side effects to Sustiva (a component of Atripla) have other alternatives in some of the newer antivirals. Additionally, there are several unique properties of these newer antivirals that set them apart from other drugs, thus making for an attractive consideration for specific situations. Isentress, for example, showed an unprecedented decline in viral load compared to Sustiva. I'll not go into details about their unique properties here but wait for another and future article of The Buzz.
Other new antiviral agents also include a second-generation non-nuke, Intelence (etravirine), and a first-in-class chemokine co-receptor (CCR5) inhibitor, Selzentry (maraviroc). These agents are also currently used for treatment-experienced patients.
HIV therapy has indeed become complicated for physicians not immersed in clinical HIV development and antiviral research; more than 20 antiviral agents have become developed providing an ever-increasing number of combinations. While posing a challenge for physicians to keep up with one of the fastest growing fields in medicine, there are ample sources for medical practitioners, as well as patients, to become more educated about their use. It is my hope that medical providers treating more than a few patients take the time to read and become knowledgeable, without relying on advertising or marketing tricks.
This brings me to the story and focus of this article. In my wildest dreams, I never expected a wake-up call such as the recent experience I'm about to describe. While routinely providing lectures to physicians who are not yet proficient with some of the newer antiviral drugs, I've observed the natural desire by many to be further educated. This is a wonderful quality about the practice of medicine: a physician's way of life is a continuous cycle of further learning, self-development and growth through acquired knowledge and experience. However, sometimes a patient suffers when their doctor has not yet taken the time for valued thought, or acquired some basic principles of treatment and understanding of the current treatment for advanced disease.
It was thus recently fated that a young man in his mid-thirties would find me and become my patient. How that happened is another story for another article, but to get to the crux, Jay was being taken care of by two infectious disease (ID) specialists on the East Coast. He was being seen for many years by his ID physician and had several AIDS defining illnesses under the care of this physician. He was very resistant to most medications and was referred to another ID physician in the closest major city to gain access to one of the newer drugs. The new drug has been highly regarded as being effective for patients such as Jay. At the time, his T-cells had already spiraled downward to barely 50, and his viral load was in the hundreds of thousands.
The medication was Isentress (raltegravir), one of the first in a new class of drugs called integrase inhibitors, a very impressive drug providing hope for many HIV-positive patients.
Jay made the extended drives to the big city and was, for the most part, adherent to a regimen that this physician designed. However, Jay never had a chance. He was unfortunately placed on an easy, yet substandard regimen; one that would be used for naïve patients and not someone with highly resistant virus.
His background treatment involved two nukes -- one that he was already resistant to, and the other he was also partially resistant to. As a result, he did not respond properly to the cocktail and thus failed treatment within two months. He was, in effect, on a mono-therapy regimen, or being administered Isentress without any protection. This also resulted in his becoming resistant to the entire integrase inhibitor class. His regular physician gave up on Jay and never offered further or proper treatment. This while his T-cells plummeted to 21 and viral load reaching 1 million. It is a wonder that he hasn't become even sicker.
You would think that in this day and age, with many new antivirals, Infectious Disease specialists taking care of HIV-infected patients, especially those who are participating in the early expanded access program for a new drug, should be familiar with its use. If not, you'd think Jay's other doctor, his primary physician who is also an ID specialist, would catch this grave but fundamental misjudgment by the other supposed experienced ID specialist/investigator who was allowed to participate in the Isentress expanded access program. Finally, you'd expect that the pharmaceutical company that allows physicians to become investigators using their new drug, of an entirely new class, would ensure that these doctors be able to have some treatment competency and be versed in its use.
Unfortunately for Jay, none of the above was true. Thus what should have been a promising option for a patient highly resistant to treatment, turned out to be a treatment disaster that reduced already minimal options left to him and narrowed his choices further and permanently for the future.
With all the new antiretrovirals that have become available, constructing a new regimen for a patient that is failing their current cocktail should be a no-brainer for the truly experienced and knowledgeable physician. Not only do we have agents in completely new classes, or antivirals that target a different aspect of the viral replicative process, we have true second-generation agents of older classes that have very specific and unique qualities. However, bridging the educational gap to physicians should be paramount. Perhaps too many new agents have confounded some physicians as to their best use. This poses questions regarding the quality of care for patients seeing those physicians who do not make it their business to keep up or take the time, especially when confronted with a treatment-needy patient.
Physicians prescribing treatment for experienced patients should become well educated and informed in the construction of effective regimens. If not, more patients will fail therapies, despite using newer agents, and we will witness a new era in resistance to these novel medications. This is compounded by the real-world reality that safe sex has virtually become extinct or non-existent within the gay community. Patients failing the newer agents can potentially open more floodgates for transmission of resistance to these newer antiviral classes. Patients should have the responsibility of taking their medications as prescribed without missing significant doses. This would help. Moreover, we need both competent construction of truly effective treatment regimens for treatment-experienced individuals, partnered with good adherence by patients. This combination should result in lower viral loads, better maintenance of effective treatment, and should help further reduce the emergence of resistance and the propensity for transmission of resistant virus to these novel classes.
Dr. Daniel Berger is a leading HIV specialist in the U.S. and is assistant professor of medicine at the University of Illinois at Chicago and medical director and founder of Northstar Medical Center, the largest private HIV treatment and research center in the Greater Chicago area. He has published extensively in such prestigious journals as The Lancet and The New England Journal of Medicine and serves on the Medical Issues Committee for the Illinois AIDS Drug Assistance Program and board of the AIDS Foundation of Chicago. Dr. Berger has been honored by Test Positive Aware Network with the Charles E. Clifton Leadership Award.
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