We do not have a crystal ball. And most of us have not been given the skills of Johnny Smith, who after a near-fatal car crash leaving him in a deep coma in the Dead Zone, regained consciousness with the discovery that he had the ability to predict the future by touching an individual or a possession. These amazing psychic powers are not common among medical doctors, but based on an insider’s view and experience in research, one can try to provide educated speculation in predicting the future of antiviral treatment.
Being involved in conducting research does have its perks. Physically observing patients on investigational compounds while studying preclinical data of proof-of-principle and Phase I studies can often be an eye-opening and inspirational experience, not to leave out fascinating. It makes coming to work sometimes better than watching Deep Space Nine or House.
While peering ahead into the future of HIV treatment, the next three to five years will incorporate new classes of drugs that are presently being studied. Taking into account toxicities and impracticalities of existing medications still in use, one can easily see substitutions in the making. This article is not meant to be gospel nor a treatise on virology, but rather speculation serving as an appetizer for what is to come. Let’s start with discussing the less useful medications; this is going to be a harsh reality for some to digest and a completely different scene from what some in the industry would like to hear. We will then move on to bandying about newer agents or constructing treatment cocktails of the not-so-distant future.
Shifting Tides in Medication Usage
As we learn more about existing meds, coupled with the emergence of better treatments, there should be a natural tendency for thoughtful HIV specialists to consider different preferences as they become available. This is the natural progression.
Nucleosides, historically the oldest class of antivirals, have been used as a backbone and are combined with more potent protease or non-nuke reverse transcriptase inhibitor (NNRTI) drugs. However, nucleosides do bear some of the greatest toxicities, including lipoatrophy (fat loss in the face, buttocks, legs, and arms), lactic acidosis, neuropathy, anemia, and a host of constitutional symptoms.
As newer, safer, and more potent agents become approved, it has become clear that drugs such as Zerit (d4T) are moving towards extinction (if not already there). Additionally, we now understand that combining Videx-EC (ddI) together with Viread (tenofovir) or Truvada for certain regimens are a concern: T-cell decreases have been described in several studies. There will be less use of ddI, and truthfully it has its own additional baggage. Finally, one needs to mention study GS-934, in which AZT was essentially compared to Viread (Combivir vs. Truvada). AZT has been shown to be associated with more lipodystrophy (body habitus changes) and constitutional symptoms and anemia.
Thus, in the nucleoside class we are generally left with more favored combination agents such as Truvada (Viread/Emtriva) and Epzicom (Ziagen/Epivir) or their individual components. With better formulations and upcoming agents discussed later in this article, the older treatments associated with various problems begin disappearing from the treatment map.
Scrutinizing the entire class of approved protease inhibitors, at first glance it appears there are many drugs, but from the standpoint of resistance there may not be as many. The older agents have cross-resistance and difficult side effects. One only needs to remember full-dose Norvir (ritonavir) or its liquid formulation. For those of you who weren’t unfortunate enough to experience it, taking liquid Norvir was akin to drinking a mixture of gasoline fluid and Drano. Also recall the frequent kidney stones observed with the once ever popular full-dose (unboosted) Crixivan (indinavir).
Thus, with all fairness, Invirase (saquinavir), Crixivan, and Viracept (nelfinavir) will not have much of a presence in the future. While the antiviral efficacy of Kaletra continues to be well proven, in the experience of many clinicians, its problems with lipids, or elevated blood fat (cholesterol and triglycerides), lipodystrophy, and diarrhea are issues that are not going away for many patients. Moreover, some patients have not experienced the purported change in toilet schedules that was expected with the new formulated tablets. Consequently, several newer alternatives such as Reyataz (atazanavir), Lexiva (fos-amprenavir), and Prezista (darunavir) are promising choices that provide inroads for reducing complications and side effects for some individuals.
Reyataz is important as a once-daily protease inhibitor, without significant elevated lipids. Lexiva has been better tolerated with less diarrhea for some patients and may prove to be equally as effective as Kaletra (KLEAN Study). Prezista (see page 13) has an outstanding and unprecedented efficacy and tolerability that was observed in experienced patients with high degrees of resistance to other antivirals. Other Prezista studies are still pending, including one in treatment-naïve patients with once-daily dosing and another comparing it to Kaletra. These newer alternatives to the older medications appear more patient friendly and put some older protease inhibitors into the no-fly zone.
Last year Aptivus (tipranavir) became approved and was developed for treatment of patients with resistance to other protease inhibitors. Unfortunately, Aptivus requires a doubling of the standard Norvir boosting dose. Also, there have been concerns with liver toxicity and more recent reports of intracranial hemorrhage. With the approval of Prezista being significantly superior, not to mention the upcoming integrase inhibitors, Aptivus will become less used by clinicians for first salvage.
Interestingly, a pharmaceutical company has taken up the challenge in attempting to develop a Norvir alternative for protease inhibitor boosting. One hears whispers that Tibotec has a candidate compound which, if successful, may be a cost-cutting, safer alternative that eventually replaces Norvir. Norvir’s astonishing price increase (not forgotten) combined with associated elevated blood lipids (cholesterol and triglycerides) has served as a good motivating factor for this line of research.
Fuzeon, the first drug developed to block HIV’s ability to fuse onto T-cells, has been an important step in providing multi-class resistant patients with an alternative for treatment (TORO I & II, RESIST, and TMC114-C202). From a practical standpoint, however, it’s a drawback to have patients be required to self inject themselves twice daily. Also, its cost stands out as the most expensive antiviral on the market, making it an easy target for searching for alternatives. Currently there are other classes of drugs, as well as new entry inhibitors in development, orally administered and one with intravenous application, that may each replace Fuzeon.
Cocktails of the Future
This next section is based on the definite trend to expand diversity and efficacy of HIV treatment. Two integrase inhibitors rapidly developing are MK0518 and GS-9137. There are also new non-nukes, TMC-125 (etravirine) and TMC-278, the entry inhibitor maraviroc (as well as another CCR5 antagonist, vicriviroc), the maturation inhibitor PA-457, and several other compounds for a list too long to provide here. If these all become available, there will be much to conjecture about the future of antiviral therapy.
Naturally, one does not yet know all possible drug interactions or the complete efficacy and safety of many new candidate treatments, but if one were to design the optimal cocktail, one could potentially conceive of several superpower regimens. A particular regimen may involve one boosted integrase inhibitor (GS-9137 at once-daily dosing) plus a once-daily co-boosted protease inhibitor (Reyataz or Prezista), and perhaps an entry inhibitor administered once every two weeks intravenously in the clinic (TNX-355). Or substitute TNX-355 with either Truvada, Epzicom, or a maturation inhibitor or maraviroc. These are but a few examples.
Integrase inhibitors utilize a new antiviral enzyme target and are moving quickly in development; they block HIV’s ability to integrate itself into the human cell’s DNA (genetic protein). At Northstar Healthcare in Chicago, we are currently conducting trials with the two lead agents in development. We learned only a few years ago that boosting blood levels of protease inhibitors was a major advance in treatment because it builds a pharmacokinetic wall opposing viral resistance. If the model of boosting holds true with integrase inhibitors, GS-9137 may demonstrate similar durability and efficacy.
For those individuals intolerant of Norvir, MK-0518 used with TMC-125 or TMC-278 and perhaps an entry inhibitor are also a possibility.
Also, one knows that the 2-log drop in viral loads observed early in Phase II for both integrase inhibitor candidates, GS-9137 and MK-0518, shows very strong potency. With multiple agents having similar effect, we can design superior cocktails with each antiviral being more potent than the last. Thus, one could expect that those antivirals providing only .5 to 1 log drop in HIV RNA eventually become un-preferred.
TMC-278 is a new potent non-nuke that may be effective against previous non-nucleoside RT resistance. Currently in Phase II, it is a very small or tiny-dosed medication that has the potential of being easily combined with many different antivirals, including Truvada, Epzicom, or Prezista. Just as Truvada and Sustiva became formulated into one Atripla pill (see page 13), one hopes that other pharmaceutical companies follow this lead and spur the development of other easily administered regimens. The single pill, once-daily Atripla, can be implemented as a complete cocktail for some patients. Consider combining TMC-278 with other treatments. While optimal dosing has not been finalized, the possibilities of combinations with a maturation inhibitor (PA-457), an integrase inhibitor, or another protease inhibitor are tantalizing and not to be scoffed at.
Finally, consider TNX-355, an entry inhibitor which is being studied and administered in clinical trials intravenously once every two weeks. If this treatment makes it through all the hoops to approval, what will we be combining it with? Could other treatments be administered less frequently, such as another fusion inhibitor? TNX-355 contains genetically engineered antibodies, known as monoclonal antibodies, that bind to the CD4 receptor on T-cells, preventing the virus from infecting healthy cells.
Conclusion
Articles in this column usually deal with fact, backed up by studies and experience. But the aim of this article is not about stating facts or predicting “how it will be.” One hopes that the ideals and futuristic treatment speculated on here provide for interesting discussion about the long-term outlook. Inspiration and spring-boards are hope for a better quality-of-life and the intent of this commentary. Notice that “cure” is never mentioned. Many older and familiar HIV medications once used or sometimes still current do not always fit the equations modeled here. It is impractical for pharmaceutical companies or physicians to expect the continuous re-cycling of medications to infinity. New targets and better, more effective treatments are steadily budding so that many HIV-positive individuals can hope to live long, productive lives.
Daniel S. Berger, M.D., is Medical Director and full-time practitioner at Chicago’s largest private HIV treatment and research center, NorthStar Healthcare, and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago. He serves as medical consultant and columnist for Positively Aware, serves on the HIV Medical Issues Committee for the Illinois AIDS Drug Assistance Program, the Board of Directors for the AIDS Foundation of Chicago and the Editorial Board of Contagion: Reports, Cases, and Commentaries in HIV and Infectious Disease Research. Dr. Berger can be reached at DSBergerMD@aol.com or 1-773-296-2400; visit www.nstarmedical.com.
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