Once again, the state of antiretroviral therapy is a combination of "good news" and "bad news." The good news is familiar to all who are involved in the treatment of HIV: since the introduction of protease inhibitors in 1995, the developed world has experienced impressive declines in both the incidence of AIDS cases and HIV-related morbidity and mortality. This is primarily due to the use of highly-active antiretroviral therapy (HAART) that can restore and protect immune system function and prevent persons with HIV from progressing to AIDS or dying from an HIV-related condition.
The bad news is also nothing new. Complete viral eradication ("cure") is likely to be impossible, necessitating lifelong antiretroviral therapy, and while many presume that antiretroviral therapy can be effective for years, the long-term durability of HAART has not been established. An extremely high degree of adherence to therapy, higher than has been demanded for any other chronic illness, is also necessary for optimal success. For those who are able to adhere to HAART, medication toxicities and the normal health issues of increasing age, some of which are synergistic, are beginning to be of equal or greater importance than the HIV-specific issues. For those who cannot or will not adhere to HAART, the impact of drug-resistance, which in HIV is likely to be lifelong, can severely limit treatment options.
While there have been comparisons between HIV and other chronic diseases like diabetes mellitus or hypertension, there remain several key differences. No other chronic disease requires such high adherence of potentially toxic drugs, with lack of near-perfect adherence leading to permanent drug resistance. For example, 75 percent adherence of atenolol does not lead to the permanent loss of the entire beta-blocker class of drugs for treating hypertension! Also, unlike with hypertension and diabetes, we do not know the long-term risks and toxicities of therapy as most of the current antiretroviral drugs have been used for less than a decade. Studying these long-term issues is difficult, especially as new drugs (with new toxicities) continue to be introduced into the mix and practice patterns continue to evolve.
For all persons on antiretroviral therapy, we clearly have a much better understanding of the importance of adherence now than we did in 1996. This is translating to better patient preparation before the initiation of HAART and more ongoing support for better adherence to antiretroviral drugs after HAART is started. This preparation and support is absolutely crucial for maximizing the chances for HAART being successful because of the stringent demands of taking antiretroviral drugs.
The push towards simpler and more tolerable regimens is due in part to this understanding of the importance of adherence. When patients are told that they have to take at least 95 percent of their medications, even the most minor side effect can become a big deal. Regimens with fewer pills and those given once daily are a significant improvement for many patients. Trizivir at a total of two pills each day continues to be a viable alternative for those with lower pre-treatment viral loads. At the time of this writing, five antiretroviral drugs from all three classes are FDA-approved for once-daily use (amprenavir, didanosine EC, efavirenz, lamivudine, and tenofovir), and there is evidence for the once-daily use of six other antiretroviral drugs either in current or pending formulations (abacavir, atazanavir, lopinavir, nevirapine, saquinavir, and stavudine). While the nature of many once-daily regimens, particularly ones that include an NNRTI, mean that they usually cannot be used in deep salvage, it is conceivable that a sequence of at least two once-daily regimens can be constructed for antiretroviral-naive patients.
For deep salvage therapy, the first fusion inhibitor, T-20, brings us a new drug target and with that an antiretroviral drug that should be active against multi-drug resistant virus. While it is only a single agent that, like other antiretroviral drugs, must be combined with other agents to prevent the emergence of drug resistance, it is an option for some who are desperate for additional options.
While there will continue to be newer agents that are simpler to take, better tolerated, and effective against resistant virus, the viral dynamics of HIV make chronic control of the virus by antiretroviral medications an ongoing uphill fight. There may come a day where ever more potent and well-tolerated medications can be given several times a week (like TB therapy), weekly (like pegylated interferon for hepatitis C), or even less frequently with a much greater "forgiveness factor" than current drugs when it comes to missing doses and timing. This would be a clear improvement from our current state.
However, in the minds of many HIV researchers and clinicians, the elusive long-term goal remains a therapeutic vaccine: a treatment that can stimulate one's own immune system to control or suppress HIV long-term rather than eradicating the virus, much as herpes simplex and varicella-zoster (the virus that causes chickenpox and shingles) are usually held in check by an intact immune system but never completely "cured." A therapeutic vaccine would also have life-changing impact in places like sub-Saharan Africa where millions without access to antiretroviral drugs are dying.
Until such time that immune-based therapy is available, we will continue to push on with what we currently have at our disposal. Often lost in the discussion of HIV therapeutics is the message of prevention. HIV infection remains highly preventable, and the advances in therapy should not lessen the message of prevention. As the recent experience in Uganda illustrates, a push towards prevention can be effective even where HAART is not widely available.
As for therapeutics, we will continue to learn how to better use the drugs that we have. Questions such as when to start therapy, how best to sequence therapy, and whether to employ strategies such as treatment interruption in specific populations will continue to be answered, albeit often not perfectly, as prospective trials are completed and retrospective cohorts continue to accumulate data.
More importantly, we have learned that many of these questions are without a definitive answer. The best answer for now is a highly individualized approach. Physicians and patients can sit down together to formulate a customized treatment plan. They can compare current medical knowledge with the unique preferences, desires, hopes, and fears of the patient.
The areas where medical knowledge leaves us with gaps in information need not be filled arbitrarily, but rather give providers the opportunity to discuss these uncertainties with the individual person. And this is something that modern medicine, for all its technology and promise, should be doing anyway.
Dr. Jonathan Uy is an Assistant Professor of Clinical Medicine in Infectious Diseases at the University of Illinois at Chicago and an Investigator with AIDS Research Alliance Chicago (ARAC).
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